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Antimicrobial resistance (AMR) presents an escalating global challenge as conventional antibiotic treatments become less effective. In response, photodynamic therapy (PDT) and photothermal therapy (PTT) have emerged as promising alternatives. While rooted in ancient practices, these methods have evolved with modern innovations, particularly through the integration of lasers, refining their efficacy. PDT harnesses photosensitizers to generate reactive oxygen species (ROS), which are detrimental to microbial cells, whereas PTT relies on heat to induce cellular damage. The key to their effectiveness lies in the utilization of photosensitizers, especially when integrated into nano- or micron-scale supports, which amplify ROS production and enhance antimicrobial activity. Over the last decade, carbon dots (CDs) have emerged as a highly promising nanomaterial, attracting increasing attention owing to their distinctive properties and versatile applications, including PDT and PTT. They can not only function as photosensitizers, but also synergistically combine with other photosensitizers to enhance overall efficacy. This review explores the recent advancements in CDs, underscoring their significance and potential in reshaping advanced antimicrobial therapeutics.
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There has been a significant volume of work investigating the design and synthesis of new crystalline multicomponent systems via examining complementary functional groups that can reliably interact through the formation of noncovalent bonds, such as hydrogen bonds (H-bonds). Crystalline multicomponent molecular adducts formed using this approach, such as cocrystals, salts, and eutectics, have emerged as drug product intermediates that can lead to effective drug property modifications. Recent advancement in the production for these multicomponent molecular adducts has moved from batch techniques that rely upon intensive solvent use to those that are solvent-free, continuous, and industry-ready, such as reactive extrusion. In this study, a novel eutectic system was found when processing albendazole and maleic acid at a 1:2 molar ratio and successfully prepared using mechanochemical methods including liquid-assisted grinding and hot-melt reactive extrusion. The produced eutectic was characterized to exhibit a 100 °C reduction in melting temperature and enhanced dissolution performance (>12-fold increase at 2 h point), when compared to the native drug compound. To remove handling of the eutectic as a formulation intermediate, an end-to-end continuous-manufacturing-ready process enables feeding of the raw parent reagents in their respective natural forms along with a chosen polymeric excipient, Eudragit EPO. The formation of the eutectic was confirmed to have taken place in situ in the presence of the polymer, with the reaction yield determined using a multivariate calibration model constructed by combining spectroscopic analysis with partial least-squares regression modeling. The ternary extrudates exhibited a dissolution profile similar to that of the 1:2 prepared eutectic, suggesting a physical distribution (or suspension) of the in situ synthesized eutectic contents within the polymeric matrix.
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Polímeros , Solubilidade , Análise dos Mínimos Quadrados , Polímeros/química , Química Farmacêutica/métodos , Maleatos/química , Composição de Medicamentos/métodos , Temperatura Alta , Ligação de Hidrogênio , Tecnologia de Extrusão por Fusão a Quente/métodos , Cristalização/métodosRESUMO
Lipid-based drug delivery systems hold immense promise in addressing critical medical needs, from cancer and neurodegenerative diseases to infectious diseases. By encapsulating active pharmaceutical ingredients - ranging from small molecule drugs to proteins and nucleic acids - these nanocarriers enhance treatment efficacy and safety. However, their commercial success faces hurdles, such as the lack of a systematic design approach and the issues related to scalability and reproducibility. This work aims to provide insights into the drug-phospholipid interaction by combining molecular dynamic simulations and thermodynamic modelling techniques. In particular, we have made a connection between the structural properties of the drug-phospholipid system and the physicochemical performance of the drug-loaded liposomal nanoformulations. We have considered two prototypical drugs, felodipine (FEL) and naproxen (NPX), and one model hydrogenated soy phosphatidylcholine (HSPC) bilayer membrane. Molecular dynamic simulations revealed which regions within the phospholipid bilayers are most and least favoured by the drug molecules. NPX tends to reside at the water-phospholipid interface and is characterized by a lower free energy barrier for bilayer membrane permeation. Meanwhile, FEL prefers to sit within the hydrophobic tails of the phospholipids and is characterized by a higher free energy barrier for membrane permeation. Flory-Huggins thermodynamic modelling, small angle X-ray scattering, dynamic light scattering, TEM, and drug release studies of these liposomal nanoformulations confirmed this drug-phospholipid structural difference. The naproxen-phospholipid system has a lower free energy barrier for permeation, higher drug miscibility with the bilayer, larger liposomal nanoparticle size, and faster drug release in the aqueous medium than felodipine. We suggest that this combination of molecular dynamics and thermodynamics approach may offer a new tool for designing and developing lipid-based nanocarriers for unmet medical applications.
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Bicamadas Lipídicas , Lipossomos , Simulação de Dinâmica Molecular , Naproxeno , Termodinâmica , Lipossomos/química , Bicamadas Lipídicas/química , Naproxeno/química , Naproxeno/administração & dosagem , Felodipino/química , Felodipino/administração & dosagem , Fosfatidilcolinas/química , Fosfolipídeos/química , Sistemas de Liberação de MedicamentosRESUMO
Therapeutic deep eutectic solvents (THEDES) have been attracting increasing attention in the pharmaceutical literature as a promising enabling technology capable of improving physicochemical and biopharmaceutical properties for difficult-to-deliver drug compounds. The current literature has explored amide local anaesthetics and carboxylic acid nonsteroidal anti-inflammatories (NSAIDs) as commonly used THEDES formers for their active hydrogen-bonding functionality. However, little is known about what happens within the "deep eutectic" region where a range of binary compositions present simply as a liquid with no melting events detectable across experimentally achievable conditions. There is also very limited understanding of how parent compounds' physicochemical properties could impact upon the formation, interaction mechanism, and stability of the formed liquid systems, despite the significance of these information in dose adjustment, industrial handling, and scaling-up of these liquids. In the current work, we probed the "deep eutectic" phenomenon by investigating the formation and physicochemical behaviours of some chosen lidocaine-NSAID systems across a wide range of composition ratios. Our data revealed that successfully formed THEDES exhibited composition dependent Tg variations with strong positive deviations from predicted Tg values using the Gordon-Taylor theory, suggesting substantial interactions within the formed supramolecular structure. Interestingly, it was found that the parent compound's glass forming ability had a noticeable impact upon such profound interaction and hence could dictate the success of THEDES formation. It has also been confirmed that all successful systems were formed based on charge-assisted hydrogen bonding within their THEDES network, affirming the significant role of partial protonisation on achieving a profound melting point depression. More importantly, the work found that within the "deep eutectic" region there was still an ideal, or thermodynamically preferrable "THEDES point", which would exhibit excellent stability upon exposure to stress storage conditions. The discoveries of this study bring the literature one step closer to fully understanding the "therapeutic deep eutectic" phenomenon. Through correlation between parent reagents' physicochemical properties and the synthesised products' characteristics, we establish a more educated process for the prediction and engineering of THEDES.
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Anti-Inflamatórios não Esteroides , Lidocaína , Lidocaína/química , Lidocaína/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/administração & dosagem , Solventes/química , Anestésicos Locais/administração & dosagem , Anestésicos Locais/química , Ligação de Hidrogênio , Química Farmacêutica/métodos , Estabilidade de MedicamentosRESUMO
Understanding the interplay between kinetics and thermodynamics of polymer-mediated liquid-liquid phase separation is crucial for designing and implementing an amorphous solid dispersion formulation strategy for poorly water-soluble drugs. This work investigates the phase behaviors of a poorly water-soluble model drug, celecoxib (CXB), in a supersaturated aqueous solution with and without polymeric additives (PVP, PVPVA, HPMCAS, and HPMCP). Drug-polymer-water ternary phase diagrams were also constructed to estimate the thermodynamic behaviors of the mixtures at room temperature. The liquid-liquid phase separation onset point for CXB was detected using an inline UV/vis spectrometer equipped with a fiber optic probe. Varying CXB concentrations were achieved using an accurate syringe pump throughout this study. The appearance of the transient nanodroplets was verified by cryo-EM and total internal reflection fluoresence microscopic techniques. The impacts of various factors, such as polymer composition, drug stock solution pumping rates, and the types of drug-polymer interactions, are tested against the onset points of the CXB liquid-liquid phase separation (LLPS). It was found that the types of drug-polymer interactions, i.e., hydrogen bonding and hydrophobic interactions, are vital to the position and shapes of LLPS in the supersaturation drug solution. A relation between the behaviors of LLPS and its location in the CXB-polymer-water ternary phase diagram was drawn from the findings.
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Celecoxib , Polímeros , Solubilidade , Termodinâmica , Água , Polímeros/química , Água/química , Celecoxib/química , Cinética , Química Farmacêutica/métodos , Transição de Fase , Separação de FasesRESUMO
The study objective was to design and characterise herein unreported polyologels composed of a range of diol and triol solvents and polyvinyl methyl ether-co-maleic acid (PVM/MA) and, determine their potential suitability for the treatment of periodontal and related diseases in the oral cavity using suitable in vitro methodologies. Polyologel flow and viscoelastic properties were controlled by the choice of solvent and the concentration of polymer. At equivalent polymer concentrations, polyologels prepared with glycerol (a triol) exhibited the greatest elasticity and resistance to deformation. Within the diol solvents (PEG 400, pentane 1,5-diol, propane 1,2-diol, propane 1,3-diol, and ethylene glycol), PEG 400 polyologels possessed the greatest elasticity and resistance to deformation, suggesting the importance of distance of separation between the diol groups. Using Raman spectroscopy bond formation between the polymer carbonyl group and the diol hydroxyl groups was observed. Polyologel mucoadhesion was influenced by viscoelasticity; maximum mucoadhesion was shown by glycerol polyologels at the highest polymer concentration (20% w/w). Similarly, the choice of solvent and concentration of PVM/MA affected the release of tetracycline from the polyologels. The controlled release of tetracycline for at least 10 h was observed for several polyologels, which, in combination with their excellent mucoadhesion and flow properties, offer possibilities for the clinical use of these systems to treat diseases within the oral cavity.
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Moisture was frequently used as dielectric heating source in classical microwave-able systems to facilitate microwave-induced in situ amorphization, however such systems may face the potential of drug hydrolysis. In this study, solid thermolytic salts were proposed to function as moisture substitutes and their feasibility and impacts on microwave-induced in situ amorphization were investigated. It was found that NH4HCO3 was a promising solid alkaline salt to facilitate both microwave-induced in situ amorphization and in situ salt formation of acidic indomethacin (IND). Moreover, it could improve the chemical stability of the drug and the dissolution performance of compacts relative to classical moisture-based compacts upon microwaving. Further mechanistic study suggested that the in situ amorphization occurred prior to the in situ salt formation, especially in formulations with low drug loadings and high solid salt mass ratios. For compacts with low polymer ratios, in situ salt formation took place subsequently, where the previously amorphized IND within compacts could interact with the NH3 gas produced in situ by the decomposition of NH4HCO3 and form the ammonium IND salt. Microwaving time showed great impacts on the decomposition of NH4HCO3 and the in situ generation of water and NH3, which indirectly affected the amorphization and salt formation of IND. In comparison to the moisture-based systems, the NH4HCO3-based system showed a number of advantages, including the reduced potential of IND hydrolysis due to the absence of absorbed moisture, a wider category of applicable polymeric carriers other than hygroscopic polymers, and an increase in drug loading up to 50% (w/w).
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Micro-Ondas , Sais , Estabilidade de Medicamentos , Cristalização , Polímeros/química , SolubilidadeRESUMO
Antimicrobial resistance is an ever-growing global concern, making the development of alternative antimicrobial agents and techniques an urgent priority to protect public health. Antimicrobial photodynamic therapy (aPDT) is one such promising alternative, which harnesses the cytotoxic action of reactive oxygen species (ROS) generated upon irradiation of photosensitisers (PSs) with visible light to destroy microorganisms. In this study we report a convenient and facile method to produce highly photoactive antimicrobial microparticles, exhibiting minimal PS leaching, and examine the effect of particle size on antimicrobial activity. A ball milling technique produced a range of sizes of anionic p(HEMA-co-MAA) microparticles, providing large surface areas available for electrostatic attachment of the cationic PS, Toluidine Blue O (TBO). The TBO-incorporated microparticles showed a size-dependent effect on antimicrobial activity, with a decrease in microparticle size resulting in an increase in the bacterial reductions achieved when irradiated with red light. The >6 log10Pseudomonas aeruginosa and Staphylococcus aureus reductions (>99.9999%) achieved within 30 and 60 min, respectively, by TBO-incorporated >90 µm microparticles were attributed to the cytotoxic action of the ROS generated by TBO molecules bound to the microparticles, with no PS leaching from these particles detected over this timeframe. TBO-incorporated microparticles capable of significantly reducing the bioburden of solutions with short durations of low intensity red light irradiation and minimal leaching present an attractive platform for various antimicrobial applications.
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Fotoquimioterapia , Fármacos Fotossensibilizantes , Fármacos Fotossensibilizantes/farmacologia , Espécies Reativas de Oxigênio/farmacologia , Fotoquimioterapia/métodos , Luz , Cloreto de Tolônio/farmacologia , Staphylococcus aureusRESUMO
Deep eutectic solvents (DES) are multicomponent liquids that are usually formed by coupling a hydrogen bond donor and acceptor leading to strong non-covalent (NC) intermolecular networking and profound depression in the melting point of the system. Pharmaceutically, this phenomenon has been exploited to improve drugs' physicochemical properties, with an established DES therapeutic subcategory, therapeutic deep eutectic solvents (THEDES). THEDES preparation is usually via straightforward synthetic processes with little involvement of sophisticated techniques, which, in addition to its thermodynamic stability, make these multi-component molecular adducts a very attractive alternative for drug enabling purposes. Other NC bonded binary systems (e.g., co-crystals and ionic liquids) are utilized in the pharmaceutical field for enhancing drug's behaviours. However, a clear distinction between these systems and THEDES is scarcely discussed in the current literature. Accordingly, this review provides a structure-based categorization for DES formers, a discussion of its thermodynamic properties and phase behaviour, and it clarifies the physicochemical and microstructure boundaries between DES and other NC systems. Additionally, a summary of its preparation techniques and their experimental conditions preparation is supplied. Instrumental analysis techniques can be used to characterize and differentiate DES from other NC mixtures, hence this review draws a road map to for this purpose. Since this work mainly focuses on pharmaceutical applications of DES, all types of THEDES including the highly discussed types (conventional, drugs dissolved in DES and polymer based) in addition to the less discussed categories are covered. Finally, the regulatory status of THEDES was investigated despite the current unclear situation.
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Solventes Eutéticos Profundos , Líquidos Iônicos , Solventes/química , Sistemas de Liberação de Medicamentos , Preparações Farmacêuticas/química , Líquidos Iônicos/químicaRESUMO
Through liquid-liquid phase separation (LLPS), it is possible to generate drug-rich nanoparticles during the dissolution of conventional amorphous solid dispersions (ASDs). These self-generated nanoparticles may improve the oral absorption of poorly water-soluble drugs by enhancing the drug's apparent solubility and effective membrane permeability. However, due to the high concentration threshold required for LLPS, conventional ASDs that can consistently generate drug-rich nanoparticles during dissolution are rare. More importantly, the quality of these meta-stable drug-rich nanoparticles is hard to control during dissolution, leading to inconsistency in formulation performances. This work has described a continuous twin-screw extrusion process capable of producing nanosized ASD (NASD) formulations that can offer better solubility and permeability enhancements over conventional ASD formulations. Two polymeric carriers, polyvinylpyrrolidone-co-vinyl acetate (PVPVA) and hydroxypropyl methylcellulose acetate succinate (HPMCAS), with a model hydrophobic drug celecoxib (BCS II), were formulated into both ASD and NASD formulations. Compared to the conventional ASD formulation, the prefabricated NASD (sizes ranging between 40 and 200 nm) embedded within a polyol matrix can be rapidly dispersed into a nanoparticle suspension in the presence of aqueous media. The resulting NASDs achieved drug loadings up to 80 % w/w and a maximum of 98 % encapsulation efficiency. Because of the TSE platform's high drug-loading capacity and high scalability, the developed method may be useful for continuously producing personalized nanomedicines.
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Benchmarking , Povidona , Solubilidade , Liberação Controlada de Fármacos , Povidona/química , Permeabilidade , Composição de MedicamentosRESUMO
The performance of vaginal drug delivery systems is dependent on their retention. This study presents a novel mathematical method to estimate the vaginal retention of semi-solids. Using creep analysis, the elastic and residual compliances are determined from the discrete retardation spectrum and used to determine the retention times (RT), defined as the time required for the formulations to enter the terminal viscous zone of deformation and hence flow. RT of commercially available products (CAP) and selected prototype formulations were determined, the estimated RT of CAP broadly aligning with their prescribed clinical usage. Candidate formulations composed of hydroxyethylcellulose (HEC, 3%/5%w/w) and polyacrylic acid (PAA, 1%/3%w/w) were manufactured using, and further diluted with simulant vaginal fluid (SVF) or simulant seminal fluid (SSF) and their RT subsequently determined. Increasing polymer concentration and pH enhanced the estimated RT whereas dilution reduced RT. Notably, the formulation composed of 5%HEC/3% PAA (SSF) maintained its RT on dilution due to swelling of suspended PAA particles, thus representing a strategy to develop vaginal semi-solids that are resistant to dilution and hence removal. The mathematical model described is reproducible, straightforward to use and is recommended as a tool in formulation development to estimate the retention of vaginal semi-solids.
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Sistemas de Liberação de Medicamentos , Vagina , Feminino , Humanos , Polímeros , GéisRESUMO
Microwave-induced in situ amorphization is a novel technology for preparing amorphous solid dispersions (ASDs) to address the challenges of their long-term physical stability and downstream processing. To date, only few types of dielectric materials have been reported for microwave-induced in situ amorphization, which restricted the extensive research of this technology. This study aimed to investigate the feasibility and mechanisms of utilizing the non-ionic surfactants, i.e. Kollisolv P124, Kolliphor RH40, D-É-tocopheryl polyethylene glycol succinate (TPGS), Tween (T) 60 (T60), T65, T80 and T85, as plasticizers to facilitate microwave-induced in situ amorphization. It was found that the successful application of surfactants could be related with their low Tm, low Mw and high HLB. Kolliphor RH40 was selected as a typical surfactant due to its excellent dielectric heating ability, plasticizing effect and solubilizing effect when facilitating amorphization. Then, the dissolution-mediated in situ amorphization mechanism was investigated and intuitively demonstrated. For the most promising formulation, i.e. microwaved systems with Korlliphor RH40 at 1.5 (w/w) plasticizer/polymer ratio, a complete and fast in vitro dissolution was observed relative to the untreated systems. In conclusion, non-ionic surfactants had the potential to facilitate microwave-induced in situ amorphization, which provided a new direction in the formulation designation for microwave-able systems.
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Polímeros , Tensoativos , Micro-Ondas , Solubilidade , Polissorbatos , PlastificantesRESUMO
Polymeric nanoparticle drug delivery systems are increasingly viewed as crucial building blocks for efficacious treatments of disease conditions. However, production methods at commercially practical scales pose a significant challenge for successfully translating such technology. This paper describes a novel, anhydrous, twin-screw extrusion (TSE) platform-based technology to overcome the issues associated with developing and scale-up production of nanoparticulate drug delivery systems. With polyol as the process medium, the proposed TSE platform enables the encapsulation of the drug and reduction of particle size in a one-step process without the requirement for organic solvents or water. pH-responsive nanoparticle drug delivery of two nonsteroidal anti-inflammatory drugs, naproxen, and celecoxib, was successfully produced using the TSE process. Remarkably, these resulted in nanoparticles with sizes ranging from 80 to 240 nm, up to 98 % drug encapsulation efficiency, and maximum production throughput of 400 g/hour. pH-responsive drug release for both naproxen and celecoxib was also achieved: immediate drug release with enhanced solubility was obtained for naproxen-Eudragit®E nanoparticles (6 times higher) at pH 1.2 and celecoxib-HPMCAS nanoparticles (15 times higher) at pH 6.8, whilst sustained drug release was achieved for naproxen-Eudragit®E nanoparticles at pH 6.8 and celecoxib-HPMCAS nanoparticles at pH 1.2. We expect this platform technology to streamline the development and scale-up production of various polymeric nanoparticle drug delivery systems.
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Nanopartículas , Naproxeno , Celecoxib , Ácidos Polimetacrílicos , Solubilidade , Tamanho da Partícula , Liberação Controlada de Fármacos , Preparações Farmacêuticas , Portadores de FármacosRESUMO
Sustained release of lidocaine from poly ethylene-co-vinyl acetate (EVA) implants can significantly improve pain management outcomes; however, poor drug loading is a major limitation. Recently, myristic acid was found to improve drug loading in EVA by inhibiting the crystallization of lidocaine. Here, lidocaine's interaction with myristic acid was studied by differential scanning calorimetry. Spectra of lidocaine-myristic acid mixtures were analysed using two-dimensional correlation (2DCOS) maps. Furthermore, spectroscopic analysis of EVA matrices containing lidocaine, alone and in combination with myristic acid, was also performed and drug release was evaluated in vitro. A eutectic was obtained on combining lidocaine and myristic acid at the molar ratio of 1:1 due to loss of myristic acid's dimeric conformation resulting in hydrogen bonding of its COOH group with lidocaine's amide I moieties. In EVA, hydrogen bonding between adjacent lidocaine molecules caused crystallization above a threshold concentration and could be inhibited by incorporation of myristic acid by eutectic formation. By altering the molecular confirmation and solid state properties of lidocaine in EVA, myristic acid reduces lidocaine crystallization, increases drug loading and influences drug release kinetics. Exploiting these interactions and promoting further hydrogen bonding through the addition of specific excipients presents a viable strategy to enhance and stabilise drug loading in polymer matrices for various applications.
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Excipientes , Lidocaína , Etilenos , Excipientes/química , Ligação de Hidrogênio , Ácido Mirístico , Polímeros/química , Compostos de VinilaRESUMO
A major hurdle in pediatric formulation development is the lack of safety and toxicity data on some of the commonly used excipients. While the maximum oral safe dose for several kinds of excipients is known in the adult population, the doses in pediatric patients, including preterm neonates, are not established yet due to the lack of evidence-based data. This paper consists of four parts: (1) country-specific perspectives in different parts of the world (current state, challenges in excipients, and ongoing efforts) for ensuring the use of safe excipients, (2) comparing and contrasting the country-specific perspectives, (3) past and ongoing collaborative efforts, and (4) future perspectives on excipients for pediatric formulation. The regulatory process for pharmaceutical excipients has been developed. However, there are gaps between each region where a lack of information and an insufficient regulation process was found. Ongoing efforts include raising issues on excipient exposure, building a region-specific database, and improving excipient regulation; however, there is a lack of evidence-based information on safety for the pediatric population. More progress on clear safety limits, quantitative information on excipients of concern in the pediatric population, and international harmonization of excipients' regulatory processes for the pediatric population are required.
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OBJECTIVES: To develop a robust tablet design for the manufacture of gastro-retentive tablets using fused deposition modelling three-dimensional printing (FDM-3DP) that can provide prolonged gastric residence time with instant floating and minimum influence of process and/or formulation variables. METHODS: Three different polymers, such as polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC) and Soluplus were used, separately, for the manufacture of tablets using FDM-3DP. Tablets were designed in a sandwich model that included voids in the internal structure to support buoyancy. KEY FINDINGS: Fabricated tablets from all polymers were instantly buoyant with no floating lag time. Floating duration was in the order: HPC > Soluplus > PVA which can be explained by the density of the tablets. PVA tablets exhibited significantly (P < 0.05) higher density values (0.86 ± 0.02 mg/mm3) than HPC and Soluplus (0.69 ± 0.03 and 0.72 ± 0.02 mg/mm3, respectively). HPC and Soluplus showed similar zero-order drug release profiles (f2 > 50) and were able to sustain the release of theophylline for 12 h, whereas complete drug release was achieved from PVA tablets after 3 h. CONCLUSIONS: Robust gastro-retentive tablets that show instant buoyancy regardless of the polymeric carrier type and composition were successfully manufactured utilising FDM-3DP. This allows for overcoming the restrictions posed by process/formulation parameters on the floatability of gastro-retentive tablets.
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Álcool de Polivinil , Teofilina , Liberação Controlada de Fármacos , Polietilenoglicóis , Polímeros , Álcool de Polivinil/química , Polivinil , Impressão Tridimensional , Comprimidos/química , Tecnologia Farmacêutica/métodosRESUMO
3D printing (3DP) by fused deposition modelling (FDM) is one of the most extensively developed methods in additive manufacturing. Optimizing printability by improving feedability, nozzle extrusion, and layer deposition is crucial for manufacturing solid oral dosage forms with desirable properties. This work aimed to use HPMCAS (AffinisolTM HPMCAS 716) to prepare filaments for FDM-3DP using hot-melt extrusion (HME). It explored and demonstrated the effect of HME-filament composition and fabrication on printability by evaluating thermal, mechanical, and thermo-rheological properties. It also showed that the HME-Polymer filament composition used in FDM-3DP manufacture of oral solid dosage forms provides a tailored drug release profile. HME (HAAKE MiniLab) and FDM-3DP (MakerBot) were used to prepare HME-filaments and printed objects, respectively. Two diverse ways of improving the mechanical properties of HME-filaments were deduced by changing the formulation to enable feeding through the roller gears of the printer nozzle. These include plasticizing the polymer and adding an insoluble structuring agent (talc) into the formulation. Experimental feedability was predicted using texture analysis results was a function of PEG concentration, and glass-transition temperature (Tg) values of HME-filaments. The effect of high HME screw speed (100 rpm) resulted in inhomogeneity of HME-filament, which resulted in inconsistency of the printer nozzle extrudate and printed layers. The variability of the glass-transition temperature (Tg) of the HME-filament supported by scanning electron microscopy (SEM) images of nozzle extrudates and the lateral wall of the printed tablet helped explain this result. The melt viscosity of HPMCAS formulations was investigated using a capillary rheometer. The high viscosity of unplasticized HPMCAS was concluded to be an additional restriction for nozzle extrusion. The plasticization of HPMCAS and the addition of talc into the formulation were shown to improve thickness consistency of printed layers (using homogeneous HME-filaments). A good correlation (R2 = 0.9546) between the solidification threshold (low-frequency oscillation test determined by parallel-plate rheometer) and Tg of HME-filaments was also established. Drug-loaded and placebo HPMCAS-based formulations were shown to be successfully printed, with the former providing tailored drug release profiles based on variation of internal geometry (infill).
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Excipientes , Tecnologia Farmacêutica , Formas de Dosagem , Liberação Controlada de Fármacos , Metilcelulose/análogos & derivados , Impressão Tridimensional , Comprimidos , Tecnologia Farmacêutica/métodosRESUMO
OBJECTIVES: The traditional manufacturing methods of solid oral dosage forms (SODFs) are reported to be time-consuming, highly expensive and not tailored to the patient's needs. Three-dimensional printing (3DP) is an innovative emerging technology that can help to overcome these issues. The aim of this review is to describe the most employed 3DP technologies, materials and the state of the art on 3DP SODFs. Characterization techniques of 3DP SODFs, challenges and regulatory issues are also discussed. KEY FINDINGS: The interest in the investigation of the suitability of 3DP as an alternative strategy for the fabrication of SODFs is growing. Different 3DP technologies and starting materials have been investigated for the development of SODFs. Numerous SODFs with complex geometries and composition, and with different release patterns, have been successfully manufactured via 3DP. Despite that, just one 3DP SODF has reached the market. SUMMARY: 3DP can be a promising alternative to the classical SODFs manufacturing methods. However, numerous technically and regulatory challenges still need to be addressed in order 3DP to be extensively used in the pharmaceutical sector.