Academic literature on the topic 'Hot-melt ram extrusion printing'

Orodispersible films (ODFs)are ultra-thin, stamp-sized, rapidly disintegrating, and attractive oral drug delivery dosage forms best suited for the pediatric and geriatric patient populations. They can be fabricated by different techniques, but the most popular, simple, and industrially applicable technique is the solvent casting method (SCM). In addition, they can also be fabricated by extrusion, printing, electrospinning, and by a combination of these technologies (e.g., SCM + printing). The present review is aimed to provide a comprehensive overview of patented technologies of the last two decades to fabricate ODFs. Through this review, we present evidence to adamantly confirm that SCM is the most popular method while electrospinning is the most recent and upcoming method to fabricate ODFs. We also speculate around the more patent-protected technologies especially in the domain of printing (two or three-dimensional), extrusion (ram or hot-melt extrusion), and electrospinning, or a combination of the methods thereof.

The rheological properties of drug–polymer mixtures have a significant influence on their processability when using transformative techniques, such as hot-melt-extrusion and material-extrusion 3D printing; however, there has been limited data on printable systems. This study investigated the rheological properties of 17 formulations of successful printed tablets for both immediate and controlled release. Hydroxypropyl cellulose was used in various ratios to obtain printable filaments in combination with various drugs (indomethacin or theophylline), polymers and disintegrants. The complex viscosity, shear thinning behavior and viscoelastic properties were affected by the drug load, polymer composite, disintegrant type, temperature and shear rate applied. Larger windows of processing viscosity were revealed. The viscosity of the printable blends could be as low as the range 10–1000 Pa·s at 100 rad/s angular frequency. All formulations showed shear thinning behavior with a broad slope of complex viscosity from −0.28 to −0.74. The addition of 30–60% drug or disintegrant tended to have greater viscosity values. While microcrystalline cellulose was found to be an alternative additive to lower the storage and loss modulus among disintegrants. This rheological data could be useful for the preformulation and further development of material-extrusion 3D-printing medicines.

Fibers and yarns are part of everyday life. So far, fibers that are also used pharmaceutically have mainly been produced by electrospinning. The common use of spinning oils and the excipients they contain, in connection with production by melt extrusion, poses a regulatory challenge for pharmaceutically usable fibers. In this publication, a newly developed small-scale direct-spinning melt extrusion system is described, and the pharmaceutically useful polyvinyl filaments produced with it are characterized. The major parts of the system were newly developed or extensively modified and manufactured cost-effectively within a short time using rapid prototyping (3D printing) from various materials. For example, a stainless-steel spinneret was developed in a splice design for a table-top melt extrusion system that can be used in the pharmaceutical industry. The direct processing of the extruded fibers was made possible by a spinning system developed called Spinning-Rosi, which operates continuously and directly in the extrusion process and eliminates the need for spinning oils. In order to prevent instabilities in the product, further modifications were also made to the process, such as a the moisture encapsulation of the melt extrusion line at certain points, which resulted in a bubble-free extrudate with high tensile strength, even in a melt extrusion line without built-in venting.

The aim of this research was the production of extrudates for the treatment of hypertension and heart failure and the investigation of the degradation of the peptidomimetic drug enalapril maleate (EM) during hot-melt extrusion (HME). A fast HPLC method was developed to quantify enalapril maleate and possible degradation products. Screening experiments revealed that the diketopiperazine derivative (Impurity D) was the main degradation product. Hot-melt extrusion of enalapril maleate with the polymer Soluplus® enabled extrusion at 100 °C, whereas a formulation with the polymer Eudragit® E PO could be extruded at only 70 °C. Extrusion at 70 °C prevented thermal degradation. A stabilizing molecular interaction between enalapril maleate and Eudragit® E PO was identified via FT-IR spectroscopy. Dissolution studies were carried out to study the influence of the formulation on the dissolution behavior of enalapril maleate. These promising results can be transferred to other thermo-sensitive and peptidomimetic drugs to produce extrudates which can be used, for instance, as feedstock material for the production of patient-specific dosage forms via Fused Deposition Modeling (FDM) 3D printing.

The development of innovative forms of combination drugs is closely related to the invention of the multilayer tablet press, polymers for pharmaceutical applications, the hot-melt extrusion process, and 3D printing in the pharmaceutical industry. However, combining multiple drugs within the same dosage form can bring many physicochemical and pharmacodynamic interactions. More and more new forms of fixed-dose combinations (FDCs) have been developed due to work to overcome the incompatibility of active substances or to obtain different drug release profiles in the same dosage form. This review provides discussions of the application of various innovation formulation technologies of FDC drugs such as bilayer system, multilayer tablet, active film coating, hot-melt extrusion, and 3D printing, taking into account the characteristics of the key ingredients in the FDC formulation and presenting technological problems and challenges related to the development of combination drugs. Moreover, the article summarizes the range of dosage forms that have been made using these technologies over the past 30 years.

This study was performed to develop novel core-shell gastroretentive floating pulsatile drug delivery systems using a hot-melt extrusion-paired fused deposition modeling (FDM) 3D printing and direct compression method. Hydroxypropyl cellulose (HPC) and ethyl cellulose (EC)-based filaments were fabricated using hot-melt extrusion technology and were utilized as feedstock material for printing shells in FDM 3D printing. The directly compressed theophylline tablet was used as the core. The tablet shell to form pulsatile floating dosage forms with different geometries (shell thickness: 0.8, 1.2, 1.6, and 2.0 mm; wall thickness: 0, 0.8, and 1.6 mm; and % infill density: 50, 75, and 100) were designed, printed, and evaluated. All core-shell tablets floated without any lag time and exhibited good floating behavior throughout the dissolution study. The lag time for the pulsatile release of the drug was 30 min to 6 h. The proportion of ethyl cellulose in the filament composition had a significant (p < 0.05) effect on the lag time. The formulation (2 mm shell thickness, 1.6 mm wall thickness, 100% infill density, 0.5% EC) with the desired lag time of 6 h was selected as an optimized formulation. Thus, FDM 3D printing is a potential technique for the development of complex customized drug delivery systems for personalized pharmacotherapy.

L'avvento di numerose tecnologie per produzione di film orodispersibili (ODF) ha suscitato un crescente interesse verso l'impiego di questa forma di dosaggio nell’ambito della personalizzazione della terapia. Difatti, la possibilità di ottenere ODF di diverse forme, colori e dimensioni permette a pazienti di identificare facilmente il medicinale, aumentando così la sicurezza e dell’aderenza al trattamento farmacologico (Capitolo 1). Tale avanzamento tecnologico deve tuttavia procedere parallelamente allo sviluppo di saggi non distruttivi e di facile esecuzione in farmacia per la determinazione e il controllo della qualità chimica e fisica degli ODF, come requisito imprescindibile alla sicurezza e all’efficacia (Capitolo 2). Scopo della presente tesi di dottorato è quello di dimostrate la possibilità di produrre film orodispersibili su piccola scala mediante l’uso di una una nuova tecnologia di stampa costituita da una siringa termostatata in grado di estrudere a velocità costante la massa fusa di principio attivo ed eccipienti su un piatto mobile. La composizione della miscela comprende una maltodestrina plasticizzata con glicerica in quanto questi eccipienti sono idenei per la produzione di ODF sia per i pazienti pediatrici, sia per gli anziani. Il metodo di preparazione prevede dei semplici passaggi: la miscelazione del principio attivo con il polimero, plasticizzzante ed eventuali altri eccipienti; il caricamento dell’impasto nella siringa e il preriscaldamento dell’impasto fino a completo rammollimento; la conseguente forzatura attraverso l’ago per depositare il film orodispersibile con una forma definita su un foglio di alluminio che costituisce il confezionamento primario. La versatilità di questo approccio è stata verificata preparando ODF contenenti principi attivi con diverse caratteristiche chimico-fisiche. Tra le varie molecule modello, il paracetamolo è stato scelto per dimostrare la fattibilità di caricare una quantità di attivo (74 mg/ 6 cm2) più elevate rispetto mercato dosaggi di ODF presenti sul mercato (100 mg/9cm2) (Capitolo 3). Nel caso dei film caricati con diclofenac sodico, utilizzato come esempio di sostanza termosensibile, non si è evidenziata la formazione di prodotti di degradazione dovute alle temperature utilizzate per rammollire la miscela (Capitolo 4). Per migliorare la managgevolezza e le proprietà organolettiche dei film, spesso sono aggiunti altri eccipienti quali edulcoranti, aromi e agenti che ne limitano l’appicicosità. In questo ambito, il diossido di titanio, selezionato come opacizzante, non solo ha permesso di migliorare le caratteristiche estetiche dei film, ma ha anche la rimozione del film dal materiale del confezionamento primario, aspetto che risulta particolarmente importante per evitarne la rottura durante la manipolazione da parte del paziente (Capitolo 4). Infine, è stata caricata nei film una quantità pari a 10 mg olanzapine, come modello di sostanza soggetta a polimorfismo. In questo caso il confronto con processi di produzione che richiedono l’utilizzo di una sospensione su base acquosa, ha permesso di evidenziare che la tecnologia proposta elimina la possibilità di conversione dalla forma I alla forma pseudopolimorfica che è caratterizzata da una minore solubilità che potrebbe influire negarivamente sulla biodisponibilità di questa molecola (Capitolo 5). In conclusione, la tecnologia basata su una modifica dell’estrusione a caldo potrebbe essere utilizzata per stampare film costituiti da maltodestrine e glicerina, limitando gli inconvenienti legati all’uso di solventi e altre temperature. Questa formulazione può essere sfruttata per ottenere film contenenti principi attivi con caratteristiche chimico-fisiche diverse, e altri eccipienti richiesti per migliorare le caratteristiche organolettiche di questa forma farmaceutica finita.
The advent of printing technologies for the production of orodispersible films (ODF) guides a growing interest in the application of these dosage forms to precision dosing in personalized medicine. Indeed, the tailoring of ODF shape, colour and/or dimension allows end-users to easily identify their own medicinal product, improving both safety and adherence (Chapter 1). At the same time, to open real perspectives towards ODF for personalized dosing, the design of such technologies should advance along with the development of easy and non-destructive assays, based on colorimetry and spectroscopy, which can allow to establish the physical and chemical quality of ODF (Chapter 2). This doctoral thesis aimed to demonstrates the feasibility of a novel printing technology to extemporaneously compound ODF on-demand. The basic idea was to propose a novel apparatus that combines a hot-melt ram extruder with the plate of a 3D-printer. As far as the formulation is concerned, maltodextrins plasticized with glycerol were selected since they are excipients accepted for both children and elderly. The preparation method consists of simple operations, involving the mixing of the drug substance with maltodextrins and other excipients, then the loading of the mixture into the ram extruder, heating, and printing of the single ODF directly on the packaging aluminium foil. The versatility of this technology was tested by loading ODF with drugs having different physicochemical characteristics. First, paracetamol was selected as a model to demonstrate the drug payload which resulted in loading up to 74 mg/ 6 cm2 and, therefore, allowing the preparation of ODF with a drug amount higher than the highest in the market (i.e., 100 mg/ 9cm2) (Chapter 3). Then, diclofenac sodium was loaded as a model of heat-sensitive and bitter drug to prepare ODF intended for the treatment of migraine in paediatric population. The data revealed that, the exposure to relatively low temperature (i.e., approximately 90 °C) during the printing limited the formation of degradation by-products of the drug (< 0.2%). Furthermore, to improve ODF palatability and patients’ handing, a combination of taste-masking agents (TMA), opacifiers, and, when required, an anti-sticking agent are often loaded into ODF. Thus, the effect of these excipients on the physical properties of ODF loaded by diclofenac was also studied. The results revealed that titanium dioxide, selected as an opacifier, improved not only the ODF aesthetic appearance, but also ODF detachment from the primary packaging material, an aspect particularly relevant to prevent breakage during handing (Chapter 4). Olanzapine (OLZ) was finally tested because it can undergo solid-state modifications under different processing conditions. In this case, the comparison on the performance of OLZ ODF prepared by the proposed technology and consolidated solvent casting technique, which requires the use of a large amount of water, revealed that hot-melt ram extrusion prevented the conversion of OLZ from anhydrous Form I to a pseudo-polymorphic form with lower solubility, which could affect the drug bioavailability (Chapter 5). In conclusion, hot-melt ram extrusion printing can be advantageously used to prepare small batches of ODF made of maltodextrins and glycerine, avoiding the use of solvent and harsh temperatures. This basic formula can be exploited to load drugs differing in physicochemical characteristics, and other excipients to provide suitable organoleptic features of the final dosage form.

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Three dimensional printing (3DP) was used to engineer novel oral drug delivery devices, with specialised design configurations loaded with multiple actives, with applications in personalised medicine. A filament extruder was used to obtain drug-loaded - paracetamol (acetaminophen) or caffeine - filaments of polyvinyl alcohol with characteristics suitable for use in fused-deposition modelling 3D printing. A multi-nozzle 3D printer enabled fabrication of capsule-shaped solid devices, containing paracetamol and caffeine, with different internal structures. The design configurations included a multilayer device, with each layer containing drug, whose identity was different from the drug in the adjacent layers; and a two-compartment device comprising a caplet embedded within a larger caplet (DuoCaplet), with each compartment containing a different drug. Raman spectroscopy was used to collect 2-dimensional hyper spectral arrays across the entire surface of the devices. Processing of the arrays using direct classical least squares component matching to produce false colour representations of distribution of the drugs showed clearly the areas that contain paracetamol and caffeine, and that there is a definitive separation between the drug layers. Drug release tests in biorelevant media showed unique drug release profiles dependent on the macrostructure of the devices. In the case of the multilayer devices, release of both drugs was simultaneous and independent of drug solubility. With the DuoCaplet design it was possible to engineer either rapid drug release or delayed release by selecting the site of incorporation of the drug in the device, and the lag-time for release from the internal compartment was dependent on the characteristics of the external layer. The study confirms the potential of 3D printing to fabricate multiple-drug containing devices with specialized design configurations and unique drug release characteristics, which would not otherwise be possible using conventional manufacturing methods.
The full-text of this article will be released for public view at the end of the publisher embargo on 10 Oct 2016.