Academic literature on the topic 'Orodispersible film'

To deliver maximum amount of paroxetine in shortest duration of time, the orodispersible films (ODF) were formulated and tested for their suitability as a carrier system. ODF were prepared by using hydroxypropyl methylcellulose and polyvinyl alcohol and different superdisintegrants at a specific proportion. The newly developed ODF were subjected to characterization for folding endurance, weight variations, thickness, disintegration time, drug release pattern and drug content. The surface morphology of orodispersible film was examined by means of scanning electron microscope. Moreover physical compatibility between the drug and excipients was guaranteed in the orodispersible film by Fourier transform infrared spectroscopy. It was found that all films prepared were transparent, smooth and elegant in appearance. ODF showed good folding endurance, uniform thickness, weight and drug content. The surface pH of all orodispersible film was found to be neutral and they disintegrate within few seconds. FTIR spectroscopy supported compatible among all excipients and they can be used together in formulation. It was concluded that stable paroxetine orodispersible films can be made by solvent casting technique with ultrafast dissolution rate.

Amphotericin B possesses high activity against Candida spp. with low risk of resistance. However, Amphotericin B’s high molecular weight compared to other antifungal drugs, such as miconazole and clotrimazole, and poor water solubility hampers its efficacy at the physiological conditions of the oropharyngeal cavity (saliva pH, limited volume for dissolution) and thereby limits its clinical use in oropharyngeal candidiasis. We have prepared fast-dissolving orodispersible films with high loading (1% w/w) using solvent casting that enables amphotericin B to remain solubilised in saliva in equilibrium between the monomeric and dimeric states, and able to produce a local antifungal effect. Optimisation of the amphotericin B-loaded orodispersible films was achieved by quality by design studies combining dextran and/or maltodextrin as dextrose-derived-polymer film formers with cellulose-derived film formers (hydroxypropylmethyl/hydroxypropyl cellulose in a 1:4 weight ratio), sorbitol for taste masking, microcrystalline cellulose (Avicel 200) or microcrystalline cellulose-carboxymethylcellulose sodium (Avicel CL-611) for enhancing the mechanical strength of the film, and polyethylene glycol 400 and glycerol (1:1 w/w) as plasticizers. The optimised amphotericin B orodispersible films (containing 1% AmB, 25% dextran, 25% maltodextrin, 5% sorbitol, 10% Avicel 200, 10% polyethylene glycol 400, 10% glycerol, 3% hydroxypropylmethyl cellulose acetate succinate, 12% hydroxypropyl cellulose) possessed a fast disintegration time (60 ± 3 s), quick release in artificial saliva (>80% in 10 min), high burst strength (2190 mN mm) and high efficacy against several Candida spp. (C. albicans, C. parapsilosis and C. krusei) (>15 mm inhibition halo). Amphotericin B orodispersible films are stable for two weeks at room temperature (25 °C) and up to 1 year in the fridge. Although further toxicological and in vivo efficacy studies are required, this novel Amphotericin B orodispersible films is a promising, physicochemically stable formulation with potential wide application in clinical practice, especially for immunocompromised patients suffering from oropharyngeal candidiasis.

Polymers constitute a group of materials having a wide-ranging impact on modern pharmaceutical technology. Polymeric components provide the foundation for the advancement of novel drug delivery platforms, inter alia orodispersible films. Orodispersible films are thin, polymeric scraps intended to dissolve quickly when put on the tongue, allowing them to be easily swallowed without the necessity of drinking water, thus eliminating the risk of choking, which is of great importance in the case of pediatric and geriatric patients. Polymers are essential excipients in designing orodispersible films, as they constitute the backbone of these drug dosage form. The type of polymer is of significant importance in obtaining the formulation of the desired quality. The polymers employed to produce orodispersible films must meet particular requirements due to their oral administration and have to provide adequate surface texture, film thickness, mechanical attributes, tensile and folding strength as well as relevant disintegration time and drug release to obtain the final product characterized by optimal pharmaceutical features. A variety of natural and synthetic polymers currently utilized in manufacturing of orodispersible films might be used alone or in a blend. The goal of the present manuscript was to present a review about polymers utilized in designing oral-dissolving films.

Orodispersible or mucoadhesive films as a patient-oriented dosage form for low-dosed drugs are usually produced using solvent casting. This paper presents a modification of the solvent casting technique that aimed to divide oral films into two or more compartments. The proposed objectives and fields of applications include improved handling properties and safety of application, the optimization of drug release kinetics and the enhancement of long-term stability when combining two or more active pharmaceutical ingredients into one oral film. A feasibility study for the combination of different film-forming polymers to generate the so-called tandem films was performed. As examples of practical implementation, orodispersible applicator films consisting of a drug-loaded section and a handheld piece were cast, and mucoadhesive buccal tandem films were cast to optimize the dissolution rate of the films.

Orodispersible sublingual films (OSFs) composed of hydrophilic polymers were loaded with poloxamer-188 and d-α-tocopheryl polyethylene glycol succinate (TPGS-1000) mixed micelles to improve the oral bioavailability of a poorly soluble drug, ebastine (EBT). Mixed micelles formed by thin-film hydration method were incorporated into orodispersible sublingual film, consisting of HPMC and glycerol, using solvent casting technique. The mixed micelles and films were thoroughly evaluated for physicochemical characterization (size, polydispersity index, zeta potential, entrapment efficiency, thickness, weight, surface pH studies, disintegration time, swelling indices, mechanical properties, FTIR, PXRD, DSC, SEM, AFM, in vitro drug release, in vivo bioavailability, and toxicological studies). The results showed that the average particle size of mixed micelles was 73 nm. The mean zeta potential and PDI of the optimal mixed micelles formulation were −26 mV and 0.16, respectively. Furthermore, the maximum entrapment efficiency 82% was attained. The film’s disintegration time was in the range of 28 to 102 s in aqueous media. The integrity of micelles was not affected upon incorporation in films. Importantly, the micelles-loaded films revealed rapid absorption, high permeability, and increased bioavailability of EBT as compared to the pure drug. The existence of ebastine loaded mixed micelles in the films enhanced the bioavailability about 2.18 folds as compared to pure drug. Further, the results evidently established in-vitro and in-vivo performance of bioavailability enhancement, biocompatibility, and good safety profile of micelles-loaded orodispersible EBT films. Finally, it was concluded that film loaded with poloxamer-188/TPGS-1000 mixed micelles could be an effective carrier system for enhancing the bioavailability of ebastine.

Two-dimensional (2D) printing is a simple technology that shows the possibility for the preparation of personalized pharmaceutical dosage forms. This technology can accurately print medicine in different sizes, which can be applied to develop a personalized, drug-loaded orodispersible film for patients with dysphagia. Seed gum from Tamarindus indica Linn was selected as the film former of the printing substrate, and sorbitol was applied as a film plasticizer. Theophylline was used as a printed model drug due to its narrow therapeutic index. From the results, the mechanical properties of the film indicated that increasing the level of sorbitol improved the flexibility and strength of the film, which rendered the gum film suitable as a printing substrate. Conversely, raising portions of the gum (more than 3.5%) led to the use of rigid and stress-resistant films that can crack during the printing process. The Fourier transform infrared result revealed that there was no interaction between theophylline and the gum after the printing process. The printed theophylline was mainly in an amorphous form based on the X-ray diffraction results. Furthermore, theophylline was deposited at the surface of the gum substrate after the drug-printing process, as depicted in the scanning electron microscope images. The printed drug on the orodispersible film can be accurately determined by varying the printing size/repeat. Lastly, the drug was completely released from the orodispersible film within 5 min. The research results showed the possibility of utilizing tamarind seed gum as a potential printing substrate for the 2D drug-printing technique. Moreover, this can be applied as an electronic prescribing system for telemedicine in the future.

Orodispersible films are an innovative dosage form. Their main advantages are the application comfort and the possibility of personalization. This work aimed to evaluate the influence of different drying times on the properties of orodispersible films of various thicknesses, prepared in two different semisolid extrusion 3D printing setups. In the first experiment, drying times were dependent on the overall print time of each batch. In the second setup, the drying time was set equal according to the longest one. The evaluated parameters were films’ weight uniformity, thickness, moisture content, surface pH, disintegration time, hardness, and tensile strength. Upon statistical comparison, significant differences in the moisture content were found, subsequently affecting the disintegration time. Moreover, statistically significant differences in films’ mechanical properties (hardness, tensile strength) were also described, proving that moisture content simultaneously affects film plasticity and related properties. In conclusion, a mutual comparison of the manufactured orodispersible films showed that the drying time affects their physical and mechanical properties. The in-process drying setup was proved to be sufficient while allowing quicker manufacturing.

There is a rising interest in the development of orodispersible films (ODFs) as an alternative to fast dissolving tablets which is attributed to their faster dissolution rate, higher durability, and better patient compliance. Owing to its rheological and also various functional properties, many researchers tried to discover some of the pharmaceutical applications of L. sativum in the development of various dosage forms, in addition to its therapeutic studies, such as binding, dissolving, gelling and sustained release dosage form. The fast-dissolving oral film of the Montelukast sodium by using Cress seed mucilage (CSM) and HPMC (15cps) is prepared by solvent casting method. The fast-dissolving oral film evaluated for folding endurance, surface pH, in-vitro disintegration time, drug content and in-vitro drug release. The physical appearance and folding endurance properties were found to be reasonably good and electron microscopy shows that films are clear, colorless with smooth surface.The drug content of all the films was in the range suggesting that drug was uniformly dispersed throughout all films. The present study was an attempt to develop and evaluate an oral fast dissolving drug delivery system using cress seed mucilage as a film former. Keywords: Orodispersible film, Montelukast sodium, Cress seed mucilage, HPMC

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.

Lors de cette dernière décennie, le développement de formes pharmaceutiques innovantes permettant d'améliorer l'efficacité, la sécurité et l'acceptabilité des médicaments pédiatriques est en pleine croissance. Les films orodispersibles (ODF) appartiennent à ces nouvelles formes galéniques améliorant la compliance des patients. Ils sont constitués d'une matrice de polymère hydrophile dans laquelle un ou des principe(s) actif(s) (PA) sont dissous ou dispersés. Après dépôt de l'ODF sur la langue ou dans la cavité buccale, la matrice se désagrège libérant le PA pour une action locale ou systémique. Dans cette étude, la mise au point d'ODF, par la méthode de coulée/évaporation de solvant a été explorée afin d'administrer un PA d'intérêt en pédiatrie, la tétrabénazine (TBZ). Les caractérisations physicochimiques et biopharmaceutiques des ODF ont mis en évidence une augmentation de la vitesse et du taux de dissolution de la TBZ induit par son état amorphe. Le système constitué d'un support polymère et d'un PA sous forme amorphe peut être assimilé aux dispersions solides amorphes (SD). Les études réalisées démontrent l'importance de la nature du polymère utilisé pour maintenir les propriétés initiales du système dans le temps. La formation de liaisons hydrogène entre la PA étudié et le polymère est un facteur essentiel pour assurer la stabilité des SD. De plus, l'incorporation de cyclodextrines (CD) prolonge l'état amorphe du PA en générant des liaisons hydrogène avec la TBZ et en l'entourant d'une barrière chimique. Cette association favorise la libération du PA par effet synergique améliorant la biodisponibilité. Cette forme innovante représente un intérêt majeur dans l'amélioration de l'observance dans le cadre d'un traitement pédiatrique
During the last decade, various strategies to develop innovating oral dosage forms for pediatric population were investigated in order to improve treatment efficiency, safety and acceptability. Among these new delivery systems, orodispersible films (ODF) present a great potential to enhance patient compliance. In ODF, drug is dissolved or dispersed in a hydrophilic film-forming polymer. Once the ODF is in the mouth, polymeric matrix disintegrates releasing the drug for local or systemic action. In this study, ODF, produced with the solvent casting/evaporation method, were developed to administer a drug of interest for pediatric population, the tetrabetazine (TBZ). Physicochemical and biopharmaceutic characterizations showed that ODF allowed a major improvement of TBZ dissolution profile in simulated saliva, mainly due to the amorphous state of the drug in ODF. ODF were identified as amorphous solid dispersion (SD) composed of both amorphous TBZ and polymer matrix. We demonstrated that the choice of the polymer plays an important role to maintain initial properties of the system and amorphous state stability over the time. H-bonding formation between TBZ and polymer is essential to assure the preservation of TBZ amorphous state. Moreover, the incorporation of cyclodextrins (CD), by generating H-bonding with TBZ, has extended its stability. By synergic effect, this association produces an improvement of drug release leading to promote bioavailability. As they are easy to swallow and allow enhancing treatment efficiency, ODF appear as suitable delivery forms for pediatric patients

Dans la dernière décennie, les autorités de santé ont promulgué une réglementation pédiatrique orientée sur le développement et la disponibilité des formulations adaptées à l'âge, la taille, l'état physiologique et les besoins de la population pédiatrique. Généralement, l'administration de médicaments par la voie orale est toujours préférée aux autres voies d'administration car elle est pratique, économique et bien acceptée. Au cours des dernières années, de nouvelles formulations solides ont été développés comme par exemple les comprimés orodispersibles car ils sont faciles à administrer, ne nécessitent pas d'eau et, dès lors que la dispersion est rapide, la biodisponibilité du médicament peut être significativement supérieure à celle observée avec les comprimés classiques offrant ainsi des solutions alternatives pour les enfants. D’autre part, les mini-granules présentent de nombreux avantages par rapport aux formes galéniques solides unitaires car ils se dispersent à travers le tractus gastro-intestinal, réduisant ainsi l'irritation locale du principe actif, et permettent l'amélioration de l'absorption du médicament ainsi que la diminution des fluctuations de concentration plasmatique. De plus, avec ces formes multiparticulaires, il est possible de contrôler la vitesse de libération du médicament, ce qui réduit les effets indésirables. Quelques études ont porté sur la compression des mini-granules non enrobés, ce qui pourraient limiter les problèmes pendant la compression comparativement aux mini-granules enrobés pour lesquels l’enrobage pourrait être détruit.L'objectif global de ce travail était de développer un comprimé multiparticulaire orodispersible (MUP-ODT) qui permet la libération contrôlée d'acétaminophène (APAP), utilisé comme principe actif modèle, contenue dans les mini-granules des comprimés orodispersibles.La première partie a déterminé les propriétés mécaniques des mini-granules d’APAP obtenus par la technique d’extrusion-sphéronisation en contenant différents types d'excipients et différents pourcentages de principe actif pour produire un système matriciel à libération contrôlée.La seconde partie de cette étude a examiné la faisabilité de comprimer des mini-granules non enrobés à base de cellulose microcristalline (MCC) dans différentes formulations orodispersibles et d’étudier l'influence du pourcentage de mini-granules, le type de désagrégant et la force de compression.La troisième partie a été dédiée à la production des MUP-ODTs qui permettent la libération contrôlée d’APAP en utilisant différents pourcentages d’Eudragit® pour créer un système matriciel sans changement significatif dans le profil de libération après la compression.Enfin, dans la dernière partie, un plan d'expérience a été effectué pour déterminer les paramètres optimaux pour produire les MUP-ODTs. L'évaluation du masquage de goût a été réalisée par la langue électronique et la méthode de dissolution à l'aide d'une pompe à seringues qui utilise de fiables volumes de milieu afin de simuler le comportement dans la bouche d’un enfant. Plusieurs polymères ont été utilisés avec succès pour produire des mini-granules d’APAP de type matriciel avec différents pourcentages de principe actif. Les MUP-ODTs ont été obtenus en montrant la faisabilité de leur production et l’obtention de bonnes propriétés mécaniques. Ils permettent la désagrégation très rapide et la possibilité de libération modifiée, tout en offrant une déglutition facile pour un enfant et une flexibilité de posologie
In the last decade, medical agencies have promoted a pediatric regulatory focusing on the development and availability of age-appropriate formulations suitable for age, size, physiological condition and treatment requirements for the pediatric population. In general, oral drug delivery is still preferred over the other drug delivery routes since it is convenient, economical and user friendly. In recent years, a number of new solid oral drug delivery platforms such as orodispersible tablets have been developed as they are easy to administer, do not require additional water and, as long as dispersion is rapid, the bioavailability of the drug can be significantly greater than those observed in conventional tablet dosage forms offering a potential alternative for pediatric patients. In parallel, multiparticulate products present many advantages compared to single-unit dosage forms as they distribute fast through the gastrointestinal tract, thus reducing local irritation caused by the active ingredient, enhancing drug absorption and decreasing fluctuation of plasma peaks. Moreover, it is possible to control the drug release rate, resulting in fewer adverse effects. Only few studies have dealt with the compaction of uncoated pellets, which potentially could provide fewer problems during compaction than coated pellets, in particular by reducing damages on the coating.The overall objective of this study was to develop a Multiple-Unit Pellet Orodispersible Tablet (MUP-ODT) allowing for the controlled release of acetaminophen (APAP), used as a model drug, which is contained in the pellets of the orodispersible tablets.The first part determined the mechanical properties of APAP pellets produced by the extrusion-spheronization technique containing different types of excipients and different drug load percentages to produce a controlled release matrix system.The second part of this study examined the feasibility to compress uncoated free drug MCC pellets with different orodispersible formulations to assess the influence of the percentage of pellets, type of disintegrants and compression force.The third part was dedicated to produce MUP-ODTs which allowing for controlled-release of APAP using different percentages of Eudragit® to create the matrix system without significant changes in the release profile after compression.Finally, a design of experiments was carried out to determinate the optimal parameters to produce MUP-ODTs.Taste-masking evaluation was realized using the electronic tongue. Dissolution test was performed using a syringe pump and small volumes of aqueous medium at low flow rates to mimic the behavior in the mouth of the child.Different polymers were successfully used to produce APAP matrix pellets with different drug loadings. MUP-ODTs were successfully obtained demonstrating their feasible production with good mechanical properties. They enable very fast disintegration and modified release properties, but also offer easy swallowing for children and dose flexibility

In order to achieve maximum patient compliance, pharmaceutical companies have directed their research to the development of innovative delivery systems. As this matter, oral films have been claimed as one of the most promising approaches as a new drug delivery for oral administration, showing great interest and a market opportunity. As a relatively new pharmaceutical form, there is a lack of information and available studies concerning this technology. Therefore, it is extremely important to investigate the characteristics of commercially available oral films, which can provide essential information to the development of a new product. The main goal of this project was the chemical, thermal and mechanical characterization of two oral films available in the market: Listerine from Pfizer and Gas-X from Novartis. The characterization of the films was carried out using different techniques: chemical characterization, by FTIR analysis; thermal characterization by TGA, DSC and DMTA; mechanical properties, by tensile tests. Other important characteristics, such as disintegration time and water content were also evaluated. In order to understand the relationship between the composition, preparation procedures and the final properties of films, an attempt to reproduce Listerine and Gas-X was carried out. Throughout this work, methodologies for characterization of films were established and some relevant conclusions were taken. On the matter, it was possible to develop a formulation with higher similarity to commercial available film (Listerine), which is extremely relevant in the contribution to the development of new technologies for oral films. The results presented in Listerine revealed the importance of the formulation used in the properties of the oral films.
Muitas indústrias farmacêuticas têm direcionado a sua área de investigação para o desenvolvimento de novos sistemas de entrega de fármacos inovadores. Desta forma, e devido às inúmeras vantagens inerentes a esta tecnologia, os filmes orais têm sido apontados como uma das abordagens mais promissoras como novo sistema para administração oral, revelando-se de grande interesse como oportunidade de mercado. Sendo uma nova forma farmacêutica, há uma falta de informação disponível e os estudos incidentes sobre este tema são muito limitados e pouco desenvolvidos. Deste modo, é extremamente importante procurar investigar as características dos filmes orais comercialmente disponíveis. Esta informação é fundamental para o desenvolvimento de novas aplicações e tecnologias de administração oral. O principal objectivo deste trabalho é a caracterização química, térmica e mecânica de dois filmes orais disponíveis actualmente no mercado: Listerine produzido pela Pzifer, e o Gas-X desenvolvido pela Novartis. A caracterização dos filmes foi realizada recorrendo a diversas técnicas. Caracterização química por análise de FTIR; caracterização térmica por TGA, DSC e DMTA; e caracterização mecânica por testes de tracção. Outras características importantes foram também avaliadas, nomeadamente, o tempo de desintegração dos filmes e o conteúdo de água residual. De forma a compreender a relação entre a composição, preparação e as propriedades finais dos filmes, procedeu-se a uma tentativa de reprodução dos filmes comerciais Listerine e Gas-X. Ao longo deste trabalho, foram desenvolvidas e estabelecidas metodologias para a caracterização de filmes orais, o que permitiu obter conclusões muito relevantes não só ao nível da influência de excipientes nas propriedades. Na verdade, conseguiu-se obter um filme com grande semelhança ao comercial (Listerine), o que se revela uma mais valia e contribuição para o desenvolvimento de novas tecnologias de filmes orais. Os resultados apresentados para o Listerine revelam a importância da formulação nas propriedades dos filmes orais.

Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2017
The use of orodispersible films has gained increasing relevance among solid pharmaceutical forms. They consist of a thin and flexible polymeric film, formulated to rapidly disintegrate in the oral cavity. Being a solid dispersion, the solid characterization of its components is of upmost importance, as it dictates the physical stability and safety of the product. The aim of this work was to characterize the drug-polymer compatibility and the solid state of a poorly water-soluble drug (olanzapine) in a polymeric orodispersible matrix, as a primary stage of product development. Methocel® (HPMC) and Soluplus® were chosen as matrix-former polymers, based on their wide-usage in previous works. Olanzapine orodipersible films were obtained through solvent-casting technique, using methanol as solvent and a proportion of drug-polymer of 1:1 (m/m %). Spectroscopic studies (Raman, FTIR, CARS, TimeGated® Raman) and thermodynamic studies (DSC) were performed to characterize olanzapine’s solid state within the orodispersible matrix. Polarized light microscopy showed refringence, thus, revealing the presence of crystals in the both Olz-HPMC and Olz-Soluplus films. Comparing to the assignment made in previous works and to the spectra obtained in this work, spectroscopic data showed peaks that did not correlate neither to form 1 nor to form 2. Furthermore, peaks were found to be shifted towards higher wavenumbers, namely peaks assigned to NH deformations. This suggests that an interaction between the drug and the polymer could be occurring. DSC data supports this hypothesis, as olanzapine’s melting point in both drug-polymer films and physical-mixtures revealed a Tonset severely lower than form 1 melting point. This work suggests that there appears to be an interaction between drug and polymers, which is proposed to be occurring through H bonding. Nonetheless, this interaction could be favourable as it could be interesting to stabilize small dimension crystals or even amorphous form of olanzapine.
Os filmes orodispersíveis constituem uma forma farmacêutica que tem ganho algum destaque no âmbito das formas farmacêuticas sólidas. Representam filmes poliméricos, delgados, flexíveis, formulados com o intuito de se desintegrarem rapidamente na cavidade oral, sem recurso a líquidos que auxiliem a deglutição. Ao se tratarem de dispersões sólidas, torna-se imprescindível a caracterização do estado sólido dos seus compostos, bem como o estudo de possíveis interações entre os diferentes componentes, tendo em vista a estabilidade física e segurança do produto final. Uma substância pode ser encontrada sob diferentes formas polimórficas, formas solvatadas ou ainda no estado amorfo, sendo que cada forma possuí diferentes propriedades físico-químicas. Em última instância, toda esta variabilidade tem repercussões na biodisponibilidade da própria substância ativa. Durante a otimização de uma forma farmacêutica sólida, o balanço entre estabilidade e solubilidade tem que ser obtido, uma vez que estes dois fatores nem sempre se mostram compatíveis. Por exemplo, o estado amorfo apresenta taxas de dissolução mais elevadas, por não ser necessário ultrapassar as energias de coesão que um cristal possuí. Ainda assim, este estado sólido apresenta a desvantagem de ser mais instável, ocorrendo cristalização durante o tempo de prateleira do produto. Uma estratégia interessante para estabilizar e alterar a taxa de dissolução de SA passa pela sua incorporação numa matriz solúvel em água, i.e, pela formulação de uma dispersão sólida. Para tal, recorre-se a polímeros capazes de formar uma matriz que, pela sua incapacidade de possuir um arranjo cristalino de grandes dimensões, criam uma estrutura na qual as moléculas (ou pequenos cristais) do farmáco se intercalam. Neste projeto, filmes orodispersíveis de olanzapina e dos polímeros HPMC e Soluplus® foram produzidos pela técnica de espalhamento (utilizando-se metanol como solvente), visando o estudo da compatibilidade entre a substância ativa e cada polímero, bem como a caracterização do estado sólido da olanzapina nos filmes obtidos. Para tal, recorreu-se a técnicas espetrofotométricas (Raman, FTIR, TimeGated® Raman e CARS) e, ainda, a estudos termodinâmicos (DSC). No âmbito do estudo de compatibilidade, proporções 1:1 (olz-polímero) foram utilizadas tanto nas misturas físicas como nos próprios filmes desenvolvidos, por se tratar da proporção que favorece a interação máxima entre os compostos. Os resultados revelaram que a matéria-prima de olanzapina se constituía pela forma polimórfica conhecida na literatura como forma 1 (polimorfo mais estável) e as suas características foram tidas como referência nos estudos efetuados posteriormente. No caso das misturas físicas, as principais características desta forma mantiveram-se preservadas, sem grandes alterações nos perfis analíticos. Ainda assim, a análise espectrofotométrica revelou ligeiras alterações que sugerem que alguma interação entre olz-polímero possa ocorrer. Mais precisamente, as bandas correspondentes a grupos moleculares envolvidos em ligações de hidrogénio encontraram-se com desvios, tendo-se observado este facto tanto no caso do polímero HPMC como para o Soluplus. Adicionalmente, o perfil do DSC revelou um ponto de fusão desviado relativamente ao obtido para a matéria-prima de olanzapina. Estes dois resultados sugerem que alguma interação possa ocorrer entre o fármaco e cada um dos polímeros. Quanto aos filmes olz-polímero, as alterações observadas são ainda mais acentuadas e complexas de se analisar. Os picos espectrofotométricos tidos como referência para a forma 1 de olanzapina revelaram alterações importantes. Sendo que a interpretação pode passar pela presença de olanzapina no estado amorfo, bem como a da presença de metanolato no filme final. Não foram encontrados dados espectrofotométricos relativos a estas formas sólidas na literatura, pelo que um próximo passo seria a sua caracterização detalhada com o intuito de se comparar com os espectros dos filmes obtidos.

Tese de doutoramento em Ciências Farmacêuticas, na especialidade de Tecnologia Farmacêutica, apresentada à Faculdade de Farmácia da Universidade de Coimbra
A forma farmacêutica Película (do inglês “Films”) é definida genericamente nas Farmacopeias como uma fina folha composta por uma ou várias camadas com ou sem fármaco, que se destina a ser colocado na cavidade oral. Estas películas são geralmente preparadas por técnicas como solvent-casting ou extrusão, podendo ser preparadas com o objetivo de apresentarem desintegração rápida ou lenta e / ou permitirem uma absorção gastrointestinal ou através mucosa oral do fármaco. Estas diferenças podem ser alcançadas por uma simples modificação da composição da formulação base. Esta versatilidade associada a outras vantagens conhecidas como a portabilidade e facilidade de administração, justificam o elevado interesse de muitas empresas no desenvolvimento desta forma farmacêutica. Foram estes os motivos que conduziram ao interesse em explorar o conhecimento em torno das películas orodispersíveis. Inicialmente, foi efetuada uma revisão bibliográfica aprofundada de forma a reunir informação que permitisse o desenvolvimento de uma Película nova e inovadora. Esta informação foi sumariada e criticamente discutida num artigo de revisão dividido em duas partes, descortinando-se desde o seu desenvolvimento primordial até ao seu crescimento e sustentabilidade de mercado. Esta extensa avaliação conduziu e confluiu para importantes orientações do trabalho experimental. Películas disponíveis comercialmente foram analisadas e caracterizadas para desenvolver conhecimento experimental e parâmetros adequados de processo e qualidade do produto. Este trabalho teve como base ferramentas estatísticas específicas como Desenho de Experiências e Quimiometria. Paralelamente, foi efetuada uma triagem a inúmeros polímeros e 3 novas películas foram desenvolvidas. Mas apenas uma, a que apresentou resultados mais promissores, foi optimizada. Esta optimização foi efetuada com base em instrumentos e abordagens sistemáticas que permitissem o controlo e melhoramento da qualidade do produto, como o conceito Quality by Design). Esta tendência regulamentar e de qualidade associada à novidade, processo de fabrico peculiar e composição complexa, desencadeou a necessidade de estabelecer linhas de orientação ou directrizes para o seu desenvolvimento. Assim, o perfil de qualidade do produto alvo foi delineado e os atributos críticos de qualidade estabelecidos para poder definir os parâmetros críticos de processo e servirem como critério de qualidade e aceitação no desenvolvimento de novas películas. A maioria das películas com rápida desintegração, normalmente designadas por películas orodispersíveis (do inglês “Orodispersible Films”) são constituídas por polímeros hidrofílicos. Esta característica costuma estar associada a baixa estabilidade e originar texturas e aparências pouco apelativas e indesejáveis, especialmente quando expostos às condições ambientais. Assim, e considerando o panorama de propriedade intelectual existente na área, películas mais estáveis e robustas foram selecionadas e preparadas. Consequentemente, películas orodispersíveis compostas por polímeros hidrofóbicos foram desenvolvidas, contribuindo para uma aplicação de patente, baseada na novidade dos polímeros utilizados e como solução alternativa para colmatar necessidades tecnológicas e terapêuticas. Finalmente, 2 fármacos diferentes foram incorporados na película orosdispersível desenvolvida e optimizada, e uma pequena transposição de escala foi também efetuada. Aproximadamente 90% de Doentes de Parkinson (DP) e cerca de 33% de doentes com Doença Neurodegenerativa (DN) apresentam ou irão desenvolver disfagia (problemas de deglutição). As películas orodispersíveis desenvolvidas, uma com Pramipexole (tratamento na DP) e outra com fármaco para tratamento da DN, são constituídas por uma matriz hidrofóbica, incluindo acetato de polivinilo, alcóol polivinilico, trietilcitrato e caraboximetilcelulose sódica. A película orodispersível para tratamento de DN foi ainda preparada numa escala ligeiramente superior de acordo com as Boas Práticas de Fabrico, de forma a obter amostras suficientes para delinear um estudo de estabilidade adequado e posteriormente efectuar um estudo de biodisponibilidade comparativa entre películas orodispersíveis e as cápsulas de fármaco para DN disponíveis no mercado (produto de referência). Esta abordagem servirá essencialmente como prova de conceito para testes posteriores de transposição de escala para um nível comercial. Em termo de conclusão, foi ainda elaborada uma pequena revisão que foca os desafios técnicos encontrados durante o processo de investigação e desenvolvimento e transposição de escala; a qual reúne informação da experiência prática, suportada com consulta bibliográfica, sugerindo igualmente possíveis alternativas e soluções para os problemas apontados. Esta tese, inclui o desenvolvimento e caracterização de inúmeras películas orodispersíveis, mas permitiu também gerar conhecimento relevante e inovação. Foi demonstrado que é possível desenvolver películas orodispersíveis constituídas essencialmente por uma matriz hidrofóbica sem comprometer a sua rápida desintegração, destronando um forte paradigma desta área de investigação. Foram ainda elucidadas e sugeridas diferentes técnicas de caracterização e métodos de análise alternativos que podem ser úteis no desenvolvimento desta forma farmacêutica. Para além disso, foram ainda desenvolvidas películas orodispersíveis de Pramipexole e películas orodispersíveis para tratamento de DN que poderão vir a colmatar as necessidades dos doentes com DP e DN, maioritariamente associadas a problemas de deglutição das formas farmacêuticas atualmente disponíveis.
“Films” or “Oral films” in the US Pharmacopeia monograph are simply defined as single or multi-layer thin sheets with or without drug substance (DS) to be placed in oral cavity. In turn, the European Pharmacopeia adds it as innovative and new dosage form. The oral films are generally prepared by solvent-casting or extrusion, being designed for fast or delayed disintegration and may allow gastrointestinal or mucosal absorption. These differences can be achieved by through the modification of the base formulation. This justifies the growing interest of many companies in the development of this dosage form in a perspective of a versatile drug delivery technology. There are also many advantages of this recent and convenient dosage form that also contributed for its rapid growth in the drug delivery market. Also, the clear success of several companies in the field roused the interest of exploring and developing our own conception and technological platform. An extensive revision of the literature was initially performed in order to gather information about this recent dosage form that allowed the further development of a new and versatile oral film technological platform. This information has been summarized and critically exposed in an extensive literature review divided in two different parts, which covers areas ranging from oral film development appearance to their growth and sustainability on the market. The output of this broad literature examination led to some considerations and orientations in the experimental part of the thesis. Marketed oral films were deeply analyzed and characterized to develop experimental knowledge and suitable quality and process parameters. This work was based on specific statistical tools, as Design of Experiments platforms and Chemometrics analysis. Simultaneously, a wide polymeric screening was performed and 3 new technological platforms were developed, but only the most promising was fully optimized. Once more, this was based on particular tools and systematic approaches that allowed controlling and improving the quality of the product, as Quality by Design concept. This quality and regulatory trend associated with the novelty, particular processing and multicomponent composition unleashed the need of establishing development guidance. Therefore, a quality target product profile (QTPP) was delineated and critical quality attributes (CQAs) stablished to further identify appropriate critical process parameters (CPPs) to function as criterion in new oral film formulations development. The majority of the fast disintegrating oral films for, commonly designated by orodispersible films (ODFs) are generally based on hydrophilic polymers. This characteristic is usually associated with lower stability, undesirable texture and appearance, especially when exposed to ordinary environment conditions. Considering this aspect and the intellectual property landscape, more stable and robust oral films, were explored, screened and developed. Consequently, oral films based on hydrophobic polymers with a fast disintegration were obtained, which led to a patent application grounded by the polymer nature differentiation, novelty and outcoming advantages. Finally, two different DS (Pramipexole and ND drug) were incorporated in the developed and optimized ODF, and a small scale-up was performed. Almost 90% of individuals with Parkinson Disease (PD) and more than 33% of Neurodegenerative Disease (ND) patients may develop or already suffer from dysphagia. Pramipexole ODF and ND drug ODF with hydrophobic polymeric matrices, including PVAc, polyvinyl alcohol, triethyl citrate and sodium carboxymethylcellulose were developed. The ND drug ODF development was further performed in a larger scale and following Good Manufacturing Practices (GMP) to obtain enough samples to delineate a suitable stability study and lately a bioavailability comparison between ND drug ODF / ND drug capsules (reference product). This approach would function as a proof-of-concept for later scale-up studies. Additionally, research and development challenges and the main issues of the slight scale transposition (manufacturing process and liquid mixture processability) were reported and analyzed in a short revision, gathering experimental experience with focused literature examination. In this thesis, several ODFs were developed and characterized, but importantly some critical knowledge and innovation was generated. For instance, was shown that it is possible to develop ODFs based on hydrophobic polymers without compromising the fast disintegration, breaking an important paradigm in the ODF research field. It was also demonstrated that different characterization techniques and alternative methods of analysis may be very helpful in oral films’ development. Another important goal was the conceptual development of a Pramipexole ODF and a relatively stable ND drug ODF that materialize an unmet need of PD and ND therapy, mostly associated to swallowing issues of the drug dosage forms available in the market.
FCT - SFRH / BDE /51271 / 2010

Nos últimos anos, a tecnologia de produção aditiva tem atraído a atenção da comunidade científica em diversas áreas. Esta tecnologia, representada através de diversas técnicas de impressão 3D, permitiu uma mudança no paradigma da projeção e do fabrico de produtos personalizados de acordo com as necessidades individuais. A tecnologia de impressão 3D está associada a um sistema informático, conhecido por CAD/CAM (do inglês, Computer-Aided Design/ Computer-Aided Manufacturing), que permite desenhar um objeto, de qualquer forma e tamanho, em computador, e, consequentemente, guardá-lo num ficheiro .STL (do inglês, Standard Tessellation Language), capaz de ler as coordenadas do objeto em qualquer impressora específica para imprimir em 3D. Charles Hull foi o inventor da técnica de estereolitografia, produzindo o primeiro aparelho utilizado para a construção de objetos 3D. Posteriormente à introdução da técnica de estereolitografia, surgiram outras técnicas de impressão 3D, nomeadamente: o jato de tinta, a extrusão e a fusão da camada de pó, sendo estas as mais utilizadas nas áreas da medicina e farmacêutica. Na presente revisão bibliográfica são descritas as diversas técnicas de impressão 3D, explorando o estado da arte relativo à sua aplicação na área da saúde. Em 2015, a FDA (do inglês, Food and Drug Administration) aprovou a comercialização do Spritam®, indicado para o tratamento da Epilepsia em crianças e idosos. Este produto foi o primeiro medicamento produzido pela impressão 3D a ser comercializado. Adicionalmente, este trabalho apresenta algumas considerações futuras, uma vez que a tecnologia de impressão 3D serviu de base para a criação de uma nova técnica, a impressão 4D, a qual utiliza materiais inteligentes no fabrico de objetos tridimensionais, que podem alterar a sua forma e tamanho mediante resposta a estímulos externos.
In recent years, the additive production technology has been attracting the attention of the scientific community in various areas. This technology, represented through various 3D printing techniques, allowed a change in the paradigm of projection and manufacture of customized products according to individual needs. 3D printing technology is associated with a computer system known as CAD/CAM (Computer-Aided Design/ Computer-Aided Manufacturing), which allows to draw an object of any shape and size, on a computer, and therefore save it in a Standard Tessellation Language (.STL) file, which can read the coordinates of the object on any specific printer to print in three dimensions. Charles Hull was the inventor of the technique of stereolithography, producing the first device used for construction of objects in three dimensions. After to introduction of the stereolithography technique, other 3D printing techniques emerged, namely inkjet, extrusion and powder bed fusion, which are the most used techniques in medicine and pharmaceutic. This bibliographic review of the different techniques of 3D printing aims to describe them, exploring the state of the art related to its application in the health area. In 2015, the Food and Drug Administration (FDA) approved the Spritam®, indicated for the treatment of Epilepsy in children and the elderly. This product was the first medicine produced by 3D printing to be commercialized. In addition, this dissertation presents some future considerations, since 3D printing technology was the basis for a new technique, 4D printing, which incorporates intelligent materials into three-dimensional objects that can change their shape and size according to external stimuli.

Orodispersible dosage forms are attractive and innovative drug delivery systems that can fulfill individual patient needs, especially in children, elderly and among dysphagic patients. Indeed, they rapidly disperse in the mouth upon contact with the saliva without the need for water or munching. Examples of such dosage forms include orodispersible tablets (ODT), and orodispersible films (ODF). The ability to obtain ODF with different dimensions (sizes and thicknesses) makes them a suitable for personalized dosing of single or a fixed-dose combination of drugs in special patient populations. Several biopolymers are currently being exploited in the development of orodispersible dosage forms including alginates due to their versatility, availability, naturally occurring, and biosafety profile. This chapter provides an appraisal on the various applications of alginates in the preparations and their role on the properties of orodispersible dosage forms and highlights future perspectives of this very versatile biopolymer for these innovative drug delivery systems.