ReviewOral films: Current status and future perspectives: I — Galenical development and quality attributes
Graphical abstract
Introduction
A thin film that readily dissolves in the oral cavity is commonly referred as orodispersible film by the European Medicines Agency (EMA) [1] or simply soluble film by the FDA [2]. Although, oral films initially appeared as innovative breath freshening formulations, it rapidly evolved to give response to different market needs, namely an easy-to-carry and easy-to-swallow drug delivery system.
The oral films are essentially complex polymeric matrices that may be used efficiently as drug release platforms. These polymeric matrices may be composed of several components in order to achieve well-designed drug-delivery platforms, but usually hydrophilic polymers are its main core. The polymers early entered into the pharmaceutical and biomedical industries as essential components of the formulations and their range of applicability easily spread to several areas, from packaging material to the most sophisticated drug delivery systems and devices. The basic understanding of the role of polymers as excipients, meaning as ingredients in drug products, is critical for formulation development and quality control. Additionally, the knowledge of polymers' basic concepts, as chemistry, properties and types may be critical to develop new or improve conventional drug delivery systems.
Both natural and synthetic polymers can be used in orodispersible dosage forms. The oral films are basically a polymeric matrix which may vary on its composition in order to achieve the desired final product properties. There are several characteristics, such as mucoadhesiveness, disintegration time, % of drug load, mechanical/handling properties (among others) which may be fine-tuned by adjusting the type, amount or grade of the polymers. Additionally, other components may be added in order design the final product according to the target product profile, depending on the drug substance and therapeutic indication. Some of these substances include plasticizers, sweeteners, flavors, colorants, stabilizers, fillers, saliva stimulating agents, buffer systems and others.
Oral films emerged as a very promising and prominent pharmaceutical dosage form in a field subdued to tablets and capsules. The state of the art was also diffused and restrained about the matter until Dixit et al. in 2009 pledge us with a comprehensive overview of the subject, which may probably function as a catalyst for several research works. Currently, several original works and patents can be found in literature, but considerable efforts still need to be carried out to optimize the performance of the films [3], [4], [5]. Regarding the pharmaceutical field, there is still a considerable lack of guidance for the manufacture, characterization and quality control of the oral films.
This review highlights the essential points of oral film development from their appearance through their market growth and formulation key points. To facilitate the readers' understanding, the review is divided into two distinct parts. The first part is focused in the galenical development and quality attributes of the oral films whereas the second part covers technological platforms, intellectual property protection and a market outlook.
Section snippets
Miscellaneous terms
Thin-film, oral film, wafer, oral strip, orodispersible film, oral thin film, oral soluble film, dissofilms, buccal soluble film, mucoadhesive film, buccal film, and transmucosal film are some of the innumerous terms that can be found in literature. Although, the terms seem to be easily differentiated, their meaning can sometimes be misinterpreted and misunderstood.
The oral films were recently introduced in the “Oromucosal Preparations” monograph of the European Pharmacopeia (Ph. Eur. 7.4) with
Why oral films? Particular features for patients and companies
The design of an oral formulation is generally based on two critical factors, drug therapy and the target population. However, the choice of the type of pharmaceutical dosage form may become very difficult when specific target groups include very young children, from birth to 8–10 years of age, and geriatric population. Regarding the pediatric segment the major challenge involves the development of a specific type of dosage form suitable for children of all ages. Additionally, for both
Polymers in oral films: the key component
Orodispersible films are basically a polymeric matrix which may be composed of one or more polymers with different physicochemical and functional properties. There are several characteristics that may be controlled depending on the type or grade of polymers: mucoadhesiveness, disintegration time, drug loading capacity, mechanical strength, elasticity, handling properties and others.
The selection of the polymer (or mixtures) for the development of oral film matrices is a critical step and may
Mucoadhesion: a polymeric inner property?
Although the mucoadhesion concept appeared early during the eighties, it was only ten years later that improved mucoadhesive polymers were introduced in the pharmaceutical field [77]. There are several theories that may explain the bioadhesion process, but none is able to explain the overall mechanism. The wetting theory is one of the oldest theories and involves notions of thermodynamic work and contact angle. Briefly, the bioadhesion in this theory is defined as the surface tension of the two
Polymer selection
As discussed on previous sections, the polymer selection during the formulation development of polymeric matrices may be critical and some points should be considered. Several examples were given related to the ability of the polymer to affect the mechanical and texture properties of the films and also their influence on the drug release. On the other hand, the inclusion of the drug substance in the polymer matrix may also affect significantly the mechanical properties of the film. Depending on
Critical quality attributes (CQA)
There are general critical quality attributes of the oral films that should be considered during their development. These properties are obviously inherent to the formulation but also significantly influenced by the manufacturing process. Hereinafter, some of the most common quality attributes that should be considered during the oral film development are described briefly.
Manufacturing process overview: from the conventional to the innovative
The two main techniques used to prepare oral films are solvent casting [45], [50], [135], [137], [138], [139], [140], [141] and hot melt extrusion [4], [46], [122] (Fig. 4). However, during the past few years some developments and innovative techniques have emerged. Some variants of these manufacturing methods of casting and extrusion have also been described and used alone or in combination, such as semisolid casting and solid-dispersion extrusion [142]. Inventive manufacturing processes as
Characterization methods
Several efforts have been made to develop suitable techniques for oral film evaluation and characterization, considering their particular characteristics. There are critical parameters that should be evaluated for the quality control of the films. Despite the lack of guidance, the European Pharmacopeia refers the need of a “suitable mechanical strength to resist handling without being damaged” and an appropriate dissolution method “to demonstrate the appropriate release of the active
Conclusion
The flexibility of this dissolvable film technology platform offers future potential for expanded applications across different delivery routes in multiple pharmaceutical, biopharmaceutical, and medical markets. It also provides an opportunity to extend revenue life cycles for existing drugs whose patent is expiring and will soon be vulnerable to generic competition. In other words, oral films allow the life cycle management of the products. Additionally, the majority of the manufacturing
Acknowledgments
This work is funded by the FCT grant, reference SFRH/BDE/51271/2010 and by the QREN SI-I&DT Empresa Individual Project No. 18472.
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