Review
Oral films: Current status and future perspectives: I — Galenical development and quality attributes

https://doi.org/10.1016/j.jconrel.2015.03.006Get rights and content

Abstract

Polymers are the most common excipients used in pharmaceutical dosage forms, and often new applications and innovative polymers appear aiming to overcome unmet needs in the drug formulation field. Orodispersible dosage forms based on polymeric matrices have currently demonstrated their prominence in accordance with the actual market requirements and patients' demands. The versatility of the polymeric oral films had proven their high value as suitable technological platforms for extension and adjustment to different delivery routes and promising markets. These are the main reasons for the increasing investment of several companies in this technology and their applicability in different therapeutic segments. This pharmaceutical form with a blustering beginning as a breath freshener had an emergent entrance in the Rx market proving its reliable value. This review describes and explores the oral film technology from its main component, the polymeric matrices, to the new and possible market applications, highlighting all the critical and important points of its development.

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.

References (159)

  • C. Woertz et al.

    Assessment of test methods evaluating mucoadhesive polymers and dosage forms: an overview

    Eur. J. Pharm. Biopharm.

    (2013)
  • R. Jayakumar et al.

    Biomedical applications of chitin and chitosan based nanomaterials—a short review

    Carbohydr. Polym.

    (2010)
  • M. Dash et al.

    Chitosan—a versatile semi-synthetic polymer in biomedical applications

    Prog. Polym. Sci.

    (2011)
  • Z. Zhu et al.

    The development of polycarbophil as a bioadhesive material in pharmacy

    Asian J. Pharm. Sci.

    (2013)
  • F. Madsen et al.

    A rheological examination of the mucoadhesive/mucus interaction: the effect of mucoadhesive type and concentration

    J. Control. Release

    (1998)
  • F. Nakamura et al.

    In vitro and in vivo nasal mucoadhesion of some water-soluble polymers

    Int. J. Pharm.

    (1996)
  • F. Cilurzo et al.

    Polymethacrylate salts as new low-swellable mucoadhesive materials

    J. Control. Release

    (2003)
  • A. Bernkop-Schnurch et al.

    Synthesis and characterisation of mucoadhesive thiolated polymers

    Int. J. Pharm.

    (2000)
  • S. Bonengel et al.

    Thiomers—from bench to market

    J. Control. Release

    (2014)
  • V.M. Leitner et al.

    Thiomers in noninvasive polypeptide delivery: in vitro and in vivo characterization of a polycarbophil–cysteine/glutathione gel formulation for human growth hormone

    J. Pharm. Sci.

    (2004)
  • M.D. Hornof et al.

    In vitro evaluation of the permeation enhancing effect of polycarbophil–cysteine conjugates on the cornea of rabbits

    J. Pharm. Sci.

    (2002)
  • A. Bernkop-Schnurch et al.

    Polycarbophil–cysteine conjugates as platforms for oral polypeptide delivery systems

    J. Pharm. Sci.

    (2000)
  • E.M. Hoffmann et al.

    Advances in orodispersible films for drug delivery

    Expert Opin. Drug Deliv.

    (2011)
  • FDA

    Dosage Form

  • A. Dinge et al.

    Formulation and evaluation of fast dissolving films for delivery of triclosan to the oral cavity

    AAPS PharmSciTech

    (2008)
  • H.G. Zerbe, J.H. Guo, A. Serino, Water soluble film for oral administration with instant wettability, in, Google...
  • G.L. Myers, E. Dadey, Sublingual and buccal film compositions, in, Google Patents,...
  • A. Breitenbach, S. BRAUN, R. Schliephacke, Orodispersible films for the manufacturing of individualised medicine or for...
  • A. Zajicek et al.

    A report from the pediatric formulations task force: perspectives on the state of child-friendly oral dosage forms

    AAPS J.

    (2013)
  • B.J. et al.

    Review: oral drug delivery in personalized medicine: Unmet needs and novel approaches

    Int. J. Pharm.

    (2010)
  • IBISWorld

    Thin Film Drug Manufacturing in the US: Market Research Report

  • C.L.P. et al.

    The generic pharmaceutical industry: moving beyond incremental innovation towards re-innovation

    GaBI J.

    (2013)
  • S.P. et al.

    Handbook of Pharmaceutical Excipients

    (2009)
  • T.D.C. Company

    Using Dow Excipients for Controlled Release of Drugs in Hydrophilic Matrix Systems

    (2006)
  • A. ElMeshad et al.

    Characterization and optimization of orodispersible mosapride film formulations

    AAPS PharmSciTech

    (2011)
  • C.G. Otoni et al.

    Effect of hydroxyl substitution and viscosity on thermal and mechanical properties of hydroxypropyl methylcellulose films

  • T.D.C. Company

    METHOCEL cellulose ethers

  • H. Wen et al.

    Oral Controlled Release Formulation Design and Drug Delivery: Theory to Practice

    (2011)
  • R. Kumria et al.

    Oral buccoadhesive films of ondansetron: development and evaluation

    Int. J. Pharm. Investig.

    (2013)
  • S.N. et al.

    Development of taste masked fast disintegrating films of levocetirizine dihydrochloride for oral use

    Curr. Drug Deliv.

    (2010)
  • A.M. Schobel, S.S.K.S. Vangala, Solid dosage form containing a taste masked active agent, in, Google Patents,...
  • K.B. Liew et al.

    Effect of polymer, plasticizer and filler on orally disintegrating film

    Drug development and industrial pharmacy

    (2014)
  • P.R. et al.

    Development of taste masked film of Valdecoxib for oral use

    Indian J. Pharm. Sci.

    (2007)
  • T.P. et al.

    Fast dissolving strips: a novel approach for the delivery of verapamil

    J. Pharm. Bioallied Sci.

    (2010)
  • A.A. et al.

    Formulation Development of Taste Rapidly Dissolving Films of Cetirizine Hydrochloride

    (2009)
  • N.M. et al.

    Formulation and evaluation of fast dissolving films for delivery of triclosan to the oral cavity

    AAPS PharmSciTech

    (2008)
  • S.S. et al.

    A review on mouth dissolving films

    Curr. Drug Deliv.

    (2009)
  • W.L. Bunnelle, R.M. Hume, L.C. Jannusch, Thermoplastic films and methods for making, in, Google Patents,...
  • K. Yasuda, T. Okubo, Y. Sawai, Rapidly soluble film-shaped preparation, in, Google Patents,...
  • H.G. Zerbe, F. Al-Khalil, Rapidly disintegrating flavored film for precooked foods, in, Google Patents,...
  • Cited by (221)

    • Pullulan hydrogels as drug release platforms in biomedicine

      2023, Journal of Drug Delivery Science and Technology
    View all citing articles on Scopus
    View full text