Technical Review Article | Open Access | Published 16th July 2024
Manufacturing Techniques, Applications and Future Perspectives of Mouth Dissolving Orodispersible Films
Abhijeet Motiwale* and Narendra Pratap Singh Sengar | EJPPS | 292 (2024) | Click to download pdf
Abstract
The orodispersible film (ODF) is a relatively new dosage form addressing many drawbacks of conventional oral dosage forms. Though its popularity is in the initial stage, continuous development of newer technologies allows the production of ODF on larger scales. The convenience of administration and the possibility of personalized therapies indicate a promising future for the dosage form. Limitations such as drug loading capacities and the availability of only a few suitable polymers may be addressed in future investigations, making ODFs an important dosage form in the healthcare industry. In the present review various aspects of ODFs are mentioned viz., manufacturing techniques and applications are highlighted.
Key-words: Orodispersible film, Mouth dissolving, Applications
Introduction
Mouth Dissolving Orodispersible Films
The oral administration of drugs stands out as one of the most preferred routes, offering numerous advantages such as patient compliance and ease of administration. Novel oral drug formulations enhance patient compliance contributing to more effective treatments, fostering innovation in the field of oral drug delivery systems¹. Though the oral solid dosage form is the most common dosage form, it has several drawbacks, such as swallowing problems in paediatric, geriatric and paralyzed patients². The oral fast-dissolving drug delivery system is a novel approach that addresses drawbacks of the conventional oral solid dosage form, and provides faster and more efficient disintegration and dissolution, while eliminating the need to swallow or chew the formulation³.
The European Pharmacopoeia defines an orodispersible film (ODF) as a drug delivery system comprising a film-forming polymer, designed for the delivery of an active principle via the oral cavity. The flexibility of these films is achieved by incorporating plasticizers⁴. An ODF when placed on tongue, is rapidly disintegrated and absorbed into blood vessels within the oral mucosa, providing good bioavailability of the active principle⁵. Different terms are used in the literature for ODF, such as quick dissolve film, melt-away film, flash-release wafer, orally dissolving film, thin strip and wafer. However, ‘buccal or oral soluble film’ is the approved term used by FDA, whereas ‘orodispersible film’ is used by European Medicines Agency⁶. This novel formulation has numerous advantages such as fewer side effects, enhanced drug absorption, and increased overall bioavailability. Additionally, it mitigates patient discomfort. ODF is more stable, biodegradable, biocompatible and non-toxic⁵.
Classification of ODFs
There are three main ways to classify ODF:
Based on rate of dissolution
a. Fast-dissolving ODFs: These have film thickness between 50µm to 150µm and can dissolve within 30 seconds. They are ideal for drugs that requires rapid release and absorption in the buccal cavity.
b. Moderate-dissolving ODFs: ODFs that requires time between 1 to 30 minutes for the complete dissolution are referred to as moderate-release ODFs. They are suitable for a broader range of drugs.
c. Slow-dissolving ODFs: These require more than 30 minutes for complete dissolution. They are found to be useful in preparing nicotine-based products to control the cravings for tobacco in dependent patients⁷.
Based on the number of layers
a. Monolayer films: A single layer of film is prepared by using active drug, polymer and other excipients.
b. Bilayer films: These consist of two layers in which one layer is made of the active principle and the second layer is prepared excipients such as permeation enhancers and taste-masking agents.
c. Multilayer films: These consist of multiple layers of excipients, sandwiching the active drug layer in the middle⁵.
Based on source of active ingredient (API)
a. Natural: Source of API is natural. For example, turmeric and ginger ODFs⁸.
b. Synthetic: Source of API is synthetic. For example, sildenafil ODF⁹.
c. Other: Micronutrients, vitamins, vaccines and minerals containing ODFs fall under a separate class⁵.
Ingredients and their roles
In order to achieve desirable quality of ODFs, several ingredients in balanced combination are used, that control the functionality of film. Some of the key ingredients used in ODFs are given here:
Active pharmaceutical ingredients: These are natural or synthetic compounds that provide pharmacotherapeutic benefits in ODFs. Highly potent APIs are generally used in ODFs¹⁰. Several pieces of literature describe limits of up to 50mg of API per dose⁽¹¹,¹²⁾.
Film forming polymers: These are the backbone of ODFs. Different types of polymers are used according to the desired properties required in the formulation. These polymers must meet requirements such as quick disintegration, drug release, folding strength, tensile strength, mechanical properties, optimum thickness and surface texture. Some examples of polymers used in ODFs are:
a. Natural polymers: Cellulose derivatives such as methylcellulose, hydroxypropyl methylcellulose and hydroxypropyl cellulose. Polysaccharides such as pullulan, chitosan, starch, pectin and sodium alginate.
b. Synthetic polymers: Polyvinyl acetate, polyvinylpyrrolidone, polyvinyl alcohol and methacrylic acid copolymers (13).
Plasticizers: Plasticizers are important components of ODFs that reduce brittleness and influence mechanical strength of the film. They lower glass transition temperature and provide flexibility to the film. They also improve flow and strength of the polymer used in the film. Plasticizers are added up to 20% w/w of the dry polymeric powder¹⁴. Some examples of plasticizers are macrogol, triethyl citrate, diethyl phthalate, sorbitol, mannitol, glycerol and propylene glycol¹³.
Sweeteners and Flavours: Sweeteners and flavours are added in ODFs to mask the unpleasant taste of API and other excipients. They improve palatability and acceptance in the patients. Some common sweeteners used in ODFs include Saccharin, Neotame, Sucralose and Aspartame¹⁵.
Saliva Stimulating Agents: Organic acids such as ascorbic acid and citric acid can be used along with saccharine to achieve synergistic saliva stimulating action. Production of saliva assists in rapid disintegration, dissolution and absorption of the ODFs¹⁴.
Manufacturing Techniques
Several manufacturing processes are used for production of ODFs. Each technique has its own advantages and limitations. Some of the most common manufacturing techniques are discussed here.
Solvent Casting Technique
This is one of the most common methods employed in the production of ODFs and was the first method introduced for their preparation. The API is dissolved in a suitable volatile solvent, chosen based on its compatibility with the API and other excipients. A solution of excipients, containing polymer, plasticizer, sweeteners, flavouring agents, and colouring agents, is prepared separately. The film dope is created by mixing both solutions to achieve uniformity. On a laboratory scale, the film dope is cast on petri dishes and spread evenly. On an industrial scale, an apparatus that can continuously cast the film on impregnated paper is used. The cast film is dried using equipment such as a hot air oven and convection chamber. Solvents are vaporized, and a dried thin film is obtained. Laminate rolls are then cut into the desired shape and size before being sent to the packaging machine. Packaging is carried out using air and moisture-resistant sealing bags, as moisture can compromise the stability of ODFs ⁽³,⁵,⁶,¹⁶⁾. This method allows the accommodation of heat-labile API into the dosage form, as the preparation involves being subjected to lower temperatures. Solvents remaining in the formulation may affect compendial compliance. Additionally, flammable ingredients require extra precautions during production, which are a few of the limitations of the process¹⁷.
Hot-melt extrusion (HME) technique
This is a one-step process that uses temperature and shear for processing of polymer blends and extruding into a die of the required size and shape. It does not require the use of any solvents. Rather, a powder blend of API and excipients is subjected over a heated barrel, that melts the polymer and produces films of uniform thickness¹⁸. Organic solvents used in the solvent casting method are hazardous to health and residues can complicate health conditions. Disposing of the waste material is also cumbersome. HME addresses these issues, as there is no use of solvents in the procedure⁽¹⁹,²⁰⁾. This single-step procedure is cost effective, and requires no compression of drugs into the film⁵. HME also has several disadvantages. The process involves melting of mixture over high temperatures that may affect stability of the API, and disturb flavours and colourants. Lack of suitable polymers that can be used in HME is another limitation of the process⁶.
Electrospinning technique
This is a relatively newer technology that is used for the manufacturing of ODFs. An electrified jet of fluid containing molten polymer is stretched and elongated to form fibres. Applying a high voltage causes surface-like charges to repel each other electrostatically, leading to the elongation of a liquid droplet into a Taylor cone. This happens because similar charges repel excessively due to the surface tension of the fluid. The solvent evaporates rapidly, and fibres start forming when the jet reaches the collector. The shape of the fibres is mainly determined by the stage of bending instability during deposition²¹. Polymers that are studied for the manufacturing of electrospun fibres for ODFs include poloxamers, gelatin and polyvinyl pyrrolidone. These polymers are not only compatible for loading food supplements and API, but also enhance solubility of the drug⁽¹⁶,²²⁾.
Printing technique
Printing technology is commonly used in the pharmaceutical industry for labelling purposes. Pad printing and screen-printing methods were formerly tested for loading active drug into transdermal formulations. Similarly, 3D printing technology has been tested for production of layered oral dosage forms, where the active drug was printed over a carrier and was inserted into a capsule after rolling up. Inkjet printers have also been tested for careful loading of active drug over orodispersible films. Other printing techniques such as dipping, impregnating and spraying were already tested for ODF production, nevertheless, disintegration and rupturing of thin film during production remains a challenge²³
Applications of ODFs
ODFs are rapidly dissolved in the buccal cavity, bypassing the need to swallow. This make ODFs ideal for variety of applications, including:
Medication Delivery:
ODFs are a suitable dosage form for delivering drugs to paediatric and geriatric patients. They also facilitate dose delivery to unconscious patients or those who have difficulty swallowing. APIs incorporated into ODFs do not undergo first-pass metabolism, thus providing enhanced bioavailability²⁴. Some examples of marketed ODFs are Benadryl® Allergy quick dissolve strips, Gaas-X® Thin Strips, Suboxone® Sublingual Film, Theraflu® Thin Strips long acting cough, Triamini® Thin Strips cold with stuffy nose, etc⁶.
Nutritional supplements:
ODFs are being used for the delivery of medicaments, however, they may be applied in the field of nutraceuticals. The development in the production methods of ODFs and introduction of 3D printing technologies opens up scope for the personalized nutritional supplementation products for the customers. Several researches shows the possibility of loading nutrients into ODFs, providing better understanding and promoting innovations in nutraceuticals field⁽²⁵,²⁶⁾.
Breath fresheners:
ODFs were initially introduced to the market as breath freshening formulations before their medicinal applications. The introduction of ODFs as breath fresheners provided insight into the need for mouth-dissolving products, laying the foundation for the further development of the ODF dosage form.⁽⁶,²⁷⁾. After the popularity of Listerine ODFs worldwide, there are now several ODF breath fresheners available on the market. Pocketpaks ™ is an ODF mouth freshening formulation produced by Pfizer that is available on the market⁵.
Future perspectives
New discoveries and continuous improvements in current technology are crucial for the development of the pharmaceutical industry. Emerging technologies and innovations enable the resolution of product limitations and drawbacks. The increasing number of innovations and patents related to ODFs in recent years suggests a promising future for this dosage form⁷. The development of ODFs is progressing along two distinct branches. The first approach involves the creation of technologies and machinery to scale up ODF production, ensuring the availability of the product at affordable prices in the market. The second approach focuses on developing personalized dosage forms utilizing technologies such as 3D printing machines. Establishing a regulatory pathway is imperative for the rational use and prescription of personalized therapies. Another critical aspect requiring attention is the maximum drug loading capacity in ODFs. Identifying suitable polymers and formulating ODFs using natural ingredients to establish a safer natural drug delivery system can significantly contribute to the bright future of ODFs as a dosage form.
The orodispersible film is a relatively new dosage form addressing many drawbacks of conventional oral dosage forms. Though its popularity is in the initial stage, continuous development of newer technologies allows the production of ODFs on larger scales. The convenience of administration and the possibility of personalized therapies indicate a promising future for the dosage form. Limitations such as drug loading capacities and the availability of only a few suitable polymers may be addressed in future investigations, making ODFs an important dosage form in the healthcare industry.
References
01. Tiwari S, Batra N. Oral Drug Delivery System: A Review. Am J Life Sci Res. 2014;2(1):27–35.
02. Schiele JT, Quinzler R, Klimm HD, Pruszydlo MG, Haefeli WE. Difficulties swallowing solid oral dosage forms in a general practice population: prevalence, causes, and relationship to dosage forms. Eur J Clin Pharmacol. 2013 Apr;69(4):937–48.
03. Arya A, Chandra A, Sharma V, Pathak K. Fast Dissolving Oral Films: An Innovative Drug Delivery System and Dosage Form. Int J ChemTech Res. 2010;2(1):576–83.
04. European Pharmacopoeia Commission. European Pharmacopoeia Ninth Edition (PhEur 9.0). In Strasbourg, France: European Directorate for the Quality of Medicines; 2016.
05. Salawi A. An Insight into Preparatory Methods and Characterization of Orodispersible Film—A Review. Pharmaceuticals. 2022 Jul 9;15(7):844.
06. Hoffmann EM, Breitenbach A, Breitkreutz J. Advances in orodispersible films for drug delivery. Expert Opin Drug Deliv. 2011 Mar;8(3):299–316.
07. Gupta MS, Kumar TP, Gowda DV. Orodispersible Thin Film: A new patient-centered innovation. J Drug Deliv Sci Technol. 2020 Oct;59:101843.
08. Gopi S, Amalraj A, Kalarikkal N, Zhang J, Thomas S, Guo Q. Preparation and characterization of nanocomposite films based on gum arabic, maltodextrin and polyethylene glycol reinforced with turmeric nanofiber isolated from turmeric spent. Mater Sci Eng C. 2019 Apr;97:723–9.
09. Radicioni M, Castiglioni C, Giori A, Cupone I, Frangione V, Rovati S. Bioequivalence study of a new sildenafil 100 mg orodispersible film compared to the conventional film-coated 100 mg tablet administered to healthy male volunteers. Drug Des DevelTher. 2017 Apr;Volume11:1183–92.
10. Visser JC, Wibier L, Mekhaeil M, Woerdenbag HJ, Taxis K. Orodispersible films as a personalized dosage form for nursing home residents, an exploratory study. Int J Clin Pharm. 2020 Apr;42(2):436–44.
11. Krampe R, Visser JC, Frijlink HW, Breitkreutz J, Woerdenbag HJ, Preis M. Oromucosal film preparations: points to consider for patient centricity and manufacturing processes. Expert Opin Drug Deliv. 2016 Apr 2;13(4):493–506.
12. Woertz C, Kleinebudde P. Development of orodispersible polymer films containing poorly water soluble active pharmaceutical ingredients with focus on different drug loadings and storage stability. Int J Pharm. 2015 Sep;493(1–2):134–45.
13. Olechno K, Basa A, Winnicka K. “Success Depends on Your Backbone”—About the Use of Polymers as Essential Materials Forming Orodispersible Films. Materials. 2021 Aug 27;14(17):4872.
14. Arora L, Chakraborty T. A review on new generation orodispersible films and its novel approaches. Indo Am J Pharm Res. 2017;7(1):7451–70.
15. H. R. D, K. K. S, Dr. S. R. C. Orodispersible film dosage form: A review. World J Pharm Res. 2014;3(5):1093–111.
16. Musazzi UM, Khalid GM, Selmin F, Minghetti P, Cilurzo F. Trends in the production methods of orodispersible films. Int J Pharm. 2020 Feb;576:118963.
17. Melegari C. Study of Different Technologies for Film Coating of Drug Layered Pellets Using Ethylcellulose as Functional Polymer. ALMA MATER Stud - Univ Bologna [Internet]. 2016 [cited 2023 Dec 13]; Available from: http://amsdottorato.unibo.it/id/eprint/7487
18. Pimparade MB, Vo A, Maurya AS, Bae J, Morott JT, Feng X, et al. Development and evaluation of an oral fast disintegrating anti-allergic film using hot-melt extrusion technology. Eur J Pharm Biopharm. 2017 Oct;119:81–90.
19. Palem CR, Kumar Battu S, Maddineni S, Gannu R, Repka MA, Yamsani MR. Oral transmucosal delivery of domperidone from immediate release films produced via hot-melt extrusion technology. Pharm Dev Technol. 2013 Feb;18(1):186–95.
20. Rathbone MJ. Modified-release drug delivery technology. Volume 1. 2nd ed. New York: Informa Healthcare; 2008. 235–256 p.
21. Xue J, Wu T, Dai Y, Xia Y. Electrospinning and Electrospun Nanofibers: Methods, Materials, and Applications. Chem Rev. 2019 Apr 24;119(8):5298–415.
22. Łyszczarz E, Brniak W, Szafraniec-Szczęsny J, Majka TM, Majda D, Zych M, et al. The Impact of the Preparation Method on the Properties of Orodispersible Films with Aripiprazole: Electrospinning vs. Casting and 3D Printing Methods. Pharmaceutics. 2021 Jul 22;13(8):1122.
23. Janßen EM, Schliephacke R, Breitenbach A, Breitkreutz J. Drug-printing by flexographic printing technology—A new manufacturing process for orodispersible films. Int J Pharm. 2013 Jan;441(1–2):818–25.
24. Morath B, Sauer S, Zaradzki M, Wagner AH. Orodispersible films – Recent developments and new applications in drug delivery and therapy. BiochemPharmacol. 2022 Jun;200:115036.
25. Yuan C, Sha H, Cui B. Orally Disintegrating Film: A New Approach to Nutritional Supplementation. Food Bioprocess Technol. 2022 Dec;15(12):2629–45.
26. Cupone IE, Roselli G, Marra F, Riva M, Angeletti S, Dugo L, et al. Orodispersible Film Based on Maltodextrin: A Convenient and Suitable Method for Iron Supplementation. Pharmaceutics. 2023 May 23;15(6):1575.
27. Borges AF, Silva C, Coelho JFJ, Simões S. Oral films: Current status and future perspectives. J Controlled Release. 2015 May;206:1–19.
Author Information
Corresponding Author: Abhijeet Motiwale* and Narendra Pratap Singh Sengar
Faculty of Pharmaceutical Sciences, Sanjeev Agrawal Global Educational University, Bhopal, (M.P.) - India
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