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Development of a dosing device for individualized dosing of orodispersible warfarin films
International Journal of Pharmaceutics 561 (2019) 314–323
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International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm
Development of a dosing device for individualized dosing of orodispersible warfarin films Svenja Niese, Jörg Breitkreutz, Julian Quodbach
T
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Heinrich Heine University Düsseldorf, Institute of Pharmaceutics and Biopharmaceutics, Universitätsstr. 1, 40225 Düsseldorf, Germany
ARTICLE INFO
ABSTRACT
Keywords: Oral film Dosing device Individualized therapy Personalized medicine Rapid prototyping Dispenser Warfarin Flexible dosing
Individualized medicine is relevant to ensure safe and efficient pharmacotherapy. It requires a suitable dosage form and a matching dosing device to enable flexible dosing serving the needs of individual dose requirements. For oral films no flexible dosing option is available until today. This study covers the development of a dosing device that enables flexible dosing of films within the pharmacopoeial requirements. The prototype was produced with the 3D-printing technique fused filament fabrication. The developed and produced prototype of the device was tested for the uniformity of doses according to Ph.Eur. 2.9.27 and 2.9.40. A ribbon as model film and an oral film with HPMC as polymer matrix met the specifications for both tests for three different lengths dispensed with the prototype of the dosing device (HPMC film: AV = 11.30 (1 cm), 12.04 (2 cm) and 10.19 (5 cm)). A second oral film with a polymer matrix from PVA and HPMC exceeded the threshold for the shortest piece of 1 cm (AV = 26.54) because of slight splintering during the cutting process, likely due to too little plasticizer in the formulation. A successful device development and a use within the specifications of the European Pharmacopoeia is demonstrated.
1. Introduction Individualized medicine gained great relevance and importance in the pharmaceutical care system over the past years. The general opinion is changing from the “one size fits all” perspective to the belief that different people require different treatments (FDA, 2018). Apart from different genetic characteristics that influence the drug action and drug metabolism, individual properties of the disease as well as external circumstances of the patient’s life can affect the drug treatment. The right medicine can be chosen by using diagnostic tests that enable prediction of the drug response as it is done for example before the treatment of breast cancer patients regarding their HER2 (human epidermal growth factor receptor 2) status prior to a treatment with the monoclonal antibody trastuzumab (Aktories, 2005; Roche Registration, 2018). The right drug dose can be predicted by different tests regarding genetic polymorphisms influencing the metabolism. An example is the active pharmaceutical ingredient (API) warfarin sodium, which has a recommendation from the US Food and Drug Administration to consider the genotype of the patient before therapy start (Bristol-Myers Squibb Company, 2017). Taking the test results and external circumstances into consideration an individual dose for the correct treatment
of the patient can be defined. Individualization of the treatment shall increase the safety of the pharmacotherapy since a lack of drug response because of insufficient dosing as well as side effects due to overdoses are avoided. To enable individualized dosing, an appropriate dosage form is necessary that allows flexible partition of a dose off of a larger unit or an accumulation of small dosage form units to the total dose (Wening and Breitkreutz, 2011). Furthermore, it is important that flexible dosing does not influence the efficacy of the medicinal product by e.g. changing the release behavior. Possible and promising dosage forms for this application are oral thin film strips. They are applied orally, which is the most accepted drug delivery route (Thabet et al., 2018; Walsh et al., 2011; Wening and Breitkreutz, 2011). Oral films are included in the oromucosal preparations monograph of the European Pharmacopoeia and are named either orodispersible or buccal films, which depends on their properties and the intended application route. They are described in detail in several research and review articles in recent years (Bala et al., 2013; Borges et al., 2015; Dixit and Puthli, 2009; Hoffmann et al., 2011). The orodispersible films (ODFs) that are used in the following study disperse rapidly in the oral cavity (Ph.Eur 9.3, 2018). They are carried with the saliva into the gastrointestinal tract for absorption
Abbreviations: API, active pharmaceutical ingredient; AV, acceptance value; HPLC, high performance liquid chromatography; HPMC, hypromellose, hydroxypropyl methylcellulose; ODF, orodispersible film; PVA, polyvinyl alcohol ⁎ Corresponding author. E-mail addresses: [email protected] (S. Niese), [email protected] (J. Breitkreutz), [email protected] (J. Quodbach). https://doi.org/10.1016/j.ijpharm.2019.03.019 Received 14 January 2019; Received in revised form 8 March 2019; Accepted 9 March 2019 Available online 13 March 2019 0378-5173/ © 2019 Elsevier B.V. All rights reserved.
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without evoking swallowing difficulties (Hoffmann et al., 2011). Because of the fast disintegration of ODFs, the flexible dosing does not influence the efficacy of the product. Cutting the oral film enables flexible dosing of this dosage form since the API dose depends on the dimensions of the film (Hoffmann et al., 2011; Thabet and Breitkreutz, 2018; Visser et al., 2015). The height of the polymer film has to be accurate and uniform throughout the whole film to ensure the correct and constant dosing of differently sized pieces (Susarla et al., 2013). In that case, the dose of a film piece is only dependent on the area, provided that the film was casted with a homogenous polymer/API mass (Jansen and Horstmann, 2014). For most personalization, the patient should be preferably able to cut the film into the size according to his current dosage need. Wening and Breitkreutz (2011) already pointed out a gap for the flexible dosing of oral films and suggested a dosing device that would dispense the desired dose of the film. To our best knowledge there is no such device available until today although several patents can be found. Patents for dispensation of film shaped material were filed already in several industry branches including the medical and pharmaceutical sector. Different ideas were published as patents for dispensing long oral film strips. Some of them already expired and some have never been granted. To show the available state of the art, examples are discussed in the following section. The patents published from Leichter and Blake (2003), Sheffield (2011), Allen et al. (1985) and Yuan (2013) present four different models to dispense an oral film strip (Fig. 1). Following the classification system presented by Wening and Breitkreutz (2011) the concepts from the listed patents for the dosing device can be categorized depending on the dose flexibility and the production/development costs. The dispenser from Leichter and Blake (2003) is a Class III device due to low dose flexibility since the rack and pinion drive only allows the dosing of one defined length when the upper housing is pushed downwards. Yet only low costs are necessary since no electrical parts are needed for operation of the device. The patented device from Sheffield (2011) is categorized as a Class I device due to its high dose flexibility because of dosing the film by a rotating knob. Additionally, the costs are kept low since no electrical power is needed as well. A disadvantage of this idea is the missing cutting unit. The film has to be teared off, which might lead to deformation and elongation of the oral films trip. This would change the length and therefore the dose of the film piece resulting in dosing inaccuracies. The device presented by Allen et al. (1985) already more than three decades ago and the device from Yuan (2013) have to be categorized as Class II devices since they show the possibility of high dose flexibility but also high production and development costs due to the battery-operated power unit that might also be prone to error. Besides the dosing device, a long oral film strip is needed for the individualization of the therapy with this dosage form. Such a long orodispersible film containing the anticoagulant API warfarin sodium as model drug for the individual therapy was developed in a previous study published by Niese and Quodbach (2019). A simple proof of concept was performed by coiling up the long oral film and dispensing it with a commercial tape dispenser. To enable and demonstrate the safe and correct dosing a more professional device is necessary and therefore developed and manufactured in course of this study. It has to comply with the specifications from the European Pharmacopoeia regarding the content of the dispensed pieces. The aim was to develop this dosing device as a Class I device with high dose flexibility and low production and development costs following the classification system from Wening and Breitkreutz (2011). The prototype shall be tested regarding the dosing process. Just recently a patent was published that presents thoughtful ideas for a dispenser of an API-loaded strip (Blomenkemper et al., 2017). The patent thoroughly describes the composition of the presented dispenser, but no data is available about the correct working and dosing of an incorporated film strip. Hence, in the current study the application and testing of the developed dispenser
is added to the device development and manufacturing to prove the correct working according to the intended purpose. The developed 3D-CAD model was manufactured via 3D-printing to enable a flexible and independent as well as cheap design and testing process. The rapid prototyping technique 3D-printing, also known as additive manufacturing, builds up a model layer by layer (Gardan, 2015) and enables a fast and easy production of highly customized and sophisticated models without specialized equipment except of the 3Dprinter (Berman, 2012; Ligon et al., 2017). 3D-printing can help to speed up the design process by producing prototypes, which are used to test and evaluate the designed object already in early development stages (Berman, 2012; Gebhardt, 2016). In this work, the 3D-printing technique fused filament fabrication was applied to produce a working model of the developed dosing device. The production of such a model via 3D-printing reduces costs due to cheap materials and independency of specialized machinery and staff (Gardan, 2015; Upcraft and Fletcher, 2003). The focus of this study was to develop and manufacture a dosing device for the flexible dosing of long oral films. For a successful implementation of such a dosing device in individualized therapy concepts for patients of all age groups, the device had to comply with pharmaceutical requirements given by the specifications of the European Pharmacopoeia that were tested with the final prototype. 2. Materials and methods 2.1. Materials Hypromellose (Hydroxypropyl methylcellulose, HPMC, Pharmacoat® 606, Shin-Etsu, Tokyo, Japan) and polyvinyl alcohol (PVA, PVA 26-88, Merck, Darmstadt, Germany) served as film forming polymers. As plasticizer glycerol (glycerol 85%, Caesar & Loretz, Hilden, Germany) and polyethylene glycol (PEG 300, Clariant, Frankfurt, Germany) were used. Demineralized water was used as solvent for the polymer solutions. The incorporated model drug was warfarin sodium (Farmak, Olomouc, Czech Republic). To produce the prototype of the dosing device, blue PLA filament (ProFillTM PLA NightBlue, 3D-printerstore.ch, Weinfelden, Switzerland) and green, orange and white PLA filaments (Prodim, Helmond, Netherlands) were used for 3D-printing. A green commercial ribbon was used as model film. The ribbon showed a defined width of 2 cm. Two sealing foils were used for film packaging. A standard aluminum foil with polyethylene lamination and an aluminum foil with a reopenable lamination called “Rayopeel” (PET 12 Traite IMP + Alu 9/000 + 50 Å Rayopeel, Amcor Flexibles, Ghent, Belgium). 2.2. Preparation of the film forming mass Two different polymer matrices were used in this study as basic film forming masses (Table 1). A pure HPMC solution and a solution containing HPMC and PVA. The HPMC solution was prepared by forming a dispersion of the polymer in the heated solvent (80 °C). The polymer dissolved while the solution cooled down and warfarin, the plasticizer and evaporated water were added to the cold polymer solution. For solutions containing HPMC and PVA, the PVA was added to cold water, which was then heated up to 90 °C to fully dissolve the PVA polymer. HPMC was then dispersed in the warm PVA solution and the mass cooled down while stirring. After cooling and complete dissolution of the polymers, warfarin, the plasticizer and evaporated water were added. 2.3. Continuous manufacturing of orodispersible films Continuous film manufacturing was performed with a pilot-scale coating bench (MBCD TGM-K-1.4, Optimags, Dr. Zimmermann, 315
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Fig. 1. Selection of oral film strip dispensing devices described in patents. a: Leichter and Blake (2003), b: Sheffield (2011), c: Allen et al. (1985), d: Yuan (2013).
Karlsruhe, Germany) as described by Niese and Quodbach (2018). The polymer mass was cast on the non-siliconized side of the intermediate liner (Silphan S75M, Siliconature, Godega di Sant'Urbano, Italy) with a wet film thickness of 250 µm. The wet film thickness was adjusted using an optical probe as in-line tool (CHRocodile S, Precitec, Gaggenau-Bad Rotenfels, Germany) with a chromatic confocal measuring principle (Niese and Quodbach, 2018).
Table 1 Formulations of warfarin ODFs (w/w). WH1 – Film with HPMC matrix
WPH2 – Film with PVA and HPMC matrix
15% HPMC 2% Glycerol 85% 2% Warfarin sodium 81% Water
13% PVA and HPMC (2:3) 1% PEG 300 2% Warfarin sodium 84% Water
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2.4. Characterization of the ODFs and the model film
2.6.3. Uniformity of mass of delivered doses from multidose container According to Ph.Eur. 2.9.27, the test for uniformity of mass of delivered doses from a multidose container was performed to investigate the correct working of the dosing device. Twenty doses of the ribbon as well as the ODFs were dispensed by the 3D-printed prototype of the dosing device (2.6.2) and weighed (2.4.1) to determine the average mass of the samples. The requirements from the European Pharmacopoeia expect that not more than two individual masses deviate by more than 10% and none by more than 20% from the calculated average mass (Ph.Eur 9.0, 2017).
2.4.1. Film weight Film weighing was conducted for individual film pieces on an analytical balance with an accuracy (d) of 0.01 mg (MC 210P, Sartorius, Göttingen, Germany). 2.4.2. Warfarin sodium assay The warfarin content of the ODF pieces was determined with a validated high performance liquid chromatography (HPLC) method that was modified from the United States Pharmacopoeia official monograph (USP 39) and described in Niese and Quodbach (2019). Ten film pieces were measured for each batch. Depending on the size of the ODF piece different volumes of solvent were used to reach the range of linearity. Samples cut from the long ODF to determine the content uniformity after preparation were 2*2.5 cm and were dissolved in 25.0 ml of distilled water resulting in a concentration of 0.1 mg/ml. The ODF pieces received from the application of the prototype (2.6) had a width of 2 cm and were 1, 2 or 5 cm in length. The pieces were dissolved in 10.0, 25.0 or 50.0 ml distilled water resulting in warfarin concentrations of 0.1, 0.08 or 0.1 mg/ml.
2.6.4. Uniformity of dosage units According to Ph.Eur. 2.9.40, the test for uniformity of dosage units was performed to evaluate the content of the dispensed sample pieces of the ODFs. Ten doses of each ODF were dispensed by the 3D-printed prototype of the dosing device (2.6.2) and the content was determined using HPLC (2.4.2). Following the testing procedure, the Acceptance values (AV) were calculated. The label claims were depending on the length of the film piece and the content of the film forming mass used for the production of the ODFs. The requirements from the European Pharmacopoeia request an AV ≤ 15. A second testing step for 20 more contents is allowed if the criterion is not met (Ph.Eur 9.1, 2017). This second evaluation step has not been performed in this work.
2.5. 3D-printing 2.5.1. 3D-model processing The software Inventor® Professional 2016 (Autodesk®, San Rafael, USA) was used to design 3D-CAD models and to create *.STL files of the objects. The files were prepared for 3D-printing with the slicing software Slic3r (Prusa Edition, version 1.39.1) by generating a layered object. The G-code was generated by converting the layered object into kinematic instructions for the 3D-printer. A layer height of 0.2 mm for regular and 0.1 mm for small and detailed objects was applied with 2 to 3 solid top and bottom layers and an infill density of 15–20%.
3. Results and discussion 3.1. Requirements on the dosing device Partly following the basic principle of the “Design control guidance for medical device manufacturers”, the design of the dosing device was inspired by the “waterfall model” that illustrates the design control influence during the design process (FDA, 1997). Initially, the potential users of the device were identified to define the user needs and the requirements on the device. Potential users of the device are all patients that are able to independently operate the device. For patients not being able to operate the device due to age or health issues caregivers and other medical staff could become a potential user group as well. The main requirement is that the user her- or himself shall be able to flexibly dose the long ODF with the device No additional manufacturing step, e.g. in a pharmacy or industry, shall be necessary as it is proposed for the personalization of an oral film by ink-jet printing (Vuddanda et al., 2018). For this work, no patient data were available for the definition of the design input. Therefore, the requirements for the device were determined theoretically. The most important requirements for the development of the dosing device are an adequate operation of the system, the stability of the incorporated ODF and the safety of the user operating the device. The operation aim is to dispense flexible doses of the long ODF by cutting various lengths from the stocked film and delivering the film pieces to the outside of the device. No electronical power unit shall be needed to operate the dosing device. A cutting unit and an exit slot for the film piece to leave the device are needed. The stocked film needs to be coiled up and stored in the device on a supply unit that might be replaceable to reduce costs when reusing the device. To enable correct dosing, a dosing unit is required that ensures precise and flexible dosing of the ODF within the specifications of the Ph.Eur. The movement of the film needs to be coordinated independently of the filling level of the device. The stability of the dosage form needs to be ensured by keeping the device tightly sealed against critical influencing factors, i.e. water vapor. When not operating the device, a closure cap shall be placed in front of the exit slot for the ODF. For further improvement of the stability for the ODF, a seal-packaging in moisture-tight material shall be used. The safety of the user shall be ensured by shielding the cutting unit to avoid accidental risk of injuries. Furthermore, the packaging has to be collected inside of the device after removing it from the ODF. This avoids accidental intake of the waste materials together with the ODF
2.5.2. Fused filament fabrication A Prusa i3 MK3 (Prusa research, Prague, Czech Republic) was used as fused filament fabrication 3D-printer in this work. The commercial PLA filaments had a diameter of 1.75 mm. A printing nozzle with a diameter of 0.4 mm was utilized and the extrusion head temperature was set to 215 °C for the first layer and 210 °C for all following layers. The temperature of the print bed was set to 60 °C and the print head fan was turned on except for the first layer to improve adherence of the printed object to the print bed. 2.6. Application of the dosing device prototype 2.6.1. Packaging of the long films The long oral films were cut manually into 2 cm wide film strips and packed in sealing foil using a continuously working sealing device (rotary sealer hm 500 DE, hawo, Obrigheim, Germany). The same was done with the green ribbon as model film with a width of 2 cm. Two different blister foils were sealed at a temperature of 160 °C and a sealing time of 5 s resulting from the not-adjustable moving velocity of the conveyer belt system. One foil consisted of an aluminum foil with a polyethylene lamination and the other of an aluminum foil with a special lamination called “Rayopeel” to enable easy reopening of the sealed foils. 2.6.2. Dosing with the dosing device prototype After packaging, the long oral films or the green ribbon (as model film) were inserted into the 3D-printed prototype of the developed dosing device. To control the correct working of the device film pieces with different lengths were dispensed. Twenty doses of each 1, 2 and 5 cm length were cut subsequently with the device. These lengths corresponded to a warfarin content of 1, 2 and 5 mg per piece in case of the oral films. 317
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unit to flexibly and precisely dose the ODF, the packaging waste unit to separate the packaging from the ODF and to collect the waste inside of the device and the cutting unit to partition off the dose of the ODF. The working principle is first briefly summarized and then explained in detail. The seal-packed ODF is coiled up on the stock roll in the right back of the device. From there, the packed film moves around the dosing roll in the left back and then through the guide bar towards the front. In the front of the device the packaging foils are opened, and each foil moves to one side and is coiled up on one of the waste rolls. The ODF is released from between the foils and leaves the device through the exit slot. The movement of the film is generated by rotating the turning knob, which then turns the waste rolls. The packaging foil is further coiled up and more packed film is delivered from the stock roll moving around the dosing roll. The dosing roll is rotated passively by the packed film, which adheres to the plastic cover of the dosing roll while moving around it. The dosing roll displays the dosing process to the outside of the device where the user sees the dose indicator rotating and presenting the delivered dose on the scale. The supply unit of the dosing device consists of a pivoted stock roll in the back of the lower housing on the right side (Fig. 2). To avoid uncontrollable movement of the roll and thereby uncontrollable unwinding of the coiled up ODF, a motion control element was necessary. Attaching pieces of felt to the bottom of the stock roll as well as to the lower housing where the stock roll is positioned increased the friction and prevented uncontrolled unwinding of the film (Fig. 4b). Unwinding of the film off of the stock roll was then only controlled by the dosing unit. A reuse option for the device was further implemented to decrease costs. The stock roll was therefore designed in two parts with the reusable lower part still pivoted on the lower housing and presenting a cross-shaped axle (Fig. 4a). The replaceable upper part shows the cross shape as a recess to be placed on the axle. No rotation of the upper on the lower part is possible due to the cross-shaped conjunction. The film is coiled up on the replaceable upper part of the stock roll and after complete dosing it can be replaced by a new supply unit. The dosing unit is essential for the functionality of the device and the correct dosing of the ODF. To avoid uncontrollable movements in the dosing system, which would cause dosing failure, the dosing roll was incorporated in the device between the supply unit and the
Fig. 2. Dosing device with the four main operating units marked in red. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
by the patient. To enable operation of the device by different user groups, the handling shall be kept as easy as possible. 3.2. Design process of the dosing device Four main operating units are necessary for the correct and safe working of the dosing device (Fig. 2). A labelled overview of the developed dosing device that defines the terminology used in the description of the device development can be found in Fig. 3. The device should comprise the supply unit to stock the coiled up ODF, the dosing
Fig. 3. Overview of the prototype of the developed dosing device. a: full top view of the device; b: close-up view of the dosing unit (3D-CAD model); c: close-up view of the cutting unit (3D-CAD model). 318
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Fig. 4. Parts of the dosing device: Two-piece structure of the stock role (a), attached felt to the stock role to increase friction (b), toothed belts (c), toothed belt connecting the waste rolls as drive system (d), toothed belt connecting the dosing roll with the indicator (e) and the dosing indicator and scale at the outside of the device (f).
packaging waste unit (Fig. 2). The exact forward motion of the film is controlled by the dosing roll and powered by the packaging waste unit consisting of two waste rolls on each side in the front of the lower housing. The use of the dosing roll enabled movement of the film that is independent of the filling level of the stock roll. Toothed belts were used as drive systems for the dosing process in the device. Toothed belt disks were attached to the top of the dosing and waste rolls to be connected via the toothed belts. Two belts were installed in the device (Fig. 4c). One belt connects the two waste rolls (Fig. 4d) and the other one connects the top of the dosing roll with the bottom of the dose indicator (Fig. 4e). The dose indicator displays the user the dosing progress on a scale (Fig. 4f). The seal-packed ODF is loaded into the device by leading the film from the stock roll around the dosing roll, through the guide bar up to the front of the housing (Fig. 2). Just before the film exits the housing, the packaging is split and each of the two foils moves to a waste roll. The foils are fixed to the waste rolls enabling parallel turns of the rolls since they are connected by a toothed belt. The foils are attached as displayed in Fig. 5a. The delivery of a dose from the device is performed when turning on the knob that is attached to the top of one waste roll and reaching to the outside of the device (Fig. 2). When the user turns this knob the waste roll rotates and moves the second waste roll as well because of the connecting toothed belt. This leads to the opening of the packaging foils and the release of the ODF from between them before it exits the device at the front (Fig. 5a). The moving foils adhere to the dosing roll since it is covered with a
plastic tube (Fig. 5b). Therefore, the dosing roll is turned passively as well. The second toothed belt transfers this movement to the dose indicator at the outside of the device and shows the patient the progress of the dispensing step. A dosing scale is positioned beneath the indicator to show the dose being delivered (Fig. 4f). At the beginning of the dosing process the scale is rotated so that the indicator points to the zero position. The user then monitors the dosing process while turning the knob and stops the process when the desired dose is reached. To avoid accidental turning of the dosing scale, it is only able to turn in the opposite direction than the dose indicator. A step-wise dosing that can be read off the scale is achieved by attaching teeth to the bottom of the dosing roll and a pin to the housing of the device (Fig. 5c). The pin reaches between the teeth and allows turning only in the counterclockwise direction where it can slide over the rounded sides of the teeth. The step-wise motion also makes a click sound that indicates proper working when operating the device. Especially for visually impaired patients this may be an additional assurance of correct dosing. The number of teeth influences the length of the dispensed film piece since it is depended on the angle of the rotary motion of the dosing roll. In the presented prototype the delivered film length per step was set to 10 mm. A number of 10 teeth was necessary to receive this dosing step. Other numbers of teeth can be chosen to change the dosing steps for example for the use of the device for children needing lower doses (Fig. 5d). The packaging waste unit is essential to activate the dosing 319
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Fig. 5. Parts of the dosing system responsible for the correct dosing process. Correct attachment of the packaging foils to the waste rolls (a), dosing roll covered with plastic tube and consisting of two pieces (b), teeth at the bottom of the dosing roll for step-wise dosing (c) and variability in number of teeth for individuality in dosing steps (d).
model. Thereby, modifications were possible already before the production of the final prototype, which improved and sped up the design process. 3D-printing was further chosen because of the main advantage, which is the independency of the service of skilled model makers. Changes to the model were easily and promptly realized to facilitate the device development. The design of the prototype in an animated 3D-CAD model enabled a first control of the functionality of the device. The animation revealed possible problems during the movement of the designed device and if parts fit together as intended. This was helpful to reduce development costs and time since try and error approaches were avoided. The 3D-CAD models were 3D-printed with commercial PLA filaments in different colors for better presentation and distinction between the different parts mentioned above (Fig. 2). A working model of the developed dosing device was 3D-printed with the main focus of the functionality and the fitting of the printed parts to the elements that were commercially acquired, e.g. the toothed belts or the packaging foils. These parts had defined dimensions so that the size of the 3Dprinted parts was adapted to it. The purchased toothed belts had to match the 3D-printed toothed belt disks and the height of the device had to be high enough to match the size of the packaging foil used to create the pouch for the film. The 3D-printed prototype is presented in Fig. 2. Pictures of the assembled prototype with open lateral walls for better demonstration of the working principle and the 3D-CAD model of the dosing device are provided in the supplementary materials (Figs. S1 and S3). A green ribbon as model film was inserted into the device to mimic the ODF that would not be visible on a picture due to its transparent appearance.
mechanism of the device as previously described (Fig. 2). For the separation of the aluminum foils it is important that the heat-sealed seam is easy to re-open and the foils are not destroyed. To ensure this, an aluminum foil with a special lamination called “Rayopeel” was used to enable easy re-opening of the sealed foils (Fig. 5a). The safety of the patient is considered by collecting the packaging waste material inside the device, coiled up on the waste rolls. The patient is not able to ingest accidentally the foil together with the dispensed ODF piece. The cutting unit of the dosing device is located in the front of the housing between the exit slot for the film piece and the guide bar leading the packed film from the dosing roll to the front part (Fig. 2). Before the blade, the packaging foils are separated, and they move to the waste rolls on each side. The film strip moves straight forward to the exit and leaves the device. The blade cuts off the delivered dose at the end of the dosing process. A custom-made triangular blade was chosen to ensure accurate cutting since this is essential for the required dosing accuracy of the API from the long ODF (Jansen and Horstmann, 2014). The blade is able to slide between the upper and lower part of the housing and penetrates the ODF first in the middle with its tip. The blade then moves through the rest of the film to cut the whole width. The movement is performed when sliding the fitting that connects the blade in the inside of the device with the user at the outside of the device. To avoid accidents, the blade was additionally covered with the enlarged outer part of the fitting (Fig. 2). The cover also ensures the correct positioning of the delivered film piece during the cutting process. The film is pushed to the right side after it left the device. This enhances the cutting process since the blade can penetrate the film at an angle of 90°. After the dosing process, the cover closes up the exit slot of the device and prevents contaminants from entering the device. Furthermore, the stability is ensured by closing up the device when not used.
3.4. Application of the dosing system 3.4.1. General considerations The developed and 3D-printed prototype of the dosing device was applied for testing of the correct dosing according to the specifications of the Ph.Eur. A commercially produced green ribbon as model film and two ODFs containing warfarin as model drug were used for the testing of the device. They all showed a width of 2 cm and were seal-packed in
3.3. Manufacturing of the dosing device The dosing device was manufactured using fused filament fabrication 3D-printing. Intermediate stages of the device were 3D-printed in parallel to the design process to validate functionality of the created 320
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aluminum pouches. The model film was used to exclude the influences from the film manufacturing process of the ODFs on the examination of the dosing process by the device. The stability of the used ODFs was tested to ensure a save use in the dosing device that is not fully air tight. The stability data for the ODF WH1 containing a HPMC matrix was presented in Niese and Quodbach (2019) and showed no changes over the storage time of three months regarding the warfarin content and the mechanical properties tested with a tensile test. The stability data for the ODF WPH2 were tested with the same methods and showed similar good results that are shown in the supplementary data (Fig. S2). Test samples were prepared by cutting film pieces of three different lengths from the films with the dosing device prototype. Samples of 1, 2 and 5 cm length, corresponding to 1, 2 and 5 steps of the dosing knob and 1, 2 and 5 mg warfarin in case of the ODFs were taken for the following tests to exemplarily mimic the intended use of the device for individualized dosing. These doses were based on the recommended daily intakes for warfarin. Cutting of ODFs showed slight differences between WH1 and WPH2 since they consisted of two different polymer matrices. The ODF WPH2 was more brittle leading to slight splintering at the edges during the cutting of the film. Improvement might be possible by adding more plasticizer to the film formulation.
5 cm model film cut with the dosing device prototype. The results are presented in Fig. 6a and Table 2 and show that the model film dosed with the developed device met the specifications for all three tested lengths. The absolute cutting and weighing error becomes more pronounced for the shorter test pieces since for the test parameters the percentage of the mass relating to the mean value is calculated. Although the absolute standard deviations shown in Table 2 increase from shorter to longer pieces, the scattering of the data points in Fig. 6a highlights the opposite trend since relative figures show the higher impact of the absolute errors on the smaller pieces (Jansen and Horstmann, 2014). Nevertheless, all tested samples met the specification of the European Pharmacopoeia because they lay within the defined thresholds. For the 2 and 5 cm pieces all samples were within the first threshold of ± 10% of the mean value and a maximum of 2 samples for the 1 cm pieces were within the second threshold of ± 20%. These data only give information about the precision of the dosing process. The accuracy is not evaluated since the measurement values are only related to the mean value. When comparing the measured masses of the film pieces to the masses of the calibration curve for the respective length the accuracy of the dosing for the model film can be proven as well. The 2 and 5 cm test pieces met the calibration curve very well with 100.7% and 100.8%, whereas slightly longer pieces were dispensed for the 1 cm samples with 102.2%. The test with the green ribbon as model film demonstrated correct working of the dosing device prototype within the specifications given by the European Pharmacopoeia. Therefore, Ph.Eur. 2.9.27 was also performed for the warfarin containing ODFs WH1 and WPH2. The results are shown in Fig. 6b and c as well as in Table 2. The results for ODF WH1 with HPMC as polymer matrix are similar as for the model film. The smaller absolute standard deviation for 1 cm pieces (Table 2) shows a higher impact in the relative figures (Fig. 6b) but all tested lengths are within the specifications. Since only the masses are evaluated, this test cannot make a predication about the accuracy of the
3.4.2. Uniformity of mass of delivered doses from multidose container Ph.Eur. 2.9.27 is the only monograph for testing the use of a multidose container. Other tests for uniformity are all intended for the examination of single-dose preparations. Ph.Eur. 2.9.27 only investigates the mass variation of the delivered doses from the multidose container as parameter, but not the drug content of the delivered singledose carriers. Since only the mass was determined, the test was first performed for the green ribbon as model film to test the dosing uniformity of the dosing device with a homogenous film that was not influenced by the ODF manufacturing process. The suitability of the green ribbon for this testing was determined by calibrating the mass of the ribbon against the cut length. The ribbon was precisely cut with a knife in different lengths. Six pieces of each 1, 2, 3 and 5 cm were cut and weighed. The resulting mass data were plotted against the cut length and the regression line showed a correlation coefficient of R2 = 0.99996 and a yintercept of 0.1 mg. The correlation between the mass and the length of the ribbon was linear and the scattering extremely low, which enabled the use of the ribbon as model film to test the correct working of the dosing device. Ph.Eur. 2.9.27 was performed with 20 test pieces each of 1, 2 and
Table 2 Masses delivered from multidose container (Ph.Eur. 2.9.27) for the model film and both warfarin ODFs. Measured mass of the film pieces (mean ± sd, n = 20). Dosed length
Mass model film [mg]
Mass WH1 [mg]
Mass WPH2 [mg]
1 cm 2 cm 5 cm
13.68 ± 0.81 26.86 ± 0.96 67.02 ± 1.39
10.16 ± 0.58 19.98 ± 0.81 50.13 ± 1.52
8.50 ± 0.99 17.25 ± 1.03 43.08 ± 0.99
Fig. 6. Masses delivered from multidose container (Ph.Eur. 2.9.27) for the model film (a) and both warfarin ODFs WH1 (b) and WPH2 (c). Measured mass of the film pieces, raw data, n = 20. Green and red lines representing the thresholds of the specifications. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) 321
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with oral films that can be performed by the patient her- or himself was successfully performed in this work. A 3D-printed prototype that operates without electrical power was designed and produced and tested according to the specifications given by different tests of the Ph.Eur. regarding the dosing uniformity. This work proofed that the flexible dosing of oral films is possible and might improve individualized therapy with this dosage form. The anticoagulant therapy with warfarin can be enabled with oral warfarin films for patients from different age groups and with diverse needs for warfarin doses. Increasing the flexibility of dosing with the dosing device, further improvements and additions would be conceivable, e.g. changing the number of teeth of the dosing roll that determines the dosing steps. Another option to increase the field of applicability for the dosing device is to insert oral films with different amounts of API incorporated into the polymer mass or films produced with different thicknesses to change the API content per area film. Then the device could be used for adults with higher loaded films and for children with films showing lower API load. The development of a functional dosing system for the therapy with oral films without the need of electronical power closed the gap for flexible dosing an oral film that was mentioned by Wening and Breitkreutz (2011). The dosing system comprises the prototype of the 3D-printed dosing device and the developed ODFs with warfarin as API. The dosing system with the ODF WH1 met the specifications for all performed tests of the European Pharmacopoeia regarding the correct dosing. Further investigations would include a more professional production of the prototype to enhance the quality of the device regarding size, stability and tightness to perform functionality tests with potential users of the dosing device.
Table 3 Test results from Ph.Eur. 2.9.40 for the warfarin ODFs. Acceptance value (n = 10) and API content (% of label claim, mean ± sd, n = 10). Film
Dosed length
Acceptance value
API content [%]
WH1
1 cm 2 cm 5 cm 1 cm 2 cm 5 cm
11.30 ✓ 12.04 ✓ 10.19 ✓ 26.54 × 11.87 ✓ 12.69 ✓
103.1 102.9 105.0 102.5 107.9 107.2
WPH2
± ± ± ± ± ±
4.1 4.4 2.8 10.6 2.3 2.9
delivered content, which is because other tests should be performed to guarantee correct and safe dosing. The results for the ODF WPH2 show higher scattering of the masses, which might be traced back to the splintering at the edges of the film that was observed during the cutting process. Since this problem only occurred in this case, it is likely due to the film formulation and not because of the dosing device. The specifications are not met for the 1 cm test pieces since one sample exceeded the second threshold of ± 20% and seven exceeded the first threshold of ± 10%. The test on uniformity of dosage units (Ph.Eur. 2.9.40) was performed as well for the delivered test samples of the ODFs because of the limitation of Ph.Eur. 2.9.27 on the evaluation regarding the accuracy of the dosing process. 3.4.3. Uniformity of dosage units Although Ph.Eur. 2.9.40 is meant for single-dose preparations it was performed in this study for the cut single doses produced by the multidose system. Since the dosing device is intended to enable flexible dosing no fixed label claim was available. To compare the AVs from the film samples delivered with the device with the single-dose preparations, the label claim was defined as the assumed content of the ODF piece with the respective length for the AV calculation (3.4.1). Ph.Eur. 2.9.40 was performed since it is the only test that compares the measured contents with the declared content of the dosage form and not only refers it to the mean value of the measured contents to evaluate the dosage uniformity. It was only performed for the two ODFs since the model film did not contain API. The results are shown in Table 3. The ODF WH1 shows AVs < 15 within the specifications for all three dosed lengths. The ODF WPH2 met the specifications only for the two longer film strips and failed for the 1 cm strip because of a high standard deviation that can be traced back to the splintering at the edges of the film during the cutting and dispensing process with the device. The mean contents exceed 100% relative to the label claim, which amounted in absolute values of 0.03 mg (1 cm), 0.06 mg (2 cm) and 0.25 mg (5 cm) for the ODF WH1. The reason for this might be that the ODF exceeded 100% already slightly in the manufacturing process. Another possible reason would be that the device cuts larger pieces than intended. Cutting samples of the ODF with a knife and determine the content would have been necessary to determine the reason for the content excess. This step was not performed during the experiments since the results met the specifications of the European Pharmacopoeia. Although the excess is higher for 5 cm long pieces than for 1 cm long pieces, the AV is lower for the 5 cm long pieces. This supports that the evaluation of relative figures, as e.g. the percentage of the label claim for the content description, disadvantages smaller pieces with lower doses. It is harder for them to comply with the specifications than for longer pieces. Especially with particular regard to flexible dosing and individualized therapy it has to be reviewed whether other test options would be necessary to fulfill the different requirements when testing flexible dosages.
Funding sources This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflict of interest The authors declare no conflict of interest. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.ijpharm.2019.03.019. References Aktories, K., 2005. Allgemeine und spezielle Pharmakologie und Toxikologie, 9th ed. Elsevier, Urban & Fischer, Munich. Allen, J.D., Cobb, M.E., Hillman, R.S., Mungall, D.R., Ostoich, V.E., Stroy, G.H., 1985. Integrated drug dosage form and metering system. US 4712460. Bala, R., Pawar, P., Khanna, S., Arora, S., 2013. Orally dissolving strips: a new approach to oral drug delivery system. Int. J. Pharm. Invest. 3, 67–76. Berman, B., 2012. 3-D printing: the new industrial revolution. Business Horizons. 55, 155–162. Blomenkemper, M., Linn, M., Hackbarth, R., Bee, M., 2017. Device and method for dispensing active ingredient-containing or active ingredient-carrying strips. WO 2017186562 A1. Borges, A.F., Silva, C., Coelho, J.F.J., Simoes, S., 2015. Oral films: current status and future perspectives I – galenical development and quality attributes. J. Controlled Release 206, 1–19. Bristol-Myers Squibb Company, 2017. Prescribing information Coumadin® [Accessed 21. 12.2018]. https://packageinserts.bms.com/pi/pi_coumadin.pdf. Dixit, R.P., Puthli, S.P., 2009. Oral strip technology: overview and future potential. J. Controlled Release 139, 94–107. FDA – Food and Drug Administration – Center for Devices and Radiological Health, 1997. Design control guidance for medical device manufacturers. FDA, 2018. Food and Drug Administration, Precision Medicine [Accessed 14.11.2018]. https://www.fda.gov/medicaldevices/productsandmedicalprocedures/ invitrodiagnostics/precisionmedicine-medicaldevices/default.htm. Gardan, J., 2015. Additive manufacturing technologies: state of the art and trends. Int. J. Prod. Res. 54, 3118–3132. Gebhardt, A., 2016. Generative Fertigungsverfahren - Additive Manufacturing und 3DDrucken für Prototyping – Tooling – Produktion, 4 ed. Carl Hanser Verlag, Munich.
4. Conclusion The development of a dosing device for the individualized therapy 322
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S. Niese, et al. Hoffmann, E.M., Breitenbach, A., Breitkreutz, J., 2011. Advances in orodispersible films for drug delivery. Expert Opin. Drug Delivery 8, 299–316. Jansen, J., Horstmann, M., 2014. Gut abschneiden-Feindosierung in oralen Filmen. TechnoPharm 4, 306–313. Leichter, R.A., Blake, W.S., 2003. Dispenser. US 7040503 B2. Ligon, S.C., Liska, R., Stampfl, J., Gurr, M., Mülhaupt, R., 2017. Polymers for 3D printing and customized additive manufacturing. Chem. Rev. 117, 10212–10290. Niese, S., Quodbach, J., 2018. Application of a chromatic confocal measurement system as new approach for in-line wet film thickness determination in continuous oral film manufacturing processes. Int. J. Pharm. 551, 203–211. Niese, S., Quodbach, J., 2019. Formulation development of a continuously manufactured orodispersible film containing warfarin sodium for individualized dosing. Eur. J. Pharm. Biopharm. 136, 93–101. Ph.Eur 9.0, 2017. 2.9.27 Uniformity of mass of delivered doses from mutidose containers. In: European Pharmacopoeia CommissionEuropean Pharmacopoeia Commission (Ed.), European Pharmacopoeia. European Directorate for the Quality of Medicines & Healthcare (EDQM). Strasbourg, France. Ph.Eur 9.1, 2017. 2.9.40 uniformity of dosage units. In: European Pharmacopoeia Commission (Ed.), European Pharmacopoeia. European Directorate for the Quality of Medicines & Healthcare (EDQM). Strasbourg, France. Ph.Eur 9.3, 2018. Oromucosal preparations. In: European Pharmacopoeia Commission (Ed.), European Pharmacopoeia. European Directorate for the Quality of Medicines & Healthcare (EDQM). Strasbourg, France. Roche Registration, 2018. Summary of product characteristics of Herceptin® i.v. Approval number: EU/1/00/145/001 [Accessed 10.10.2018]. https://www.roche.de/dok/
Herceptin-reg-150-mg-fachinfo-0-na-attach.pdf. Sheffield, W., 2011. Dispenser for an orally dissolvable strip. US 8499965 B2. Susarla, R., Sievens-Figueroa, L., Bhakay, A., Shen, Y., Jerez-Rozo, J.I., Engen, W., Khusid, B., Bilgili, E., Romañach, R.J., Morris, K.R., Michniak-Kohn, B., Davé, R.N., 2013. Fast drying of biocompatible polymer films loaded with poorly water-soluble drug nano-particles via low temperature forced convection. Int. J. Pharm. 455, 93–103. Thabet, Y., Breitkreutz, J., 2018. Orodispersible films: product transfer from lab-scale to continuous manufacturing. Int. J. Pharm. 535, 285–292. Thabet, Y., Klingmann, V., Breitkreutz, J., 2018. Drug formulations: standards and novel strategies for drug administration in pediatrics. J. Clin. Pharmacol. 58, 26–35. Upcraft, S., Fletcher, R., 2003. The rapid prototyping technologies. Assembly Autom. 23, 318–330. Visser, J.C., Woerdenbag, H.J., Crediet, S., Gerrits, E., Lesschen, M.A., Hinrichs, W.L.J., Breitkreutz, J., Frijlink, H.W., 2015. Orodispersible films in individualized pharmacotherapy: the development of a formulation for pharmacy preparations. Int. J. Pharm. 478, 155–163. Vuddanda, P.R., Alomari, M., Dodoo, C.C., Trenfield, S.J., Velaga, S., Basit, A.W., Gaisford, S., 2018. Personalisation of warfarin therapy using thermal ink-jet printing. Eur. J. Pharm. Sci. 117, 80–87. Walsh, J., Bickmann, D., Breitkreutz, J., Chariot-Goulet, M., EuPFI,, 2011. Delivery devices for the administration of paediatric formulations: overview of current practice, challenges and recent developments. Int. J. Pharm. 415, 221–231. Wening, K., Breitkreutz, J., 2011. Oral drug delivery in personalized medicine: unmet needs and novel approaches. Int. J. Pharm. 404, 1–9. Yuan, X., 2013. Drug dispensing and dosing method and device. US 2014242098 A1.
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Development of a dosing device for individualized dosing of orodispersible warfarin films Svenja Niese, Jörg Breitkreutz, Julian Quodbach
T
⁎
Heinrich Heine University Düsseldorf, Institute of Pharmaceutics and Biopharmaceutics, Universitätsstr. 1, 40225 Düsseldorf, Germany
ARTICLE INFO
ABSTRACT
Keywords: Oral film Dosing device Individualized therapy Personalized medicine Rapid prototyping Dispenser Warfarin Flexible dosing
Individualized medicine is relevant to ensure safe and efficient pharmacotherapy. It requires a suitable dosage form and a matching dosing device to enable flexible dosing serving the needs of individual dose requirements. For oral films no flexible dosing option is available until today. This study covers the development of a dosing device that enables flexible dosing of films within the pharmacopoeial requirements. The prototype was produced with the 3D-printing technique fused filament fabrication. The developed and produced prototype of the device was tested for the uniformity of doses according to Ph.Eur. 2.9.27 and 2.9.40. A ribbon as model film and an oral film with HPMC as polymer matrix met the specifications for both tests for three different lengths dispensed with the prototype of the dosing device (HPMC film: AV = 11.30 (1 cm), 12.04 (2 cm) and 10.19 (5 cm)). A second oral film with a polymer matrix from PVA and HPMC exceeded the threshold for the shortest piece of 1 cm (AV = 26.54) because of slight splintering during the cutting process, likely due to too little plasticizer in the formulation. A successful device development and a use within the specifications of the European Pharmacopoeia is demonstrated.
1. Introduction Individualized medicine gained great relevance and importance in the pharmaceutical care system over the past years. The general opinion is changing from the “one size fits all” perspective to the belief that different people require different treatments (FDA, 2018). Apart from different genetic characteristics that influence the drug action and drug metabolism, individual properties of the disease as well as external circumstances of the patient’s life can affect the drug treatment. The right medicine can be chosen by using diagnostic tests that enable prediction of the drug response as it is done for example before the treatment of breast cancer patients regarding their HER2 (human epidermal growth factor receptor 2) status prior to a treatment with the monoclonal antibody trastuzumab (Aktories, 2005; Roche Registration, 2018). The right drug dose can be predicted by different tests regarding genetic polymorphisms influencing the metabolism. An example is the active pharmaceutical ingredient (API) warfarin sodium, which has a recommendation from the US Food and Drug Administration to consider the genotype of the patient before therapy start (Bristol-Myers Squibb Company, 2017). Taking the test results and external circumstances into consideration an individual dose for the correct treatment
of the patient can be defined. Individualization of the treatment shall increase the safety of the pharmacotherapy since a lack of drug response because of insufficient dosing as well as side effects due to overdoses are avoided. To enable individualized dosing, an appropriate dosage form is necessary that allows flexible partition of a dose off of a larger unit or an accumulation of small dosage form units to the total dose (Wening and Breitkreutz, 2011). Furthermore, it is important that flexible dosing does not influence the efficacy of the medicinal product by e.g. changing the release behavior. Possible and promising dosage forms for this application are oral thin film strips. They are applied orally, which is the most accepted drug delivery route (Thabet et al., 2018; Walsh et al., 2011; Wening and Breitkreutz, 2011). Oral films are included in the oromucosal preparations monograph of the European Pharmacopoeia and are named either orodispersible or buccal films, which depends on their properties and the intended application route. They are described in detail in several research and review articles in recent years (Bala et al., 2013; Borges et al., 2015; Dixit and Puthli, 2009; Hoffmann et al., 2011). The orodispersible films (ODFs) that are used in the following study disperse rapidly in the oral cavity (Ph.Eur 9.3, 2018). They are carried with the saliva into the gastrointestinal tract for absorption
Abbreviations: API, active pharmaceutical ingredient; AV, acceptance value; HPLC, high performance liquid chromatography; HPMC, hypromellose, hydroxypropyl methylcellulose; ODF, orodispersible film; PVA, polyvinyl alcohol ⁎ Corresponding author. E-mail addresses: [email protected] (S. Niese), [email protected] (J. Breitkreutz), [email protected] (J. Quodbach). https://doi.org/10.1016/j.ijpharm.2019.03.019 Received 14 January 2019; Received in revised form 8 March 2019; Accepted 9 March 2019 Available online 13 March 2019 0378-5173/ © 2019 Elsevier B.V. All rights reserved.
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without evoking swallowing difficulties (Hoffmann et al., 2011). Because of the fast disintegration of ODFs, the flexible dosing does not influence the efficacy of the product. Cutting the oral film enables flexible dosing of this dosage form since the API dose depends on the dimensions of the film (Hoffmann et al., 2011; Thabet and Breitkreutz, 2018; Visser et al., 2015). The height of the polymer film has to be accurate and uniform throughout the whole film to ensure the correct and constant dosing of differently sized pieces (Susarla et al., 2013). In that case, the dose of a film piece is only dependent on the area, provided that the film was casted with a homogenous polymer/API mass (Jansen and Horstmann, 2014). For most personalization, the patient should be preferably able to cut the film into the size according to his current dosage need. Wening and Breitkreutz (2011) already pointed out a gap for the flexible dosing of oral films and suggested a dosing device that would dispense the desired dose of the film. To our best knowledge there is no such device available until today although several patents can be found. Patents for dispensation of film shaped material were filed already in several industry branches including the medical and pharmaceutical sector. Different ideas were published as patents for dispensing long oral film strips. Some of them already expired and some have never been granted. To show the available state of the art, examples are discussed in the following section. The patents published from Leichter and Blake (2003), Sheffield (2011), Allen et al. (1985) and Yuan (2013) present four different models to dispense an oral film strip (Fig. 1). Following the classification system presented by Wening and Breitkreutz (2011) the concepts from the listed patents for the dosing device can be categorized depending on the dose flexibility and the production/development costs. The dispenser from Leichter and Blake (2003) is a Class III device due to low dose flexibility since the rack and pinion drive only allows the dosing of one defined length when the upper housing is pushed downwards. Yet only low costs are necessary since no electrical parts are needed for operation of the device. The patented device from Sheffield (2011) is categorized as a Class I device due to its high dose flexibility because of dosing the film by a rotating knob. Additionally, the costs are kept low since no electrical power is needed as well. A disadvantage of this idea is the missing cutting unit. The film has to be teared off, which might lead to deformation and elongation of the oral films trip. This would change the length and therefore the dose of the film piece resulting in dosing inaccuracies. The device presented by Allen et al. (1985) already more than three decades ago and the device from Yuan (2013) have to be categorized as Class II devices since they show the possibility of high dose flexibility but also high production and development costs due to the battery-operated power unit that might also be prone to error. Besides the dosing device, a long oral film strip is needed for the individualization of the therapy with this dosage form. Such a long orodispersible film containing the anticoagulant API warfarin sodium as model drug for the individual therapy was developed in a previous study published by Niese and Quodbach (2019). A simple proof of concept was performed by coiling up the long oral film and dispensing it with a commercial tape dispenser. To enable and demonstrate the safe and correct dosing a more professional device is necessary and therefore developed and manufactured in course of this study. It has to comply with the specifications from the European Pharmacopoeia regarding the content of the dispensed pieces. The aim was to develop this dosing device as a Class I device with high dose flexibility and low production and development costs following the classification system from Wening and Breitkreutz (2011). The prototype shall be tested regarding the dosing process. Just recently a patent was published that presents thoughtful ideas for a dispenser of an API-loaded strip (Blomenkemper et al., 2017). The patent thoroughly describes the composition of the presented dispenser, but no data is available about the correct working and dosing of an incorporated film strip. Hence, in the current study the application and testing of the developed dispenser
is added to the device development and manufacturing to prove the correct working according to the intended purpose. The developed 3D-CAD model was manufactured via 3D-printing to enable a flexible and independent as well as cheap design and testing process. The rapid prototyping technique 3D-printing, also known as additive manufacturing, builds up a model layer by layer (Gardan, 2015) and enables a fast and easy production of highly customized and sophisticated models without specialized equipment except of the 3Dprinter (Berman, 2012; Ligon et al., 2017). 3D-printing can help to speed up the design process by producing prototypes, which are used to test and evaluate the designed object already in early development stages (Berman, 2012; Gebhardt, 2016). In this work, the 3D-printing technique fused filament fabrication was applied to produce a working model of the developed dosing device. The production of such a model via 3D-printing reduces costs due to cheap materials and independency of specialized machinery and staff (Gardan, 2015; Upcraft and Fletcher, 2003). The focus of this study was to develop and manufacture a dosing device for the flexible dosing of long oral films. For a successful implementation of such a dosing device in individualized therapy concepts for patients of all age groups, the device had to comply with pharmaceutical requirements given by the specifications of the European Pharmacopoeia that were tested with the final prototype. 2. Materials and methods 2.1. Materials Hypromellose (Hydroxypropyl methylcellulose, HPMC, Pharmacoat® 606, Shin-Etsu, Tokyo, Japan) and polyvinyl alcohol (PVA, PVA 26-88, Merck, Darmstadt, Germany) served as film forming polymers. As plasticizer glycerol (glycerol 85%, Caesar & Loretz, Hilden, Germany) and polyethylene glycol (PEG 300, Clariant, Frankfurt, Germany) were used. Demineralized water was used as solvent for the polymer solutions. The incorporated model drug was warfarin sodium (Farmak, Olomouc, Czech Republic). To produce the prototype of the dosing device, blue PLA filament (ProFillTM PLA NightBlue, 3D-printerstore.ch, Weinfelden, Switzerland) and green, orange and white PLA filaments (Prodim, Helmond, Netherlands) were used for 3D-printing. A green commercial ribbon was used as model film. The ribbon showed a defined width of 2 cm. Two sealing foils were used for film packaging. A standard aluminum foil with polyethylene lamination and an aluminum foil with a reopenable lamination called “Rayopeel” (PET 12 Traite IMP + Alu 9/000 + 50 Å Rayopeel, Amcor Flexibles, Ghent, Belgium). 2.2. Preparation of the film forming mass Two different polymer matrices were used in this study as basic film forming masses (Table 1). A pure HPMC solution and a solution containing HPMC and PVA. The HPMC solution was prepared by forming a dispersion of the polymer in the heated solvent (80 °C). The polymer dissolved while the solution cooled down and warfarin, the plasticizer and evaporated water were added to the cold polymer solution. For solutions containing HPMC and PVA, the PVA was added to cold water, which was then heated up to 90 °C to fully dissolve the PVA polymer. HPMC was then dispersed in the warm PVA solution and the mass cooled down while stirring. After cooling and complete dissolution of the polymers, warfarin, the plasticizer and evaporated water were added. 2.3. Continuous manufacturing of orodispersible films Continuous film manufacturing was performed with a pilot-scale coating bench (MBCD TGM-K-1.4, Optimags, Dr. Zimmermann, 315
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Fig. 1. Selection of oral film strip dispensing devices described in patents. a: Leichter and Blake (2003), b: Sheffield (2011), c: Allen et al. (1985), d: Yuan (2013).
Karlsruhe, Germany) as described by Niese and Quodbach (2018). The polymer mass was cast on the non-siliconized side of the intermediate liner (Silphan S75M, Siliconature, Godega di Sant'Urbano, Italy) with a wet film thickness of 250 µm. The wet film thickness was adjusted using an optical probe as in-line tool (CHRocodile S, Precitec, Gaggenau-Bad Rotenfels, Germany) with a chromatic confocal measuring principle (Niese and Quodbach, 2018).
Table 1 Formulations of warfarin ODFs (w/w). WH1 – Film with HPMC matrix
WPH2 – Film with PVA and HPMC matrix
15% HPMC 2% Glycerol 85% 2% Warfarin sodium 81% Water
13% PVA and HPMC (2:3) 1% PEG 300 2% Warfarin sodium 84% Water
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2.4. Characterization of the ODFs and the model film
2.6.3. Uniformity of mass of delivered doses from multidose container According to Ph.Eur. 2.9.27, the test for uniformity of mass of delivered doses from a multidose container was performed to investigate the correct working of the dosing device. Twenty doses of the ribbon as well as the ODFs were dispensed by the 3D-printed prototype of the dosing device (2.6.2) and weighed (2.4.1) to determine the average mass of the samples. The requirements from the European Pharmacopoeia expect that not more than two individual masses deviate by more than 10% and none by more than 20% from the calculated average mass (Ph.Eur 9.0, 2017).
2.4.1. Film weight Film weighing was conducted for individual film pieces on an analytical balance with an accuracy (d) of 0.01 mg (MC 210P, Sartorius, Göttingen, Germany). 2.4.2. Warfarin sodium assay The warfarin content of the ODF pieces was determined with a validated high performance liquid chromatography (HPLC) method that was modified from the United States Pharmacopoeia official monograph (USP 39) and described in Niese and Quodbach (2019). Ten film pieces were measured for each batch. Depending on the size of the ODF piece different volumes of solvent were used to reach the range of linearity. Samples cut from the long ODF to determine the content uniformity after preparation were 2*2.5 cm and were dissolved in 25.0 ml of distilled water resulting in a concentration of 0.1 mg/ml. The ODF pieces received from the application of the prototype (2.6) had a width of 2 cm and were 1, 2 or 5 cm in length. The pieces were dissolved in 10.0, 25.0 or 50.0 ml distilled water resulting in warfarin concentrations of 0.1, 0.08 or 0.1 mg/ml.
2.6.4. Uniformity of dosage units According to Ph.Eur. 2.9.40, the test for uniformity of dosage units was performed to evaluate the content of the dispensed sample pieces of the ODFs. Ten doses of each ODF were dispensed by the 3D-printed prototype of the dosing device (2.6.2) and the content was determined using HPLC (2.4.2). Following the testing procedure, the Acceptance values (AV) were calculated. The label claims were depending on the length of the film piece and the content of the film forming mass used for the production of the ODFs. The requirements from the European Pharmacopoeia request an AV ≤ 15. A second testing step for 20 more contents is allowed if the criterion is not met (Ph.Eur 9.1, 2017). This second evaluation step has not been performed in this work.
2.5. 3D-printing 2.5.1. 3D-model processing The software Inventor® Professional 2016 (Autodesk®, San Rafael, USA) was used to design 3D-CAD models and to create *.STL files of the objects. The files were prepared for 3D-printing with the slicing software Slic3r (Prusa Edition, version 1.39.1) by generating a layered object. The G-code was generated by converting the layered object into kinematic instructions for the 3D-printer. A layer height of 0.2 mm for regular and 0.1 mm for small and detailed objects was applied with 2 to 3 solid top and bottom layers and an infill density of 15–20%.
3. Results and discussion 3.1. Requirements on the dosing device Partly following the basic principle of the “Design control guidance for medical device manufacturers”, the design of the dosing device was inspired by the “waterfall model” that illustrates the design control influence during the design process (FDA, 1997). Initially, the potential users of the device were identified to define the user needs and the requirements on the device. Potential users of the device are all patients that are able to independently operate the device. For patients not being able to operate the device due to age or health issues caregivers and other medical staff could become a potential user group as well. The main requirement is that the user her- or himself shall be able to flexibly dose the long ODF with the device No additional manufacturing step, e.g. in a pharmacy or industry, shall be necessary as it is proposed for the personalization of an oral film by ink-jet printing (Vuddanda et al., 2018). For this work, no patient data were available for the definition of the design input. Therefore, the requirements for the device were determined theoretically. The most important requirements for the development of the dosing device are an adequate operation of the system, the stability of the incorporated ODF and the safety of the user operating the device. The operation aim is to dispense flexible doses of the long ODF by cutting various lengths from the stocked film and delivering the film pieces to the outside of the device. No electronical power unit shall be needed to operate the dosing device. A cutting unit and an exit slot for the film piece to leave the device are needed. The stocked film needs to be coiled up and stored in the device on a supply unit that might be replaceable to reduce costs when reusing the device. To enable correct dosing, a dosing unit is required that ensures precise and flexible dosing of the ODF within the specifications of the Ph.Eur. The movement of the film needs to be coordinated independently of the filling level of the device. The stability of the dosage form needs to be ensured by keeping the device tightly sealed against critical influencing factors, i.e. water vapor. When not operating the device, a closure cap shall be placed in front of the exit slot for the ODF. For further improvement of the stability for the ODF, a seal-packaging in moisture-tight material shall be used. The safety of the user shall be ensured by shielding the cutting unit to avoid accidental risk of injuries. Furthermore, the packaging has to be collected inside of the device after removing it from the ODF. This avoids accidental intake of the waste materials together with the ODF
2.5.2. Fused filament fabrication A Prusa i3 MK3 (Prusa research, Prague, Czech Republic) was used as fused filament fabrication 3D-printer in this work. The commercial PLA filaments had a diameter of 1.75 mm. A printing nozzle with a diameter of 0.4 mm was utilized and the extrusion head temperature was set to 215 °C for the first layer and 210 °C for all following layers. The temperature of the print bed was set to 60 °C and the print head fan was turned on except for the first layer to improve adherence of the printed object to the print bed. 2.6. Application of the dosing device prototype 2.6.1. Packaging of the long films The long oral films were cut manually into 2 cm wide film strips and packed in sealing foil using a continuously working sealing device (rotary sealer hm 500 DE, hawo, Obrigheim, Germany). The same was done with the green ribbon as model film with a width of 2 cm. Two different blister foils were sealed at a temperature of 160 °C and a sealing time of 5 s resulting from the not-adjustable moving velocity of the conveyer belt system. One foil consisted of an aluminum foil with a polyethylene lamination and the other of an aluminum foil with a special lamination called “Rayopeel” to enable easy reopening of the sealed foils. 2.6.2. Dosing with the dosing device prototype After packaging, the long oral films or the green ribbon (as model film) were inserted into the 3D-printed prototype of the developed dosing device. To control the correct working of the device film pieces with different lengths were dispensed. Twenty doses of each 1, 2 and 5 cm length were cut subsequently with the device. These lengths corresponded to a warfarin content of 1, 2 and 5 mg per piece in case of the oral films. 317
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unit to flexibly and precisely dose the ODF, the packaging waste unit to separate the packaging from the ODF and to collect the waste inside of the device and the cutting unit to partition off the dose of the ODF. The working principle is first briefly summarized and then explained in detail. The seal-packed ODF is coiled up on the stock roll in the right back of the device. From there, the packed film moves around the dosing roll in the left back and then through the guide bar towards the front. In the front of the device the packaging foils are opened, and each foil moves to one side and is coiled up on one of the waste rolls. The ODF is released from between the foils and leaves the device through the exit slot. The movement of the film is generated by rotating the turning knob, which then turns the waste rolls. The packaging foil is further coiled up and more packed film is delivered from the stock roll moving around the dosing roll. The dosing roll is rotated passively by the packed film, which adheres to the plastic cover of the dosing roll while moving around it. The dosing roll displays the dosing process to the outside of the device where the user sees the dose indicator rotating and presenting the delivered dose on the scale. The supply unit of the dosing device consists of a pivoted stock roll in the back of the lower housing on the right side (Fig. 2). To avoid uncontrollable movement of the roll and thereby uncontrollable unwinding of the coiled up ODF, a motion control element was necessary. Attaching pieces of felt to the bottom of the stock roll as well as to the lower housing where the stock roll is positioned increased the friction and prevented uncontrolled unwinding of the film (Fig. 4b). Unwinding of the film off of the stock roll was then only controlled by the dosing unit. A reuse option for the device was further implemented to decrease costs. The stock roll was therefore designed in two parts with the reusable lower part still pivoted on the lower housing and presenting a cross-shaped axle (Fig. 4a). The replaceable upper part shows the cross shape as a recess to be placed on the axle. No rotation of the upper on the lower part is possible due to the cross-shaped conjunction. The film is coiled up on the replaceable upper part of the stock roll and after complete dosing it can be replaced by a new supply unit. The dosing unit is essential for the functionality of the device and the correct dosing of the ODF. To avoid uncontrollable movements in the dosing system, which would cause dosing failure, the dosing roll was incorporated in the device between the supply unit and the
Fig. 2. Dosing device with the four main operating units marked in red. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
by the patient. To enable operation of the device by different user groups, the handling shall be kept as easy as possible. 3.2. Design process of the dosing device Four main operating units are necessary for the correct and safe working of the dosing device (Fig. 2). A labelled overview of the developed dosing device that defines the terminology used in the description of the device development can be found in Fig. 3. The device should comprise the supply unit to stock the coiled up ODF, the dosing
Fig. 3. Overview of the prototype of the developed dosing device. a: full top view of the device; b: close-up view of the dosing unit (3D-CAD model); c: close-up view of the cutting unit (3D-CAD model). 318
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Fig. 4. Parts of the dosing device: Two-piece structure of the stock role (a), attached felt to the stock role to increase friction (b), toothed belts (c), toothed belt connecting the waste rolls as drive system (d), toothed belt connecting the dosing roll with the indicator (e) and the dosing indicator and scale at the outside of the device (f).
packaging waste unit (Fig. 2). The exact forward motion of the film is controlled by the dosing roll and powered by the packaging waste unit consisting of two waste rolls on each side in the front of the lower housing. The use of the dosing roll enabled movement of the film that is independent of the filling level of the stock roll. Toothed belts were used as drive systems for the dosing process in the device. Toothed belt disks were attached to the top of the dosing and waste rolls to be connected via the toothed belts. Two belts were installed in the device (Fig. 4c). One belt connects the two waste rolls (Fig. 4d) and the other one connects the top of the dosing roll with the bottom of the dose indicator (Fig. 4e). The dose indicator displays the user the dosing progress on a scale (Fig. 4f). The seal-packed ODF is loaded into the device by leading the film from the stock roll around the dosing roll, through the guide bar up to the front of the housing (Fig. 2). Just before the film exits the housing, the packaging is split and each of the two foils moves to a waste roll. The foils are fixed to the waste rolls enabling parallel turns of the rolls since they are connected by a toothed belt. The foils are attached as displayed in Fig. 5a. The delivery of a dose from the device is performed when turning on the knob that is attached to the top of one waste roll and reaching to the outside of the device (Fig. 2). When the user turns this knob the waste roll rotates and moves the second waste roll as well because of the connecting toothed belt. This leads to the opening of the packaging foils and the release of the ODF from between them before it exits the device at the front (Fig. 5a). The moving foils adhere to the dosing roll since it is covered with a
plastic tube (Fig. 5b). Therefore, the dosing roll is turned passively as well. The second toothed belt transfers this movement to the dose indicator at the outside of the device and shows the patient the progress of the dispensing step. A dosing scale is positioned beneath the indicator to show the dose being delivered (Fig. 4f). At the beginning of the dosing process the scale is rotated so that the indicator points to the zero position. The user then monitors the dosing process while turning the knob and stops the process when the desired dose is reached. To avoid accidental turning of the dosing scale, it is only able to turn in the opposite direction than the dose indicator. A step-wise dosing that can be read off the scale is achieved by attaching teeth to the bottom of the dosing roll and a pin to the housing of the device (Fig. 5c). The pin reaches between the teeth and allows turning only in the counterclockwise direction where it can slide over the rounded sides of the teeth. The step-wise motion also makes a click sound that indicates proper working when operating the device. Especially for visually impaired patients this may be an additional assurance of correct dosing. The number of teeth influences the length of the dispensed film piece since it is depended on the angle of the rotary motion of the dosing roll. In the presented prototype the delivered film length per step was set to 10 mm. A number of 10 teeth was necessary to receive this dosing step. Other numbers of teeth can be chosen to change the dosing steps for example for the use of the device for children needing lower doses (Fig. 5d). The packaging waste unit is essential to activate the dosing 319
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Fig. 5. Parts of the dosing system responsible for the correct dosing process. Correct attachment of the packaging foils to the waste rolls (a), dosing roll covered with plastic tube and consisting of two pieces (b), teeth at the bottom of the dosing roll for step-wise dosing (c) and variability in number of teeth for individuality in dosing steps (d).
model. Thereby, modifications were possible already before the production of the final prototype, which improved and sped up the design process. 3D-printing was further chosen because of the main advantage, which is the independency of the service of skilled model makers. Changes to the model were easily and promptly realized to facilitate the device development. The design of the prototype in an animated 3D-CAD model enabled a first control of the functionality of the device. The animation revealed possible problems during the movement of the designed device and if parts fit together as intended. This was helpful to reduce development costs and time since try and error approaches were avoided. The 3D-CAD models were 3D-printed with commercial PLA filaments in different colors for better presentation and distinction between the different parts mentioned above (Fig. 2). A working model of the developed dosing device was 3D-printed with the main focus of the functionality and the fitting of the printed parts to the elements that were commercially acquired, e.g. the toothed belts or the packaging foils. These parts had defined dimensions so that the size of the 3Dprinted parts was adapted to it. The purchased toothed belts had to match the 3D-printed toothed belt disks and the height of the device had to be high enough to match the size of the packaging foil used to create the pouch for the film. The 3D-printed prototype is presented in Fig. 2. Pictures of the assembled prototype with open lateral walls for better demonstration of the working principle and the 3D-CAD model of the dosing device are provided in the supplementary materials (Figs. S1 and S3). A green ribbon as model film was inserted into the device to mimic the ODF that would not be visible on a picture due to its transparent appearance.
mechanism of the device as previously described (Fig. 2). For the separation of the aluminum foils it is important that the heat-sealed seam is easy to re-open and the foils are not destroyed. To ensure this, an aluminum foil with a special lamination called “Rayopeel” was used to enable easy re-opening of the sealed foils (Fig. 5a). The safety of the patient is considered by collecting the packaging waste material inside the device, coiled up on the waste rolls. The patient is not able to ingest accidentally the foil together with the dispensed ODF piece. The cutting unit of the dosing device is located in the front of the housing between the exit slot for the film piece and the guide bar leading the packed film from the dosing roll to the front part (Fig. 2). Before the blade, the packaging foils are separated, and they move to the waste rolls on each side. The film strip moves straight forward to the exit and leaves the device. The blade cuts off the delivered dose at the end of the dosing process. A custom-made triangular blade was chosen to ensure accurate cutting since this is essential for the required dosing accuracy of the API from the long ODF (Jansen and Horstmann, 2014). The blade is able to slide between the upper and lower part of the housing and penetrates the ODF first in the middle with its tip. The blade then moves through the rest of the film to cut the whole width. The movement is performed when sliding the fitting that connects the blade in the inside of the device with the user at the outside of the device. To avoid accidents, the blade was additionally covered with the enlarged outer part of the fitting (Fig. 2). The cover also ensures the correct positioning of the delivered film piece during the cutting process. The film is pushed to the right side after it left the device. This enhances the cutting process since the blade can penetrate the film at an angle of 90°. After the dosing process, the cover closes up the exit slot of the device and prevents contaminants from entering the device. Furthermore, the stability is ensured by closing up the device when not used.
3.4. Application of the dosing system 3.4.1. General considerations The developed and 3D-printed prototype of the dosing device was applied for testing of the correct dosing according to the specifications of the Ph.Eur. A commercially produced green ribbon as model film and two ODFs containing warfarin as model drug were used for the testing of the device. They all showed a width of 2 cm and were seal-packed in
3.3. Manufacturing of the dosing device The dosing device was manufactured using fused filament fabrication 3D-printing. Intermediate stages of the device were 3D-printed in parallel to the design process to validate functionality of the created 320
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aluminum pouches. The model film was used to exclude the influences from the film manufacturing process of the ODFs on the examination of the dosing process by the device. The stability of the used ODFs was tested to ensure a save use in the dosing device that is not fully air tight. The stability data for the ODF WH1 containing a HPMC matrix was presented in Niese and Quodbach (2019) and showed no changes over the storage time of three months regarding the warfarin content and the mechanical properties tested with a tensile test. The stability data for the ODF WPH2 were tested with the same methods and showed similar good results that are shown in the supplementary data (Fig. S2). Test samples were prepared by cutting film pieces of three different lengths from the films with the dosing device prototype. Samples of 1, 2 and 5 cm length, corresponding to 1, 2 and 5 steps of the dosing knob and 1, 2 and 5 mg warfarin in case of the ODFs were taken for the following tests to exemplarily mimic the intended use of the device for individualized dosing. These doses were based on the recommended daily intakes for warfarin. Cutting of ODFs showed slight differences between WH1 and WPH2 since they consisted of two different polymer matrices. The ODF WPH2 was more brittle leading to slight splintering at the edges during the cutting of the film. Improvement might be possible by adding more plasticizer to the film formulation.
5 cm model film cut with the dosing device prototype. The results are presented in Fig. 6a and Table 2 and show that the model film dosed with the developed device met the specifications for all three tested lengths. The absolute cutting and weighing error becomes more pronounced for the shorter test pieces since for the test parameters the percentage of the mass relating to the mean value is calculated. Although the absolute standard deviations shown in Table 2 increase from shorter to longer pieces, the scattering of the data points in Fig. 6a highlights the opposite trend since relative figures show the higher impact of the absolute errors on the smaller pieces (Jansen and Horstmann, 2014). Nevertheless, all tested samples met the specification of the European Pharmacopoeia because they lay within the defined thresholds. For the 2 and 5 cm pieces all samples were within the first threshold of ± 10% of the mean value and a maximum of 2 samples for the 1 cm pieces were within the second threshold of ± 20%. These data only give information about the precision of the dosing process. The accuracy is not evaluated since the measurement values are only related to the mean value. When comparing the measured masses of the film pieces to the masses of the calibration curve for the respective length the accuracy of the dosing for the model film can be proven as well. The 2 and 5 cm test pieces met the calibration curve very well with 100.7% and 100.8%, whereas slightly longer pieces were dispensed for the 1 cm samples with 102.2%. The test with the green ribbon as model film demonstrated correct working of the dosing device prototype within the specifications given by the European Pharmacopoeia. Therefore, Ph.Eur. 2.9.27 was also performed for the warfarin containing ODFs WH1 and WPH2. The results are shown in Fig. 6b and c as well as in Table 2. The results for ODF WH1 with HPMC as polymer matrix are similar as for the model film. The smaller absolute standard deviation for 1 cm pieces (Table 2) shows a higher impact in the relative figures (Fig. 6b) but all tested lengths are within the specifications. Since only the masses are evaluated, this test cannot make a predication about the accuracy of the
3.4.2. Uniformity of mass of delivered doses from multidose container Ph.Eur. 2.9.27 is the only monograph for testing the use of a multidose container. Other tests for uniformity are all intended for the examination of single-dose preparations. Ph.Eur. 2.9.27 only investigates the mass variation of the delivered doses from the multidose container as parameter, but not the drug content of the delivered singledose carriers. Since only the mass was determined, the test was first performed for the green ribbon as model film to test the dosing uniformity of the dosing device with a homogenous film that was not influenced by the ODF manufacturing process. The suitability of the green ribbon for this testing was determined by calibrating the mass of the ribbon against the cut length. The ribbon was precisely cut with a knife in different lengths. Six pieces of each 1, 2, 3 and 5 cm were cut and weighed. The resulting mass data were plotted against the cut length and the regression line showed a correlation coefficient of R2 = 0.99996 and a yintercept of 0.1 mg. The correlation between the mass and the length of the ribbon was linear and the scattering extremely low, which enabled the use of the ribbon as model film to test the correct working of the dosing device. Ph.Eur. 2.9.27 was performed with 20 test pieces each of 1, 2 and
Table 2 Masses delivered from multidose container (Ph.Eur. 2.9.27) for the model film and both warfarin ODFs. Measured mass of the film pieces (mean ± sd, n = 20). Dosed length
Mass model film [mg]
Mass WH1 [mg]
Mass WPH2 [mg]
1 cm 2 cm 5 cm
13.68 ± 0.81 26.86 ± 0.96 67.02 ± 1.39
10.16 ± 0.58 19.98 ± 0.81 50.13 ± 1.52
8.50 ± 0.99 17.25 ± 1.03 43.08 ± 0.99
Fig. 6. Masses delivered from multidose container (Ph.Eur. 2.9.27) for the model film (a) and both warfarin ODFs WH1 (b) and WPH2 (c). Measured mass of the film pieces, raw data, n = 20. Green and red lines representing the thresholds of the specifications. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) 321
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with oral films that can be performed by the patient her- or himself was successfully performed in this work. A 3D-printed prototype that operates without electrical power was designed and produced and tested according to the specifications given by different tests of the Ph.Eur. regarding the dosing uniformity. This work proofed that the flexible dosing of oral films is possible and might improve individualized therapy with this dosage form. The anticoagulant therapy with warfarin can be enabled with oral warfarin films for patients from different age groups and with diverse needs for warfarin doses. Increasing the flexibility of dosing with the dosing device, further improvements and additions would be conceivable, e.g. changing the number of teeth of the dosing roll that determines the dosing steps. Another option to increase the field of applicability for the dosing device is to insert oral films with different amounts of API incorporated into the polymer mass or films produced with different thicknesses to change the API content per area film. Then the device could be used for adults with higher loaded films and for children with films showing lower API load. The development of a functional dosing system for the therapy with oral films without the need of electronical power closed the gap for flexible dosing an oral film that was mentioned by Wening and Breitkreutz (2011). The dosing system comprises the prototype of the 3D-printed dosing device and the developed ODFs with warfarin as API. The dosing system with the ODF WH1 met the specifications for all performed tests of the European Pharmacopoeia regarding the correct dosing. Further investigations would include a more professional production of the prototype to enhance the quality of the device regarding size, stability and tightness to perform functionality tests with potential users of the dosing device.
Table 3 Test results from Ph.Eur. 2.9.40 for the warfarin ODFs. Acceptance value (n = 10) and API content (% of label claim, mean ± sd, n = 10). Film
Dosed length
Acceptance value
API content [%]
WH1
1 cm 2 cm 5 cm 1 cm 2 cm 5 cm
11.30 ✓ 12.04 ✓ 10.19 ✓ 26.54 × 11.87 ✓ 12.69 ✓
103.1 102.9 105.0 102.5 107.9 107.2
WPH2
± ± ± ± ± ±
4.1 4.4 2.8 10.6 2.3 2.9
delivered content, which is because other tests should be performed to guarantee correct and safe dosing. The results for the ODF WPH2 show higher scattering of the masses, which might be traced back to the splintering at the edges of the film that was observed during the cutting process. Since this problem only occurred in this case, it is likely due to the film formulation and not because of the dosing device. The specifications are not met for the 1 cm test pieces since one sample exceeded the second threshold of ± 20% and seven exceeded the first threshold of ± 10%. The test on uniformity of dosage units (Ph.Eur. 2.9.40) was performed as well for the delivered test samples of the ODFs because of the limitation of Ph.Eur. 2.9.27 on the evaluation regarding the accuracy of the dosing process. 3.4.3. Uniformity of dosage units Although Ph.Eur. 2.9.40 is meant for single-dose preparations it was performed in this study for the cut single doses produced by the multidose system. Since the dosing device is intended to enable flexible dosing no fixed label claim was available. To compare the AVs from the film samples delivered with the device with the single-dose preparations, the label claim was defined as the assumed content of the ODF piece with the respective length for the AV calculation (3.4.1). Ph.Eur. 2.9.40 was performed since it is the only test that compares the measured contents with the declared content of the dosage form and not only refers it to the mean value of the measured contents to evaluate the dosage uniformity. It was only performed for the two ODFs since the model film did not contain API. The results are shown in Table 3. The ODF WH1 shows AVs < 15 within the specifications for all three dosed lengths. The ODF WPH2 met the specifications only for the two longer film strips and failed for the 1 cm strip because of a high standard deviation that can be traced back to the splintering at the edges of the film during the cutting and dispensing process with the device. The mean contents exceed 100% relative to the label claim, which amounted in absolute values of 0.03 mg (1 cm), 0.06 mg (2 cm) and 0.25 mg (5 cm) for the ODF WH1. The reason for this might be that the ODF exceeded 100% already slightly in the manufacturing process. Another possible reason would be that the device cuts larger pieces than intended. Cutting samples of the ODF with a knife and determine the content would have been necessary to determine the reason for the content excess. This step was not performed during the experiments since the results met the specifications of the European Pharmacopoeia. Although the excess is higher for 5 cm long pieces than for 1 cm long pieces, the AV is lower for the 5 cm long pieces. This supports that the evaluation of relative figures, as e.g. the percentage of the label claim for the content description, disadvantages smaller pieces with lower doses. It is harder for them to comply with the specifications than for longer pieces. Especially with particular regard to flexible dosing and individualized therapy it has to be reviewed whether other test options would be necessary to fulfill the different requirements when testing flexible dosages.
Funding sources This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflict of interest The authors declare no conflict of interest. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.ijpharm.2019.03.019. References Aktories, K., 2005. Allgemeine und spezielle Pharmakologie und Toxikologie, 9th ed. Elsevier, Urban & Fischer, Munich. Allen, J.D., Cobb, M.E., Hillman, R.S., Mungall, D.R., Ostoich, V.E., Stroy, G.H., 1985. Integrated drug dosage form and metering system. US 4712460. Bala, R., Pawar, P., Khanna, S., Arora, S., 2013. Orally dissolving strips: a new approach to oral drug delivery system. Int. J. Pharm. Invest. 3, 67–76. Berman, B., 2012. 3-D printing: the new industrial revolution. Business Horizons. 55, 155–162. Blomenkemper, M., Linn, M., Hackbarth, R., Bee, M., 2017. Device and method for dispensing active ingredient-containing or active ingredient-carrying strips. WO 2017186562 A1. Borges, A.F., Silva, C., Coelho, J.F.J., Simoes, S., 2015. Oral films: current status and future perspectives I – galenical development and quality attributes. J. Controlled Release 206, 1–19. Bristol-Myers Squibb Company, 2017. Prescribing information Coumadin® [Accessed 21. 12.2018]. https://packageinserts.bms.com/pi/pi_coumadin.pdf. Dixit, R.P., Puthli, S.P., 2009. Oral strip technology: overview and future potential. J. Controlled Release 139, 94–107. FDA – Food and Drug Administration – Center for Devices and Radiological Health, 1997. Design control guidance for medical device manufacturers. FDA, 2018. Food and Drug Administration, Precision Medicine [Accessed 14.11.2018]. https://www.fda.gov/medicaldevices/productsandmedicalprocedures/ invitrodiagnostics/precisionmedicine-medicaldevices/default.htm. Gardan, J., 2015. Additive manufacturing technologies: state of the art and trends. Int. J. Prod. Res. 54, 3118–3132. Gebhardt, A., 2016. Generative Fertigungsverfahren - Additive Manufacturing und 3DDrucken für Prototyping – Tooling – Produktion, 4 ed. Carl Hanser Verlag, Munich.
4. Conclusion The development of a dosing device for the individualized therapy 322
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