Patent Description:
Documents <CIT> and <CIT> disclose a device, system, respectively a method of solid freeform fabrication of an object, and computer software, wherein the system refers to solid freeform fabrication, an equal term for fused filament fabrication. However, no reference is made in this document to pharmaceutical products. Accordingly, there is no reference to the accuracy of the process to produce specific patterns, which is essential though when it comes to be applied on pharmaceutical products. There is only referred therein to patterns having a thickness of <NUM>,<NUM>. According to the International Organization for Standardization and the document <NPL>), the accuracy of an additive manufacturing process, such as 3D printing process, is determined as the closeness of agreement between an individual result and an accepted reference value. No data are provided on the accuracy of the printing process, regarding the formation of Braille characters, as long as they describe the Braille characters as candidate patterns.

No specific dimensions of the patterns are provided in said document. As a result, there is no complete reference to the minimum dimensions (x-y-z) of Braille dots that could be efficiently fabricated on the surface of the main object with the specific equipment. However, for pharmaceutical Braille, very specific definitions on the parameters are required to form the encoded text, as described in the European standard EN <NUM> and the International standard ISO <NUM>:<NUM> (Packaging - Braille on packaging for medicinal products), following the Marburg Medium spacing convention for Braille.

There is no reference to the orientation of the pattern, regarding the position of the main object, or any other process parameters. Consequently, the thickness of the pattern is not correlated to a specific axis during the build cycle. Specific functionalities of the patterns regarding the end-user are not mentioned. Neither are specific functionalities regarding the main object. The design of objects is defined by inputting data regarding their shape, resp. dimensions, and the selection of a suitable material for the achievement of specific physicochemical properties of the object is defined as well, such as mechanical properties, color, magnetic behavior etc..

<CIT> relates to pharmaceutical products wherein a coated dosage with a backing layer and a method for producing are disclosed. The pharmaceutical dosage forms reported in this document are tablets. This document discloses a coating layer covering the whole body of the object (tablet) and a laser drilling for the formation of identifiers. Laser drilling is a subtractive manufacturing technique. In detail, a coating layer is formed around the tablet, and the laser drilling process selectively removes parts of the layer to result in the distinctive character.

Neither this document nor the related <CIT> discloses the formation of identifiers in a multi-step fashion, i.e. production of the tablet by compression -coating of the tablet with a material layer- formation of identifiers by laser drilling. As a result, the identifiers are formed in a post-production process. There are significant differences regarding the Braille dot specifications, as in the case of the latter documents <CIT> and <CIT> respectively.

<CIT> discloses a method of coding drug pills. As in said previous documents, the identifiers are formed by a subtractive method, i.e. engraving of the formulation. The formulation is referred as a tablet. No coating or backing layer is disclosed in this document.

The document further discloses the formation of identifiers as a post-production process, regarding the production method of the tablet, a multi-step process. But no reference is made to Braille.

In document <CIT>, the formation of identifiers is disclosed to be accomplished by compression, local application of heat, embossing, grinding or etching. Again, no reference is made to Braille.

Document <CIT> discloses a tablet with contrasting indicia and method, wherein the pharmaceutical dosage forms are tablets, but not films. Again, the identifiers are formed by compression, and no reference is made to Braille.

Document<CIT>details the drug formulation options for special patient groups, e.g. pediatric patients, the elderly with dysphagia, uncooperative or nauseated/vomiting patients. There is no reference to other special groups, as in the case of subjects with visual impairment. The document describes the fabrication of films via two-dimensional inkjet printing, and thus, jetting of a drug-loaded ink onto suitable substrates for inkjet printing. Further, this document reveals the creation of identifying agents on the surface of the films, in the form of quick response (QR) codes, which are intended for the identification of the drug and the critical treatment information by using a special application in mobile phones. This can be rather considered as an asset in the supply chain of pharmaceuticals though, rather than facilitating identification and promoting independence in the identification of pharmaceutical products by visually impaired populations.

Document <CIT> by Eleftheriadis et al. yet describes the formation of multilayered buccal films by using the 3D printing technology. However, this document has no reference to printing of special identifying structures on the surface of the films, which is presently aimed at with Braille characters for visually impaired patients.

Further, there are commercial buccal films in the drug market, e.g. Onsolis - (https://www. com/prolonsolis. This formulation is marked by a coded identifying number on one side of the film, providing the drug strength. However, this number is only indicative of the dosage strength, and cannot be considered as an identifying agent needed for visually impaired people, which Is the presently targeted population group. This identifying element is debossed on the surface of the films, which is the exact opposite process of embossing, thus producing identifying characters in the form of indents instead of raised characters, whereas only the latter can facilitate identification of the dosage unit by visually impaired patients, and as described in ISO <NUM>:<NUM> (Packaging - Braille on packaging for medicinal products). This formulation thus leads away from the target.

Identification of the proper dosage form, that is relevant to a specific active pharmaceutical ingredient or a suitable strength is of critical importance to achieve the optimal therapeutic effects In treatments for diseases. According to the EU Directive <NUM>/<NUM>/EC - Article 56a [<NUM>], the incorporation of Braille-encoded information on secondary pharmaceutical packaging (cartons) is mandatory. Since the end of <NUM>, the name and strength of pharmaceutical products shall be given in Braille format, to facilitate identification of the medicinal products intended for human use by visually impaired populations.

Toward this direction, the cooperation between the European Blind Union (EBU) and the Royal National Institute of Blind people yielded the unified specifications for Braille labeling of pharmaceutical products. Special attention was given to the dot height developed on the pharmaceutical packaging via embossing, to optimize the large variances achieved by the current Braille-generating technology, as well as the deviations presented among the countries in the European Union [<NUM>,<NUM>].

The conducted research on the specifications of the dots resulted in the establishment of the Marburg Medium spacing convention for Braille, exclusively intended for industrial use in pharmaceutical packaging. This standard is recommended and described by the European Committee for Standardization (EN <NUM>) [<NUM>] and the International Organization for Standardization (ISO <NUM>:<NUM>) [<NUM>].

However, a variety of pharmaceutical products exist in the market, containing individually enclosed dosage forms with varying scales of drug dose, e.g. Emend® (Aprepitant, <NUM>/<NUM>) or intended for multiphasic self-administration during the treatment period provided to the patient, e.g. Divina (Estradiol Valerate <NUM> / Estradiol Valerate <NUM> and Medroxyprogesterone Acetate <NUM>). In such cases, Braille encoding in the external packaging is considered problematic, due to inconvenient identification -or at least unsatisfactory- of the proper strength by visually impaired people, which thus again leads away from the target.

To summarize, 3D Braille printing as such is known in the art yet.

The 3D printing of pharmaceutical multilayer films for buccal administration is known yet from XP055730678 and XP085862481, but not 3D printing of Braille characters on medicinal products. In the prior art, no Braille-type medicinal product (oral mucosa, pills) was detected on the drug. Even more, there is no disclosure in the prior art of Braille 3D printing on the back layer of a multilayer oral mucosa.

Embossing of characters on pills is also generally known in the art.

XP055730678 yet discloses a buccal dosage form intended for buccal administration of a pharmaceutically active substance to users, which is multilayer yet as bilayer and multilayer films, and comprises a first layer consisting of a drug-loaden film compartment and backing layer as a second layer forming a backing layer to which said first layer is attached, wherein it further comprises a set of identifiers arranged in said second layer of said form.

XP085862481 also discloses a buccal dosage form for buccal administration of a pharmaceutically active substance which is multilayered and comprises a first layer consisting of a film compartment loaded with a drug and backing layer as a second layer forming a backing layer to which said first layer is attached with the development of 3D printed buccal films, also with a set of identifiers arranged in said second layer of said form.

Other known problems are related to the dimensions of the dots, maintaining their target specifications over time. Post-production alterations on the initially set target are often evidenced. This phenomenon, widely known as "settling", takes place over a large period after initial production, related to the nature of the material, the original dot height, as well as storage, transportation, and handling conditions [<NUM>].

From another point of view, there are several therapies for diseases that require varying dosage of the active ingredient, although the pharmaceutical products are available in the market in quantized strengths. In such cases, management and/or segmentation of the marketed product is a common approach even from health professionals, to achieve the required dose strengths with unknown bioavailability and unwanted pharmacokinetic behaviour.

According to prior art, the formation of various patterns on the surface of flat objects, but non-related to pharmaceutical products, has been reported via solid freeform fabrication [<NUM>]. Furthermore, different kinds of encoded identifiers onto pharmaceutical products have been realized by various methods. But none of them reached the aimed achievement to be fulfilled according to the presently targeted development. Principally, the complete process included multiple steps for the preparation of the final product. The identifiers were generated by compression [<NUM>,<NUM>], engraving [<NUM>], laser drilling [<NUM>], local application of heat [<NUM>], embossing [<NUM>], grinding or etching [<NUM>],.

The invention aims at providing a solution to the technical problem stated above. The present invention thus aims to the simultaneous resolution of the highlighted complications related to the development of Braille-characters on the secondary pharmaceutical packaging of personalized medications and to allow a haptic perception thereof by the targeted visually impaired populations. The present invention is considered an industrially oriented approach, in the context of patient-centricity, with special attention to visually impaired populations.

The invention relates to a multi-layered buccal dosage form, as defined in claim <NUM> as a buccal dosage form intended for the buccal administration of an active pharmaceutical compounds formulation to visually impaired users and a production method and apparatus therefore as defined in the other independent claims.

According to a further particular embodiment of the buccal dosage form of the invention, the identifiers are arranged in a rectangular pattern with varying dimensions with proper dimensions of said rectangle patterns, by means whereof dosage forms have different doses of the active pharmaceutical ingredient API.

According to a more particular embodiment of the buccal dosage form according to the invention, the area of the Braille-containing compartment of said backing layer is in compliance with the dimensions of the drug-loaded compartment of said first layer.

According to a yet more particular embodiment of the buccal dosage form according to the invention, said second layer forming a screen limits the drug release towards the oral cavity of the a visually impaired user, by protecting the drug-loaded compartment of said first layer from the salivary fluids of said user, thus preventing an excessive swallowing of the released drug by said user, wherein the second layer enhances an unidirectional release of the drug toward the buccal epithelium of the user, particularly wherein the thickness of said backing layer is about <NUM>,<NUM>.

A specific embodiment of the buccal dosage form of the invention is as defined in claims <NUM>, respectively <NUM>.

The present invention also relates to a method for producing a multi-layered buccal dosage form, wherein the invention's method is as defined in claim <NUM>.

Accordingly, the proposed invention includes a method of fabricating drug-loaded films attached to a backing layer, which incorporates Braille-encoded characters, to facilitate the haptic identification of the correct dose of the active pharmaceutical compound by visually impaired populations, which is to be considered a very specific and narrow field. The dosage forms are intended for the buccal administration of active pharmaceutical compounds. The presence of a backing layer actually forms a screen acting as a limiting barrier against the release of the drug toward the oral cavity, which thus prevents the extended swallowing of the released drug and promotes instead a unidirectional release toward the buccal epithelium, as it suits. Furthermore, the backing layer provides the substrate for the formation of the Braille characters thereon, so as to protrude therefrom.

The current invention details the development of a multi-layered buccal dosage form by said FFF. The formulation comprises a drug-loaded compartment, presenting different dosage strengths of the active pharmaceutical compound or ingredient designated hereafter as API and a drug-free compartment, providing the properties of a backing layer. During the same of the build cycle of the said FFF process, Braille characters are formed onto the backing layer, so as to protrude therefrom indicating the dosage strength of the formulation, in order to make them palpable by a visually impaired user, on the one hand, and also perceptible by the latter with regard to the said dosage strength, which is a critical issue here.

In the present invention, the patterns are oriented toward the z-axis, regarding the orientation of the surface of the drug-loaded compartment. The global orientation of z-axis is defined in ISO/ASTM <NUM>.

Thus, the object according to the invention notably differs from the above depicted closest state of the art in the characteristics associated with the identifiers which form Braille characters on the backing layer and which convey information about the particular drug load of the film. Besides, <CIT> does not involve drug-layered laminates. 3D Braille printing as such is also known therein. However, there is no evidence in the prior art of 3D printing on the defined pharmaceutical films, and therefore, there is no evidence of 3D printed Braille characters on medicinal products.

Although references to 3D printing are essentially only in the method of production using 3D printing, Braille characters on medicinal products before were not disclosed in said prior art. So, there is no relevant disclosure of the distinctive features referred to above. As commercially available films, such as e.g. Onsolis in<CIT> are known yet to carry dose power printed on them in visible characters for the sighted in "Dosage Forms and Power" which is per se not applicable though for visually impaired users, precisely because they cannot see, even though Braille characters may be placed directly on the film.

According to a more particular embodiment of the method according to the invention, the invention is as defined in claim <NUM>.

According to a still more particular embodiment of the method of the invention, drug-free filaments and drug-loaded filaments of hydroxypropyl methylcellulose, HPMC, are produced using said Hot Melt Extrusion process step a, wherein the first phase consists of said Hot Melt Extrusion of filaments and with specific parameters, preparing said filaments, wherein said filaments constitute the feedstock or raw materials for the realization of said FFF process step b, on the one hand, and a subsequent phase defining the fabrication procedure in the prescribed order of steps, consisting of the design of buccal films with Braille characters, on the other hand.

A preferred embodiment according to the invention thus includes an example wherein the production process comprises at least the following phases: drug-free and drug-loaded filaments of hydroxypropyl methylcellulose HPMC, drug-free and drug-loaded filaments resp. are produced using a hot melt extrusion process. The hot melt extrusion process of said drug-free filaments and drug-loaded filaments is detailed hereafter, which process comprises at least the following phases a & b: first an a phase including a Hot Melt Extrusion of filaments and specific parameters. This phase a represents the preparation of filaments. Filaments are the feedstock (raw materials) for the realization of the FFF process b. In a similar manner, the design-procedure of the objects which is the way that the shapes are designed in the CAD software, will be a separate phase from the fabrication of the formulations.

According to a preferred embodiment of the method of the invention, drug-loaded filaments and drug-free filaments of HPMC are produced using.

According to a specific embodiment of the method of the invention, the filaments of HPMC are produced with different compositions using a single-screw hot melt extruder, which is operated at a certain screw speed, particularly of substantially <NUM> rpm, wherein the composition of filament is of substantially <NUM>% w/w HPMC and <NUM>% w/w Ketoprofen, and the composition of filament is of substantially <NUM>% w/w HPMC and <NUM>% w/w polyethylene glycol PEG <NUM>, wherein the extrusion process for both filaments is conducted in the range of <NUM>-<NUM>, herewith increasing the flow of the molten polymer.

Said filaments A' and B' of HPMC with different compositions are produced using a single-screw hot melt extruder (Filabot Original, Filabot Inc. , VT, USA). The device operates at a screw speed of <NUM> rpm. The composition of filament A' was <NUM>% w/w HPMC and <NUM>% w/w Ketoprofen. The composition of filament B' was <NUM>% w/w HPMC and <NUM>% w/w polyethylene glycol PEG <NUM>. The extrusion process for both filaments was conducted in the range <NUM>-<NUM>, to improve the flow of the molten polymer in the heating-chamber of the device. The device was equipped with a nozzle of <NUM>,<NUM> diameter, to result in filaments with a target diameter of <NUM>,<NUM> ± <NUM>,<NUM>, taking into consideration the Barus effect.

The drug loaded compartment of said first layer and the backing layer containing the Braille characters, resp. the rectangle patterns with varying dimensions can be designed in a computer-aided script-based design software (OpenSCAD), considering the Ketoprofen content of the drug-loaded filaments, wherein the dimensions of the rectangle patterns are selected to produce dosage forms with different doses of the active pharmaceutical ingredient API, wherein the drug-loaded compartment is prone to drug release toward all directions, particularly wherein the whole design containing said drug-loaded compartment, said backing layer, and said Braille dots, is exported as a stereolithography (. stl) file format.

According to another embodiment of the method of the invention, the dosage forms are films, wherein the formation of the drug-loaded compartment, the backing layer and the identifiers are solely fabricated in a one-step process expressed as one "build cycle", by 3D printing.

The present invention further also relates to a device for carrying out a method as defined above wherein said device comprises a single-screw hot melt extruder, operating at a certain screw speed, particularly of substantially <NUM> rpm, by means whereof both filaments A' and B' of HPMC are produced with different compositions, particularly wherein the composition of the one filament is of substantially <NUM>% w/w HPMC and <NUM>% w/w Ketoprofen, and the composition of the other filament is of substantially <NUM>% w/w HPMC and <NUM>% w/w polyethylene glycol, PEG <NUM>, wherein the extrusion process for both filaments is conducted in the range of <NUM>-<NUM>, herewith increasing the flow of the molten polymer in the heating-chamber of said device, wherein said device is equipped with a nozzle of a diameter particularly of substantially <NUM>,<NUM>, thereby yielding filaments with a target diameter of <NUM>,<NUM> ± <NUM>,<NUM>.

Finally, the present invention also relates to a method as defined in claim <NUM>, wherein the produced filaments are utilized for the fabrication of buccal films with Braille characters in a three-dimensional 3D printing process, to manufacture the dosage forms, based on the designed digital stl templates, wherein the FFF process is performed using a specified printer at an extrusion temperature of <NUM>, to generate a smooth flow of the molten polymeric filament from the nozzle of the device, and a build platform temperature of <NUM>, thereby increasing adhesion of the object on the platform during the build cycle, wherein the printing speed is set to <NUM>/s, by means whereof the Braille dots are accurately reproduced onto the free surface of the backing layer, wherein the process parameters are properly selected with consideration of the specific material used.

In the invention, the Braille patterns characterize the object as It is, by indicating specific properties of the drug loaded compartment, e.g. drug dose, directly to the visually impaired user in that the drug dose is transformed to specific dimensions of the object, to achieve the target strength of said API in such a way that this essential information is directly by the interested user who is visually impaired, only by a simple tactile contact between this user and the protruding identifiers, to allow them to get right away the medical and pharmaceutical information he needs for taking the right medication with the good dosage. Thus, there is a significant difference in the inputting data and the target property of the fabricated object, compared to prior art.

<FIG> shows the invention relating to a multi-layered buccal dosage form <NUM>, which comprises a drug loaded compartment <NUM> and a backing layer <NUM>, incorporating Braille characters <NUM> protruding therefrom, wherein <FIG> represents a preferred embodiment of a final multi-layered buccal dosage form F0, with a dose strength of <NUM>. The invention also relates to a method for producing the latter, wherein the production process may comprise two phases: a first phase a in connection with the development of feedstock by hot melt extrusion and a second phase b in connection with 3D printing of buccal films with braille characters by FFF as shown in <FIG>.

The drug loaded compartment <NUM> and the backing layer <NUM>, containing the Braille characters <NUM>, are designed in a computer-aided script-based design software (OpenSCAD). The description of the design of buccal films is detailed hereafter: after the abovementioned phase a, a subsequent phase b is carried out which is indicative of the fabrication procedure, wherein an overview of the exact sequence of steps followed is set out.

The design of buccal films <NUM> with Braille characters <NUM> is performed. Rectangle patterns <NUM> with varying dimensions were designed in a computer-aided script-based design software (OpenSCAD). Considering the Ketoprofen content of the drug-loaded filaments <NUM>, proper dimensions of the rectangle patterns <NUM> were selected, to facilitate the development of dosage forms <NUM> with different doses of the API shown in <FIG> and represented in Table <NUM> below. The drug-loaded compartment <NUM> is prone to drug release toward all possible directions.

Table <NUM> shows the determination of the dimensions of the 3D-printed Braille dots, as described in ISO <NUM>:<NUM> (mean ± SD, number of samples = <NUM>).

The area of the Braille-containing compartment <NUM> (in x-y orientation) is designed in compliance with the dimensions of the drug-loaded compartment <NUM>, whereas the thickness is <NUM>,<NUM>. The backing layer <NUM> is intended to act as a substrate for the formation of Braille identifiers <NUM>, and as an isolating screen serving as effective barrier which limits the drug release towards the oral cavity, by protecting the drug-loaded compartment <NUM> from the salivary fluids of the targeted user. Thus, the incorporation of the backing layer facilitates the release of the drug toward the buccal epithelium of the visually impaired user.

The Braille characters <NUM> are designed on top <NUM> of the backing layer <NUM>. In one embodiment, the Braille characters <NUM> were designed in compliance with the Marburg Medium spacing convention for Braille, recommended by the European Blind Union (EBU) for pharmaceutical packaging, i.e. <NUM>,<NUM> dot diameter <NUM>, <NUM>,<NUM> horizontal and vertical dot spacing <NUM> and <NUM> respectively, <NUM>,<NUM> horizontal character spacing <NUM>,<NUM> vertical line spacing (h1). The dot height <NUM> was set at <NUM>,<NUM>. For comparison purposes modifications over the EBU specifications have been further evaluated. Thus, in another embodiment, the dot height <NUM> was raised at <NUM>,<NUM>. In a further embodiment, the Braille characters were formed by setting the dot diameter <NUM> to <NUM>,<NUM>, the horizontal and vertical dot spacing <NUM>,<NUM> resp. to <NUM>,<NUM>, the horizontal character spacing to <NUM>,<NUM> and the vertical line spacing to <NUM>,<NUM>. The dot height <NUM> was set at <NUM>,<NUM>.

The Braille-containing backing-layer <NUM> was subsequently attached to the top surface of the drug-loaded compartment <NUM>. The whole design shown in <FIG>, containing the drug-loaded compartment <NUM>, the backing layer <NUM>, and the Braille dots <NUM>, was exported as a stereolithography stl file format, wherein <FIG> is a representative digital stereoscope image of Braille dots formed onto a buccal formulation F0 with a dosage strength of <NUM>, in compliance with the Marburg Medium specifications.

Fabrication of buccal films with Braille characters <NUM> is further set out. The produced filaments were utilized in a three-dimensional 3D printing process, i.e. FFF, to manufacture the dosage forms, based on the designed digital stl templates. The FFF process was performed using a Makerbot Replicator 2X printer (Makerbot Inc. , USA), at an extrusion temperature of <NUM>, to facilitate the smooth flow of the molten polymeric filament from the nozzle of the device, and a build platform temperature of <NUM>, to enhance the adhesion of the object on the platform during the build cycle. The printing speed was set to <NUM>/s, to accurately reproduce the developed Braille dots <NUM> onto the surface of the backing layer <NUM>. The process parameters were properly selected, with consideration of the specific material used.

In one embodiment, the dimensions of the drug-loaded compartment <NUM> are selected to produce a dose strength of <NUM>. The rationale behind the selection of the specific dose strength was to result in a Braille format, with the most sparse distribution of Braille dots <NUM>, scattered over the area of the backing layer <NUM>, to evaluate the accuracy and repeatability of the 3D printing process, as well as the readability of the Braille characters <NUM> by visually impaired people.

In another embodiment, the dimensions of the drug-loaded compartment <NUM> are selected to result in a dose strength of <NUM>. The rationale behind the selection of the specific dose strength was to result in a Braille format with more dense distribution of Braille dots over the area <NUM> of the backing layer <NUM> (compared to <NUM>), to evaluate the accuracy and repeatability of the 3D printing process, as well as the readability of the Braille characters <NUM> by visually impaired people.

In a further embodiment, the Braille characters are designed in compliance with the Marburg Medium spacing convention for Braille, i.e. <NUM>,<NUM> dot diameter <NUM>, <NUM>,<NUM> horizontal and vertical dot spacing <NUM>,<NUM> resp. , <NUM>,<NUM> horizontal character spacing <NUM>,<NUM> vertical line spacing. The dot height <NUM> was set at <NUM>,<NUM> (formulations F0).

In another embodiment, the specifications of the Braille dots <NUM> were modified, for comparison reasons, i.e. <NUM>,<NUM> dot diameter, <NUM>,<NUM> horizontal and vertical dot spacing, <NUM>,<NUM> horizontal character spacing, <NUM>,<NUM> vertical line spacing. The dot height <NUM> was set at <NUM>,<NUM> (formulations F1).

In a further embodiment, the specifications of the Braille dots <NUM> were modified, for comparison reasons, i.e. <NUM>,<NUM> dot diameter, <NUM>,<NUM> horizontal and vertical dot spacing, <NUM>,<NUM> horizontal character spacing, <NUM>,<NUM> vertical line spacing. The dot height <NUM> was set at <NUM>,<NUM> (formulations F2).

The filaments A' and B' are loaded in the FFF printer, as feedstock for the fabrication of the drug-loaded compartment <NUM> and the backing layer <NUM> containing the Braille characters <NUM>, respectively. The fabrication process of buccal films and the selected parameters is detailed above. The FFF process parameters are selected to accurately reproduce the final formulations, considering a tolerance of ± <NUM>,<NUM> for the dimensions of the produced Braille dots, as proposed in the International Standard ISO <NUM>:<NUM>. This represents the contribution of the specific parameters to the technical effect.

Results related to the morphological assessment of the printed Braille dots are set out hereafter with morphology of the 3D printed Braille dots. The potential of 3D printing to develop Braille characters <NUM> over polymeric buccal films, complying with the EBU recommendation, was assessed by a Digital stereoscope (Celestron Digital Microscope Pro, Celestron, California, USA). The obtained images shown in <FIG> presented excellent repeatability in the production of Braille dots <NUM> as visible from abovementioned Tables <NUM> & <NUM> below, wherein <FIG> is a similar representative digital stereoscope image of Braille dots formed onto a buccal formulation F2 with a dosage strength lower than in <FIG>, with dimensions and spacing significantly enhanced, compared to the Marburg Medium standard, with a dosage strength of <NUM>.

Table <NUM> shows the determination of the height of the 3D-printed Braille dots, before and after haptic evaluation by visually impaired people (mean ± SD, number of samples n = <NUM>).

The dimensions and spacing of dots <NUM> for formulations F0 (x-y plane) were in agreement with the EBU specifications for pharmaceutical packaging and labeling, considering a tolerance of ± <NUM>,<NUM> for the dimensions of the produced Braille dots <NUM> (ISO <NUM>:<NUM>). The dot height <NUM> was verified in at least three places over the area of printed text by covering at least three Braille dots <NUM>, using a spring-loaded micrometer with a spring-force of <NUM> N (ISO <NUM>:<NUM>). The recorded values for formulations F0 satisfied the criteria for embossed materials or other production methods (ISO <NUM>:<NUM>). In all cases, the dot height <NUM> was in good agreement with the predesigned patterns. The results were indicative of the accuracy of the FFF process toward the development of buccal dosage forms <NUM> containing Braille-encoding, which complies with the EBU recommendations.

An in vivo Assessment of the 3D-printed Braille text is presented hereafter.

The fabricated formulations were subjected to haptic assessment by visually impaired people. The protocol for conducting this study was approved by the Research Ethics Committee of Aristotle University of Thessaloniki (<NUM>/<NUM> and <NUM>/<NUM>). The participants (N = <NUM>) were recruited with the contribution of the Center for Education and Rehabilitation for the Blind (CERB, Thessaloniki, Greece).

The participants were asked to provide details on their Braille experience, expressed in years, and the frequency of using their Braille-reading skills. The categorization of the characteristics of the participants are summarized in Table <NUM> below wherein it represents main characteristics of the participants with N = <NUM>.

Table <NUM> shows the haptic evaluation of the 3D printed formulations by visually impaired people.

The participants were asked on their opinion on the current state of Braille encoding on pharmaceutical packaging. The participants described the identification of Braille information as problematic, related to a variety of issues, as presented in Table <NUM> below showing the reported issues identified on the current state of Braille on pharmaceutical packaging with N = <NUM>:.

In most of the cases, the poor material quality and the handling-related deformation of the Braille sets were the main reported issues.

The participants were asked to evaluate the presence of Braille text onto the formulations of the study. The reported scores are summarized in Table <NUM> below.

The similar performance of formulations F0 and F1 was evidenced, presenting scores of <NUM>,<NUM> ± <NUM>,<NUM> and <NUM>,<NUM> ± <NUM>,<NUM>, respectively, indicative of the insignificant effect of increasing the dot height <NUM> from <NUM>,<NUM> (F0) to <NUM>,<NUM> (F1). The minimum SD values represented the optimal convergence of the recorded scores, highlighting the insignificant effect of experience and reading habits of the participants on the identification and the specifications preference of Braille sets.

Modifications over the Marburg Medium spacing convention for Braille rendered a negative haptic performance, as indicated by the evaluation of F2 with a score of <NUM>,<NUM> ± <NUM>,<NUM>. Moreover, the maximum SD value indicated the divergent view of the participants, regarding their background on Braille reading and experience, as well as their personal preference.

After identification and evaluation of the Braille sets, the participants were asked to further examine the formulation for at least <NUM>. The aim behind this request was to evaluate the effect of extended human handling on the dot height. The post-evaluation values of the redetermined dot heights <NUM> is presented in Table <NUM> above. It was evidenced that the Braille sets maintained their initial dot height.

The overall impression of the participants on the fabrication of Braille encoding over the body of the dosage form was recorded. The participants identified several cases in which the reported invention stands superior to the current state of Braille texts in pharmaceutical packaging as represented in Table <NUM> below. In terms of user independence, the reported invention provides the ability of massive storage of dosage forms by visually impaired people, as in the case of loss or deformation of the original packaging, as well as for multiphasic administration and transferring issues.

Table <NUM> shows cases in which the participants identified the reported invention as superior to the current state of pharmaceutical Braille.

Claim 1:
Buccal dosage form intended for the oral administration of an active pharmaceutical compounds formulation to visually impaired users, which is multi-layered,
wherein it comprises a first layer (<NUM>) consisting of a drug loaded film compartment and a second layer (<NUM>) to act as a substrate for the formation and as an isolating screen serving as effective barrier which limits the drug release towards the oral cavity or promoting unidirectional release of the drug and forming a support layer for formation of Braille identifiers (<NUM>), on which said first layer (<NUM>) is arranged and attached thereto at a first side (<NUM>) of said second layer (<NUM>),
wherein said second layer (<NUM>) further comprises a set of dedicated identifiers (<NUM>) which are arranged on said second layer (<NUM>) of said dosage form (<NUM>) representing the load,
wherein said second layer (<NUM>) constitutes a substrate for said identifiers (<NUM>) in said dosage form (<NUM>) on the side (<NUM>) thereof (<NUM>) which is opposite to its said fixation side (<NUM>),
wherein said Identifiers (<NUM>) indicate the dosage strength of said formulation, wherein said identifiers (<NUM>) are grouped together into predetermined identifiers patterns (<NUM>) corresponding to a specific load,
in that said identifiers (<NUM>) are perceptible by said visually impaired user straightforwardly by a tactile contact therewith, and
in that said identifiers (<NUM>) are formed by Braille-coded characters which are supported on said second layer (<NUM>) and which are protruding from said second layer (<NUM>), thereby forming specific Braille-coded patterns (<NUM>), wherein each said specific Braille-coded pattern (<NUM>) represents a specific load individually for said visually impaired user.