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Pharmacology & Pharmacy
The interest in buccal drug delivery is under consideration due to some distinct properties compared to the traditional pharmaceutical formulations for oral administration: significantly higher bioavailability, a faster absorption rate of the drug, and substantial compliance for special needs patients. Oral films are obtained through various technologies, from conventional tools to 3D and 4D printing approaches. Three-dimensional printing can solve the formulation problems of producing oral films (OFs).
- three-dimensional printing technologies
- oral films
1. Introduction
Oral administration is most widely used because of the low cost of therapy, convenience, and self-medication. Due to high patient compliance, over 70% of commercially available drugs are formulated for oral administration. A relatively new formulation consists of oral films (OF) adapted for buccal drug administration, avoiding gastric pH, first-pass metabolism, and enzymatic degradation of active pharmaceutical ingredients (API), and providing effective therapy for patients with special needs [1,2,3]. Oral films are novel drug delivery systems containing active ingredients in water-soluble polymer matrixes [4]. They release the drug when placed in the oral cavity by dissolving or adhering to the buccal mucosa [5]. Their action can be topical [6,7,8] or systemic [9,10,11]. The variety of active ingredients contained in OF is wide: plant extracts [12,13,14,15], herbal compounds [16,17,18], nutraceuticals [19], conventional drugs [20,21,22,23,24,25,26], antibiotics [27], antivirals [28,29], vaccines [30], insulin [31], and other proteins [32].
Oral films can be orodispersible films (fast-dissolving oral films or oral dissolving films—ODF) [33,34,35,36,37,38,39,40,41,42,43,44,45] and mucoadhesive buccal films (MBF) [46,47,48,49,50,51,52,53]. The ODFs are formulated for rapid drug release and subsequent absorption in the oral cavity or digestive tract [54,55,56]. MBFs are designed for prolonged drug release [57,58,59]. Due to their properties, OFs are considered patient-centered pharmaceutical formulations [60]. Oral film formulations ensure high patient compliance due to accessibility, application/removal, retention, and analgesia [6]. They are usually prepared by classical methods (solvent and semisolid casting methods, melt extrusion, solid dispersion extrusion, and rolling) [33,61]. Currently, the most advanced tools use 3D printing technology and classical methods [62,63].
2. Oral Films as Innovative Dosage Forms
The main constituents of oral films are polymers, plasticizers, and API. To increase their acceptability, they could also contain other components: taste correctors, disintegration promoters, flavors, salivary secretion stimulants, and coloring agents [64,65].
Film-forming polymers provide rapid disintegration in the oral cavity and mechanical strength.
Plasticizers are responsible for the flexibility of the film, lowering the melting temperature during hot melt extrusion, increasing the film-forming ability of the polymers, and other mechanical properties. They can significantly affect the solubility and absorption of active ingredients and can be used as solubility and absorption enhancers.
Mucoadhesive polymers are required to provide optimal adherence to the buccal mucosa. The most commonly used ones are Methyl Cellulose (MC), Carboxymethyl Cellulose (CMC), Ethyl Cellulose (EC), Hydroxyethyl Cellulose (HEC), Hydroxypropyl Methyl Cellulose (HPMC), Hydroxypropyl Cellulose (HPC), Polyvinyl Alcohol (PVA), and Polyvinyl Pyrrolidone (PVP) [1,4,63,66].
Oral films’ evaluation regards multiple aspects like physicochemical and pharmacotechnical properties. In addition, oral films containing API are compared with placebo.
Physicochemical investigations are assessed using specific methods. FT-IR spectrophotometry allows the examination of the infrared spectra of all formulation components; thus, unwanted interactions between them and pure API could be detected. Oral film morphology is examined using SEM. The X-ray diffraction analysis helps to determine the crystallized or amorphous nature of the oral films’ constituents. Differential scan calorimetry (DSC) analysis determines if the API is compatible with auxiliary substances.
The pharmacotechnical evaluation measures moisture absorption capacity, tensile strength, elongation, thickness folding endurance, pH value, swelling degree, disintegration time, dissolution rate, and release kinetics.
The aspect of solubility in saliva is more formula-oriented than API solubility. The solubility of many APIs can be increased by selecting the optimal pH, salt form, and solubility enhancers in saliva medium to accommodate most of Biopharmaceutics Classification System (BCS) classes 1–3. With tensioactives or other methods like cyclodextrin complexation and pegilation, the list for BCS classes three and four can be increased.
The most important aspects that should be considered include good taste for better patient acceptance, high moisture resistance and a suitable tension surface to withstand the stresses of moisture and mouth movement, good solubility in saliva, the ability to be ionized in the oral cavity, and the ability to penetrate the oral mucosa to ensure a rapid therapeutic effect.
Key aspects resulting from the literature search highlight the following: not requiring water at the disposal, no risk of suffocation, increased stability compared with liquid form, ease of application for the patient, and suitability for patients with mental disorders, dysphagia, and swallowing disorders. From the active dosage and bioavailability standpoint, oral films provide increased API bioavailability, a low dosage, ease of dosing, a high absorption rate, and are more practical.
These limitations could be diminished by the current innovative manufacturing methods for OFs through 3D printing technology.
3. Three-Dimensional Printing Technologies for Oral Films
Three-dimensional printing [69,70,71,72,73,74,75,76,77,78,79] can solve the formulation problems of producing OFs. Currently, buccal dosage forms are reserved for potent agents due to the limited capacity of drug incorporation. Three-dimensional printing techniques could be used to superimpose the layers of OF to accommodate more active ingredients per unit area. They also consider the mucosal surface’s limited area for drug absorption and may provide a potential solution for incompatible ingredients by compartmentalizing the buccal film layers [2]. In addition, 3D printing could provide a platform for controlled drug release over longer periods, reducing the frequency of administration.
3.1. Three-dimensional Inkjet Printing
Three-dimensional inkjet printing is an extension of conventional inkjet printing limited to a single-layer coating [3,80,81,82]. Three-dimensional inkjet printing (material jetting) enables multilayer buildup in the vertical direction using a layer-by-layer printing tool [83]. A computer-aided design (CAD) of the 3D structural system emphasizes the printing instructions; the size of each layer is automatically generated by easy-to-use software algorithms [83].
Thus, multilayer OFs achieve all the characteristics of inkjet printing: good printing resolution and a wide range of liquids or suspensions that can be used as ink materials.
Each layer must be cured before the subsequent inks are applied. The type of ink applied has a significant effect on the curing stages. Low-temperature curing by IR lamps or UV/Vis light is the most commonly used mechanism in 3D inkjet printing processes. They can be quickly set up during 3D inkjet printer setup [84].
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Advantages
Three-dimensional inkjet printing represents a suitable method for personalized OFs.
The complexity of the structured layers did not significantly affect the manufacturing time compared to the overall size of the printed object. Manufacturing costs are very predictable and are limited to the necessary materials to be printed, each layer’s curing time, and the inkjet printer’s energy consumption. The production time can be significantly reduced (e.g., from a few days to a few hours). In addition, this method can be used to combine very different liquid inks (with different viscosities and solubilities) [83].
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Limitations
The cure time limits the 3D inkjet’s potential to obtain fast-printed complex 3D structures. The layer thickness is also limited.
The solvents used to print the top layers could influence the underlying layers. Their properties (adhesion and delamination) could affect the entire printed structure [83].
3.2. Extrusion-Based 3D Printing Methods
3.2.1. Fused Deposition Modeling
Fused Deposition Modeling (FDM) is one of the most popular techniques in 3D printing. By depositing thermoplastic filaments layer by layer and extruding them through a nozzle (either melted or softened), the 3DP structure is created, following a CAD geometry. The material is heated above its melting point in the head of the 3D printer (hot melt extrusion, or HME); then, the mixture of polymer and agent melts and deposits layer by layer as fine filaments [85]. They solidify quickly and produce the desired 3D structure. FDM enables mold reproducibility and uniformity of active ingredient concentration [86].
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Advantages
FDM allows a wide range of filaments: Polylactic acid (PLA), Polyethylene Terephthalate Glycol (PETG), Polyvinylalcohol (PVA), Polycaprolactone (PCL), Acrylonitrile Butadiene Styrene (ABS), Polyphenylsulphone (PPSF), Acrylonitrile Styrene Acrylate (ASA) [85,87]. It represents a significant advantage, according to various 3D-printed structures’ destinations. Due to the FDM 3D printing technique, they cannot be easily contaminated. FDM also offers appreciable mechanical strength for 3D-printed structures [88]. It can obtain different release profiles for the printed dosage forms by changing the formulation’s 3D model design, infill percentage, or surface area [85,89].
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Limitations
FDM is a multistep process involving prior filament preparation by HME. During processing, the repeated thermal stress led to the potential degradation of heat-sensitive drugs/polymers [90]. Even if FDM can print many details, the finest ones are limited [85,87] by the nozzle size, layer thickness, and polymer type. The final 3D-printed product’s stability and strength depend on the mechanical properties of the filaments [91]. Polymers that harden faster (with a more significant difference between TG and melting point) in the cooling step give sharper detail levels.
3.2.2. Pressure-Assisted Microsyringe (PAM)/Semisolid Extrusion (SSE)
The PAM/SSE technique uses viscous and semisolid materials for microsyringes [91,92,93]. It uses compressed air to extrude the semisolid material, leading to 3D-printed microstructures. In the PAM/SSE process, the starting material’s viscosity is highly significant and must be adjusted. If the viscosity is high, the material can clog the nozzle; if the viscosity is low, the 3D structure will not have mechanical stability during the layer formation, and the nozzle will drip. The desired 3D model structure is generated using CAD software and converted to a .stl file. After that, it is loaded into the 3D printer equipment. The CAD file changes allow the required transformations of the final 3D-printed object [91].
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Advantages
Compared to FDM, PAM/SSE ensures continuous 3D-printed form fabrication at room temperature. The filament prior preparation through HME is unnecessary [92,94]; thus, PAM/SSE is suitable for thermo-labile drugs. The 3D printing process is computer-controlled; production time, manual labor, and costs are diminished [91] compared to conventional techniques.
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Limitations
Incorporating solvents raises concerns about safety and stability during manufacturing and drying [92]. Optimizing the initial viscosity affects the integrity of the 3D-printed product. Nose plugging can occur during the 3D printing process. Printing optimization is essential to ensuring the mechanical uniformity and durability of the 3D-printed structure. Only aqueous solvents are suitable for the PAM /SSE technique [92].
3.2.3. Direct Powder Extrusion (DPE)
As SSE, DPE avoids the initial filament fabrication by HME. Thus, the production cost is significantly reduced, the formulation development is accelerated, and attention is moved to the single 3DP process [91].
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Advantages
Thermal stresses are avoided, so the mechanical stability of the filaments is not a problem for manufacturing, unlike the FDM process. Single-step printing is a convenient and more practical method for on-site fabrication in hospitals and pharmacies [91].
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Limitations
The final product has surface roughness and variable weight. If the melt residence time in the heating zone of the extruder is long, the rheological properties of the drug/excipients could be affected, and the risk of API’s thermal degradation could be substantial. Due to pneumatic pressure, material oxidation before printing can occur [91].
3.3. Liquid Crystal Display 3D Printing
Liquid crystal display (LCD) 3D printing is an emerging technology with low-cost equipment [95]. It is one of the three currently available photocuring three-dimensional printing technologies. LCD 3D printers are based on UV wavelengths. The UV light comes from an array of light-emitting diodes (LEDs) that shine through the LCD [96], used as an imaging system. As control parameters, the exposure time and scanning speed correspond to varying degrees of polymerization, influencing the light density in the projection process and the scan type. The most critical parameters in LCD 3DP are exposure time, wavelength, and amount of power supply [97]. Unlike UV light, visible light-induced photopolymerization is safe for the human body and ensures high light penetrability. Developments of photosensitive systems that can operate in visible light has attracted great interest recently and is strongly supported by LED development. Three-dimensional printers using such LED technology (e.g., LED projectors) have recently been introduced on the market [98]. With the printing process in visible light, there are many possibilities for developing new resin formulations [68] with safer photoinitiators and polymers.
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Advantages
LCD machines have good resolution and are low-cost. Currently, the LCD 3D photocuring machine is applied in dentistry, jewelry, toys, etc.
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Limitations
LCDs have a short functioning life and need to be periodically replaced; only 10% of the light can penetrate the LCD screen, while the rest of it is absorbed. The partial light leakage could lead to the exposure of photosensitive resin at the bottom. The liquid tank needs to be cleaned regularly. The adhesions of the printed part to the screen can determine failed prints.
As an overview, the advantages and limitations of all methods previously discussed are summarized in Table 1.
Table 1. Advantages and limitations of 3D printing technologies in oral film manufacturing.
| Printing Technique | Advantages | Limitations |
|---|---|---|
| 3D Inkjet Printing | - Suitable for personalized oral films | - Cure time limits fast-printed complex structures |
| - Complexity of structured layers does not significantly impact manufacturing time | - Solvents used for top layers can affect underlying layers | |
| - Predictable fabrication costs | ||
| Extrusion-Based 3D Printing Methods | - Wide range of filaments available | - Thermal stress may lead to the potential degradation of heat-sensitive drugs/polymers |
| - Shapes’ reproducibility and API concentrations’ uniformity | - Limitations on achieving fine details due to nozzle size, layer thickness, and polymer type | |
| - Different release profiles are achievable by changing the 3D model design, infill percentage, or surface area | - Final product stability and strength depend on the mechanical properties of the filaments | |
| Pressure-Assisted Microsyringe (PAM) |
- Continuous 3D printing at room temperature | - Concerns regarding safety and stability during solvent incorporation and drying processes |
| - Suitable for thermo-labile drugs | - Nozzle clogging may occur during the printing process | |
| Semisolid Extrusion (SSE) | - Computer-controlled process with reduced production time, manual labor, and costs | - Optimization of printing pressure is essential for mechanical uniformity and durability |
| - Only aqueous solvents are appropriate | ||
| Direct Powder Extrusion (DPE) | - Significantly reduced production cost | - Surface roughness and variable weight in the final product |
| - Accelerated formulation development | - Risk of thermal degradation of API due to melting residence time and potential material oxidation | |
| Liquid Crystal Display 3D Printing | - Good resolution and low cost | - Short functioning life of LCDs and the need for periodic replacement |
| - Safe visible light-induced photopolymerization | - Light leakage from LCDs and exposure of the photosensitive resin | |
| - Liquid tank requires regular cleaning | ||
| - Adhesion issues between printed parts and screen |
This entry is adapted from the peer-reviewed paper 10.3390/pr11092628
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