2.1 Chemical drugs

Both water-soluble and poorly water-soluble chemical drugs can be incorporated into ODFs.^{10, 11} When a drug is absorbed via the buccal route, the absorption of the drug is mainly passively diffuse across the lipid membranes via para-cellular and trans-cellular pathways, therefore, both hydrophilic and lipophilic drugs could be transported.¹²

Water-soluble drugs can be easily dissolved with saliva in the oral cavity, however, the excessive first-pass metabolism and short half-life of drugs may lead to poor bioavailability after oral administration, for example, propranolol.¹³ Therefore, frequent administration might be needed for drugs with short biological half-life. As ODFs are an easy administration dosage form, hence, ODFs are capable to be utilized for administration frequently even without of consuming extra water.

In addition, poorly water-soluble drugs can be embedded in ODFs as well, despite their characteristics of limited aqueous solubility and slow dissolution rate limit the oral bioavailability.¹⁴ Different strategies have been made to improve solubility of poorly water-soluble drugs in ODFs formulation. For instance, micronization, nanoparticle technology,¹⁵ solid dispersion,¹⁴ solubility enhancers,¹⁶ all these techniques contributed to enhanced dissolution rate and bioavailability of the drug as well as improving the incorporated amount of drug. Among these methods, particle size reduction technologies are commonly used to increase surface aera of drugs, and hence enhance its bioavailability.¹⁰ Recently, Nguyen et al. nanosized the poorly water-soluble loratadine by wet balling milling technique, afterward embedded it on ODFs, which showed enhanced bioavailability in rats compared to the raw loratadine.¹⁰ The ODFs based on amorphous solid dispersions enhance dissolution rate of the drug via formation of interaction between the drug and soluble carriers.^{17, 18} Senta-Loys et al.¹⁷ proposed tetrabenazine dispersed in citric acid and polymer to form amorphous solid dispersions in ODFs delivery platform. In their study, the dissolution rate of tetrabenazine was considerably improved, tetrabenazine could even remained in amorphous state during 6 months storage when HPMC or pullulan was used as the polymer.¹⁸ In terms of nanotechnology, on the one hand, nanoparticles contributed to protecting the incorporated API against degradation from the digestive enzymes or acidic pH condition. On the other hand, the ingredients of nanoparticles like lipids enhance the absorption of the API via the lipolysis pathway.^{15, 19} Lately, Steiner et al.¹⁵ used five formulation strategies to incorporate different poorly water-soluble APIs in ODFs, including preparation of amorphous solid dispersions, incorporation of APIs in lipid nanosuspension and lipid nanoemulsion, wet-milling APIs into nanoparticles or microparticles, afterward APIs were embedded into ODFs (Figure 2). The results demonstrated that amorphous solid dispersions-based ODFs and lipid nanoemulsion containing ODFs showed the most desirable characteristics with fast disintegration. However, different solubility-enhancing formulation strategy has its pros and cons. The suitable formulation method should be considered according to the lipophilicity of APIs as well.²¹ Additionally, thiolation of polymeric excipients enables to improve the solubility of less water-soluble drugs as well. The inter- and intrachain disulfide bonds during the swelling process can improve the stability of carrier matrix and achieve sustained or controlled drug release.^{22, 23} Furthermore, solubility enhancers (such as organic solvent and organic acid) were also employed with poorly soluble drugs. For example, organic acid could affect pH-dependent solubility like weakly acidic or basic molecule. However, the recrystallization of API and the containing traces of solvent residues should be considered.¹⁶

2.2 Vaccine

Oral administration of vaccine remains to be a challenging task due to its low inherent stability, degradation, and metabolism, causing poor bioavailability. Many efforts have been applied to preserve vaccine in ODFs while maintaining its stability and activity.²⁴ Tian et al.²⁵ first incorporated protein in the trehalose and pullulan-based ODFs and used it for protein delivery in oral cavity (Figure 3A). Afterward, they developed an ODF containing influenza virus vaccine and achieved the vaccine remaining stable even at high temperature (60°C) or humidity (56% relative humidity) conditions for 1 month.⁵ Moreover, Bajrovic et al.²⁴ suggested that influenza virus vaccine formulated in an ODF platform and administered via oral route induced similar immune responses or even better than those that were administered via intramuscular route (Figure 3B,C). In sum, ODFs are flexible, portable, and enables to maintain vaccine stability during transportation, as well as ODFs with ease of administration are cost-effective, which allows ODFs a kind of potential alternative carrier for vaccine, especially during the outbreak of epidemic and pandemic.

Remarkably, the current coronavirus disease 2019 (COVID-19) has highlighted the importance of using vaccine for reducing infection and transmission of SARS-CoV-2 and preventing serious illness or death from COVID-19. At present, several vaccines for COVID-19 have been developed, however, most of them are intramuscular injections. Those aqueous vaccines need to be maintained in cold-chain condition during transportation and storage, increasing costs and even limiting the utilization of COVID-19 in some tropical countries. Hence, using an alternative dosage form would be beneficial not only to the government for reducing shipping cost, but also to the patients who have needle phobia. In 2021, oral recombinant vaccines against COVID-19 have been developed by Vaxart, which was the world's first oral pill vaccine for COVID-19. Vaxart announced the this oral vaccine had positive results in a clinical phase II study.²⁶ Based on this, ODFs would also be a promising carrier for vaccine against COVID-19, because ODFs cost even less than the manufacturing of solid tablets, and also some problems of tablets can be obviated, such as the risk of choking.

2.3 Probiotics

Probiotics have shown great potential in the treatment of oral diseases and improving oral health, including caries and caries-associated microbes, periodontal diseases, oral candida, and halitosis.²⁷ Probiotics are living microorganisms, they may easily lose probiotic viability in harsh stomach conditions. Therefore, the alternative delivery route such as delivering to the oral cavity is preferred, which is capable to rapidly disintegrate and release incorporated probiotics in the mouth, thereby bypassing acidic condition of gastrointestinal tract.²⁸ Studies have shown that administration of probiotics using ODFs is an ideal alternative dosage form as the viability of probiotic can be maintained in ODFs.²⁹ For example, an ODF loaded with probiotic Enterococcus faecium CRL 183 was proposed by Lordello et al.⁷ The probiotic in the ODFs maintained high viability up to 90 days of storage and high antifungal activity to prevent oral candidiasis. Saha et al.³⁰ formulated ODFs with carboxymethyl cellulose (CMC) as film-forming polymer and delivered Lactobacillus fermentum NCIMB 5221 for the treatment of periodontitis. Probiotics maintained their probiotic viability in this CMC-based ODFs within 150 days of storage at room temperature under ambient humidity. Lately, various techniques have been explored to increase the loading of probiotics and prolong its release in the oral cavity with the aim to achieve better antifungal activity of probiotics. For instance, an ODF was prepared with xylitol using inkjet printing for oral delivery of Streptococcus salivarius. This ODFs made of S. salivarius and xylitol caused 2.86-Log reduction of S. mutans numbers after co-incubation and achieved complementary and enhanced antibacterial activity against S. mutans.^{29, 31}

2.4 Herbal extracts

Natural or herbal pharmaceuticals are widely used in Asian countries. These natural pharmaceutics have gained constant interest from many researchers due to their extensive pharmacological effects, including anti-inflammatory and antioxidant activity (curcumin),³² anticancer (Cucurbitacin B),³³ anesthetic activity (Jambu).³⁴ However, the poor aqueous solubility, fast degradation at physiological pH, the lack of flexible and high patient-compliance dosage form have hindered the extensive application of natural pharmaceuticals. Nowadays, researchers have investigated the incorporation of natural pharmaceuticals into ODFs. For example, Indonesian medicinal plants were embedded in ODFs allowing them to be more flexible for intraoral delivery.³⁵ Nguyen et al.⁶ prepared an ODF with the loading of Panax notoginseng showing high stability at acidic pH, fast disintegration, and in vitro release. As the stability of herbal extracts can be maintained in ODFs with the ease of administration for elderly people, ODFs containing herbal extracts could overcome their inborn defects and serve as an efficient carrier for those people in the treatment of chronic diseases.

3.1 Oral inflammation

The most common oral mucosal disorders are oral ulcer, erosive lesions, oral mucositis, and stomatitis.³⁵ Oral ulcer is often recurrent, painful, and slow to heal and is estimated to affect around 20% of the general population.³⁸ When a situation gets worse, bullous, erosive lesions would form. Topical treatment of oral ulcers and erosive lesions using ODFs offers the formation of a layer above the wound surface to protect it against secondary infection and further possible irritation, thus enhancing the therapeutic effect on ulceration. Moreover, oral mucositis and stomatitis were the main adverse effect of cytotoxic chemotherapy and radiation therapy for cancer patients. The chemotherapy drugs and radiation would cause damage on mucosal epithelial cells, increasing the risk of oral infection and inflammation. However, the current market lacks local, long-acting oral infections dosage forms, rather than mouthwash or oral ointments. ODFs seem to be an alternative formulation to mouthwash or oral ointments.⁷ Pechová et al.³⁹ incorporated a topical anti-inflammatory drug benzydamine hydrochloride into the ODFs. In addition to film-forming polymers and plasticizer, the sweeteners and a superdisintegrant Kollidon® CL-F were also used in this ODF.

3.2 Cardiovascular diseases

Cardiovascular diseases include several heart and blood vessels-related disorders. According to World Health Organization (WHO), cardiovascular diseases cause the highest amount of death globally. It is estimated 17.9 million people die each year from cardiovascular diseases.³⁷ Extensive drugs were used for the treatment of cardiovascular diseases. There are also many commercially available dosage forms for these drugs, such as oral tablets, capsules (Table 2). However, some of these drugs (e.g., propranolol) may suffer from extensive first-pass metabolism after oral administration, thus leading to low bioavailability. Moreover, fixed-dose cardiovascular drugs in form of tablets or capsules are not suitable for pediatric use. Therefore, many research works have been done to incorporate cardiovascular drugs, for example, propranolol, enalapril maleate, metoprolol tartrate in ODFs.^{11, 40, 41} The ODFs containing enalapril maleate fabricated by inkjet printing were developed. The therapeutic single dose for children 0.5 mg enalapril has been successfully printed onto the film. The hydrochlorothiazide films were used to imprint with enalapril ink for further investigation of the enalapril immigration, and no enalapril immigration was observed.⁸ Zhao et al. reported the amlodipine besylate-loaded ODFs using an electrospinning technique, showing the enhanced physicochemical properties.⁴² The angiotensin-converting enzyme inhibitor captopril can also be loaded in ODFs for hypertension.⁴³ Based on the numerous advantages of ODFs as mentioned above, to utilize ODFs in the treatment of cardiovascular diseases would considerably improve patient compliance, especially for hypertensive patients after stroke.

3.3 Pain disorders

Pain relief medicines or analgesia are in high demand for many pain disorders needed for systemic delivery, for example, back pain, headaches or migraine, joint pain, and even cancer pain. As the fast onset of action of drugs is highly required for treating pain disorders, the combination of analgesia with ODFs seems to be prominent. The nonsteroidal anti-inflammatory drugs (NSAIDs) are mostly utilized as pain relief medicines. Among these NSAIDs ibuprofen is the most prominent drug and has been widely used for many pain disorders.⁴⁴ While, opioid analgesics may be needed for some pains failed to be relieved by NSAIDs, but there are underling risks for abuse liability. Buprenorphine is the only opioid agent that can be safely used for pain relief and also used for opioid dependence treatment.⁴⁵ Pergolizzi Jr et al. designed a buprenorphine buccal film by using BEMA® technology for the treatment of low back pain. This buprenorphine-incorporated film showed higher pain reduction compared with placebo films and good tolerability during 12 weeks clinical studies.⁴⁶ Another kind of opioid analgesia, fentanyl is 80–100 times stronger than morphine. Fentanyl buccal film was approved by the FDA for the treating of cancer pain with the name of Onsolis®. In Phase III trial, fentanyl buccal film exhibited high clinic efficacy and good tolerability by reducing the common adverse events (e.g., vomiting, nausea, fatigue).⁴⁷ In addition to pain, associated symptoms could occur (e.g., nausea and vomiting) in the meanwhile. A combination of pain relief (sumatriptan succinate) and antiemetic (prochlorperazine maleate) for treating migraine and associated nausea and vomiting was loaded in ODFs for rapid release of drugs. The obtained ODFs have demonstrated desirable characteristics with fast disintegration time and 100% permeation through ex vivo goat mucosa.⁴⁸

3.4 Nausea and vomiting

Motion sickness may cause nausea, vomiting, dizziness or vertigo. Besides, patients after treated with chemotherapy, radiotherapy may also vomit. But drugs for the treatment of nausea and vomiting can be easily expelled by vomiting, thus the sufficient dose and intended treatment may not be reached. To avoid this problem, researchers incorporated oral antiemetic to ODFs.⁴⁹ Meclizine hydrochloride was reported to load in ODFs for the treatment of nausea and vomiting associated with motion sickness.⁵⁰ Besides, Yildiz Pekoz et al.⁵¹ prepared dimenhydrinate loaded films, which can be sustained release. Also, the dimenhydrinate administered by buccal route bypass the first-pass metabolism, resulting in the two-fold higher AUC than oral delivery route, thus bioavailability is enhanced.

3.5 Mood or mental disorders

Mood and mental disorders include depression, anxiety, bipolar disorder, neuroses, psychoses, and schizophrenia. As the administration of ODFs does not need any water and can be easily applied, allowing ODFs more suitable to be used for these disorders. ODFs have more accurate doses and better patient compliance than other dosage forms. In the pediatric population suffering from hyperkinetic movement, adult tablets were usually administered due to the lack of suitable pediatric dosage forms. Senta-Loys et al.¹⁷ developed a tetrabenazine incorporated ODFs for the treatment of pediatric hyperkinetic movement, which simplify drug administration and would benefit to children. Aripiprazole is an antipsychotic indicated for the treatment of bipolar disorder and schizophrenia. Lee et al.⁵² designed a three-dimensional (3D)-printed aripiprazole incorporated ODFs, which showed accelerated water penetration and disintegration compared with films prepared by solvent-casting method. Olanzapine, an antipsychotic, was commercially available as orodispersible tablets (ODTs) Zyprexa®. Olanzapine-embedded ODFs were fabricated to obviate problems happened during manufacturing, storage, and handling of ODTs, such as frangibility.¹⁴

3.6 Erectile dysfunction

Sildenafil citrate is the most commonly used drug for the treatment of male erectile dysfunction. The commercial dosage form of sildenafil citrate for clinical use is a tablet, which causes inconvenience during administration especially when water is not nearby. In this case, the fast disintegration ODFs are more suitable to be the deliver platform for sildenafil citrate with its ease of administration and carrying.⁵³ While, the extensive first-pass metabolism and poor aqueous solubility of sildenafil citrate contribute to the poor oral bioavailability. Hosny et al. used hydroxybutyl-β-cyclodextrin to improved solubility of sildenafil citrate, and incorporated it into ODFs. From in vivo studies on human volunteers, sildenafil-loaded films exhibited more than 2.2 folds higher oral bioavailability than commercial tablets.⁵⁴ A pharmacokinetics of sildenafil-loaded ODFs (at the dose of 100 mg) was reported to show similar results as sildenafil in conventional tablet (Viagra®) after single-dose administration to 53 healthy male volunteers, which satisfied the criterion of bioequivalence.⁵⁵ Cocci et al.⁵⁶ concluded that ODFs were an efficient and safe carrier for sildenafil, which serves as a interchangeable formulation for more precise and tailored delivery of sildenafil.

3.7 Pulmonary diseases

Pulmonary infections like tuberculosis remain to be a challenge worldwide. Nowadays, the main treatment for tuberculosis now is injection. However, long-term drug administration, low patient compliance, high dose, and frequent dosing intervals all contribute to the rising risk of drug resistance. To avoid this issue, many new delivery systems have been developed, including ODFs.^{57, 58} Matawo et al.⁵⁹ reported an ODF containing pyrazinamide as a potential alternative with flexible dosing for pediatrics. In addition to tuberculosis, employing ODFs as carrier for the treatment of some chronic obstructive pulmonary disease has gained researchers' interests as well. The ease of administration, high patient compliance, and avoiding the risk of choking make ODFs a desirable alternative dosage form to asthma, bronchiolitis, and prophylaxis of apnea. Speer et al. developed the theophylline-loaded matrix particles incorporated ODFs for obstructive pulmonary diseases, which had prolonged release till 1000 min depend on the size of incorporated particles.⁶⁰ Khan et al.⁶¹ reported an ODF with the loading of antibacterial agent cefixime trihydrate for infections of the respiratory tract. According to their research, β-cyclodextrins were used to improve poor water solubility and bad taste of cefixime trihydrate.

3.8 Special applications

The mucoadhesive buccal films (MBFs) is another kind of oromucosal films, which mainly placed to the buccal mucosa.⁵⁹ As drugs enable to be absorbed rapidly via buccal delivery and circumvent high hepatic first-pass metabolism as well as prevent degradation in the harsh gastrointestinal environment, the bioavailability of drugs can be improved. MBFs were mainly used for the treatment of local disorders, such as oral mucositis and stomatitis, oral cancer, and topical anesthetics in the oral cavity.⁶²

Due to the above-mentioned advantages, ODFs are gaining popularity, especially for pediatric and geriatric patients who are suffering from dysphagia or an increased the risk of choking. With the growing interest of ODFs, researchers have investigated ODFs delivery system for some new applications. For instance, a high drug-loading ODFs has been developed, which contained 30 mg racecadotril for the treatment of acute diarrhea in pediatric patients.⁶³ The anti-histamine drug loratadine has been embedded into ODFs. As ODFs provides the possibility of adjusting dose by dividing the films into appropriate parts, it could be a suitable alternative for a traditional antiallergic agent for pediatrics.⁶⁴ The nutritional supplements could also be delivered by ODFs. The ODFs containing vitamin D3 for daily supplementation were reported by IBSA.⁶⁵ Later, the bioavailability of the vitamin D3-loaded ODFs was compared with the marketed oral vitamin D3 preparation in healthy volunteers. The ODFs with the loading of vitamin D3 showed a slightly higher in rate (C_max) and extent of absorption (AUC _0−t and AUC _0–∞) than vitamin D3 oral solution. Therefore, these results proved that ODFs could be a promising alternative to the commercial vitamin D3 oral solution.⁶⁶

An acceptable taste is important for ensuring patient acceptability and compliance. The taste should be taken into consideration when preparing formulations, especially for pediatrics, who are more sensitive to bitterness. Flavor and sweetening agents were usually used to improve palatability of drugs. Taste-masking polymers can be employed as a popular method for masking the bitter tastes of incorporated drugs, for example, ethylcellulose.⁶⁷ When sweeteners are insufficient to overwhelm the bitterness, forming the barrier between drugs and taste buds by using microparticles or forming complexes with cyclodextrins were also efficient taste-masking technologies.^{68, 69}

4.1 Inkjet printing

Inkjet printing is used for the fabrication of ODFs which provides flexible dosing to meet different requirements of individuals. There are three main steps using inkjet printing to manufacture ODFs: (i) the preparation of drug suspension as the ink, (ii) the deposition of the ink onto the ODFs in a defined pattern and (iii) the drying.⁶⁷ Due to the high precision and accuracy of printing technology, even very small volumes of drugs could be dispensed onto film substrate allowing to deliver the precise therapeutic dose for pediatric patients. Also, inkjet printing provides a great possibility for personalized medicine owing to its high printing accuracy and flexibility. Therefore, inkjet printing technique could be employed in a hospital setting for the preparation of ODFs with tailored dose in the future.

To obtain desirable drug embedded ODFs by inkjet printing, both ink formulation and substrate properties should be taken into consideration. To avoid blockage of nozzle, viscosity and surface tension of printable ink formulation are the most important parameters. The viscosity of print inks must not exceed 20 mPa.s to assure the flowability of the ink. The viscosity cannot be too low, because otherwise ink would be ejected too early and form the fluid tail, which produces satellite droplets. Hence, the manufacturer recommended having a viscosity in the range between 8 mPa.s and 20 mPa.s, which provides the surface tension in the range of 24–36 mN/m.⁸ As viscosity considerably effects the printing process, ink formulation usually contains viscosity modifiers and surfactants. Glycerol, polyvinyl alcohol, and sodium carboxymethyl cellulose (CMC) are commonly used as viscosity modifiers.⁷¹ In addition, the contact angle between printing droplets and substrate is an essential element for inkjet printing. The high contact angle usually indicates poor ink spreading, which leads to insufficient absorption of inks into substrate, hence, crystallization of drugs may easily occur. Various technologies have been used to decrease contact angle, for example, by improving hydrophilicity of ODFs with hydrophilic component (HPMC).⁷²

As ODFs are edible, flexible and uniform, which act as a suitable candidate for printing substrate. In addition to ink formulation, the properties of substrate are of crucial importance to obtain the optimal printing ODFs. Firstly, sufficient mechanical properties of ODFs are the key characteristics for the printability, handling, and transporation of the printing ODFs. For example, Visser et al. defined the limits for mechanical properties of plain ODFs. The tensile strength and elongation at break can be set to higher than 2 N/mm² and 10%, respectively. The Young's modulus of optimal plain ODFs should be lower than 430 N/mm².⁷³ The fast disintegration of ODFs is considered essential as well. The disintegration time had to be 30 s or less.⁷⁴ The good absorption capacity of the substrate ensures the ink drug penetrates inside the film matrix rather than sliding away from the substrate surface, thus improving drug loading and preventing drug crystallization. Edinger et al. used mesoporous fumed silica as porosity enhancing agent to enhance the absorptivity of the substrate.⁷⁵ Additionally, the thickness, palatability, and taste of the printing substrate greatly affects patient acceptability and need to be considered as well.

4.2 3D printing

The 3D printing, also known as additive manufacturing, is able to build up 3D geometries in a layer-by-layer fashion with the help of computer-aided design (CAD). In inkjet printing, the inks need to be formulated individually for different active ingredients to achieve suitable properties before printing, while the production process of 3D printing is relatively simple for operation in the hospital setting. Plus, 3D printing technique is cost-effective and considerably improves dose accuracy, the application of 3D printing in ODFs provides the opportunity for producing tailor-made and individualized medicines in hospital pharmacies.

One of the typical 3D printing techniques that is frequently used for the production of ODFs is fused deposition modeling (FDM) 3D printing. FDM is a continuous process and usually involves three main steps for the manufacturing of ODFs: (i) mixing and melting drug and excipients into liquid state, (ii) using hot-melt extrusion (HME) to obtain drug-loaded printing filaments, and (iii) printing and deposition of the filaments to form the 3D ODFs. The multi-step 3D printing was able to simplified, for example, Cho et al.¹⁴ proposed holt-melt pneumatic extrusion-based 3D printing. The main limitation of FDM is the high processing temperature, leading to the degradation of thermolabile drugs. Thermoplastic polymers are commonly used in FDM to avoid the exposure of high temperature during extrusion, polylactic acid (PLA), polyvinylpyrrolidone (PVP), and polyvinyl alcohol (PVA)⁷⁶ are most commonly used thermo-resistant polymers. In additional to high temperatures, disintegration time of 3D-printed ODFs may be prolonged due to the formation of filaments. Musazzi et al.⁷⁰ proposed the hot melt ram extrusion 3D printing for the manufacture of ODFs. In their research, the drug (paracetamol) maltodextrins, excipients and plasticizer were mixed and heated, followed by printing directly on the packaging foil and sealing the ODFs.⁷⁰ During printing process, the critical parameters that must be controlled are the infill density, speed of extruder, layer height, and the temperature of both nozzle and building platform.⁹

Semi-solid extrusion (SSE) 3D printing, also called pressure-assisted microsyringe, is another typical 3D printing technique that is commonly used for the fabrication of ODFs. SSE 3D printing is the one-step process to fabricate ODFs at room temperature without the preparation of drug-loaded filaments. The semisolid materials are extruded continuously layer-by-layer through a syringe-based nozzle onto the build plate, followed by in-process drying. The semi-solids formulation contains drug, excipients, and solvent. Therefore, the optimal mixture of these components is of utmost importance for the successful printing of ODFs by SSE. For example, the semi-solids formulation needs to have appropriate rheological characteristics and extrudability for desirable flowability to pass through nozzle before printing. Panraksa et al.⁷⁷ investigated various hydrophilic polymers as printing material that are suitable for ODFs fabrication by SSE 3D printing. In this study, ODFs prepared by 5% sodium carboxymethylcellulose showed fast disintegration time with desirable printing resolution as well as accurate dimensions.⁷⁷ Drying condition needs to be considered as well, otherwise shrinking or deformation may easily occur during the drying process.⁹ Chemical drugs such as levocetirizine hydrochloride, warfarin, and mirtazapine have been used in SSE 3D printing for ODFs fabrication.^78-80