Next-generation pharmaceuticals: the rise of sildenafil citrate ODF for the treatment of men with erectile dysfunction

ABSTRACT

Orodispersible film (ODF) is one of the novel formulations that disintegrate rapidly in the mouth without the requisite for water compared to other conventional oral solid dosage formulations. This delivery system serves as a convenient mode of administration, especially in patients who have dysphagia and fluid restriction, being beneficial to pediatric, geriatric, and bedridden patients. A novel sildenafil ODF containing sildenafil citrate is formulated to be used in patients with erectile dysfunction (ED). This review discusses the advantages of ODF in improving compliance and satisfaction in these patients and describes the manufacturing techniques, evaluation tests, bioequivalence, and stability studies of sildenafil ODF. This formulation offers unique benefit to patients with ED by improving their acceptance and compliance and respecting their privacy and the need for a discreet treatment. Moreover, the comparison of pharmacokinetic parameters between the sildenafil ODF administered with and without water and the conventional film-coated tablet were similar. It also demonstrated reliable performance that yielded a consistent product, meeting all specifications at release and after three weeks of storage under stressed conditions (60°C). Sildenafil ODF warrants improved ease of intake, taste, portability, storage, and compliance among ED patients, making it the potential most preferred formulation and drug of choice.

Plain Language Summary

Erectile dysfunction (ED) prevails as an unprecedented diagnosis and undertreated condition. It is considered as the perfect gender-dependent (early) biomarker of non-communicable diseases (NCDs) including central and peripheral cardiovascular disease, with a heightened risk of related mortality. The effective management of ED reduces these risk factors and halts the progression of disease. Sildenafil citrate, a selective phosphodiesterase-5 inhibitor, is recommended as a first-line treatment for ED owing to its proven efficacy and established safety profile. Recently, a novel sildenafil orodispersible film (ODF) dosage form, which offers rapid disintegration in seconds when placed on the tongue, was developed. We conducted this narrative review to understand the advancements, advantages, and disadvantages of these innovative formulations. ODFs are innovative and sophisticated drug delivery systems that offer several advantages over conventional formulations. The unique benefits of sildenafil ODF includes administration of the film before engaging in sexual activity without the need for water and rapid disintegration of ODF within seconds unlike traditional pills. The sildenafil ODF also demonstrated reliable performance at elevated temperature (stress test), ensuring the stability of the pharmaceutical product during transport, storage, and handling. ODFs have transformed the conventional ways of oral drug delivery. The sildenafil ODF is widely prescribed and preferred among ED patients as it respects patients’ privacy with its ease of use, portability, efficacy, and safety.

1. Introduction

Oral medications remain the most preferred and accustomed method of drug delivery owing to several advantages they offer, including convenience of self-administration and high patient compliance among others [1]. However, some patient groups, including the geriatric and pediatric groups, individuals with Parkinson’s disease or Alzheimer’s disease and psychiatric conditions, and patients with dysphagia, often confront challenges in swallowing and chewing solid oral dosage forms [1–3].

Thus, to overcome these issues, extensive efforts were taken to create novel oral drug delivery systems with the aim of providing drugs that could dissolve or disperse in the oral cavity and form solution or suspension without the requirement of water. These fast-dissolving oral drug delivery systems were first devised in the late 1970s and became prominent as oral mucosal dosage formulations. Currently, they are available in various forms, including adhesive tablets, gels, ointments, patches, and mouth-dissolving films for buccal delivery [4].

These buccal drug delivery systems over time became a suitable alternative drug form for tablets or capsules. In addition, the oral cavity serves as an ideal route of administration due to its highly vascularized thin membranous structure. Apparently, the lower enzymatic activity in the oral mucosa provides greater permeability and rapid absorption of several drugs, especially drugs with low aqueous solubility. It also bypasses first-pass metabolism, potentiates higher systemic bioavailability of active pharmaceutical ingredients (APIs), and ensures a rapid onset of action [5].

Oral disintegrating tablets (ODTs) are a kind of oral solid dosage form intended to disintegrate swiftly within seconds of placement on the tongue without necessitating water or chewing [5,6]. Orodispersible films (ODFs) are a drug delivery system that encompasses thin, flexible sheets manufactured with or without plasticizers that usually disperse or disintegrate promptly, usually within seconds, once placed in the mouth. They are designed to be positioned in the buccal cavity either above the tongue or between the gums and cheeks and get directly absorbed into the blood stream. They can be used to deliver different categories of medications, including prescription and non-prescription, or over-the-counter drugs [5]. The use of ODFs is well-known to resolve issues related to conventional oral dosage forms that include but are not limited to (i) accelerating the time of drug release, (ii) prolonged duration of drug action, (iii) reduced number of dose administrations, and (iv) maximized efficacy of APIs [7]. Besides, this innovative drug delivery system or film technology offers an array of benefits during the pharmacokinetics and pharmacodynamic aspects of the drugs, including (i) improved absorption and metabolism, (ii) site-specific action, (iii) lowering of side effects, and (iv) most significantly enhancing the drug’s bioavailability. ODFs also confer expeditious dissolution, pertinent drug loading capacities, and improved stability and durability of drug formulations. Moreover, they are safe, secure, nontoxic, bioresorbable, and biodegradable. Furthermore, as ODTs evolved, the ODFs achieved patient compliance by circumventing discomfort due to their user-friendly advantages. Thus, the ODFs provide immediate release and disintegration; rapid onset of action; and disease- and target-specific drug action that results in instant and effective reduction of symptoms, relieves discomfort, and restores normal physiological function. These advantages have compelled patients to adhere to their therapy and complete the duration of treatment, resulting in improved quality of life (Figure 1) [8,11–13].

Figure 1.

Comparison between ODF and ODT.

This figure is modified and re-represented from refs [6,8,12,13].

Although there are several names employed to refer oral film dosage forms like thin strips, oral thin films, quick dissolve films, oral films, melt-away films, orally dissolving films, and wafers, they are officially named as ODF by the European Medicines Agency (EMA) or as soluble films by the United States Food and Drug Administration (U.S. FDA) [9]. According to European Pharmacopeia (Ph. Eur.), ODFs are delineated as sheets, either single or multilayered, made up of appropriate materials and are designed for rapid dispersion once placed in the mouth. In fact, they instantaneously disintegrate/disperse in saliva, resulting in the formation of solution or suspension, which facilitates rapid absorption and distribution of the drug into the blood circulation [5]. This review discusses the advantages of ODFs in improving compliance and satisfaction in patients with erectile dysfunction (ED) and describes the bioequivalence and stability studies of sildenafil citrate ODF.

2. Search strategy

An online PubMed literature search was conducted to identify English language publications from inception to March 2024 using combinations of the terms erectile dysfunction, ED, phosphodiesterase type 5 inhibitor, phosphodiesterase 5 inhibitor, phosphodieseterase-5 (PDE5) inhibitor, sildenafil, vardenafil, tadalafil, avanafil, drug formulations, drug delivery, buccal mucosa, orally dispersible, orally disintegrating, orodispersible, ODT, ODF, oral dispersible formulations, novel drug delivery, innovative technologies, manufacturing methods, stability studies, stress test, bioequivalence, and regulatory requirements. Other relevant articles were identified by manually reviewing the reference list of selected articles.

3. Orodispersible dosage forms

Orodispersible dosage forms have an ever growing presence in the pharmaceutical market considering that their administration can enhance the bioavailability of most of the drugs and their prescription can ameliorate patient adherence and/or compliance [10]. This novel technique has transformed the usual drug delivery methodology for oral drugs. These modified dosage forms, oral films, have replaced oral tablets as they have achieved altered drug release characteristics and faster disintegration. Also, conventional tablets may get easily broken down, necessitating considerable packaging during handling, storage, and transit, while oral films are flexible, handy, and can be kept for long-term use [14].

An ideal and authentic rapid dissolving delivery system is expected to possess the following properties: (i) optimal stability and transportability, (ii) uncomplicated handling and administration, (iii) no distinctive packaging material or processing requirements, (iv) no requirement of water for application, and (v) acceptable palatability. In addition, the film should be thin and elegant in appearance, available in various sizes and shapes, unobstructive, adhere to the oral cavity easily, disintegrate fast without requiring water, and release the drug rapidly. In addition, the suitable drug candidate must exhibit these ideal characteristics. The drug should have a pleasant taste, lesser and moderate molecular weight, and excellent stability and solubility in water and saliva; remain partially unionized at the neutral pH of oral cavity; and easily permeate through the oral mucosal tissue [4]. Table 1 lists the advantages and disadvantages of the ODF, respectively. The existence of numerous polymers, excipients, and manufacturing technologies has leveraged the development of a distinct range of ODFs [13]. The constituents of oral films can vary depending on the particular formulation and intended purpose [16]. Irrespective of the site of action, local or systemic, a wide range of drugs can be formulated as ODFs. Those films that are indicated for fluid-filled blisters, local anesthetics, toothaches, and mouth ulcers are few examples of ODFs that exhibit local action. For systemic action, they are used for managing cough, throat pain, migraine headaches, central nervous system disorders, gastric ailments, pain, and nausea or for delivering vitamins or nutraceutics [6].

Table 1.

Advantages and disadvantages of ODF.

Advantages of ODF	Disadvantages of ODF
✓ Convenient dosing	✓Does not allow incorporation of drugs at higher dose, as the ideal dose ranges between 1 and 30 mg
✓ Requires no water	✓ Those drugs that fail to ionize at oral pH and do not get absorbed through active diffusion cannot be incorporated as ODF
✓ No risk of choking	✓ The hygroscopic nature of ODFs makes them vulnerable to deterioration
✓ Taste masking	✓ Technical limitations to achieving optimum thickness while casting the film
✓ Increased stability	✓Technical challenge with achieving dose uniformity
✓Aids to incorporate drugs at reduced/low doses	✓Necessitates the provision of special equipment for packing and storage
✓Drugs that are incompatible with the gastrointestinal tract and with bioavailability issues can be formulated	✓ Films require moisture-protective packaging
✓Enhanced patient compliance
✓ The drug shows better bioavailability as it by passes enterohepatic circulation
✓Exhibits site-specific and localized action
✓Ensues rapid disintegration and dissolution owing to the availability of large surface area in the oral cavity
✓Accurate dosing in comparison to liquid dosage forms
✓Films can be manufactured in varied shapes and sizes due to its thin, flexible, and stable properties
✓ Provides immediate drug effects and quick relief in emergency conditions

This table is modified and re-represented from [4,6,9,10,13,15].

ODF, orodispersible film.

4. Manufacturing methods of ODTs and ODFs

To start with ODTs, there are two broad classifications used in their manufacturing such as lyophilized systems and compressed tablet-based systems [4,13,15,17,18]. The performance of ODTs relies on manufacturing processes that increase the tablet’s porous structure, ensures appropriate mixing of disintegrating agents, and employs highly water-soluble excipients that allow quick ingress of water. These parameters are highly essential in facilitating rapid disintegration and dissolution of ODTs when placed in the mouth [19]. Also, a striking balance between rapid disintegration and fragility must be demonstrated to reduce the challenges during handling, packaging, administration, and storage.

4.1. Manufacturing of ODTs

4.1.1. Lyophilization

Lyophilization, also known as freeze drying, is a technique that utilizes the sublimation effect, wherein solid ice is transformed directly into vapor phase, bypassing the liquid phase entirely, and often used to manufacture ODTs. This technology entails molding the drug in suspension or solution along with other structural excipients into tablet-shaped units, followed by freezing and lyophilization in the pack or mold forms. The resultant tablet-matrix offers high porosity, which is beneficial for rapid saliva or water penetration and quick disintegration [20,21]. The freeze-dried formulations exhibit ideal pharmacological properties including low dosage, microscopic particle size, chemical stability, and easy handling and transport. However, the fabrication process is expensive and time-consuming [22–24].

4.1.2. Compressed tablet systems

Compressed tablet-based systems harness the conventional tableting technology by direct compression of the mixture of API and excipients. This technique deliberates to achieve substantial disintegration and packaging requirements [4,8,17]. It allows tablets to be crushed straight from medication and excipient mixes without any need for prior processing. These excipient mixes including super disintegrants, effervescent agents, and sugar-based components offer compressibility, enhanced flow, and disintegrating properties. This technology allows fabrication of tablets at high doses using conventional equipment, making it a more simple, accessible, and cost-effective method compared to other techniques like wet granulation. Care must be taken while choosing the type of disintegrant and effervescent and pressure applied during compression as soft pills may exhibit poor mechanical strength and stability and large, hard tablets may take longer time to disintegrate [23,25].

4.1.3. Tablet molding technology

This technique molds the powder mixture, additives, and water-soluble ingredients together under pressure into highly porous ODTs. This technology utilizes either solvent-based or heat-based molding techniques. In the solvent method or compression molding, the powder blend is moistened with a hydroalcoholic solvent (ethanol or water), which is then molded into tablets under suitable pressure lower than those employed in conventional tablet compression method and air-dried. This process ensures formation of highly porous structure which has increased solubility and accelerated dissolution rate. In the heat molding method, the molten matrix consisting of dispersed or dissolved drug under ambient pressure is molded into tablet molds. This technique offers instantaneous drug release, rapid drug absorption through the oral mucosa, reduced first-pass hepatic metabolism, and increased bioavailability. However, due to lower mechanical strength, these molded tablets may be fragile and break easily during handling, storage, and transportation [23,25–27].

4.1.4. Spray-drying technology

This technology produces extremely porous powders that can be used to manufacture fast-dissolving tablets. In this method, the active ingredient is mixed with a number of additives and excipients to form a highly porous and finely powdered substance. A variety of ingredients such as gelatins, mannitol, croscarmellose sodium, and sodium starch glycolate in combination with acidic (citric acid) and alkaline materials (sodium bicarbonate) are employed to enhance the disintegration and dissolution of these tablets. A particulate support matrix is formulated using hydrolyzed and non-hydrolyzed gelatins, and mannitol as a bulk forming agent and sodium starch glycolate and croscarmellose sodium as a disintegrating agent are blended with active ingredients. This formulation is spray-dried using a spray drier and the resultant mixture is subsequently compressed to form tablets. The ODTs fabricated using this technique showed swift disintegration and dissolution in aqueous solution in <20 seconds. The disadvantages of spray-dried technology include high production cost and special packaging requirements due to its inherent fragility [23,26,28–31]. Figure 2 illustrates the process of spray-drying technology.

Figure 2.

Spray drying technique.

This spray drying process diagram is modified and re-represented from ref [23].

4.1.5. Melt granulation

This unique method is widely used in the preparation of ODTs through clustering or agglomerating pharmaceutical powders using a meltable binder superpolystate or PEG-6-stearate. This superpolystate is a hydrophilic waxy binder with an inherent melting point of 33–37°C and exhibits hydrophilic–lipophilic balance value of 9. These properties make them unveil excellent binding capacity, heighten physical resistance, and aid in rapid disintegration and dissolution when used in the preparation of ODTs. The APIs along with excipients are mixed using high shear mixers with this binder to form granules. The temperature of granules is increased either using a heating jacket or by heat generated due to friction between granules and impeller blades to improve the mechanical integrity of the granules. These stable granules are cooled and allowed to solidify and compressed into tablets. This method does not use water or organic solvents during manufacturing, which makes them better than conventional granulation and can be a beneficial method to prolong the dissolution rate of poorly water-soluble drugs [32]. The preparation process is faster and has less energy consumption than wet granulation [23,33,34].

4.1.6. Cotton candy process

This process is also called as “sugar floss” or “candy floss technique” as it utilizes a unique spinning mechanism to produce floss-like crystalline structure, which appears similar to a cotton candy [32,35]. In this technique, a matrix is built using polysaccharides or saccharides and with concurrent actions of flash melting and spinning. This causes the formation of floss matrix, which is either partially or entirely recrystallized to enhance the flow properties and compressibility. The floss matrix is further pulverized, mixed and blended with a mixture of API and excipients, and ultimately compressed into ODTs. This process is beneficial for accommodating excessive doses of APIs. ODTs prepared using this method exhibit excellent mechanical strength compared to other techniques. Since the method uses high temperatures, thermolabile drugs cannot be formulated as ODT through this approach [23,36,37].

4.1.7. Nanoionization

This recently developed nanomelt technology produces nanocrystals by reducing the particle size of drugs to nanosize using a wet milling process. The drug nanocrystals are the combined with stabilizers, which, by adsorbing onto their surfaces, prevent them from clumping and aid integrate them in ODTs. This technique is best suitable for those drugs that are marginally or poorly water-soluble and have wide dose range (up to 200 mg of drug per unit). The ODTs have considerably fast nanoparticle dissolution, increased absorption, and improved bioavailability. This lowers dose requirements and cost-effectiveness compared to other conventional technologies, which makes it a popular technique [28,32].

4.1.8. Patented technologies

There are several patented technologies developed including Zydis [38], Quick-dis, Oraquick, Durasolv [39], Shearform [40], Flashtab [41], Flashdose [42], Wowtab [43], Nanocrystal [44], Lyoc [45], Ziplet, Pharmaburst [46], and Frosta [47] technologies that utilize the varied conventional and innovative techniques to manufacture mouth-dissolving tablets [32,33,48]. Gupta et al. [33] and Bidkar et al. [32] have discussed elaborately on the manufacturing methodologies leveraged in the production of orodispersible tablets through patented technologies. Further description is outside the scope of this article.

4.2. Manufacturing of ODFs

Over the years, manufacturing of ODFs has evolved from technologies that were used to produce transdermal patches, namely, hot-melt extrusion, perforated film technology, and solvent casting technique [6,33,49]. These ever-emerging sophisticated manufacturing methods have succeeded in the production of dosage forms that are stable, thin, and flexible with considerable mechanical and tensile strength. In addition, they can be fabricated in varied sizes and shapes, offering optimal transport and storage options [8]. Table 2 highlights the standard composition and critical quality attribute of ODFs.

Table 2.

Standard composition and critical quality attributes of ODF.

Contents	Amount
API	5–30% w/w
Water-soluble polymer	45% w/w
Plasticizers	0–20% w/w
Surfactants	q.s.
Sweetening agents	3–6% w/w
Saliva stimulating agents	2–6% w/w
Fillers, colors, flavors	q.s.
Quality Attributes for ODF	Specifications
Physical attributes
Size	Length, width, and thickness must be of specified dimensions for convenient placement of the film upon the surface of the tongue. The size of the film should be 1 cm × 1 cm, and the thickness must be of 100 µm.
Mechanical characteristics	High tensile strength, high elongation at tear of break, and low/reduced Young’s modulus.
Identification	Positive for drug
Assay	100% w/w of label claim
Content uniformity	Conforms to USP <905> uniformity of dosage units
Disintegration time	Not more than 60 seconds
Dissolution	Acceptance criteria similar to the conventional immediate-release solid dosage forms

w/w, weight by weight. This table is modified and re-represented from refs [4,5,18].

ODF, orodispersible film; USP, United States Pharmacopeia; w/w, weight/weight.

During preparation of orally disintegrating formulations, it’s important to conisder numerous parameters such as tensile strength, pH, thickness and the selection of an appropriate polymer blend suitable for drug release. The crucial step in the formulation of orodispersible film depends on judicial selection of polymers and polymer blends and the appropriate method of preparation [50]. The primary methods used in the formulation of ODFs include the solvent casting technique, semisolid casting, solid dispersion extrusion, electrospinning, hot-melt extrusion (HME), and rolling and the other prominent emerging techniques of 3-dimensional printing (3DP) for personalized dosing [51].

4.2.1. Solvent casting

Currently, solvent casting is considered as the most fundamental, commonly employed, feasible and direct technique for manufacturing of oral films. On a laboratory setting and small scale, the ODFs are prepared by mixing different polymers and other basic ingredients, which are dissolved in an appropriate solvent to form a homogenous solution. This resultant solution is subsequently casted onto a petri dish or a substrate and kept overnight for drying in oven that aids in the formation of a thin film. However, choosing a suitable temperature for drying is critical during the preparation of ODFs, as higher temperatures can cause mechanical instability, shrinking of films, and API degradation.

Apparently during the fabricating process of ODFs on a large industrial scale, the solvent casting method consists of several steps encompassing definite dispensing of the API, excipients, and FDA-approved class III solvents. These ingredients are mixed in a low or high-shear mixer to form homogenous dispersion under thermostatic control. Enough caution is ensued while introducing encapsulated drug actives in high-shear mixers, as it may cause peeling off of the encapsulating material. The resultant slurry is subjected to solvent evaporation at predetermined temperature in a hot-air oven. This mixture is later smeared onto a liner employing a knife-over-roll coater, which is supplied with an accurate pin gauge. Subsequently, the dried laminates are rolled onto the master rolls, nicked into discrete dose units based on the specific dimensions, and packed within tamper-proof pouches or sachets. Nevertheless, the solvent casting offers a number of benefits including excellent physical qualities, simple and reduced production costs, and uniformity of the thickness of the film [52]. The large-scale production of ODFs using this technique must consider the crucial challenges, which may heighten with the scale of production. These are some of the challenges that are not limited to equipment adaptation; preservation of coveted film characteristics; maintaining uniformity and homogeneity of the film; avoidance of inconsistencies during mixing and casting processes; ensuring complete drying to prevent changes in the membrane structure, drug dissolution, and release pattern; preserving the integrity of film without any defects such as cracking or irregular thickness; prevention of entrapment of air bubbles; film shriveling; and rippling effect. An optimum temperature needs to be maintained as well because the presence of humidity may induce undesired polymorphic transitions [2,5,33]. These challenges demand proper planning and optimization of processes, maintenance of optimum temperature and humidity, and conscientious batch-to-batch consistency and conform to regulatory standards in order to deliver high-quality ODFs during the industrial scale-up [5,52] (Figure 3). Shi et al. (2014) prepared, characterized, and conducted in vitro evaluation of a polyvinyl alcohol/sodium alginate-based orodispersible film containing sildenafil citrate. They recommended that this simple solvent casting method might serve as an alternative to conventional sildenafil tablets for the treatment of erectile dysfunction [53]. Owing to the several advantages, this technique is successfully employed in the development of sublingual films for various generics and products, including everolimus ODF for the treatment of advanced cancer [54], pregabalin for the treatment of epilepsy [55], and aripiprazole for the treatment of several mental disorders [56].

Figure 3.

Solvent casting technique.

This solvent casting process diagram is modified and re-represented from refs [5,49].

4.2.2. Electrospinning method

This method is also known as “electrostatic spinning” and utilizes solvents for the fabrication of ODFs, which is featured by a high-porous inner structure [7]. In this technique, the spherical shaped polymer solution droplets are transposed to conical shape, which results in the formation of nanosized fiber filaments. These electrospin nanofibers offer distinct properties including increased surface area-to-volume ratio and along with other mechanical attributes. This facilitates the customization of ODFs to demonstrate special functions like controlled release, tissue engineering, filtration, and other purposes with respect to energy storage.

This solvent-based technology requires a specialized electrospinning device. The solvent formulation is pumped through a metallic needle at controlled rate. A high-voltage electric current is passed through this needle that ejects out as a dispersion jet/spinneret and collects on an opposite-charged collector. The API can be introduced initially or at the end of the spinning process [57,58]. The factors such as polymer concentration, shear force, viscosity of the polymer solution, strength of the electric field applied, and spinning distance must be optimized for obtaining the appropriate diameter and structure of nanofibers [59]. These ODFs made up of nanofibers can be designed and fabricated to different shapes and dimensions. This nanofiber-fabricated ODFs enable its usage in personalized medicine or targeted therapies that eventually can be tailored to patient-specific needs. These films also offer excellent benefits including remarkable mechanical robustness, flexibility, dose precision, controlled release of drugs at a preset rate, enhanced bioavailability, and faster T_max (time taken to reach the maximum concentration). Similar to the solvent casting method, the electrospinning technique employs organic solvents, which pose undesired environmental issues [2,33]. Ravasi et al. (2023) most recently evaluated the feasibility of electrospinning technique in the manufacturing of pullulan-based sildenafil ODFs intended for treating pediatric patients with pulmonary hypertension. Interestingly, the electrospun products in the ODFs showed faster disintegration process (i.e., occurring within few seconds) and were very well compliant with Ph. Eur. and USP limits. They suggested that fabricating relevant ODFs particularly through the electrospinning technique is promising for increasing sildenafil bioavailability and lowering its dosages [60].

4.2.3. Printing technologies

Printing technologies are an innovative and promising technique used in ODF manufacturing for the design of personalized medicine. They comprise two-dimensional (2D) ink-jet printing, 3D-printing, fused deposition modeling (FDM), additive printing, semi-solid extrusion (SSE) 3D printing, and flexographic printing [2,7]. In case of 2D-printing, a substrate, usually an edible carrier is selected upon which an aqueous or non-aqueous drug (ink) is printed in a defined motif [62,63]. While in 3D-printing, ODFs are printed layer-by-layer three-dimensionally with stepwise addition of additives or excipients [61–63].

4.2.3.1. 2D printing.

4.2.3.1.1. Inkjet printing (IJP)

In this method, initially drug is either dissolved or suspended in liquid to form ink. This ink is deposited on edible substrate in a defined pattern and dried. The properties of substrate and ink formulation define the quality of drug-embedded ODFs. The ink formulation is prepared based on the printer system and the method of drop generation employed. The ink drops could be spawned continuously as in continuous jetting-printing or on-demand in a drop-on-demand printing system. The print heads in these printing techniques could have a single or multiple nozzles. Precaution must be taken to evade blockage of nozzle, which rather depends on the viscosity, quality and surface tension, and other parameters of ink formulation. It is important to set the viscosity of print inks in the optimum range of 8 mPa.s and 20 mPa.s in order to obtain surface tension between 24 and 36 mN/m. This can be achieved through usage of viscosity modifiers and surfactants like sodium carboxymethyl cellulose, glycerol, polyvinyl alcohol, etc. These modifiers may also be beneficial in reducing the fluid tail and satellite droplet formation, which may lead to uneven deposition of ink on the substrate. The other disadvantage of IJP is poor ink spreading and inadequate ink absorption that may eventually lead to crystallization of drugs. This can be reduced by decreasing the contact angle amidst printing droplets and substrate by usage of the hydrophilic component, hydroxypropyl methylcellulose (HPMC), which enhances the hydrophilicity of ODFs. In addition, alterations in mechanical properties of the film must be considered as they may influence the stability of ODF, which can be dealt by coating the ODF postproduction. This technique allows relatively low loading doses compared to others but offers high precision and accuracy. This advantage has been successfully utilized for designing personalized medicine and those drugs that require precise dosing like drugs with narrow therapeutic index or high potency [7,61–63].

4.2.3.1.2. Flexographic printing

Flexographic printing is the most recent technique that is a flexible and cost-effective alternative to the IJP and solvent casting methods. In solvent casting and hot extrusion methods, the API gets integrated into the formulation in the initial steps prior to film formation. This can add unwanted stresses at various stages of manufacturing, handling, transport, and storage that may influence the quality and stability of APIs. The flexographic printing technique reduces this undue stress on APIs during mixing, solvent evaporation, and drying and is specifically beneficial in handling labile APIs. Similar to IJP, this method is favorable in the fabrication of thermolabile drugs and highly potent low-dose APIs as ODFs [33,64].

This method transfers the prepared ink formulation through a fountain roll onto an anilox roller on a drug-free ODF layer. The excess is carefully scrapped using a doctor’s blade. In the subsequent step, the ink solution or suspension is then transferred from the anilox roller to the plate cylinder and onto drug-free ODF. The solution is then passed through the impression cylinder for printing the drug-loaded ODFs. Finally, after solvent drying, they are cut into required dimensions and shapes [7,65]. This printing method enables flexible fabrication process as it supports multiple printing cycles and can be set up in both in laboratory setting and industrial scale. This technique can be combined with other manufacturing methods like IJP to design both standard release and prolonged-release drug delivery systems [33].

4.2.3.2. 3D printing

This printing method also referred to as additive manufacturing produces precisely designed ODFs by utilizing the contemporary computer‐aided design (CAD), which develops 3D geometries in a sequential layer‐by‐layer fashion [61,66]. This technique is relatively simple and cost-effective and shows flexibility in designing and dose accuracy. This method allows accurate drug loading, notably for drugs with narrow therapeutic index, and aids in manufacturing personalized medicine. This helps to tailor the therapeutic approaches to meet the unique physiological requirements of individual patients [66]. The utilization of this additive manufacturing technique has significantly lowered the preparation time along with tremendous improvement in the mechanical characteristics of films. There are several 3D printing techniques, like the fused deposition method, hot-melt extrusion, and print-fill, which utilizes thermoplastic polymers that serve as the primary component [67]. These fabricated personalized films have the capability to be used in a clinical setting, as they substantially enhance the therapeutic efficacy, minimize adverse drug reactions, and aid in improved patient outcomes [5,68,69].

4.2.3.2.1. Fused deposition modeling and hot-melt extrusion

Fused deposition modeling or fused filament fabrication is a nozzle-based deposition technique. In this 3D printing method, API is embedded in a molten thermoplastic polymer filament, which gets extruded through a nozzle, maintained at a high-temperature, and deposited as incremental layers—with quick solidification to a build plate. Several factors need to considered during the manufacturing of ODFs through this technique, including API content and filament dimension uniformity, optimum temperature and printing speed, and the impact of API presence in the polymer matrix on printing parameters. This technology is widely used in pharmaceutical industries for the manufacturing of immediate-release and extended-release formulations [67]. This method is promising in fabricating those drugs that are poorly/sparingly water soluble, thus improving their dissolution rate. It does not require solvents making it environmentally safe, has a lesser cost, and is suitable for both large- and small-scale production [70].

4.2.3.2.2. Semi-solid extrusion

This 3D printing technique is also known as a pressure‐assisted microsyringe method used for the manufacture of ODFs. In this method, excipients, additives, and active ingredients are either dissolved or dispersed in a solution and dried at room temperature to form a semisolid mixture. This semisolid material is extruded incessantly layer-by-layer through a syringe‐based nozzle onto the build plate. This is followed by in‐process drying, which forms a critical step and may influence the physical properties of the incorporated excipients, drug, and overall quality of ODFs [18]. This method fabricates ODFs through a one‐step process without necessitating the preparation of API-loaded filaments, unlike other 3D printing technologies. The SSE is the utmost successful 3D printing method for fabricating ODFs. The optimum mixture of drug, excipients, and solvent defines the ideal rheological characteristics of the semi-solid formulation. This is extremely important as it affects the extrudability of semi-solid formulation in desired flow through the nozzle before printing. Studies have shown that ODFs have exhibited fast disintegration time, appropriate printing resolution, and precise dimensions due to incorporation of 5% sodium carboxymethylcellulose during the preparation. Since this method avoids any processes at elevated temperatures, it allows usage of thermosensitive polymers for the fabrication of ODFs [61,71,72].

5. Evaluation tests for ODF

The assessment and characterization of ODFs involve an array of essential tests to warrant their quality, organoleptic properties, and performance. These tests comprise assessments of thickness, weight uniformity, film robustness and durability, flexibility, water absorption or uptake capacity, swelling, surface features, and moisture content. The other tests involve disintegration and release tests, tensile properties, tensile strength, puncture resistance, elongation at break, elastic modulus, porosity, folding durability and endurance, taste evaluation, and uniformity of drug content. These tests are indispensable in pharmaceutical formulation development for evaluating the quality of ODFs. A compilation of commonly used in vitro techniques that evaluate the mechanical characteristics is provided in Supplementary Table S1.

5.1. Bioequivalence and stability testing

Several studies have demonstrated bioequivalence between sildenafil ODF formulation and conventional film-coated tablets (FCTs). This display of bioequivalent pharmacokinetics between the two formulations supports and recommends the use of innovative ODF formulation as a befitting alternative to the customary oral solid dosage form [73–75].

Two randomized cross-over studies were conducted to examine the pharmaceutical equivalence of 50 mg sildenafil citrate ODF with the marketed 50 mg sildenafil citrate FCT with and without water. The study recruited 42 and 80 healthy male volunteers in the first and second studies, respectively. Bioequivalence was demonstrated for sildenafil citrate ODF with water in comparison with the sildenafil citrate FCT as the ratios of adjusted geometric means (90% confidence interval [CI]) were utmost plasma concentration: 1.02 [94.91–108.78] and area under the plasma concentration–time curve: 1.09 [104.49–113.21]) for sildenafil citrate ODF with water vs sildenafil citrate FCT with water. The bioequivalence was demonstrated as the resultant ratios were within the approved range of 80% to 125%. Furthermore, the pharmacokinetic parameters in the successive study also established the bioequivalence for sildenafil citrate ODF (without water) with that of sildenafil citrate FCT with water. The ratios of adjusted geometric means (90% CI) were maximum plasma concentration: 1.02 (95.47–109.36) and area under the plasma concentration–time curve: 1.06 (103.42–108.40) for sildenafil citrate ODF without water vs sildenafil citrate FCT with water. The occurrence of adverse events was observed at similar rates for both the formulations in all the studies, which were of mild intensity. The study results demonstrated the bioequivalence and supported the interchangeability of new sildenafil citrate ODF formulation with the marketed FCT formulation [76].

5.2. Stress test

The usage of ODFs is convenient among patients due to its durability, ease of administration with no suffocation risk, and ease of carrying the strips without the need for a secondary container [8]. Among other advantages, the sildenafil ODF offers unique benefit to patients with ED in respecting their privacy. While the shame and the stigma culturally linked to the ED management is considered a major unmet need of the patients treated with phosphodiesterase 5 inhibitors (PDE5-Is), the ODF allows them to carry the drug in their pockets, in the most discreet way, and then be placed on the tongue before engaging in sexual activity [8,77,78]. Furthermore, the absence of the need to swallow the drug with water further increases the ease of use and the potential reduction of the stigma of being treated with a traditional pill. In fact, when the film is placed upon the tongue or in the oral cavity, it gets immediately hydrated by saliva without any need of water followed by rapid disintegration and drug release for oro-mucosal and/or systemic absorption [76].

To further demonstrate the possibility to safely store the drug in the pocket, maximizing the need for a discreet treatment, a stress test has been conducted on sildenafil ODF by exposing it to elevated temperatures (60 degrees Celsius) for three weeks, mimicking extreme storage conditions and followed by evaluation of its physical and chemical stability. Ensuring the stability of pharmaceutical products is crucial to maintain their efficacy, safety, and quality throughout their shelf life, particularly critical in the case of sildenafil ODF. This test was conducted in Kyukyu Pharmaceutical Co., Ltd, Toyama Plant, Japan. A thin pale red-colored ODF containing 50 mg sildenafil was formulated to dissolve in the oral cavity. Three batches of samples were subjected to a stability study at 60°C stress for three weeks. Subsequently, they were assessed for the amount of API assay (95.0%−105.0% of labeled amount), degradation, disintegration, dissolution rate (over 80% for 45 mm), and water content. All the test items of this stability study met the specifications and showed negligible differences between the samples. The amount of degradation products demonstrated an increasing trend over time in all conditions, but all met the required specification. The purity testing for the degradation product (0.2% or less) showed significant results (p value < 0.05) at initial and 60°C in all the three samples. The process was evaluated across a range of manufacturing conditions, and all intermediates and sildenafil ODF showed reliable performance that yielded a consistent product meeting all specifications at release and after three weeks of storage under stressed conditions. These results, shown in Table 3, indicate the robust performance of the sildenafil ODF across a range of manufacturing conditions. In addition, the water content stayed in a tight range regardless of the film casting parameters, and this remains true of the packaged product even after 3 weeks at 60°C.

Table 3.

List of items evaluated in the stress test.

		Control		Negative		Positive
Parameter	Specification	Initial	60°C 3W	Initial	60°C 3W	Initial	60°C 3W
Description	Product is a pale red, film-like oral disintegrating formulation.	Meets the criteria
Purity [1] degradation product	UK-111,868 is ≤ 0.2%	<0.05%*	0.17%	<0.05%*	0.17%	<0.05%*	0.16%
	Other individual degradation products is ≤ 0.2%	<0.05%*	<0.05%*	<0.05%*	<0.05%*	<0.05%*	<0.05%*
	The total amount of these degradation products is ≤ 0.5%	<0.05%*	0.17%	<0.05%*	0.17%	<0.05%*	0.16%
Purity [2] residual solvents	Ethanol is 10 mg/sheet or less	3.7 mg	3.9 mg	5.8 mg	2.9 mg	2.6 mg	2.7 mg
Disintegration	After 3 minutes, it has collapsed.	Meets the criteria
Dissolution	Dissolution rate over 80% for 45 min.	93–101%	93–102%	93–105%	95–102%	91–106%	96–103%
Assay	95.0–105.0% of labeled amount	100.67%	100.93%	101.30%	101.73%	102.22%	101.28%
Water content	-	1.943%	1.679%	1.798%	2.036%	1.795%	1.672%

3W, 3 weeks.

This table illustrates the results from stress test studies, VGRS0-P-21-01 and VGRS0-P-21-02.

6. Discussion

ED is defined as the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance [76,79–81]. ED still prevails as an unprecedented diagnosis and undertreated condition that contributes to increased physical and psychosocial burden. It negatively impacts the wellbeing, relationships, and health-related quality of life (HR-QoL) of patients and their partners [82,83], and thus, any treatment interventions that substantially revive sexual function have the prospect to reinforce patient health and overall HR-QoL.

ED may present with clinically relevant forms but also subclinical conditions deserving medical attention. Worldwide, various forms of ED are diagnosed in up to 150 million men and it has been projected to surge to 322 million cases by 2025. ED has affected 52% of men in the age group of 40 and 70 years and 70% of men above 70 years [84–87]. The primary risk factors include diabetes mellitus, hypertension, and hyperlipidemia and modifiable risk factors like obesity, physical inactivity, alcoholism, and cigarette smoking [88–90]. In addition, there is increasing evidence that ED can be considered as the perfect gender-dependent (early) biomarker of non-communicable diseases (NCDs) including peripheral vascular disease and cardiovascular disease, with a heightened risk of cardiovascular mortality as largely demonstrated by epidemiological studies [91]. Indeed, ED can be considered a symptom for underlying NCD that may be explained as the classical canary in the coalmine [92].

The management of ED includes the identification and control of risk factors and appropriate pharmacological and non-pharmacological therapy. The treatment strategies undoubtedly can reduce the initial symptoms and halt the progression of the disease. Some of the treatment approaches encompass psychosexological strategies, intraurethral or intracavernosal alprostadil self-injections, vacuum-assisted erection devices, low-intensity extracorporeal shock wave treatment, and penile implants. Nevertheless, after the efforts to modify unhealthy lifestyle and control risk factors and comorbidities, pharmacological management with oral PDE5-Is stays as the first-line treatment choice for ED because of its proven efficacy and better safety profile [8].

The PDE5-Is inhibit the PDE5 enzyme concentrated in the smooth muscle cells in the blood vessels [93]. Due to this inhibition, PDE5-Is prevent the enzyme-initiated degradation of cyclic guanosine monophosphate (cGMP), which causes elevation of cGMP in the vascular smooth muscle. Elevated cGMP levels lead to dilatation of the blood vessels due to phosphorylation of various downstream effector molecules, ensuring relaxation of smooth muscles [94]. Inhibiting PDE5 produces a dilatation of the penile arteries that leads to a more prolonged and stable erection. Futhermore, PDE5-Is improve endothelial function and decrease apoptosis of smooth muscle cells in the corpus cavernosum [93,95]. Till date, the PDE5 inhibitors approved for the treatment of ED by the US Food and Drug Administration and European Union (EU) include sildenafil, tadalafil, vardenafil, and avanafil [82,96–98].

Sildenafil citrate, the first-in-class PDE5-I, is the most potent and selective inhibitor of cGMP-specific PDE5. Since its launch for the treatment of ED in 1998 in the market, there has been a well-established evidence base for its effectiveness and safety of sildenafil. It is the most efficacious drug, from a vascular perspective, among other PDE5-Is [99].

This established efficacy of sildenafil in ED is irrespective of confounding factors including age, baseline severity, or etiology of ED [100]. Although, sildenafil ODT is marketed at various strengths of 25, 50, and 100 mg, 50 mg is the recommended dose for most of the patients with directions to be approximately taken one hour before sexual activity. The dose can be titrated to a maximum of 100 mg or reduced to 25 mg considering individual patient’s needs, tolerability, and efficacy. Headache and flushing are the most commonly reported side effects [101]. Sildenafil is supplied in both solid film-coated tablet (FCT) and orodispersible tablet formulations. The sildenafil ODT and ODFs are made available through implementation of innovative manufacturing technologies [8,102]. It is also offered as chewable tablets and an orally soluble orodispersible film formulation [82]. B. Damle et al. conducted a randomized clinical trial that reported bioequivalence of sildenafil ODT with or without water compared to marketed film-coated tablets. This study also identified the effect of food on the release pattern of drug and demonstrated the benefits of the administration of sildenafil ODT on empty stomach [103]. Similarly, Yuan Lv et al. examined and reported the bioequivalence of sildenafil citrate ODF and FCT with and without water in 2 randomized crossover studies [75].

Owing to its unique pharmacological characteristics, quick disintegration within seconds, the novel sildenafil ODF is widely prescribed and preferred among ED patients. A study conducted in Japan surveyed 25 patients with ED regarding the ease of consumption and portability with the use of sildenafil ODF formulation. The survey items comprised (i) portability, (ii) storage techniques, (iii) ease of consumption, (iv) comfortableness, (v) extent of self-consciousness with their partner, (vi) thoughts on administering the film formulation, (vii) comparison with the tablets, and (viii) efficacy and adverse reaction. Of all the participants, 61.5% of the patients who switched from tablets to film quoted that storage and portability were improved and were comfortable during consumption. The study reported that most of their patients felt more at ease (69.2% who swapped from tablets to film and 75.0% belonged to the prescribed film-only category) and more comfortable with the film (61.5% who switched from tablets to film and 66.7% belonged to the prescribed film-only category). Mild hot flashes and headache were the only two adverse reactions with no severe adverse reaction reported by the study participants. The survey demonstrated improved ease of intake and portability with the orodispersible film compared to tablets [104].

However, the efficacy of PDE5-Is has been thoroughly established, and the documented evidence reveals that a prominent proportion of patients discontinued this pharmacological therapy prematurely. There is a gradual dissatisfaction noticed with the prescribed therapy among patients despite their successful intercourse. Studies depict that approximately 50% of men abandon their treatment with PDE5-Is in conventional formulations within a year [105]. There is an immense need to understand individual patient’s needs and expectations regarding treatment for ED and also to comprehend their personal experiences and preferences. This will be instrumental in deciphering successful patient outcomes and satisfaction regarding the pharmacological therapy [8]. ODFs were developed to overcome the above drawbacks of conventional oral solid dosing forms and to significantly improve patients’ compliance and acceptability to the pharmacological therapy. ODFs are innovative and sophisticated drug delivery systems that disintegrate instantly in the mouth without the need for water. They unveil a prudent and easy mode of administration, with no risk of choking or inconvenience during swallowing. These attributes of ODFs improve compliance specifically in patients with dysphagia, and children and elderly population with comorbidities (e.g., renal impairment or congestive heart failure) when compared with conventional tablets or capsules. This noninvasive drug delivery system offers an altered clinical profile as it surpasses the enterohepatic circulation [8]. Since the drug gets absorbed majorly from buccal mucosal tissues, it also reduces the risk of formation of toxic metabolites due to lowered hepatic metabolism [106].

ODFs with their convenience, together with superior dosing accuracy and swift onset of action, have transpired in strong patient preference among various patient groups. Since each film or strip consists of precise quantities of the APIs and is devoid of physiological variability in the gastrointestinal tract, there is minimal intersubject variability in clinical response unveiled by ODFs [107]. Given all these advantages, growing body of research illustrates that majority of patients and prescribers prefer orodispersible dosage forms over conventional oral solid dosage forms [108,109].

There are fewer limitations with ODFs such as complex manufacturing processes and requirement of specialized equipment that may significantly increase the production costs. Also, these innovative formulations may face different challenges compared to traditional dosage forms during application and regulatory approval processes, necessitating additional studies to evaluate safety, efficacy, and stability. Nevertheless, in spite of these challenges, ODFs have demonstrated significant potential in improving patient compliance and convenience, particularly in patients with swallowing difficulties. Further ongoing research and development in this field could lead to significant innovations and advancements in drug delivery systems [110,111],

7. Conclusions

Both ODTs and ODFs provide patient convenience and compliance compared to conventional solid dosage forms due to their rapid disintegration, dissolution, faster absorption, and enhanced bioavailability. With the availability of numerous modern technologies and careful selection of excipients, ODFs and ODTs provide excellent flexibility in drug design and aids in tailor-made precision medicine at lower doses. Sildenafil ODF, an innovative dosage form, can be used for the treatment of ED as it better addresses the unmet needs and expectations of men with ED. Sildenafil ODF showed unwavering performance that yields a consistent product, meeting all specifications at release and after three weeks of storage under stressed conditions (temperature up to 60°C). It offers unique and sustainable advantages to ED patients, including a pleasant mint taste, convenience, privacy, and storage options, making it the potential drug of choice and the most preferred formulation.

8. Future perspective

Orodispersible films are a promising drug delivery system with several key trends and advancements. The emergence of innovative manufacturing techniques including 2D (two-dimensional) and 3D (three-dimensional) printing technologies helps in the incorporation of nanoparticles that can substantially improve drug delivery in coming years. ODFs can personalize therapy by specifically tailor-made therapy according to individual patient’s needs. This patient-centric approach improves the patient compliance that would be highly beneficial in early treatment and management of erectile dysfunction (ED). Sildenafil citrate ODF with its distinctive efficacy and safety profile provides greater patient convenience of use without the need for water and through its rapid onset of action and enhanced bioavailability. This innovative drug formulation of sildenafil may help in recognition of its benefits in both prescribers and patients and effectively reduce the morbidity and mortality associated with ED and its comorbidities. In addition to the effective use of sildenafil citrate, various new advancements are emerging in the treatment of ED. These include but not limited to gene therapy, stem cell therapy, platelet-rich plasma, shock-wave therapy, amongst others. These developments aim to provide more effective and safer treatment alternatives for ED, potentially transforming its management in the near future.

Funding Statement

The stress test study was funded by Viatris Inc. EAJ was partially supported by the Italian Ministry of University and Research PRIN [grant # P2022SE38P_004]<<Exploring the role of medicines in the induction as well as the management of sexual dysfunction through analysis of Big Data and “Smart data”>>.

Article highlights

• Erectile dysfunction (ED) is a potential biomarker of cardiovascular and peripheral vascular disease. Early identification and management of ED can effectively treat the initial symptoms and arrest the worsening of the disease and its comorbidities.

• Sildenafil citrate, a selective phosphodiesterase-5 inhibitor, is a first-line agent, approved and marketed by European union and USFDA. Its safety and efficacy profile is very well established and it has been used in effective management of ED, regardless of associated comorbidities.

• Orodispersible dosage forms are one of the novel drug delivery systems that are designed and developed to improve efficacy, safety, patient compatibility, and acceptance.

• Sildenafil ODF offers ease of administration, accurate dosage, rapid bioavailability, and ease of carrying in pockets that has improved medication compliance compared to other formulations.

• Studies have demonstrated bioequivalence and supports the interchangeability of new sildenafil ODF formulation with the marketed FCT formulation.

• The results of stress test unveiled reliable performance of sildenafil ODF with acceptable physical and chemical stability exemplifying the possibility to safely store the drug in the pocket.

• The development of orodispersible formulation for sildenafil offers convenience and better addresses the needs and expectations of patients with ED.

Author contributions

CRediT: Conceptualization: EAJ, TH, and SV; data curation: EAJ, TH, and SV; formal analysis: EAJ, TH, and SV; funding acquisition: EAJ; investigation: EAJ, TH, and SV; methodology: EAJ, TH, and SV; project administration: EAJ, TH, and SV; resources: EAJ, TH, and SV; software: EAJ, TH, and SV; supervision: EAJ, TH, and SV; validation: EAJ, TH, and SV; visualization: EAJ, TH, and SV; writing – original draft: EAJ, TH, and SV; writing – review and editing: EAJ, TH, and SV

Data availability statement

The original contributions presented in the study are included in the article, and further inquiries can be directed to the corresponding author.

Disclosure statement

EAJ is a Professor of endocrinology and sexual medicine, University of Rome Tor Vergata, Rome, Italy. He is a paid speaker for several pharmaceutical companies like Bayer, Ibsa, Menarini, Otsuyka, Recordati, Pfizer, and Viatris. SV is an employee of Mylan Pharmaceuticals Pvt Ltd., a Viatris Company. TH is an employee of Viatris Inc. and holds stocks. The authors have indicated that they have no other conflicts of interest regarding the content of this article.

Supplemental data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/20415990.2024.2445501