Bioequivalence study of a new sildenafil 100 mg orodispersible film compared to the conventional film-coated 100 mg tablet administered to healthy male volunteers

Mean body weight was 75.91 kg (range 56.2–99.6 kg).

Shipping Information

The mean ± standard deviation (SD) of plasma sildenafil pharmacokinetic parameters and the results of their statistical comparisons for the pharmacokinetic set (n=53) are summarized in Table 3. Figure 2 shows the sildenafil pharmacokinetic profiles of the two investigational medicinal products up to 24 h after sildenafil 100 mg test and reference treatments.

The mean plasma concentration–time profiles up to 24 h of sildenafil 100 mg orodispersible film and the film-coated tablet were nearly superimposable. The mean ± SD of plasma N-desmethyl-sildenafil pharmacokinetic parameters and the results of their statistical comparisons for the pharmacokinetic set (n=53) are summarized in Table 4. The mean plasma concentration–time profiles of N-desmethyl-sildenafil were nearly superimposable (Figure 3). The bioequivalence test was fully satisfied for sildenafil and N-desmethyl-sildenafil in terms of rate and extent of bioavailability (Cmax, AUC0–t, and AUC0–f). Specifically, 90% CIs of the test/reference ratio of geometric means were fully comprised within the bioequivalence acceptance range 80%–125% (Table 3, sildenafil; Table 4, N-desmethyl-sildenafil). The majority of subjects (28/53; 52.8%) judged the palatability of the sildenafil 100 mg orodispersible film to be good/acceptable. Sildenafil administered as a single dose of test or reference product was well tolerated. With the exception of a transient aspartate aminotransferase increase, possibly related to the reference product, in one subject, no unexpected TEAEs were observed. Overall, 37 TEAEs were reported by 22 (41.5%) subjects: 20 TEAEs were experienced by 14 (26.4%) subjects with the test product and 17 TEAEs were experienced by 13 (24.5%) subjects with the reference product (Table 5). All reported TEAEs were deemed related to the treatment by the investigator. The most common sildenafil 100mg hexal TEAE was headache, which was observed in 7 (13.2%) subjects with test and 9 (17.0%) subjects with reference. No subjects withdrew from the study as a consequence of a TEAE.

Packaging & Storage Information

Mean body weight was 75.91 kg (range 56.2–99.6 kg). The mean ± standard deviation (SD) of plasma sildenafil pharmacokinetic parameters and the results of their statistical comparisons for the pharmacokinetic set (n=53) are summarized in Table 3. Figure 2 shows the sildenafil pharmacokinetic profiles of the two investigational medicinal products up to 24 h after sildenafil 100 mg test and reference treatments. The mean plasma concentration–time profiles up to 24 h of sildenafil 100 mg orodispersible film and the film-coated tablet were nearly superimposable. The mean ± SD of plasma N-desmethyl-sildenafil pharmacokinetic parameters and the results of their statistical comparisons for the pharmacokinetic set (n=53) are summarized in Table 4.

Faster Effect

The mean plasma concentration–time profiles of N-desmethyl-sildenafil were nearly superimposable (Figure 3). The bioequivalence test was fully satisfied for sildenafil and N-desmethyl-sildenafil in terms of rate and extent of bioavailability (Cmax, AUC0–t, and AUC0–f). Specifically, 90% CIs of the test/reference ratio of geometric means were fully comprised within the bioequivalence acceptance range 80%–125% (Table 3, sildenafil; Table 4, N-desmethyl-sildenafil). The majority of subjects (28/53; 52.8%) judged the palatability of the sildenafil 100 mg orodispersible film to be good/acceptable. Sildenafil administered as a single dose of test or reference product was well tolerated.

4.2. Manufacturing of ODFs

With the exception of a transient aspartate aminotransferase increase, possibly related to the reference product, in one subject, no unexpected TEAEs were observed. Overall, 37 TEAEs were reported by 22 (41.5%) subjects: 20 TEAEs were experienced by 14 (26.4%) subjects with the test product and 17 TEAEs were experienced by 13 (24.5%) subjects with the reference product (Table 5). All reported TEAEs were deemed related to the treatment by the investigator. The most common sildenafil 100mg hexal TEAE was headache, which was observed in 7 (13.2%) subjects with test and 9 (17.0%) subjects with reference. No subjects withdrew from the study as a consequence of a TEAE. One subject discontinued the study due to pretreatment AEs. No serious AEs or other significant AEs occurred in the study. Apart from the single transient increase in aspartate aminotransferase levels, no significant effects of treatment on blood pressure, heart rate, body weight, electrocardiogram, or other laboratory parameters were observed. Over recent years, various innovative drug delivery systems, including films, gels, chewing gums, and drug-loaded micro- and nanoparticles, have been developed as alternatives to conventional dosage forms with the aim of improving patient convenience and acceptability and enhancing compliance. Orodispersible films (variously termed as quick dissolving film, thin strips, oral films, orally dissolving film, etc) disintegrate in patients’ mouth without the need for water and consist of a thin oral strip comprising a hydrophilic, film-forming polymer, and the active pharmaceutical ingredient. The film is hydrated by saliva when placed on the tongue or oral cavity, and disintegrates rapidly to release the medication for local (oromucosal) and systemic (gastrointestinal) absorption. Ideally, film-forming hydrophilic polymers for use in orodispersible films should be nonirritant, nontoxic, and tasteless; quickly disintegrate, possess sufficient peel, shear, and tensile strength; and inexpensive and stable.14 The hydrophilic polymers are combined with other excipients to improve the physical properties (eg, plasticizers), to incorporate active pharmaceutical substances (eg, surfactants) and to improve palatability.

The films are formulated using various methods, including solvent casting, hot-melt extrusion, semisolid casting, solid dispersion extrusion, and rolling; solvent casting and spraying methods are most commonly used.14,16 The pharmaceutical development of the IBSA 100 mg orodispersible film was based on the use of maltodextrins as the film-forming agent, glycerin as a plasticizer, and water as a solvent. Polyvinyl acetate was introduced to improve the mechanical properties and tensile strength of the films. The sildenafil IBSA 100 mg orodispersible film was prepared by the solvent casting method, consisting of spreading and drying of a viscous mixture composed of active principle and excipients in a suitable solvent. The mixture, homogeneous and without bubble and clumps, is spread on a liner and dried, allowing the production of a film with a homogeneous and smooth surface and a thickness of ~220 μm. The resulting film is then cut into pieces of required size.

• Sildenafil oral strips provide a non-invasive way to treat ED.
• They avoid swallowing pills, which some patients find difficult.
• Strips are often manufactured with pleasant flavors to enhance appeal.
• The medication’s effect can be influenced by food intake.
• Alcohol consumption may reduce effectiveness or increase side effects.
• Sildenafil strips should be used as prescribed and not mixed with other ED drugs.
• These strips are designed for quick absorption in the oral mucosa.
• Overuse or misuse can lead to adverse health effects.
• Proper dosing helps minimize risks of prolonged erections or priapism.
• Sildenafil strips do not cure ED but help manage symptoms.
• They may be used in combination with psychological or lifestyle interventions.
• Always check expiration dates before using sildenafil strips.

The novelty of the IBSA orodispersible film is described in the patent WO 2014/049548. Unlike many of the films that have been considered to be state-of-the-art, the sildenafil IBSA orodispersible film does not use pullulan, an ingredient that is expensive and difficult to source, as the film-forming component. Formulations based on other film-forming polymers are available, but with some limitations in terms of physical properties or dissolution behavior.

6. Discussion

Maltodextrins, defined as non-sweet, nutritive saccharide mixtures with a dextrose equivalent (DE) of <20,20 are obtained from the partial hydrolysis of starch with suitable acids and/or enzymes and are a suitable ingredient for manufacturing orodispersible films. They can differ in average molecular size, with the DE value (ie, the proportion of reducing sugars relative to dextrose expressed as a percentage on a dry basis) commonly used in classification. However, maltodextrins usually require the addition of a hydrocolloid at concentrations >10% to reduce dissolution time. However, hydrocolloids tend to become a gel when they are in contact with saliva; thus, they give the sensation of poor dissolution in the mouth. On the contrary, oral films based on maltodextrins without hydrocolloids tend to have poor physical properties, with hardening during storage.

8.7 Hepatic Impairment

The current IBSA formulation avoids hardening of the films based on maltodextrin and plasticizer by incorporating a homopolymer of vinyl acetate into the composition and is thus able to replace pullulan while maintaining its benefits, conferring advantages in terms of solubility and film formation to the sildenafil orodispersible film product. Manufacturing an orodispersible film with the tensile properties required for packaging and handling procedures is a critical issue in the development of orodispersible films. The flexibility and strength of the film could affect cutting, film formation, and packaging during the manufacturing process. To facilitate handling, the oral film should be flexible while exhibiting a tensile strength that guarantees a suitable stiffness. Elongation at break should be low to avoid deformation of films during the manufacturing process.

What to do in case of an overdose of these strips?

During the development of the IBSA orodispersible film, tensile properties were evaluated, and tensile strength, elongation at break, and tensile energy to break were calculated to determine the appropriate tensile properties. The study described in this paper was conducted to compare the pharmacokinetic and blue sildenafil safety profiles of the new sildenafil 100 mg orodispersible film formulation in healthy male volunteers. In the study, the 90% CIs for sildenafil Cmax, AUC0–t, and AUC0–f were within the range of 80%–125% used for the assessment of bioequivalence according to the current European guidance on the investigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev. Therefore, the sildenafil 100 mg orodispersible film (test) and the 100 mg film-coated tablet (reference) were found to be bioequivalent with respect to sildenafil rate and extent of absorption. Bioequivalence was also shown in terms of rate and extent of bioavailability of the sildenafil metabolite, N-desmethyl-sildenafil. Maltodextrins, defined as non-sweet, nutritive saccharide mixtures with a dextrose equivalent (DE) of <20,20 are obtained from the partial hydrolysis of starch with suitable acids and/or enzymes and are a suitable ingredient for manufacturing orodispersible films.

10. Overdosage

The time to reach peak drug concentration of sildenafil and N-desmethyl-sildenafil did not differ significantly between the two investigational products. Safety data confirmed a favorable safety profile of the test and reference investigational products, administered as a single oral dose of 100 mg sildenafil. AEs occurred at similar rates between the two formulations and all AEs were of mild or moderate severity. There were no serious AEs and no subjects withdrew because of treatment-related AEs. Patient satisfaction with erectile dysfunction treatments is a complex and personal issue, and there is no clearly established and robust evidence base to demonstrate a preference between different PDE5 inhibitors.3,21–24 The needs and expectations of patients vary widely, and involving the patient and, if possible, his sexual partner in the decision-making process by providing relevant information about the therapy options, including expected benefits and possible adverse effects or complications, is important in deciding on the most appropriate approach for treating erectile dysfunction.1 Patient satisfaction is determined not only in terms of erectile response and side effects, but also in how well the treatment meets patient needs and expectations and the dynamics of the relationship.

Product Image

Therefore, follow-up evaluation to review the success of the intervention, identify any side effects, discuss patient satisfaction with treatment, and revisit their expectations are essential to ensure optimal long-term treatment strategy. The availability of alternative oral dosage forms that offer advantages over conventional tablet formulations broadens the prescribing options of physicians. The IBSA sildenafil orodispersible film was developed to provide a safe, efficacious, and stable orodispersible film formulation that was pharmaceutically equivalent to the conventional marketed branded film-coated tablets. As noted, orodispersible films have the advantages of conventional tablets (precise dosage and ease of administration) and those of liquid dosage forms (ease of swallowing and rapid bioavailability). The IBSA formulation offers a convenient, discrete method of intake with a rapid onset of action and the added patient convenience and acceptability of a dosage form that does not require administration with water, of particular benefit for men who have difficulty with swallowing conventional film tablet dosage forms or in whom daily fluid intake is restricted, as the orodispersible film does not require administration with water.

7.4 Ritonavir and other CYP3A4 inhibitors

They can differ in average molecular size, with the DE value (ie, the proportion of reducing sugars relative to dextrose expressed as a percentage on a dry basis) commonly used in classification. However, maltodextrins usually require the addition of a hydrocolloid at concentrations >10% to reduce dissolution time. However, hydrocolloids tend to become a gel when they are in contact with saliva; thus, they give the sensation of poor dissolution in the mouth. On the contrary, oral films based on maltodextrins without hydrocolloids tend to have poor physical properties, with hardening during storage. The current IBSA formulation avoids hardening of the films based on maltodextrin and plasticizer by incorporating a homopolymer of vinyl acetate into the composition and is thus able to replace pullulan while maintaining its benefits, conferring advantages in terms of solubility and film formation to the sildenafil orodispersible film product.

• Sildenafil strips are an alternative to traditional pill forms.
• The strips dissolve quickly, eliminating need for water to swallow.
• They are convenient for on-the-go use and discreet consumption.
• Possible side effects include headache, flushing, and dizziness.
• Sildenafil strips should be used approximately one hour before activity.
• Not suitable for individuals with certain health conditions; consult a doctor.
• They are typically used in men aged 18 and above.
• The medication works by increasing blood flow to the penis.
• Sildenafil strips can be part of a broader erectile dysfunction treatment plan.
• Side effects may vary depending on individual health status.
• Erectile response may improve with proper use and dosing.
• They are available through licensed pharmacies and online sources.

Manufacturing an orodispersible film with the tensile properties required for packaging and handling procedures is a critical issue in the development of orodispersible films.

Frequently Asked Works

One subject discontinued the study due to pretreatment AEs. No serious AEs or other significant AEs occurred in the study. Apart from the single transient increase in aspartate aminotransferase levels, no significant effects of treatment on blood pressure, heart rate, body weight, electrocardiogram, or other laboratory parameters were observed. Over recent years, various innovative drug delivery systems, including films, gels, chewing gums, and drug-loaded micro- and nanoparticles, have been developed as alternatives to conventional dosage forms with the aim of improving patient convenience and acceptability and enhancing compliance. Orodispersible films (variously termed as quick dissolving film, thin strips, oral films, orally dissolving film, etc) disintegrate in patients’ mouth without the need for water and consist of a thin oral strip comprising a hydrophilic, film-forming polymer, and the active pharmaceutical ingredient.

Why Strips?

The film is hydrated by saliva when placed on the tongue or oral cavity, and disintegrates rapidly to release the medication for local (oromucosal) and systemic (gastrointestinal) absorption. Ideally, film-forming hydrophilic polymers for use in orodispersible films should be nonirritant, nontoxic, and tasteless; quickly disintegrate, possess sufficient peel, shear, and tensile strength; and inexpensive and stable.14 The hydrophilic polymers are combined with other excipients to improve the physical properties (eg, plasticizers), to incorporate active pharmaceutical substances (eg, surfactants) and to improve palatability. The films are formulated using various methods, including solvent casting, hot-melt extrusion, semisolid casting, solid dispersion extrusion, and rolling; solvent casting and spraying methods are most commonly used.14,16 The pharmaceutical development of the IBSA 100 mg orodispersible film was based on the use of maltodextrins as the film-forming agent, glycerin as a plasticizer, and water as a solvent. Polyvinyl acetate was introduced to improve the mechanical properties and tensile strength of the films. The sildenafil IBSA 100 mg orodispersible film was prepared by the solvent casting method, consisting of spreading and drying of a viscous mixture composed of active principle and excipients in a suitable solvent.

8.2 Lactation

The mixture, homogeneous and without bubble and clumps, is spread on a liner and dried, allowing the production of a film with a homogeneous and smooth surface and a thickness of ~220 μm. The resulting film is then cut into pieces of required size. The novelty of the IBSA orodispersible film is described in the patent WO 2014/049548. Unlike many of the films that have been considered to be state-of-the-art, the sildenafil IBSA orodispersible film does not use pullulan, an ingredient that is expensive and difficult to source, as the film-forming component. Formulations based on other film-forming polymers are available, but with some limitations in terms of physical properties or dissolution behavior. The flexibility and strength of the film could affect cutting, film formation, and packaging during the manufacturing process. To facilitate handling, the oral film should be flexible while exhibiting a tensile strength that guarantees a suitable stiffness. Elongation at break should be low to avoid deformation of films during the manufacturing process. During the development of the IBSA orodispersible film, tensile properties were evaluated, and tensile strength, elongation at break, and tensile energy to break were calculated to determine the appropriate tensile properties. The study described in this paper was conducted to compare the pharmacokinetic and blue sildenafil safety profiles of the new sildenafil 100 mg orodispersible film formulation in healthy male volunteers. In the study, the 90% CIs for sildenafil Cmax, AUC0–t, and AUC0–f were within the range of 80%–125% used for the assessment of bioequivalence according to the current European guidance on the investigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev. Therefore, the sildenafil 100 mg orodispersible film (test) and the 100 mg film-coated tablet (reference) were found to be bioequivalent with respect to sildenafil rate and extent of absorption.

• Sildenafil oral strips are a fast-acting form of erectile dysfunction medication.
• They are administered orally, dissolving quickly on the tongue for rapid effect.
• Sildenafil strips are often flavored to improve the user experience.
• They contain the same active ingredient as traditional sildenafil tablets.
• These strips are designed for people seeking discreet medication options.
• Onset of action for sildenafil strips can be within 15-30 minutes.
• Proper storage of sildenafil strips involves keeping them in a cool, dry place.
• Dosage strength varies, typically available in 25mg, 50mg, and 100mg.
• Using sildenafil strips without medical consultation is not recommended.
• They may interact with other medications like nitrates or alpha-blockers.
• Sildenafil oral strips are approved for the treatment of erectile dysfunction.
• Users should follow prescribed dosages for safety and effectiveness.

Bioequivalence was also shown in terms of rate and extent of bioavailability of the sildenafil metabolite, N-desmethyl-sildenafil. The time to reach peak drug concentration of sildenafil and N-desmethyl-sildenafil did not differ significantly between the two investigational products. Safety data confirmed a favorable safety profile of the test and reference investigational products, administered as a single oral dose of 100 mg sildenafil. AEs occurred at similar rates between the two formulations and all AEs were of mild or moderate severity. There were no serious AEs and no subjects withdrew because of treatment-related AEs. Patient satisfaction with erectile dysfunction treatments is a complex and personal issue, and there is no clearly established and robust evidence base to demonstrate a preference between different PDE5 inhibitors.3,21–24 The needs and expectations of patients vary widely, and involving the patient and, if possible, his sexual partner in the decision-making process by providing relevant information about the therapy options, including expected benefits and possible adverse effects or complications, is important in deciding on the most appropriate approach for treating erectile dysfunction.1 Patient satisfaction is determined not only in terms of erectile response and side effects, but also in how well the treatment meets patient needs and expectations and the dynamics of the relationship. Therefore, follow-up evaluation to review the success of the intervention, identify any side effects, discuss patient satisfaction with treatment, and revisit their expectations are essential to ensure optimal long-term treatment strategy. The availability of alternative oral dosage forms that offer advantages over conventional tablet formulations broadens the prescribing options of physicians. The IBSA sildenafil orodispersible film was developed to provide a safe, efficacious, and stable orodispersible film formulation that was pharmaceutically equivalent to the conventional marketed branded film-coated tablets.

As noted, orodispersible films have the advantages of conventional tablets (precise dosage and ease of administration) and those of liquid dosage forms (ease of swallowing and rapid bioavailability). The IBSA formulation offers a convenient, discrete method of intake with a rapid onset of action and the added patient convenience and acceptability of a dosage form that does not require administration with water, of particular benefit for men who have difficulty with swallowing conventional film tablet dosage forms or in whom daily fluid intake is restricted, as the orodispersible film does not require administration with water.