Data Insights
The study results demonstrated the bioequivalence and supported the interchangeability of new sildenafil citrate ODF formulation with the marketed FCT formulation [Citation76]. 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 [Citation8]. 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 [Citation8,Citation77,Citation78]. 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 [Citation76]. 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.
Vasodilator; Phosphodiesterase Type 5 Inhibitor compounded for dogs and cats.
This test was conducted in Kyukyu Pharmaceutical Co., Ltd, Toyama Plant, Japan.
- Common side effects include headache, flushing, and dizziness.
- Allergic reactions are rare but require immediate medical attention.
- Effects usually last for 4 to 6 hours.
A thin pale red-colored ODF containing 50 mg sildenafil was formulated to dissolve in the oral cavity.
| Drug Class | Potential Effect | Clinical Note |
|---|---|---|
| Nitrates | Severe hypotension | Absolute contraindication |
| Alpha-blockers | Increased risk of hypotension | Use with caution |
| CYP3A4 inhibitors (e.g., ketoconazole) | Increased sildenafil levels | Dose adjustment needed |
| Other vasodilators | Enhanced vasodilatory effects | Monitor blood pressure |
Three batches of samples were subjected to a stability study at 60°C stress for three weeks.
| Parameter | Value | Description | Notes |
|---|---|---|---|
| Absorption time | 30-60 minutes | Time to reach peak plasma levels | Faster onset compared to tablets |
| Peak plasma concentration | 150-200 ng/mL | Max systemic concentration | Varies per dose and individual |
| Half-life | 4-5 hours | Time to reduce concentration by half | Helps determine dosing intervals |
| Bioavailability | 40-50% | Fraction reaching systemic circulation | Slightly variable across patients |
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.
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| Kamagra | 100mg | 60 + 4 Pills | 201.34€ 191.75€ | |
| Viagra Generic | 100mg | 10 Pills | 28.91€ 27.53€ | |
| Kamagra | 100mg | 180 + 6 Pills | 436.79€ 415.99€ | |
| Viagra Generic | 150mg | 120 + 8 Pills | 177.58€ 169.12€ | |
| Kamagra Soft Tabs | 100mg | 12 Pills | 57.55€ 54.81€ | |
| Kamagra Oral Jelly | 100mg | 220 + 18 Sachets | 662.24€ 630.70€ | |
| Viagra Generic | 200mg | 120 + 8 Pills | 204.80€ 195.05€ | |
| Viagra Generic | 100mg | 120 + 6 Pills | 149.50€ 142.38€ | |
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| Viagra Generic | 50mg | 90 + 6 Pills | 107.37€ 102.26€ |
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.
7. Drug Interactions
These results, shown in , 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. ED is defined as the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance [Citation76,Citation79–81]. 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 [Citation82,Citation83], 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.
Ethics declarations
The study results demonstrated the bioequivalence and supported the interchangeability of new sildenafil citrate ODF formulation with the marketed FCT formulation [Citation76]. 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 [Citation8]. 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 [Citation8,Citation77,Citation78]. 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.
2.2 Recommended Dosage in Pediatric Patients
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 [Citation76]. 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.
2.1 Recommended Dosage in Adults
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. 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 [Citation84–87]. The primary risk factors include diabetes mellitus, hypertension, and hyperlipidemia and modifiable risk factors like obesity, physical inactivity, alcoholism, and cigarette smoking [Citation88–90]. 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 sildenafil oral jelly 100 mg disease, with a heightened risk of cardiovascular mortality as largely demonstrated by epidemiological studies [Citation91]. Indeed, ED can be considered a symptom for underlying NCD that may be explained as the classical canary in the coalmine [Citation92]. 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 [Citation8]. The PDE5-Is inhibit the PDE5 enzyme concentrated in the smooth muscle cells in the blood vessels [Citation93]. 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 [Citation94].
- The solution is usually flavored for better taste.
- Dosing involves measuring with a provided syringe or dropper.
- It offers rapid absorption into the bloodstream.
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 [Citation93,Citation95]. 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 [Citation82,Citation96–98]. 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 [Citation99].
Revatio dosage forms
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 , 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. ED is defined as the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance [Citation76,Citation79–81]. ED still prevails as an unprecedented diagnosis and undertreated condition that contributes to increased physical and psychosocial burden.
Clinical monitoring
It negatively impacts the wellbeing, relationships, and health-related quality of life (HR-QoL) of patients and their partners [Citation82,Citation83], 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 [Citation84–87]. The primary risk factors include diabetes mellitus, hypertension, and hyperlipidemia and modifiable risk factors like obesity, physical inactivity, alcoholism, and cigarette smoking [Citation88–90].
Cite this article
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 sildenafil oral jelly 100 mg disease, with a heightened risk of cardiovascular mortality as largely demonstrated by epidemiological studies [Citation91]. Indeed, ED can be considered a symptom for underlying NCD that may be explained as the classical canary in the coalmine [Citation92]. 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. This established efficacy of sildenafil in ED is irrespective of confounding factors including age, baseline severity, or etiology of ED [Citation100].
8. Future perspective
The sildenafil ODT and ODFs are made available through implementation of innovative manufacturing technologies [Citation8,Citation102]. It is also offered as chewable tablets and an orally soluble orodispersible film formulation [Citation82]. 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 [Citation103]. examined and reported the bioequivalence of sildenafil citrate ODF and FCT with and without water in 2 randomized crossover studies [Citation75].
5.2. Stress test
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).
Aqueous Solubility and Dissolution Profile of Prepared Sildenafil-Loaded Formulations
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 [Citation104]. 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. 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 [Citation101]. 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 [Citation8,Citation102]. It is also offered as chewable tablets and an orally soluble orodispersible film formulation [Citation82].
Article highlights
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 [Citation8]. The PDE5-Is inhibit the PDE5 enzyme concentrated in the smooth muscle cells in the blood vessels [Citation93]. 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 [Citation94]. Inhibiting PDE5 produces a dilatation of the penile arteries that leads to a more prolonged and stable erection.
5.1. Bioequivalence and stability testing
Futhermore, PDE5-Is improve endothelial function and decrease apoptosis of smooth muscle cells in the corpus cavernosum [Citation93,Citation95]. 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 [Citation82,Citation96–98]. 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 [Citation99].
Less common
This established efficacy of sildenafil in ED is irrespective of confounding factors including age, baseline severity, or etiology of ED [Citation100]. 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 [Citation101]. Sildenafil is supplied in both solid film-coated tablet (FCT) and orodispersible tablet formulations. 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 [Citation103]. examined and reported the bioequivalence of sildenafil citrate ODF and FCT with and without water in 2 randomized crossover studies [Citation75]. 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 [Citation104]. 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.