Sildenafil Oral Solution for Pulmonary Hypertension

The specific peak disappeared in the amorphous microspheres and solid SNEDDS.

17. Patient Counseling Information

The plasma concentration–time profiles of sildenafil are shown in Figure 8. Compared with drug powder, three formulations including amorphous microspheres, crystalline microspheres and solid SNEDDS produced significantly increased plasma concentrations at 0.08, 0.25, 0.5, 1.0 and 1.5 h (p < 0.05). Amorphous microspheres and solid SNEDDS generated significantly increased plasma concentrations compared to the crystalline microspheres at 0.08, 0.25, 0.5 and 1.0 h (p < 0.05). In addition, solid SNEDDS produced relatively higher plasma concentrations than amorphous microspheres up to 2 h. The conforming pharmacokinetic parameters in rats are exhibited Table 2.

Drugs you should not use with sildenafil

All the prepared formulations showed significantly enhanced AUC values when compared to the drug powder (p < 0.05). The values were ranked in the following order: solid SNEDDS (1508.78 ± 343.95 h⋅ng/mL) ≥ amorphous microspheres (1339.90 ± 416.52 h⋅ng/mL) ≥ crystalline microspheres (1042.90 ± 119.90 h⋅ng/mL) > drug powder (733.57 ± 184.15 h⋅ng/mL). In addition, amorphous microspheres and solid SNEDDS produced significantly improved Cmax values compared with crystalline microspheres and the drug powder (p < 0.05); the performance order was as follows: solid SNEDDS ≥ amorphous microspheres > crystalline microspheres > drug powder. Among the formulations, solid SNEDDS produced the highest increase in oral bioavailability, according to the AUC and Cmax values. However, there was no major difference in other pharmacokinetic parameters, such as Tmax, t1/2 and Kel, among the drug powder and formulations. In contrast to the amorphous microspheres, a small endothermic peak was observed in crystalline microspheres, corresponding to the melting point of sildenafil. The results of X-ray diffraction are depicted in Figure 5B. Several representative peaks are shown over a range of diffraction angles in sildenafil, indicating crystalline characteristics. Both physical mixtures exhibited similar peak patterns, similar to that of the drug powder.

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Conserving the designated peak pattern indicated that the drug presented good compatibility with the ingredients. The unique pattern was not observed in amorphous microspheres or solid SNEDDS. However, a peak pattern was detected for the crystalline microspheres, analogous to the sildenafil powder. Based on the thermal analysis and solid-state characterisation, the crystal form of sildenafil changed to an amorphous form in amorphous microspheres and solid SNEDDS, while it was preserved in the crystalline microspheres.

Side Effect	Frequency	Severity	Notes
Headache	Common	Mild	Usually resolves with continued use
Flushing	Common	Mild	Dilation of blood vessels
Dyspepsia	Less common	Mild	Indigestion or stomach discomfort
Nasal congestion	Less common	Mild	Due to vasodilation
Visual disturbances	Rare	Moderate	Blurred vision or color perception changes

As the drug was completely dissolved in ethanol or liquid SNEDDS, the physicochemical characteristics were altered in the amorphous microspheres and solid SNEDDS. Nevertheless, sildenafil was not dissolved but was suspended in distilled water for preserving the crystalline characteristics in the crystalline microspheres. Aqueous solubility results are presented in Figure 6. All three formulations showed significantly increased solubility compared to the drug powder (p < 0.05). Compared to the drug powder, amorphous microspheres, crystalline microspheres and solid SNEDDS enhanced sildenafil solubility by 79, 55 and 82 times, respectively. Additionally, amorphous microspheres and solid SNEDDS demonstrated highly improved solubility compared with crystalline microspheres (p < 0.05). Solid SNEDDS showed the highest aqueous solubility among the formulations, although there were no significant differences between solid SNEDDS and amorphous microspheres.

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The dissolution profile reflected the trend in aqueous solubility results (Figure 7). All of the manufactured drug delivery systems produced an enhanced dissolution rate (%) compared to the drug powder at every sampling time (p < 0.05). Solid SNEDDS presented superior dissolution rate (%) to other formulations. Both solid SNEDDS and amorphous microspheres gave a significantly improved dissolution rate (%) at 45 min, compared with crystalline microspheres (drug powder; 8.4 ± 1.3%, amorphous microspheres; 74.3 ± 0.9%, crystalline microspheres; 45.9 ± 1.3%, solid SNEDDS; 76.6 ± 6.0%) (p < 0.05). Those results can be explained by the fact that three different aqueous microenvironments in each formulation resulted increased solubility and dissolution. In crystalline microspheres, the creation of hydrophilic microenvironment on the surface of a hydrophobic drug was a crucial factor for enhancing the aqueous solubility. When the water contacted with the surface of the formulation, PVP and sildenafil citrate 120 mg Labrasol rapidly leached out, forming aqueous microenvironment on the drug surface. In this microenvironment, which was not observed in a simple blend of drug and hydrophilic excipients, the drug was instantaneously super-saturated, and the solubility highly increased. In amorphous microspheres, particle size reduced and crystal form changed to amorphous form.

5. Evaluation tests for ODF

These mechanisms enhanced the aqueous solubility of sildenafil in amorphous microspheres. In solid SNEDDS, crystalline form of the drug changed to amorphous form and particle size was considerably reduced. Those results are consistent with the amorphous microspheres. On the other hand, different property was observed in solid SNEDDS, compared to amorphous microspheres. When solid SNEDDS contacted water, o/w nanoemulsions were spontaneously formed.44 In this system, the drug was encapsulated in the oil phase surrounded by hydrophilic surfactants, resulting the hydrophobic drug super-saturated in water.

Why it’s used

Moreover, “nano-scale” nanoemulsions might possess larger surface area than “micro-scale” microspheres, facilitating the hydration of the drug. For those reasons, solid SNEDDS could exhibit relatively higher aqueous solubility and dissolution rate (%) than amorphous microspheres. Overall, sildenafil dissolved better in water when it was converted to its amorphous form than when it remained crystalline. In the amorphous state sildenafil 100g of the drug, it is reasonable to assume that the solid SNEDDS is more appropriate system than amorphous microspheres in increasing aqueous solubility, though there was no significant difference between the two systems. When the three sildenafil-loaded systems were stored under room temperature (25 ± 1 °C) for 6 months, significant differences were not observed in terms of content (> 97%), solubility and dissolution profile (data not shown). The reduced particle size resulted increased surface area of amorphous microspheres in contact with water. Consequently, the increased surface area promoted the drug to immediately hydrate in water, preventing aggregation and leading improved aqueous solubility. In addition, it is well reported that amorphous state possesses higher free energy than crystal state. This excess free energy in amorphous microspheres provided an energy advantage when the drug dissolved in water. Furthermore, the polymer (PVP) in amorphous microspheres prevented the drug from recrystallizing and the surfactant (Labrasol) lowered the surface tension between water and the drug, producing drug-loaded polymer-based micelles. These mechanisms enhanced the aqueous solubility of sildenafil in amorphous microspheres. In solid SNEDDS, crystalline form of the drug changed to amorphous form and particle size was considerably reduced. Those results are consistent with the amorphous microspheres. On the other hand, different property was observed in solid SNEDDS, compared to amorphous microspheres. When solid SNEDDS contacted water, o/w nanoemulsions were spontaneously formed.44 In this system, the drug was encapsulated in the oil phase surrounded by hydrophilic surfactants, resulting the hydrophobic drug super-saturated in water.

Related/similar drugs

The specific peak disappeared in the amorphous microspheres and solid SNEDDS. In contrast to the amorphous microspheres, a small endothermic peak was observed in crystalline microspheres, corresponding to the melting point of sildenafil. The results of X-ray diffraction are depicted in Figure 5B. Several representative peaks are shown over a range of diffraction angles in sildenafil, indicating crystalline characteristics. Both physical mixtures exhibited similar peak patterns, similar to that of the drug powder.

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Conserving the designated peak pattern indicated that the drug presented good compatibility with the ingredients. The unique pattern was not observed in amorphous microspheres or solid SNEDDS. However, a peak pattern was detected for the crystalline microspheres, analogous to the sildenafil powder. Based on the thermal analysis and solid-state characterisation, the crystal form of sildenafil changed to an amorphous form in amorphous microspheres and solid SNEDDS, while it was preserved in the crystalline microspheres. As the drug was completely dissolved in ethanol or liquid SNEDDS, the physicochemical characteristics were altered in the amorphous microspheres and solid SNEDDS. Moreover, “nano-scale” nanoemulsions might possess larger surface area than “micro-scale” microspheres, facilitating the hydration of the drug.

• The solution is usually flavored for better taste.
• Dosing involves measuring with a provided syringe or dropper.
• It offers rapid absorption into the bloodstream.

For those reasons, solid SNEDDS could exhibit relatively higher aqueous solubility and dissolution rate (%) than amorphous microspheres. Overall, sildenafil dissolved better in water when it was converted to its amorphous form than when it remained crystalline. In the amorphous state sildenafil 100g of the drug, it is reasonable to assume that the solid SNEDDS is more appropriate system than amorphous microspheres in increasing aqueous solubility, though there was no significant difference between the two systems. When the three sildenafil-loaded systems were stored under room temperature (25 ± 1 °C) for 6 months, significant differences were not observed in terms of content (> 97%), solubility and dissolution profile (data not shown). The plasma concentration–time profiles of sildenafil are shown in Figure 8. Compared with drug powder, three formulations including amorphous microspheres, crystalline microspheres and solid SNEDDS produced significantly increased plasma concentrations at 0.08, 0.25, 0.5, 1.0 and 1.5 h (p < 0.05). Amorphous microspheres and solid SNEDDS generated significantly increased plasma concentrations compared to the crystalline microspheres at 0.08, 0.25, 0.5 and 1.0 h (p < 0.05).

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Nevertheless, sildenafil was not dissolved but was suspended in distilled water for preserving the crystalline characteristics in the crystalline microspheres. Aqueous solubility results are presented in Figure 6. All three formulations showed significantly increased solubility compared to the drug powder (p < 0.05). Compared to the drug powder, amorphous microspheres, crystalline microspheres and solid SNEDDS enhanced sildenafil solubility by 79, 55 and 82 times, respectively. Additionally, amorphous microspheres and solid SNEDDS demonstrated highly improved solubility compared with crystalline microspheres (p < 0.05).

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Solid SNEDDS showed the highest aqueous solubility among the formulations, although there were no significant differences between solid SNEDDS and amorphous microspheres. The dissolution profile reflected the trend in aqueous solubility results (Figure 7). All of the manufactured drug delivery systems produced an enhanced dissolution rate (%) compared to the drug powder at every sampling time (p < 0.05). Solid SNEDDS presented superior dissolution rate (%) to other formulations. Both solid SNEDDS and amorphous microspheres gave a significantly improved dissolution rate (%) at 45 min, compared with crystalline microspheres (drug powder; 8.4 ± 1.3%, amorphous microspheres; 74.3 ± 0.9%, crystalline microspheres; 45.9 ± 1.3%, solid SNEDDS; 76.6 ± 6.0%) (p < 0.05). In addition, solid SNEDDS produced relatively higher plasma concentrations than amorphous microspheres up to 2 h. The conforming pharmacokinetic parameters in rats are exhibited Table 2. All the prepared formulations showed significantly enhanced AUC values when compared to the drug powder (p < 0.05). The values were ranked in the following order: solid SNEDDS (1508.78 ± 343.95 h⋅ng/mL) ≥ amorphous microspheres (1339.90 ± 416.52 h⋅ng/mL) ≥ crystalline microspheres (1042.90 ± 119.90 h⋅ng/mL) > drug powder (733.57 ± 184.15 h⋅ng/mL).

Condition	Approved Dose	Typical Usage	Notes
Erectile Dysfunction	20 mg-100 mg	Administer 30-60 min before activity	Dose depends on severity
Pulmonary Arterial Hypertension	5 mg-20 mg	Usually 3 times daily	Under medical supervision
Raynaud's Phenomenon	Off-label	20 mg before episodes	Not officially approved

In addition, amorphous microspheres and solid SNEDDS produced significantly improved Cmax values compared with crystalline microspheres and the drug powder (p < 0.05); the performance order was as follows: solid SNEDDS ≥ amorphous microspheres > crystalline microspheres > drug powder.

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The trend in the pharmacokinetics was consistent with the solubility and dissolution profiles. It can be inferred that the oral bioavailability of sildenafil was superior when the drug was in an amorphous form than when exposed to the hydrophilic microenvironment while retaining its crystalline form in the gastrointestinal tract. Comparing the two amorphous-form-inducing systems, solid SNEDDS had a relatively higher AUC and Cmax values than amorphous microspheres, even if they were not significantly different. The results indicated that relatively higher aqueous solubility and dissolution rate (%) of solid SNEDDS resulted in relatively higher oral bioavailability than amorphous microspheres. Furthermore, it is assumed that the oil phase in solid SNEDDS played as a permeation enhancer in the gastrointestinal tract, leading to slightly improved drug absorption.

12.2 Pharmacodynamics

The effects of three different aqueous microenvironments on the sildenafil 100mg blue pill oral bioavailability of sildenafil were evaluated in this study. Amorphous microspheres, crystalline microspheres and solid SNEDDS considerably improved the solubility, dissolution rate (%) and oral bioavailability of sildenafil compared to the drug powder. The superiority of the drug delivery systems was in the following order: solid SNEDDS ≥ amorphous microspheres > crystalline microspheres. Solid SNEDDS exhibited relatively higher aqueous solubility, dissolution rate (%) and oral bioavailability than amorphous microspheres, although there were no significant differences between the two systems. As a result, the solid SNEDDS, which converts the crystalline form of the drug to its amorphous form via an o/w nanoemulsion, could be recommended for enhancing the oral bioavailability of sildenafil in this research. Among the formulations, solid SNEDDS produced the highest increase in oral bioavailability, according to the AUC and Cmax values. However, there was no major difference in other pharmacokinetic parameters, such as Tmax, t1/2 and Kel, among the drug powder and formulations. The trend in the pharmacokinetics was consistent with the solubility and dissolution profiles. It can be inferred that the oral bioavailability of sildenafil was superior when the drug was in an amorphous form than when exposed to the hydrophilic microenvironment while retaining its crystalline form in the gastrointestinal tract.

Aspect	Oral Solution	Tablets
Onset of action	Faster due to quicker absorption	Slightly slower
Ease of dose adjustment	Easy to modify dose in small increments	Fixed doses
Swallowing difficulties	Easier for children and elderly	Requires swallowing whole
Taste masking	Usually palatable with flavors	No taste masking needed
Storage and stability	Sensitive to temperature and light	Generally more stable

Comparing the two amorphous-form-inducing systems, solid SNEDDS had a relatively higher AUC and Cmax values than amorphous microspheres, even if they were not significantly different. The results indicated that relatively higher aqueous solubility and dissolution rate (%) of solid SNEDDS resulted in relatively higher oral bioavailability than amorphous microspheres. Furthermore, it is assumed that the oil phase in solid SNEDDS played as a permeation enhancer in the gastrointestinal tract, leading to slightly improved drug absorption. The effects of three different aqueous microenvironments on the sildenafil 100mg blue pill oral bioavailability of sildenafil were evaluated in this study. Amorphous microspheres, crystalline microspheres and solid SNEDDS considerably improved the solubility, dissolution rate (%) and oral bioavailability of sildenafil compared to the drug powder. The superiority of the drug delivery systems was in the following order: solid SNEDDS ≥ amorphous microspheres > crystalline microspheres. Solid SNEDDS exhibited relatively higher aqueous solubility, dissolution rate (%) and oral bioavailability than amorphous microspheres, although there were no significant differences between the two systems. As a result, the solid SNEDDS, which converts the crystalline form of the drug to its amorphous form via an o/w nanoemulsion, could be recommended for enhancing the oral bioavailability of sildenafil in this research. In addition, further experiments should be performed, including dissolution-equivalent study on various pHs, stability study and pharmacokinetic investigation in larger animal models, prior to carry out clinical research. This work was supported by the National Research Foundation of South Korea (NRF) grant funded by the South Korea government (MEST) (No. The authors would like to gratefully acknowledge the Bio-Medical Engineering Core Facility Center at Dankook University for providing critical reagents and equipment.

13. Nonclinical Toxicology

In addition, further experiments should be performed, including dissolution-equivalent study on various pHs, stability study and pharmacokinetic investigation in larger animal models, prior to carry out clinical research. This work was supported by the National Research Foundation of South Korea (NRF) grant funded by the South Korea government (MEST) (No. The authors would like to gratefully acknowledge the Bio-Medical Engineering Core Facility Center at Dankook University for providing critical reagents and equipment. Sung Giu Jin reports grants from the National Research Foundation of South Korea, outside the submitted work. The authors report no other potential conflicts of interest for this work.

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Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Efficacy and safety of Sildenafil treatment in pulmonary hypertension caused by chronic obstructive pulmonary disease: a meta-analysis. Physicochemical characterization of sildenafil-loaded solid lipid nanoparticle dispersions (SLN) for pulmonary application. Electrospun gelatin nanocontainers for enhanced biopharmaceutical performance of piroxicam: in vivo and in vitro investigations. Sung Giu Jin reports grants from the National Research Foundation of South Korea, outside the submitted work. The authors report no other potential conflicts of interest for this work. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Efficacy and safety of Sildenafil treatment in pulmonary hypertension caused by chronic obstructive pulmonary disease: a meta-analysis. Physicochemical characterization of sildenafil-loaded solid lipid nanoparticle dispersions (SLN) for pulmonary application. Electrospun gelatin nanocontainers for enhanced biopharmaceutical performance of piroxicam: in vivo and in vitro investigations.

2. Search strategy

Those results can be explained by the fact that three different aqueous microenvironments in each formulation resulted increased solubility and dissolution. In crystalline microspheres, the creation of hydrophilic microenvironment on the surface of a hydrophobic drug was a crucial factor for enhancing the aqueous solubility. When the water contacted with the surface of the formulation, PVP and sildenafil citrate 120 mg Labrasol rapidly leached out, forming aqueous microenvironment on the drug surface. In this microenvironment, which was not observed in a simple blend of drug and hydrophilic excipients, the drug was instantaneously super-saturated, and the solubility highly increased. In amorphous microspheres, particle size reduced and crystal form changed to amorphous form.

4.1. Manufacturing of ODTs

The reduced particle size resulted increased surface area of amorphous microspheres in contact with water. Consequently, the increased surface area promoted the drug to immediately hydrate in water, preventing aggregation and leading improved aqueous solubility. In addition, it is well reported that amorphous state possesses higher free energy than crystal state. This excess free energy in amorphous microspheres provided an energy advantage when the drug dissolved in water. Furthermore, the polymer (PVP) in amorphous microspheres prevented the drug from recrystallizing and the surfactant (Labrasol) lowered the surface tension between water and the drug, producing drug-loaded polymer-based micelles.