Potential Side Effects and Management

As a result, the physicochemical properties of the drug were changed, thereby the oral bioavailability increased.16 In contrast, crystalline systems are generated using distilled water as a solvent. The use of distilled water allows free from the residual organic solvent issue. Furthermore, improved oral bioavailability of the drug was achieved without alteration of physicochemical properties.17,18 Self-nanoemulsifying drug delivery systems (SNEDDS) are composed of oil, surfactant and co-surfactant.19,20 When water penetrates drug-loaded SNEDDS, oil-in-water (o/w) nanoemulsions are naturally created. These nano-sized emulsions have a large surface area in contact with water, which increases the solubility of the drug. Likewise, o/w nanoemulsion is formed in the gastrointestinal (GI) tract, when drug-loaded SNEDDS is mixed with GI fluid. Furthermore, oil exerts permeation enhancement, resulting in increased absorption in the GI tract.21–23 To improve convenience and stability, porous inorganic carriers are usually added and spray dried for producing solid SNEDDS.24 For these reasons, solid SNEDDS has been widely studied for improving oral bioavailability of poorly water-soluble drugs, these days. Recently, amorphous microspheres, crystalline microspheres and solid SNEDDS are three representative drug delivery systems for improving the oral bioavailability of poorly water-soluble drugs. Therefore, in order to increase the aqueous solubility and oral bioavailability of sildenafil the most, those three representative techniques must be compared. Additionally, this is the first study that has compared microspheres and solid SNEDDS in order to improve the oral bioavailability of sildenafil, till date. Spray-dryer was used to fabricate each drug delivery system. Spray-drying was chosen due to its widespread use in pharmaceutical industry and laboratory-scale experiments.25–27 Compared to other techniques, such as supercritical fluid-based approach or microfluidics, spray-dryer has several advantages including continuous mode of operation, reproducibility and low production cost.28–30 Amorphous microspheres, crystalline microspheres and solid SNEDDS were compared according to aqueous solubility, dissolution profile and physicochemical properties. The schematic design of this study is illustrated in Figure 1. Each physicochemical property was expected to induce different solubilising mechanisms and aqueous microenvironments.31 These differences resulted in performance order in aqueous solubility, according to the previous studies.32 Moreover, pharmacokinetic studies in rats were conducted to compare the oral bioavailability of sildenafil among amorphous microspheres, crystalline microspheres, solid SNEDDS and drug powder. Finally, a drug delivery system exhibiting the highest oral bioavailability of sildenafil was selected.

• Sildenafil oral solution is a liquid form of erectile dysfunction medication.
• It allows for easier swallowing compared to pills.
• Typically, it's used when oral tablets are unsuitable.

Sildenafil (base) was supplied by Huons Pharm. Polyvinylpyrrolidone (PVP, K30), Solutol HS15 and Cremophor EL were purchased from BASF (Ludwigshafen, Germany). Dextran, polyvinyl alcohol (PVA), hydroxypropyl methylcellulose 2910 (HPMC), pyrogenic silica (HDK N20 Pharma), hydroxypropyl cellulose low viscosity (HPC-L), carboxymethyl cellulose sodium (Na-CMC), poloxamer 188, PEG 4000 and hydroxypropyl beta-cyclodextrin (HP-β-CD) were kindly offered from Hanmi Pharm. Soybean oil, sorbitan monooleate (Span 80), olive oil, polysorbate (Tween 80) and corn oil were provided by Daejung Chem. Medium-chain triglycerides (Captex 300) were purchased from Abitec (Columbus, OH, USA). Mineral oil and linseed oil were obtained from Samchun Chemical Co.

Materials and Methods

To optimise the ratio of polymer, surfactant and sildenafil, solubility and dissolution tests were performed. After selecting the configuration of amorphous microspheres, the solvent was changed from ethanol to distilled water to manufacture the crystalline microspheres. Then, the resultant suspension was spray dried while continuously stirring using a magnetic bar (500 rpm). The inlet temperature was maintained at 140 °C and the outlet temperature was set at 80–90 °C. The pneumatic nozzle, pump rate, aspirator value and spraying air pressure were consistent with the preparation conditions of the amorphous microspheres.

Cite this article

The composition of liquid SNEDDS was selected on the basis of an aqueous solubility test. Afterwards, numerous ratios of oil, surfactant and co-surfactant were combined to create liquid SNEDDS formulations. The formulations containing various mixtures of oil, surfactant and co-surfactant were plotted in ternary-phase diagram (Figure S1). Furthermore, their dispersion in water was visually evaluated. Additionally, the nanoemulsion droplet size was assessed only for the formulations providing excellent nanoemulsifying ability (achieving the visual standard of the preceding experiment). (Pyeongtaek, South Korea). Gelatin and sesame oil were purchased from Wako Chemicals Co. (Tokyo, Japan). All other chemicals and solvents were of reagent grade; they were used with or without further purification. Male Sprague-Dawley (SD) rats weighing 300 ± 20 g were supplied by Orient Bio (Sungnam, South Korea). All healthy rats were stored in animal cages at 25–27 °C and 55 ± 5% relative humidity during the whole process. The SD rats were fasted for 12 h; however, they were allowed free access to water before drug administration and pharmacokinetic handling. The entire animal care and processes for the animal studies were conducted according to the NIH Policy. Additionally, the protocols of pharmacokinetic studies were accepted by the Institutional Animal Care and Use Committee (IACUC) at Hanyang University. Approximately 100 mg of sildenafil (to reach a supersaturated state) was added to 1 mL of 1% (w/v) hydrophilic polymer aqueous solution (PVP, Na-CMC, gelatin, PVA, HP-β-CD, HPC-L HPMC and dextran), 5% (w/v) surfactant aqueous solution (Tween 80, Span 80, Cremophor EL, Labrafil M2125CS, Solutol HS15, Plurol diisosterarique Capryol 90, Lauroglycol FCC, poloxamer 188, PEG 4000, Transcutol HP and Labrasol), and pure oil (mineral oil, soybean oil, corn oil, olive oil, linseed oil and Captex 300) to perform the solubility test. After 5 min of vortex-mixing, the samples were placed in a shaking water bath (Daihan Scientific, Wonju, South Korea) for 5 days (25 °C and shaking speed of 100 rpm) to generate a supersaturated state. Three days later, the samples were centrifuged (10,000 × g for 15 min) using a 5430R centrifuge (Eppendorf, Hamburg, Germany).

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Next, the supernatant sildenafil products over the counter was filtered (0.45 μm, nylon) and diluted with the mobile phase for analysing sildenafil by utilising a high-performance liquid chromatography (HPLC) system (Agilent 1260 Infinity, Agilent Technologies, Santa Clara, CA, USA).

Brand names

The nanoemulsion droplet size was analysed via a Zetasizer Nano ZS (Malvern Instruments, Worcestershire, UK). Among the formulations, the liquid SNEDDS with the smallest emulsion droplet size was selected. Next, sildenafil was incorporated into the chosen liquid SNEDDS and highly porous inorganic materials with large specific surface areas (500 mg) were added for solidification. The suspension flowed through a pneumatic nozzle of 0.7 mm diameter in a Büchi mini spray dryer (B-290; Flawil, Switzerland) at a flow rate of 5.0 mL/min. The inlet temperature was set at 130 °C and the outlet temperature was maintained at 80 °C.

Are you currently using Sildenafil (Viagra, Revatio)?

The aspirator was set at 90% and the pressure of the spraying air was 4 kg/cm2. During the entire spray-drying process, the suspension was continuously stirred (500 rpm) using a magnetic bar to maintain a stable suspension state. The shape and surface of the samples were examined by employing an S-4800 scanning electron microscope (Hitachi; Tokyo, Japan). Double-sided adhesive tape was utilized to fix the samples. To render the sample electrically conductive, a platinum coating (4 min at 15 mA) was applied by utilising the EmiTeck Sputter Coater (K575 K) at a speed of 6 nm/min under vacuum (0.8 Pa). The HPLC system was arrayed with the Agilent Chem Station software, G1311C 1260 Quat Pump and G1314B 1260 VWD VL detector.

• It is not recommended for use in children or women.
• Overdose symptoms include dizziness, vision changes, and prolonged erections.
• Seek urgent medical help in case of overdose.

The mobile phase, column and gradient methods used were consistent with those used in previous studies.20 According to the aqueous solubility tests, suitable polymer and surfactant were chosen. Sildenafil-loaded amorphous microspheres were manufactured by mixing numerous ratios of polymer, surfactant and sildenafil in ethanol. The experimental plan of formulations is shown in Table S1. The resultant clear solution was introduced into a Büchi mini spray dryer and continuously pushed to the pneumatic nozzle (0.7 mm diameter) by employing a peristaltic pump at a flow rate of 5.4 mL/min.

Supplemental data

As a result, the physicochemical properties of the drug were changed, thereby the oral bioavailability increased.16 In contrast, crystalline systems are generated using distilled water as a solvent. The use of distilled water allows free from the residual organic solvent issue. Furthermore, improved oral bioavailability of the drug was achieved without alteration of physicochemical properties.17,18 Self-nanoemulsifying drug delivery systems (SNEDDS) are composed of oil, surfactant and co-surfactant.19,20 When water penetrates drug-loaded SNEDDS, oil-in-water (o/w) nanoemulsions are naturally created. These nano-sized emulsions have a large surface area in contact with water, which increases the solubility of the drug. Likewise, o/w nanoemulsion is formed in the gastrointestinal (GI) tract, when drug-loaded SNEDDS is mixed with GI fluid.

Sildenafil Oral Suspension Dosage and Administration

Furthermore, oil exerts permeation enhancement, resulting in increased absorption in the GI tract.21–23 To improve convenience and stability, porous inorganic carriers are usually added and spray dried for producing solid SNEDDS.24 For these reasons, solid SNEDDS has been widely studied for improving oral bioavailability of poorly water-soluble drugs, these days. Recently, amorphous microspheres, crystalline microspheres and solid SNEDDS are three representative drug delivery systems for improving the oral bioavailability of poorly water-soluble drugs. Therefore, in order to increase the aqueous solubility and oral bioavailability of sildenafil the most, those three representative techniques must be compared. Additionally, this is the first study that has compared microspheres and solid SNEDDS in order to improve the oral bioavailability of sildenafil, till date. Spray-dryer was used to fabricate each drug delivery system. The inlet temperature was set at 90 °C and the outlet temperature was maintained at 60–70 °C. The aspirator was fixed at 100% and the pressure of the spraying air was 4 kg/cm2. To optimise the ratio of polymer, surfactant and sildenafil, solubility and dissolution tests were performed. After selecting the configuration of amorphous microspheres, the solvent was changed from ethanol to distilled water to manufacture the crystalline microspheres. Then, the resultant suspension was spray dried while continuously stirring using a magnetic bar (500 rpm). The inlet temperature was maintained at 140 °C and the outlet temperature was set at 80–90 °C.

13. Nonclinical Toxicology

Spray-drying was chosen due to its widespread use in pharmaceutical industry and laboratory-scale experiments.25–27 Compared to other techniques, such as supercritical fluid-based approach or microfluidics, spray-dryer has several advantages including continuous mode of operation, reproducibility and low production cost.28–30 Amorphous microspheres, crystalline microspheres and solid SNEDDS were compared according to aqueous solubility, dissolution profile and physicochemical properties. The schematic design of this study is illustrated in Figure 1. Each physicochemical property was expected to induce different solubilising mechanisms and aqueous microenvironments.31 These differences resulted in performance order in aqueous solubility, according to the previous studies.32 Moreover, pharmacokinetic studies in rats were conducted to compare the oral bioavailability of sildenafil among amorphous microspheres, crystalline microspheres, solid SNEDDS and drug powder. Finally, a drug delivery system exhibiting the highest oral bioavailability of sildenafil was selected. Sildenafil (base) was supplied by Huons Pharm.

8.7 Patients with Renal Impairment

Polyvinylpyrrolidone (PVP, K30), Solutol HS15 and Cremophor EL were purchased from BASF (Ludwigshafen, Germany). Dextran, polyvinyl alcohol (PVA), hydroxypropyl methylcellulose 2910 (HPMC), pyrogenic silica (HDK N20 Pharma), hydroxypropyl cellulose low viscosity (HPC-L), carboxymethyl cellulose sodium (Na-CMC), poloxamer 188, PEG 4000 and hydroxypropyl beta-cyclodextrin (HP-β-CD) were kindly offered from Hanmi Pharm. Soybean oil, sorbitan monooleate (Span 80), olive oil, polysorbate (Tween 80) and corn oil were provided by Daejung Chem. Medium-chain triglycerides (Captex 300) were purchased from Abitec (Columbus, OH, USA). Mineral oil and linseed oil were obtained from Samchun Chemical Co. The pneumatic nozzle, pump rate, aspirator value and spraying air pressure were consistent with the preparation conditions of the amorphous microspheres.

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

The composition of liquid SNEDDS was selected on the basis of an aqueous solubility test. Afterwards, numerous ratios of oil, surfactant and co-surfactant were combined to create liquid SNEDDS formulations. The formulations containing various mixtures of oil, surfactant and co-surfactant were plotted in ternary-phase diagram (Figure S1). Furthermore, their dispersion in water was visually evaluated. Additionally, the nanoemulsion droplet size was assessed only for the formulations providing excellent nanoemulsifying ability (achieving the visual standard of the preceding experiment). The nanoemulsion droplet size was analysed via a Zetasizer Nano ZS (Malvern Instruments, Worcestershire, UK). Among the formulations, the liquid SNEDDS with the smallest emulsion droplet size was selected. Next, sildenafil was incorporated into the chosen liquid SNEDDS and highly porous inorganic materials with large specific surface areas (500 mg) were added for solidification. The suspension flowed through a pneumatic nozzle of 0.7 mm diameter in a Büchi mini spray dryer (B-290; Flawil, Switzerland) at a flow rate of 5.0 mL/min. The inlet temperature was set at 130 °C and the outlet temperature was maintained at 80 °C. The aspirator was set at 90% and the pressure of the spraying air was 4 kg/cm2.

• Patients should avoid heavy meals before taking sildenafil solution.
• Use caution if combining with other blood pressure medications.
• Regular medical check-ups are advised during treatment.

During the entire spray-drying process, the suspension was continuously stirred (500 rpm) using a magnetic bar to maintain a stable suspension state.

1. Introduction

Particle-size analysis was carried out using Mastersizer 3000 (Malvern, Worcestershire, UK). The instrument was optimised under the following conditions: air pressure, 1 bar; feed rate, 50%; gab, 1. The thermal analysis was conducted via a differential scanning calorimetry (DSC Q200; TA Instruments, New Castle, DE, USA). Each sample (approximately 5 mg) was placed in standard aluminium pans and dry nitrogen was employed as the effluent gas. All samples were scanned at a temperature ramp speed of 10 °C/min and heat flow from 0 to 300 °C.

Other Interactions

X-ray powder scattering measurements were performed by means of an X-ray diffractometer (D/MAX-2500, Rigaku, Japan) at room temperature. An angular increment of 0.02° per second was selected over a range of 2θ angles from 3° to 50°. Dissolution profiles of sildenafil-loaded amorphous microspheres, crystalline microspheres, solid SNEDDS and the drug powder (equivalent to 10 mg of sildenafil) were investigated using Vision Classic 6 (Hanson Research Co.; Los Angeles, CA, USA). USP apparatus II (paddle method) was utilised. The dissolution medium was 900 mL of distilled water and the temperature was maintained at 37 ± 0.5 °C. The shape and surface of the samples were examined by employing an S-4800 scanning electron microscope (Hitachi; Tokyo, Japan). Double-sided adhesive tape was utilized to fix the samples.

Condition	Recommended Range	Notes
Temperature	2°C to 25°C	Keep away from freezing or excessive heat
Light exposure	Store in opaque container	Protect from light
Humidity	Dry environment	Avoid moisture to prevent degradation
Shelf life	24 months	Check expiry date before use

To render the sample electrically conductive, a platinum coating (4 min at 15 mA) was applied by utilising the EmiTeck Sputter Coater (K575 K) at a speed of 6 nm/min under vacuum (0.8 Pa). Particle-size analysis was carried out using Mastersizer 3000 (Malvern, Worcestershire, UK). The instrument was optimised under the following conditions: air pressure, 1 bar; feed rate, 50%; gab, 1. The thermal analysis was conducted via a differential scanning calorimetry (DSC Q200; TA Instruments, New Castle, DE, USA).

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

Each sample (approximately 5 mg) was placed in standard aluminium pans and dry nitrogen was employed as the effluent gas. All samples were scanned at a temperature ramp speed of 10 °C/min and heat flow from 0 to 300 °C.

Frequently asked questions

(Pyeongtaek, South Korea). Gelatin and sesame oil were purchased from Wako Chemicals Co. (Tokyo, Japan). All other chemicals and solvents were of reagent grade; they were used with or without further purification. Male Sprague-Dawley (SD) rats weighing 300 ± 20 g were supplied by Orient Bio (Sungnam, South Korea).

Corresponding author

All healthy rats were stored in animal cages at 25–27 °C and 55 ± 5% relative humidity during the whole process. The SD rats were fasted for 12 h; however, they were allowed free access to water before drug administration and pharmacokinetic handling. The entire animal care and processes for the animal studies were conducted according to the NIH Policy. Additionally, the protocols of pharmacokinetic studies were accepted by the Institutional Animal Care and Use Committee (IACUC) at Hanyang University. Approximately 100 mg of sildenafil (to reach a supersaturated state) was added to 1 mL of 1% (w/v) hydrophilic polymer aqueous solution (PVP, Na-CMC, gelatin, PVA, HP-β-CD, HPC-L HPMC and dextran), 5% (w/v) surfactant aqueous solution (Tween 80, Span 80, Cremophor EL, Labrafil M2125CS, Solutol HS15, Plurol diisosterarique Capryol 90, Lauroglycol FCC, poloxamer 188, PEG 4000, Transcutol HP and Labrasol), and pure oil (mineral oil, soybean oil, corn oil, olive oil, linseed oil and Captex 300) to perform the solubility test. X-ray powder scattering measurements were performed by means of an X-ray diffractometer (D/MAX-2500, Rigaku, Japan) at room temperature. An angular increment of 0.02° per second was selected over a range of 2θ angles from 3° to 50°. Dissolution profiles of sildenafil-loaded amorphous microspheres, crystalline microspheres, solid SNEDDS and the drug powder (equivalent to 10 mg of sildenafil) were investigated using Vision Classic 6 (Hanson Research Co.; Los Angeles, CA, USA). USP apparatus II (paddle method) was utilised.

Key takeawaysAI

After 5 min of vortex-mixing, the samples were placed in a shaking water bath (Daihan Scientific, Wonju, South Korea) for 5 days (25 °C and shaking speed of 100 rpm) to generate a supersaturated state. Three days later, the samples were centrifuged (10,000 × g for 15 min) using a 5430R centrifuge (Eppendorf, Hamburg, Germany). Next, the supernatant sildenafil products over the counter was filtered (0.45 μm, nylon) and diluted with the mobile phase for analysing sildenafil by utilising a high-performance liquid chromatography (HPLC) system (Agilent 1260 Infinity, Agilent Technologies, Santa Clara, CA, USA). The HPLC system was arrayed with the Agilent Chem Station software, G1311C 1260 Quat Pump and G1314B 1260 VWD VL detector. The mobile phase, column and gradient methods used were consistent with those used in previous studies.20 According to the aqueous solubility tests, suitable polymer and surfactant were chosen.

6.1 Clinical Trials Experience

Sildenafil-loaded amorphous microspheres were manufactured by mixing numerous ratios of polymer, surfactant and sildenafil in ethanol. The experimental plan of formulations is shown in Table S1. The resultant clear solution was introduced into a Büchi mini spray dryer and continuously pushed to the pneumatic nozzle (0.7 mm diameter) by employing a peristaltic pump at a flow rate of 5.4 mL/min. The inlet temperature was set at 90 °C and the outlet temperature was maintained at 60–70 °C. The aspirator was fixed at 100% and the pressure of the spraying air was 4 kg/cm2. The dissolution medium was 900 mL of distilled water and the temperature was maintained at 37 ± 0.5 °C.