Over the past decade, there has been significant interest in the clinical management of male sexual dysfunction resulting from advances in the pharmacological treatment of erectile dysfunction (ED), coupled with the finding that ED is a very common problem.1 For example, the Men's Attitudes to Life Events and Sexuality (MALES) Study found a prevalence of self-reported ED of 22% among men in the United States.1 Since its approval in 1998, sildenafil citrate (Viagra; Pfizer Inc, New York, NY) has shown clinical benefit for the treatment of ED and is known to exert its pharmacological effect by selectively inhibiting the cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) enzyme.2 However, for some patients, swallowing the tablets may prove difficult. For example, patients undergoing chemotherapy and radiation therapy may experience dysphagia or xerostomia (dry mouth), making swallowing tablets difficult.3,4 Furthermore, the need to use water as an aid in the administration of conventional solid dosage forms has the potential to interrupt the sexual encounter, thereby reducing spontaneity and decreasing the quality of the experience.
Therefore, an easy-to-take oral formulation that dissolves rapidly in the mouth can be taken without water and can be discreetly dosed before the sexual encounter would provide advantages over currently available oral ED treatments. Advances in drug delivery systems such as the PharmFilm technology (MonoSol Rx, LLC, Warren, NJ) have resulted in the development of an oral soluble film (OSF) formulation that provides a water-soluble polymer matrix for drug delivery. When applied to the tongue, the OSF dissolves rapidly and releases the drug into the saliva.
A randomized single-dose study was conducted in healthy, nonsmoking male volunteers under fasting conditions to assess the bioequivalency of 2 sildenafil OSF 100 mg formulations (MonoSol Rx, LLC) as compared with sildenafil citrate 100 mg tablets. A secondary end point was included to evaluate the relative safety and tolerability of the study drugs.
The clinical study was designed as a pilot, single-dose, randomized, open-label, 3-period, 6-sequence, 3-treatment, single-center, crossover, comparative bioavailability study of 2 formulations of sildenafil OSF 100 mg and sildenafil citrate 100 mg tablets. The pharmacokinetic performance of each product was studied using a crossover design with 18 healthy, nonsmoking (for at least 6 months before first drug administration) male volunteers. Each subject was administered an oral dose of 1 × sildenafil OSF 100 mg, the alternative sildenafil OSF 100 mg, or 1 × sildenafil citrate 100 mg tablet under fasting conditions. The open-label study was conducted at Bio Pharma Services Inc in Toronto, ON, Canada, and it was postulated that blinding of the investigator/clinic staff and subjects was not necessary as the pharmacokinetic profiles of sildenafil would not be affected by previous knowledge of which study treatment was administered.
The study was conducted in accordance with current US Food and Drug Administration guidance documents,5 Good Clinical Practice, as established by the International Conference on Harmonization, the basic principles defined in Division 5 of the Canadian Food and Drug Regulations, the Belmont Report, and the principles enunciated in the World Medical Association Declaration of Helsinki (Fortaleza, Brazil, October 2013). The protocol and informed consent form were reviewed and approved by the Institutional Review Board (Optimum Clinical Research Inc), and all subjects provided written informed consent before participating.
The positive control article used in the study, that is, the reference listed drug, was Viagra (sildenafil citrate) 100 mg tablets and was purchased from a commercial supplier. The 2-film Test Articles each contained 140 mg of sildenafil citrate (equivalent to 100 mg of the active moiety) and were manufactured by MonoSol Rx, LLC (Portage, IN) using a solvent-casting process. Using this method, the film formulations were prepared by adding a known quantity of sildenafil citrate to an aqueous mixture containing the film-forming polymers, plasticizers, sweeteners, flavors, opacifiers, acidulant, colorant, and either 0.09% (wt/wt) carboxymethylcellulose (CMC) (ie, the 0.09% CMC film, treatment A) or 2.98% (wt/wt) CMC (ie, the 3% CMC film, treatment B). The resulting homogenous viscoelastic matrix was coated as a film onto an inert substrate using a reverse roll-coating method. The wet film was then dried to specified water content in a forced-air, horizontal, custom drying oven. After drying, the self-supporting film was removed from the substrate, cut into individual dosage units, and hermetically sealed between 2 layers of polyester/foil laminate. Components of the film formulations are provided in Table 1.
Inclusion criteria included healthy nonsmoking (for at least 6 months before first drug administration) males, ≥18 years of age with a body mass index between ≥18.5 and ≤29.9 kg/m2, systolic blood pressure (BP) between ≥100 and ≤140 mm Hg, diastolic BP between ≥60 and ≤90 mm Hg, heart rate (HR) between ≥50 and ≤100 beats per minute, and determined to be in good health by medical history, physical examination, vital signs, laboratory results, and electrocardiogram. Individuals were required to have clinical laboratory values within the acceptable range, unless values were deemed by the principal investigator/subinvestigator as not clinically significant. Furthermore, individuals needed to fast for >14 hours and able to consume standard meals. Finally, participants had to agree not to have a tattoo or tongue or body piercing until the end of the study and had to agree not to drive or operate heavy machinery if experiencing dizziness, drowsiness, or visual abnormalities after drug administration until full mental alertness and/or normal vision was regained. Exclusion criteria included (1) being unable or unwilling to provide informed consent; (2) known history or presence of any clinically significant hepatic, renal/genitourinary, gastrointestinal, cardiovascular, cerebrovascular, pulmonary, musculoskeletal, neurological, psychiatric, ophthalmologic, otologic, dermatological, or hematological disease or condition, unless determined as not clinically significant by the principal investigator/subinvestigator; (3) presence of any clinically significant illness or presence of any significant physical or organ abnormality within 30 days before first dosing, as determined by the principal investigator/subinvestigator; (4) clinically significant history or presence of any clinically significant gastrointestinal pathology (eg, chronic diarrhea, inflammatory bowel disease), unresolved gastrointestinal symptoms (eg, diarrhea, vomiting), or other conditions known to interfere with the absorption, distribution metabolism, or excretion of the drug experienced within 7 days before first drug administration, as determined by the principal investigator/subinstigator; (5) individuals having undergone any major surgery within 6 months before the start of the study, unless deemed otherwise by the principal investigator/subinvestigator; (6) individuals having tongue piercings and/or mouth jewelry or having had a tattoo or body piercing within 30 days before first drug administration; (7) individuals having a positive test result for any of the following: HIV, hepatitis B surface antigen, hepatitis C, drugs of abuse, breath alcohol test or cotinine; (8) at screening, individuals with orthostatic hypotension defined as ≥20 mm Hg reduction in systolic BP, a ≥10 mm Hg reduction in diastolic BP, and/or the development of significant postural symptoms when going from the supine to standing position; (9) at screening, individuals with a QTc interval >450 milliseconds; (10) individuals with a known history or presence of any of the following: alcohol abuse or dependence within 1 year before first drug administration, drug abuse or dependence, hypersensitivity or idiosyncratic reaction to sildenafil citrate, its excipients, and/or related substances; food allergies and/or presence of any dietary restrictions or severe allergic reactions; (11) individuals with abnormal dietary patterns (for any reason) during the 4 weeks preceding the study, including fasting, high protein diets, etc; (12) individuals who were intolerant to and/or had difficulty with blood sampling through venipuncture; (13) individuals who donated plasma by plasma pheresis within 7 days before first drug administration or who donated 50–499 mL of blood 30 days before first drug administration, or who donated 500 mL of blood 56 days before first drug administration; (14) individuals who had participated in another clinical trial or who received an investigational drug within 30 days before first drug administration; (15) individuals who consumed food or beverages containing caffeine/methylxanthines, poppy seeds, and/or alcohol within 48 hours before dosing, or containing grapefruit and/or pomelo within 10 days before first drug administration; or (16) individuals having difficulty swallowing whole tablets and/or orally disintegrating film. In addition, subjects were ineligible if they had used (1) any prescription medication within 14 days before the first drug administration; (2) any enzyme-modifying drugs, including strong inhibitors of cytochrome P450 (CYP) enzymes and strong inducers of CYP enzymes in the previous 30 days before first drug administration; (3) any over-the-counter medications, including oral multivitamins, herbal and/or dietary supplement, and/or teas within 14 days before first drug administration; or (4) any type of nitrate drug therapy, alpha blockers, other PDE5 inhibitors, or endothelin receptor antagonist within 30 days before first drug administration.
The dosing regimen involved randomization of each subject to 1 of 6 dosing sequences: A-B-C, B-C-A, C-A-B, A-C-B, B-A-C, or C-B-A, where treatments A, B, and C were identified as follows:
- Treatment A—Sildenafil OSF 0.09% CMC 100 mg
- Treatment B—Sildenafil OSF 3% CMC 100 mg
- Treatment C—Reference product, sildenafil citrate 100 mg tablets.
Subjects received a single dose of the test drug on day 1 of each study period. In accordance with Food and Drug Administration regulatory requirements, the 100 mg strength was used for this bioequivalence study because it is the strength of the reference listed drug.6
Subjects were confined to the clinical facility from at least 10 hours before each drug administration until at least 24 hours postdose, for a total of at least 34 hours for each study period. Subjects fasted overnight for at least 10 hours before each drug administration and then for at least 4 hours after each drug administration. Each subject was scheduled to receive a total of 3 treatments by the end of the study. The washout interval between drug administrations was 7 days.
During each treatment period, blood samples for pharmacokinetic analysis were collected predose and at 0.167, 0.333, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12, 18, and 24 hours postdosing. Blood samples were collected into prechilled 3.0 mL K2EDTA Vacutainer tubes by direct venipuncture or by indwelling catheter. Samples were then placed in a refrigerated centrifuge within 60 minutes from the time of collection and centrifuged at 3000 revolutions per minute for 10 minutes under refrigerated (approximately 4°C) conditions. After centrifugation, the plasma was aspirated and aliquoted into 2 prechilled clear polypropylene tubes. A minimum of 1.0 mL plasma was transferred to the first tube, and remaining plasma (if any) was pipetted into the second tube. Pending shipment, the samples were stored at −60°C or colder in a freezer within 70 minutes from the start of centrifugation. Throughout sample collection and after centrifugation, the samples were maintained in an ice bath until stored in the freezer. Plasma samples were shipped to the bioanalytical facility (Covance Bioanalytical Services, LLC, Indianapolis, IN) by overnight courier packed on dry ice.
The sildenafil concentration of each plasma sample was determined using a validated high performance liquid chromatography with mass spectrometric detection (HPLC-MS/MS) analytical method. Specifically, sildenafil and the added internal standards were extracted from each sample by liquid–liquid extraction. After solvent evaporation under nitrogen, the residue was reconstituted and analyzed using liquid chromatography with tandem mass spectrometric detection. At a minimum, each analytical run included a calibration curve, a matrix blank, a control zero (matrix blank containing internal standard), a reagent blank, and duplicate quality control (QC) samples at 3 concentrations within the calibration range. The samples were interspersed with calibration standards and QC samples within the analytical run. Dilution QC samples were also included in analytical runs where samples were diluted before analysis. Study samples were reassayed if values exceeded the curve range or when analytical problems were identified. Samples were also reassayed to determine incurred sample reproducibility and were pooled together to determine incurred sample stability. Based on concentration levels, the maximum plasma concentration (Cmax), time at which Cmax observed (Tmax), area under the plasma concentration–time curve from time 0 to the last measured concentration (AUC0–t), area under the plasma concentration–time curve from time 0 to infinity (AUC0–∞), AUC0–t,/AUC0–∞, time required to reduce the plasma concentration to one-half its initial value (t1/2), and lambda were estimated for sildenafil to characterize the pharmacokinetic profile of each study drug.
Subject safety was assessed by continuous health monitoring and scheduled recording of safety measurements throughout the study. Medical history, physical examination, vital signs, laboratory results, and electrocardiogram were conducted to screen volunteers before study starts. The clinical staff monitored vital signs (BP and HR) at predose (within 12 hours before drug administration) and at 1 and 24 hours after dosing in each study period. Subjects were instructed to inform clinic personnel of any untoward medical symptoms and/or events that arose during the course of the study. Before subsequent periods, subjects were questioned concerning unusual symptoms that may have occurred after the previous administration of the study drugs. The principal investigator/subinvestigator evaluated the relationship of all adverse events (AEs) to the study drugs. Each AE was assessed as mild, moderate, or severe as defined in the protocol. The principal investigator/subinvestigator also approved the subjects for subsequent dosing. At the conclusion of the study, each subject received a physical examination, including vital sign measurements (BP, HR, temperature, and respiration rate) and an evaluation of clinical laboratory tests (hematology, serum chemistry, and urinalysis).
Descriptive statistics (minimum, maximum, median, mean, SD, and coefficient of variability) of all pharmacokinetic parameters were provided for the test and reference products. Analysis of variance, including sequence, subjects nested within sequenced period, and treatment, was performed on the natural log-transformed data for AUC0–t, AUC0–∞, and Cmax, and on the untransformed data for Tmax, lambda, and t1/2. In addition, Tmax was determined using a nonparametric test. The 90% confidence interval (CI) of the test/reference ratios of geometric means for AUC0–t, AUC0–∞, and Cmax were calculated based on the least square means and estimation of the analysis of variance.
A total of 18 subjects were enrolled, and subject disposition is summarized in Figure 1. One subject was dismissed after the second dosing sequence due to noncompliance (prescription medication). All plasma sildenafil concentrations and pharmacokinetic parameters were based on data from all subjects.
The demographics and baseline characteristics of the study population are summarized in Table 2. The mean age was 44 years, and the mean body mass index was 27. About one-half of the study subjects were white, about one-third were black, and the remaining subjects were of other races.
Plasma sildenafil pharmacokinetics
The mean plasma sildenafil concentration versus time profiles of the 2 sildenafil OSF formulations were nearly identical to that of the sildenafil citrate tablets. Each profile exhibited a maximum sildenafil concentration at approximately 1 hour postdose, followed by a decline over the next 23 hours (Figure 2). Plasma sildenafil pharmacokinetic parameters were also similar among all 3 treatment groups (Table 3). The mean AUC0–t values for treatment A—sildenafil OSF 0.09% CMC 100 mg, treatment B—sildenafil OSF 3% CMC 100 mg, and treatment C—reference product, sildenafil citrate 100 mg tablets were 1277.616, 1300.832, and 1313.070 ng·h−1·mL−1, respectively, and the mean sildenafil Cmax values were 452.500, 442.000, and 470.882 ng/mL, respectively. The median Tmax for all 3 treatment groups was 0.75 hours.
The rate and extent of sildenafil absorption parameters (AUC0–t, AUC0–∞, and Cmax) for both OSF formulations of sildenafil and the reference product, sildenafil citrate tablets, were found to be similar (Table 4).
Both OSF formulations of sildenafil were bioequivalent to sildenafil citrate tablets. The 90% CIs of the ratios of treatment A—sildenafil OSF 0.09% CMC 100 mg versus treatment C—reference product, sildenafil citrate 100 mg tablets for the absorption parameters, AUC0–t, AUC0–∞, and Cmax were (88.12, 110.64), (87.89, 110.25), and (84.20, 121.36), respectively, all within the 80%–125% range for bioequivalence. Similarly, the 90% CIs of the ratios of treatment B—sildenafil OSF 3% CMC 100 mg versus treatment C—reference product, sildenafil citrate 100 mg tablets for the absorption parameters, AUC0–t, AUC0–∞, and Cmax were (89.76, 112.70), (89.77, 112.61), and (82.65, 119.13), respectively, also all within the 80%–125% range. Intrasubject variability was calculated to be approximately 19.36% for AUC0–t, approximately 19.27% for AUC0–∞, and approximately 31.55% for Cmax for sildenafil (Table 4).
Both sildenafil OSF formulations and the reference product were well tolerated by all subjects. There were 15 AEs involving 9 subjects in the study, all of mild severity. No serious AEs were reported during the conduct of the study, and no AEs associated with clinical laboratory tests were experienced by any subject after study.
There were 9 AEs associated with 6 subjects who received treatment A—sildenafil OSF 0.09% CMC 100 mg, which consisted of cough (n = 2), nasal congestion (n = 2), catheter site hematoma (n = 1), catheter site pain (n = 1), headache (n = 1), nasopharyngitis (n = 1), and somnolence (n = 1). Of these findings, the relationship to the study drug was considered unrelated (n = 3), unlikely (n = 3), possible (n = 2), and probable (n = 1). One subject experienced 1 instance of cough after drug administration which resolved after pharmacological actions.
There were 4 AEs associated with 3 subjects who received treatment B—sildenafil OSF 3% CMC 100 mg, which consisted of somnolence (n = 1), nasal congestion (n = 1), pyrexia (n = 1), and feeling hot (n = 1). Of these, the relationship to the study drug was considered unrelated (n = 2), unlikely (n = 1), and possible (n = 1). One subject experienced 1 instance of pyrexia after drug administration which resolved after pharmacological action.
There were 2 AEs associated with 2 subjects who received treatment C—reference product, sildenafil citrate 100 mg tablets, which consisted of somnolence (n = 1) and laceration (n = 1). Of these, the relationship to the study drug was considered unrelated (n = 1) and unlikely (n = 1).
This randomized single-dose study evaluated the bioequivalence of sildenafil from 2 formulations of sildenafil OSF 100 mg and sildenafil citrate 100 mg tablets in healthy, nonsmoking male volunteers under fasting conditions. Both OSF formulations and the reference product, sildenafil citrate tablets, demonstrated overall similar plasma sildenafil concentrations postdose. The criterion for bioequivalence of plasma sildenafil exposure was met for all parameters (AUC0–t, AUC0–∞, and Cmax). Both sildenafil OSF formulations and the reference product, sildenafil citrate tablets, were well tolerated by all subjects. All 15 reported AEs were of mild severity, and of these findings, only 3 were considered possibly related to the study drug and only 1 was considered probably related to the study drug.
In conclusion, the pharmacokinetic results of this study demonstrated that a single dose of sildenafil OSF 0.09% CMC 100 mg and sildenafil OSF 3% CMC 100 mg under fasting conditions were bioequivalent to sildenafil citrate 100 mg tablets. The treatments had similar safety profiles and were well tolerated. As an easy-to-take oral formulation that dissolves rapidly in the mouth, can be taken without water, and can be discreetly dosed, sildenafil OSF may provide an attractive alternative to sildenafil citrate oral tablets.
The PharmFilm drug delivery technology was developed by and is the property of MonoSol Rx, LLC, (Warren, NJ). MonoSol Rx, LLC used this proprietary technology to develop and produce the 2 sildenafil OSF formulations.
The clinical comparisons between the 2 formulations of sildenafil OSF and sildenafil citrate tablets were conducted at BioPharma Services Inc (Toronto, ON, Canada) under the supervision of Drs. Fathi Abuzgaya, Ziba Fadavi, Asif Khan, Ola Kassim, and Reza Behjati. The bioanalytical testing was performed at Covance Laboratory Inc (Indianapolis, IN), and the statistical analyses were performed at BioPharma Services Inc (Toronto, ON, Canada). MonoSol Rx, LLC provided funding for the study.
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Keywords:Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
sildenafil; oral soluble film; bioequivalence; erectile dysfunction