NZ625922B2 - Oral spray formulations and methods for administration of sildenafil - Google Patents

Abstract

The present disclosure is directed to chemically-stable and pharmaceutically acceptable sildenafil (1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyloral-1H-pyrazolo[4,3-d] pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine) spray formulations for the treatment of diseases such as pulmonary arterial hypertension and/or SSRI-induced sexual dysfunction, wherein the oral spray formulation has a pH of about 1.5 to less than 2.4. The present disclosure is also directed to methods for treating diseases such as pulmonary arterial hypertension and/or SSRI-induced sexual dysfunction. al hypertension and/or SSRI-induced sexual dysfunction, wherein the oral spray formulation has a pH of about 1.5 to less than 2.4. The present disclosure is also directed to methods for treating diseases such as pulmonary arterial hypertension and/or SSRI-induced sexual dysfunction.

Description

/067763 TITLE OF THE INVENTION ORAL SPRAY ATIONS AND S FOR ADMINISTRATION OF SILDENAFIL REFERENCE TO RELATED APPLICATION This application claims the benefit ofpriority ofUS. Provisional Application Serial Number 61/566,879, filed December 5, 2011. The foregoing application is incorporated herein by reference in its ty.

FIELD OF THE INVENTION This present sure relates to methods and formulations for delivery of sildenafil, and derivatives thereof, to the circulatory system by administration via an oral spray formulation to treat disease, such as pulmonary arterial hypertension and selective serotonin reuptake inhibitor (SSRI) induced sexual dysfunction.

BACKGROUND OF THE INVENTION The US. Food and Drug Administration (FDA) has approved sildenafil citrate s for the treatment of pulmonary al hypertension (WHO Group 1) under the brand name REVATIO®. The recommended dose of REVATIO® is 20 mg three times a day.

Sildenafil citrate was first approved by the FDA for the treatment of male erectile dysfimction under the brand name VIAGRA®.

Sildenafil is reported to be a selective inhibitor of cyclic—GMP—specific phosphodiesterase type 5 (PDES). Its effects in treating pulmonary arterial hypertension (and erectile dysfilnction) occur by enhancing the downstream effects of nitric oxide (NO) mediated vasorelaxation. PDES is found in pulmonary vascular smooth muscle and the corpus osum, as well as in tissues such as vascular and visceral smooth muscle and in platelets. Sildenafil increases cyclic-GMP (cGMP) by ting PDE5. PDES is responsible for degradation of cGMP. As a result, sildenafil increases cGMP within pulmonary vascular smooth muscle cells‘ In patients with pulmonary ension, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilation in the systemic circulation (see, e.g., REVATIO® product literature).

In addition to its therapeutic benefits in es such as pulmonary arterial hypertension (PAH) and erectile dysfunction, sildenafil is reported to be efficacious in the treatment of sexual dysfunctions ated with SSRI administration. See, e.g., Stimmel, GL, PCT/U52012/067763 l dysfunction and psychotropic tions” CNS Spectr. (2006) 11:8(Suppl 9):24-30 and Wang, W-F et al. “Selective serotonin reuptake inhibitors in the treatment of premature ejaculation” Chin Med J (2007) 120(11):1000-1006. Sexual dysfunctions are a main side effect of SSRIs, and include difficulties with libido, arousal, delayed or absent orgasm (e.g., anorgasmia in women), and delayed ation, anejaculation, or erectile dysfunction in men. Ibid. In patients suffering from sexual dysfunction as a result of SSRI treatment, stration of sildenafil as adjunct therapy may improve and sustain arousal, for example, in the patient by increasing blood flow, and afil is thought to exert an indirect beneficial effect on other aspects of sexual response via the same mechanism. See, e.g., Stimmel, GL.

CNS Spectr. (2006) uppl 9):24-30.

Sildenafil has been proposed as a possible therapeutic in the treatment of a number of other conditions as well. These include female sexual dysfunction, including sexual dysfunction associated with menopause, such as lties with sexual arousal. See, e,g., Mattar, CN et al. “Care ofwomen in menopause: sexual function, dysfunction and therapeutic modalities” Ann Acad Med Singapore (2008) 37:215—223. Other conditions for which sildenafil may provide a therapeutic benefit include high-altitude illness (see, e.g.

Luks, AM et al CHEST (2008) 133:744-755), pain, stroke, multiple sclerosis, and irritable bowl syndrome (see, eg, Sharma, R Indian J Med Sci (2007) 61:667-679 and Uthayathas, S et al. Pharmacological Reports (2007) -163).

Despite its effectiveness in treating es such as PAH and erectile dysfunction, the administration of solid oral sildenafil dosage forms may also cause undesirable side effects.

At high dosages, the incidence of such side effects increase, for example, abnormal vision problems ng from blue or green halo effects to blurring), sia, nasal congestion, blinding headaches, flushing, redness, diarrhea, dizziness, rash, and urinary tract infection.

Other more serious side effects may occur in some cases resulting from a physiological predisposition, adverse drug ction or potentiation, or by drug abuse. Such side effects include syncope (loss of consciousness), priapism (erection g 4 hours or more), and increased cardiac risk (coital coronaries). In particular, hypotension crisis may result from the combination of sildenafil citrate and c es, causing death in some cases.

Hence, its administration to patients who are concurrently using organic nitrates (such as nitroglycerin) in any form is contraindicated. Moreover, the long-term effects of large doses of sildenafil-containing drugs are unknown (Handy B., “The Viagra® Craze,” Time, pp. 50- 57 (May 4, 1998)).

PCT/U52012/067763 Many drugs exhibit low bioavailabilities owing to extensive first pass lism.

Differences in bioavailability may have profound clinical significance. Sildenafil citrate, for example, ts only a 40% ilability after oral stration via tablet form, of which the active metabolite accounts for about one-half.

Compared to the administration of solid oral dosage forms absorbed in the gastrointestinal tract, the oral cavity presents the possibility for more rapid and nt drug delivery e of its rich ar supply. The oral cavity exhibits a minimal barrier to drug transport and may result in a rapid rise in serum concentration of drug.

However, the ation of dosage forms for administration to the oral mucosa often poses non-trivial problems. For significant drug absorption to occur across the oral mucosa, the drug must have a prolonged exposure to the mucosal surface and the formulation must be both chemically stable and pharmaceutically acceptable to patients.

WO 01/35926 discloses afll dosage forms for non-oral use, such as nasal delivery. However, there is currently no commercially available dosage form for oral spray delivery of afil.

Thus, there is an ongoing need and desire for discreet and convenient sildenafil dosage forms for the treatment of diseases such as pulmonary arterial hypertension and SSRI- induced sexual dysfunction, which are both chemically stable and pharmaceutically acceptable.

SUMMARY OF THE INVENTION The present disclosure is directed to methods and formulations for treating diseases such as pulmonary arterial hypertension and/or SSRI—induced sexual dysfunction In particular, this disclosure relates to the oral administration of sildenafil or sildenafil citrate.

The disclosure herein is directed to an oral spray formulation for delivery of sildenafil to treat diseases such as pulmonary arterial hypertension and/or SSRl-induced sexual ction. The sildenafil oral spray formulation may be a clear, colorless to light yellow, solution ed to be sprayed directly into the mouth, over or under the tongue.

In one aspect, the oral spray formulation may comprise sildenafil or a pharmaceutically acceptable salt thereof. In another aspect, the oral spray formulation may se sildenafil citrate.

In yet another aspect, the oral spray formulation comprising sildenafil or a pharmaceutically acceptable salt thereofmay have a pH of about 1.5 to less than 3.0. In some PCT/U52012/067763 ments, the pH of the formulation is about 2.2 :: 0.5. In a certain embodiment, the pH of the formulation is about 2.2.

In still another aspect, the oral spray formulation may comprise a polar solvent. The polar solvent may comprise propylene glycol and ethyl alcohol. In certain ments, the ratio of propylene zethyl alcohol is about 62.5:37.5 % V/v.

In one aspect, said polar solvent may comprise one or more pH—adjusting agents. The pH—adjusting agents may be acidifying , alkalizing agents, or a combination thereof. In one aspect, the ying agent may be hydrochloric acid (HCl). In a particular embodiment, the HCl is present in an amount of about 10% v/v of the formulation. In another aspect, the alkalizing agent may be sodium hydroxide (NaOH). In a particular embodiment, the NaOH is present in an amount of about 2.1 % v/v of the formulation.

In one aspect, the oral spray formulation comprising sildenafil or a pharmaceutically acceptable salt thereofmay further comprise a taste-masking agent. In certain embodiments, the taste—masking agent comprises mint. In some ments, the mint is peppermint or int. In other embodiments, the oral spray formulation finther comprises a fruit and/or chocolate flavor. In some embodiments, the oral spray formulation comprises a sweetener. In a n embodiment, the sweetener is sucralose.

In another aspect, the oral spray formulation may further comprise one or more pharmaceutically acceptable excipients, rs, or a combination f.

The disclosure herein is also directed to a method for ng a disease such as PAH or nduced sexual dysfunction, which may comprise administering to a patient in need thereof a sildenafil oral spray ation. In some embodiments, the afil exposure in the patient results in a ln-transformed dose-adjusted to 25 mg geometric mean AUCo_t(ng- hr/mL) of approximately 299.36. In other embodiments, the sildenafil exposure in the patient results in a ln-transformed dose-adjusted to 25 mg geometric mean AUC0_,(ng-hr/mL) of imately 323.16. In yet other embodiments, the sildenafil exposure in the patient results in a ln-transforrned dose-adjusted to 25 mg geometric mean AUC0., (ng-hr/mL) of approximately 304.98. In some embodiments, the sildenafil exposure in the patient results in a 1n-transformed dose-adjusted to 25 mg geometric mean AUCo.int(ng-hr/mL) of approximately 310.60. In other embodiments, the sildenafil exposure in the patient results in a 1n-transformed dose-adjusted to 25 mg geometric mean AUCO.inf (ng-hr/mL) of approximately 331.22. In yet other embodiments, the sildenafil exposure in the patient results in a nsformed dose-adjusted to 25 mg geometric mean AUCO.jn_f (ng-hr/mL) of approximately 31 1.05.

PCT/U52012/067763 In certain ments, the sildenafil is present in an oral spray formulation of the invention in an amount of about 7 to about 9 % W/V of the formulation. In certain embodiments, it is present in an amount of about 8.31 % W/V of the ation. In other embodiments, the sildenafil salt is present in an amount of about 10 to about 12 % w/v of the formulation. In a particular embodiment, the sildenafil salt is present in an amount of about 11.67 % W/v ofthe formulation.

In some embodiments, the amount of sildenafil in an oral spray ation of the ion that is administered per spray is 10 mg. In other embodiments, the amount of sildenafil administered per spray is 20 mg. In yet other embodiments, the amount of sildenafrl administered per spray is 30 mg.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 (Figure 7.2.6—1-1) is a graph depicting non—dose-adjusted mean plasma sildenafrl concentration (0—24 hours) N=24.

Figure 2 e 7.2.6.2-1) is a graph depicting dose-adjusted mean plasma sildenafil concentration (0-24 hours) N=24.

Figure 3 (Figure 7.2.6.3-1) is a graph depicting non—dose-adjusted mean plasma N- desmethylsildenafil concentration (0-24 hours) N=24.

Figure 4 e 7.2.6.4-1) is a graph ing dose-adjusted mean plasma N- desmethylsildenafil concentration (0-24 hours) N=24.

Figure 5 (Figure 7.2.6.6-1) is a graph depicting mean plasma N— hylsildenafil/sildenafrl ratio (0-4 hours) N=24.

DETAILED PTION Sildenafil is designated chemically as 1-[[3-(6,7-dihydromethyloxopropyl- 1H-pyrazolo[4,3-d] pyrimidinyl)ethoxyphenyl] sulfonyl] methylpiperazine.

The oral spray formulation disclosed herein comprises sildenafil or a pharmaceutically acceptable salt thereof. The term “pharrnaceutically acceptable salts” refers to salts ed from pharmaceutically acceptable non-toxic acids including organic and inorganic acids. Such acids e acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethane-sulfonic, fiJrnaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, and p-toluenesulfonic acids.

N-desmethylsildenafil is one known active metabolite of sildenafil.

PCT/U52012/067763 Sildenafll, administered as the commercially available REVATIO® formulation for the ent of pulmonary arterial hypertension (WHO Group I) to improve exercise ability and delay clinical ing, is ed in the gastrointestinal tract after oral stration, with absolute bioavailability of about 40%. Based on the REVATIO® manufacturer’s product literature, maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When the REVATIO® formulation is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in Tmax of 60 minutes and mean reduction in Cmax of 29%. The mean steady state volume of distribution (Vss) for sildenafil is edly 105 L, indicating bution into the tissues.

The oral spray ation disclosed herein is formulated for delivery via the oral cavity. The sildenafil oral spray formulation may be delivered transmucosally, sublingually, via the buccal cavity, Via mucosal membranes and/or through the gastrointestinal tract.

The oral spray formulation of the instant ation is suitable for use in the treatment of one or more diseases for which sildenafil stration is considered efficacious. es of such es include PAH, SSRI—induced sexual dysfunction, and erectile dysfunction. In certain embodiments, a afil oral spray formulation ofthe instant application is suitable for use in the treatment of HIV—associated PAH; hemolysis associated PAH; portopulmonary hypertension; PAH in pediatric patients (e.g., idiopathic PAH, post op congenital heart defect , and Eisenmenger syndrome); pulmonary hypertension associated with heart failure, cardiac surgery, and cardiac transplant; pulmonary thromboembolic disease; pulmonary fibrosis associated pulmonary hypertension; and/or altitude-associated pulmonary hypertension. See, e.g., Barnett, CF et al. Vascular Health and Risk Management (2006) 2(4):411-422. In other embodiments, a sildenafil oral spray ation of the instant application is suitable for use in the treatment of female sexual dysfunction, including sexual ction associated with menopause, such as difficulties with sexual arousal. In yet other embodiments, a sildenafil oral spray formulation of the instant application is suitable for use in the treatment of high-altitude illness, pain, stroke, multiple sclerosis, and/or irritable bowl syndrome.

The oral spray formulation as disclosed may comprise sildenafil base or a pharmaceutically acceptable salt f in an amount of about 6 to about 14% WW, about 7 to about 13% W/v, or about 8 to about 12% W/v of the formulation. In one aspect, the oral spray formulation may comprise sildenafil or a pharmaceutically acceptable salt thereof in an amount of about 8 to about 10% W/v of the formulation.

PCT/U52012/067763 In another aspect, the oral spray formulation as disclosed may se sildenafil base in an amount of about 6 to about 10% W/V, about 7 to about 9% W/v, or about 8% W/v of the formulation. In yet another aspect, the oral spray formulation may comprise sildenafil base in an amount of about 8.31% w/v of the formulation.

In one aspect, the oral spray formulation as disclosed may comprise sildenafil citrate in an amount of about 10 to about 14% W/v, about 11 to about 13% w/v, or about 12% W/v of the formulation. In another , the oral spray formulation may comprise sildenafil citrate in an amount of about 11.67% W/v of the formulation.

The oral spray formulation as disclosed may r sildenafil base or a pharmaceutically acceptable salt thereof in an amount (per spray) of about 3 to about 25 mg, about 6 to about 20 mg, about 8 to about 18 mg, about 10 to about 16 mg, or about 12 to about 14 mg.

In one aspect, the oral spray formulation may deliver sildenafil base in an amount (per spray) of about 6 to about 14 mg, or about 8 to about 12 mg. In another aspect, the oral spray formulation may deliver about 10 mg per spray.

In yet r aspect, the oral spray formulation may r afil citrate in an amount (per spray) of about 10 to about 18 mg, or about 12 to about 16 mg. In still another aspect, the oral spray formulation may deliver about 14 mg per spray.

In one aspect, one to five sprays of the oral spray formulation may be administered to a patient. In another aspect, one to three sprays of the sildenafil formulation are delivered to a patient. In yet another aspect, the spray may deliver about 100 to about 120 pl (about 0.1 to about 0.12 mL) ofthe formulation. In still another aspect, the spray may deliver about 120 pl ofthe formulation. In some embodiments, the spray rs about 200 to about 250 pl of the formulation. In certain embodiments, the spray delivers about 250 pl of the formulation.

The oral spray formulation as disclosed may have a pH of about 1.5 to less than 3.0.

In one , the pH ofthe oral spray formulation may be 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, or 2.9. In another aspect, the pH ofthe oral spray formulation of the may be about 2.2i0.5, or about 2.3i0.5.

Polar solvents of the disclosed oral spray formulation may include, but are not limited to, ethyl alcohol, propylene glycol, glycerol and polyethylene glycols having a nominal molecular weight of 200-600 g/mol, N— methylpyrrolidone, or ations thereof. In one aspect, the polar solvent may se propylene glycol and dehydrated alcohol (e. g., ethyl alcohol). ene glycol and dehydrated alcohol may be comprised within the oral spray formulation at a propylene glycolzalcohol ratio of about 70:30% v/v, about 65:35% v/v, about 60:40% v/v, about 55:45% v/v, or about 50:50% v/v. In another aspect, the propylene glycolzalcohol ratio may be about 62.5:37.5% v/v.

In one aspect, propylene glycol is present in an amount of about 55% v/v and ethyl alcohol is present in an amount of about 33% v/v of the final oral spray formulation.

Formulations as disclosed may comprise one or more pH-adjusting agents. pH- adjusting agents may include acidifying agents or alkalizing agents. Acidifying agents of the present invention may include, but are not limited to, hydrochloric acid, citric acid, lactic acid, glycolic acid, acetic acid, glacial acetic acid, malic acid, and proprionic acid. Alkalizing agents of the present invention may include, but are not limited to, sodium hydroxide, edetol, potassium carbonate, potassium hydroxide, sodium borate, sodium ate, sodium citrate, sodium lactate, and sodium ate. In one aspect, the oral spray formulation may se an acidifying agent, an alkalizing agent, or a combination f. The acidifying agent may be present in the solvent in an amount of about 5 to about 15% v/v of the solvent, or about 10% v/v of the solvent. The alkalizing agent may be present in the solvent in an amount of about 1.5 to about 4% v/v of the solvent, or about 2.1% v/v of the solvent.

The Cmax obtained after administration of the disclosed oral spray formulation may be, but is not limited to, about 50 to about 150% of a reference Cam. In one aspect, the nce Cmax may be the me obtained following administration of sildenafil citrate tablets. In r , the Cmax obtained after administration of the disclosed oral spray formulation may meet bioequivalence standards, as set forth by the FDA, including that the 90% confidence al of the geometric mean ratio of Cmax between the test and reference product fall within 80-125%.

The AUC obtained after stration of the disclosed oral spray formulation may be, but is not limited to, about 50 to about 150% of a reference AUC. In one aspect, the reference AUC may be the AUC obtained following administration of sildenafil citrate tablets. In another aspect, the AUC obtained after administration of the disclosed oral spray formulation may meet bioequivalence standards, as set forth by the FDA, including that the 90% confidence interval of the geometric mean ratio ofAUC between the test and reference product fall within 80-125%.

The me ed after stration of the disclosed oral spray ation may be, but is not limited to, about 50 to about 150% of a reference Tum. In one aspect, the reference me may be the me obtained following administration of sildenafil citrate s. In r aspect, the Tmax obtained after administration of the disclosed oral spray formulation PCT/U52012/067763 may meet ivalence standards, as set forth by the FDA, including that the 90% confidence interval of the geometric mean ratio of Tmax between the test and reference product fall Within EEO-125%. The oral spray formulation as disclosed may further comprise one or more pharmaceutically acceptable excipients, carriers, or a combination thereof.

Excipients may e, but are not limited to, co-solvents and/or lizing agents, penetration enhancers, stabilizing agents, buffering agents, tonicity agents, icrobial agent, and ity-modifying agents.

Co-solvents may include, but are not limited to, ethyl alcohol, propylene , glycerol and polyethylene glycols having a nominal molecular weight of 200—600 g/mol, and N—methyl-Z—pyrrolidone.

Solubilizing agents may include, but are not limited to, purified diethylene glycol monoethyl ether, extrins, glycerol monostearate, lecithin, poloxomer, polyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, stearic acid, citric acid, and ascorbic acid and the like; surface active agents such as polysorbates, sorbiton esters, polyvinyl l, benzal konium chloride, benzithonium chloride, cetrimide, docusate sodium, sodium lauryl sulphate, and nol.

Solubility enhancers may include, but are not limited to, DL— methionine, caffeine, nicotinamide, in, benzyl alcohol, ethanol, and Transcutol (diethylene glycol monoethyl ether). In certain embodiments, a formulation of the invention comprises caffeine as a solubility enhancer. In further embodiments, caffeine is present in the formulation in an amount of about 25 mg/mL. In certain embodiments, a formulation ofthe invention comprises nicotinamide as a solubility enhancer. In firrther embodiments, nicotinamide is present in the ation in an amount of about 5 % w/w.

Buffering agents may include, but are not limited to, hydrochloric acid, sodium acetate, glacial acetic acid, orthophosphoric acid, and potassium dihydrogen orthophosphate.

Stabilizing agents may include, but are not limited to, sodium metabisulphite, sodium bisulphite, disodium EDTA, and ascorbic acid.

Anti-microbial agents may include, but are not d to, benzyl alcohol, benzalkonium chloride, phenyl mercuric acetate, and phenylethyl alcohol.

Viscosity-modifying agents may e, but are not limited to, ypropyl methylcellulose, and poly acrylic acid, or water e polymers such as carbopol, sodium ymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and various grades of polyvinylpyrrolidone (e.g., K-lS, K-30, K-60, and K-90).

PCT/U52012/067763 In certain embodiments, it may be ble to increase the mucosal (e.g., oral mucosal) residence time of sildenafil that is administered to a patient in an oral spray formulation as disclosed herein. ingly, in n embodiments, an oral spray formulation of the instant application may comprise one or more permeation enhancers and/or mucoadhesives. Examples of suitable permeation enhancers include nicotinamide, caffeine, peppermint oil, sodium glycocholate, phospholipids, alkyl rides, aprotinin, benzalkonium chloride, ceramides, cetylpyridinium chloride, chitosan, chitosan—4- thiobutylamidine, cyclodextrins, dextran sulfate, dodecyl azacycloheptyl-Z-ketone, ether lipids (plasmologens), glycerol, ylated sphingosines, lauric acid, ryl ether, lysophosphatidylcholine, menthol, methoxysalicylate, atidyl choline, l-palmitoyl—Z- glutaroyl—sn—glycero—3-phosphocholine, polycarbophil cysteine, poly-L—arginine, polyoxyethylene, polyoxyethylenelauryl ether, polysorbate 80, propylene glycol, EDTA, sodium deoxycholate, sodium glycocholate, sodium glycodeoxycholate, sodium lauryl sulfate, sodium salicylate, sodium taurocholate, sodium taurodeoxycholate, sodium taurodihydrofilsidate, sphingolipids, and sterols. Examples of suitable mucoadhesives include hydroxypropyl cellulose, gelatin, inked rylic acid, polymethacrylic acid, polyhydroxyethyl methacrylic acid, hydroxypropyl methyl cellulose, polyethylene glycol, sodium carboxymethyl cellulose, onic acid, chitosan, polycarbophil, pectin, xanthan gum, alginate, copolymers of dextran, polyacrylamide, acacia, copolymer of caprolactone and ethylene oxide, carbopol 934, tragacanth, and eudragit.

The oral spray formulation as disclosed may comprise taste-masking or flavoring agents. masking or flavoring agents as used herein are agents that may hide or minimize an undesirable flavor such as a bitter or sour flavor. Examples of taste-masking or flavoring agents suitable for use in the formulations of the present invention include, but are not limited to, synthetic or natural mint oil, Spearmint oil, citrus oil, fruit flavors (e.g., citrus, such as orange, lemon, lime; strawberry; cherry; grape; melon; and mixtures thereof), chocolate, spice (e. g., anise, cinnamon), vanilla, bubblegum, and sweeteners (e.g., , aspartame, saccharin, and sucralose). In certain embodiments, the oral spray formulation comprises a sweetener that is sucralose. In certain embodiments, the taste-masking or ng agent is mint. In certain embodiments, the mint is peppermint. In further embodiments, the mint is a strong mint, e.g., peppermint oil NF, In yet other embodiments, a formulation of the invention comprises a taste-masking or flavoring agent that is chocolate mint, PCT/U52012/067763 Taste-masking and/or flavoring agents may be evaluated in a formulation ofthe invention according to the Flavor Profile Method (see Keane, P. The Flavor Profile Method.

In C. Hootrnan (Ed), Manual on ptive Analysis Testing for Sensory Evaluation ASTM Manual Series: MNL 13. ore, MD (1992)), for example, to identify, terize, and/or quantify sensory attributes of products, e.g., basic , aroma, texture, and mouthfeel.

In certain embodiments, a ation ofthe invention comprises a taste—masking and/or flavoring agent that achieves an intensity similar to that of a common breath mint spray. In some embodiments, the buffer strength of the formulation is reduced (e.g., through a reduction in NaOH levels) to achieve a desired balance in formulation taste (e. g., balanced basic tastes).

The oral spray formulation as disclosed may be packaged in amber Type 1 glass Schott bottles configured with 100 or 120 pl snap—on er pumps, or Within any type of pharmaceutically—acceptable package, container, pump, or bottle.

In one aspect, the oral spray formulation as sed consists of sildenafil citrate, propylene glycol, ethyl l, hydrochloric acid, and sodium hydroxide.

In another aspect, the oral spray formulation consists of sildenafil citrate, propylene glycol, ethyl alcohol, hydrochloric acid, sodium hydroxide, and a taste—masking agent.

In yet another aspect, the oral spray formulation consists essentially of sildenafil e, propylene glycol, ethyl alcohol, hydrochloric acid, and sodium hydroxide.

In still another aspect, the oral spray formulation consists essentially of sildenafil e, propylene glycol, ethyl alcohol, hydrochloric acid, sodium hydroxide, and a taste— g agent.

The following non-limiting examples will further describe the disclosed oral spray formulation.

EXAMPLE 1 The commercially available, citrate salt form of sildenafil was selected as the active pharmaceutical ient in the development of an oral spray form.

The final solvent system included a combination of 62.5% v/v propylene glycol to 37.5% v/v alcohol mixture acidified with 0.5 mL dilute HCl and pH adjusted to 2.0 or less using 5N NaOH. This combination was able to solubilize 12 to 14% w/v sildenafil citrate and keep the API in solution.

Table Composition of the formulation vehicle designed to deliver 14 mg citrate salt 2012/067763 (10 mg base equivalent) per 0.12 mL spray Ingredient Concentration Target amounts in 250 Sildenafil citrate 11.67% w/v 29.175 g Propylene glycol/ethanol ~70% WV 175 mL Mixture 62.5%/37.5% v/v or 68.4%/31.6%w/w Diluted HCL (10%v/V) 10% WV 25 mL 5N NaOH 2.1% V/v 5.25 mL Propylene glycol/ethanol Qs 250 mL mixture The sildenafil citrate solution (having a salt concentration of 11.67% w/v (11.67 mg/mL)) may be stered to a patient in a commercially available pump spray designed to deliver 14 mg salt/120 pl of spray (or 10 mg base/120 pl of spray).

The formulation e was stable when stored 250C/60% RH and 40°C/75% RH for six months.

EXAMPLE 2 Subjects are ed sildenafil citrate in an oral spray dosage form as a part of a single—dose study. One subset of subjects is administered one spray of an oral spray sildenafll formulation comprising 14 mg sildenafil citrate per spray (providing a total administered amount equivalent to 10 mg sildenafll base). A second subset of subjects is administered two sprays of an oral spray sildenafil formulation comprising 14 mg afil citrate per spray (providing a total administered amount equivalent to 20 mg sildenafil base). A third subset of subjects is administered three sprays of an oral spray afil formulation sing 14 mg sildenafil e per spray (providing a total administered amount equivalent to 30 mg sildenafil base).

EXAMPLE 3 A relative bioavailability study ofsildenafil oral spray at 10 mg, 20 mg, and 30 mg doses versus 25 mg VIAGRA® tablets underfasting conditions This study assessed the relative bioavailability of sildenafil oral spray compared to that ofVIAGRA® tablets by Pfizer Labs following a single oral dose [1 x 14 mg/0.12 mL sildenafil citrate oral spray (equivalent to 10 mg sildenafil base), 2 x 14 mg/0. 12 mL afil citrate oral sprays (equivalent to 20 mg sildenafil base), 3 x 14 mg/0.12 mL WO 85904 sildenafil citrate oral sprays alent to 30 mg sildenafil base), or 1 X 25 mg tablet] in healthy adult subjects when administered under fasting conditions Secondary objectives were to assess the relative safety of the afil oral spray following single oral dose administration compared to that ofVIAGRA® tablets.

Assessments include evaluation of changes in orthostatic hypotension, oral irritation, vital sign assessments, 12—lead electrocardiogram (ECG), and clinical assessments.

STUDY DESIGN This was an open-label, single-dose, randomized, eriod, four—treatrnent crossover study under fasting conditions. The total number of healthy adult male subjects ed in the study was twenty—four (24). The total duration of the study, screening through study exit, was imately nine weeks with at least a three—day washout period between doses. At study check-in, the subjects reported to the clinical site at least 36 hours prior to Day 1 dosing for Period I and at least 12 hours prior to Day 1 dosing for s II, III, and IV. Subjects were required to stay for at least 24 hours after each treatment period.

Following each washout period, subjects returned to the clinical facility to be dosed with the alternative treatments as per the ization. Blood sample tion was obtained within 90 minutes, but no later than 30 minutes, prior to dosing (0 hour) and after dose administration at 0.083,0.167,0.25,0.33,0.50,0.75,1, 3,4,6,8, 10, 12, 16, and 24 hours. The actual time of sample collection was documented. During each study period, a total of 18 blood samples were collected for a total of 72 samples and 432 mL total volume.

The actual time of sample collection was documented.

Bioanalfiical Sample Analyses The sildenafil and N-desmethylsildenafil plasma concentrations were measured using a validated bioanalytical method and according to the standard operating procedures and FDA Guidelines. The validated detection range for sildenafil is 1 to 300 ng/mL in human plasma. The validated detection range for N-desmethylsildenafil is 0.25 to 75 ng/mL in human plasma.

Pharmacokinetic Data es Pharmacokinetic parameters for plasma sildenafil and N-desmethylsildenafil concentration were calculated using standard noncompartmental approaches as indicated below: AUC0_. The area under the plasma concentration versus time curve, from time 0 to the last measurable concentration, as calculated by the linear trapezoidal method.

PCT/U52012/067763 AUCOM The area under the plasma concentration versus time curve from time 0 to infinity.

AUC0_M is calculated as the sum of the AUC0_. plus the ratio of the last able plasma concentration to the elimination rate constant.

AUCM/AUCMM The ratio of t to AUCOM Cm Maximum measured plasma concentration over the time span specified.

Tmax Time of the m measured plasma concentration. If the maximum value occurs at more than one time point, Tmax is defined as the first time point with this Value.

Kel Apparent first-order terminal elimination rate constant calculated from a semi- log plot of the plasma concentration versus time curve. The parameter will be calculated by linear least-squares regression analysis in the terminal log-linear phase (three or more non-zero plasma concentrations).

TyZ The apparent first-order terminal elimination half-life will be ated as 0.693/Kel.

Ratio The ratio of lite/parent will be ed at each concentration as well for Metabolite/Parent PK parameters Cum, AUCM, and AUCMuf.

No value of Kel, AUCO.jnf, or Ty. will be reported for cases that do not exhibit a terminal log- linear phase in the concentration versus time profile. Other pharmacokinetic parameters may be calculated if deemed necessary.

Statistical Analyses Arithmetic means, standard deviations and coefficients of variation were calculated for the parameters listed above. Additionally, geometric means were calculated for AUCM, AUCo.inf, and Cm.

Analyses of variance (ANOVA) were performed on the ln-transformed pharmacokinetic parameters AUC0_,, AUCO_mf, and cum. The ANOVA model includes sequence, formulation and period as fixed effects and subject nested within sequence as a random effect. Sequence is tested using subject nested within ce as the error term. A % level of significance is used to test the sequence effect. Each analysis of variance includes calculation of squares means, the difference between adjusted formulation means and the standard error ated with this difference. The above statistical analyses were performed using the appropriate SAS® procedure.

In agreement with the two one-sided test for bioequivalence, 90% confidence intervals for the difference between drug formulation least-squares means (LSM) were calculated for the parameters AUCo.., AUCO.mf, and Cmax using ln-transformed data. The nce intervals are sed as a percentage relative to the LSM of the nce formulation.

Ratios of means were calculated using the LSM for ln—transforrned AUC0.¢, nf, and Cm“. The geometric mean values are reported. Ratios of means are expressed as a percentage ofthe LSM for the reference formulation.

PCT/U52012/067763 Bioequivalence is based on the 90% confidence als for sildenafil.

Mouth Preparation Between 1.25 hours (study hour -1.25) and 1 hour (study hour -1) prior to dosing, including Period I Day —1 placebo dose, subjects brushed their teeth and tongue with toothpaste ed by the clinical site. After completing the brushing, subjects immediately rinsed their mouths three times with approximately 80 mL of room temperature water to total 240 mL (8 fluid ounces).

Saliva pH Assessments Saliva pH was measured at 2300 hours (:: 30 minutes) on Day -1, and on Day 1 within 30 minutes prior to teeth and tongue brushing, within 30 minutes of completion of teeth and tongue brushing, and within 15 minutes prior to dosing. For the placebo dose (Day —1 of Period I), the saliva pH was measured at 2300 hours (:: 30 minutes) on Day -2, and on Day —1 within 30 minutes prior to teeth and tongue brushing, within 30 minutes of completion of teeth and tongue brushing, and within 15 minutes prior to placebo dosing. The pH was measured using pH test strips with a range of 5 — 9. Any subject that had a pH of 5 was additionally tested with pH test strips with a range of 0 - 6.

Oral Spray stration Within 30 minutes prior to stration, the spray product bottle was primed by actuating five sprays ing to priming ctions provided by the sponsor prior to study start. A new spray bottle was used for each t for each dose.

At the time of dosing, subjects were instructed to open their mouths and place their relaxed tongues against their bottom rows of teeth. Study staff then administered the appropriate number of sprays according to the randomization schedule.

After dosing, subjects were instructed to close their mouths and place their tongues against their bottom row of teeth for two minutes. Subjects were instructed not to swallow or swish around the product in their mouth during the two minutes. After two minutes, the subjects were instructed to swallow and any deviation from this time was ed. After swallowing was complete, an ive oral irritation assessment (soft tissue irritation within the labial or buccal mucosa and tongue) was performed.

Reference Product Administration A single 25 mg dose of Viagra® s (1 x 25 mg) was administered on Day 1 dosing with approximately 240 mL (8 fluid ounces) of room temperature water. Site personnel ensured the entire dose and fluid were swallowed.

Post-Dose uestionnaire PCT/U52012/067763 Immediately after dosing was completed and at one hour after dosing, subjects were queried on the following regarding the test product: 0 Taste of the product - Willingness to take the product again - Any presence of excessive salivation If oral irritation ted beyond one hour, subjects were queried at all irritation evaluations after one hour with the following: "How does your mouth feel?" STUDY PROCEDURES Study In (Day -2 of Period I) At study check-in, the subjects reported to the clinical site at least 36 hours prior to Day 1 dosing and were required to stay for 24 hours after Day 1 . The subjects were evaluated to assess if they continued to meet the study inclusion/exclusion and restriction criteria. Water was allowed ad libitum during fasting. Supine and standing blood pressure and heart rate, and an electrocardiogram were ted. A urine sample was collected for a drug abuse screen.

Subjects began fasting at least ten hours prior to dosing on Day —1. Throughout the study, standardized meals and beverages were served. Meals were the same in content and quantity during each confinement period. At 2300 hours (:: 30 minutes), saliva pH was measured prior to nighttime teeth brushing Subjects were instructed to go to bed after completing this ment.

On Day -1 of Period I only, ts received three sprays of the placebo test product at 24 hours prior to Period I Day 1 dosing. Dose preparation and administration were identical to the test product procedures.

Study Check-In (Day -1 of Periods II, III, & IV) At study check-in, the subjects reported to the clinical site at least 12 hours prior to Day 1 dosing and were required to stay for 24 hours after Day 1 dosing. The subjects were briefly evaluated to assess if they continued to meet the study inclusion/exclusion and restriction criteria. Water was allowed ad m during fasting. Supine and standing blood re and heart rate, and an electrocardiogram were collected. A urine sample was collected for a drug abuse screen. Subjects began fasting at least ten hours prior to dosing on Day 1. Throughout the study, standardized meals and beverages were served. Meals were the same in t and quantity during each confinement period. At 2300 hours (:: 30 minutes), saliva pH was measured prior to nighttime teeth brushing. ts were instructed to go to bed after completing this assessment.

Stud Da Procedures :1 -1 of Period I Prior to placebo dosing, the following activities were completed: - Measured saliva pH before t brushed their teeth and the tongue - Subjects brushed their teeth and tongue prior to dose administration 0 Measured saliva pH after subject brushed their teeth and tongue 0 Measured saliva pH within 15 minutes prior to dose administration 0 Assessed the oral cavity for baseline oral irritation prior to placebo stration 0 No fluid was allowed from one hour prior to dose administration until one hour after dosing.

At 24 hours prior to Day 1 dosing, each t was dosed sequentially with one dose (three sprays) ofplacebo oral spray during Period I for a total of one dose per subject.

After placebo , the following activities were completed: - Both objective and subjective oral irritation assessments were med immediately after dosing and at one hour after placebo dose stration.

- A fast was maintained until at least four hours after placebo dosing. During the study confinement period, fluid consumption resumed at no sooner than one hour after dose administration When fluids are not restricted, they were allowed ad libitum.

- Subjects were not allowed to brush their teeth and tongue for the first two hours after dosing.

- Lunch was provided at study hour 4.25 after placebo dose administration.

- Dimer was provided at study hour 10.25 after o dose administration.

- An evening snack was provided at 10.5 hours prior to dose administration on Day 1.

- At 2300 hours (2: 30 minutes), saliva pH was measured prior to nighttime teeth and tongue brushing. Subjects were instructed to go to bed after completing this assessment.

- Subjects began fasting at least ten hours prior to dosing on Day 1.

Day 1 Prior to dosing, the ing activities were completed: ' Collected supine and standing blood pressure and heart rate. 0 Measured saliva pH before subject d their teeth and the tongue. 0 Subjects brushed their teeth and tongue prior to dose administration.

PCT/U52012/067763 0 Measured saliva pH after subject brushed their teeth and tongue. - ted a pre—dose 0 hour blood sample for pharmacokinetic analysis. 0 Measured saliva pH within 15 minutes prior to dose administration. - ed the oral cavity for baseline oral irritation.

- No fluid, except that given with nce drug stration, was allowed from one hour prior to dose administration until one hour after dosing.

Each subject was dosed sequentially with one dose (1 x 14 mg/0.12 mL oral spray, 2 X 14 mg/0.12 mL oral spray, 3 x 14 mg/0.12 mL oral spray, or I x 25 mg ) in each of the four dosing periods for a total of four doses per t.

After , the following activities were completed: 0 Both objective and subjective oral irritation assessments were performed immediately after dosing and at one hour after dose administration.

- A fast was maintained until at least four hours after . During the study confinement period, fluid consumption resumed no sooner than one hour after dose administration. When fluids were not restricted, they were allowed ad libitum.

- Subjects were not allowed to brush their teeth and tongue for the first two hours after dosing.

- Subjects were closely supervised and within sight of study personnel for four hours after receiving their initial dose.

. The subjects remained seated upright for the first four hours after dosing, except as otherwise required for study procedures or personal needs. ts were not allowed to lie down (except as directed by Clinical staff secondary to adverse events) for the first four hours after dosing. Subjects did not engage in any strenuous activity while d to the clinic and followed the rules governing their activities as set forth by the clinic.

' Lunch was provided at study hour 4.25.

- Dinner was provided at study hour 10.25 - An evening snack was provided at study hour 14.25.

- Blood sample collections were obtained as per the profile.

- Supine and standing blood pressure and heart rate were measured at approximately one hour after each dose.

' An electrocardiogram was measured at approximately one hour after each dose.

- All subjects were evaluated for the presence of any adverse events.

Day 2 PCT/U52012/067763 0 Blood sample collections were obtained as per the profile.

- Supine and standing blood pressure and heart rate was ed at approximately 24 hours after each dose.

- All subjects were evaluated for the ce of any adverse events prior to release from the study site.

- Prior to release, ts were evaluated to ensure it was safe for them to be released from the study site. 0 Subjects were released from the study site at approximately 24 hours after dose administration.

ORAL IRRITATION ASSESSNIENTS Immediately prior to the first dose (0 hour) of each oral spray treatment, including placebo administration and at time intervals as specified below, each volunteer's oral cavity was assessed for local tion. Local irritation was evaluated relative to the zero hour observation. Whenever possible, the same evaluator performed all of the evaluations for a single subject throughout all study periods. If irritation was found, a specific description defining the location, degree, and extent of irritation was given. Irritation assessment information and time to irritation resolution was recorded in the CRF.

Irritation Assessment le Irritation assessments were collected at the following time : Prior to each oral spray administration, immediately after swallowing (2 minutes), and at 1 hour post administration.

If any irritation persisted beyond the one hour ment, assessments continued every two hours until resolution up to ten hours post-dose. If irritation was still reported at ten hours, the subject was assessed by the Investigator as to whether the t should be discontinued from the study. Any assessments after one hour also included a subjective evaluation question.

Irritation Assessment The examination consisted of a visual inspection/evaluation of the soft tissue for tion of the labial and buccal mucosa and . The time and date of these examinations was recorded. A small flashlight or other similar device was used to facilitate the examinations. The oral mucosa surfaces, right and left, and labial junctions and tongue were examined for irritation and graded according to the ing classification system.

Irritation Assessment Scale Numerical Grade Brythema - Oral Mucosa (Left and Right) and Tongue 0 No ma 1 Very slight erythema (barely perceptible) 2 Slight ma (edges of area well defined by definite raising) 3 Moderate erythema (raised approximately 1.0 mm) 4 Severe erythema (raised more than 1.0 mm extending beyond the area of exposure) STUDY SUBJECTS Disposition of Subjects —eight (28) volunteers checked in for Period I and a total of 24 subjects were enrolled. The study was conducted with 24 (23 ted) healthy adult males.

Subjects checked into the clinical facility on 30 July 2010 for Period 1, on 06 August 2010 for Period 11, on 13 August 2010 for Period III, and on 20 August 2010 for Period IV.

Check-in occurred two days prior to dose administration for Period I and one day prior to dose stration for Periods II, III, and IV. The subjects remained confined at the clinical facility until after the 24-hour blood sample collection of each period.

Table 6.1-1 presents all tinued subjects, the reason(s) for discontinuation, and time points during the study at which each subject was tinued.

Table 6.1-1 Discontinued Subjects 24 Withdrew prior to Period IV check-in due to crsonal reasons schedule conflict nAmerican Indian or Alaskan Native Table 6.1-2 presents the number of subjects who were randomized according to each treatment sequence and the post-randomization discontinuation that occurred over the course of the study.

Table 6.1-3 presents the summary of subject disposition by study period.

WO 85904 PCT/U52012/067763 Table 6.1-2 Summary of Subject ition by Sequence 3m cm_— Sub'em Randomized unnu— Sub'ects Who Successfull Com . leted the Stud nun-l.— —nn--_- mum-“n.- -—i—“-z---_- Treatment A: Sildenafil Citrate Oral Spray 11.55% w/w (1 spray, ent to 10 mg slldenafil); Treatment B: Sildenafil e Oral Spray 11.55% WW (2 , equivalent to 20 mg sildenafil); Treatment C: Sildenafil Citrate Oral Spray 11.55% w/w (3 sprays, equivalent to 30 mg sildenafil); Treatment D: ® tablets 25 mg Table 6.1-3 Summary of Subject Disposition by Study Period —----I II III IV --'2- mun-unm- ——-—u-_-_n-_ _—--_““_ PHARMACOKINETIC EVALUATIONS Data Sets Analyzed Twenty—four (24) subjects were enrolled in the study and all subjects were healthy adults.

Twenty-four (24) subjects began the study and 23 subjects completed the clinical portion of the study in its entirety.

Data for all 24 subjects were used in the statistical analysis for sildenafil and N- desmethylsildenafil for the Test Product A (1 Spray; 10 mg) versus Reference Product D (1 Tablet, 25 mg) comparisons and Test t C (3 Sprays; 30 mg) versus Reference Product D (1 Tablet, 25 mg) comparisons. Subject 24 elected to withdraw from the study prior to Period IV check-in due to a schedule conflict. Data for 23 of 24 subjects were used in the statistical analysis for sildenafil and N—desmethylsildenafll for the Test Product B (2 Sprays; 20 mg) versus Reference Product D (1 Tablet, 25 mg) comparisons. Actual times were used in the calculation of pharmacokinetic parameters.

Bioanalytical Method Summary The bioanalytical laboratory of Cetero Research — Toronto determined the afll and N—desmethylsildenafil plasma concentrations. The is was performed on a PCT/U52012/067763 Micromass Quattro Ultima MS system, equipped with Z-spray. The positive ions were measured in MRM mode. The analyte was quantitated using a liquid—liquid extraction procedure. Following extraction, a 20 11L aliquot was injected onto an LC/MSIMS system.

The data was acquired by, and ated on, ass "Mass lynx“ re version 4.1.

Linear sion with l/x2 weighting was used to obtain the best fit ofthe data for the calibration curve. The lower limit of quantitation (LLOQ) was LOGO/0.2500 ng/mL and the upper limit of quantitation (ULOQ) was 300.0/75.00 ng/mL for sildenafill N- desmethylsildenafil. Calibration curve standards and quality control (QC) samples for sildenafil and N-desmethylsildenafil met the acceptance criteria for the runs used for the final data, demonstrating satisfactory performance of the method during the analysis of study subject samples.

Pharmacokinetic Results and Tabulations of individual Subject Data Statistical Analytical Issues The pharmacokinetic parameters were calculated using WinNonlin®, Version 5.0.1, software ed specifically for analyzing pharmacokinetic data. WinNonlin® Model 200 for extravascular input was utilized.

An Analysis of Variance (ANOV A) was performed on each of the pharmacokinetic ters using SAS® re. The ANOV A model containing factors for sequence of products, subjects within sequence, periods and products was utilized in comparing the effects between the test and reference products.

Handling of Dropouts or Missing Data Plasma level data from subjects who ted the study were included in the final data analysis. Plasma level data from subjects who withdrew or were discontinued for any reason were not used in the final analysis. Data from subjects with missing concentration values (e.g., missed blood draws, lost samples, samples unable to be fied) were used if pharmacokinetic parameters could be estimated using ing data points; otherwise, data from these subjects were excluded from the final analysis.

Pharmacokinetic Results Sildenafil(Non-Dose-Adjusted) Table 7.2.6.1-1 summarizes the non-dose-adjusted sildenafil pharmacokinetic parameters for each product using partmental analysis.

PCT/U52012/067763 Table 7.2.6.1-1 Summary Statistics and Pharmacokinetic Parameter Values for Non- Dose-Adjusted afll Data for the Noucompartmental Analysis ArithmeticMeanC‘ACV) Median ' Parameter ne forT , Test Product A Test Product B Test Product C Reference Product D s... .20... n-hn’mL 70.51 44.86 39.88 49.18 . ~hr/rnL 69.56 44.36 39.62 48.90 : mL 68.35 45.35 38.90 51.32 in 0.50—3.00 0.33-2.05 0.50-2 00 0.50-2.00 Ia- 27.03 34.05 36.79 36.08 hr 32.36 34.02 34 73. 39.82 Treatment A: Sildenafll e Oral Spray 11.55% w/w (1 spray, equivalent to 10 mg sildenafll); Treatment B: Sildenafil Citrate Oral Spray 11.55% w/w (2 sprays, equivalent to 20 mg sildenafil); Treatment C: Sildenafll Citrate Oral Spray 11.55% w/w (3 sprays, equivalent to 30 mg siidenafil); Treatment D: Viagra® tablets 25 mg Overall, plasma sildenafil concentrations were well characterized at the 10 mg, 20 mg, and 30 mg oral spray doses and at the 25 mg oral tablet dose, and declined in a monoexponential manner following oral sprays and oral tablet administration in healthy adult male volunteers.

In l, when oral spray sildenafil 10 mg, 20 mg, and 30 mg test products were administered to y adult males, the overall extent of sildenafil exposure and peak plasma concentrations, as assessed by mean AUC and Cm“, respectively, increased tionally with increasing doses from 10 mg to 30 mg. For all treatments, maximum sildenafil trations tended to be rapidly reached by approximately 100 hour after dose. The mean terminal ives values were, in general, similar for all four treatments, with estimated mean half-lives between 2.25 and 3.14 hours.

Tables 7.2.6.1-2, 7261-3, and 7.2.6.1-4 summarize the s of the analyses performed on the pharmacokinetic parameters for non-dose—adjusted sildenafil.

Table 7.2.6.1-2 Geometric Means, Ratios of Means, and 90% Confidence Intervals ol' Ln-Transl'ormed Non-Dose ed Sildenafil Data for Test t A (1 Spray; 10 mg) versus Reference Product I) (25 mg); (N = 24) M90% C: m—38.46 96.97 —-€1~E!IEI- AUC“ n--hr/mL 41.28 49.05 AUCmnf n-hr/mL 124.24 272.68 .m- 41.84, 49.62 Treatment A: Sildenafil Citrate Oral Spray 11.55% w/w (1 spray, equivalent to 10 mg sildenafil); PCT/U52012/067763 Treatment D: Viagra@ s 25 mg Table 7.2.6.1-3 Geometric Means, Ratio- of Means, and 90% Confidence Intervals of Ln-Transformed Non-Dose Adjusted Sildenafil Data for Test Product B (2 Sprays; 20 mg) versus Reference Product D (25 mg); (N = 23) 90% c1 m—m—84.69 75.40 95.13 AUC. n-hr/mL 258.53 96.89 88.82 105.68 AUC n_-hr/mL 264.97 273.35 96.94 88.96 105.63 Treatment B: Sildenafll Citrate Oral Spray 11.55% w/w (2 sprays, equivalent to 20 mg afil); Treatment D: Viagra® tablets 25 mg Table 7.2.6.1-4 Geometric Means, Ratios of Means, and 90% nce Intervals of Ln-Transformed se Adjusted Sildenafil Data for Test t C (3 Sprays; 30 mg) versus Reference Product D (25 mg); (N = 24) Treatment C: Sildenafil Citrate Oral Spray 11.55% w/w (3 sprays, lent to 30 mg sildenafil); Treatment D: Viagra® tablets 25 mg When PK parameters AUC and Cmax for oral spray products Test A (10 mg), Test B (20 mg), and Test C (30 mg) were not dose—adjusted to the Reference D tablet (25 mg), the relative bioavailability of sildenafil in the test oral spray products as compared to the reference tablet product demonstrated that: - The non-dose adjusted AUCs of sildenafil for the 2 spray (20 mg dose) Test B product were comparable to the 25 mg tablet Reference D product. The point estimate for Cmax was approximately 15% lower than the 25 mg Reference D tablet and the lower limit of the 90% CI for Cmax was only slightly below the lower acceptance range at 75.40%. 0 As expected, the AUCs and me values for the l spray (10 mg dose) Test A product were significantly lower, and for the 3 spray (30 mg dose) Test C product were significantly higher than the Reference D product (25 mg tablet).

Sildenafil (Dose-Adjusted) Table 2-1 presents a summary of the dose-adjusted sildenafil pharmacokinetic ters for each t using noncompartmental analysis.

PCT/U52012/067763 Table 7.2.6.2-1 Summary Statistics and Phannacokinetic Parameter Values for Dose- Adjusted Sildenafil Data for the Noncompartmental Analysis Arithmetic Mean (%CV) Median ' .ne for '1'. "mm” mmama mmamc nce mama IS-n -l0m- Sins-20111 Sn .-30m l'l‘ablet 25m n-hr/mL 70 51 44.86 39.88 49.18 n-hr/mL 69.56 44.36 39.62 48.90 111 19 107.32 107.46 n mL 6835 45.35 38.90 51.32 Treatment A: Sildenafil Citrate Oral Spray 11.55% w/w (1 spray, equivalent to 10 mg afil); Treatment B: afll Citrate Oral Spray 11.55% w/w (2 , equivalent to 20 mg siidenafil); Treatment C: Sildenafil Citrate Oral Spray 11.55% w/w (3 sprays, equivalent to 30 mg sildenafil); Treatment D: Viagra® tablets 25 mg The dose-adjusted Cmax for the sildenafil oral spray ts Test A (10 mg), Test B (20 mg), and Test C (30 mg) was comparable to the Reference D tablet (25 mg), whereas overall extent of sildenafil exposure as assessed by djusted AUC was consistently higher than the Reference D tablet (25 mg) with AUCM range of 328 to 344 ng—hr/mL for the oral spray compared to 294 ng—hr/mL for the reference 25 mg tablet and with AUC 0.in range of 334 to 356 ng—hr/mL for the oral spray compared to 301 ng-hrlmL for the reference 25 mg tablet.

The peak plasma concentrations, as assessed by Cum, were comparable across all test doses (oral spray of 10 mg, 20 mg, and 30 mg) to the reference dose (oral tablet of 25 mg).

For all treatments, the peak plasma concentrations ranged from 103.26 ng/mL — 111 .19 ng/mL.

Tables 7262—2, 7262-3, and 7262-4 summarize the results ofthe es performed on the cokinetic parameters for dose-adjusted sildenafil.

Table 7.2.6.2-2 Geometric Means, Ratios of Means, and 90% Confidence Intervals of Ln-Transformed Dose-Adj usted Slldenafil Data for Test Product A (1 Spray; 10 mg) versus Reference Product D (25 mg); (N = 24) 90% Cl m—mr- 96197 mm- 88-36 111.28 AU . n-hrlmL mm- 266.20 In 103.1512259 2O AUCW(rig-11:11:11.) 7, 124.02) Treatment A: Sildenafil Citrate Oral Spray 11.55% w/w (1 spray, equivalent to 10 mg sildenafil); Treatment D: Viagra® tablets 25 mg Table 7.2.6.2-3 Geometric Means, Ratios of Means, and 90% Confidence Intervals of Ln-Transformed Dose-Adjusted Sildenafil Data for Test Product B (2 Sprays; 20 mg) versus Reference Product D (25 mg); (N =. 23) Treatment B: Sildenafil Citrate Oral Spray 11.55% w/w (2 sprays, lent to 20 mg sildenafil); ent D: Viagra® tablets 25 mg Table 2-4 Geometric Means, Ratios of Means, and 90% Confidenee Intervals of Ln-Transformed Dose-Adjusted afil Data for Test Product C (3 Sprays; 30 mg) versus Reference Product D (25 mg); (N = 24) —_-m——ammu— nent C: Sildenafll Citrate Oral Spray 11.55% w/w (3 , lent to 30 mg sildenafil); Treatment D: Viagra® tablets 25 mg When PK parameters AUC and Cmax for oral spray products Test A (10 mg), Test B (20 mg), and Test C (30 mg) were dose-adjusted to the Reference D tablet (25 mg), the relative bioavailability of sildenafil in the test oral spray products as compared to the reference tablet product demonstrated that: 0 The dose-adjusted Cmax values of sildenafil for the 10 mg, 20 mg, and 30 mg oral spray products were comparable to the Reference D product (25 mg tablet) and all were within the 90% CI. 0 The Test/Reference ratio point estimates for the dose-adjusted AUCo_mf for all the sildenafil oral spray doses were approximately 114 % to 121 %. The upper limit ofthe 90 % CI was 124 % for Test A (10 mg) and Test C (30 mg) doses, just below the 125% upper limit. The Test/Reference ratio point estimates for the dose-adjusted AUCM for all the sildenafil oral spray doses were approximately 112 % to 121 %. The upper limit of the 90 % CI was 123 % for Test A (10 mg) and 125 % for Test C (30 mg) doses. For the Test B (20 mg) oral spray, the point estimates for AUCs were approximately 21 % higher and the 90% CI for AUCs were above the upper acceptance range at 132 %.

These data indicate that the overall ic sildenafil exposure for the oral spray test product is more systemically bioavailable than the 25 mg oral tablet reference t, likely due to ng first pass metabolism through transmucosal absorption.

N-desmethylsildenafil (Non-Dose-Adj usted) Table 7.2.6.3—1 presents a summary of the non-dose—adjusted N—desmethylsildenafil pharmacokinetic parameters for each product using noncompartmental analysis.

Table 7.2.6.3—1 y Statistics and Pharmacokinetic Parameter Values for Non- Dose-Adjusted ethylsildenafil Data for the Noncompartmental Analysis Arithmetic Mean (%CV) Median ' Ie for'l‘ , ISI-I'I‘Wm ISI'I '20In Sta '30“: lTable 25m n-hr/mL 41.21 37.52 36.06 31.44 11: -ChrlmL 40.51 37.10 35.72 31.11 :31]. 34.19 36.47 30.52 38.26 0.33-2.00 0.50-2.05 0.50-2.00 0.50—2.00 ”hr 26.65 33.77 29.29 25.90 47.61 35.61 27.37 30.71 Treatment A: Sildenafil Citrate Oral Spray 11.55% w/w (1 spray, equivalent to 10 mg sildenafil); Treatment B: Sildenafil Citrate Oral Spray 11.55% w/w (2 sprays, equivalent to 20 mg sildenafil); Treatment C: Sildenafil Citrate Oral Spray 11.55% w/w (3 sprays, equivalent to 30 mg siidenafil); Treatment D: ® tablets 25 mg In general, the overall extent ofN-desmethylsildenafil exposure and peak plasma concentrations for oral spray products Test A (10 mg), Test B (20 mg), and Test C (30 mg), as assessed by mean AUCs and Cm“, increased proportionally with increasing doses from 10 mg to 30 mg. For all doses of the sildenafil oral spray treatments, the time to reach maximum N-desmethylsildenafil concentrations was slightly slower than the oral tablet reference product Tmax of 0.75 hours; however, the ranges of Tmax for all test sildenafil oral sprays and the reference oral tablet were similar. The mean al ife values were, in general, similar for all four treatments.

Tables 7.2.6.3—2, 7.2.6.3-3, and 7.2.6.3-4 ize the results of the analyses performed on the pharmacokinetic parameters for non—dose-adjusted N-desmethylsildenafil.

PCT/U52012/067763 Table 7.2.6.3—2 Geometric Means, Ratios of Means, and 90% Confidence Intervals of Ln-Transformed N-desmethylsildenafil Data for Test Product A (1 Spray; 10 mg) versus Reference Product D (25 mg); (N = 24) Treatment A: Sildenafil e Oral Spray 11.55% w/w (1 spray, equivalent to 10 mg sildenafil); Treatment D: Viagra® tablets 25 mg Table 7.2.6.3-3 Geometric Means, Ratios of Means, and 90% Confidence Intervals of Ln-Trnnsformed N-desmethylsildenafil Data for Test t B (2 Sprays; 20 mg) versus Reference Product D (25 mg); (N = 23) Test B 65.07 AUG-f n-hr/mL 67.84 Treatment B: Sildenafil Citrate Oral Spray 11.55% w/w (2 sprays, equivalent to 20 mg sildenafil); Treatment D: Viagra® s 25 mg Table .4 Geometric Means, Ratios of Means, and 90% Confidence Intervals of Ln-Transformed N-desmethylsildenafil Data for Test Product C (3 Sprays; 30 mg) versus Reference t D (25 mg); (N = 24) ———m90%Cl 2923 .m- 10865 118-94 AUC n- -hr/InL 102.9] 81.90 125.65 11695 134 99 AUC_ n llr/mL 105.88 84.49 125.32 116.93 134.31 Treatment C: Sildenafil Citrate Oral Spray 11.55% w/w (3 sprays, equivalent to 30 mg siidenafil); Treatment D: Viagra® tablets 25 mg When N—desmethylsildenafil PK parameters AUC and Cmax for oral spray products Test A (10 mg), Test B (20 mg), and Test C (30 mg) were not dose-adjusted to the Reference D tablet (25 mg), the relative ilability ofN—desmethylsildenafil in the test oral spray ts as compared to the reference tablet product demonstrated that: ° The point estimates for non-dose—adjusted AUCs ofN-desmethylsildenafil between the 10 mg, 20 mg, and 30 mg test oral spray doses were, in general, comparable to the difference to the 25 mg reference tablet.

- The point estimates for Cmax between the 10 mg, 20 mg, and 30 mg test oral spray doses were lly less than the difference to the 25 mg reference oral tablet.

N—desmethylsildenafil (Dose-Adjusted) PCT/U52012/067763 Table 7.2.6.4—1 presents a summary of the dose-adjusted N-desmethylsildenafil pharmacokinetic parameters for each product using noncompartmental analysis.

Table 4-1 Summary Statistics and Pharmacokinetic Parameter Values for Dose- Adjusted N-delmethylsildenafil Data for the Noncompartmental Analysis etic Meal (%CV) Median ' n forT.

W WW 0m Sum :"m- S-I'l '30m [Tab] '25ll n-lirlml. 4] .21 37.52 36.06 31.44 n-hrlmL 40.51 37.10 35.72 31.1] n L 34.19 36.47 30.52 38.26 Treatment A: Sildenafil Citrate Oral Spray 11.55% w/w (1 spray, equivalent to to mg sildenafll); Treatment B: Sildenafll Citrate Oral Spray 11.55% w/w (2 , equivalent to 20 mg siidenafil); Treatment C: Sildenafll Citrate Oral Spray 11.55% w/w (3 sprays, equivalent to 30 mg sildenafil); Treatment D: Viagra® tablets 25 mg After dose—adjusting the PK parameters AUC and Cmax ofN-desmethylsildenafil for oral spray products Test A (10 mg), Test B (20 mg), and Test C (30 mg) to the Reference D tablet (25 mg), the overall extent of exposure of N—desmethylsildenafil, as assessed by AUC, shows a trend to slightly se with increasing doses from 10 mg to 30 mg. However, the dose-adjusted peak N-desmethylsildenafil plasma concentrations, as assessed by Cmax, were similar for the test oral spray doses of 20 mg and 30 mg, but slightly less for the test oral spray dose of 10 mg. For all four products, the peak plasma concentrations ranged from 21.94 ng/mL - 29.04 ng/mL.

Tables 7.2.6.4-2, 7.2.6.4-3, and 4-4 summarize the results of the es performed on the phannacokinetic ters for dose-adjusted N-desmethylsildenafil.

Table 4—2 Geometric Means, Ratios of Means, and 90% Confidence Intervals of Dose-Adjusted Ln-Transformed N-desmethylsildenalil Data for Test Product A (1 Spray; 10 mg) versus Reference Product D (25 mg); (N =24) 90% C: .78 m— 70.42 84.40 70.67 8628 80-31, 92-70 AUCMdgg-hr/mL) (82.46, 94.72) Treatment A: Sildenafil Citrate Oral Spray 11.55% w/w (1 spray, equivalent to 10 mg sildenafil); Treatment D: Viagra® tablets 25 mg Table 7.2.6.4-3 Geometric Means, Ratios of Means, and 90% Confidence Intervals of Ln—Transformed Dole-Adjusted N-desmethylsildenafll Data for Test Product B (2 Sprays; 20 mg) versus Reference t D (25 mg); (N=23) 90% C1 2708 87-29 79-70. 95.62 AUC. n-hr/mL 81.34 82.68 98.38 91.59105.“ AUCeiur n-hr/mL 84.80 85.28 99.43 92.80 106.54 Treatment B: Sildenafil Citrate Oral Spray 11.55% w/w (2 sprays, equivalent to 20 mg afil); ent D: Viagra® tablets 25 mg Table 7.2.6.44 ric Means, Ratios of Means, and 90% Confidence Intervals of Ln-Transformed Dose-Adjusted N-desmethylsildenafil Data for Test Product C (3 Sprays; 30 mg) versus Reference Product D (25 mg); (N=24) 90% c1 mm-M-mm 152.71.99.12 AUC n-hr/mL 85.76 97-46 112.49 AUC._ n--11mn1. 84.49 104.43 97.44 111.92 Treatment C: Sildenafil Citrate Oral Spray 11.55% w/w (3 sprays, equivalent to 30 mg sildenafil); Treatment D: Viagra® tablets 25 mg After dose—adjusting the PK parameters AUC and Cmax ofN—desmethylsildenafil for oral spray products Test A (10 mg), Test B (20 mg), and Test C (30 mg) to the nce D tablet (25 mg), the PK and statistical results trated that, with the exception of the Cmax for the test oral spray 10 mg and 20 mg doses, the AUCs and Cmax values were all within the 90 % CI criteria of 80 %-125 %.

Dose fionality The results for dose tionality at doses of single 10 mg, 20 mg, and 30 mg oral spray administrations of sildenafil demonstrate that, While the AUCinf increases linearly with dose, it does not do so in exactly a dose proportional manner; specifically, a slightly greater than roportional increase is observed. As the results in the Table 7.2.6.5-1 demonstrate, a mean 2.24 and 3.13 fold increase in AUij‘ is observed from 1 to 2 sprays and l to 3 sprays, respectively. Similar greater than non-proportional dose results following single oral dose stration of sildenafil tablets in healthy male volunteers have been reported by Nichols et a1. and, as noted in that study and in this study, the extent of this non- proportionality is unlikely to be clinically significant.

PCT/U52012/067763 Table 7.2.6.5-1 Dose Proportionality for afil Test Oral Spray —-.I_—II-ltoZSra lto3Srss _—-— ——-E_ Standard Deviation “— 22731 2723 Treatment A: Sildenafil Citrate Oral Spray 11.55% w/w (l spray, eqUTvalent to 10 mg slldenafil); Treatment B: Sildenafil Citrate Oral Spray 11.55% WW (2 sprays, lent to 20 mg siidenafil); Treatment C: Sildenafil Citrate Oral Spray 11.55% w/w (3 sprays, lent to 30 mg siidenafil) Metabolite/ Parent Ratio (N—desmethylsildenafil/SildenafiI Ratio) Table 7.2.6.6-1 summarizes the Metabolite/ Parent Ratio (N-desmethylsildenafil/ Sildenafil) pharmacokinetic ters for each treatment test product.

Table 7.2.6.6-1 Summary Statistics and Pharmacokinetie Parameter Values for Metabolite! Parent Ratio (Ndesmethylsildenafill Sildenafil) Arithmetic Mean '7.

Par-mm Test Product A Test Product C Reference Product I) ISn'mm ZSI-l‘l‘wlll SimN-Sllm lTab 25m mmAU. 41.90 38.01 35.76 46.49 -m—AUCnm 40.42 37.18 35.39 45.97 . 45.31 45.40 33.68 48.46 Treatment A: Sildenafil Citrate Oral Spray 11.55% w/w (1 spray, lent to 10 mg siideuafil); Treatment B: Sildenafil Citrate Oral Spray 11.55% w/w (2 sprays, equivalent to 20 mg sildenafil); ent C: Sildenafil e Oral Spray 11.55% w/w (3 sprays, equivalent to 30 mg siidenafil); Treatment D: Viagra® tablets 25 mg Tables 7.2.6.6—2, 7.2.6.6-3, and 6-4 summarize the results of the analyses performed on the pharmacokinetic ters for N—desmethylsildenafil/Sildenafil Ratio.

Table 7.2.6.6-2 Geometric Menus, Ratios of Means, and 90% Confidence Intervals of Ln-Trausformed N-dosmetllylsildenafil/ Sildenafil Ratio for Test Product A (1 Spray; 10 mg) versus Reference Product D (25 mg); (N=24) “IE-m 90% c1 —-m.‘fl- 77.84 71.32 84.96 -_-E--E- 76.56 71.78 81.66 _-fl--E-— 73.01 83.01 Treatment A: Sildenafil Citrate Oral Spray 11.55% w/w (1 spray, equivalent to 10 mg siidenafil); ent D: Viagra® tablets 25 mg 2012/067763 Table 7.2.6.6-3 Geometric Means, Ratios of Menus, and 90% nce Intervals of Ln-Transl'ormed N-dumethylsildenafil/ afll Ratio for Test Product B (2 Sprays; 20 mg) versus Reference Product D (25 mg); (N = 23') m_—__ 90% Cl _.E--M-— 75 .72, 90.34 _m——-—- -——-E--E- 76.7s 87.27 Treatment B: Sildenafil Citrate Oral Spray 11.55% w/w (2 sprays, equivalent to 20 mg siidenafil); Treatment D: Viagra® tablets 25 mg Table 7.2.6.64 Geometric Means, Ratios of Means, and 90% Confidence Intervals of nsformed N-desmetliylsildenafill Sildenafil Ratio for Test Product C (3 Sprays; 30 mg) versus Reference Product D (25 mg); (N=24) M—m— _-E--E--flifi--—- m-mI—mfl-m _——-—-E_ Treatment C: Sildenafil Citrate Oral Spray 11.55% w/w (3 sprays, equivalent to 30 mg siidenafil); Treatment D: Viagra® tablets 25 mg Overall, the results of metabolite to parent (M/P) ratios analysis demonstrated that the formation of the metabolite, as assessed by the M/P ratios for the Test A (10 mg) and Test B (20 mg) oral spray doses were less than the M/P ratio of the Reference D (25 mg) tablet, whereas the M/P ratios for the Test C (30 mg) oral spray dose were comparable to the M/P ratios observed for the Reference D (25 mg) tablet.

The M/P ratio for each concentration time point was calculated for each treatment and plotted versus time to ly assess the rate of formation of lite. This was done up to four hours post—dose. This plot is shown in Figure 7.2.6.6-1. It can be noted that there was an immediate peak in the M/P ratio for the reference oral tablet, whereas the M/P ratio with time for all doses of the test oral spray doses were significantly slower than the nce tablet.

This observation indicates that there is a marked decrease in the rate of metabolite formation in the test oral spray products compared to the reference oral tablet product and indicative that the test oral spray is, for the most part, ing first pass metabolism due to transmucosal absorption.

Saliva pH Assessments The transmucosal absorption of drugs may be dependent on the pH of the oral cavity when stered to patients. ore, in this study saliva pH was measured in healthy male adult volunteers at 2300 hours (:: 30 minutes) on Day —1 and on Day 1 within 30 2012/067763 minutes prior to teeth and tongue brushing. There was minimal change in saliva pH pre- and post-teeth and tongue brushing. Saliva pH was then ed within 30 s of completion of teeth and tongue brushing (N 45 minutes se), and within 15 minutes prior to dosing. The pH was measured using pH test strips with a range of 5-9. No subject had a pH of 5, therefore, there was no additional testing with pH test strips with a range of 0—6. There were no iable differences found in saliva pH between treatments or periods at 45 minutes and 15 minutes prior to dose administration, as shown in the Table 7.2.7-1.

Table 7.2.7-1 Summary of Mean Saliva pH by Treatment and by Period Mun Saliva Ii : n 45 and 15 minutes Prior In Dose Administration Tut B Test C Reference D Iran Win In . 20m 3st. *30m- lTIlJl 25m mmummmm mum—___.z-m MIME-___M-m “mum-“mm Treatment A: Slldenafil CItrate Oral Spray 11.55% w/w (1 spray, equvalent to 10 mg afil); Treatment B: Sildenafil e Oral Spray 11.55% w/w (2 sprays, equivalent to 20 mg sildenafil); Treatment C: Sildenafil Citrate Oral Spray 11.55% w/w (3 sprays, equivalent to 30 mg sildenafil); Treatment D: Viagra® tablets 25 mg Post-Dose Questionnaire Immediately after dosing was completed (2 minutes) and at 1 hour after dosing, subjects were queried on the following regarding the test t (oral spray): - Taste of the t - Willingness to take the product again 0 Any presence of excessive salivation Table 7.2.8-1 Summary ofTaste Questionnaire Results swallo n-stdose swallowin- -- -dose w” est-dose “mu-Jim“Menntlstesenre1=bad:5=v _T.—-'Jll—'!-—29Willinless to take the - roduct 3 % Affirmative ms nses Presence ofan excessive salivation Afiinmtive res- mm 96 6 01'24 25% 3 on4 12.5% 9 of23 39% 3 of23 13% 12 of24 50% 2 on4 8% ] Treatment A: Sildenafil Citrate Oral Spray 11.55% w/w (1 spray, eqUIvalent to 10 mg sildenafil); Treatment B: Sildenafil Citrate Oral Spray 11.55% w/w (2 sprays, equivalent to 20 mg sildenafil); Treatment C: Sildenafil Citrate Oral Spray 11.55% w/w (3 sprays, equivalent to 30 mg sildenafil) PCT/U52012/067763 Oral Irritation Assessment The examination consisted of a visual inspection/evaluation of the soft tissue for irritation of the labial and buccal mucosa and tongue. The oral mucosal es, right and left, and labial junctions and tongue were examined for irritation and graded according to the ing classification system described below.

Numerical Grade Erythema — Oral Mucosa (Left and Right) and Tongue 0 No erythema 1 Very slight erythema (barely perceptible) 2 Slight erythema (edges of area well defined by definite raising) 3 Moderate erythema (raised approximately 1.0 mm) 4 Severe erythema (raised more than 1.0 mm extending beyond the area of exposure) Evaluation of soft tissue irritation within the labial or buccal mucosa and of the tongue were done after both active and placebo dosing. Irritation assessments were collected at the following time points: Prior to each oral spray administration, immediately after swallowing (2 minutes), and at 1 hour post administration. If any irritation persisted beyond the one hour assessment, assessments continued every two hours until resolution up to ten hours post-dose. If irritation was still reported at ten hours, the subject was assessed by the Investigator as to whether the t should be tinued from the study. Any assessments after one hour also included a subjective evaluation question.

The s of the oral irritation assessment found no oral irritation following administration of o (3 sprays). Additionally, no oral irritation was found following administration of Test A (1 spray), Test B (2 sprays), or Test C (3 sprays), when observed ately after administration (held for two minutes, then swallowed), and when observed at 1 hour post-dose.

DISCUSSION The dose-adjusted Cmax values of sildenafil for oral spray ts Test A (10 mg), Test B (20 mg), and Test C (30 mg) were, in general, able to the Reference D (25 mg) oral tablet. The Test/Reference ratio point estimates for the dose-adjusted AUCs for all the sildenafil oral spray doses were approximately 112 % to 121 % and the 90 % CI for AUCs were 124 % to 132 % with an upper acceptance range of 125 %. In addition, the non-dose- adjusted point estimates for AUCs for the Test B 2 spray dose (20 mg) oral spray were approximately 97 %, demonstrating comparable bioavailability to the Reference D (25 mg) oral tablet. These data indicate that the l sildenafil exposure for the test oral spray PCT/U52012/067763 product is more systemically bioavailable than the reference oral tablet, likely due to avoiding first pass metabolism through transmucosal absorption.

Sildenafil is known to be metabolized to its major metabolite N—desmethylsildenafil through first pass metabolism by more than 50 % [absolute bioavailability is 41 % (range 25- 63 %)]. The pharmacokinetic and statistical results ing administration of the sildenafil oral spray in healthy adult male subjects demonstrated sed systemic exposure that can reasonably be uted to oral transmucosal absorption processes.

The assessment ofM/P ratio (metabolite (N-desmethylsildenafil) to parent (sildenafil) ratio) for the oral spray products Test A (10 mg), Test B (20 mg), and Test C (30 mg) as compared to the Reference D (25 mg) oral tablet demonstrated differences in the rate of formation of the metabolite indicative of trans mucosal absorption There was minimal change found in the mean saliva pH between treatments and s in this study, therefore subject saliva pH was not likely a contributing factor in the apparent transmucosal absorption observed following the oral spray stration.

There was no oral irritation observed in any of the subjects following administration of afil oral spray o or active doses (up to 3 sprays, 30 mg dose).

Overall, sildenafil citrate was well tolerated in doses of 10 mg, 20 mg, 30 mg, and was well tolerated as a single oral dose of25 mg (1 X 25 mg ) administered to healthy adult subjects under fed conditions.

EXAMPLE 4 OBJECTIVE The objective ofthe following was to evaluate the partial AUC exposures of sildenafil in the first, fourth, h and twenty-fourth hour (AUC0_1, AUCM, AUCMZ and AUC0_24) for the 10, 20 and 30 mg Test oral spray products to that of the 25 mg tablet nce product of sildenafil.

STUDY DESIGN A randomized, four-way crossover design was used in this study to compare the relative bioavailability (rate and extent of absorption) of one test product at three different dose levels (10 mg, 20 mg, and 30 mg) with one reference product under fasting conditions.

In this study, one test formulation at three different dose levels (10 mg, 20 mg, and 30 mg of an oral dose of Sildenafil Citrate Oral Spray 14 mg/0.12 mL were compared with VLAGRA® mg Tablets.

Twenty-four healthy male adult subjects and no ates were randomly assigned to one of four sequences of the following products: PCT/U52012/067763 Test Product (A): Sildenafil Citrate Oral Spray 1 1.55% w/w; (1 Spray; 10 mg) Test Product (B): Sildenafil Citrate Oral Spray 11.55% w/w; (2 Spray; 20 mg) Test Product (C): Sildenafil e Oral Spray 11.55% w/w; (3 Spray; 30 mg) Reference Product (D): Viagra® tablets 25 mg; The four sequences were as follows: Sequence 1 = ABC D Sequence 2 = B D A C Sequence 3 = CAD B Sequence 4 = D C B A A single oral dose of test or reference product was administered to volunteers on four separate occasions under fasting conditions with at least a 3-day washout period between doses. Food and fluid intake were controlled during each confinement period.

The pharmacokinetic parameters for both se adjusted and dose adjusted AUC 0. 1, AUC o4, AVC 0.12 and AUC 0.24 of sildenafll and its metabolite, N—desmethylsildenafll were calculated using WinNonlin®, Version 5.0.1, re designed cally for analyzing pharmacokinetic data. WinNonlin® Model 200 for extravascular input was utilized.

An analysis of variance (ANOVA) was performed on each ofthe partial AVC 0.1, AUC 0.4, AUC 0.12 and AUC 0.24 pharmacokinetic parameters using SAS® re. The ANOVA model containing factors for sequence of products, subjects within sequence, periods and products was utilized in comparing the effects between the test and reference products. AUC0_24 calculation for ty of the subjects could not be calculated due to BLQ concentration values at hour 24.

PHARMACOKINETIC RESULTS AND DISCUSSION Table 1 ts a summary ofthe sildenafil cokinetic parameters for each t using noncompartrnental analysis.

PCT/U52012/067763 Table l Summary Statistics and Partial AUC Values for Non-Dose Adjusted Sildenafil ArltimcfieMeau(%CV) W... W“ lS-ra‘lo l, 25-mn'20 JS-ra 30m 25 w ”hr/ml. 70.53 68 57 78 06 n 1-hrImL 66.54 42.74 7.7 45 29 n : -hr/mL 68.42 42.3 5 38. lo 47.65 670.90 66l.69 515.90 :1 -hrlmL 12.16 46.74 “' Not calculated due to BLQ at the 24 hour time point Source: Tables l.l.] — I.l.4 In general, When oral spray sildenafll 10, 20 and 30 mg Test products were administered to healthy adult males, the partial extent of sildenafil exposure as assessed by non—dose adjusted AUC 0.1 AUC 0.4, and AUC 0.12 increased proportionally With sing doses.

The non—dose adjusted partial, AUCs of sildenafil Oral Spray and the nce Tablet as presented in Table 1 demonstrates that partial AUC 0.1, AUC 0.4, AUC 0.12 and AUC 0.24 is consistent With the AUCm and AUCO.inf (Table 7.2.6.1—1) difference ed between the oral spray and reference tablet With the 2 spray 20 mg dose having ial the same AUC as the 25 mg reference tablet.

Tables 2, 3, and 4 summarize the statistical results ofthe analyses performed on the partial AUC intervals for non-dose ed sildenafil.

Table 2 Summary of Statistical Analysis Partial AUC Non-Dose ed Tut Product A l S ra ' 10 m 1 vs. Reference Product 1 Tut Product A (1 Spray; l0 mg) vs. nu Product I) Geometrle Means, Ratio of Means, and 90% Confidence Interval: LII-Transformed Data Slldcuafll (Non-Dole Adjuated) " Not edculamd due to BLQ at the 24 hour time point Source: Table: 1.2.1 PCT/U52012/067763 Table 3 Summary of Statistical Analysis Partial AUC Non-Dose Adjusted Test Product B S ra 20 In 1 vs. Reference t 25 m 1 Test t B (2 Spray; 20 ml) VI. Reference Product D Geometric Means. Ratio 0! Menu. and 90% Confidence ab Ill-Transformed Data Slldalalll (Non-Dose Arliuated) N=23 mum-mm:— .r/mL - 28.75 89.58 _(63.07. 127.25) AUC... 1m «moss» m (89.08, 105.69) " Not calculaud due to BLQ at the 24 hour time point Source: Tables 1.22 Table 4 Summary of Statistical Analysis Partial AUC Non-Dose Adjusted Test Product C ; vs. Reference t 25 In ; Tut Product C (3 Spray; 30 mg) VI. Reference Product D Geometric Means, Ratio of Mean, and 90% Confidence lutervah [in-Transformed Data afil (Non-Dose Adjusted) N=24 90% Cl - (81.91.165.51) AUC...

AUC”: n ‘ rlml. — ” Not calculated due to BLQ at the 24 hour time point Source: Tables l.2.3 When PK parameters AUC 0.1, AUC 0.4, AUC 0.12 for oral spray products Test A (10 mg), Test B (20 mg), and Test C (30 mg) were not dose—adjusted to the Reference D tablet (25 mg), statistical results for partial extent of sildenafil exposure from 0 to 1, 4, 12 and 24 hours in the test oral spray ts as compared to the reference tablet t demonstrated that: 7 there was a significant difference for partial AUC 0.1, AUC 0.4, AUC 0.12 for nondose adjusted Test product A (l oral spray, 10 mg dose) of sildenafil as compared to the 25 mg tablet Reference D product. The extent of sildenafil exposure as calculated to one hour (AUC 0.1) was approximately 63 % lower while AUC calculated to 4 and 12 hours were approximately 55 % lower, respectively, than the Tablet Reference product consistent with the dose difference. (Refer to Table 7 the extent of exposure as calculated to 4 and 12 hrs (for non-dose adjusted AUC 0.4, AUC 0.12) Test product B (2 oral sprays, 20 mg dose) were comparable to the mg tablet Reference D product as these values were within the 90 % CI.

However, partial AUC calculated to 1 hr was not contained within the 90 % CI, although the point estimate was only slightly lower at approximately 10 %. (As ted in Table 3). — for Test Product C, 30 mg oral spray t, the non-dose adjusted partial AUC 0.1, AUC 04, AUC 0.12 of sildenafil was in general, reflective of the difference in dose from the 25 mg tablet Reference product (approximately 16,34 and 37 % higher, tively) and all the values calculated for partial AUC from 0 to 1, 4 and 12 hrs were not within the 90 % CI (Refer to Table 4). afil (Dose ed) Table 5 presents a summary ofthe dose adjusted sildenafil acokinetic parameters for each product using noncompartmental analysis.

Table 5 Summary Statistics and Partial AUC Values for Dou- Adjusted to mg Sildenafll ArllhmeficMau-( “rm Prod-cu “I‘m Product 3 Referencemm D ls ;l0ll 25- 'ZOII 3Sn'30 .

AUC“ 3633 47.50 43 45 51.89 "lm'ml. 59 09 70.53 68.57 73.06 ' L 66.54 42.74 37.77 . ‘lIr/ml. 68.42 42.35 38.10 47.65 ”hr/ml. W 46-74 ” Not calculamd due to 81.0 at the 24 hour time poinl Source: Tables 2.1.! - 2.1.4 tical results presented in Table 5 for dose—adjusted partial PK parameters AUC o- ], AUC 0.4, AUC 0.12 and AUC 0.24 demonstrates that: » the dose adjusted AUC 0.4 for the afil oral spray 10, 20 and 30 mg were in general comparable to the 25 mg Reference Tablet Sildenafil » in general partial AUC calculated from 0 to 12 hrs for all 3 oral spray Test products of sildenafil was slightly higher than the 25 mg Reference tablet product (by approximately 11 to 19%. respectively).

PCT/U52012/067763 » these results indicate that the partial extent of sildenafll exposure calculated for the first hour (AUC 0.1) were lower and for the next 4 hours (AUCM) comparable but then higher when calculated to 12 hrs (AUC0_12) for all the oral spray Test products as compared to the oral tablet Reference product.

Tables, 6, 7 and 8 summarize the results ofthe analyses performed on the pharmacokinetic parameters for dose adjusted sildenafil.

Table 6 Summary of Statistical is Partial AUC Dose Adjusted Test Product A l S ra ' 10 m_ vs. nce t 25 In Tell Pmdnet A (1 Spray; 10 II) VI. Reference Produet D Geometric Meal, Ratio ofMean, and 90% Confidence Interval: ansformed Data Slldelafil (DoaeAdjutted) —_—mm- (64.30, [29.92) (102.47, l24.l9) (105.25, 124.7!) “ Not calculated due to BLQ at the 24 hour time point Source: Tables 2.2.] Table 7 Summary of Statistical Anulylis l AUC Dose Adjusted Test Product B (2 Spray; 20 mg) VI. Reference Product (25 mg) Tent Product B (2 Spray; 2|! mg) VI. Referenee Product D Geometric Means. Ratio ofMann, and 90% Confidence Interval: la-‘l‘ranlformed Data Slidenalll (Dole Adjusted) N-13 _mmmADC” 0m 159-06) _--—mADC... mmmAUCM: ‘ r/Ial.

” Not calculated due to BLQ at the 24 hour time point Source: Table: 2.2.2 2012/067763 Table 8 Summary of Statistical Analysis Partial AUC Dose Adjusted Test Product C (3 Spray; 30 mg) vs. Reference Product (25 mg) Test Product C (3 Spray; 30 lug) vs. Reference Product D Geometric Menus, Ratio of Menus. and 90% Confidence Intervals LII-Transformed Data Slldemfll (Dose Adjusted) N=24 elt 90%c1 w(101.32, 122.30) m(104.57, 123.91) ” Not calculated due to 31.0 at the 24 hour time point When PK ters partial AUC 0.1, AUC 0.4, and AUC 0.12 for sildenafll were dose ed to the 25 mg Reference Tablet formulation the partial systemic exposure of sildenafil in the oral spray products as compared to the Reference 25 mg tablet formulation demonstrated that (refer to Tables 6 to 8): ~ the values of dose adjusted AUC calculated from 0 to 4 and to 12 hours of sildenafil for the 10 mg and 30 mg oral spray products were in general, comparable to the 25 mg tablet Reference product and were within the 90 % CI., The 20 mg Test product B which was ly higher compared to the 25 mg tablet Reference product and was not within the 90% CL ~ the values obtained for partial AUC calculated from 0 to 1 hr were, in general, not within the 90 % CI indicating that partial extent of sildenafil exposure ated to 1 hour for all oral spray Test products were not able to the 25 mg tablet Reference product. ~ as the % Test / Reference point estimates te, the partial systemic sildenafil exposure at AUC 0,1, AUC 04, and AUC 0.12 for the 20 mg oral spray (Test Product B) was slightly more systemically bioavailable than the oral 25 mg reference tablet ( 112 % vs 119.5% vs 1213 %, respectively).

PCT/U52012/067763 N-desmethylsildenafil Partial AUC (Non-Dose Adjusted) Table 9 presents a y ofthe N—desmethylsildenafil partial AUC for each product using noncompartmental analysis.

Table 9 Summary Statistics and Partial AUC Values for Non-Dose Adjusted N—desmethylslldeuafll ArithnelleMcau %CV) ..... lS-ra'lllll Sra-Nm 38-ru 30m 25 H n_~hrImL 780 67.48 66.83 63.65 'hr/ml. 39.4 37.04 36.28 3 L44 L 37.65 35.26 30.02 mnghr/ml. am -.25 " Not calculated due to BLQ It the 24 hour time point Source: Tables 3.1.] — 3.1.4 Statistical results as presented in Table 9 for non-dose adjusted l AUC parameters AUC 0.1, AUC 0.4, AUC 0.12 and AUC 0.24 of the metabolite N- desmethylsildenafil, demonstrates that : N in general, for all doses of the sildenafll oral spray product, the extent of N—desmethylsildenafil exposure as assessed by partial AUC calculated from 0 to 4 and 12 hours, increased proportionally with increasing doses from 10 to 30 mg.

N in general the differences found between the N—desmethylsildenafil partial AUC were consistent with the dose difference ofthe oral spray and 25 mg reference tablet.

Tables 10, 11, and 12 ize the results of the analyses performed on the partial AUC parameters for non-dose ed N—desmethylsildenafil.

PCT/U52012/067763 Table 10 Summary of Statlatlcal Analysis Partial AUC Non-Dose ed Teat Product I S re 10 m ;V vs. Reference Product 5 In 1 Test Product A (1 Spray; 10 mg) VI. uce Product D Geometric Means, Ratlo a! Mean, and 90% nce lutervala Lu-Traurl‘urmcd Data N-deumetllyhlldeuafll (Non-Does Adjusted) N-24 _nm-AUCM (”ms-H) AUC... "“8 4857 34-76 (3225.37.47) A"can ” Not calculated due to BLQ at the 24 hour time point Source: Tables 3.2.l Table 11 Summary of Statistical Analysis Partial AUC Non-Dose Adjusted Tut Product Test Product 3 (2 Spray: 20 mg) VI. Idem Product Geometrle Meena. Ratio of Mean, and 90% Confidence Interval: Lu-Trausl‘omed Date N-damethylllldalufll (Non-Due Adjusted) Table 12 Summary istical is Partial AUC se Adjuated Test Product 38 ra '30Iu_ va.RefcrcuceProduct 25m Tent Product C (3 Spray; 30 In) VI. Reference Product D Geometric Mean, Ratlo of Means. and 90% Confidence Interval! Lu-Trauaforlned Data N-desmdhyllildeuafll (Non-Due Adjusted) —_——mm Ian-m"— _mnm _mmm— Source: Tebls 3.2.3 The non-dose adjusted to the 25 mg reference tablet N—desmethylsildenafil l AUC o- 1, AUC 0.4, AUC 0.12 and AUC 0.24 of the oral spray doses as compared to the Reference 25 mg tablet formulation demonstrated that: » the point estimates for non-dose adjusted partial AUC as calculated from 0 to 1 hour 1) smethylsildenafil for the 10, 20 and 30 mg oral spray doses were in general, lower to the difference in doses to the 25 mg tablet reference tablet » the point estimates for partial AUC as calculated to 4, 12 and 24 hours for the 10 mg and 20 mg oral spray doses were generally consistent with the ence in mg dose to the 25 mg oral tablet N-desmethylsildenafil Partial AUC (Dose Adjusted) Table 13 presents a summary of the dose adjusted N—desmethylsildenafil pharmacokinetic parameters for each product using noncompartmental analysis.

Table 13 Summary Statistics and Partial AUC Values for Dose- AdjusM to mg N—desmethylsildeuafil Arithmetic Men 39C I’m-cur Tumama Tu: Proamc Reference Pmduetl) IS 10m Sn 20m Sn 30 25 M “’C‘“ 9'” "" z-Iu'ImL 78.0 67.48 66.33 63.65 H 1 ‘hr/ml. 39.4 37.04 36.28 3| .44 I 'hl'lmL 37.65 35.26 35.15 30.02 AUC“. “ 108.93 6932 n : 'hl'lmL 28.07 32.30 “ Not calculated due to BLQ at the 24 hour time point Source: Tables 4.1.l — 4.! .4 After dose adjusting the partial AUC0_1 for the 10, 20 and 30 mg oral spray doses, were found to be less than the 25 mg oral tablet dose.

The dose- adjusted AUCs calculated from 0 to 4 and 12 hours for the metabolite of Test products A, B and C were in l, comparable while no specific trend was observed for AUC0.24 for all the oral spray Test products to the Reference Tablet product.

Tables 14, 15, 16 summarize the results of the analyses performed on the l AUC for dose adjusted N—desmethylsildenafll.

PCT/U52012/067763 Table 14 Summary of Statistical Analysls Partial AUC Don Adjusted Test Product A lS-ra ' 10m va.ReferenceProduct 25m_ Test t A (1 Spray; 10 mg) vs. Meme: Product D Geometric Means, Ratio “Means, and 90% Confidence al: LII-Transformed Data N-deemetilylsildenufll (Dose Adimted) N=14 “’C" n—-— .54 43.51 (26.94, 70.28) AUCH 422‘ «sows-es) “’C‘“ -_ — 70-95 76-21 (fl-04.99.51) _—— —-Ir/mL " Not ated due to BLQ at the 24 hour time point Source: Tables 4.2.] Table 15 Summary of Statistical Analysis Partial AUC Dose Adjusted Test Product B 2 S ra ‘ 20 m vs. Reference Product 25 m Testmm 3 (2 Spray; 20 mg) vs. Reference Product D Geometric Meaua, Ratio ofMe-ns, and 90% Confidence Interval: LII-Transformed Data N-dumetilybildenafll (Due Mjmd) N=23 90% c1 (ms. 101.09) "”°“ - -—47.08 48.75 96.58 (89.56. ) 76.51 76.65 99.83 (93.31, 106.80) .. r/ml.

Source: Tables 4.2.2 PCT/U52012/067763 Table 16 Summary of Statistical Analysis Partial AUC Dose Adjusted Test Product C 3 S-ra ' 30 m vs. Referencel’roduct 25 In Test Product C (3 Spray; 30 mg) va. Moreno: Product I) Gannon-ll: Meant, Ratio of Means. and 90% Confidence Intervals LII-Transformed Data tlnylalldenafil (Dole Adjusted) N=24 [mm-m— AUC... 64.82 (40.13, 104.69) .- - Jar/ml.

AUC“ “-03 98-» mum») AUC“: 78-76 memos» AUC»: “-53 l03.77 (84.75, 127.05) . --lIrIIIL Source: Tablet 423 When comparing the dose adjusted partial AUC 0.1, AUC 04, AUC 0.12 and AUC 0.24 N—desmethylsildenafrl for the oral spray doses, the cokinetic and statistical results for the N—desmethylsildenafil trated that: N for the 1 spray (10 mg dose), 2 spray (20 mg dose) and 3 spray (30 mg dose) the AUC values ofthe metabolite as calculated to 4 and 12 hours were in general, all Within the 90 % CI criteria of 80-125 % and therefore considered comparable to the 25 mg tablet nce product.

N the values obtained for partial AUC calculated to the first hour demonstrated that, in general for all oral spray Test products, values for AUCo_1were substantially lower than the tablet Reference product.

Metabolite/Parent Ratio Partial AUC methylsiidenafil/Sildenafil Ratio) Table 17 presents a summary ofthe Metabolite/Parent Ratio (N— desmethylsildenafil/Sildenafil) pharmacokinetic ters for each product.

WO 85904 PCT/U52012/067763 Table 17 Summary Statistics and Partial AUC Values for Metabolite/Parent Ratio (N-desmethylsildenafil/Sildeuafil) ArithmeticMe-fiSfiCV) ...........

ISn'IOm Sra'zIm Sun'n --—m70.09 56.31 43.62 37.91 36.00 45.49 40.54 37.03 34.57 --_-_-s--a- “ Not calculawd due to BLQ at the 24 hour time point Source: Tables 5.1.1 —5.l.4 Tables 18, 19, and 20 summarize the results ofthe analyses performed on the pharmacokinetic parameters for N—desmethlyl sildenafil/Sildenafil Ratio.

Table 18 Summary of Statistical Analysis l AUC M/P Ratio Test Product lS'ra ' 10 m vs. nceProduet 25 u‘ Test Product A (I Spray; 10 ml) vs. Reference Product D Geometric Means, lhtlo of Means. and 90% Confidence Interval; Lu-Traustormed Data N-damdllylslldcuatlllSlldenlfll Ratio N=24 m (7.73.6052) m77.29 (72.37, 82.54) “ Not calculated due to BLQ at the 24 hour time point Source: Tables 5.2.! Table 19 Summary of Statistical Analysis Partial AUC MIP Ratio Test Product 2 S ra ' 20 .. - vs. Reference Product 5 m: Test Product B (2 Spray; 2|) ml) VI. llefereoce Product D Geometric Means. Ratio of Means, and 90% Confidence Intervals lat-Transformed Data N-deeuletllyhlldmatll/Slldeuatll Ratio N=23 MERE- ————— “ Not calculated due to BLQ atthe 24 me point Source: Table: 5.2.2 PCT/U52012/067763 Table 20 Summary of Statistical Analysis Partial AUC M/P Ratio Test Product 38 n ' 30 In vs. nce Product 25 n: TestfiotluctCOSpnyflOmng Mama!) Geometric Means, Ratio of Means, and 90% Confidence Intervals [in-Transformed Dull N-damethylllltlenafll/Sfldmfll Ratio N-24 [ME—m_— 90% C! —mn (32.39, 93.97) ‘“ Not calculated due to BLQ at the 24 hour time point Source: Table: 5.2.3 Overall, the ion of the metabolite as ed by the M/P ratio for the 10, 20 and 30 mg oral spray doses demonstrates that the most substantive difference was seen for AUC (0-1) interval. These differences were also essentially ndent of the Test as dose (1 spray, 2 sprays and 3 sprays) as only minimal differences were seen between numbers of sprays. There was essentially no difference in l AUC M/P ratio seen for the AUC 0.4 and AUC 0.12 hour intervals.

DISCUSSION The partial AUC assessment indicates that the most ntive difference between the sildenafil OS and the reference Viagra® tablet occurs at AUC (0—1) interval. There are then no substantive differences found in the partial AUC intervals 0-4, 0-12 and 0-24 between the test OS and the reference tablet. This was again demonstrated with the ratio of lite/parent where the most substantive difference is seen for AUC (0-1) interval.

These differences were also essentially independent ofthe sildenafll OS dose (1 spray, 2 sprays and 3 sprays).

REFERENCES Food and Drug Administration. Guidance for Industry: Bioavailability and Bioequivalence s for Orally Administered Drug Products - General Considerations.

Center for Drug Evaluation and Research, March 2003.

Chow, SC. and. J.P. Liu. Design and Analysis of Bioavailability and Bioequivalence PCT/U52012/067763 Studies, Second Edition, Revised and Expanded. New York: Marcel Dekker, Inc., 2000.

Pharsight Corporation. WinNonlin® User's Guide. Pharsight Corporation, 1998-2005.

SAS Institute, Inc. SAS Doc®, Version 9.1. Cary, NC: SAS Institute, Inc., 2002-2006.

Pharmacokinetics of sildenafll after single oral doses in y male subjects: absolute bioavailability, food effects and dose tionality. Donald J. Nichols, Gary J.

Muirhead, Jane A. Harness Br. J. Clin Pharmaco, Vol 53 supp. pages: 58-128, Feb2002 Comparative human pharmacokinetics and metabolism of single-dose oral and intravenous sildenafil authors: Gary J. Muirhead, David J. Rance, Br. J. Clin Pharmaco, Vol 53 supp. Pages, 133-208, Mar 2002.

* * * Having thus described in detail preferred embodiments of the present invention, it is to be understood that the invention defined by the above paragraphs is not to be limited to particular details set forth in the above description as many apparent variations thereof are le without ing from the spirit or scope of the present invention.

The terms “include,” “includes,” or “including” shall be deemed to be followed by the words ut limitation” unless otherwise indicated.

Each patent, patent application, and publication cited or described in the present application is hereby orated by reference in its ty as if each individual patent, patent application, or publication was specifically and individually indicated to be incorporated by reference.

Claims (26)

WHAT IS CLAIMED IS:

1. An oral spray formulation for the treatment of pulmonary arterial ension and/or SSRI-induced sexual dysfunction, comprising sildenafil base or a pharmaceutically acceptable salt thereof, wherein the pH of the ation is 1.5 to 2.4.

2. Use of sildenafil base or a pharmaceutically acceptable salt f at a pH of between 1.5 and 2.4 for the preparation of an oral spray medicament to treat pulmonary arterial hypertension and/or SSRI-induced sexual dysfunction.

3. The oral spray formulation of claim 1 or the use of claim 2, wherein the sildenafil base is present in an amount of 7 to 9 % w/v of the formulation.

4. The oral spray formulation or use of claim 3, wherein the sildenafil base is t in an amount of 8.31 % w/v of the formulation.

5. The oral spray formulation of claim 1 or the use of claim 2, wherein the sildenafil salt is present in an amount of 10 to 12 % w/v of the formulation.

6. The oral spray formulation or use of claim 5, wherein the sildenafil salt is present in an amount of 11.67 % w/v of the formulation.

7. The oral spray formulation or use of claim 5, wherein the sildenafil salt is sildenafil

8. The oral spray formulation of claim 1 or the use of claim 2, n the formulation comprises a polar solvent.

9. The oral spray formulation or use of claim 8, wherein the polar solvent comprises propylene glycol and ethyl alcohol.

10. The oral spray formulation or use of claim 9, wherein the ratio of propylene glycol:ethyl alcohol is 62.5:37.5 % v/v.

11. The oral spray formulation of claim 1 or the use of claim 2, wherein the formulation comprises one or more pH-adjusting .

12. The oral spray formulation or use of claim 11, wherein the pH-adjusting agents are acidifying agents, alkalizing agents or combinations thereof.

13. The oral spray formulation or use of claim 12, n the acidifying agent is hydrochloric acid (HCl).

14. The oral spray formulation or use of claim 13, wherein the HCl is t in an amount of 10% v/v of the formulation.

15. The oral spray formulation or use of claim 12, wherein the alkalizing agent is sodium hydroxide (NaOH).

16. The oral spray formulation or use of claim 15, wherein the NaOH is present in an amount of 2.1 % v/v of the formulation.

17. The oral spray formulation of claim 1 or the use of claim 2, wherein the formulation further comprises one or more of the ing: a taste -masking agent, a flavour or a sweetener.

18. The oral spray formulation of claim 1 or the use of claim 2, wherein the formulation ses one or more pharmaceutically acceptable excipients, rs or a combination thereof.

19. The oral spray formulation of claim 1 or the use of claim 2, wherein the pH of the formulation is 2.2.

20. The oral spray ation of claim 1 or the use of claim 2, wherein the amount of sildenafil administered per spray is 10 mg.

21. The oral spray formulation of claim 1 or the use of claim 2, wherein the amount of sildenafil administered per spray is 20 mg.

22. The oral spray formulation of claim 1 or the use of claim 2, wherein the amount of sildenafil administered per spray is 30 mg.

23. The oral spray formulation or use of claim 17, wherein the taste-masking agent comprises mint.

24. The oral spray formulation or use of claim 23, wherein the mint is peppermint or spearmint.

25. The oral spray formulation or use of claim 17, wherein the flavour is chosen from one or more of the ing: a fruit flavour, a chocolate flavour.

26. The oral spray formulation or use of claim 17, wherein the sweetener is sucralose.