Saturday, 1 February 2014


Figure imgf000078_0003


CAS NO  139755-83-2
Sildenafil citrate, sold as ViagraRevatio and under various other trade names, is a drug used to treat erectile dysfunction and pulmonary arterial hypertension (PAH). It was originally developed by British scientists and then brought to market by the US-based pharmaceutical company Pfizer.[1]It acts by inhibiting cGMP-specific phosphodiesterase type 5 (PDE5), an enzyme that promotes degradation of cGMP, which regulates blood flow in the penis. Since becoming available in 1998, sildenafil has been the prime treatment for erectile dysfunction; its primary competitors on the market are tadalafil (Cialis) and vardenafil (Levitra)

Erectile dysfunction (or ED), also called male impotence, describes a mans inability to achieve and maintain an erection sufficient for mutually satisfactory sexual intercourse with his partner. By itself, ED is not a disease but more of a signal that something else may be a problem.
Viagra works best if taken 30-60 minutes before sexual activity. Only 1 tablet should be taken per day. It should be taken on an empty stomach. Increasing the dosage beyond the recommended amounts will not improve the response and will only result in greater side effects.
Sildenafil is a vasoactive agent used to treat erectile dysfunction and reduce
symptoms in patients with pulmonary arterial hypertension (PAH).
Sildenafil elevates levels of the second messenger, cGMP, by inhibiting its breakdown
via phosphodiesterase type 5 (PDE5). PDE5 is found in particularly high
concentrations in the corpus cavernosum, erectile tissue of the penis.
It is also found in the retina and vascular endothelium.
Increased cGMP results in vasodilation which facilitates generation and
maintenance of an erection. The vasodilatory effects of sildenafil also help reduce
symptoms of PAH.
Sildenafil citrate, sold as ViagraRevatio and under various other trade names,
is adrug used to treat erectile dysfunction and pulmonary arterial
hypertension (PAH).
It was originally developed by British scientists and then brought to market by the
US-basedpharmaceutical company Pfizer

It acts by inhibiting cGMP-specific phosphodiesterase type 5, an enzyme that promotes degradation of cGMP, which regulates blood flow in thepenis.
Since becoming available in 1998, sildenafil has been the prime treatment for erectile dysfunction; its primary competitors on the market are tadalafil (Cialis) and vardenafil (Levitra).
VIAGRA® (sildenafil citrate) , an oral therapy for erectile dysfunction, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).
Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate and has the following structural formula:
  (sildenafil citrate) Structural Formula Illustration
Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7. VIAGRA (sildenafil citrate) is formulated as blue, film-coated rounded-diamond-shaped tablets equivalent to 25 mg, 50 mg and 100 mg of sildenafil for oral administration. In addition to the active ingredient, sildenafil citrate, each tablet contains the following inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, lactose, triacetin, and FD & C Blue #2 aluminum lake.

Target is cyclic guanosine monophosphate phosphodiesterase type 5 receptor.
Fluforma is a company which found the genome explorations and target identification
through affymetrix microarrays.
High throughput functional assays of Si Rna’s inhibit the expression of target,
chromatographic techniques, spectrophotometric methods, adsorptive
stripping voltametry.
Gingel showed that a 50mg dose given daily for 28 days consecutively
improved errections in almost 90% of patients.
Structural validation techniques are NMR technique, Infrared spectrum, HPLC, Mass spectroscopy and Liquid chromatography.


The chemical name of sildenafil is 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl]-1- methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one and its formula is C22H30N6O4S. The melting point of sildenafil is 189-190oC. Its solubility is 3.5 mg/mL in water.
The 1H NMR data of sildenafil is given below. The abbreviations used are s for singlet, d for doublet, t for triplet and q for quartet. The chemical shifts are given in ppm (parts per million) and are followed by the number of Hydrogens the peaks account for:

1H NMR data:
peak (ppm)integrationmultiplicity
broad s
broad s
broad s

Viagra aims at inhibiting the enzyme phosphodiesterase PDE5. It must therefore have a structure that is similar in some places to the substrate. However, there are many other constraints as there are several different types of PDE enzymes which are found in different parts of the body. Of the 7 types of PDE, three selectively hydrolyse cGMP relative to cAMP. PDE5 itself can be found in several parts of the body : the lungs, platelets and various forms of smooth muscle. Selectivety was a very important factor in the research for an inhibitor of PDE5.

The research on a molecule to inhibit PDE type 5 started with the molecule Zaprinast (1) which is shown on the right. The research established that derivatives of pyrazolo[4,3-d]pyrimidin-7-one (2) gave more potent cGMP PDE5 inhibition. The studies carried out compared many molecules by changing the substituents on them and comparing the inhibitory data of these molecules. To establish the selectivity of the compound, the compounds were also screened against the other widespread cGMP enzymes, PDE1 which was isolated from rat liver and PDE3 which was isolated from rat platelet. Further studies showed that sildenafil was the best PDE5 inhibitor.

The different functional groups on the molecule were established by comparing the affinities of the molecules to the different PDE enzymes and establishing the selectivity of each compound made. Of course, high selectivity for PDE type 5 was looked for.

Viagra mimics the guanosine base of cGMP and the extension of 3-substituent fills a space in the enzyme active site occupied by ribose. Substituents on the 5'-position of the phenyl ring reproduce the role of the phosphate bonding.

To improve the solubility of the drug, polar substituents were added which gave compounds with a lower lipophilicity. This was found to also increase the enzyme affinity.
Sidenafil gave an excellent combination of enzyme inhibitory potency, selectivity, solubility and in vivo characteristics.

It is interesting to compare the structure of sidenafil with that of cGMP (cyclic guanosine monophosphate), which is the molecule that usually interacts with PDE5. The drug that was being developed by the researchers had to have some similarity so that it could bind to the active site of the enzyme, PDE5. The 2 dimensional structure of cGMP is given above the 3 dimensional picture, however the latter can be used to view the molecule in 2D as well, with any orientation of the molecule. The first figure also shows that cGMP and pyrazolo[4,3-d]pyrimidin-7-one, which is one of the parent molecules of sildenafil, have a similar size, shape and dipole moment. These were characteristics that were looked for in a molecule that would inhibit PDE5. The following molecule is cGMP :

Sildenafil is the active ingredient in Viagra ™ and it is chemically designated as 5-[2- ethoxy-5 -(4-methyl)piperazine- 1 -yl-sulfonyl)phenyl]- 1 -methyl-3-n-propyl- 1 ,6-dihydro- 7H-pyrazolo[4,3-d]pyrimidin-7-one, and the following chemical structure V:
Figure imgf000003_0001
Sildenafil is originally disclosed in US Patent No. 5,250,534 and it has been found to be particularly useful in the treatment of inter-alia male erectile dysfunction. Multi step syntheses for the production of Sildenafil are disclosed in US'534 with a yield of 27%.
An improved process for its preparation is described in a later application i.e. US Patent No. 5,955,611 which consisting the preparation of 5-chlorosulfonyl-2-ethoxybenzoic acid and converting it into 2-ethoxy-5-(4-methylpiperazin-l-ylsulfonayl)benzoic acid. The acid is then condensed with 4-amino-l-methyl-3-n-propylpyrazole-5-carboxyamide in the presence of N,N'-carbonyldiimidazole, and the resulting 4-[2-ethoxy-5-(4- methylpiperzin-l-ylsulfonyl)benzamido]-l-methyl-3-n-propylpyrazolo-5-carboxyamide is cyclized in an alkaline, neutral or acid solution to yield Sildenafil with about 47% yield.
Patent application number WO 2001/22918 describes the process for the preparation of Sildenafil wherein the process involves the reaction step between 2-ethoxy-5-(4-methyl- piperazine- 1 -sulfonyl)benzaldehyde and 4-amino- 1 -methyl-S-n-propyl-pyrazole-S- carboxamide to form an intermediate which is further cyclised to form Sildenafil.
Patents/ patent applications US6204383, US20030069422, US20030144530, US 20040106796, US 20040110948, EP 0812845, EP 1002798, EP 1077214, WO 01/19827, WO 04/31134 also discloses several processes for the preparation of Sildenafil citrate.

Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7. Sildenafil citrate has most recently been utilized as the basis for an oral therapy for erectile dysfunction and has been marketed by Pfizer Labs under the trademark Viagra®. Publications relating to benign visual side-effects (e.g., blue-shift in vision, light-sensitivity, and blurring noted to occur in some patients) of sildenafil prompted the FDA to insist on product insert warnings.

Sexual dysfunction

The primary indication of sildenafil is treatment of erectile dysfunction (inability to sustain a satisfactory erection to complete intercourse). Its use is now standard treatment for erectile dysfunction in all settings, including diabetes.[2]
People on antidepressants may experience sexual dysfunction, either as a result of their illness or as a result of their treatment. A 2003 study showed that sildenafil improved sexual function in men in this situation.[3] Following up reports from 1999,[4] the same researchers found that sildenafil improved sexual function in female patients on antidepressants as well.[5]

Pulmonary hypertension

As well as erectile dysfunction, sildenafil citrate is also effective in the rare disease pulmonary arterial hypertension (PAH). It relaxes the arterial wall, leading to decreased pulmonary arterial resistance and pressure. This, in turn, reduces the workload of the right ventricle of the heart and improves symptoms of right-sided heart failure. Because PDE5 is primarily distributed within the arterial wall smooth muscle of the lungs and penis, sildenafil acts selectively in both these areas without inducing vasodilation in other areas of the body. Pfizer submitted an additional registration for sildenafil to the United States Food and Drug Administration (FDA), and sildenafil was approved for this indication in June 2005. The preparation is named Revatio, to avoid confusion with Viagra, and the 20 milligram tablets are white and round. Sildenafil joins bosentan and prostacyclin-based therapies for this condition.[6]

The synthesis of sildenafil citrate was first reported in the Bioorganic & Medicinal Chemistry Letters, Vol 6, pp. 1819, 1824, 1996. The reaction scheme is reproduced below. Sildenafil was reported in this journal as "a potent and selective inhibitor of type 5 PDE with utility for the treatment of male erectile dysfunction".

The first step of the synthesis is the reaction of a diketoester (1) and hydrazine to give the pyrazole ring. The regioselective N-methylation of the pyrazole and hydrolysis gives a carboxylic acid (3). Compound (3) is then reacted with HNO3 and H2SO4 to give a nitrated product.
This is then followed by a carboxamide formation and the reduction of the nitro group. The compound (4) is then acylated under basic conditions and this produces the pyrazolopyrimidinone (6). (6) is then chlorosulphonylated selectively on the 5'-position of the phenyl ring. This can then couple with an amine to give sildenafil (7).
The yield of each step is given on the reaction scheme. 

This is the original synthesis which was reported in the literature when the molecule was first synthesised. A variant of the synthesis was published but the changes it involved only consisted in the change of a few reactants, and no major changes were reported. This synthesis appeared in the January 1999 issue of Chemistry in Britain. This journal only reported the original discovery synthesis and said that the synthesis used commercially had not been published.

The drug is commercially manufactured by an alternative route. The reaction scheme is described in the patent which was published on 17 decembre 1997. However, the synthesis used in the commercial manufacture could be different to this. The patent was filed by the Pfizer Research and Development Company. The scheme is reproduced below.

The synthesis was described in a lot of detail, including the solvents that were the best to use, however, these details have not been reproduced here. These and further details about the synthesis can be found on the original patent document.

The reaction pathway is explained in more detail below.
Compound 2 can be prepared by the chlorosulphonation of 2-ethoxybenzoic acid (1). The conversion of compound 2 to compound 4 is achieved by N-sulphonation of 1-methylpiperazine and may be conducted in a one or two step procedure. Coupling of compound 4 with compound 6 can be achieved by any of the known amide bond-forming reactions. The aminopyrazole (6) is obtainable by the conventional reduction of the corresponding nitropyrazole (5). The resulting solution of compound 6 may be used directly after filtration in the coupling reaction with compound 4.
The cyclisation of compound 7 to give sildenafil has been achieved in yields up to 95%. Thus the overall yield of sildenafil based on compound 1 as a starting material, depending on whether the one or two step sulphonylation procedure is used can be as high as 51.7% or 47.8% respectively. This compares favourably with the first synthesis in which the overall yield is 27.6%.
The cyclisation of compound 7 to sildenafil can be conducted under neutral or acidic conditions. Under neutral conditions, compound 7 is heated, optionally in the presence of a solvent and/or optionally in the presence of a dehydrating agent and/or mechanical water removal system. Under acidic conditions, the reaction is carried out with a prolic acid or Lewis acid optionally in the presence of a solvent.

The reagents employed in the reactions can vary, but the following are among the ones recommended by the submitters of the patent:
The first step is the chlorosulphonylation of 2-ethoxybenzoic acid. This can be achieved by reacting 1 equivalent mole of thionyl chloride with 4 equivalent mole of chlorosulphonic acid. Addition of 1-methylpiperazine to an aqueous suspension of compound 2 is a suitable reaction to obtain compound 4 in one step. The carboxylic function of compound 4 can be activated using a 5% excess of N,N'-carbonyldiimidazole in ethyl acetate. This intermediate can then be reacted with imidazolide and compound 6. Compound 6 is obtainable by reduction of the corresponding nitropyrazole 5 for example by using palladium catalysed hydrogenation in ethyl acetate. Compound 7 is then cyclised to complete the reaction scheme and give sildenafil.
Information about the synthesis used to manufatcure Viagra was not available, and the two presented above are only the ones which were published. It is not surprising that the commercial manufacture of the drug is by a pathway that is not published.



Figure imgf000007_0001

Example 1
Preparation of 2- hydroxy-5-(4 methyl)-l-piperazinyl sulphonyl) benzoic acid Step-1: Preparation of 5-Chlorosulfonyl-2-hydroxy benzoic acid
To the chilled chlorosulfonic acid (1012 g), salicylic acid (200 g) was added at 0-50C over a period of 1 hour 40 min. The temperature of the reaction mixture was maintained at 20-250C for 2 hrs. Then thionyl chloride (172.4 g) was added over a period of 15 min and maintained for 12 hrs. The product formed was poured onto ice and maintained for lhr. The product was filtered and washed with DM water to get 5-Chlorosulfonyl-2- hydroxy benzoic acid.
Step-2: Preparation of 2-hydroxy-5-(4-methyI)-l-piperazinylsulphonyl)benzoic acid
5-Chlorosulfonyl-2-hydroxy benzoic acid (40Og) obtained in step 1 was dissolved in acetone (1200 ml) and cooled to 5-100C. To this clear solution N-methyl piperazine (254 g) was added and maintained for 2 hrs. The product formed was filtered, washed with water and purified in methanol to get 308 g of the titled compound.
NMR Data:
1H-NMR (300 MHz in DMSO-d6): δ 2.78 (3H, s), 3.17 (8H, brs), 6.85(1H, d, J = 8.7),
7.52 - 7.56 (IH, dd, J=8.7, 2.7), 7.95 (IH, d, J = 2.7)
13C-NMR (75 MHz in DMSO-d6): δ 41.98, 43.36, 51.60, 117.58, 118.33, 119.46,
130.28, 132.01, 167.63, 170.35.
Melting point: 268-2720C
Purity by HPLC: 99.4% Example 2
Preparation of 4-[2-hydroxy-5-(4-methyI-l-piperazinyIsulphonyl)benzamido]-l- methyl-3-n-propyl-lH-pyrazole-5-carboxamide
2-Hydroxy-5-(4-methyl-l-piperazinylsulphonyl)benzoic acid (10Og) was dissolved in dichloromethane (500 ml) and triethylamine (50 ml) followed by distillation to get residual mass. The residual mass was dissolved in dichloromethane (1500ml) followed by the addition of 1,3-dicyclohexylcarbodiimide (75.6 g) and 1-hydroxybenzotriazole (45g). The reaction mixture was stirred at 27-280C and then 4-amino-l-methyl-3-n-propyl- pyrazole-5-carboxamide (60.6 g) was added. The reaction mixture was heated to reflux temperature and maintained for 3 hours. Filtered the undissolved material at hot and washed the cake with dichloromethane (200ml). The filtrate was distilled out completely to get residue. Dissloved the residue in methanol (300ml) at 4O0C and then cooled the mass to 27-280C and stirred overnight. Further, cooled the mass to 5-70C and stirred for lhr. Filtered the product and washed the cake with chilled methanol (100ml) and dried to get 130 g of title compound.
NMR Data:
1H-NMR (300 MHz in DMSO-d6): δ 0.87 (3H, t, J = 7.5), 1.53-1.60 (2H, m), 2.39- 2.46(5H, m), 2.72 (4H, brs), 2.96 (4H, brs), 3.17 (3H, s), 3.91 (3H, s), 6.93 (H, d, J = 8.7), 7.57-7.61 (H, dd, J=8.7 & 2.1), NH2-(2H, brs, J =7.69 & 7.72), 8.15 (IH, d, J=2.1) 11.5 (OH, br).
13C-NMR (75 MHz in DMSO-(I6): 613.80, 21.37, 27.45, 44.05, 44.75, 48.60, 52.87, 116.37, 118.06, 119.67, 120.03, 130.64, 132.17, 132.38, 146.16, 160.83, 166.33, 166.89.
Purity by HPLC: 97.5%
Example 3
Preparation of 5-[2-hydroxy-5-(4-methylpiperazinyl-l-yl-sulphonyl)phenyl]-l- methyl -3-n- propyl-l,6-dihydro-7H-pyrazolo-[4,3-d]pyrimidin-7-one Sodium hydroxide (34 g) was added into diethylene glycol (780ml) and then heated to 110-1150C. 4-[2-hydroxy-5-(4-methyl-l-piperazinylsulphonyl)benzamido)-l-methyl-3-n- propyl-lH-pyrazole-5-carboxamide (130 g) obtained from example 2 was added to the above reaction mixture. The reaction mixture was maintained at 125-13O0C for 4-6 hrs. The reaction mixture was cooled to room temperature and then DM water (1300ml) was added slowly over 20min at 250C and maintained at this temperature for 1 hour. Filtered the mass and filtrate pH was adjusted to 6.5-7.5 with dilute hydrochloric acid at room temperature and stirred at room temperature for 2-3hrs. Product was filtered and slurried the cake with excess DM Water followed by purification in methanol to get 91 g of titled compound.
NMR Data:
1H-NMR (300 MHz in DMSO-d6): δ 0.96 (3H, t, J=7.2), 1.71-1.83 (2H, m), 2.41 (3H, s), 2.78-2.83 (6H, m), 2.99 (4H, brs), 4.15 (3H3 s), 6.93 (IH, d, J=8.7), 7.54-7.57 (IH, dd, J=8.7, 2.1), 8.47 (lH, d, J=2.1).
13C-NMR (75MHz in DMSO-d6): 513.84, 21.52, 27.20, 37.80, 43.94, 44.72,- 52.80, 115.97, 119.82, 120.19, 124.48, 128.71, 131.13, 136.46, 143.82, 151.26, 154.05, 167.24.
Purity by HPLC: 97.8%
Example 4
Preparation of 5-[2-ethoxycarbonyloxy-5-(4-methylpiperazin-l-yl-sulfonyI)phenyl]- l-methyI-3n-propyI-l,6-dihydro-7H-pyrazolo-[4,3-d]pyrimidin-7-one
5-[2-hydroxy-5-(4-methylpiperazinyl-l -yl-sulphonyl)phenyl]- 1 -methyl-3 -n- propyl- 1 ,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (90 g) obtained from example 3 was dissolved in dichloromethane (360 ml) and added triethyl amine (41 ml) at room temperature and stirred for 10 min. The reaction mixture was cooled to 0-50C and followed by the addition of ethyl chloro formate (24ml) over 30 min under nitrogen atmosphere. The temperature of the reaction was raised slowly to 28-3O0C and maintained for 24 hrs. The reaction mixture was cooled to 0-50C and kept it for 1 hr. The product formed was filtered, washed with dichloromethane, dried and purified from methanol (270ml) to obtain 81 g of the title compound.
NMR Data:
1H-NMR (300 MHz in DMSO-d6): δ 0.92 (3H, t, J=7.2), 1.17 (3H, t, J=7.2), 1.68-1.75 (2H, m), 2.16 (3H, s), 3.99 (4H, br), 2.73 (2H, t, J=7.0), 4.12-4.19 (2H, t, J=6.9), 4.15 (3H, s), 7.71 (IH, d, J = 8.7), 7.93-7.97 (IH, dd, J=8.7 & 2.1), 8.01 (IH, d, J=2.0)
13C-NMR (75 MHz in DMSO-d6): 513.47, 13.80, 21.57, 27.03, 37.90, 45.72, 53.49, 65.12, 124.51, 127.65, 130.14, 130.61, 132.82, 137.30, 144.96, 146.51, 151.38, 151.66, 154.36.
Purity by HPLC: 98.6%
Example 5
Preparation of 5-[2-ethoxy-5-(4-methyl piperazine-l-ylsulfonyl)phenyl]-l-methyl-3- n-propyl-1 ,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (Sildenafil base)
5-[2-Ethoxycarbonyloxy-5-(4-methylpiperazin-l-yl-sulfonyl)phenyl]-l-methyl-3-n- propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (50g) was dissolved in ethanol (750ml) in an autoclave and then added dicyclohexylcarbodimide (29.8g). The reaction temperature was raised to HO0C with internal pressure of 1.8-4.0 kg/cm and maintained for 6 hours followed by cooling to room temperature. The solvent was distilled off to get the crude Sildenafil base. The base thus obtained was dissolved in dichloromethane (380ml), filtered and filtrate was distilled out completely to get solid material, which is again dissolved in a mixture dichloromethane and isopropyl ether. The crude obtained was recrystallized from ethanol (260ml) to obtain 17.4gm of pure Sildenafil base.
Purity by HPLC: 99.77% Example 6
Preparation of 5-[2-Ethoxy-5-(4-methylpiperazine-l-yI-sulfonyl)phenyl]-l-methyl- 3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one citrate (Sildenafil Citrate)
Sildenafil base (50 g) was dissolved in acetone (850 ml) at 550C and then slowly added citric acid solution (20 g in 100 ml acetone) over 45 min and maintain the reaction mixture for about 30 min. The reaction mixture was cooled, filtered and dried to get 65 g of Sildenafil citrate.
Purity by HPLC: 99.85%

Chemical synthesis

The preparation steps for synthesis of sildenafil are as follows:[45]
  1. Methylation of 3-propylpyrazole-5-carboxylic acid ethyl ester with hot dimethyl sulfate
  2. Hydrolysis with aqueous NaOH to free acid
  3. Nitration with oleum/fuming nitric acid
  4. Carboxamide formation with refluxing thionyl chloride/NH4OH
  5. Reduction of nitro group to amino
  6. Acylation with 2-ethoxybenzoyl chloride
  7. Cyclization
  8. Sulfonation to the chlorosulfonyl derivative
  9. Condensation with 1-methylpiperazine.







Patent issues and expirations

European Union

Pfizer's patent on sildenafil citrate expired in some member countries of the EU, Austria, Denmark, France, Germany, Ireland, Italy, The Netherlands, Spain, Sweden, United Kingdom as well as Switzerland on 21 June 2013.[60][61][62] A UK patent held by Pfizer on the use of PDE5 inhibitors (see below) as treatment of impotence was invalidated in 2000 because of obviousness; this decision was upheld on appeal in 2002.[63][64]

United States

In 1992 Pfizer filed a patent covering the substance sildenafil and its use to treat cardiovascular diseases.[65] This patent was published in 1993 and expired in 2012. In 1994 Pfizer filed a patent covering the use of sildenafil to treat erectile dysfunction.[66] This patent was published in 2002 and will expire in 2019. Teva sued to have the latter patent invalidated, but Pfizer prevailed in an August 2011 federal district court case.[67]
The patent on Revatio (indicated for pulmonary arterial hypertension rather than erectile dysfunction) expired in late 2012. Generic versions of this low-dose form of sildenafil have been available in the U.S. from a number of manufacturers including Greenstone, Mylan and Watson, since early 2013.[68] There is no legal barrier to doctors prescribing this form of sildenafil "off label" for erectile dysfunction, although the dosage typically required for treating ED requires patients to take multiple pills.


In Canada, Pfizer's patent 2,324,324 for Revatio (sildenafil used to treat pulmonary hypertension) was found invalid by the Federal Court in June 2010, on an application by Ratiopharm Inc.[69][70]
On November 8, 2012 the Supreme Court of Canada ruled that Pfizer's patent 2,163,446 on Viagra was invalid from the beginning because the company did not provide full disclosure in its application. The decision, Teva Canada Ltd. v. Pfizer Canada Inc., pointed to section 27(3)(b) of The Patent Act which requires that disclosure must include sufficient information "to enable any person skilled in the art or science to which it pertains" to produce it. It added further: "As a matter of policy and sound statutory interpretation, patentees cannot be allowed to 'game' the system in this way. This, in my view, is the key issue in this appeal."[71]
Teva Canada launched Novo-Sildenafil, a generic version of Viagra, on the day the Supreme Court of Canada released its decision.[72][73][74] To remain competitive, Pfizer then reduced the price of Viagra in Canada.[75] However, on November 9, 2012, Pfizer filed a motion for a re-hearing of the appeal in the Supreme Court of Canada,[76] on the grounds that the court accidentally exceeded its jurisdiction by voiding the patent.[77] Finally, on April 22, 2013, The Supreme Court of Canada invalidated Pfizer's patent altogether.[78]


Manufacture and sale of sildenafil citrate drugs known as "generic viagra" is common in India, where Pfizer's patent claim does not apply. Trade names include Kamagra (Ajanta Pharma), Silagra (Cipla), Edegra (Sun Pharmaceutical), Penegra (Zydus Cadila), and Zenegra (Alkem Laboratories).


Manufacture and sale of sildenafil citrate drugs known as "generic viagra" is common in China, where Pfizer's patent claim is not widely enforced.

Other countries

Egypt approved Viagra for sale in 2002, but soon afterwards allowed local companies to produce generic versions of the drug, citing the interests of poor people who would not be able to afford Pfizer's price.[79]
Pfizer's patent on sildenafil citrate expired in Brazil in 2010.[80]


  1. Jump up to:a b Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, Naylor AM, Osterloh IH, Gingell C (June 1996). "Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction". Int. J. Impot. Res. 8 (2): 47–52.PMID 8858389.
  2. Jump up^ Vardi M, Nini A (2007). "Phosphodiesterase inhibitors for erectile dysfunction in patients with diabetes mellitus". In Vardi, Moshe. Cochrane Database Syst Rev (1): CD002187.doi:10.1002/14651858.CD002187.pub3PMID 17253475.
  3. Jump up^ Nurnberg HG, Hensley PL, Gelenberg AJ, Fava M, Lauriello J, Paine S (January 2003)."Treatment of antidepressant-associated sexual dysfunction with sildenafil: a randomized controlled trial"JAMA 289 (1): 56–64. doi:10.1001/jama.289.1.56PMID 12503977.
  4. Jump up^ Nurnberg HG, Hensley PL, Lauriello J, Parker LM, Keith SJ (August 1999). "Sildenafil for women patients with antidepressant-induced sexual dysfunction"Psychiatr Serv 50 (8): 1076–8. PMID 10445658.
  5. Jump up^ Nurnberg HG, Hensley PL, Heiman JR, Croft HA, Debattista C, Paine S (2008). "Sildenafil Treatment of Women With Antidepressant-Associated Sexual Dysfunction". JAMA 300 (4): 395–404. doi:10.1001/jama.300.4.395PMID 18647982.
  6. Jump up^ "FDA Approves Pfizer's Revatio as Treatment for Pulmonary Arterial Hypertension" (Press release). Pfizer. June 6, 2005. Archived from the original on August 28, 2005.
  7. Jump up^ Richalet JP, Gratadour P, Robach P, et al. (2005). "Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension". Am. J. Respir. Crit. Care Med. 171 (3): 275–81.doi:10.1164/rccm.200406-804OCPMID 15516532.
  8. Jump up^ Perimenis P (2005). "Sildenafil for the treatment of altitude-induced hypoxaemia". Expert Opin Pharmacother 6 (5): 835–7. doi:10.1517/14656566.6.5.835PMID 15934909.
  9. Jump up^ Fagenholz PJ, Gutman JA, Murray AF, Harris NS (2007). "Treatment of high altitude pulmonary edema at 4240 m in Nepal". High Alt. Med. Biol. 8 (2): 139–46.doi:10.1089/ham.2007.3055PMID 17584008.
  10. Jump up^ "Pill Identifier". Retrieved 2009-02-10. "This site is intended for viewing by the USA audience only. If you are in another country, local laws may not permit access to the medical information contained in this site."
  11. Jump up to:a b c "Viagra Prescribing Information" (PDF). Pfizer. October 2007. Archived from the original on 14 November 2012. Retrieved 14 November 2012.
  12. Jump up^ "Viagra and vision". VisionWeb. 29 October 2001. Retrieved 2009-02-10.
  13. Jump up^ "FDA Updates Labeling for Viagra, Cialis and Levitra for Rare Post-Marketing Reports of Eye Problems"United States Food and Drug Administration. 8 July 2005. Archived from the original on February 23, 2008. Retrieved 2009-02-10.
  14. Jump up^ Pomeranz HD, Bhavsar AR (March 2005). "Nonarteritic ischemic optic neuropathy developing soon after use of sildenafil (viagra): a report of seven new cases". J Neuroophthalmol 25 (1): 9–13. doi:10.1097/00041327-200503000-00003PMID 15756125.
  15. Jump up^ Egan R, Pomeranz H (February 2000). "Sildenafil (Viagra) associated anterior ischemic optic neuropathy". Arch. Ophthalmol. 118 (2): 291–2. PMID 10676804.
  16. Jump up^ Pomeranz HD, Smith KH, Hart WM, Egan RA (March 2002). "Sildenafil-associated nonarteritic anterior ischemic optic neuropathy". Ophthalmology 109 (3): 584–7. doi:10.1016/S0161-6420(01)00976-9PMID 11874765.
  17. Jump up^ Cunningham AV, Smith KH (March 2001). "Anterior ischemic optic neuropathy associated with viagra". J Neuroophthalmol 21 (1): 22–5. doi:10.1097/00041327-200103000-00006.PMID 11315976.
  18. Jump up^ Boshier A, Pambakian N, Shakir SA (September 2002). "A case of nonarteritic ischemic optic neuropathy (NAION) in a male patient taking sildenafil". Int J Clin Pharmacol Ther 40 (9): 422–3. PMID 12358159.
  19. Jump up^ Akash R, Hrishikesh D, Amith P, Sabah S (August 2005). "Case report: association of combined nonarteritic anterior ischemic optic neuropathy (NAION) and obstruction of cilioretinal artery with overdose of Viagra". J Ocul Pharmacol Ther 21 (4): 315–7.doi:10.1089/jop.2005.21.315PMID 16117695.
  20. Jump up^ "FDA Announces Revisions to Labels for Cialis, Levitra and Viagra"United States Food and Drug Administration. 18 October 2007. Archived from the original on 11 July 2007. Retrieved 10 February 2009.
  21. Jump up^ "Viagra (sildenafil citrate) tablets". page 29: Pzifer. October 2007. Retrieved 2009-10-25.
  22. Jump up^ Kloner RA (2005). "Pharmacology and drug interaction effects of the phosphodiesterase 5 inhibitors: focus on alpha-blocker interactions". Am J Cardiol 96 (12B): 42M–46M.doi:10.1016/j.amjcard.2005.07.011PMID 16387566.
  23. Jump up^ Cheitlin MD, Hutter AM Jr, Brindis RG, Ganz P, Kaul S, Russell RO Jr, Zusman RM (1999). "ACC/AHA expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. American College of Cardiology/American Heart Association". Journal of the American College of Cardiology 33 (1): 273–82. doi:10.1016/S0735-1097(98)00656-1.PMID 9935041.
  24. Jump up^ Peterson K (2001-03-21). "Young men add Viagra to their drug arsenal". USAToday.
  25. Jump up to:a b c d e Smith KM, Romanelli F (2005). "Recreational use and misuse of phosphodiesterase 5 inhibitors". J Am Pharm Assoc (2003) 45 (1): 63–72; quiz 73–5.doi:10.1331/1544345052843165PMID 15730119.
  26. Jump up^ Sildenafil Will Not Affect Libido - Fact!
  27. Jump up to:a b Mondaini N, Ponchietti R, Muir GH, Montorsi F, Di Loro F, Lombardi G, Rizzo M (June 2003). "Sildenafil does not improve sexual function in men without erectile dysfunction but does reduce the postorgasmic refractory time". Int. J. Impot. Res. 15 (3): 225–8.doi:10.1038/sj.ijir.3901005PMID 12904810.
  28. Jump up^ McCambridge J, Mitcheson L, Hunt N, Winstock A (March 2006). "The rise of Viagra among British illicit drug users: 5-year survey data". Drug Alcohol Rev 25 (2): 111–3.doi:10.1080/09595230500537167PMID 16627299.
  29. Jump up^ Eloi-Stiven ML, Channaveeraiah N, Christos PJ, Finkel M, Reddy R (November 2007). "Does marijuana use play a role in the recreational use of sildenafil?". J Fam Pract 56 (11): E1–4.PMID 17976333.
  30. Jump up^ "The 2007 Ig Nobel Prize Winners". Improbable Research. 4 October 2007. Retrieved 2009-02-10.
  31. Jump up^ Agostino PV, Plano SA, Golombek DA (June 2007). "Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules"Proc. Natl. Acad. Sci. U.S.A. 104 (23): 9834–9. doi:10.1073/pnas.0703388104PMC 1887561PMID 17519328.
  32. Jump up^ Teri Thompson, Christian Red, Michael O'Keefffe, and Nathaniel Vinton (10 June 2008)."Source: Roger Clemens, host of athletes pop Viagra to help onfield performance"Daily News (Daily News). Retrieved 2009-02-10.
  33. Jump up^ Busbee J (2012-11-28). "Bears’ Brandon Marshall says some NFL players use Viagra … ON THE FIELD"Yahoo! Sports. Retrieved 2012-11-28.
  34. Jump up^ Siegel-Itzkovich J (July 1999). "In brief: Viagra makes flowers stand up straight"BMJ 319(7205): 274B. doi:10.1136/bmj.319.7205.274aPMC 1126921PMID 10426724.
  35. Jump up^ "Prolongation of the shelf life of fruits and flowers". Biology Department, University of Hamburg. Retrieved 28 November 2012.
  36. Jump up^ Oh SS, Zou P, Low MY, Koh HL. Detection of sildenafil analogues in herbal products for erectile dysfunction (2006). "Detection of sildenafil analogues in herbal products for erectile dysfunction". Journal of Toxicology and Environmental Health Part A 69 (21): 1951–1958.doi:10.1080/15287390600751355PMID 16982533.
  37. Jump up^ Venhuis BJ, Blok-Tip L, de Kaste D (2008). "Designer drugs in herbal aphrodisiacs".Forensic Science International 177 (2–3): 25–27. doi:10.1016/j.forsciint.2007.11.007.PMID 18178354.
  38. Jump up^ FDA letter to Libidus distributor
  39. Jump up^ FDA Warns Consumers About Dangerous Ingredients in "Dietary Supplements" Promoted for Sexual Enhancement
  40. Jump up^ Hidden Risks of Erectile Dysfunction "Treatments" Sold Online
  41. Jump up^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 9th edition, Biomedical Publications, Seal Beach, CA, 2011, pp. 1552–1553.
  42. Jump up^ Sung, B. J.; Hwang, K.; Jeon, Y.; Lee, J. I.; Heo, Y. S.; Kim, J.; Moon, J.; Yoon, J.; Hyun, Y. L.; Kim, E.; Eum, S.; Park, S. Y.; Lee, J. O.; Lee, T.; Ro, S.; Cho, J. (2003). "Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules". Nature 425 (6953): 98–102. doi:10.1038/nature01914PMID 12955149. edit
  43. Jump up to:a b Webb, D.J.; Freestone, S.; Allen, M.J.; Muirhead, G.J. (March 4, 1999). "Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist". Am. J. Cardiol. 83 (5A): 21C–28C. doi:10.1016/S0002-9149(99)00044-2PMID 10078539.
  44. Jump up^ "Viagra Clinical Pharmacology". 2008. Retrieved 2008-08-20.
  45. Jump up^ Dunn PJ (2005). "Synthesis of Commercial Phosphodiesterase(V) Inhibitors". Org Process Res Dev 2005 (1): 88–97. doi:10.1021/op040019c.
  46. Jump up^ "Research"ABM. Abertawe Bro Morgannwg University Health Board. 4 July 2008. Archived from the original on 26 September 2008. Retrieved 6 August 2008. "Our clinicians regularly offer patients the opportunity to take part in trials of new drugs and treatments. Morriston Hospital in Swansea, was the first in the world to trial Viagra!"
  47. Jump up^ Terrett NK, Bell AS, Brown D, Elllis P (1996). "Sildenafil (Viagra), a potent and selective inhibitor of Type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction". Bioorg Med Chem Lett 6 (15): 1819–1824. doi:10.1016/0960-894X(96)00323-X.
  48. Jump up^ Kling J (1998). "From hypertension to angina to Viagra". Mod. Drug Discov. 1: 31–38.ISSN 1532-4486OCLC 41105083.
  49. Jump up^ Viagra sales peak at $1,934m in 2008
  50. Jump up^ Bellis M. "Viagra, the patenting of an aphrodisiac". Retrieved 2009-02-10.
  51. Jump up^ Ciment, J (1999). "Missouri fines internet pharmacy"BMJ (British Medical Journal) 319(7221): 1324. doi:10.1136/bmj.319.7221.1324gPMC 1174637PMID 10567131.
  52. Jump up^ Devine, Amy (September 29, 2008). "Chemists plan to sell Viagra on the internet"Daily Record. Retrieved 2012-04-30.
  53. Jump up^ "Urban Dictionary: Vitamin V". Urban Dictionary. January 16, 2009. Retrieved 2013-12-27.
  54. Jump up^ Keith A (2000). "The economics of Viagra". Health Aff (Millwood) 19 (2): 147–57.doi:10.1377/hlthaff.19.2.147PMID 10718028.
  55. Jump up^ McGuire S (2007-01-01). "Cialis gaining market share worldwide"Medical Marketing & Media. Haymarket Media. Archived from the original on 2009-01-03. Retrieved 2009-02-10.
  56. Jump up^ Mullin, Rick (June 20, 2005). "Viagra"Chemical & Engineering News 83 (25). Retrieved 2008-08-20.
  57. Jump up^ Berenson, Alex (December 4, 2005). "Sales of Impotence Drugs Fall, Defying Expectations"The New York Times. Retrieved 2013-12-27.
  58. Jump up^ "Over-the-counter Viagra piloted". BBC News. BBC News. 11 February 2007. Retrieved 2009-02-10.
  59. Jump up^ "Pfizer to sell Viagra online, in first for Big Pharma: AP". CBS News. Retrieved 6 May 2013.
  60. Jump up^ "Actavis Launches Generic Viagra in Europe as Patents Expire". Retrieved 2013-10-25.
  61. Jump up^ Jim Edwards (October 21, 2009). "What Will Happen When Viagra Goes Generic?". Retrieved 2013-12-27.
  62. Jump up^ "Is Viagra about to lose its pulling power in the UK?". The Guardian. Retrieved 13 June 2013.
  63. Jump up^ Murray-, Rosie (23 January 2002). "Viagra ruling upsets Pfizer". London: Telegraph Media Group Limited. Archived from the original on 22 August 2009. Retrieved 10 February 2009.
  64. Jump up^ "Pfizer Loses UK Battle on Viagra Patent"UroToday. Thomson Reuters. 17 June 2002. Archived from the original on 25 June 2007. Retrieved 10 February 2009.
  65. Jump up^ U.S. Patent 5,250,534
  66. Jump up^ U.S. Patent 6,469,012
  67. Jump up^ "Pfizer Wins Viagra Patent Infringement Case Against Teva Pharmaceuticals". Bloomberg. August 15, 2011. Retrieved 2012-04-01.
  68. Jump up^ "Pfizer's Revatio Goes Generic". Zacks Equity Research. November 15, 2012. Retrieved 2013-10-05.
  69. Jump up^ "Revation patent ruled invalid for lack of sound prediction and obviousness"Canadian Technology & IP Law. Stikeman Elliott. 2010-06-18. Retrieved 2012-11-14.
  70. Jump up^ "Pfizer Canada Inc. v. Ratiopharm Inc., 2010 FC 612". CanLII.
  71. Jump up^ Teva Canada Ltd. v. Pfizer Canada Inc. 2012 SCC 60 at par. 80 (8 November 2012)
  72. Jump up^ John Spears (2012-11-08). "Supreme Court ruling could lead to cheaper versions of Viagra"The [Toronto] Star. Retrieved 2012-11-14.
  73. Jump up^ Ken Hanly (2012-11-08). "Canadian Supreme court rules Viagra patent invalid"Digital Journal. Retrieved 2012-11-14.
  74. Jump up^ "Viagra patent tossed out by Supreme Court: Decision allows generic versions of drug to be produced"CBC News. 2012-11-08. Retrieved 2012-11-14.
  75. Jump up^ "Pfizer Canada drops Viagra price after generic versions get Supreme Court green light".Financial Post. 2012-11-22. Retrieved 2013-12-27.
  76. Jump up^ "SCC Case Information, Docket No. 33951". Retrieved 2012-11-14.
  77. Jump up^ Kirk Makin (2012-11-15). "In rare move, Pfizer asks Supreme Court to reconsider ruling that killed Viagra patent"The Globe and Mail. Retrieved 2012-11-15.
  78. Jump up^ Gowling Lafleur Henderson LLP, Hélène D'Iorio (2013-04-22). "The Supreme Court of Canada holds Pfizer’s Viagra patent invalid"Lexology. Retrieved 2013-12-27.
  79. Jump up^ Allam, Abeer (October 4, 2002). "Seeking Investment, Egypt Tries Patent Laws"New York Times. Retrieved 2013-12-27.
  80. Jump up^ Viagra patent expires in June, says Brazilian court

External links


  1. Hello, I read your article with interest and I have a question, what do you think about generic sildenafil such as silagra-100 and others, are they safe for long-term use?

  2. The producers of this generic Viagra didn't spend a lot cash in direction of its improvement and so they have solely reproduced the formulation. As such the value of generic Viagra is so low-cost and inexpensive to widespread man. You cannot resist its sale.Allover this is a great blog. If you want to know more about this visit here Pharmacy XL.

  3. Thanks for such things and it would be helpful for us. and i really think it would be good knowledge. As such the value of generic Viagra is so low-cost and inexpensive to widespread man. You cannot resist its sale.Buy aurogra 100 mg online


  4. Viagra Tablets
    Online Shopping in Pakistan !

    Viagra Tablets
    in Islamabad !

    Viagra Tablets
    in Lahore !

    Viagra Tablets
    in Karachi !

    Viagra Tablets
    in Hyderabad !

  5. Very useful information for people, I think this is what everyone needs. Look here : .

  6. I was looking for something like this…I found it quiet interesting, hopefully you will keep posting such blogs…
    .Keep sharing you can fildena 100mg

    at affordable price.
    fildena 100mg

    Sildenafil 100mg

    Sildenafil Citrate 100mg

    Cenforce 100

    Cenforce 150

    Cenforce 200

    Fildena 100

    buy vidalista 20 mg online

  7. The British scientists made so many Tablets for sexual activites such as:- sildenafil, viagra, Revatio and various other drugs used to treat pulmonary arterial hypertension. But I think Viagra is the best tablet i ever used.

  8. The problem of ED arises with lack of blood flow in the penile area. The oral medications are helpful to relax the blood vessels and increase the flow of blood by giving long erection. Sildenafil citrate 100mg pills

  9. vidalista-20 acheter-vidalista-france vidalista-france

  10. cenforce-france fildena-francais

  11. This comment has been removed by the author.

  12. Many people who utilized Siltada accomplished better and longer sensual experiences unafraid of losing an erection. Siltada 120mg is a mix of Sildenafil and Tadalafil

  13. Thanks to the benefits of Kamagra online UK against erectile dysfunction, many couples have found that they enjoyed sex more, and some couples had sex more frequently. While Kamagra Oral Jelly UK it is not considered an aphrodisiac, some couples have reported an increase in the sexual arousal and desire. Some men even state that their orgasms are more intense.

  14. Many of the individuals are nowdays experiencing the sleeping related issue, must contact us. Here you will get appropriate treatment with respect to your concern. Buy Modalert Online UK, which helps each person in reducing stress by providing proper rest to stay stable in their daily working schedule.

  15. sildenafil citrate 100mg best price

    Thanks for this amazing and useful information. Hope you’ll like mine… is an online pharmacy store that sells the best Sildenafil Citrate – Generic Viagra Generic ED medication to men suffering with erectile dysfunction, Impotency problem and premature ejaculation. We provide medicines at best reasonable price in USA. We have built up ourselves as a leader in the category of online pharmacies since the inception our operation. We have taken continuous efforts towards providing quality and high standard products to our customers by confirming to the standards of manufacturing and quality control. Before providing the medications we rectify the medicines through testing and checking of the products, the medications sold by us are approved by the FDA (Food and Drug Administration) due to the existence of the active ingredients in the product.

  16. Sildenafil 50mg tablet can help men who cannot achieve or sustain an erection for the desired time during sensual coupling. It helps improve the ED condition and promotes the lifestyle of a person by improving quality life. The medicine is useful in mid-aged and older men providing effective results.

  17. Did you realize that activity would one say one is of the most ideal methods for restoring Erectile Dysfunction? Numerous men go directly to drugs for assisting with erection issues, yet these medications don't offer a fix, just a transitory solution. What's more, why hazard all the reactions? Regularly the reason for Erectile Dysfunction is poor course (ie poor blood flow to the penis), elevated cholesterol levels, and potentially low testosterone levels. Cenforce 100mg can help to increase it easily. Doing normal activity will expand your flow, will help lower cholesterol levels, and can help support testosterone levels.
    Similar products:-
    Cenforce 150
    Cenforce 200
    Malegra 100
    Vidalista 60
    Fildena 100
    malegra 150

  18. Cenforce 200mg – Best ED medicine | Warning
    Cenforce 100contains Sildenafil Citrate 200 mg, the double Dose of uncommon Viagra, and is made by Centurion Laboratories in India. Its sensibility props up 4 to 5 hours. Drinking liquor before taking it can cause a momentary inadequacy in getting erection. Take this prescription 30 to 45 minutes sooner. Whenever taken, don't take it again inside 24 hours. Fat rich food should be kept up a fundamental distance from before taking it.
    nitrates like isosorbide mononitrate, amyl nitrite, isosorbide dinitrate, nitroglycerin, methscopolamine nitrate; cisapride; nitroprusside; Other Sildenafil things (Caverta, Silagra, Eriacta, and so on.);
    Read also:-
    Cenforce 150
    Cenforce 200
    Fildena 100
    Vidalista 60
    Cenforce 100

  19. As for the possibility of the generic fix, there is no match. Regularly, it is prescribed to use a single pill of prescription in a day before the execution. These generic pills require some place in the scope of an opportunity to display its outcomes. No other stupidity medication can raise a confinement against Cenforce 100mg

    Cenforce 100 Review
    cenforce 150 paypal
    cenforce 200 price

    Related More product-->
    Cenforce 100 Review
    cenforce 150 paypal
    cenforce 200 price
    vidalist 20

  20. Hello I am Oloo Hanrry working with Alled Mart online Pharmacy specialists in Erectile Dysfunction issues. Cenforce is being advertised in the dosing extent of Cenforce 100 comes as tablet arranging.

    Sildenafil Citrate 100mg
    cenforce 150
    cenforce 200

    View More product-->
    Cenforce 100
    cenforce 150
    cenforce 200
    kamagra 100mg
    vidalist 20

  21. Best Article buy pain meds online Excellent post. I appreciate this site. Stick with it! Because the admin of this web page is working, no doubt very quickly it will be well-known, due to its quality contents.This website was how do you say it? Relevant!! Finally, I’ve found something that helped me.
    Best Article buy Roxicodone Online Excellent post
    buy Xanax Online
    buy Oxycodone Online

    Best Article buy medications online Excellent post. I appreciate this site. Stick with it! Because the admin of this web page is working, no doubt very quickly it will be well-known, due to its quality contents.This website was how do you say it? Relevant!! Finally, I’ve found something that helped me.
    buy Roxicodone Online

  22. Thank you so much for this information. People use Viagra because they have some health problems like Erectile Dysfunction and Premature Ejaculation. Generic medicines work well in any types of disease.
    buy tadalafil is used to treat erectile dysfunction and buy Cialis is a medication used to treat erectile dysfunction and sildenafil citrate online is used to treat erectile dysfunction (impotence) in me and buy dapoxetine for the treatment of premature ejaculation, If anyone wants to buy this medicines so you can buy from Online Generic Medicine , they provides all types of medicine like isotretinoin online ( its use to treat acne ) and Order soma ( its use to treat pain and injury )