Sildenafil citrate is very old molecule which has a surprising history while the molecule was in research and development. It is a patented molecule invented by Pfizer. Originally, the scientist team were looking for the beneficial actions of this molecule in angina pectoris and blood pressure. But in clinical trials, they found that the drug has lesser action on heart and has marked influence on the penile muscles. It exerts the dilatory effects on the penile tissue and was found to be helpful in erectile dysfunction, the disorder that affects the social life of most of the world’s population.

The mechanism of action of sildenafil citrate is related to the enzyme inhibition. The enzyme, phosphodiesterase type-5 is responsible for degradation of cGMP, which exhibits nitric oxide (NO), mediated vasodilator effects. Sildenafil inhibits this enzyme and prevents cGMP from degradation and hence vasculature gets vasodilated. There is marked presence of this enzyme in some specific parts of body. Abundant levels of this enzyme are found in penile tissue, pulmonary artery. This lead to discovery of sildenafil as a novel medication in pulmonary arterial hypertension (PAH) with similar mechanism of action. In June 2005, Pfizer got US FDA approval for Sildenafil citrate tablets to market it for treating pulmonary arterial hypertension under brand “RevatioTM”. The immediate release tablets have a dose of 20 mg thrice a day for treating PAH.

However, such conventional formulations are associated with many side effects, prominent among them is dose dependent side effects due to dose fluctuation in blood. Due to short half life of sildenafil, the dosing frequency of conventional tablets is thrice a day so as to maintain the effective plasma levels of drug to achieve therapeutic action throughout the day. Frequent administration may be associated with the poor patient compliance due to number of factors like, dose related side effect on erectile tissue, priapism, cyanopsia etc. By sustained release dosage form, the side effects of sildenafil can be alleviated by controlling the fluctuations in the drug plasma levels while maintaining the plasma levels of drug throughout the time needed. This is the major advantage of formulating the sustained release formulation esp tablet, of sildenafil.

Currently, there are immediate release tablets, oral suspension and intravenous injection of sildenafil citrate available in the market for treatment of symptoms of PAH. On comparison of sildenafil formulation (phosphodiesterase inhibitor type-5) as suitable treatment option with the other available treatment options like endothelin receptor antagonists and prostacyclin analogues than it has got distinctive advantages over them. Drawbacks of presently available treatment options are stated in Table 1

Table 1 Drawbacks of currently available treatment options for pulmonary arterial hypertension.

Therapeutic category and specific agent	Route of administration/ Dosage form	Drawbacks
Phosphodiesterase inhibitor Type 5: Sildenafil Citrate	Oral : Immediate release tablets, solution Intravenous injection	While treating for PAH, frequent administration can cause dose fluctuation and danger of dose related side effect due to presence of target enzyme in penile tissue. Dose related cyanopsia, priapism. Injections are painful and create patient non-compliance. Presence of lag time between doses (esp night time) in which levels below therapeutic range are obtained leading to no therapeutic effect.
Endothelin receptor antagonist: Bosentan, Ambrisentan	Oral: Conventional tablets	They are very costlier agents. Elevated hepatic enzymes levels and frequent measuring of enzymes levels in needed while patient is treated with bonsentan. Regular blood count is needed in case of Ambrisentan treatment.
Prostacyclin analogues: Epoprostentol, Iloprost, Teprostinil	Intravenous injection, Inhalation, Subcutaneous injection.	I.v./s.c. injections and inhalations has many limitations and it may pose a serious challenge to drug administration. It may cause pump malfunctioning of syringe, strict manufacturing conditions, catheter related infections and even sepsis can result with intravenous epoprostenol. Infusion-site pain is problematic with subcutaneous teprostinil. Multiple daily inhalations cause iloprost therapy tedious.

Above all problems can cause decrease in patient compliance, leading to in-efficient therapy with this options. Hence sildenafil sustained release therapy may eradicate above problems and may help to increase patient compliance leading to effective therapy.

Looking at above limitations of other formulations of sidenafil and other treatment options for PAH, sustained release formulation esp tablets of sildenafil looks to be the best available treatment option for pulmonary arterial hypertension. Also the dosing frequency can be reduced to twice a daily so that the lag time between doses at night can be eradicated (a common problem between doses with conventional tablets which will have no therapeutic effects in that period), which can make the patient’s sleep comfortable without symptoms of PAH, as symptoms of PAH generally exacerbate at night due to supine position. Moreover the patient can work smoothly throughout the daytime without increasing the work load on heart due to elimination of lag time, sustained release profile of drug and minimum side effects.

Looking at above all benefits of sustained release technology, the research should now be focused on the developing the new modified release formulations to treat pulmonary hypertension especially matrix tablets. Due to the fact that the currently available treatment options for PAH are uncomfortable to patient and the dose related side effects of conventional sildenafil tablets, there is an urgent need of development of sustained release formulation of sildenafil citrate, that can minimise the fluctuations of drug plasma levels by maintaining the drug levels between therapeutic window and minimizing the side effects.