An in vitro and in vivo comparative study of directly compressed solid dispersions and freeze dried sildenafil citrate sublingual tablets for management of pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a life-threatening disease. It is characterized by elevations in the pulmonary arterial pressure and pulmonary vascular resistance, leading to right ventricular failure and premature death (1). Treatments of PAH include medications, oxygen, and lung transplant. The main medications for pulmonary 411 Acta Pharm. 62 (2012) Original research paper DOI: 10.2478/v10007-012-0027-9 An in vitro and in vivo comparative study of directly compressed solid dispersions and freeze dried sildenafil citrate sublingual tablets for management of pulmonary arterial hypertension Sildenafilcitrate (SILD) orodispersable sublingual tablets (ODSTs) have been developed using two comparative techniques for improving their oral disintegration, dissolution and bioavailability in order to manage acute attacks of pulmonary arterial hypertension (PAH). The techniques employed were direct compression of SILD-poloxamer 188 solid dispersions (SDs) and freeze drying using various excipients. The physicochemical and solid--state properties, as well as the dissolution behavior of the tablets were evaluated. Moreover, SILD bioavailability in human volunteers from the prepared ODSTs was compared to that of the conventional oral tablet. Incorporation of SD of poloxamer188 in sublingual tablets together with Pharmaburst using the direct compression technique enhanced the extent and dissolution rate of SILD with 100 % of drug being dissolved after 7 minutes. However, the lyophilization process was superior in enhancing dissolution and 100 % of SILD was dissolved after only one minute. Moreover, the in vivo study showed that the AUC 0-12 of lyophilized tablets was significantly higher than that of directly compressed tablets, with bioavailability values of 159.81 and 140.85 %, respectively, compared to the commercial oral product.Keywords: sildinafil, orodispersable sublingual tablets, pulmonary arterial hypertension, poloxamer 188, solid dispersions, direct compression, freeze drying * Correspondence; e-mail: amany.kamel@yahoo.com Unauthenticated Download Date | 5/8/18 9:59 AM hypertension include: endothelin receptor antagonists, prostacyclin analogs and phosphodiesterase type 5 inhibitors (PDE5Is).Sildenafil citrate (SILD), a selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5), was approved by the FDA for the treatment of PAH in 2005. It improves cardiovascular diseases and is useful for patients with congestive heart failure as well as secondary pulmonary hypertension. It relaxes the arterial wall, and hence decreases the pulmonary arterial resistance and pressure. This improves symptoms of right-sided heart failure by reducing the workload of the right ventricle of the heart. Since PDE5 is primarily distributed within the arterial wall smooth muscle of the lungs and penis, SILD acts selectively in both of these areas without inducing vasodilation in other areas of the body,which is considered to be an advantage of SILD(2-3). SILD decreases myocardial apoptosis, fibrosis, and hypertrop...

Mechanisms of increased bioavailability through amorphous solid dispersions: a review

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Sublingual Administration of Sildenafil Oro-dispersible Film: New Profiles of Drug Tolerability and Pharmacokinetics for PDE5 Inhibitors

“…We might then hypothesize that sub-lingual Sild absorption is favored by a prolonged drug-mucosa contact. Indeed, this phenomenon is generally pursued for oral trans-mucosal drugs, where the use of mucoadhesive polymers is recommended to assure prolonged period of contact between the formulation and the oral mucosa ( Lam et al, 2014 ), in particular from those drugs, like Sild, affected by low water solubility ( Zayed et al, 2012 ; Sun et al, 2014 ). These preliminary results are also suggestive of a possible improvement of the clinical efficacy for this class of drugs compared to original formulations.…”

Substantially increased sildenafil bioavailability after sublingual administration in children with congenital heart disease: two case reports

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