Abstract
Telmisartan (TEL, an antihypertensive drug) belongs to Class II of the Biopharmaceutical Classification System (BCS) because of its poor aqueous solubility. In this study, we enhanced the solubility, bioavailability, and stability of TEL through the fabrication of TEL-loaded pH-modulated solid dispersion (TEL pHM-SD) using hot-melt extrusion (HME) technology. We prepared different TEL pHM-SD formulations by varying the ratio of the drug (TEL, 10–60% w/w), the hydrophilic polymer (Soluplus®, 30–90% w/w), and pH-modifier (sodium carbonate, 0–10% w/w). More so, the tablets prepared from an optimized formulation (F8) showed a strikingly improved in vitro dissolution profile (~30-fold) compared to the free drug tablets. The conversion of crystalline TEL to its amorphous state is observed through solid-state characterizations. During the stability study, F8 tablets had a better stability profile compared to the commercial product with F8, showing higher drug content, low moisture content, and negligible physical changes. Moreover, compared to the TEL powder, in vivo pharmacokinetic studies in rats showed superior pharmacokinetic parameters, with maximum serum concentration (Cmax) and area under the drug concentration–time curve (AUC0–∞) of the TEL pHM-SD formulation increasing by 6.61- and 5.37-fold, respectively. Collectively, the results from the current study showed that the inclusion of a hydrophilic polymer, pH modulator, and the amorphization of crystalline drugs in solid dispersion prepared by HME can be an effective strategy to improve the solubility and bioavailability of hydrophobic drugs without compromising the drug’s physical stability.
Highlights
Hypertension is a condition with a rise in blood pressure and is considered a global health issue that affects 25% of adults [1]
The solubility of TEL was highest at strong alkaline conditions i.e., 2557.7 μg/mL at pH 10 followed by the acidic environment (97.2 μg/mL at pH 1.2) (Table 1)
We have successfully developed a microenvironment pH-modulated amorphous solid dispersion (SD) system of poorly water-soluble and ionizable TEL using hot-melt extrusion (HME) technology
Summary
Hypertension is a condition with a rise in blood pressure and is considered a global health issue that affects 25% of adults [1]. 24 h) compared to commercially available Sartans such as Losartan, Valsartan, and Irbesartan, making it possible for once-daily dosing to induce effective blood pressure control throughout the day, thereby improving the overall quality of patients’ life [4,5]. Though TEL is in the limelight as an effective antihypertensive drug, its highly pH-dependent and poor solubility features cause inconsistent absorption and insignificant bioavailability (~43%), leading to its suboptimal therapeutic activity [7,8]. Commercially available TEL products, MICARDIS® , are loaded with a high concentration of hygroscopic excipients, strong alkalizers such as sodium hydroxide that makes the product unstable when exposed to environmental conditions. A drug delivery technique that can enhance the solubility, dissolution, and pharmacokinetic features of TEL, providing product stability under environmental storage conditions, is highly desired
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