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. 2021 Jan 18;14(1):73.
doi: 10.3390/ph14010073.

Hot-Melt Extruded Amorphous Solid Dispersion for Solubility, Stability, and Bioavailability Enhancement of Telmisartan

Bhupendra Raj Giri  1 , Jaewook Kwon  1 , Anh Q Vo  2   3 , Ajinkya M Bhagurkar  2 , Suresh Bandari  2 , Dong Wuk Kim  1
Affiliations

Hot-Melt Extruded Amorphous Solid Dispersion for Solubility, Stability, and Bioavailability Enhancement of Telmisartan

Bhupendra Raj Giri et al. Pharmaceuticals (Basel). .

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.

Keywords: bioavailability; hot-melt extrusion (HME); pH-modifier; solid dispersion; solubility; stability; telmisartan.

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Conflict of interest statement

The authors declare no conflict of interest in this work.

Figures

Figure 1
Figure 1
Aqueous solubility of TEL in different: (A) polymer solutions (1% w/v) and (B) alkalizer solutions (1% w/v). Each value represents the mean ± SD (n = 3).
Figure 2
Figure 2
Aqueous solubility of different HME TEL-loaded pH-modulated solid dispersion prepared by varying drug/carrier ratios. Each value represents the mean ± SD (n = 3).
Figure 3
Figure 3
Dissolution profiles of drugs from tablets containing pure TEL powder, TEL-loaded pH-modulated solid dispersion tablet (F8), and a commercial product (MICARDIS®). Each value represents the mean ± SD (n = 3).
Figure 4
Figure 4
Scanning electron micrographs: (A) TEL powder; (B) Soluplus ®; (C) Sodium carbonate (SC); and (D) TEL-loaded pH-modulated solid dispersion (F8).
Figure 5
Figure 5
DSC thermograms of (A) TEL powder; (B) Soluplus®; (C) Sodium carbonate (SC); (D) physical mixture (PM); and (E) TML-loaded pH-modulated solid dispersion (F8).
Figure 6
Figure 6
X-ray powder diffraction of (A) TEL powder; (B) Soluplus®; (C) Sodium carbonate (SC); (D) physical mixture (PM); and (E) TEL-loaded pH-modulated solid dispersion (F8).
Figure 7
Figure 7
The stability test, the physical appearance of Pure TEL tablet (left side); TEL-loaded tablet (F8, middle); and Commercial tablet (MICARDIS®, right side).
Figure 8
Figure 8
Stability testing. (A) In vitro dissolution rate; (B) drug content; and (C) water content of pure TEL tablet, TEL-loaded solid dispersion tablet (F8), and commercial tablet (MICARDIS®) during storage. Each value represents the mean ± SD (n = 3).
Figure 9
Figure 9
Plasma concentration–time profiles of TEL after oral administration of free drug (TEL), commercial formulation, or prepared amorphous solid dispersion formulation (F8) in rats. Each value represents the mean ± SD (n = 6).
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