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. 2018 Nov 5:12:3753-3766.
doi: 10.2147/DDDT.S173326. eCollection 2018.

Hydralazine HCl rapidly disintegrating sublingual tablets: simple dosage form of higher bioavailability and enhanced clinical efficacy for potential rapid control on hypertensive preeclampsia

Samar Genedy  1 , Ahmed Khames  2   3 , Amal Hussein  4 , Hatem Sarhan  4
Affiliations

Hydralazine HCl rapidly disintegrating sublingual tablets: simple dosage form of higher bioavailability and enhanced clinical efficacy for potential rapid control on hypertensive preeclampsia

Samar Genedy et al. Drug Des Devel Ther. .

Abstract

Background: Hypertensive disorders are the most common complication in pregnancy which can even lead to maternal mortality. Hydralazine hydrochloride (HHC), a direct-acting vasodilator, is intravenously used as the first-line therapy in controlling hypertension in pregnancy (preeclampsia). It suffers poor oral bioavailability (26%-50%) due to first-pass metabolism.

Objective: This work aims for the preparation of HHC rapidly disintegrating sublingual tablets of higher absorption rate, short onset of action, and higher bioavailability for rapid control on blood pressure (BP) in hypertensive emergencies especially preeclampsia.

Methods: HHC sublingual tablet mixtures were prepared using starch sodium glycolate and Pharmaburst as super disintegrants at three different levels by direct compression and were subjected to full in vitro evaluation; the drug bioavailability from the optimized sublingual tablet formula was assessed in comparison to conventional oral tablets in rabbits, and the clinical efficacy on controlling BP in induced preeclampsia like mouse model was also studied.

Results: The results indicated compatibility of the prepared tablet mixtures, good flow, and acceptable mechanical strength. Sublingual tablet formula containing Pharmaburst (7%) that showed fastest disintegration (21 seconds) and 100% drug release within 5 minutes was selected for further bioavailability and pharmacodynamic studies. The drug bioavailability was significantly increased with C max = 28.2767±4.61 µg/mL, AUC(0-α) = 52.85±3.18 µg.h/mL, and T max = 0.33±0.011 hour in comparison to 18.0633±23.2 µg/mL, 33.18±5.18 µg⋅h/mL, and 0.75±0.025 hour for conventional oral tablets. Results of pharmacodynamic studies proved significant rapid control on both systolic and diastolic BP to normal values within only 30 minutes without any significant difference from intravenous data.

Conclusion: These results confirm the suitability of the prepared HHC sublingual tablets for use in rapid control on hypertensive crisis especially in pregnant women as an alternate to parenteral administration.

Keywords: absorption from buccal cavity; hypertension; l-NAME; pre-eclampsia like mouse model; preeclampsia; sublingual tablets.

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Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
DSC thermograms of HHC and its physical mixtures with (A) Avicel, (B) d-Mannitol, and (C) SSG. Abbreviations: DSC, differential scanning calorimetry; HHC, hydralazine hydrochloride; SSG, starch sod-glycolate.
Figure 2
Figure 2
DSC thermograms of HHC and its physical mixtures with (A) Pharmaburst, (B) talc, and (C) saccharin sodium. Abbreviations: DSC, differential scanning calorimetry; HHC, hydralazine hydrochloride; SSG, starch sod-glycolate.
Figure 3
Figure 3
FTIR spectra of HHC and its physical mixtures with (A) Avicel, (B) d-Mannitol, and (C) SSG. Abbreviations: FTIR, fourier transform infrared spectroscopy; HHC, hydralazine hydrochloride; SSG, starch sod-glycolate.
Figure 4
Figure 4
FTIR spectra of HHC and its physical mixtures with (A) Pharmaburst, (B) talc, and (C) saccharin sodium. Abbreviations: FTIR, fourier transform infrared spectroscopy; HHC, hydralazine hydrochloride.
Figure 5
Figure 5
Dissolution profiles of HHC from sublingual tablets prepared using (A) SSG and (B) Pharmaburst in comparison to plain drug. Abbreviation: HHC, hydralazine hydrochloride.
Figure 6
Figure 6
Mean plasma concentration–time curves of the prepared HHC sublingual tablet formula (F6) in comparison to conventional HHC oral tablets in rabbits. Abbreviations: HHC, hydralazine hydrochloride; OHHC, oral test group; SHHC, sublingual test group.
Figure 7
Figure 7
Bar chart of (A) BP of pregnant rats before and after treatment with l-NAME in comparison to non-pregnant rats. (B) The effect of HHC in different dosage forms on BP of pregnant rats. Abbreviations: DBP, diastolic blood pressure; HHC, hydralazine hydrochloride; IVC, IV control group; IVHHC, IV test group; l-NAME, N(omega)-nitro-l-arginine methyl ester; NP, non-pregnant; NPT, non-pregnant treated; OC, oral control group; OHHC, oral test group; PT, pregnant treated; SBP, systolic blood pressure; SC, sublingual control group; SHHC, sublingual test group.
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