Ultrahigh verapamil-loaded controlled release polymeric beads using superamphiphobic substrate: D-optimal statistical design, in vitro and in vivo performance

Abstract

Controlled-release multiparticulate systems of hydrophilic drugs usually suffer from poor encapsulation and rapid-release rate. In the present study, ultra-high loaded controlled release polymeric beads containing verapamil hydrochloride (VP) as hydrophilic model drug were efficiently prepared using superamphiphobic substrates aiming to improve patient compliance by reducing dosing frequency. Superamphiphobic substrates were fabricated using clean aluminum sheets etched with ammonia solution and were treated with 1.5% (w/v) perfluorodecyltriethoxysilane (PFDTS) alcoholic solution. The effect of the main polymer type (lactide/glycolide (PLGA) 5004A, PLGA 5010, and polycaprolactone (PCL)), copolymer (Eudragit RS100) content together with the effect of drug load on encapsulation efficiency (EE%) and in vitro drug release was statistically studied and optimized via D-optimal statistical design. In vivo pharmacokinetic study was carried out to compare the optimized system relative to the market product (Isoptin). Results revealed that superamphiphobic substrates were successfully prepared showing a rough micro-sized hierarchical structured surface upon observing with scanning electron microscope and were confirmed by high contact angles of 151.60 ± 2.42 and 142.80°±05.23° for water and olive oil, respectively. The fabricated VP-loaded beads showed extremely high encapsulation efficiency exceeding 92.31% w/w. All the prepared systems exhibited a controlled release behavior with Q12 h ranging between 5.46 and 95.90%w/w. The optimized VP-loaded system composed of 150 mg (1.5% w/v) PCL without Eudragit RS100 together with 160 mg VP showed 2.7-folds mean residence time compared to the market product allowing once daily administration instead of three times per day.

Superhydrophobic Substrates for Ultrahigh Encapsulation of Hydrophilic Drug into Controlled-Release Polyelectrolyte Complex Beads: Statistical Optimization and In Vivo Evaluation

“…On the other hand, the amount of the encapsulated drug was extracted with water for 24 h after complete crushing of the solidified beads. Extracted drug in water was measured using a UV Spectrophotometer (UV-1800; Shimadzu, Kyoto, Japan) at λ max 278 nm [24]. A blank superhydrophobic layer was treated similarly to ensure the absence of any leaked materials that could interfere with the UV absorption at the pre-mentioned λ max .…”

“…Plasma concentrations of VP were determined using a selective, sensitive and accurate LC-MS/MS method that was developed and validated before use [24]. Briefly, VP was analyzed in plasma samples using Triple Quadrupole LC-MS/MS Mass Spectrometer (AB Sciex Instruments, Framingham, MA, USA).…”

In Vitro and In Vivo Studies of a Verapamil-Containing Gastroretentive Solid Foam Capsule

“…It is well absorbed from the gastrointestinal tract, while it has low bioavailability (<20%) due to its lower solubility in the higher pH of the intestine (0.44 mg/mL at pH = 7.32) and short half-life (t1/2 is approximately 5 h) [7,26,27]. According to earlier results, gastroretention can improve the bioavailability of verapamil [9,22]. All types of GR systems are used in verapamil formulations, including low-density [19][20][21], high-density [22], and mucoadhesive systems [14][15][16].…”

“…These systems can float on the surface of stomach juice or sink to the bottom of the stomach to avoid passage into the duodenum [19][20][21]. High-density formulations are more resistant to stomach motion and transport, so they anchor at the bottom of the stomach and release the API [22]. Low-density formulations have been shown to remain in the stomach longer than other systems which have a similar density to gastric fluid [18,23].…”

“…According to earlier results, gastroretention can improve the bioavailability of verapamil [9,22]. All types of GR systems are used in verapamil formulations, including low-density [19][20][21], high-density [22], and mucoadhesive systems [14][15][16]. Nevertheless, to the best of our knowledge, the active substance has not yet been marketed in a gastrointestinal formulation in Europe.…”