Solusome nanovesicle tablets melt in the mouth to supercharge ebastine delivery

For millions of people who live with allergic rhinitis, chronic hives, and other itchy skin conditions, ebastine has long been a quiet workhorse. This second-generation antihistamine relieves symptoms without the drowsiness that plagued earlier allergy drugs, and its long duration of action means a single daily dose is usually enough. Yet ebastine carries a stubborn pharmaceutical flaw: the molecule is so lipophilic that it barely dissolves in water, which limits how quickly it dissolves in the gut and, in turn, how much of the dose actually reaches the bloodstream. A research team writing in the journal Pharmacia now reports a delivery system designed to fix exactly that problem, combining two ideas that rarely travel together in a single tablet: nanoscale lipid vesicles and tablets that dissolve on the tongue without any water.

The new dosage form is what pharmaceutical scientists call an oral lyophilisate, a tablet produced by freeze-drying a drug-containing solution or suspension inside a blister mold. Because the water is removed by sublimation rather than evaporation, the finished tablet is riddled with pores, giving it a sponge-like architecture. When placed on the tongue, saliva floods through those channels and the tablet falls apart within seconds, which is why oral lyophilisates are prized for children, older adults, and anyone who struggles to swallow conventional pills. Fast disintegration can also speed absorption and shorten the time it takes for a drug to start working. The trade-offs are real, however: freeze-drying is expensive and slow, and the resulting tablets are brittle, humidity-sensitive, and demand special packaging.

Ebastine posed a second challenge on top of the formulation hurdles. Under the Biopharmaceutics Classification System it is a Class II drug, meaning dissolution in the digestive tract is the bottleneck that constrains its bioavailability. With a log P of 7.64 and a molecular weight of 469.7 g/mol, the compound is a large, greasy molecule that is nearly insoluble in water. Freeze-drying rules also impose dose limits: water-insoluble drugs should not exceed 400 mg to preserve the porous structure, and drug particles should be smaller than 50 micrometers so they do not sediment during manufacturing or leave a gritty texture in the mouth. Ebastine’s poor solubility therefore made it an ideal candidate for nanosizing before it was ever mixed with tablet excipients.

The team’s answer was a vesicular carrier they describe as a Solusome, a modified lipid-based nanovesicle built from phosphatidylcholine bilayers with a solubilizing agent woven into the membrane. Unlike conventional liposomes, which can suffer from limited drug loading, leakage, and physical instability, Solusomes are designed to improve entrapment efficiency, membrane flexibility, and permeability. Unlike mixed micelles, they retain a bilayer capable of hosting both hydrophilic and lipophilic drugs. In this study the researchers prepared ebastine-loaded Solusomes by the thin-film hydration technique: the drug and phospholipid were dissolved in ethanol, evaporated under vacuum to leave a thin lipid film on the walls of a round-bottomed flask, and then hydrated with phosphate buffer containing Soluplus, a graft copolymer supplied by BASF that acts as the stabilizing agent. Bath sonication with repeated on-off cycles broke the dispersion down to a fine, aggregate-free suspension.

The particle measurements confirmed that the process worked. Dynamic light scattering showed the nanovesicles had a mean diameter of 65.86 nanometers with a polydispersity index of 0.1088 before concentration. After the dispersion was reduced in volume by rotary evaporation, a delicate step in which pressure and temperature were ramped gradually to prevent foaming, the particles measured 82.39 nanometers with a polydispersity index of 0.09213. Both sets of values fall comfortably within the ranges regarded as acceptable for pharmaceutical use, which matters because the concentrated vesicle dispersion had to survive the concentration step without aggregating before it could be blended with the tablet matrix.

Building the tablets themselves required a careful balance of four excipients. Gelatin served as the matrix-forming agent that gives the lyophilisate its structure, polyvinylpyrrolidone K90 acted as a hydrophilic binder, glycine functioned as a bulking agent and disintegration accelerant, and mannitol was added at a fixed 15 percent as a bulking agent with a pleasant mouthfeel. The concentrated Solusome dispersion was mixed with these components, poured into blister cavities, and freeze-dried in two stages: primary drying at minus 50 degrees Celsius under high vacuum, followed by secondary drying at 0 degrees Celsius. Rather than testing formulations one by one, the researchers used a Box-Behnken experimental design in Design-Expert software, which proposed 13 formulations varying the percentages of gelatin, PVP K90, and glycine across three levels each.

The statistical analysis revealed a clear tug-of-war between the two most important ingredients. Gelatin concentration had a highly significant effect on disintegration time: as the gelatin percentage rose, the tablets took longer to fall apart, because denser networks of cross-linked gelatin strands form harder, more rigid matrices that dissolve slowly. The same trend worked in reverse for friability, the measure of how much weight tablets lose when tumbled in a rotating drum. More gelatin meant fewer broken tablets, since stronger gels resist mechanical damage. PVP K90 showed the opposite pattern on disintegration, cutting the time dramatically as its percentage increased, thanks to its water-binding and complexing properties, although it had no significant effect on friability. Glycine, despite its theoretical role in creating aqueous channels, showed no statistically significant influence on either response.

The optimized formula, designated F7, combined 3 percent gelatin, 2.5 percent PVP K90, and 7.5 percent glycine, and achieved the highest desirability score in the design. Its mean disintegration time was 31.9 seconds, close to the 30-second benchmark set by the United States Pharmacopeia for orodispersible tablets, and its friability was 0.991 percent, just inside the 1 percent limit considered acceptable. In dissolution testing in hydrochloric acid at pH 1.2, the F7 tablets released more than 98 percent of the drug within 40 minutes, while pure ebastine managed only 42 percent over the same period. The researchers attribute this to the Noyes-Whitney equation: nanoscale vesicles present a vastly greater surface area and improved wettability, accelerating dissolution. Interestingly, the release profile was prolonged rather than instantaneous, which the team explains as controlled diffusion of the drug through the vesicular bilayer after the tablet disintegrates, not slow tablet breakdown.

Compatibility studies confirmed that the improvements came from physics rather than chemistry. Fourier transform infrared spectroscopy preserved all the characteristic absorption bands of ebastine, including ring C-H stretching near 3051 wavenumbers and ketonic carbonyl stretching at 1678 wavenumbers, with no new peaks or spectral shifts, ruling out chemical interaction or degradation during formulation and freeze-drying. Differential scanning calorimetry told a different story about the drug’s solid state: the melting endotherm of pure ebastine appeared at 85.96 degrees Celsius, but in the loaded nanovesicles the peak dropped to 82.44 degrees Celsius and diminished in intensity, suggesting partial conversion to an amorphous form. Powder X-ray diffraction reinforced this finding, showing that the sharp crystalline peaks of pure ebastine largely vanished in the vesicle formulation. Amorphization raises the free energy of the drug and improves wettability, which directly boosts dissolution without altering the molecule itself.

The most striking evidence came from the animal study. Male Wistar rats received either the F7 oral lyophilisate dispersed in water or a conventional aqueous suspension of pure ebastine, both by oral gavage at 10 milligrams per kilogram. Because ebastine undergoes extensive first-pass metabolism into its active metabolite carebastine, the researchers tracked carebastine in plasma by HPLC. The optimized formulation produced a maximum plasma concentration of 188.60 nanograms per milliliter at 4 hours, compared with 75.33 nanograms per milliliter for the suspension, and the area under the concentration-time curve reached 2670.32 nanogram-hours per milliliter against 701.9 for the pure drug, a statistically significant difference. Overall, the Solusome tablets raised oral bioavailability 3.21-fold. The authors caution that the preliminary pharmacokinetic study used only three rats per group, following the 3Rs principle to minimize animal use, and recommend larger studies to confirm the findings. Even so, the results suggest that pairing porous freeze-dried tablets with lipid nanovesicles could give poorly soluble drugs like ebastine a faster onset, easier swallowing, and substantially more drug delivered per dose.

Subject of Research: Development of ebastine-loaded Solusome nanovesicle oral lyophilisates with improved dissolution and bioavailability

Article Title: Formulation, in vitro , and in vivo evaluation of ebastine Solusome nanovesicle-based oral lyophilized tablets

Article References: Alkufi, H. K., Salih, O. S., & Taher, S. S. (2026). Formulation, in vitro, and in vivo evaluation of ebastine Solusome nanovesicle-based oral lyophilized tablets. Pharmacia, 73, Article e200581. https://doi.org/10.3897/pharmacia.73.e200581

Image Credits: AI Generated

DOI: 10.3897/pharmacia.73.e200581

Keywords: ebastine, Solusome nanovesicles, oral lyophilisates, orodispersible tablets, freeze-drying, Soluplus, drug bioavailability, nanotechnology, antihistamine, dissolution, pharmacokinetics, drug delivery