Effects of Postprandial Factors and Second Meal Intake Time on Bioequivalence Investigation of Tadalafil-Loaded Orodispersible Films in Human Volunteers.

Tadalafil (TD) has poor water solubility but is well absorbed without affecting food intake when administered orally. Owing to patient adherence and therapeutic characteristics, a TD-loaded orodispersible film (TDF) is preferable. However, the mechanistic role of dietary status on the clinical pharmacokinetic analysis of TDF in human volunteers should be investigated because the gastrointestinal environment varies periodically according to meal intervals, although commercial 20 mg TD-loaded tablets (TD-TAB, Cialis® tablet) may be taken with or without food. TDF was prepared by dispersing TD in an aqueous solution and polyethylene glycol 400 to ensure good dispersibility of the TD particles. In the fasting state, each T/R of Cmax and AUC between TD-TAB and TDF showed bioequivalence with 0.936-1.105 and 1.012-1.153, respectively, and dissolution rates in 1000 mL water containing 0.5% SLS were equivalent. In contrast, TDF was not bioequivalent to TD-TAB under the fed conditions by the Cmax T/R of 0.610-0.798. The increased dissolution rate of TDF via the micronization of drug particles and the reduced viscosity of the second meal content did not significantly affect the bioequivalence. Interestingly, an increase in second meal intake time from 4 h to 6 h resulted in the bioequivalence by the Cmax T/R of 0.851-0.998 of TD-TAB and TDF. The predictive diffusion direction model for physical digestion of TD-TAB and TDF in the stomach after the first and second meal intake was successfully simulated using computational fluid dynamics modeling, accounting for the delayed drug diffusion of TDF caused by prolonged digestion of stomach contents under postprandial conditions.

Roles of Fatty Acid Chain Length and Enzyme-Oriented Drug Controlled Release from pH-Triggering Self-Assembled Fatty Acid Conjugated Quetiapine Nanosuspensions.

Background: Quetiapine (QTP) is a first-line antipsychotic drug, but its therapeutic druggability and patient adherence were limited due to high oral dose strength, low bioavailability and physicochemical/biopharmaceutical issues. Purpose: To investigate the roles of fatty acid chain length and enzyme-oriented QTP controlled release from pH-triggering self-assembled fatty acid conjugated QTP nanosuspensions (NSPs). Methods: QTP was conjugated with different chain length fatty acids (C10-decanoic acid, C14-myristic acid, C18-stearic acid) to obtain QTP-fatty acid conjugates (QFCs: QD, QM, QS) by exploiting 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/4-dimethylaminopyridine (EDC/DMAP) conjugation chemistry. Then, the solubility, partitioning coefficient (log P), cell viability and cleavage kinetics of QFCs were evaluated. The pH-triggering self-assembled behaviors of QFCs to form QTP-fatty acid NSPs (QDN, QMN, QSN) by varying pH, QFC concentration and proton-to-QTP ratios were characterized. The morphological images, critical micelle concentration (CMC), physicochemical properties and enzyme-oriented QTP controlled release of NSPs were examined. Results: Three QFCs were synthesized with different chain length fatty acids from QTP after desalting fumarate from QTP fumarate. The pH, QFC concentration and proton-to-quetiapine molar ratio could influence physicochemical properties and nanonization behaviors of QFCs. All three QFCs showed no effect on the viability of myoblast cells. The pH-triggering self-assembly of amphiphilic QFCs to form nanoparticles (NPs) occurred as the amine moiety of QTP was readily ionized in a strongly acidic environment (pH 1.2). Interestingly, the longer the fatty acid chain length, the lower water solubility, the higher log P (lipophilicity) and the smaller NP particle size were observed. The conversion rate of QFCs to liberate QTP by esterase in human plasma and liver S9 fractions was also inversely proportional to the fatty acid carbon chain length. Interestingly, the freeze-dried QMN showed the esterase-oriented controlled release of QTP over one month, unlike the initial burst release of QDN or the slowly delayed release pattern of QSN. Conclusion: A new pH-triggering self-assembled nanonization platform was developed using different chain length fatty acid conjugated QTP in low pH environment. By varying fatty acid chain length, the enzyme-oriented QTP controlled release dosage form was challenged to enhance the therapeutic effectiveness of QTP.

Polyelectrolyte-based solid dispersions for enhanced dissolution and pH-Independent controlled release of sildenafil citrate.

The aim of this study was to design a novel matrix tablet with enhanced dissolution and pH-independent controlled release of sildenafil citrate (SIL), a drug with pH-dependent solubility, by using solid dispersions (SDs) and polyelectrostatic interactions. SIL-loaded SDs were prepared using various polymeric carriers such as poloxamer 188, poloxamer 407, Soluplus®, polyvinylpyrrolidone (PVP) K 12, and PVP K 17 by the solvent evaporation method. Among these polymers, Soluplus® was found to be the most effective in SDs for enhancing the drug dissolution over 6 h in pH 6.8 intestinal fluid. SIL was well dispersed in Soluplus®-based SDs in an amorphous form. When the Soluplus®-based SDs were added in the tablet containing positively charged chitosan and negatively charged Eudragit® L100, the drug release rate was further modulated in a controlled manner. The charge density of the tablet was higher at pH 6.8 than at pH 1.2 due to the polyelectrostatic interaction between chitosan and Eudragit® L100. This interaction could provide a pH-independent controlled release of SIL. Our study demonstrates that a combinatory approach of Soluplus®-based SDs and polyelectrostatic interactions can improve the dissolution and pH-independent release performance of SIL. This approach could be a promising pharmaceutical strategy to design a matrix tablet of poorly water-soluble drugs for the enhanced bioavailability.

Investigation of Cannabinoid Acid/Cyclodextrin Inclusion Complex for Improving Physicochemical and Biological Performance.

This study aimed to investigate the enhancement of cannabinoid acid solubility and stability through the formation of a cannabinoid acid/cyclodextrin (CD) inclusion complex. Two cannabinoid acids, tetrahydro-cannabinolic acid (THCA) and cannabidiolic acid (CBDA), were selected as a model drug along with five types of CD: α-cyclodextrin (α-CD), ß-cyclodextrin (ß-CD), γ-cyclodextrin (γ-CD), hydroxypropyl-ß-cyclodextrin (HP-ß-CD), and methylated-ß-cyclodextrin (M-ß-CD). Phase solubility studies were conducted using various types of CD to determine the complex stoichiometry. The preparation methods of the CD inclusion complex were optimized by adjusting the loading pH solution and the drying processes (spray-drying, freeze-drying, spray-freeze-drying). The drying process of the cannabinoid acid/M-ß-CD inclusion complex was further optimized through the spray-freeze-drying method. These CD complexes were characterized using solubility determination, differential scanning calorimetry (DSC), field-emission scanning electron microscopy (FE-SEM), X-ray diffraction (XRD), and 1H NMR spectroscopy. DSC, XRD, and FE-SEM studies confirmed the non-crystalline state of the cannabinoid acid/CD inclusion complex. The permeation of THCA or CBDA from the M-ß-CD spray-freeze-dried inclusion complex was highly improved compared to those of cannabis ethanolic extracts under simulated physiological conditions. The stability of the cannabinoid acid/M-ß-CD inclusion complex was maintained for 7 days in a simulated physiological condition. Furthermore, the minimum inhibitory concentration of cannabinoid acid/M-ß-CD inclusion complex had superior anti-cancer activity in MCF-7 breast cancer cell lines compared to cannabinoid acid alone. The improved physicochemical and biological performances indicated that these CD inclusion complexes could provide a promising option for loading lipophilic cannabinoids in cannabis-derived drug products.

Pomegranate-Derived Exosome-Like Nanovesicles Alleviate Binge Alcohol-Induced Leaky Gut and Liver Injury.

Alcoholic liver disease (ALD) is damage to the liver and mainly caused by binge alcohol. ALD have decreased junctional protein expression and modulated intestinal permeability. We investigated whether plant-releasing exosome-like nanovesicles can prevent liver damage and leaky gut from binge alcohol. In this study, we characterized the exosome-like nanovesicles from pomegranate juice and confirmed the round shape of a lipid bilayer. After 14 days of pomegranate-derived exosome-like nanovesicle (PNVs) pretreatment, binge alcohol (6 g/kg/dose) was administered to mice three times orally every 12 h. Exposure to binge alcohol increased levels of oxidative and nitric oxide stress marker proteins such as CYP2E1, 3-Nitrotyrosine, and inducible nitric oxide synthase in both liver and gut damage. Also, binge alcohol significantly elevated the plasma endotoxemia, inflammatory fatty liver, and leaky gut. However, PNVs reduced the oxidative stress and apoptosis marker proteins and prevented the leaky gut and endotoxemia. Markedly, PNV treatment significantly prevented a decrease in the amount of intestinal junctional proteins and an increase in leaky gut in mice exposed to alcohol. These results showed that PNVs can prevent leaky gut and liver damage caused by binge alcohol and suggest that it may be useful hepatoprotective or intestinal protective agents for the first time.

Dual thermal stabilizing effects of xanthan gums via glycosylation and hydrogen bonding and in vivo human bioavailability of desmopressin in orodispersible film.

Desmopressin acetate (DDAVP), a nonapeptide drug, is easily destroyed by heat in the manufacturing process of orodispersible film (ODF). A new challenging study was conducted to improve thermal stability through glycosylation and hydrogen bonding using carbohydrate gums (agar, arabic gum, carrageenan, xanthan gum) using the solvent casting method. Among gum types, xanthan gum strongly showed dual stabilizing effects of DDAVP via covalent glycosylation and hydrogen bonding, minimizing total impurities and optimizing physicochemical properties of ODF under accelerated conditions for six months. The optimized ODF formulation (O-DDAVP ODF) at a DDAVP and xanthan gum ratio of 1:1.5 had a pharmaceutically equivalent dissolution profile as compared with a commercial 0.2 mg commercial Minirin® tablet in four different media: pH 1.2, pH 4.0, and pH 6.8 buffers and deionized water. Furthermore, O-DDAVP ODF showed in vivo bioequivalence to Minirin® tablets in healthy human volunteers. Glycosylation-oriented stabilization of peptide drug using pharmaceutically active excipients against thermal denaturation could be challenged to design patient-friendly ODF.