Preparation and evaluation of proliposomes formulation for enhancing the oral bioavailability of ginsenosides.

Background: This research main objective was to evaluate a proliposomes (PLs) formulation for the enhancement of oral bioavailability of ginsenosides, using ginsenoside Rg3 (Rg3) as a marker. Methods: A novel PLs formulation was prepared using a modified evaporation-on-matrix method. Soy phosphatidylcholine, Rg3-enriched extract, poloxamer 188 (Lutrol® F 68) and sorbitol were mixed and dissolved using a aqueous ethanolic solution, followed by the removal of ethanol and lyophilization. The characterization of Rg3-PLs formulations was performed by powder X-ray diffractometry (PXRD), transmission electron microscopy (TEM) and in vitro release. The enhancement of oral bioavailability was investigated and analyzed by non-compartmental parameters after oral administration of the formulations. Results: PXRD of Rg3-PLs indicated that Rg3 was transformed from crystalline into its amorphous form during the preparation process. The Rg3-encapsulated liposomes with vesicular-shaped morphology were generated after the reconstitution by gentle hand-shaking in water; they had a mean diameter of approximately 350 nm, a negative zeta potential (-28.6 mV) and a high entrapment efficiency (97.3%). The results of the in vitro release study exhibited that significantly more amount of Rg3 was released from the PLs formulation in comparison with that from the suspension of Rg3-enriched extract (control group). The pharmacokinetic parameters after oral administration of PLs formulation in rats showed an approximately 11.8-fold increase in the bioavailability of Rg3, compared to that of the control group. Conclusion: The developed PLs formulation could be a favorable delivery system to improve the oral bioavailability of ginsenosides, including Rg3.

Photobleaching-mediated charge-convertible cyclodextrin nanoparticles achieve deep tumour penetration for rectal cancer theranostics.

Although charge-converting nanoparticles (NPs) potentially penetrate tumours deeply, conventional charge conversion strategies possess limitations, including low selectivity and slow, inconsistent conversion rate within the tumour microenvironment. In this study, we synthesized a zwitterionic near-infrared cyclodextrin derivative of heptamethine cyanine and complexed it with pheophorbide-conjugated ferrocene to produce multifunctional theranostic nanotherapeutics. Our NPs demonstrated enhanced tumour-targeting ability, enabling the highly specific imaging of rectal tumours, with tumour-to-rectum signal ratios reaching up to 7.8. The zwitterionic surface charge of the NPs was rapidly converted to a cationic charge within the tumours on 880 nm near-infrared laser irradiation, promoting the tumoural penetration of NPs via transcytosis. After penetration, photodynamic/chemodynamic therapy was initiated using a 660 nm laser. Our NPs eradicated clinically relevant-sized heterotopic tumours (~250 mm3) and orthotopic rectal tumours, displaying their potential as theranostic nanoplatforms for targeting rectal cancer.

Tailoring renal-clearable zwitterionic cyclodextrin for colorectal cancer-selective drug delivery.

Although cyclodextrin-based renal-clearable nanocarriers have a high potential for clinical translation in targeted cancer therapy, their designs remain to be optimized for tumour retention. Here we report on the design of a tailored structure for renal-clearable zwitterionic cyclodextrin for colorectal cancer-selective drug delivery. Twenty cyclodextrin derivatives with different charged moieties and spacers are synthesized and screened for colloidal stability. The resulting five candidates are evaluated for biodistribution and an optimized structure is identified. The optimized cyclodextrin shows a high tumour accumulation and is used for delivery of doxorubicin and ulixertinib. Higher tumour accumulation and tumour penetration facilitates tumour elimination. The improved antitumour efficacy is demonstrated in heterotopic and orthotopic colorectal cancer models.

Bentonite as a water-insoluble amorphous solid dispersion matrix for enhancing oral bioavailability of poorly water-soluble drugs.

Bentonite (BT), an orally administrable natural clay, is widely used for medical and pharmaceutical purposes due to its unique properties, including swelling, adsorption and ion-exchange. However, its application as a matrix of amorphous solid dispersion (ASD) formulations is rarely reported, despite the fact that drugs can adsorb to BT in an amorphous state. The objective of this study was to explore the feasibility of BT as a water-insoluble ASD matrix for enhancing the oral bioavailability of poorly water-soluble drugs, including sorafenib (SF). We prepared a novel BT-based ASD of an SF-BT composite (SFBTC) by adsorbing SF onto BT under acidic conditions using the ionic interaction between cationic SF and negatively charged BT. Scanning electron microscopy (SEM), powder X-ray diffractometry (pXRD), and differential scanning calorimetry (DSC) analyses revealed that SF adsorbed to BT in an amorphous state at SF:BT ratios from 1:3 to 1:10. In pharmacokinetic studies in rats, SFBTC (1:3) significantly improved the oral bioavailability of SF, and the AUClast of SFBTC (1:3) was 3.3-fold higher than that of NEXAVAR®, a commercial product of SF. An in vitro release study under sink conditions revealed that SFBTC (1:3) completely released SF in a pH-dependent manner, while a nonsink condition study indicated the generation of supersaturation under intestinal pH conditions. A kinetic solubility study showed that the release of SFBTC (1:3) followed the diffusion-controlled mechanism, which is a typical characteristic of water-insoluble matrix-based ASDs. The pharmacokinetic studies of drug-BT composites of various drugs belonging to BCS class II indicated that the pKa value of the adsorbed drugs is one of the most important factors determining their dissolution and oral bioavailability. These results suggest that BT could be a promising water-insoluble ASD matrix for improving the oral bioavailability of poorly water-soluble drugs, including SF.

Combined Orobol-Bentonite Composite Formulation for Effective Topical Skin Targeted Therapy in Mouse Model.

Purpose: Orobol is an isoflavone that has a potent skin protection effect. The objective of this study was to prepare a novel bentonite-based composite formulation of orobol to enhance topical skin delivery. Methods: The composition was optimized based on the orobol content in the composite and the in vitro release studies, followed by the in vitro and in vivo hairless mouse skin deposition studies. Physicochemical characterizations of the composite formulation were performed by powder X-ray refractometry (XRD) and scanning electron microscopy (SEM). The in vitro cytotoxicity and in vivo toxicity studies were conducted in human keratinocytes and in hairless mouse, respectively. Results and Discussions: The in vitro release of orobol from the bentonite composites was higher than that from the suspension, which was further increased with the addition of phosphatidylcholine. The composite formulation significantly enhanced the in vitro and in vivo skin deposition of orobol in hairless mouse skin compared to the orobol suspension. Moreover, the addition of phosphatidyl choline not only improved the dissolution and incomplete release of orobol from the bentonite composite but also enhanced the deposition of orobol in the skin. XRD histograms and SEM images confirmed that the enhanced dissolution of orobol from the composite was attributed to its amorphous state on bentonite. The in vitro and in vivo toxicity studies support the safety and biocompatibility of the orobol-loaded bentonite composite formulation. Conclusion: These findings suggest that the orobol-loaded bentonite composite formulation could be a potential topical skin delivery system for orobol.

Effect of phosphatidylcholine in bentonite-quetiapine complex on enhancing drug release and oral bioavailability.

Bentonite (BT) is a biocompatible clay mineral that has advantageous properties as a pharmaceutical excipient. However, the application of BT in controlled-release oral formulations has been challenging due to incomplete drug release from BT-drug complexes. The objective of this study was to investigate the effect of modifying BT with zwitterionic phosphatidylcholine (PC) to enhance the dissolution of drugs, thereby increasing their oral bioavailability. Quetiapine (QTP) was chosen as a model drug, and the composition of the complex (BT-PC-QTP) was optimized to have the maximum QTP content and increase the total amount of QTP released. The in vitro release study showed that the incorporation of an appropriate amount of PC into BT improved the low release rate of the BT-QTP complex at pH 7.4, while the pH-dependent release property of BT was maintained. In an in vivo pharmacokinetic study in rats, the oral administration of the BT-PC-QTP complex showed significantly higher Cmax and AUC values than the BT-QTP complex. Moreover, BT-PC-QTP showed a 2.4-fold enhancement of oral bioavailability compared to the QTP powder group. The scanning electron microscopy (SEM), powder X-ray diffraction (pXRD), and differential scanning calorimetry (DSC) studies confirmed that the intercalation of PC and QTP into BT resulted in the adsorption of QTP in an amorphous state. The characterization of the nanoparticles generated from the BT-PC-QTP complex supported that PC enhanced the dissolution of QTP by forming nanosized PC particles. Taken together, the modification of BT with PC can be applied in pharmaceutical industry as a platform strategy to control the release of the BT-drug complex and enhance the oral bioavailability of poorly water-soluble drugs.

Preparation and characterization of sorafenib-loaded microprecipitated bulk powder for enhancing oral bioavailability.

The aim of this study was to prepare and evaluate Eudragit-based microprecipitated bulk powder (MBP) formulations to enhance the oral bioavailability of sorafenib. Cationic Eudragit E PO and anionic Eudragit S100 were selected for MBP preparation. Ursodeoxycholic acid (UDCA)-incorporated MBP was also prepared to study the synergistic effect of UDCA in enhancing the bioavailability of sorafenib. Sorafenib-loaded MBPs were successfully prepared by a pH-controlled precipitation method using an aqueous antisolvent. Submicron-sized particles of MBPs were observed by scanning electron microscopy, and the amorphous form of sorafenib in MBPs was confirmed by powder X-ray diffraction. MBPs of cationic and anionic Eudragits showed different in vitro dissolution and pharmacokinetic profiles in rats. Sorafenib in Eudragit E PO-based MBP (E PO-MBP) was rapidly dissolved at low pH conditions (pH 1.2 and 4.0), but was precipitated again at pH 4.0 within 4 h. Dissolution of sorafenib from Eudragit S100-based MBP (S100-MBP) was high at pH 7.4 and did not precipitate for up to 4 h. After oral administration to rats, all MBPs, compared with powder, improved the oral absorption of sorafenib, with S100-MBP showing 1.5-fold higher relative oral bioavailability than E PO-MBP. Moreover, incorporation of UDCA in S100-MBP (S100-UDCA-MBP) further increased the Cmax and oral bioavailability of sorafenib, although the dissolution was not significantly different from that of S100-MBP. Taken together, Eudragit-based MBP formulations could be a promising strategy for enhancing the oral bioavailability of sorafenib.

Ferrous sulfate-directed dual-cross-linked hyaluronic acid hydrogels with long-term delivery of donepezil.

Ferrous sulfate (FeSO4)-directed dual-cross-linked hydrogels were designed for application in single-syringe injections. The use of FeSO4, rather than other iron salts, can modulate the gelation time and make it available for subcutaneous injection with a single syringe. These hydrogels are based on hyaluronic acid-dopamine (HA-dp) that contain donepezil (DPZ)-entrapping poly(lactic-co-glycolic acid) (PLGA) microsphere (MS). Although DPZ has been administered orally, its sustained release formulation via subcutaneous injection may reduce the dosing frequency for patients with Alzheimer's disease. The HA-dp conjugate was synthesized via an amide bond reaction for coordination of dp with a metal ion (Fe2+ or Fe3+) and self-polymerization of dp. The HA-dp/DPZ-loaded PLGA MS (PD MS)/FeSO4 gel system was considerably hardened via both the coordination of the metal ion with HA-dp and covalent bonding of dp. In addition, a quick restoration of the collapsed gel structure and sustained DPZ release from the HA-dp/PD MS/FeSO4 structure were achieved. The pharmacokinetic parameters after its subcutaneous injection in a rat indicate the sustained release and absorption of DPZ from the HA-dp/PD MS/FeSO4 system. The proposed system can be prepared by a simple method and can be efficiently and safely used for the long-term delivery of DPZ after the subcutaneous injection.

Development of an oral bentonite-based modified-release freeze-dried powder of vactosertib: Pharmacokinetics and anti-colitis activity in rodent models of ulcerative colitis.

Vactosertib is a novel inhibitor of transforming growth factor-ß signaling. Clinical applications of vactosertib have been challenging since conventional oral formulations such as immediate-release tablets demonstrate a rapid rise and fast decline in plasma concentrations. In this study, a novel bentonite-based, modified-release, freeze-dried powder of vactosertib was developed and evaluated to determine its potential in the treatment of ulcerative colitis. The formulation released vactosertib slowly and steadily in an in vitro drug release test. The extent of vactosertib released from the formulation was markedly low (18.0%) at pH 1.2 but considerably high (95.6%) at pH 7.4. Compared with vactosertib oral solution, the formulation demonstrated a 52.5% lower mean maximum concentration of vactosertib and three times longer median time to maximum concentration without a significant change in the extent of vactosertib absorption in a rodent colitis model. Furthermore, colitis mice administered with this formulation showed a significant reduction in the total histopathological score by 30% compared with those administered with the positive control, whereas the administration of vactosertib oral solution resulted in only a 10% reduction. Collectively, this novel formulation resolved the pharmacokinetic drawbacks of vactosertib and is expected to enhance its therapeutic effect by delivering vactosertib to the colitis lesions in the lower gastrointestinal tract.

Preparation and Evaluation of Eudragit L100-PEG Proliponiosomes for Enhanced Oral Delivery of Celecoxib.

PEGylated Eudragit L100 (ELP)-containing proliponiosomes (PLNs) were developed for improved oral delivery of celecoxib (CXB). The successful introduction of PEG 2000 or 5000 to Eudragit L100 (EL) was confirmed via proton nuclear magnetic resonance analysis of which calculated molar substitution ratio of PEG to EL was 36.0 or 36.7, respectively. CXB, ELP, phospholipid, and non-ionic surfactants were dissolved in dimethyl sulfoxide and lyophilized to produce CXB-loaded PLNs (CXB@PLNs). The physical state of CXB@PLNs was evaluated using differential scanning calorimetry and powder X-ray diffractometry, which revealed that crystalline CXB was transformed into amorphous form after the fabrication procedure. The reconstitution of CXB@PLNs in aqueous media generated CXB-loaded liponiosomes with nano-sized mean diameters and spherical morphology. CXB@PLNs displayed enhanced dissolution rate and permeability compared to CXB suspension. In vivo pharmacokinetic studies performed on rats demonstrated the improved oral bioavailability of CXB@PLNs compared to that of CXB suspension. No serious systemic toxicity was observed in the blood biochemistry tests performed on rats. These results suggest that the developed PLNs could be promising oral delivery systems for improving the bioavailability of poorly water-soluble drugs, such as CXB.

Preparation and evaluation of celecoxib-loaded proliposomes with high lipid content.

A novel proliposomal formulation for improved oral delivery of celecoxib (CXB) was developed using a solid dispersion technique. CXB, soy phosphatidylcholine (SPC), sorbitol, and poloxamer 188 were dissolved in a water/ethanol binary solvent system. Subsequent solvent-evaporation and lyophilization steps produced CXB-loaded proliposomes (CXBPLs) with high lipid content (as SPC, ≈20% [w/w]). Powder X-ray diffractometry and differential scanning calorimetry analyses revealed that the physical state of CXB was transformed from crystalline to amorphous after the preparation process. Reconstitution of CXBPLs with gentle shaking by hand generated CXB-loaded liposomes with nano-sized mean diameter, negative zeta potential, vesicular-shaped morphology, and high CXB entrapment efficiency (≈84.7%). CXBPLs exhibited improved dissolution rate and permeability compared with free CXB and Celebrex (a commercial product of CXB). In the pharmacokinetic study performed in rats, the CXBPL-treated group showed a 1.7-fold increase in the bioavailability of CXB compared with the free CXB-treated group (p < 0.05). The histological observation with hematoxylin and eosin staining demonstrated no additional detrimental effect of CXBPLs on the intestinal epithelia of rats compared with that of free CXB. These results suggest that the developed proliposomes provide an efficient and safe way of enhancing the oral bioavailability of poorly water-soluble drugs.