Enhanced Oral Bioavailability and Anti-Echinococcosis Efficacy of Albendazole Achieved by Optimizing the "Spring" and "Parachute".

Maximizing the pharmacological efficacy of albendazole (ABZ), an anti-echinococcosis drug, is essential in the long-term treatment of patients with echinococcosis. As a weakly alkaline drug, ABZ has a pH-dependent solubility that decreases dramatically from gastric fluid (pH 1.4) to intestinal fluid (pH 6.5), where it is absorbed. In this study, we endeavored to develop an optimized tablet formulation of ABZ to improve its dissolution and oral bioavailability from two aspects: a faster initial dissolution in the gastric pH condition (i.e., the "spring") and a more prolonged drug supersaturation in the intestinal pH condition (i.e., the "parachute"). To achieve this goal, ABZ-HCl salt was selected first, which demonstrated a higher intrinsic dissolution rate under pH 1.4 compared with the ABZ free base that is used in the commercial product Albenda. Second, by comparing the ABZ supersaturation kinetics under pH 6.5 in the presence of various polymers including poly(vinylpyrrolidone) (PVP), PVP/VA, hydroxypropyl methylcellulose (HPMC), and HPMC acetate succinate (HPMC-AS), HPMC-AS was found to be the most effective crystallization inhibitor for ABZ, likely due to the hydrophobic interaction between ABZ and HPMC-AS in an aqueous environment. The newly designed tablet formulation containing ABZ-HCl and HPMC-AS showed ∼3 times higher oral bioavailability compared with that of Albenda in Beagle dogs. More significantly, the anti-echinococcosis efficacy of the improved formulation was 2.4 times higher than that of Albenda in a secondary hepatic alveolar echinococcosis Sprague-Dawley rat model. The strategy of simultaneously improving the spring and parachute of an oral formulation of ABZ, by using a highly soluble salt and an effective polymeric crystallization inhibitor, was once again proven to be a viable and readily translatable approach to optimize the unsatisfactory oral medicines due to solubility and bioavailability limitations.

Improving Drug Delivery of Micellar Paclitaxel against Non-Small Cell Lung Cancer by Coloading Itraconazole as a Micelle Stabilizer and a Tumor Vascular Manipulator.

Although polymeric micelles of paclitaxel (PTX) significantly reduce excipient-induced toxicity compared with Taxol, they exhibit few clinical advantages in tumor inhibition and overall survival. To improve, itraconazole (ITA), an antifungal drug with potent anti-angiogenesis activity, is co-encapsulated together with PTX within the PEG-PLA micelles. The strong intermolecular interactions between the payloads inhibit drug crystallization and prevent drugs from binding with external proteins, render super-stable micelles upon dilution and exposure to biological environment, and enter the tumor cells through endocytosis. The co-encapsulated micelles show strong anti-proliferation potency against non-small-cell lung cancer (NSCLC) and even PTX resistant NSCLC cells in vitro and significantly improve the drug accumulation within the tumor in vivo. Compared with PTX monotherapy or combination therapy using individual PTX and ITA micelles, the co-encapsulated micelle demonstrates strikingly superior efficacy in tumor growth inhibition, recurrence prevention, and reversion of PTX resistance, in Kras mutant patient derived xenografts, orthotropic models, and paclitaxel-resistance subcutaneous models. Besides the pharmacokinetic improvement, therapeutic benefits are also contributed by angiogenesis inhibition and blood vessel normalization by ITA. Utilizing the pharmaceutical and pharmacological synergies between the therapeutic agents, a simple yet effective design of a combination cancer nanomedicine that is industrially scalable and clinically translatable is achieved.

Intermolecular Interactions between Coencapsulated Drugs Inhibit Drug Crystallization and Enhance Colloidal Stability of Polymeric Micelles.

Novel "pairs" of drugs possessing pharmacological synergies could be encapsulated into polymeric micelles and exert superb therapeutic effects in vivo upon intravenous administration, with the prerequisite that the micelles remain stable. NADP(H) quinone oxidoreductase 1 (NQO1) inhibitors, such as ß-lapachone (LPC) and tanshinone IIA (THA), are structurally and pharmacologically similar molecules that are poorly water-soluble, crystallize extremely fast, and demonstrate synergistic anticancer effect when used together with paclitaxel (PTX). However, when coencapsulated with PTX in poly(ethylene glycol)-b-poly(d,l-lactic acid) (PEG-PLA) micelles, only PTX/LPC but not the PTX/THA pair yields satisfactory colloidal stability. To reveal the molecular mechanism contributing to the colloidal stability of the coencapsulated micelles, we investigated the molecular interactions of PTX/LPC and PTX/THA, through both experimental methods (crystallization kinetics, 13C NMR) and molecular dynamic simulation. We observed that PTX was capable of inhibiting LPC but not THA crystallization both in an aqueous environment and in the solid state, which could be attributed to the strong hetero-intermolecular interactions (π-π, H-bonding) between LPC and PTX, which disrupted the homo-intermolecular interactions between LPC molecules and thus formed a favorable miscible binary system. In comparison, the lack of a strong PTX/THA interaction left the strong THA/THA stacking interaction undisturbed and the fast THA crystallization tendency unrestrained. We conclude that the intermolecular interactions, i.e., the "pharmaceutical synergy", between the coencapsulated drugs critically control the colloidal stability of polymeric micelles and, therefore, should be evaluated when coencapsulated drug delivery systems are designed for optimal therapeutic benefits.

Tumor Progression of Non-Small Cell Lung Cancer Controlled by Albumin and Micellar Nanoparticles of Itraconazole, a Multitarget Angiogenesis Inhibitor.

Itraconazole (ITA), an old and widely prescribed antifungal drug with excellent safety profile, has more recently been demonstrated to be a multitarget antiangiogenesis agent affecting multiple angiogenic stimulatory signals and pathways, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor receptor 2 (VEGFR2) glycosylation, and mammalian target of rapamycin (mTOR). In this study, we developed two nanoparticle formulations, i.e., polymer micelles (IP2K) and albumin nanoparticles (IBSA), to solubilize the extremely hydrophobic and insoluble ITA to allow intravenous administration and pharmacokinetics (PK)/pharmacodynamics (PD) comparisons. Although none of the formulations showed strong antiproliferation potency against non-small cell lung cancer (NSCLC) cells in vitro, when administrated at the equivalent ITA dose to a NSCLC patient-derived xenograft (PDX) model, IBSA retarded while IP2K accelerated the tumor growth. We attributed the cause of this paradox to formulation-dependent PK and vascular manipulation: IBSA demonstrated a more sustained PK with a Cmax of 60-70% and an AUC ∼2 times of those of IP2K, and alleviated the tumor hypoxia presumably through vascular normalization. In contrast, the high Cmax of IP2K elevated tumor hypoxia through a strong angiogenesis inhibition, which could have aggravated cancer aggressiveness and accelerated tumor growth. Furthermore, IBSA induced minimal hepatic and hematologic toxicities compared to IP2K and significantly enhanced the in vivo tumor inhibition activity of paclitaxel albumin nanoparticles when used in combination. These findings suggest that formulation and pharmacokinetics are critical aspects to be considered when designing the ITA angiogenesis therapy, and IBSA could potentially be assessed as a novel and safe multitarget angiogenesis therapy to be used in combination with other anticancer agents.

Crystallization of bifonazole and acetaminophen within the matrix of semicrystalline, PEO-PPO-PEO triblock copolymers.

The morphology and microstructure of crystalline drug/polymer solid dispersions could influence their physical stability and dissolution performance. In this study, the drug crystallization mechanism within PEG, PPG, and poloxamer matrix was investigated, and the resultant microstructure of various solid dispersions of acetaminophen (ACM) and bifonazole (BFZ) in the aforementioned polymers was characterized by differential scanning calorimetry (DSC), polarized optical microscopy (POM), and wide/small-angle X-ray diffraction (WAXD/SAXS). With a stronger molecular interaction with the PEG segments, ACM decreased the crystallization onset temperature and crystallinity of PEG and poloxamers much more than BFZ. The stronger molecular interaction and better miscibility between ACM and PEG also induced a more defective lamellar structure in the ACM solid dispersions compared with that in the BFZ systems, as revealed by DSC and SAXS investigation. Observed under polarized optical microscopy, PEG, PPG, and poloxamer could all significantly improve the crystallization rate of ACM and BFZ, because of the largely reduced Tg of the solid dispersions by these low Tg polymers. Moreover, when the drug loading was below 60%, crystallization of BFZ in PEG or poloxamer occurred preferably along the radial direction of PEG spherulite, rather than the perpendicular direction, which was attributed to the geometric restriction of well-ordered polymer lamellar structure in the BFZ solid dispersions. Similar phenomena were not observed in the ACM solid dispersions regardless of the drug loading, presumably because ACM could diffuse freely across the perpendicular direction of the PEG spherulite, through the well-connected interlamellar or interfibrillar spaces produced by the defective PEG lamellar structure. The different drug-polymer interaction also caused a difference in the microstructure of polymer crystal, as well as a difference in drug distribution within the polymer matrix, which then synergistically facilitated a "confined crystallization" process to reduce the drug crystallite size below 100 nm.

Clinical application of computer-designed polystyrene models in complex severe spinal deformities: a pilot study.

Surgical treatment of complex severe spinal deformity, involving a scoliosis Cobb angle of more than 90 degrees and kyphosis or vertebral and rib deformity, is challenging. Preoperative two-dimensional images resulting from plain film radiography, computed tomography (CT) and magnetic resonance imaging provide limited morphometric information. Although the three-dimensional (3D) reconstruction CT with special software can view the stereo and rotate the spinal image on the screen, it cannot show the full-scale spine and cannot directly be used on the operation table. This study was conducted to investigate the application of computer-designed polystyrene models in the treatment of complex severe spinal deformity. The study involved 16 cases of complex severe spinal deformity treated in our hospital between 1 May 2004 and 31 December 2007; the mean +/- SD preoperative scoliosis Cobb angle was 118 degrees +/- 27 degrees. The CT scanning digital imaging and communication in medicine (DICOM) data sets of the affected spinal segments were collected for 3D digital reconstruction and rapid prototyping to prepare computer-designed polystyrene models, which were applied in the treatment of these cases. The computer-designed polystyrene models allowed 3D observation and measurement of the deformities directly, which helped the surgeon to perform morphological assessment and communicate with the patient and colleagues. Furthermore, the models also guided the choice and placement of pedicle screws. Moreover, the models were used to aid in virtual surgery and guide the actual surgical procedure. The mean +/- SD postoperative scoliosis Cobb angle was 42 degrees +/- 32 degrees, and no serious complications such as spinal cord or major vascular injury occurred. The use of computer-designed polystyrene models could provide more accurate morphometric information and facilitate surgical correction of complex severe spinal deformity.

Oral bioavailability enhancement of ß-lapachone, a poorly soluble fast crystallizer, by cocrystal, amorphous solid dispersion, and crystalline solid dispersion.

The aim of this paper was to compare the in vitro dissolution and in vivo bioavailability of three solubility enhancement technologies for ß-lapachone (LPC), a poorly water soluble compound with extremely high crystallization propensity. LPC cocrystal was prepared by co-grinding LPC with resorcinol. LPC crystalline and amorphous solid dispersions (CSD and ASD) were obtained by spray drying with Poloxamer 188 and HPMC-AS, respectively. The cocrystal structure was solved by single crystal x-ray diffraction. All formulations were characterized by WAXRD, DSC, POM and SEM. USP II and intrinsic dissolution studies were used to compare the in vitro dissolution of these formulations, and a crossover dog pharmacokinetic study was used to compare their in vivo bioavailability. An 1:1 LPC-resorcinol cocrystal with higher solubility and faster dissolution rate was obtained, yet it converted to LPC crystal rapidly in solution. LPC/HPMC-AS ASD was confirmed to be amorphous and uniform, while the crystal and crystallite sizes of LPC in CSD were found to be ∼1-3 µm and around 40 nm, respectively. These formulations performed similarly during USP II dissolution, while demonstrated dramatically different oral bioavailability of ∼32%, ∼5%, and ∼1% in dogs, for CSD, co-crystal, and ASD, respectively. CSD showed the fastest intrinsic dissolution rate among the three. The three formulations showed poor IVIVC which could be due to rapid and unpredictable crystallization kinetics. Considering all the reasons, we conclude that for molecules with extremely high crystallization tendency that cannot be inhibited by any pharmaceutical excipients, size-reduction technologies such as CSD could be advantageous for oral bioavailability enhancement in vivo than technologies only generating transient but not sustained supersaturation.

[Application of freeze-dried cancellous allograft in treatment of spinal tuberculosis].

OBJECTIVE: To investigate the efficacy of freeze-dried cancellous allograft in the treatment of spinal tuberculosis. METHODS: From January 1999 to August 2004, there were 31 cases of spinal tuberculosis who underwent surgery. The freeze-dried cancellous allograft was used as grafting material in all the cases. The cancellous allograft was packed in a titanium mesh cage or an artificial vertebrae, and then used as a strut graft anteriorly to implant into the bone defect after the radical debridement, and the instrumentation was done. RESULTS: Twenty-three cases were followed up 1.5 years to 5 years (3.7 years on average), and bony fusion was achieved in 21 cases 6 months later. In 2 cases ceasing antituberculous therapy after 2 months of operation, the local recurrence was obvious. The loosened screw was noticed in one of these two cases, who had tuberculosis in lumbar spine. When antituberculous therapy continued, the bony fusion was observed in these two cases 12 months later. No further position change of the instrument was noticed in the patient carrying loosened screw, but the kyphosis of the thoracolumbar spine aggravated. CONCLUSION: Freeze-dried cancellous allograft could be used in the treatment of spinal tuberculosis. To achieve good results of allograft incorporation and remodeling, the rigid instrumentation should be performed, postoperative antituberculous therapy is also important.