Discovery of a Long-Acting Parathyroid Hormone 1-34 Analogue to Treat Hypoparathyroidism.

Hypoparathyroidism (HP) is a rare disease with clinical manifestations of hypocalcemia and hyperphosphatemia, resulting from deficient or absent parathyroid hormone (PTH) secretion. Conventional treatment for patients with HP involves extensive calcium and vitamin D supplementation. In 2015, PTH1-84 was approved by the United States Food and Drug Administration as an adjunct for HP patients who cannot be well-controlled on conventional treatment. However, PTH1-84 therapy requires a daily injection, leading to poor patient compliance. The purpose of this study was to develop a long-acting PTH1-34 analogue by increasing its affinity to albumin. Three PTH1-34 variants were generated by substituting two of the three lysine (Lys) residues with arginine, reserving a single Lys as the modification site in each sequence. A series of side chains, containing fatty acid, deoxycholic acid, or biotin groups, were synthesized to modify these PTH1-34 variants by using a solid-liquid phase synthesis approach. In vitro bioactivity and albumin affinity tests were used to screen these new PTH1-34 analogues. Finally, Lys27-AAPC was selected from 69 synthesized analogues as a candidate therapeutic compound because it retained potency and exhibited a high albumin-binding capacity. In pharmacodynamic experiments, Lys27-AAPC demonstrated enhanced and prolonged efficacy in serum calcium elevating relative to PTH1-84. Moreover, a lyophilized powder for injection containing Lys27-AAPC was developed for further testing and represented a potential long-acting HP treatment.

The synthesis and activity evaluation of N-acylated analogs of echinocandin B with improved solubility and lower toxicity.

Presently, echinocandins have been recommended as the first-line drugs for the treatment of invasive candidiasis. However, low oral bioavailability and solubility limit their application. To improve this situation, this study chose amino acid and fatty acid as raw materials to modify the nucleus of echinocandin B. Six N-acylated analogs were screened from the derivatives that possessed potent antifungal activity and good water solubility. Based on antifungal susceptibility and hemolytic toxicity, compound 5 as the candidate had good antifungal activity and no hemolytic effect. Moreover, compared with anidulafungin, compound 5 showed a comparable fungicidal effect, much higher solubility, and lower toxicity. In conclusion, compound 5 has the potential for further research and development on account of reserved antifungal activity, high solubility, and low toxicity.

Enhanced Physical Stability and Synchronized Release of Febuxostat and Indomethacin in Coamorphous Solids.

Coamorphous formulation, a homogeneous monophasic amorphous system composed of multiple components, has been demonstrated as an effective approach for delivering drugs with poor aqueous solubility. In this study, we prepared the coamorphous system composed of two poorly soluble drugs febuxostat (FEB) and indomethacin (IMC) by using cryogenic milling. The combination of these two drugs in the coamorphous form can attain a synergistic effect, especially on gout therapy. Coamorphous solid of FEB and IMC in 1:1 molar ratio exhibited superior physical stability compared with the individual amorphous components, as evidenced by X-ray powder diffractions after 30 days of storage at ambient and elevated temperature. In addition, the FEB-IMC coamorphous system has been demonstrated to show enhanced dissolution performance. The intrinsic dissolution rates of two components in the coamorphous system exhibited the synchronized drug release. Based on the FT-IR spectroscopy, the excellent physical stability and synchronized release of FEB-IMC coamorphous system could be attributed to the heterodimer structure formed by strong hydrogen bonding interactions between these drugs. Furthermore, the supersaturation potential of FEB-IMC coamorphous solids was also investigated through the cosolvent quenching method. The FEB-IMC coamorphous system can effectively inhibit the fast crystallization of FEB in the supersaturated solution. However, the maximum achievable supersaturation of IMC in the coamorphous system decreases to only one fifth of that achieved for the pure amorphous IMC. These results are relevant for understanding the physical stability and complex solution behaviors of the coamorphous formulation.

Simultaneously Improving the Physicochemical Properties, Dissolution Performance, and Bioavailability of Apigenin and Daidzein by Co-Crystallization With Theophylline.

Co-crystals have received increasing attention during the past decades for their ability to modify the solubility and other physicochemical properties of active pharmaceutical ingredients. Apigenin (Agn) and Daidzein (Dai) are flavonoid compounds with a variety of biological effects. However, the bioavailability and clinical applications of flavonoid compounds are usually limited by their poor aqueous solubilities. In this study, theophylline (Thp) is used as a coformer to co-crystallize with Agn and Dai. The solid-state properties of the co-crystals of Thp with Agn and Dai are characterized by powder X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, Raman spectroscopy, and nuclear magnetic resonance experiments. In addition, both co-crystals show a greater resistance to hydration than Thp alone. The solubilities, intrinsic dissolution rates, and permeabilities of Agn-Thp co-crystal and Dai-Thp co-crystal are improved compared with those of parent flavonoids. The pharmacokinetic study shows that the bioavailabilities of both co-crystals are enhanced in comparison with the corresponding physical mixtures and parent flavonoids. This study demonstrates that the co-crystallization by using theophylline is a promising strategy to improve physicochemical properties and bioavailability of flavonoid compounds.

Long-Acting Release Microspheres Containing Novel GLP-1 Analog as an Antidiabetic System.

Glucagon-like peptide 1 (GLP-1) has recently received significant attention as an efficacious way to treat diabetes mellitus. However, the short half-life of the peptide limits its clinical application in diabetes. In our previous study, a novel GLP-1 analog (PGLP-1) with a longer half-life was synthesized and evaluated. Herein, we prepared the PGLP-1-loaded poly(d,l-lactide- co-glycolide) microspheres to achieve long-term effects on blood glucose control. The incorporation of zinc ion into the formulation can effectively decrease the initial burst release, and a uniform drug distribution was obtained, in contrast to native PGLP-1 encapsulated microspheres. We demonstrated that the solubility of the drug encapsulated in microspheres played an important role in in vitro release behavior and drug distribution inside the microspheres. The Zn-PGLP-1 microspheres had a prominent acute glucose reduction effect in the healthy mice. A hypoglycemic effect was observed in the streptozotocin (STZ) induced diabetic mice through a 6-week treatment of Zn-PGLP-1-loaded microspheres. Meanwhile, the administration of Zn-PGLP-1 microspheres led to the ß-cell protection and stimulation of insulin secretion. The novel GLP-1 analog-loaded sustained microspheres may greatly improve patient compliance along with a desirable safety feature.

Facile formation of co-amorphous atenolol and hydrochlorothiazide mixtures via cryogenic-milling: Enhanced physical stability, dissolution and pharmacokinetic profile.

The development of poorly water-soluble drugs faces the risk of low bioavailability and therapeutic efficacy. The co-amorphous drug delivery system has recently gained considerable interest because it offers an alternative approach to modify properties of poorly water-soluble drugs. Herein, we developed a co-amorphous system of atenolol (ATE) and poorly water-soluble hydrochlorothiazide (HCT) by means of cryogenic milling. The co-administration of ATE and HCT has been reported to show therapeutic advantages for patients with uncomplicated hypertension. The co-amorphous ATE-HCT sample with 1:1 molar ratio showed excellent physical stability, which could be attributed to the formation of strong molecular interactions between ATE and HCT as evidenced by FT-IR spectra. Compared to the pure crystalline form, amorphous form and physical mixture, HCT in the co-amorphous form exhibited the significantly increased intrinsic dissolution rate, as well as the enhanced bioavailability in the pharmacokinetic study. It was found that the enhanced bioavailability of HCT in the co-amorphous formulation was achieved by the synergistic effect of amorphized HCT and the water-soluble coformer ATE. The present study provides an improved approach to implement the combination therapy of ATE and HCT for potential clinical treatments.