High loading of trimethylglycine promotes aqueous solubility of poorly water-soluble cisplatin

Abstract

Trimethylglycine (TMG) is a cheap, natural, and highly biocompatible compound. Therefore, it has been used in the fields of food and life sciences, but the application of solid TMG is limited to utilisation as an “additive”. In the present study, we focussed on the high solubility of TMG in water, derived from the aprotic zwitterionic structure, and proposed TMG as the chemical accounting for a major portion of the aqueous solution (e.g., 50 wt%). High loading of TMG shifted the properties of water and enabled the dissolution of poorly water-soluble cisplatin, an anticancer agent, at high concentration (solubility of cisplatin: 0.15 wt% in water vs 1.7 wt% in TMG aqueous solution). For hepatic arterial infusion, this can reduce the amount of cisplatin administered from 40 to 4 mL. It enables simple injection using a syringe, without the need for catheters and automatic pumps, leading to critical alleviation of the risk to patients. Furthermore, we produced a dry powder from a cisplatin-containing TMG aqueous solution via freeze-drying. Powders can be conveniently stored and transported. Furthermore, cisplatin is often used as a mixture with other drugs, and cisplatin aqueous solutions are not preferred as they dilute the other drugs.

Amino Acids as Chelating Ligands for Platinum: Enhanced Stability in an Aqueous Environment Promoted by Biocompatible Molecules

“…Trimethylglycine. Kadokawa et al 35 reported that a highly concentrated solution of trimethyl glycine (TMG, also known as betaine) is able to improve the solubility of cisplatin in water without affecting the pharmacological proprieties of this drug. The mechanism behind this effect seems to lie in the hydrogen bond acceptor property of the carboxylate of TMG, which establishes hydrogen bonds with the amino groups of cisplatin.…”

The Behavior of Nanovesicles of Physicochemical Profiles: Compose of β-Cyclodextrin and Cisplatin for Anti-Tumor Activity and Decrease Toxicity Affected Normal Surrounding Tumor Tissues

“…This study of all procedures for CP-LPS and β-CD-CP-LPS was fulfilled in an ordinary method. The solubility of CP is 2.5 mg in 1 mL of water at 30 ℃, approximately and the solubility of CP can increase to 4 mg in 1 mL of water at 35 ℃ [15,16]. Nevertheless, in part of ultrasonic sonication, liposomal preparation increased the temperature to 40 ℃.…”

“…The liposomal NVs were kept in transparent vials and stored at room temperature 30 ± 2, 45 ± 2 and containing the drug-loaded vesicles were analyzed with UV spectroscopy (Perkin Elmer Lambda Bio UV/Vis Spectrometer) at 301 nm [15][16][17][18].…”

“…All experiments were performed in triplicate. The supernatants of these samples were analyzed with UV spectroscopy (Perkin Elmer Lambda Bio UV/Vis Spectrometer) at 301 nm [15][16][17][18] to determine the amount of CP that had been released compared with a standard curve. CP encapsulation efficiency (%) was determined by the ratio of the drug encapsulated in the NVs and the initial amount of drug used in the process.…”

“…LPS, and plain DPPC/CHL (6:4 molar ratios, 40 mM, LPS) formulations were studied the physical stabilities at 3 temperatures (4 ± 2, 30 ± 2 ℃ at 75 % R.H. ± 5 %, 45 ± 2 ℃ at 75 % R.H. ± 5 %) [19] for 3 months, white dispersions, translucent, pH 6.0 ± 0.3, no sedimentation, and phase separation of both formulations exhibited at 45 ± 2 ℃ after 2 weeks (Tables 2 and 3). The inclusion complex was prepared by mixing CP/CD in the 1:1 molar ratio allowing one drug molecule to interact with one HPβCD molecule [9,15]. The encapsulation efficiency of β-CD-CP-LPS was calculated in the CP term, as shown in Table 4.…”