Modulation of the Gal-9/TIM-3 Immune Checkpoint with α-Lactose. Does Anomery of Lactose Matter?

The disaccharide lactose is an excipient commonly used in pharmaceutical products. The two anomers, α- and β-lactose (α-L/β-L), differ by the orientation of the C-1 hydroxyl group on the glucose unit. In aqueous solution, a mutarotation process leads to an equilibrium of about 40% α-L and 60% β-L at room temperature. Beyond a pharmaceutical excipient in solid products, α-L has immuno-modulatory effects and functions as a major regulator of TIM-3/Gal-9 immune checkpoint, through direct binding to the β-galactoside-binding lectin galectin-9. The blockade of the co-inhibitory checkpoint TIM-3 expressed on T cells with anti-TIM-3 antibodies represents a promising approach to combat different onco-hematological diseases, in particular myelodysplastic syndromes and acute myeloid leukemia. In parallel, the discovery and development of anti-TIM-3 small molecule ligands is emerging, including peptides, RNA aptamers and a few specifically designed heterocyclic molecules. An alternative option consists of targeting the different ligands of TIM-3, notably Gal-9 recognized by α-lactose. Modulation of the TIM-3/Gal-9 checkpoint can be achieved with both α- and β-lactose. Moreover, lactose is a quasi-pan-galectin ligand, capable of modulating the functions of most of the 16 galectin molecules. The present review provides a complete analysis of the pharmaceutical and galectin-related biological functions of (α/β)-lactose. A focus is made on the capacity of lactose and Gal-9 to modulate both the TIM-3/Gal-9 and PD-1/PD-L1 immune checkpoints in oncology. Modulation of the TIM-3/Gal-9 checkpoint is a promising approach for the treatment of cancers and the role of lactose in this context is discussed. The review highlights the immuno-regulatory functions of lactose, and the benefit of the molecule well beyond its use as a pharmaceutical excipient.

Safety verification for polysorbate 20, pharmaceutical excipient for intramuscular administration, in Sprague-Dawley rats and New Zealand White rabbits

Human serum albumin (HSA) has been widely used as a pharmaceutical excipient in Botulinum toxin serotype A (BoNT/A) products that are indicated for use in therapeutics and cosmetics. However, HSA as a human-derived material has some concerns, such as the potential risk of transmission of infectious agents, an insufficient supply, and difficulty in maintaining a certain quality. For those reasons, newly developed BoNT/A products (CORETOX®, Medytox, Inc., Republic of Korea) contained polysorbate 20, a non-human-derived excipient, to replace the HSA. However, most safety studies of polysorbate 20 have been conducted with non-invasive routes of administration, and thus there are a few studies on the safety of polysorbate 20 when administered intramuscularly. To secure the in vivo safety profile of polysorbate 20, a four-week repeated intramuscular dose toxicity study (0.02, 0.1, and 0.4 mg/kg, one injection every two weeks for a total of three injections) was conducted in 66 Sprague-Dawley (SD) rats. An intradermal irritation study was further conducted with 18 New Zealand White (NZW) rabbits. The toxicological evaluation of HSA (0.06 and 0.12 mg/kg) was also carried out as a comparative substance. Systemic and local toxicities were not observed in any of the SD rats or NZW rabbits based on clinical signs, body weight, hematology, clinical biochemistry, macroscopic findings on necropsy, histopathology of the injection site, and allergic reactions. The current study suggested that intramuscular administration of polysorbate 20 was considered to be safe at a level similar to that of HSA, which has an in vivo safety profile accumulated over the years. This provided the basis for the in vivo safety profile of polysorbate 20 administered intramuscularly and the scientific reliability of the use of polysorbate 20 as an alternative to HSA, which is used as an excipient for various pharmaceuticals in terms of its safety.

The potential of banana fruit Ranggap (Musa paradisiaca var. Troglodytarum) as an excipient alternative to oral tablet dosage form

Introduction: Starch is one of the ingredients that has many benefits, including in the pharmaceutical field, especially as a pharmaceutical excipient in pharmaceutical formulations. Aim: This study aims to isolate, characterise, and formulate the starch of banana fruit (Musa paradisiaca var. Troglodytarum) into tablet dosage forms. Methods: The characteristics of the perceived banana starch can be said to be comparable to that of corn starch so that it is expected to be used as a source of starch which can be used as a pharmaceutical excipient. The starch of isolated banana fruit was used as a filler, binder, and crusher in the wet granulation method tablet formulations with concentrations of 2%, 3%, and 5%. Results: The physicochemical characteristics of starch isolated from banana fruit are considered to meet the requirements of pharmaceutical excipients required in the Handbook of Pharmaceutical Excipients 6th edition and the United States Pharmacopeia 32nd edition. Conclusion: Of the total formulas tested, tablets with binder content of banana starch 3%, 5% and 10% corn starch meet the tablet evaluation requirements.

The potential of banana fruit Ranggap (Musa paradisiaca var. Troglodytarum) as an excipient alternative to oral tablet dosage form

Introduction: Starch is one of the ingredients that has many benefits, including in the pharmaceutical field, especially as a pharmaceutical excipient in pharmaceutical formulations. Aim: This study aims to isolate, characterise, and formulate the starch of banana fruit (Musa paradisiaca var. Troglodytarum) into tablet dosage forms. Methods: The characteristics of the perceived banana starch can be said to be comparable to that of corn starch so that it is expected to be used as a source of starch which can be used as a pharmaceutical excipient. The starch of isolated banana fruit was used as a filler, binder, and crusher in the wet granulation method tablet formulations with concentrations of 2%, 3%, and 5%. Results: The physicochemical characteristics of starch isolated from banana fruit are considered to meet the requirements of pharmaceutical excipients required in the Handbook of Pharmaceutical Excipients 6th edition and the United States Pharmacopeia 32nd edition. Conclusion: Of the total formulas tested, tablets with binder content of banana starch 3%, 5% and 10% corn starch meet the tablet evaluation requirements.

Investigation of Plantago ovata Husk as Pharmaceutical Excipient for Solid Dosage Form (Orodispersible Tablets)

The objective of the study was to investigate the suitability of the Plantago ovata (PO) husk as a pharmaceutical excipient. Various phytoconstituents of the husk were determined according to the standard test procedures. The Plantago ovata husk was evaluated for various pharmaceutical parameters related to flow, swelling index, and compressibility index. Orodispersible tablets (ODTs) were prepared, containing different concentrations (2.5, 3, 5, 7.5, 10, and 15% w / w ) of the Plantago ovata husk. Before compression, all the formulations were evaluated for their flow. Compressed ODTs were evaluated for physical characteristics (physical appearance, weight and weight variation, thickness, and moisture content), mechanical strength (crushing strength, specific crushing strength, tensile strength, and friability), disintegration behavior (disintegration time and oral disintegration time), drug content, and in vitro drug release. Phytochemical evaluation of the Plantago ovata husk confirmed the presence of various phytoconstituents like alkaloids, tannins, glycosides, saponins, flavonoids, and phenols. SEM photograph of the Plantago ovata husk showed that it has a fibrous structure, with a porous and rough surface. The Plantago ovata husk had a high swelling index (380%) which decreased by pulverization (310%). Precompression evaluation of the powder blend for all the formulations of ODTs showed good flow properties, indicating that the Plantago ovata husk improved the rheological characteristics of the powder blend. Compressed ODTs had good mechanical strength, and their friability was within the official limits (<1%). Best disintegration was observed with formulation F-6 containing 10% w / w of the Plantago ovata husk. It is concluded that the Plantago ovata husk can be used as a disintegrant in the formulation of ODTs.