Glyceryl Laurate Tablets: Effect of the Excipients and Granule Size on the Tablet Quality

Glyceryl laurate (GL), also known as glycerol monolaurate or monolaurin, is a naturally occurring compound. It was first available as a dietary formulation in the mid-60s of the 20th century and today it is known as a dietary supplement suitable for supporting the immune system, a healthy balance of intestinal microflora, or as a product to maintain beneficial yeast levels (Barker et al., 2019; Fosdick et al., 2022; Luo et al., 2022). The richest source is coconut oil, but GL is also found in breast milk and palm oil. In addition to natural sources, it is produced by partial esterification of pure glycerol, chemical glycerolysis of fats and oils by inorganic catalysts, or enzymatic glycerolysis (Nandi et al., 2004; Nitbani et al., 2022; Serri and Muhammad Shahrin, 2019). The formation of an ester bond between lauric acid and glycerol occurs in two isoforms, that is, α-glyceryl laurate and β-glyceryl laurate. However, chemically synthesized α-monolaurin seems to be more active (Dayrit, 2015). It does not have an irritating effect, is nontoxic, and can be used as a food additive or taken as a nutritional supplement daily. GL belong to substances generally recognized as safe (Feltes et al., 2013). It acts as a nonionic, hydrophilic–lipophilic surfactant with excellent emulsifying properties, which is the reason for its wide application in the food, cosmetic, and pharmaceutical industries (Feltes et al., 2013). Due to its antimicrobial activity, it is also used as a preservative and can extend the shelf life of food. Oh and Marshall (1992) compared the minimal inhibitory concentration (MIC) of GL and other common food antimicrobials (e.g., propyl parahydroxybenzoate, butylated hydroxyanisole, etc.) against Listeria monocytogenes and found the lowest MIC of GL (10 μg mL⁻¹ at pH 7.00).

Generally, the mechanism of action of surfactants on the intestinal microbiota may consist in modifying the viscosity and motility of mucin or the cytoplasmic membrane of bacteria colonizing the intestine. Alternatively, they reduce adhesion and thus the ability of bacteria to adhere to the surface. It is assumed that the antimicrobial activity of GL with different mechanisms of action is determined precisely by its nature, which is described by several works (Churchward et al., 2018; Yoon et al., 2018; 2015).

GL is incorporated into the cell membrane and causes its damage by solubilizing lipids and phospholipids. It disrupts signal transduction and transcription in the cell and prevents replication, thus preventing the spread of bacteria. In addition, GL stabilizes the human host cell membrane (Dayrit, 2015; Projan et al., 1994). It is proved that GL inhibits the production of exotoxin and other proteins at the level of bacterial DNA. Besides that, it blocks the production of beta-lactamases that are responsible for resistance to penicillins and cephalosporins (Subroto and Indiarto, 2020).

GL-inactivated lipid coat bacteria include L. monocytogenes, Helicobacter pylori, Hemophilus influenzae, Staphylococcus aureus, Streptococcus agalactiae, and streptococci (group A, B, F, and G) (Lieberman et al., 2006). Besides that, it acts on the species Bacillus cereus/stearothermophillus/subtilis and Enterococcus faecalis (Subroto and Indiarto, 2020).

In addition, a beneficial effect of GL on maintaining healthy vaginal microflora has been demonstrated as it can inhibit the pathogens Candida vaginalis and Gardenella vaginalis without adversely affecting the beneficial bacterial strains of Lactobacillus and altering the vaginal pH (Strandberg et al., 2010). Besides Candida albicans, GL exhibits antifungal activity against Aspergillus sp., Penicillium sp., Cladosporium sp., Fusarium sp., Alternaria sp., Fonsecaea pedrosoi, and Cryptococcus neoformans (Nitbani et al., 2022).

The mechanism of antiviral action consists in damaging the lipid envelope of the virus. Since GL is of the same size as the lipid molecules of the virus, it is absorbed into its fat layer. The virus thus loses its binding ability, is unable to enter the host cells, and continues to infect and replicate. When GL attaches to the virus envelope, the virus becomes more sensitive to the immune system. It also disrupts virus replication by blocking DNA replication signals and the process of maturation and spread of viruses (Arora et al., 2010; Peterson and Schlievert, 2006; Projan et al., 1994). GL works against various viruses, especially enveloped lipid sheaths (human immunodeficiency virus, measles virus, herpes simplex virus, herpes viridae, human lymphotropic virus, vesicular stomatitis virus, visna virus, cytomegalovirus, Epstein–Barr virus, influenza virus, pneumovirus, sarcoma virus, syncitial virus, rubeola virus) (Lieberman et al., 2006). It also inhibits various influenza and respiratory viruses (RSV, HP1V2, H1N1, paramyxo and myxoviruses). GL-like, monocaprine and monocapryline, also have good results against influenza viruses, Their virucidal activity increases at lower pH (about 4.2) (Arora et al., 2010). Welch et al. reported that GL inhibits the replication of enveloped mumps, yellow fever, and Zika virus at concentrations of 80 μg/mL (Welch et al., 2020). Since the chemical structure of GL is similar to the structure of soaps, it could be equally effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), destroying viral membranes and preventing RNA synthesis, binding to the host cell, and virus maturation (Subroto and Indiarto, 2020).

GL also plays a particularly important role in the development of infants’ immune systems and their ability to resist various infections. It occurs naturally in breast milk. At an amount of about 3 mg mL⁻¹, it forms an important part of its lipid composition (Nitbani et al., 2022; Subroto and Indiarto, 2020). The support for the immune system happens through modulating lymphocyte production and controlling immune cell proliferation. GL may also play a role in inhibiting the production of proinflammatory cytokines (Subroto and Indiarto, 2020). GL has another benefit for the human body. It is a so-called bioactive lipid able to reduce serum cholesterol levels and thus prevent cardiovascular disease (Eyres et al., 2016).

The study aimed to evaluate the influence of the substitution of sucrose laurate with sucrose ester in the composition of GL granules and the effect of the excipients and the granule size on the quality of the compressed tablets. Through melt granulation, the excipients were effectively agglomerated with a meltable binder. There was no need of water, other organic solvents, or subsequent drying of the material. It is a time- and energy-saving technique. The principle of the granule preparation consisted in creating a solid solution from components of suitable properties and subsequent disaggregation of this solution using a high-shear mixer. The rest of the powder components were added to the solid solution, which, due to heat and mixing, formed the final granules, which were then pressed through various sieves.

Ryoto^® sugar ester L1695 (sucrose laurate) and GL were obtained from K2pharm s.r.o. (Opava, Czech Republic). Sucrose ester Sisterna^® SP70 (E473) (sucrose stearate/palmitate) was purchased from Sisterna (Roosendaal, the Netherlands). Sorbitol and microcrystalline cellulose were obtained from CentralChem (Bratislava, Slovakia). (+)-Lactic acid 80% liquid was obtained from PENTA s.r.o. (Prague, Czech Republic). Talc was purchased from Galvex (Banská Bystrica, Slovakia). Magnesium stearate and aminoacetic acid were obtained from Sigma-Aldrich/Merck KgaA (Darmstadt, Germany).

Using melt granulation and addition of other excipients, especially microcrystalline cellulose, partial prevention of the adhesion of the material to the punches was achieved, resulting in the compression of the quality tablets when granules of smaller grain size (less than 1.25 mm) were used. Finally, it can be concluded that sucrose ester is a suitable substitute for sucrose laurate, without having a significant effect on the quality of pressed tablets, as long as a suitable granule size is used. The mentioned tablet production is not suitable for large-scale manufacture. During the manual pressing of the tablets by an eccentric press, it was possible to check the press punches during the process and possibly clean them, which is inadmissible and nonsecurable in the case of large-scale production. Therefore, it would be more appropriate to pack the final granules into hard capsules. Even in this case, the better flow properties of the granules with a smaller size were demonstrated. The results of the comparison of GL granules containing various surfactants, as well as the influence of the modified granulation technique on the properties of the granules are the subject of another, more extensive study.