Diethylene glycol monoethyl ether: Physicochemical Properties,Mechanisms and Safety assessment as the pharmacological excipient

Introduction

Diethylene glycol monoethyl ether (DEGME; Figure 1), an ethylene oxide derivative, is used as a solvent in numerous products in the pharmaceutical, cosmetics and food industry. It has application as an effective solubilizer in oral, topical, transdermal and injectable human and veterinary pharmaceutical products. It is noteworthy that the industrial grades of this solvent contain significant levels of ethylene glycol and DEG impurities. It is a protic solvent/solubilizer, also known as 2-(2-ethoxy ethoxy) ethanol, ethoxydiglycol. Diethylene glycol monoethyl ether has been approved by the United States Food and Drug Administration (FDA) for use as an excipient and cosolvent in pharmaceutical formulation and the food industry. It has been used in solutions, ointments, sprays, capsules, and creams to deliver poorly water soluble drugs (4, 5). DEGME is listed on the United States Pharmacopeia (USP 24-NF 19) and European Pharmacopeia (4th edition) monographs.[1] 

Physicochemical Properties 

Diethylene glycol monoethyl ether is a slightly viscous liquid that is miscible with most known cosolvents, surfactants, and oils in the liquid state. The physicochemical features of DEGME are listed in Table 1. Diethylene glycol monoethyl ether can improve the solubility of various poorly water soluble drugs by playing the role of a surfactant (HLB 4.2) and solvent [2].

Mechanisms of diethylene glycol monoethyl ether as excipients 

Osborne et al. reviewed various articles to investigate the mechanism of diethylene glycol monoethyl ether in skin penetration and permeation. They revealed that the efficiency of diethylene glycol monoethyl ether as a solubilizer /penetration enhancer depends on its performed concentration alone or in combination with other excipients [3]. Diethylene glycol monoethyl ether can easily penetrate the stratum corneum and interact strongly with water through the intercellular route. This diethylene glycol monoethyl ether /water interaction may alter the stratum corneum barrier in a number of ways. As diethylene glycol monoethyl ether penetrates the stratum corneum, it changes the molecular mobility of proteins and lipids in the stratum corneum and decreases the skin's barrier function. Furthermore, transdermal penetration of DEGME increases drug solubility in the stratum corneum and reduces the skin barrier for active ingredients. Additionally, it increases the retention of the stratum corneum for non-permeable active ingredients [3].

Safety assessment of diethylene glycol monoethyl ether using in vitro and in vivo models.

Based on the available scientific literature, The Scientific Committee on Consumer Products (SCCP) conducted a risk assessment of diethylene glycol monoethyl ether in 2006, which led one of the member states to put some restrictions on the use of this substance. The available‘Toxicological reports’were found unsatisfactory by the SCCP as they contained only summaries without details . An isolated case report cited that the accidental ingestion of approximately 300 ml of a liquid containing 47% diethylene glycol monoethyl ether (approx. 2000 mg/kg) by a male led to the occurrence of severe symptoms of central nervous, respiratory injury, thirst, acidosis and albumin in the urine. The subject recovered following symptomatic treatment. Although in 2013, the SCCP revised the systemic daily dose of DEGME in cosmetic products for dermal application, its use in products for oral hygiene and the eyes were not evaluated. Reports from India highlighted that the use of 99.8% diethylene glycol monoethyl ether in the painkiller injectables might cause damage to the kidneys, therefore, a thorough safety assessment of DEGME becomes crucial. Preliminary in vitro findings have also indicated that diethylene glycol monoethyl ether was able to inhibit the growth of Neuro2A neuroblastoma cell line in dose as well as time-dependent manner.[4]

Methods: Considering the above reports and lack of scientific conclusions, studies were performed in Human embryonic kidneys cells, HEK 293 to evaluate the effect of diethylene glycol monoethyl ether exposure and further its safety assessment was carried out in Swiss albino mice. Ninety-nine percent pure form of diethylene glycol monoethyl ether was used to rule out any possibility of impurity associated toxic effects.

In vitro effects of DEGME (0.5-25 mg/ml) were assessed in the HEK293 human embryonic kidney cells. In vivo effects were evaluated after single acute exposure of diethylene glycol monoethyl ether via intraperitoneal route in Swiss albino mice and further, a 28 days subchronic exposure study was conducted where diethylene glycol monoethyl ether was administered orally, once daily.[4]

Results: Diethylene glycol monoethyl ether was cytotoxic to HEK293 cells, and an IC50 of 15 mg/ml was established. An increase in the intracellular levels of ROS and alteration in the mitochondrial membrane potential led to nuclear fragmentation and induction of apoptosis in these cells. Survival rate of animals administered intraperitoneally with a single acute dose of 1000 mg/kg diethylene glycol monoethyl ether was 100% with no significant changes in the behavioural and histological parameters. However, the dose of 3000 mg/kg and above led to total mortality within 14 days of acute exposure. Subchronic oral exposure of 500-2000 mg/kg diethylene glycol monoethyl ether showed no significant changes in the hematological, biochemical and histopathological parameters.[4]

Conclusion

In summary, a comprehensive evaluation of toxicological parameters of diethylene glycol monoethyl ether indicate that its effects vary depending on the route of administration and duration of exposure. No evidence of nephrotoxicity was observed in the kidneys of subchronically treated mice, except minimal increase of focal MNCs and minimal dilation of Bowman’s capsule. Howerever, the decrease in survival rates after acute i.p exposure and the cytotoxic effects of diethylene glycol monoethyl ether in the human embryonic kidney cells indicate that the nephrotoxic potential of this excipient cannot be ruled out. It is clear that additional work and full-scale investigations focussed on DEGME’s toxicological potential and mechanisms of action are required before its use in clinical formulations.

References

[1] Hashemzadeh N, Jouyban A. Review of Pharmaceutical Applications of Diethylene Glycol Monoethyl Ether. J Pharm Pharm Sci. 2022;25:340-353. doi:10.18433/jpps32921

[2] Ha E-S, Lee S-K, Choi DH, Jeong SH, Hwang S-J, Kim M-S. Application of diethylene glycol monoethyl ether in solubilization of poorly water-soluble drugs. Journal of Pharmaceutical Investigation. 2020; 50 (3): 231-250. DOI:10.1007/s40005-019-00454-y

[3] Osborne DW, Musakhanian J. Skin penetration and permeation properties of Transcutol®—neat or diluted mixtures. American Association of Pharmaceutical Scientists 2018; 19 (8): 3512-3533. DOI:10.1208/s12249-018-1196-8

[4] Srivastava S, Mishra S, Dewangan J, et al. Safety assessment of the pharmacological excipient, diethylene glycol monoethyl ether (DEGEE), using in vitro and in vivo systems [published correction appears in Daru. 2022 Dec;30(2):443-445. doi: 10.1007/s40199-022-00442-y.]. Daru. 2019;27(1):219-231. doi:10.1007/s40199-019-00264-5

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