Deep Eutectic Solvents for Subcutaneous Delivery of Protein Therapeutics

Abstract

Proteins are among the most common therapeutics for the treatment of diabetes, autoimmune diseases, cancer, and metabolic diseases, among others. Despite their common use, current protein therapies, most of which are injectables, have several limitations. Large proteins such as monoclonal antibodies (mAbs) suffer from poor absorption after subcutaneous injections, thus forcing their administration by intravenous injections. Even small proteins such as insulin suffer from slow pharmacokinetics which poses limitations in effective management of diabetes. Here, a deep eutectic‐based delivery strategy is used to offer a generalized approach for improving protein absorption after subcutaneous injections. The lead formulation enhances absorption of mAbs after subcutaneous injections by ≈200%. The same composition also improves systemic absorption of subcutaneously injected insulin faster than Humalog, the current gold‐standard of rapid acting insulin. Mechanistic studies reveal that the beneficial effect of deep eutectics on subcutaneous absorption is mediated by their ability to reduce the interactions of proteins with the subcutaneous matrix, especially collagen. Studies also confirm that these deep eutectics are safe for subcutaneous injections. Deep eutectic‐based formulations described here open new possibilities for subcutaneous injections of therapeutic proteins.

Deep Eutectic Solvents: An Eco‐friendly Design for Drug Engineering

“…itraconazole [a] anti-fungal [136] posaconazole [a] anti-fungal choline chloride glycolic acid piroxicam [a] non-steroidal anti-inflammatory drug solubility enhancement of itraconazole, piroxicam, lidocaine, and posaconazole by 6700, 430, 28, and 6400-fold, respectively, as compared to their water solubility lidocaine [a] local anesthetic choline chloride propylene glycol dapsone [a] FDA-approved for acne treatment. It also has therapeutic activities for a range of dermatological diseases solubility enhancement and topical delivery of dapsone with solubility of 500 mg/mL in DES compared with its solubility in water (380 mg/L) [137] betaine ethylene glycol mesalazine [a] treatment of Crohn's disease and ulcerative colitis the mesalazine solubility in DES + water mixtures increased by increasing mass fractions of DES [138] choline (or acetyl choline) glycolate, lactate, propionate, hexenoate, or geranate insulin [a] and monoclonal antibodies subcutaneous delivery of protein therapeutics incorporation of insulin and monoclonal antibodies in DESs showed an improvement in the pharmacokinetics of insulin and the bioavailability of monoclonal antibodies [139] citric acid arginine mesoporous silica nanoparticles containing nanoceria and methotrexate topical management of rheumatoid arthritis using DES-NPs hydrogel DES-NPs hydrogel formulation resulted in sustained penetration and accumulation of NPs at rheumatoid arthritis sites [140] choline chloride malonic acid tadalafil [a] wound healing and antimicrobial activity tadalafil was dissolved in DES for topical application to avoid systemic exposure. Then, Lidocaine was added to the formulation to provide a local anesthetic effect.…”

Ionic Liquids: New Forms of Active Pharmaceutical Ingredients with Unique, Tunable Properties

“…Compounds delivered with CAGE include nobiletin, mannitol, cefadoxil, ,, insulin, acarbose, ruxolitinib, sorafenib, imiquimod, triamcinolone acetonide, curcumin . Permeation of dextrans with different molecular weights was also reported, opening the door to delivery of proteins, peptides, and even antibodies . CAGE was able to deliver bovine serum albumin (BSA, MW ≈ 66 kDa), ovalbumin (OVA, Mw ≈ 45 kDa), and insulin (Mw ≈ 5.8 kDa) across porcine skin and significantly reduce blood glucose levels in rats when insulin-CAGE was topically administered …”

“…383 Permeation of dextrans with different molecular weights was also reported, 384 opening the door to delivery of proteins, peptides, and even antibodies. 385 CAGE was able to deliver bovine serum albumin (BSA, MW ≈ 66 kDa), ovalbumin (OVA, Mw ≈ 45 kDa), and insulin (Mw ≈ 5.8 kDa) across porcine skin and significantly reduce blood glucose levels in rats when insulin-CAGE was topically administered. 386 The exact role of the system components in the transdermal transport of drugs is still unclear, but changes in the stratum corneum lipid content were detected by FTIR, suggesting that CAGE acts as a lipid extractor of stratum corneum components.…”

Has the Toxicity of Therapeutic Deep Eutectic Systems Been Assessed?

“…Pharmacokinetics of subcutaneous insulin administration using deep eutectics (SPADES-insulin) was compared against the equivalent dose of the clinical gold standard of the fast-acting insulin analog (Humalog) in male Wistar non-fasting rats and improved the systemic absorption of subcutaneously injected insulin faster than Humalog. The toxicity was analyzed in healthy female Balb/c mice receiving a single subcutaneous injection of DES solutions and demonstrated that SPADES is a safe and non-toxic formulation [85]. In a new paper, DESs were introduced as novel chemical penetration enhancers for transdermal iontophoresis of insulin across rat skin.…”