Ionic liquids (ILs) have been used as solvents or materials, or both, in many applications, including pharmaceutics and medicine due to their exceptional properties consisting of the combination of “green”...
Ionic liquid (IL)-based drug delivery systems have attracted considerable interest owing to their intrinsic tunability and ability to transport small or large molecules through the skin. However, the development of "green" ILs remains challenging. Herein, eight potentially "green" fatty acid-based amino acid ILs (FAAAE-ILs) were synthesized, and their potency in transdermal drug delivery was investigated using ibuprofen and a peptide drug. The synthesized ILs were characterized to evaluate their physicochemical, thermal, and biological (cytotoxicity) properties. The in vitro skin permeability of the synthesized FAAAE-ILs was evaluated through pig skin. All of the FAAAE-ILs are liquid at room temperature and freely miscible with pharmaceuticals-permitted solvents/agents (e.g., isopropyl myristate (IPM), Span-20, and DMSO). In vitro cytotoxicity study showed that the cell viability of all FAAAE-ILs (10% in IPM) was at least 10 times lower than that for a conventional chemical permeation enhancer (CPE), sodium lauryl sulfate. FAAAE-ILs facilitated excellent ibuprofen solubility through multiple hydrogen bonding interactions between the drug and the ILs. An in vitro permeation study showed that the FAAAE-ILs were more effective in enhancing the permeability of drug molecules than the conventional CPE transcutol. The linoleate-based ILs showed a higher degree of permeation than the oleatebased ILs. Among the linoleate-based ILs and ibuprofen formulations (drug in 10% IL in IPM), the L-proline ethyl ester linoleate ([L-ProEt][Lin])-based formulation exhibited best results, followed by β-alanine ethyl ester linoleate, D-proline ethyl ester linoleate, and L-leucine ethyl ester linoleate after 48 h. Interestingly, the same FAAAE-IL ([L-ProEt][Lin])-containing formulation showed significant enhancement of peptide penetration across pig skin compared with CPE-containing formulations (10% in IPM). The results demonstrate that the FAAAE-IL is a promising green alternative to conventional CPEs for the transdermal delivery of small and large therapeutic molecules.
The transdermal delivery of sparingly soluble drugs is challenging due to of the need for a drug carrier. In the past few decades, ionic liquid (IL)-in-oil microemulsions (IL/O MEs) have been developed as potential carriers. By focusing on biocompatibility, we report on an IL/O ME that is designed to enhance the solubility and transdermal delivery of the sparingly soluble drug, acyclovir. The prepared MEs were composed of a hydrophilic IL (choline formate, choline lactate, or choline propionate) as the non-aqueous polar phase and a surface-active IL (choline oleate) as the surfactant in combination with sorbitan laurate in a continuous oil phase. The selected ILs were all biologically active ions. Optimized pseudo ternary phase diagrams indicated the MEs formed thermodynamically stable, spherically shaped, and nano-sized (<100 nm) droplets. An in vitro drug permeation study, using pig skin, showed the significantly enhanced permeation of acyclovir using the ME. A Fourier transform infrared spectroscopy study showed a reduction of the skin barrier function with the ME. Finally, a skin irritation study showed a high cell survival rate (>90%) with the ME compared with Dulbecco’s phosphate-buffered saline, indicates the biocompatibility of the ME. Therefore, we conclude that IL/O ME may be a promising nano-carrier for the transdermal delivery of sparingly soluble drugs.
Paclitaxel (PTX) injection (i.e., Taxol) has been used as an effective chemotherapeutic treatment for various cancers. However, the current Taxol formulation contains Cremophor EL, which causes hypersensitivity reactions during intravenous administration and precipitation by aqueous dilution. This communication reports the preliminary results on the ionic liquid (IL)-based PTX formulations developed to address the aforementioned issues. The formulations were composed of PTX/cholinium amino acid ILs/ethanol/Tween-80/water. A significant enhancement in the solubility of PTX was observed with considerable correlation with the density and viscosity of the ILs, and with the side chain of the amino acids used as anions in the ILs. Moreover, the formulations were stable for up to 3 months. The driving force for the stability of the formulation was hypothesized to be the involvement of different types of interactions between the IL and PTX. In vitro cytotoxicity and antitumor activity of the IL-based formulations were evaluated on HeLa cells. The IL vehicles without PTX were found to be less cytotoxic than Taxol, while both the IL-based PTX formulation and Taxol exhibited similar antitumor activity. Finally, in vitro hypersensitivity reactions were evaluated on THP-1 cells and found to be significantly lower with the IL-based formulation than Taxol. This study demonstrated that specially designed ILs could provide a potentially safer alternative to Cremophor EL as an effective PTX formulation for cancer treatment giving fewer hypersensitivity reactions.
Since
injection administration for diabetes is invasive, it is
important to develop an effective transdermal method for insulin.
However, transdermal delivery remains challenging owing to the strong
barrier function of the stratum corneum (SC) of the skin. Here, we
developed ionic liquid (IL)-in-oil microemulsion formulations (MEFs)
for transdermal insulin delivery using choline–fatty acids
([Chl][FAs])comprising three different FAs (C18:0, C18:1,
and C18:2)as biocompatible surface-active ILs (SAILs). The
MEFs were successfully developed using [Chl][FAs] as surfactants,
sorbitan monolaurate (Span-20) as a cosurfactant, choline propionate
IL as an internal polar phase, and isopropyl myristate as a continuous
oil phase. Ternary phase behavior, dynamic light scattering, and transmission
electron microscopy studies revealed that MEFs were thermodynamically
stable with nanoparticle size. The MEFs significantly enhanced the
transdermal permeation of insulin via the intercellular route by compromising
the tight lamellar structure of SC lipids through a fluidity-enhancing
mechanism. In vivo transdermal administration of low insulin doses
(50 IU/kg) to diabetic mice showed that MEFs reduced blood glucose
levels (BGLs) significantly compared with a commercial surfactant-based
formulation by increasing the bioavailability of insulin in the systemic
circulation and sustained the insulin level for a much longer period
(half-life > 24 h) than subcutaneous injection (half-life 1.32
h).
When [Chl][C18:2] SAIL-based MEF was transdermally administered, it
reduced the BGL by 56% of its initial value. The MEFs were biocompatible
and nontoxic (cell viability > 90%). They remained stable at room
temperature for 3 months and their biological activity was retained
for 4 months at 4 °C. We believe SAIL-based MEFs will alter current
approaches to insulin therapy and may be a potential transdermal nanocarrier
for protein and peptide delivery.
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