Ionic Liquid
for Transdermal DDS
230907 Literature seminar #3
M2 Yuto Azumaya

Contents
1. Introduction
2. Application
1. CAGE system
2. LBIL system

3. Summary and perspective

Introduction : ionic liquidHP

https://products.kanto.co.jp/web/index.cgi?c=t_product_table&pk=49

Introduction : application of Ion Liquid

Today’s topic

20120511 Literature seminar

Introduction : Ion Liquid for pharmaceutical use
solubilize poorly soluble drug molecules

Avoidance of crystal polymorphism
Improvement of drug efficacy and stability
Application to other DDS systems

Eur J Pharm Sci ,2008,33,326

Transdermal permeation enhancer
today’s topic

Introduction : Comparison of three different routes of drug administration• Transdermal
not or less invasive
ease on application
avoid first pass netabolism
Skin irritation
Limited to Suitable drug
• MW<600 Da• a water/octanol
partition coefficient in
the range of 1–3• a low melting point• oralEasy to swallow and convenient
Various dosage form
Degradation by digestive system or liver• injection
100% bioavailability
accurate dose
Invasive painful
expert personnel needed

Drug Deliv. and Transl. Res. 2022,12, 758

Introduction : transdermal drug delivery• Other method• Transdermal
not or less invasive
ease on application
avoid first pass netabolism
Skin irritation
Limited to Suitable drug
• MW<600 Da• a water/octanol
partition coefficient in
the range of 1–3• a low melting point

J Control Release,2022,351,361

There is a need to develop more hypoallergenic and efficient transdermal delivery methods.

Introduction : the first application of IL to TDDS+
acyclovir
Sparcely soluble

Ionic liquid

Tween-80
Span20(surfactant)
MicroEmulsion

Solubilization with IL → ME formulation improves delivery efficiency※Transdermal delivery enhancement of IL was not clear

Chem. Commun., 2010,46, 1452

Introduction : Transdermal penetration promoting effect of IL

Hydrophilic IL

Hydrophobic IL

In ME formulations incorporating hydrophobic ionic liquids
Enhanced transdermal delivery capacity was observed→Advance as a carrier for transdermal absorption enhancement
Considerations at that time on the effect of promoting transdermal delivery
Ionic liquids are known to act as cationic surfactants→Ionic surfactants penetrate the stratum corneum, extracting lipids fromthe stratum corneum and disrupting lipid bilayer packing in the tissue
Anionic surfactants can enhance stratum corneum hydration in vivo
→These two actions were thought to improve skin penetration.
Int. J. Pharm.,2013,441,620

Introduction : Biocompatibility concerns and improvements• Bio-ILex)

Biocompatibility concerns
Mainly membrane perturbation by cationic sidechains and hydrophobic anions

IL using biologically-derived molecules→ Aiming to improve biocompatibility.
Amino acids, fatty acids, choline, etc...

Introduction : today’s main topics• Request for IL-DDS• Transdermal delivery capacity• Biocompatibility (hypoallergenic, low toxicity, etc.)• Main Topic
CAGE system

Choline + Geranic acid

LBIL system

Cationic phospholipid + Fatty acid

Contents
1. Introduction
2. Application
1. CAGE system
2. LBIL system

3. Summary and perspective

Application: What is CAGE system?

An ionic liquid (or deep eutectic solvent) composed ofcholine and geranic acidHas a transdermal penetration enhancing effectlow cytotoxicity
First released in 2014, used for deep skin DDS ofantibiotics
2017: applied for protein delivery
S., Adv. Healthcare Mater. 2017, 6, 1601411.

Application: CAGE system mechanism study

Evaluate delivery efficiency of dextrins of various molecular weights

modeling macromolecular drug delivery

Confirmation of SC lipid migration into IL(FT-IR)→Extraction action of lipids
Smaller decrease in diffusion with increasing molecularweight→Suggests a potentially more favorable mode ofmacromolecular delivery
J Control Release.,2019,311,162

Application: systematic study

Maximum efficiency when cation : fatty acid = 1:2(Considered just the right balance betweenhydrophobicity and distribution to skin)Adv. Mater. 2019, 31, 1901103.

Application: systematic study

Fatty acids: hydrophobic and highly unsaturated promotedelivery more
The smaller the interaction between ions, the higher theefficiency (NOESY)
The number of cross peaks between alkyl chains wasinversely correlated with the delivery efficiency rank.
Ability to penetrate stratum corneum depends on fatty acid anions
Strong interactions between ions inhibit distribution to the skinAdv. Mater. 2019, 31, 1901103.

Application: recent development

RSC Adv., 2022, 12, 25977

Contents
1. Introduction
2. Application
1. CAGE system
2. LBIL system

3. Summary and perspective

Application: LBIL system

Application: LBIL – based TDDS

The merit of oligonucleotides TDDS
Avoid severe injection site reactions and pain
Avoid side effects from systemic drug exposure.

barrier of SC→ Transdermal delivery capability of IL

cell membrane→ Ability of cationic qualities to be delivered intracellularly

ACS Appl. Mater. Interfaces 2023, 15, 28, 33299

Application: LBIL – based TDDS of oligonucleotide

TDDS of trabedersen(α-TGFβ)
Tumor shrinkage in model mice was confirmed.
No side effects were observed.
→Expected to be developed as an alternative
administration method to intravenous injection

ACS Appl. Mater. Interfaces 2023, 15, 28, 33299

Contents
1. Introduction
2. Application
1. CAGE system
2. LBIL system

3. Summary and perspective

Summary• Summary• Ionic liquids: liquid salts at room temperature, which have been applied in various ways to date
• Transdermal delivery enhancers• ILs can deliver various drug molecules transdermally→Expected to be developed as a transdermal delivery method in clinical practice• problems• More detailed study of delivery mechanisms and biotoxicity• Further functionalization• Research for clinical application