Drug Permeation

Anatomy of the skin

I II Chemical Enhancer

Contents

Transdermal Point of View

Therapy

III IV
Anatomy of
the skin cell
Anatomy of the human skin cell

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Anatomy of the human skin cell

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Anatomy of the human skin cell CER (AP) & CER (EOS):
Barrier Function

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Anatomy of the human skin cell
Formation of Ceramide
● CER synthesis begins in the stratum basale.

● CERs are glucosylated or converted to sphingomyelin

(SM) in the Golgi apparatus and packaged into secretory

vesicles.

● Vesicles exocytosis glucosyl-CERs and sphingomyelins

into the extracellular space where b-glucocerebrosidase

and sphingomyelinase convert them back into CERs.

● CERs, free fatty acids, and cholesterol organise into

lamellar layers (within stratum corneum).

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Anatomy of the human skin cell
Ceramide in Barrier Function
● Hydrophobic Barrier: Ceramide hydrophobic

nature repels water, preventing it from passing

through the skin’s surface.

● Structural Integrity: Ceramides act like glue to

hold the skin’s matrix—or structure—together,

keeping the skin firm and supple.

⇒ This intact structure is less permeable to water,

thereby reducing TEWL.

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Anatomy of the human skin cell
Route of permeation of SC
Intracellular Route:

● Dominant Pathway

● Requires a series of partitioning and

diffusion stages in and out of the relatively

Hydrophobic corneocytes, the lipid envelope

surrounding the corneocytes and the

intercellular matrix.

● Alternate structures of bilayers (both

aqueous and lipid domains).

Anatomy of the human skin cell

Route of permeation of SC
Step 1: Solubilisation into the Stratum Corneum

● The solute first needs to be solubilised into the outermost lipid (fat) layer of the SC.

Step 2: Diffusion through the SC

● This process is influenced by the interactions between the solute and the skin, as well as the

interactions between the CE and the skin.

Anatomy of the human skin cell

Route of permeation of SC
Step 3: Permeation into the corneocyte

● During the diffusion process, the solute may also permeate, or penetrate, into these cells.

Step 4: Partition and diffusion in the viable epidermis and papillary dermis

● The solute undergoes another series of partitions and diffusion in these layers.
Anatomy of the human skin cell

Route of permeation of SC
Step 5: Absorption & Distribution in papillary dermis:

● The solute is absorbed by the capillary plexus (a network of blood vessels).

● Then distributed into the systemic circulation, which is the part of the cardiovascular system.
Anatomy of the human skin cell
Drug - CE - Skin Interaction
Drug-Skin interactions:

● Allow the drug can penetrate the skin or not

Solvent-Skin interactions:

● Increase/Decrease the penetration of a drug

across the skin

Drug-Solvent (CE) interactions:

● Effect on the rate and extent of release of drug.

Chemical
Enhancer
Chemical Enhancer - Enhance Drug Penetration

Azone
Chemical Structure:

● Consists of seven-membered polar head group attached to a 12-carbon chain (dodecyl chain).

● This structure is amphiphilic, meaning it has both hydrophilic (water-loving) and hydrophobic

(water-repelling) properties
Chemical Enhancer - Enhance Drug Penetration

Azone
Interaction with Lipid Bilayer:

● The seven-membered polar head group aligns with the polar plane of the bilayer (which is in

contact with water), while the dodecyl chain embeds itself in the lipid region of the bilayer

(which is hydrophobic)
Chemical Enhancer - Enhance Drug Penetration

Azone
Disruption of Lipid Packing

● Azone disrupts the highly ordered packing of lipids in the bilayer. This disruption creates

more free space and increases the fluidity of the bilayer ⇒ Easier for substances to pass.
Chemical Enhancer - Enhance Drug Penetration

Azone
Limitations

● Azone have to conjugate with Propylene Glycol (PG) rather than alone

● Azone is not popular for the commercial purpose because it can cause skin irritation

dramatically
Chemical Enhancer - Enhance Drug Penetration

Fatty Acids - Isopropyl Myristate (IPM)

Structure

● IPM has both polar (Isopropyl) and non polar parts (Myristate)

Interaction with Lipid Bilayer

● Isopropyl group ‘anchors’ itself in the polar region of the lipid bilayer.

● Lipophilic myristate part of IPM embeds itself among the nonpolar tails of the lipid molecules
Chemical Enhancer - Enhance Drug Penetration

Fatty Acids - Oleic Acid (OA)

Structure

● OA is an unsaturated lipophilic C fatty acid

● Double bonds in their structure help them to

+ Disrupt the tightly packed arrangement of lipids in the skin more effectively

+ Increase fluidity of lipid bilayer ⇒ Easy to pass

+ Form solvated complexes with polar molecules, which can help increase the diffusivity
Chemical Enhancer - Enhance Drug Penetration
● Reducing Lipid Transition Temperature ™: The transition temperature ™ is the temperature at which a

lipid changes from a gel-like state to a liquid-crystalline state by a double bond of OA (Kink structure).

OA interacts with the SC lipids and reduces their ™ ⇒ Lipids become more fluid at lower temperatures.

● Increasing Conformational Freedom of Lipid Alkyl Chains: By reducing the Tm, OA allows these chains

to have more freedom of movement at temperatures higher than their ™ ⇒ Disrupt the tightly packed

structure of the SC, creating more space for substances to pass through.
Chemical Enhancer - Enhance Drug Penetration

Limitations:

● Dermal side effects of unsaturated fatty acids - Due to acidic property of

carboxylic terminal

Overcome:

● Modification of the carboxyl terminal ⇒ Reduce the acidic nature of fatty acid

● Test with other substances with the same lipophilicity characteristic

Chemical Enhancer - Enhance Drug Penetration
● Test with other substances with the same lipophilicity

● Experiment on rat skin

Dimethyl Sulphoxides (DMSO)
Disruption of Protein Configuration

● Displacement of Protein-Water Interactions: Proteins in the skin are surrounded by a layer of

water molecules, forming protein-water interactions.

● When DMSO is applied, it can displace these water molecules and cause DMSO surround the

protein ⇒ Disrupting the protein-water interactions (Hydrogen bond & Hydrophobic interactions)
 Chemical Enhancer - Enhance Drug Penetration
Dimethyl Sulphoxides (DMSO)
Disruption of Lipid

● Formation of Solvation Shell: At higher concentrations (above 60%), DMSO forms a large

solvation shell around the polar head group of lipids. Then, displacing the water molecules that

were originally interacting with the polar head group of the lipids.

● Loosening of Lipid Packing: The formation of the DMSO solvation shell disrupts the packing of

the lipids more severely compared to water

● Increase in Aqueous Region: The disruption of lipid packing leads to an increase in the aqueous

region in the intracellular pathway ⇒ Create more space for hydrophilic compounds to pass.
Transdermal
Therapy
Transdermal Therapy - Transdermal Patch
Transdermal Therapy - Transdermal Patch
Structure of Transdermal Patch
Backing Layer

● The outermost layer of the patch

● Protect the other layer from the environment

● Usually made of flexible, waterproof materials

Adhesive Layer

● Attach the patch to the skin and keep it in place

● Consist of strong, hypoallergenic adhesive that is gentle

on the kin
Transdermal Therapy - Transdermal Patch
Drug Layer

● Contain drugs that are delivered through the skin

● It is formulated to release the drugs at a constant rate over a

period of time

Membrane Layer

● Control the rate at which the drugs are released

● Made of semi-permeable materials that allow drugs to pass

through the membrane at a controlled rate

Liner layer

● Act as protector for the patch and adhesive

 Transdermal Therapy - Transdermal Patch

Tyeps of Transdermal Patches

Drug-in-Adhesive System

● This is the most simplest form of membrane permeation control system. The adhesive layer in

this case contains drugs and serves as glue to link other layers. The drug mixture is sandwiched

between the Liner and Backing Layer.

 Transdermal Therapy - Transdermal Patch

Tyeps of Transdermal Patches

Reservoir System

● The drug mixture is stored in the reservoir (serves as a container) that is located between the

backing layer and the rate-controlling membrane.

● Drugs can be released through the microporous rate-controlling membrane (which serves as

pores for the drug can pass through with the controlled rate.
 Transdermal Therapy - Transdermal Patch

Matrix System

● The drug mixture is stored in the hydrophilic or lipophilic polymer matrices (Fat-loving ⇒ Easy to

mix with lipid and oil). This system does not have a rate-controlling membrane.
 Transdermal Therapy - Transdermal Patch

Micro-Reservoir System

● This system combines the advantages of both Matrix & Reservoir System.

+ Reservoirs control the “when” (the drug is released when the reservoir degrades or dissolves),

+ Lipophilic polymer controls the “how fast” (the rate at which the drug diffuses out of the

reservoir)
Transdermal Therapy - Microneedle-Based Patch
Transdermal Therapy - Microneedle-Based Patch
 Transdermal Therapy - Microneedle-Based Patch
Solid Type

● Consist of solid needles that penetrate the skin to create tiny channels

Hollow Type

● Having a hollow core that allows for the delivery of drugs/fluids into the skin

Coated Type

● Have a coating that dissolves upon penetration of the skin ⇒ Release drugs/substances

Dissolving Type

● Microneedles are made of materials that dissolve in the skin ⇒ Controlled release of drugs
Dissolving Type

● Belong to the “Dissolving Type”

Characteristic

● Having excellent water solubility, biocompatibility, biodegradability & mechanical properties

● Control the amount of drug encapsulated in the needles and delivery at slow rate
Point of View
 POINT OF VIEW
Pathway: Intracellular Pathway

● Shortest Route
● Targeted delivery of drugs to specific cells
● Avoid 1st pass metabolism that can cause reduction in drug concentration

Drug & Chemical Enhancer: Hydrophilic/Lipophilic & DMSO

● Due to the special structure of Stratum Corneum (Lipid Bilayer) ⇒ Hydrophilic &
Lipophilic are suitable
● Disruption of Protein Configuration & Lipid ⇒ Easier to penetrate the skin and other
biological membrane
● Limited side effects with human’s skin compared with OA (unsaturated) or Azone
(Skin irritation)
 POINT OF VIEW
Transdermal Patch: Micro-Reservoir System

● Drug & Enhancer after designing are placed in the Drug + Polymer layer of
Transdermal Patch
● With the special characteristic of this system: Container & Control rate ⇒ Drug
release are controlled

Microneedle-Based Patches: Dissolving Type & Polymer as Material

● Can deliver a precise dose with the slow rate ⇒ Maintain steady concentration of
drug in the body over a long period ⇒ Avoiding high peaks of the durg’s concentration
●
References
● Du, H., Liu, P., Zhu, J., Lan, J., Li, Y., Zhang, L., Zhu, J., & Tao, J. (2019). Hyaluronic Acid-Based Dissolving Microneedle Patch Loaded with Methotrexate for Improved

Treatment of Psoriasis. ACS Applied Materials & Interfaces, 11(46), 43588–43598. https://doi.org/10.1021/acsami.9b15668

● Golden, G. M., McKie, J. E., & Potts, R. O. (1987a). Role of stratum corneum lipid fluidity in transdermal drug flux. Journal of Pharmaceutical Sciences, 76(1), 25–28.

https://doi.org/10.1002/jps.2600760108

● Haque, T., & Talukder, M. (2018). Chemical enhancer: a simplistic way to modulate barrier function of the stratum corneum. Advanced Pharmaceutical Bulletin, 8(2),

169–179. https://doi.org/10.15171/apb.2018.021

● Notman, R., Otter, W. K. D., Noro, M. G., Briels, W. J., & Anwar, J. (2007). The permeability enhancing mechanism of DMSO in ceramide bilayers simulated by molecular

dynamics. Biophysical Journal, 93(6), 2056–2068. https://doi.org/10.1529/biophysj.107.104703

● Ochalek, M., Podhaisky, H., Ruettinger, H., Neubert, R. H., & Wohlrab, J. (2012). SC lipid model membranes designed for studying impact of ceramide species on drug

diffusion and permeation, Part III: Influence of penetration enhancer on diffusion and permeation of model drugs. International Journal of Pharmaceutics, 436(1–2),

206–213. https://doi.org/10.1016/j.ijpharm.2012.06.044

● Wong, W. F., Ang, K. P., Sethi, G., & Looi, C. Y. (2023). Recent Advancement of Medical Patch for Transdermal Drug Delivery. Medicina-lithuania, 59(4), 778.

https://doi.org/10.3390/medicina59040778

● Meckfessel, M. H., & Brandt, S. (2014). The structure, function, and importance of ceramides in skin and their use as therapeutic agents in skin-care products. Journal of the

American Academy of Dermatology, 71(1), 177–184. https://doi.org/10.1016/j.jaad.2014.01.891

● Karande, P., Jain, A. K., Ergun, K., Kispersky, V. F., & Mitragotri, S. (2005). Design principles of chemical penetration enhancers for transdermal drug delivery. Proceedings of

the National Academy of Sciences of the United States of America, 102(13), 4688–4693. https://doi.org/10.1073/pnas.0501176102
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