Topical And Transdermal Delivery Workshop

Question 1

Scenario : Your company has developed a new drug called lucamine bromide, which works on nicotine receptors in brain and could help with smoking cessation. The goal is to create a topical formulation for this drug.

What is the difference between systemic and local treatment? Which type is required for lucamine bromide in this case?

Answer 1

Systemic Treatment
- The drug is absorbed into the bloodstream and distributed throughout the body, affecting multiple organ systems or tissues.

Local Treatment
- The drug is applied directly to the site where its effects are needed, minimizing distribution to other parts of the body.

Which Type is Required for Lucamine Bromide?
For smoking cessation, the primary target is nicotine receptors in the brain. Since lucamine bromide must reach these receptors to exert its effect, systemic treatment is required.

Local treatment is not suitable for lucamine bromide in the context of smoking cessation because the drug’s site of action (nicotine receptors) is located in the brain, not at or near the site of topical application.

Question 2

What problems might arise when trying to deliver lucamine bromide through the skin? Include a discussion on how drugs penetrate the skin.

Answer 2

The skin is designed to protect the body from external substances, making it difficult for drugs to pass through.

There are three pathways of penetration :
- Transcellular (through cell)
- Intercellular (between cells)
- Appendageal (my hair follicles and sweat glands)

Drugs larger than 500 Daltons have difficulty penetrating the skin and so if bromide has a high molecular weight this could limit its ability to cross the skin barrier

If bromide is highly hydrophilic, it will struggle to penetrate the lipophilic stratum corneum

If bromide is ionised that physiological pH it’s penetration will be limited as charged molecules are poorly absorbed through the skin

The skin environment, i.e. moisture could degrade bromide before it penetrate

General issues with transdermal drug delivery include:
- Differences in skin thickness/hydration
- Some formulations can irritate the skin
- Drugs deliver through the skin may take longer to reach therapeutic levels due to slow diffusion
- only small lipophilic and non-ion drugs are ideal for transdermal delivery

Question 3

Higher the molecular weight ….

Answer 3

More hydrophobic

Question 4

Describe the relationship between the log K (octanol/water) value and skin
permeability for lucinesters

Answer 4

The octanol/water partition coefficient, often represented as logKow
​
Skin permeability typically increases with higher logKow
​
Compounds with a log K value between 1 and 3 generally have the best skin permeability.

Too hydrophilic (log K < 1):
- These compounds have difficulty crossing the lipophilic SC because they do not dissolve well in the lipid-rich environment.

Too lipophilic (log K > 3):
- These compounds may dissolve well in the SC but become “trapped” there and fail to partition into the hydrophilic deeper skin layers or systemic circulation.

Lucinesters, or esters of lucamine bromide, would have different log K values depending on their specific chemical modifications

Question 5

Why is it important to consider the partition coefficient (P) when designing transdermal drug delivery systems? How would this affect the formulation of different lucinesters?

Answer 5

The partition coefficient is a key factor in determining how a drug interacts with the skin, how well it penetrates the skin barrier, and how effectively it reaches systemic circulation or the target tissues.

main reasons why the partition coefficient is crucial in transdermal drug design:
1. Skin Barrier Penetration:
• The skin’s outer layer is lipophilic and the partition coefficient helps predict how well a drug will move from the formulation into the skin.

2. Balance of Lipophilicity and Hydrophilicity:
   • Log P helps balance lipophilicity and hydrophilicity .
   • Drugs that are too lipophilic (>logP) get trapped in the SC= poor diffusion into deeper skin layers or systemic circulation.
   • On the other hand, drugs that are too hydrophilic (<logP) may struggle to penetrate the skin barrier and remain on the surface
3. Drug Retention and Release:
   • A drug’s partition coefficient influences its ability to be released from the delivery vehicle and absorbed into the skin.
   • If the log P is too high, the drug has poor solubility in the vehicle and will not be released efficiently.
   • if the log P is too low, the drug may not leave the vehicle or penetrate the skin effectively.

Question 6

Given the absorption rates (0.25 μg/cm2/hour for ointment and 0.04 μg/cm2/hour for cream), why is the absorption higher for the ointment? Which formulation would be more appropriate?

Answer 6

Ointments are oily and highly occlusive

They form a thick impermeable layer on skin, reducing water evaporation and increasing skin hydration and this softens the SC

Ointments are lipophillic so better at dissolving lipophillic drugs and enhancing their penetration

Ointments provide longeralsting and sustained release of drug

Ointments is more appropriate if higher systemic absorb t ion is needed or for prolonged drug delivery or patients with dry and damaged skin

Cream is more appropriate if lower systemic absorbtion is needed if patient doesnt like greasy or for conditions needing local action