Research on the Application of Nanoformulation in Transdermal Drug Delivery System

As a promising systemic drug delivery method, transdermal drug delivery system (TDDS) is easier and more convenient to operate than traditional oral, intravenous and subcutaneous injection methods. It can improve patient compliance while also avoiding First-pass effect and drug side effects. As the largest organ of the human body, the skin is also the body’s first line of defense against foreign microorganisms and chemical substances. Its drug permeability is lower, which is orders of magnitude different compared to the epithelial cells of the gastrointestinal tract and lungs. Therefore, how to pass through the many barriers of human skin is the first problem faced during transdermal drug delivery. In the past 20 years, with the continuous development of nanotechnology, various nanoformulations have been increasingly used in transdermal drug delivery. These nano-preparation transdermal delivery systems can greatly enhance the penetration of drugs into the skin and improve the transdermal efficiency of drugs due to their nanoscale size and unique physical and chemical properties. This article will review the overview, preparation methods, advantages and research progress of various nano-preparation transdermal delivery systems based on the literature in recent years.

Skin Barrier

Skin Physiological Structure

Human skin is composed of three layers with different compositions and structures. From the outside to the inside, they are the epidermis, dermis and subcutaneous tissue. In addition, there are hair follicles, sweat glands, sebaceous glands and other appendages. The epidermis can be divided into stratum corneum (SC), stratum lucidum, stratum granulosum, stratum spinosum and stratum basale from outside to inside. The four layers except the stratum corneum are composed of living cells and are collectively called the active epidermis; the stratum corneum is mainly composed of dead and dehydrated anucleate keratinocytes and the lipid matrix between keratinocytes. The internal structure of the stratum corneum is tightly packed and highly hydrophobic, which allows it to play a major role in the skin’s permeability barrier. The structure of the stratum corneum is often simply represented as a “bricks and mortar” model, in which keratinocytes are stacked and staggered like bricks, and a lipid matrix fills the gaps between keratinocytes, but this model is not entirely accurate. New models of lipid matrices include asymmetric (bilayer unfolding) models, domain mosaic models, sandwich models, single gel phase models, etc., which better describe the architecture of lipid matrices. The dermis under the epidermis is composed of fiber network, matrix and cells. The fiber network is a dense network structure formed by collagen, elastin, etc., which can provide mechanical strength to the skin; the matrix is mainly composed of a variety of hydrophilic proteoglycans, filling Between the fiber network; the cells in the dermis are mainly fibroblasts, followed by immune cells such as macrophages, mast cells, and dendritic cells, which are responsible for the immune response of the skin. In addition, the roots of capillaries, lymphatic vessels, nerve endings, and various appendages are also in the dermis. The subcutaneous tissue in the deepest layer of the skin is mainly composed of loose connective tissue and fat, which plays a role in buffering and energy storage.

Skin Absorption Route

The pathways through which drugs enter the systemic circulation through the skin include the epidermal pathway and the adnexal pathway]. The epidermal pathway is the process in which drugs penetrate the epidermis into the dermis, then diffuse into capillaries and then transfer to the systemic circulation. The epidermal pathway includes the transcellular pathway and the interstitial pathway, in which drugs diffuse across keratinocytes and through the lipid matrix between keratinocytes, respectively. In the epidermal pathway, drugs are mainly transported by passive diffusion through the concentration difference between the skin surface and the deep skin layer, and the special composition and structure of the stratum corneum make it the main barrier for drug transport. In the adnexal route, the drug enters the dermis directly through the openings of the skin appendages and reaches the systemic circulation. Generally speaking, the epidermal pathway is the main pathway for drug transdermal absorption. Although the adnexal pathway has a faster penetration rate, the appendages only account for 0.1% of the skin surface area. Therefore, when drugs are absorbed through the epidermal pathway, after steady state is reached, uptake by the adnexal pathway can be neglected. However, ionic drugs and hydrophilic macromolecule drugs are extremely difficult to penetrate into the stratum corneum, so these drugs are mainly absorbed through the adnexal pathway. In addition, nanopreparations such as lipid nanoparticles (LN), polymeric nanoparticles (PNP), and nanocrystals (NC) can aggregate in hair follicles to form drug reservoirs and accelerate drug transdermal absorption through the adnexal pathway.

Nanoformulation Transdermal Delivery System

Nanopreparations refer to drug carriers or drug particles with a size below 1000 nm, and their nanosize can bring unique physical and chemical properties. Nanoformulations commonly used in transdermal delivery systems in current research include nanoemulsion, lipid-based nano-vesicles, LN, PNP, NC, lyotropic liquid crystal (LLC), etc.. These nanopreparations provide a new platform for transdermal delivery through unique penetration promotion mechanisms and drug release mechanisms. Their advantages and disadvantages in drug transdermal delivery and formulation preparation are as follows:

1. Nanoemulsion

Advantage

• The preparation process is simple and easy to expand;
• Has a sustained release effect;
• Reduce drug irritation and side effects

Shortcoming

• Poor thermodynamic stability, leading to aggregation, flocculation and other phenomena;
• The potential biological toxicity of some non-natural emulsifiers needs to be further studied.

2. Lipid Nanovesicles

Advantage

• Strong lipophilicity and easy to penetrate the stratum corneum;
• It has strong elasticity and deformability and can pass through skin pores completely;
• It can be loaded with both hydrophilic and lipophilic drugs;
• Can be used as a drug storage to extend the residence time

Shortcoming

The preparation is time-consuming, costly and low-yield, making it unsuitable for large-scale ​production.

3. Lipid Nanoparticles

Advantage

• The drug loading rate is high and the drug can be maintained at a high concentration on the skin surface and tissues for a long time;
• Improve drug stability and reduce drug irritation to skin;
• Strong occlusive effect, which can reduce skin moisture loss and facilitate drug penetration

Shortcoming

• There are problems with particle size growth, gelation, and drug precipitation during storage;
• Some drugs have a burst release phenomenon

4. Polymer Nanoparticles

Advantage

• Improve drug stability, reduce drug degradation and denaturation, and reduce drug irritation;
• Form a drug reservoir in the hair follicles, release it sustainably, and reduce the side effects of toxic drugs;
• Targeted drug delivery can be achieved through surface modification

Shortcoming

• Solvent residue is prone to occur during the preparation process;
• Some polymers have cytotoxicity issues

5. Nanocrystals

Advantage

• Composed of pure drugs, the drug loading rate is close to 100%;
• The dosage of stabilizer is low, the local irritation is small, and the safety is high;
• The preparation process is mature and perfect, easy for large-scale production

Shortcoming

Physical stability is poor, with aggregation and settling, Ostwald ripening, Phenomenon such as crystal transformation

6. Lyotropic Liquid Crystal Nanoparticles

Advantage

• High bioadhesion, can adhere to the skin surface and release drugs for a long time;
• Good biocompatibility;
• There is a wide range of drug candidates that can be loaded, which has the advantage of drug loading;
• High stability and can exist stably in excess water

Shortcoming

• The intermediate product has high viscosity and requires high preparation process;
• The quality standards of preparation materials need to be established and improved, and the preparation process needs to be industrialized.

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