The aim of this work was to test the in-vitro permeability of APIs (active pharmaceutical ingredients) across perforated and unperforated skin. Both, traditional adhesive matrices and hydrogel matrices were developed and tested. The result of this work is that it is possible to deliver model substances greater than 500Da through the skin barrier by perforating the epidermis.
Transdermal therapeutic systems (TTS) are dosage forms developed to transport an active pharmaceutical ingredient through the skin. This is done by applying a patch to the skin and is therefore a pain-free method. Since the establishment of this method, TTS have been a good alternative to traditional dosage forms such as tablets, injection needles and suppositories.
However, there is a crucial limit to TTS. APIs which are significantly greater than 500Da (500g/mol) cannot pass through the skin barrier. As several publications (cf. Cormier et al., 2004, Roxhed, 2007 and Yu et al., 2015) have shown, there is a possibility to transport APIs which are greater than 500Da through the skin. Combining TTS with microneedles (MN) is a way to produce microchannels through which the API can then pass the skin barrieCustomary MN systems were not sufficient to perforate the skin barrier. Hypodermic needles, however, are suitable to perforate the stratum corneum (SC). Consequently, the combination of TTS technology with MN technology is possible and should be further developed. Nevertheless, suitable MN have to be found. Hollow needles which are incorporated into a hydrogel matrix are a very promising option for a future product.
Table of Contents
4. Introduction
5. Theoretical background
5.1 The barrier of the skin and transdermal therapeutic systems
5.2 Transdermal therapeutic systems in combination with microneedles
5.3 In-vitro skin permeation tests
6. Materials and methods
6.1 Chemicals and reagents
6.2 Methods
6.2.1 API coating
6.2.2 Skin preparation
6.2.3 Skin perforation
6.2.4 Verifying the integrity and perforation of the skin
6.2.5 Penetration assessment
6.2.6 In-vitro skin permeation tests
7. Statistical analysis
8. Results
8.1 Skin perforation tests
8.2 In-vitro skin permeation tests
9. Discussion and conclusion
10. Sources
Research Objectives and Core Topics
This thesis investigates the feasibility of combining Transdermal Therapeutic Systems (TTS) with microneedle (MN) technology to overcome the size-related limitations of traditional skin-penetration methods for large-molecule APIs, specifically targeting the improvement of drug delivery through perforated skin.
- Development of suitable MN-based perforation techniques for the skin barrier.
- Evaluation of hydrogel versus silicone matrix systems for optimal API release.
- In-vitro skin permeation testing (IVSP) for large-molecule model substances.
- Analysis of perforation integrity using advanced microscopic and tomography methods.
- Validation of the TTS model through mass balance and permeation kinetics.
Excerpt from the Book
5.2 Transdermal therapeutic systems in combination with microneedles
One of the greatest challenges for tL is the development of new TTS. One innovative possibility is the combination of TTS and MN. MN are long enough to penetrate the outer layer of the skin but too short to irritate nerves and blood vessels. They can be used to deliver APIs with larger molecules into the skin, an application that is largely pain-free. MN create tiny holes in the outermost layer of the skin (cf. Donnelly et al., 2010, p. 337), which significantly increases the rate at which the active substance is absorbed (cf. Kim et al., 2012, p. 1562). The main motivation to use MN is that systemic absorption can be achieved under minimally invasive conditions in cases where regular passive diffusion technologies are not effective enough. So far, numerous commercial MN systems are available, which are used in medical or cosmetic contexts.
While the application is largely pain-free, it still causes minimal reversible injuries of the epidermis resulting in the exudation of hydrophilic fluids. Traditional matrix systems, however, usually contain lipophilic adhesive matrices based on, for example, acrylate, silicone or styrene. A hydrophilic matrix system might be better suited for a combination of TTS with MN, because in this case the matrix as well as the exuded fluids are hydrophilic.
Summary of Chapters
4. Introduction: Outlines the motivation for developing new TTS-MN combinations to enable transdermal delivery of large-molecule drugs.
5. Theoretical background: Explains the barrier function of the skin, the mechanics of TTS, and the rationale for using microneedles and in-vitro permeation testing.
6. Materials and methods: Details the specific chemicals, matrix manufacturing processes, skin preparation, and analytical techniques used to measure skin perforation and drug release.
7. Statistical analysis: Describes the methods used for data validation, including the application of the Dean-Dixon outlier test.
8. Results: Presents the findings of perforation efficacy tests and the subsequent API permeation performance comparing hydrogel and silicone matrices.
9. Discussion and conclusion: Interprets the findings, confirming that hydrogel matrices outperform silicone for this application, and suggests future improvements for integrated applicator design.
10. Sources: Provides the comprehensive list of scientific literature and patents referenced in the thesis.
Keywords
Transdermal therapeutic systems, TTS, microneedles, skin barrier, stratum corneum, in-vitro skin permeation, hydrogel matrix, silicone matrix, API release, perforation, TEWL, multiphoton tomography, desmopressin, fluorescein isothiocyanate-dextran, drug delivery.
Frequently Asked Questions
What is the primary focus of this thesis?
The work focuses on the technical feasibility of combining TTS with microneedles to enhance the transdermal delivery of pharmaceutical ingredients that exceed the typical 500 Dalton size limit.
Which types of matrix systems were compared?
The research compared traditional lipophilic silicone-based matrices with hydrophilic hydrogel-based matrices to determine which system is better suited for use with microneedle-perforated skin.
What is the central research question?
The study asks whether a combination of TTS and microneedles can effectively transport large-molecule model substances across the skin barrier while determining the most suitable matrix architecture.
Which methods were used to verify skin integrity and perforation?
The author employed several advanced diagnostic tools, including Transepidermal Water Loss (TEWL) measurements, multiphoton tomography (5D-IVT), confocal laser scanning microscopy (VivaScope), and micro-computed tomography (SKYSCAN).
What does the main part of the thesis cover?
It covers the experimental development of matrix patches, the methodology for creating consistent skin perforations, and the analytical quantification of drug release via HPLC under sink conditions.
Which keywords best describe this research?
Key terms include Transdermal therapeutic systems, microneedles, stratum corneum, in-vitro permeation, and hydrogel versus silicone matrix performance.
Why were hydrogel matrices found to be superior?
The results indicated that hydrogel matrices provide a higher flux rate for large molecules, likely because the hydrophilic matrix and the exuded skin fluids allow for a more continuous path for the API compared to the silicone matrix.
Did the microneedle devices perform as expected?
No, the study found that conventional commercial derma stamps were often insufficient or suffered from bent needles during the attempted perforation of full-thickness skin, suggesting a need for specialized integrated applicators.
- Quote paper
- Sebastian Kerski (Author), 2015, Feasibility Experiments for the Development of Innovative Transdermal Systems, Munich, GRIN Verlag, https://www.grin.com/document/946557
