Transdermal patch

Contraceptive patch for demonstration purposes without active ingredient

A transdermal patch is a dosage form for the systemic administration of drugs in patch form. It is stuck to the skin and releases the active ingredient in a controlled manner, which is then absorbed through the skin . The active ingredient reaches the blood vessel system without being broken down prematurely in the gastrointestinal tract or the liver . The term transdermal therapeutic system (TTS) or transdermal drug delivery system (TDDS) is also used as a synonym ; however, with the advent of technological developments, these are reserved for transdermal dosage forms that actively release the active ingredient, i.e. H. by the action of external forces (e.g. electricity, ultrasound, chemical reaction). Transdermal patches, on the other hand, passively release the active ingredient over a longer period of time and are intended to be stuck to the intact skin.

Transdermal patches must still be differentiated from locally (topically) effective patches (see article medicinal patches ).

application areas

Transdermal patches have been used in various fields of application for over twenty years.

The administration of nicotine by means of a nicotine patch , which is supposed to help smokers to quit , is particularly well known . Transdermal administration of certain hormones is also possible ( see hormone patches ). There are transdermal patches for estrogens or estrogen / gestagen combinations - as they are used for hormone replacement therapy for menopausal symptoms or for contraception - or for testosterone .

Other drugs that can be administered transdermally include scopolamine (against motion sickness ), nitroglycerine (to prevent angina pectoris and heart attack ), clonidine (to treat high blood pressure ), the opioids fentanyl and buprenorphine (to treat severe pain), rotigotine (for Treatment of Parkinson's disease ) and rivastigmine (used to treat Alzheimer's disease ).

Technical aspects

All systems have a backing layer , which protects the plaster and its contents from the outside and is optionally printed with information. On the skin side, it is provided with a release liner , which covers the sticky side of the plaster. The release liner is removed before the patch is applied and is often siliconized for easier removal .

With regard to the technique of controlled release of active substance from the patch, a distinction is made:

• Matrix patch : the active ingredient is contained in a matrix consisting of one or more layers, which lies directly on the skin with the help of an adhesive layer. The rate of diffusion of the active ingredient out of the matrix determines the rate of resorption. In special cases there can be an additional membrane between the matrix and the adhesive layer, which controls the flow of active ingredients.

• Membrane plaster (also called depot plaster ): a reservoir of the active ingredient lies beneath a carrier film, which is released into the skin in a controlled manner through a porous membrane.

In order for the drug release to be controlled by the therapeutic system, the absorption through the skin must proceed faster than the drug release through the plaster membrane or out of the matrix. If necessary, absorption accelerators can be incorporated into the plaster to accelerate the passage through the skin. Examples are sulfoxides and urea .

In the case of the above-mentioned types of plaster, the active ingredient diffuses through the skin and enters the bloodstream via the blood vessels close to the skin. Diffusion is a passive process. The active ingredients only penetrate the skin to a small extent through pores and hair follicles, but mostly through microscopic cell gaps or through the cells themselves. This requires that the active ingredients have sufficient lipophilicity (fat solubility).

Further developments are active transdermal systems that use iontophoretic or sonophoretic methods as well as systems with microcannulas or needles. The latter penetrate the upper layers of the skin and get directly to their place of action or into the outer blood vessels. Iontophoretic systems, on the other hand, are a non-invasive technique; they apply a weak electric field to push the drug through the skin. An example of an iontophoretic transdermal patch is a system with fentanyl that releases a dose of 40 micrograms at the push of a button by the patient ( IONSYS , no longer on the market).

For transdermal application, only active ingredients with a relatively small molecule size are generally suitable, which, moreover, are already effective in very small doses (highly potent drugs). In the case of a high-dose drug such as acetylsalicylic acid, the plaster would have to make up a large part of a person's body surface in order to absorb the active ingredient in a tablet. Large molecules such as peptides , especially insulin or vaccines , have so far not been able to be applied via a plaster. However, this could be possible through alternative patches under research with thousands of microcannulas that are intended to penetrate the skin, with active iontophoretic systems, through the use of ultrasound or with nanoemulsions or particles. A new development will be vaccination via the transdermal system.

Advantages and disadvantages of the patch

The main advantage of applying active ingredients by means of transdermal patches is that a patch often only has to be changed after several days. Most of the patches are worn over a period of three days. From this time on, the microclimate of the skin underneath the patch can change unfavorably and the disadvantages of this application outweigh the conventional forms of administration. Exceptions to this three-day change are hormone plasters for contraception, which are worn for seven days.

After single administration of oral non-retarded or sublingual dosage forms, sufficiently high levels of activity are only achieved for shorter periods of 4–16 hours. Some active ingredients are also partially broken down by the gastric and intestinal fluids and, after being absorbed in the intestine, by the liver metabolism ( first-pass effect ), which is why drug levels similar to those of the plaster can only be achieved with higher doses of the active ingredient.

After transdermal administration, on the other hand, skin-permeable substances enter the bloodstream directly (or via the fat depot tissue after a few hours) without any further changes. The release can only be controlled slowly, so that dose adjustments in the event of rapidly changing disease events (e.g. breakthrough pain) are difficult. Here, the therapy is usually supplemented by sublingual, buccal or oral dosage forms with a rapid onset of action .

Transdermal patches have a delayed onset of action. The targeted plasma levels are usually only reached after 5 to 6 half-lives of the respective active substance. Thus, transdermal patches are not suitable for acute therapy. The active ingredient is only released at a constant rate as long as the concentration gradient between the plaster reservoir and the skin is sufficiently high. They can only be used as long as the release kinetics are approximately zero order, i.e. the release rate is not significantly reduced. For this reason, the plasters have to be removed from the application site, although a considerable part of the active ingredient is still unused in the plaster. The disposal is particularly problematic in the case of pain plasters with narcotics, because the remaining amount is quite capable of causing death through respiratory depression in opiate-naïve people. This effect is counteracted by so-called multilayer systems. With this form of the matrix plaster, the concentration of the active ingredient increases towards the outside, a rapid decrease in the concentration in the layer close to the skin and thus a potentially lower effectiveness should be prevented. The effect persists after the patch has been removed, as a drug depot builds up in the subcutaneous fatty tissue.

A potential danger from so-called depot patches is what is known as dose dumping , which can cause the entire (liquid) active ingredient reservoir to be suddenly released if the system is mechanically destroyed. This risk has been counteracted by the further development of the matrix plasters, which have the active ingredient bound in the matrix. It is possible to cut transdermal matrix patches to adjust the dose, but should be carried out by trained personnel, as incorrect dosages can occur.

Transdermal patches are usually much more expensive than retarded oral dosage forms.

Active ingredient release from transdermal patches

To ensure the effectiveness and safety of the drug formulation, the pharmacopoeia provides for the release of active ingredients to be checked, which must be within the limits specified for the preparation. The limit values ​​are determined and specified in pharmaceutical development; they ensure that, on the one hand, the rate of release required for therapeutic effectiveness is achieved and, on the other hand, no toxic amounts of active substance escape from the plaster. The test takes place in a cylindrical vessel of standardized size with a hemispherical bottom and a capacity of 1 liter, which is filled with a defined amount of a suitable aqueous test liquid. The temperature is set to 32 ° C., the transdermal patch fixed on a device is inserted and the concentration of the released active ingredient in the test liquid mixed by agitation is measured at several specified times.

For the fixation of the plaster or - if necessary and possible - a plaster cut, three devices are described which can be used depending on the composition, shape and dimensions of the plaster.

• Release disc: The transdermal patch is applied with the active ingredient-containing side up on a disc with wire mesh made of stainless steel . For this purpose, the patch can be cut to a suitable size, provided it is not a membrane patch. In the case of a membrane plaster, “dose dumping”, that is, the immediate release of the entire active ingredient, is to be feared. The release disc with the adhesive plaster is placed on the bottom of the test vessel and the test liquid is mixed with a paddle stirrer at a defined speed of rotation (e.g. 100 revolutions per minute). A distance of 25 mm is required between the underside of the stirring blade and the top of the transdermal patch on the disc.

• Extraction cell : The so-called extraction cell consists of a holder, a cover with a central opening and, if necessary, a membrane that is applied to the plaster to isolate it from the test liquid in the event that this changes the physico-chemical properties of the plaster or adversely affect. After clamping the plaster into the extraction cell and placing it in the test vessel, the extraction cell holds the plaster flat with the release side facing up and parallel to the lower edge of the stirring blade, maintaining a distance of 25 mm between the lower side of the stirring blade and the surface of the extraction cell. The test liquid is mixed with a blade stirrer at a defined speed of rotation.

• Rotating cylinder : The blade stirrer apparatus from the test with the release disk is used, but a stainless steel cylinder is used in place of the stirrer blade . The plaster is applied to the cylinder with the release side outwards by brushing it with glue or by applying double-sided adhesive strips and carefully pressing on. The glue or adhesive strips must not interfere with the release of the active substance and the plaster should enclose the cylinder. The cylinder provided with the plaster is inserted into the apparatus and immediately set in rotation at the specified number of revolutions.

A sample is taken from the test vessel at several specified times and the volume removed is supplemented if necessary. The content of the sample is measured using a suitable analytical method.

The test is carried out with several patches.

Individual evidence

1. ↑ Guideline on quality of transdermal patches. EMA / CHMP / QWP / 608924/2014 (PDF; 224 kB), from October 23, 2014.
2. ↑ Entry of the Transdermal System in the Standard Terms Database of the EDQM , Concept creation date 2006-03-14.
3. ↑ ^{a b} European Pharmacopoeia, 9th edition, Grundwerk 2017, Monograph 1011, Transdermal Plaster .
4. ↑ European Medicines Agency recommends suspension of the approval for IONSYS® , press release Janssen-Cilag GmbH November 20, 2008.
5. ↑ Influenza vaccine in the plaster , Pharmazeutische Zeitung, issue 29/2010.
6. ↑ Fentanyl Patch Can Be Deadly to Children , FDA 2018.
7. ↑ Pain patches: This is how they should be disposed of , Pharmazeutische Zeitung, June 7, 2018.
8. ↑ New dosage forms improve tolerance , Pharmazeutische Zeitung, June 9, 1997.
9. ↑ ^{a b} European Pharmacopoeia, 9th edition, Grundwerk 2017, Section 2.9.4 Release of active ingredients from transdermal patches .

literature

• U. Schmidt: Transdermal plasters - drugs to stick on . Spectrum of Science 10/2003, 42
• A. Wokovich: Transdermal drug delivery system (TDDS) adhesion as a critical safety, efficacy and quality attribute. Eur J Pharm Biopharm . 2006 Aug; 64 (1): 1.
• K. Mäder, U. Weidenauer: Innovative dosage forms: A textbook for study and practice. Wissenschaftliche Verlagsgesellschaft, Stuttgart, 2009. ISBN 978-3-8047-2455-6

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