The transdermal patch is different from oral, injection and other dosage forms. It is applied on the skin surface and works through diffusion. The diffusion speed is affected by the drug concentration. Its quality key requirement is to deliver the drug through the skin at a certain rate. Moreover, the specifications of transdermal patches are different from other dosage forms, such as drug delivery rate, drug loading, patch area, drug loading+patch area, etc.

（1）Specification of transdermal patch in Europe and America

The specifications of transdermal patches marketed in Europe and the United States are indicated by the drug delivery rate (mg · h-1 or mg/24h), which is the rate at which transdermal patches deliver drugs through the skin into the blood circulation.

（2）Specification of Japanese transdermal patch

Transdermal patches marketed in Japan are marked by drug load, that is, the drug dose contained in each patch (mg/patch).

（3）Specifications of transdermal patch in China

According to the Chinese Pharmacopoeia (2020), the specification of a preparation refers to the quality (or potency) or content (%) or charge of the main drug contained in each piece, tablet or other unit preparation.
At present, the specifications of transdermal patches already on the market in China are in confusion, including drug loading, patch area and drug delivery rate
It refers to specifications, or both of them are used as specifications and other multiple marking methods, with different forms.

Table 1 Comparison of specifications of some transdermal patches marketed in the United States, Europe, Japan and China (source: Chinese Journal of Clinical Pharmacology)

Connotation of transdermal patch specification

（1）Meaning of transdermal patch delivery rate

In order to ensure that the active ingredients of transdermal patches reach and maintain the expected drug release rate during the use period after application, ensure the amount of drug injected into the blood, and thus ensure the efficacy, transdermal patches usually have an excessive drug load, that is, their actual drug load is higher than the total amount of drug release, and a certain amount of drug will still remain in the patches after use. Different from the specifications of oral or injectable preparations, i.e. drug loading, transdermal patches need to have excessive drugs and residues, so it is unreasonable to use the drug loading of transdermal patches or patch area to indicate their specifications.

Both Europe and the United States require the use of drug delivery rate to mark the specifications of transdermal patches. It is clearly stipulated that the specification of transdermal patches (dosage strength) is defined as the total amount of active ingredients released into the body per unit time, usually the amount of drug released into the body every 24 hours. The most common methods to determine this rate are PK and backward extrapolation through drug residues, specifically, ① PK method: quantifying the amount of drug released into the human circulatory system through human pharmacokinetics test; ② Drug residue backdating: the amount of active ingredients remaining in the patch after a certain time of application is measured to calculate the amount of drug released during the application period. The calculation formula is drug delivery rate=(drug load - residual amount)/application time

（2）Regulatory Requirements on Delivery Rate of Transdermal Patch in China

As already described in the previous article, the specifications of transdermal patches that have been marketed in China at this stage are confused and there is no unified form. However, the regulatory documents also have certain statements on the drug delivery rate. The Chinese Pharmacopoeia (2020 Edition) has clear provisions on transdermal patches: transdermal patches should indicate the total action time and drug release rate of the patch, the drug dose contained in each patch and the effective area of drug release in the label and/or instructions; When the drug release rate cannot be marked, the drug dose contained in each patch, the total action time and the effective area of drug release shall be indicated.

（3）Relationship between drug delivery rate of transdermal patch and drug loading and patch area

Although the drug delivery rate can essentially reflect the PK and clinical data of transdermal patches, the drug loading and patch area can sometimes intuitively bring convenience to drug use. For example, in order to guide clinical medication, FDA needs to specify the drug load and patch area in the Label, and explain the corresponding relationship between drug delivery rate and drug load and patch area. Such as the FDA approved rotigotine transdermal patch (Neupro).

Table 2 Corresponding relationship between drug delivery rate, drug loading and patch area of Neupro

（4）Requirements for drug delivery rate of transdermal patch generic drugs

European and American regulators have clearly stipulated that in order to achieve bioequivalence, the amount of generic drugs released from the patch to the human body must be consistent with the reference preparation, and the application time must be consistent with the reference preparation. Therefore, the drug delivery rate (drug release amount/application time) must be consistent with the reference preparation, and the drug loading amount and patch area can be inconsistent.

China's regulatory Technical Guidelines for Pharmaceutical Research of Transdermal Patch of Chemical Generic Drugs (2020) pointed out that the drug loading, iron and area of generic drugs may be different from that of reference preparations, but generally they should have the same or higher patch area activity, and should ensure the same dose delivered within the same time, and should minimize drug residues in the patch.

Epilogue

Transdermal patches are used to complete the skin surface. The process of drug delivery through the skin into the blood circulation is a key step to determine the clinical efficacy of transdermal patches. Therefore, the drug delivery rate is one of the most essential and critical quality and efficacy attributes of transdermal patches. The design, development and production of transdermal patches should aim to achieve a specific drug delivery rate. The drug delivery rate is more consistent with the concept of transdermal patch specification.

At present, the specifications of transdermal patches listed in Europe and the United States are all marked by drug delivery rate, but the specifications of transdermal patches listed in China are confused and inconsistent, with total drug load, patch area, release rate as the specifications, or both as the specifications. This will bring many problems to the supervision: ① The domestic specifications of different imported original varieties are confused. ② It brings obstacles to generic drug enterprises in the reference reference preparation and research and development process.

In order to solve these problems, we should first clarify and unify the definition of transdermal patch specifications in China. It is suggested to refer to European and American practices and mark the specifications with "drug delivery rate".