Drug transdermal delivery system (Transdermal drug delivery system, TDDS) or transdermal absorption preparation refers to the drug preparation administered on the skin surface, through which the drug enters the circulatory system for local or systemic treatment. In recent years, a number of modified new drug transdermal preparations have been approved clinically or marketed. This paper summarizes the key points of modified transdermal preparations from the category 2.2 of improved new drugs approved by CDE.

1. Clinical need considerations

 From the perspective of application field, the improvement of transdermal preparation is mainly Parkinson's, senile dementia, depression, schizophrenia, anti-inflammatory analgesia and other fields, these fields need long-term administration, and it is expected that drugs can be released slowly. Transdermal preparations can avoid the first-pass effect of gastrointestinal tract and liver of oral preparations, improve drug bioavailability; improve adverse reactions such as gastrointestinal irritation of oral preparations, and avoid contraindications and risk of oral combination drugs; provide steady and lasting effective blood concentration, reduce the number of drugs, facilitate drug administration, and improve patient compliance.

 Case 1: Agomelatine is a novel antidepressant drug that regulates biological rhythm while activating the melatonin receptors MT1 and MT2 and antagonizing the 5-HTc receptor. The drug was approved in the European Union in February 2009 and marketed in China in April 2011. However, there has serious first-pass effect, low bioavailability and obvious individual differences, resulting in poor efficacy stability of oral tablets. In addition, there are adverse reactions such as liver injury and gastrointestinal tract. On May 24,2024, CDE announced that the clinical application of Agomilatine transdermal patch submitted by Xinwen Biomedical Technology (Jiashan) Co., Ltd. was successfully approved. This is the world's first transdermal patch of Agomelatine to treat adult depression, and it will be the first to enter the clinic in China. Agomeratine transdermal patch avoids the severe first-pass effect of oral medication, damages the liver, improves the clinical effectiveness and safety of drug administration, avoids the contraindications and risk of combination medication, and provides a safe and effective treatment plan for depressed patients.

 Case 2: Azenapine is a dibenzoxoxypyrrole, and is currently recognized as an effective treatment for atypical schizophrenia. Early oral bioavailability was very low, and the hepatic first pass effect in the form of sublingual lozenges was approved by FDA on July 30,2009. However, there is the disadvantage of not lasting effect, need to be given twice a day. In addition, the inconvenience of sublingual administration has also led to poor sales of the drug. On 13 January 2023, CDE approved the clinical trial of asenapine transdermal patch jointly developed by Lizhu Medical Research Institute and LIAN HONG KONG LIMITED (Lean Hong Kong Limited) and LTS Lohmann Therapie-Systeme AG, Germany. For the treatment of adult schizophrenia, bipolar I disorder manic episodes or mixed episodes. Azenapine transdermal patch maintains a relatively stable plasma concentration twice a week; sublingual tablet administered twice daily reduces administration and improves patient compliance, and is more suitable for schizophrenic patients who cannot swallow or refuse oral medication.

 Case 3: On October 31,2023, Luye Pharmaceutical Group announced that the patch (twice / W) administered twice a week had been approved by the Chinese National Medical Products Administration for the treatment of symptoms of mild and moderate Alzheimer's disease. Lisstigmine is the first-line medication for the treatment of mild and moderate Alzheimer's disease. Compared with oral preparations, the mens transdermal patch (2 times / W) effectively reduces the incidence of gastrointestinal adverse reactions such as nausea and vomiting through the innovation of drug administration route and administration regimen, provides good drug convenience for patients with dysphagia, and improves the pain points of drug management for patients and their caregivers. Compared with the transdermal patch administered once a day, the product is administered skin twice a week, reduce the frequency of administration, simplify medication management, and improve medication compliance, providing a new option for patients who need long-term medication.

Case 4: Guangdong Red Coral Pharmaceutical Co., Ltd. developed a long-term praxipseole dermal patch (23mg: 25cm2) for the first time at home and abroad. Compared with pramipexole tablets, the drug was administered through the skin every 3 days, which could significantly improve the medication compliance and reduce the mental pressure and nursing burden of patients. Clinical approval of the CDE was obtained in June 2022.

2. Nature of pharmaceutical care considerations

 Only drugs with lipophilic properties can efficiently cross the cuticle, so that transdermal patch drugs must have some desirable physicochemical properties to penetrate the cuticle. Drugs with hydrophilic structures or ionotropic drugs can be designed as microneedle patches. In addition, choosing the appropriate excipient based on the basic properties of the drug is also an important consideration.

Case: Dexmedetomidine is a relatively selective α 2-adrenoceptor agonist with sedative effects. The free base of dexmedetomidine has better lipophilicity and high permeability coefficient. Based on this pharmacological characteristics, Yichang Renfu developed it into a transdermal patch, which can maintain the efficacy for more than 72 hours, and was approved as IND in March 2022. Guangzhou Xinji Pharmaceutical Co., Ltd. developed dexmedetomidine hydrochloride into a microneedle patch, and the declared indication was preoperative sedation for children. The soluble microneedle has only a micron size, which is painless or slightly painful when used, which reduces the pain of injection administration and improves patient compliance. Compared with traditional percutaneous preparations, soluble microneedles can directly penetrate the skin stratum corneum barrier and deliver the drug to the epidermis or superficial dermis, which can be quickly absorbed into the blood, greatly improving the bioavailability and efficacy of the drug. The drug fills the gap in the clinical needs of the vast majority of pediatric patients. In May 2024, the clinical application of dexmedetomidine hydrochloride microneicular patch submitted by Guangzhou Xinji Pharmaceutical was successfully approved and officially entered the clinical trial stage.

3. Clinical study is under consideration

 According to the approved experience in Europe and America, the modified transdermal patch should be bridging with control drugs, and focus on revealing the clinical characteristics and unique adverse reactions of percutaneous administration. The key to the clinical studies of modified transdermal patches is the bioequivalence study of a single multiple administration with the control drug. Non-inferiority trials, if bioequivalent, may be conducted, such as placebo and active control, and long-term safety studies may be required. In addition, appropriate pharmacoor pharmacodynamic studies can be carried out, such as the PK characteristics of enzyme to investigate the effects of age, gender, race and application site on product PK, the quantity-effect relationship between adhesion and residual amount, etc. Domestic declaration of 2.2 class transdermal preparation has been listed in Europe and the United States with the same varieties, so clinical can choose the listed products for control, such as: beautiful group an evaluation of asenapine transdermal patch in healthy adults TCM kinetic characteristics and safety of clinical research (CTR20240253) in 2019 FDA approved Novel pharmaceutical Secuado® for control drugs.

Transdermal drug delivery system has become the third largest drug delivery system besides oral and injection, and has become a hot spot for the development of improved preparation due to its safety and effective compliance. With the development of new auxiliary materials and pharmaceutical equipment, the application prospect of transdermal preparations will be broader. More and more enterprises have arranged transdermal preparations, which can get some inspiration from the approved products.

reference documentation:

1.https://www.cde.org.cn/main/xxgk/listpage/4b5255eb0a84820cef4ca3e8b6bbe20c

2. Li Jinzhou, Ma Wenyan, Mi Xuan, by Chunna. Exploration and thinking on the clinical research requirements of transdermal patches in the United States and Europe [J]. Chinese medicine affairs, 2022,36(6):713-722.DOI:10.16153/j.1002-7777.2022.06.015.

3. Drug Clinical Trial Registration and Information Disclosure Platform (chinadrugtrials.org.cn)

4. Official websites of each company