Recently, Kelun Pharmaceutical announced that its subsidiary Hunan Kelun Pharmaceutical's chemical drug "bupivacaine liposome injection" has been approved for market by the National Medical Products Administration (FDA) under the brand name Brico ®）， According to the approval of Class 3 chemical drugs, it is considered to have passed the quality and efficacy consistency evaluation of generic drugs.

Brico from Kelun Pharmaceutical ® It is the second bupivacaine liposome injection product to be launched in China. Hengrui Pharmaceutical's bupivacaine liposome injection generic drug (trade name: Aihengping) was approved in November 2022, becoming the world's first generic drug and the first domestically marketed long-acting postoperative analgesic drug. In July of this year, Aihengping was approved for market by the FDA, becoming the first manufacturer in the world to receive approval for this generic drug in the United States.

Behind the consecutive successful breakthroughs of domestic pharmaceutical companies, there is a growing market demand for long-acting postoperative pain relievers globally and in China.

The incidence of postoperative pain in China is still relatively high
Postoperative pain refers to acute trauma and damage to internal organs caused by surgical procedures, as well as pain caused by inflammatory stimulation around nerve endings. Postoperative pain occurs after awakening from anesthesia, with a peak pain period of 24 to 48 hours after surgery and a duration generally not exceeding 3 to 7 days. Postoperative pain can have adverse effects on patients' cardiovascular function, respiratory function, neuroendocrine, immune, and psychological emotions in the short term. If postoperative pain is not effectively controlled in the acute phase, it may develop into chronic postoperative pain, which can last for half a year or even decades.

Postoperative pain management is an important part of ensuring the effectiveness of postoperative analgesia. The goal of postoperative pain management includes providing sustained and effective pain relief while ensuring safety. At present, although there have been research reports on the therapeutic effects of non pharmacological treatments such as physical therapy, music, and distraction, the treatment of acute pain after surgery is still mainly based on pharmacological therapy.

The main drugs currently used for postoperative analgesia in clinical practice include opioid analgesics, nonsteroidal anti-inflammatory drugs, and local anesthetics. Among them, local anesthetics exert regional analgesic effects through local nerve block, which has fewer systemic adverse reactions compared to other types of analgesics. However, the duration and intensity of action are often insufficient. The duration of nerve block is usually less than 8 hours, and postoperative pain management usually takes several days. Clinically, non continuous multiple injections of local anesthetics, continuous infusion of drugs through epidural or peripheral nerve insertion catheters, disposable pumps, and other methods can be used to achieve postoperative analgesia lasting for several days.

Continuous infusion of local anesthetics can effectively control pain and reduce the use of postoperative opioids, but it requires relatively expensive equipment and continuous monitoring, and long-term indwelling catheters can easily cause catheter displacement and complications. Frequent administration can also increase blood drug concentration fluctuations, reduce patient compliance, cause pain and inconvenience to patients, and lead to serious side effects.

Although postoperative pain management has been carried out in China for more than 20 years, the number of postoperative pain patients in China is still relatively large. According to data from the National Bureau of Statistics, the number of surgeries performed on hospitalized patients in China's medical and health institutions reached 82.7175 million in 2022. In 2023, a cross-sectional study of more than 100 medical centers in Chinese Mainland showed that the incidence of moderate and severe postoperative pain reached 48.7%, including 32.2% of patients with severe postoperative pain. This means that the total number of postoperative pain patients with varying degrees in China may reach over 40 million.

How to treat postoperative pain with bupivacaine liposomes?
Bupivacaine is an amide based local anesthetic that blocks the transmission of nerve pulses by reversibly blocking fast voltage-gated sodium ion channels, thereby achieving analgesic effects. Its hydrochloride salt, namely bupivacaine hydrochloride, was already marketed as a local anesthetic in the United States as early as 1972, with trade names including Marcain, Marcaine, Sensorcaine, and Vivacaine. It is mainly used for local infiltration anesthesia, peripheral nerve block, and intraspinal block.

Short acting bupivacaine preparations can maintain anesthesia effects for 3-6 hours or longer, but cannot cover the peak pain period of three to four days after surgery. In this context, in 2011, the FDA approved the bupivacaine liposome injection developed by Pacira BioSciences for direct injection into surgical sites to help control postoperative pain. The product, Exparel, was the first long-acting postoperative analgesic drug to be marketed in the United States. In 2018, the FDA approved the expansion of its use, including the administration of intermuscular groove brachial plexus block during the perioperative or postoperative period to produce local postoperative analgesia.

Public data shows that Exparel's global sales reached $480 million in 2023, equivalent to approximately RMB 3.4 billion, with a compound annual growth rate of 40% since 2012. The specific sales trend is shown in the following figure.

Exparel's product sales can still approach $500 million with only two indications, mainly due to its unique mechanism of action and high price.

Multicapsular liposomes (MVL) is a non concentric liposome based on the storage foam technology. Its interior is composed of many aqueous chambers that are tightly filled in the form of non concentric circles. It can accumulate at the injection site to form a drug reservoir. Drug release effect is achieved through the dissolution of the lipid chamber. Each aqueous chamber is separated by a lipid bilayer, which has a high drug encapsulation rate and recovery rate. It can be used for the encapsulation of small molecule drugs and macromolecular drugs such as proteins and polypeptides. Polycystic liposomes have large vesicles, high drug loading capacity, high encapsulation efficiency, and good biocompatibility. They are currently used for the development of long-acting sustained-release formulations. Bupivacaine lipid injection sustained-release drug by encapsulating multiple vesicular structures in liposomes, not only extending the analgesic effect to 72 hours, but also reducing the side effects caused by bupivacaine.

Long acting analgesic preparations need to balance the safety and efficacy of the drug, as well as the speed and stability of onset. As the world's first approved long-acting local anesthetic, Exparel has been involved in over 100 clinical trials for intraoperative and postoperative pain relief in procedures such as cystectomy, hemorrhoidectomy, prostatectomy, knee replacement surgery, thoracic surgery, as well as pediatric drug clinical trials. The clinical results support Exparel's application in almost all surgeries for local infiltration anesthesia and postoperative pain relief; For different surgeries, the use of opioids can be avoided or reduced by 45% to 78%; And compared with ordinary injection, it can maintain effective blood drug concentration within 72 hours while always being below the CNS toxicity limit without drug burst release behavior, and there are no reported cases of CNS adverse reactions. In addition, studies have shown that the peak blood concentration of bupivacaine liposomes is lower than that of bupivacaine hydrochloride, which may to some extent reduce the risk of central and cardiac related toxicity.

Exparel is expensive to use in the United States, with a 20ml bottle of Exparel priced at approximately $376, while the same size of bupivacaine hydrochloride is priced at $38 per bottle.
Development direction of future long-acting postoperative analgesic preparations
Long acting postoperative analgesic preparations still belong to the drug field that needs to be explored. After Exparel was launched, the FDA approved four non opioid postoperative long-acting analgesics, all of which are improved formulations of bupivacaine.

Improved long-acting local anesthetics have become a hot topic in the research and development of postoperative analgesics in China. At present, the bupivacaine liposomes of Hengrui Pharmaceutical and Kelun Pharmaceutical have been approved for market in November 2022 and August 2024, respectively. In addition, two bupivacaine active ingredients and five ropivacaine active ingredient long-acting injection formulations have entered the application or clinical stage.

There is still a lot of room for development in the category of long-acting postoperative pain relief preparations. As the first drug to be listed in the long-acting postoperative pain relief preparation category, bupivacaine liposomes have been successfully included in the medical insurance drug list through national negotiations, with a price of 382 yuan per domestically produced bupivacaine liposome injection compared to the high medication cost of the original drug in the United States. The continuous increase in the number of surgeries in China is driving the demand for bupivacaine liposomes, and the launch of new indications will continue to drive the market space of this variety. Moreover, the research and development barriers determine its good competitive landscape, which has considerable market potential.

Source: https://news.yaozh.com/archive/44217.html

责编: editor