Recently, Kelun Pharmaceutical announced that its subsidiary Hunan Kelun Pharmaceutical's chemical drug "Bupivacaine Liposome Injection" was approved for marketing by the National Medical Products Administration (trade name Bruco®), which was approved according to Class 3 chemical drugs and deemed to have passed the generic drug quality and efficacy consistency evaluation.

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

Behind the successful breakthroughs of domestic pharmaceutical companies is the growing market demand in the field of long-acting postoperative analgesic preparations in the world and China.

The incidence of postoperative pain in China is still high.

Postoperative pain refers to pain caused by acute trauma and damage to internal organs caused by surgical operations and inflammatory stimulation around nerve endings. Postoperative pain occurs after waking up from anesthesia, with the peak pain period being 24 to 48 hours after surgery, and the duration generally does not exceed 3 to 7 days. Postoperative pain can have adverse effects on the patient's 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 effect of postoperative analgesia. The goals of postoperative pain management include continuous and effective analgesia under the premise of safety. Although non-drug treatments such as physical therapy, music, distraction and other methods have different research reports on therapeutic effects, the treatment of acute pain after surgery is still mainly based on drug therapy. The

main drugs currently used for clinical postoperative analgesia include: opioid analgesics, nonsteroidal anti-inflammatory drugs and local anesthetics. Among them, local anesthetics exert regional analgesic effects through local nerve blocks. Compared with other types of analgesics, they have fewer systemic adverse reactions, but they often have insufficient duration and intensity of action. The duration of nerve blocks is usually less than 8 hours, and the management of postoperative pain usually takes several days. Clinically, non-continuous multiple injections of local anesthetics, continuous infusion of drugs through epidural or peripheral nerve insertion catheters, and disposable pumps can be used to achieve postoperative analgesia 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 are prone to catheter displacement and complications. Frequent administration will 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 patients with postoperative pain in China is still large. According to data from the National Bureau of Statistics: In 2022, the number of inpatient surgeries in China's medical and health institutions will reach 82.7175 million. A cross-sectional study of more than 100 medical centers in mainland China in 2023 showed that the incidence of moderate to severe pain after surgery reached 48.7%, including 32.2% of patients suffering from severe postoperative pain. This means that the total number of patients with different degrees of postoperative pain in China may reach more than 40 million.

How does bupivacaine liposome treat postoperative pain?

Bupivacaine is an amide local anesthetic that blocks the transmission of nerve impulses by reversibly blocking fast voltage-gated sodium ion channels, thereby achieving analgesic effects. Its hydrochloride, bupivacaine hydrochloride, was launched as a local anesthetic in the United States as early as 1972. The trade names include Marcain, Marcaine, Sensorcaine and Vivacaine, and are mainly used for local infiltration anesthesia, peripheral nerve block and spinal block.

The anesthetic effect of short-acting bupivacaine preparations can last for 3-6 hours or longer, which 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 the surgical site to help control postoperative pain. The trade name is Exparel, which is the first long-acting postoperative analgesic drug to be marketed in the United States. In 2018, the FDA approved its expanded scope of use, including perioperative or postoperative administration through interscalene brachial plexus block to produce local analgesia after surgery.

Public data shows that in 2023, Exparel's global sales will reach US$480 million, equivalent to approximately RMB 3.4 billion, with a compound growth rate of 40% since 2012. With
only two indications, Exparel's product sales can still be close to US$500 million, mainly due to the product's unique mechanism of action and high price.

Multivesicular liposomes (MVL) are non-concentric liposomes based on reservoir foam technology. Their interior is composed of many aqueous chambers tightly packed in the form of non-concentric circles. They can accumulate to form a drug reservoir at the injection site, and achieve drug sustained release through lipid chamber dissolution. Each aqueous chamber is separated by a lipid bilayer, which has a high drug encapsulation rate and recovery rate. They can be used for encapsulation of small molecule drugs and polymer drugs such as proteins and peptides. Multivesicular liposomes have large vesicles, large drug loading, high encapsulation rate, and good biocompatibility. They are currently used to develop long-acting sustained-release preparations. Bupivacaine lipid injection releases drugs through liposomes with multiple vesicle structures, which not only prolongs the analgesic effect to 72 hours, but also reduces the side effects of bupivacaine. Long-

acting analgesic preparations need to balance the safety and long-term effectiveness of drugs, and the speed and stability of onset. As the world's first approved long-acting local anesthetic, Exparel has been involved in more than 100 clinical trials involving intraoperative and postoperative analgesia for bunionectomy, hemorrhoidectomy, prostatectomy, knee replacement, thoracic surgery, etc., as well as pediatric drug clinical trials. Clinical results support the use of Exparel for local infiltration anesthesia and postoperative analgesia in almost all surgeries; for different surgeries, it can avoid or reduce the use of 45% to 78% of opioids; and compared with ordinary injections, it can maintain effective blood drug concentrations within 72 hours while always being below the CNS toxicity limit and without drug burst release, and no CNS adverse reactions have been reported. In addition, studies have shown that the peak blood drug concentration of bupivacaine liposomes is lower than that of bupivacaine hydrochloride, which may reduce the risk of central and cardiac toxicity to a certain extent.

Exparel is expensive in the United States. A 20 ml bottle of Exparel costs about $376, while a bottle of bupivacaine hydrochloride of the same size costs $38.

Future development direction of long-acting postoperative analgesic preparations

Long-acting postoperative analgesic preparations are still a drug field to be explored. After Exparel was launched, the FDA approved four non-opioid long-acting postoperative analgesics, all of which are improved preparations of bupivacaine.

Improved long-acting local anesthetics have become a hot spot for the research and development of postoperative analgesics in China. At present, the bupivacaine liposomes of Hengrui Pharmaceuticals and Kelun Pharmaceuticals were approved for marketing in November 2022 and August 2024, respectively. Two other bupivacaine active ingredients and five ropivacaine active ingredients have entered the application or clinical stage for long-acting injection preparations.

There is still a lot of room for development in the category of long-acting postoperative analgesics. As the first drug to be launched in the category of long-acting postoperative analgesics, bupivacaine liposomes have a price of 382 yuan per vial compared to the high cost of original drugs in the United States, and have been successfully included in the list of medical insurance drugs through national negotiations. The growing number of domestic surgeries has driven the demand for bupivacaine liposomes. The launch of new indications will continue to promote the market space of this variety, and the research and development barriers determine its good competitive landscape, which has considerable market potential.

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