Decoding the "bioweapon" botulinum toxin

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This article comprehensively interprets the source development, functional application, preparation process indicators, etc. of botulinum toxin, and analyzes the market status and trend from the aspects of products and representative manufacturers. 1. Introduction and development of botulinum toxin.


Introduction to botulinum toxin

Botulinum toxin is a bacterial exotoxin produced by Clostridium botulinum during reproduction, which can bind to receptors at motor neuron endings and neuromuscular junctions, and enter nerve endings by cellular swallowing to inhibit the release of acetylcholine, thereby blocking impulse conduction and paralyzing muscle relaxation [1]. The effects of botulinum toxin generally last for 3 to 6 months, after which the regrowth of nerve endings allows nerve impulses to be conducted again and the muscles return to their original state, at which point re-injection of botulinum toxin is still effective.

Botulinum toxin is generally divided into eight types, A, B, C1, C2, D, E, F, and G depending on the antigen [2]. Among the eight botulinum toxins, botulinum toxin type A has the strongest virulence, the best stability, and is easy to prepare and preserve, and is widely used in clinical practice. Botulinum toxin type A belongs to the Zn2+-dependent proteolytic enzyme family and consists of a heavy chain of 100 kD and a light chain of 50 kD. Among them, the heavy chain can specifically bind to the nerve cell membrane into the cell; Light chains can specifically hydrolyze the SNAP-25 protein (synaptosome-associated protein-25) on the presynaptic membrane, thereby affecting the activity of SNARE (soluble NSF-attachment protein receptor) protein involved in endocytosis and exocytosis function, resulting in acetylcholine-containing vesicles that cannot bind to the cytoplasmic membrane of the presynaptic membrane, so that they cannot be released, and the affected nerve impulses cannot stimulate the innervated muscle contraction. 

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History of botulinum toxin

Botulinum toxin was first used as a biochemical weapon in history, which can damage the nervous system of living organisms, causing dizziness, difficulty breathing, muscle weakness and other symptoms. Later, botulinum toxin was used clinically to treat facial spasms and other muscle movement disorders.

In 1986, J.C., a professor of ophthalmology at the University of British Columbia School of Medicine in Vancouver, Canada, accidentally discovered that botulinum toxin can make patients' eye wrinkles disappear. Since then, the medical aesthetic industry has expanded its range of applications, such as slimming calves, reshaping faces, and removing scars.

In 1989, botulinum toxin type A was approved by the U.S. Food and Drug Administration (FDA) for muscle tone disorders over the age of 12.

In 2002, botulinum toxin type A was approved for the treatment of moderate to severe glabellar wrinkles;

In 2004, botulinum toxin type A was approved for the treatment of axillary hyperhidrosis. Since then, botulinum toxin type A has been used in dermatology, plastic surgery, neurology, rehabilitation, urology, pain, ophthalmology, otolaryngology and other fields.


Listed products

At present, there are 4 products of botulinum toxin type A on the market in China: Botulinum Toxin (Allergan Corporation of the United States), Hengli Botulinum Toxin (Lanzhou Institute of Biological Products), Dysport (Ipsen Company of the United Kingdom), and Letybo White Poison (Daedong Pharmaceutical of South Korea). Other international products Xeomin (Merz, Germany), Nabota Green toxin (Daehuong Pharmaceutical, Korea), Hutox Orange toxin  (Hutox, Korea), Jetema Botulinum toxin  (Jetema, Korea), Medytox Powder toxin  + Small Golden Bottle (Pacific Pharmaceutical, South Korea).

Botulinum Toxin

Botulinum toxin application and management

The botulinum toxin medical beauty market focuses on two functions: wrinkle removal and face slimming. The anti-wrinkle function of botulinum toxin mainly targets dynamic wrinkles such as eyebrow lines, forehead lines, and crow's feet. By blocking the nerve impulses between nerves and muscles, the overcontracted muscles are relaxed, and the effect of wrinkle removal is achieved. Botulinum toxin can also act on the masseter muscle to achieve the effect of face slimming, and the corresponding product is face slimming injection. At the same time, the application of botulinum toxin also extends to the latissimus cervico, trapezius muscle and gastrocnemius muscle to reshape the contour muscles to achieve the effect of slimming shoulders and slimming calves.

Pharmaceutical manufacturers shall formulate an annual production plan for botulinum toxin type A preparations, strictly follow the annual production plan and drug GMP requirements, and designate pharmaceutical wholesale enterprises with biological product business qualifications as distributors of botulinum toxin type A preparations.

Dispersion refers to the diffusion range of botulinum toxin injected into muscle tissue, centered on the injection point, and the dispersion degree is not a single determined value, but is closely related to concentration, injection volume, drug molecular particles, structural looseness, etc. Dispersion is popular, you can imagine a drop of water on paper, the size of a scattered water pattern.

The lower the dispersion, the better, which means that it will not diffuse the surrounding muscle tissue, if the diffusion of botulinum toxin is too good, it will lead to the dispersion of the part that needs to be injected, and then cause muscle stiffness or no effect, the lower the dispersion, the more accurate it will be, hitting where to be thin, will not cause other parts of the depression or expression muscle stiffness. For example, the diffusion area after Botulinum Toxin injection is 0.5 square centimeters, and the dispersion area of Hengli botulinum toxin is 1 square centimeter. 


Excipient proteins

(1) Medical gelatin comes from pigs or cattle, the extraction process is simple, the yield is high, but it is easy to produce drug resistance;

(2) Human serum albumin is derived from human blood, and the probability of drug resistance is low, but the extraction process is complex and the yield is limited;

(3) The resistance of drug without auxiliary protein is lower than that of human serum albumin and medical gelatin. 

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Medical market botulinum toxin market size

ISAPS data shows that in 2019, the number of cases diagnosed and treated by botulinum toxin programs in the United States was about 7.698 million, with a penetration rate of 4.3%. China's formal market has great potential for future development.

According to sales statistics, the terminal sales of China's formal botulinum toxin market in 2019 was 3.6 billion yuan, with a compound annual growth rate of 31.6% from 2015 to 2019. From 2015 to 2019, the global botulinum toxin market grew at a compound annual growth rate of 9.1%, which was much lower than China's compound annual growth rate from 2015 to 2019, and China's botulinum toxin market was in a stage of rapid development. It is estimated that the scale of China's formal botulinum toxin market is expected to reach 8 billion yuan in 2024.