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US-12624346-B2 - Vacuum drying method for botulinum toxin

US12624346B2US 12624346 B2US12624346 B2US 12624346B2US-12624346-B2

Abstract

The present invention relates to a vacuum drying method for botulinum toxin, and specifically to a vacuum drying method for botulinum toxin, comprising the steps of: a) first drying of a solution containing botulinum toxin at a temperature of 5° C. to 30° C. under a pressure of 0.01 to 2 mmHg; b) a second drying of the first-dried product obtained in step a) at a temperature of 5° C. to 20° C. under a pressure of 0.01 to 1 mmHg; and c) final drying of the second-dried product obtained in step b) at a temperature of 5° C. to 30° C. under a pressure of 0.01 to 0.5 mmHg. The present invention can advantageously improve yield, stability and manufacturing efficiency, compared to conventional methods for vacuum drying botulinum toxin by freeze-drying.

Inventors

  • Hak Kun KIM
  • Jin Hee Ahn
  • Seul Gi KWON

Assignees

  • PROTOX INC.

Dates

Publication Date
20260512
Application Date
20211007
Priority Date
20201007

Claims (14)

  1. 1 . A vacuum drying method for botulinum toxin comprising the steps of: a) first, drying a solution containing botulinum toxin at a temperature of 5° C. to 30° C. under a pressure of 0.09 to 2 mmHg while increasing the temperature at a rate of 0.1° C./min to 2° C./min from an initial temperature of 5° C. or higher; b) second, drying the first-dried product obtained in step a) at a temperature of 5° C. to 20° C. under a pressure of 0.09 to 1 mmHg; and c) third, drying the second-dried product obtained in step b) at a temperature of 5° C. to 30° C. under a pressure of 0.01 to 0.5 mmHg.
  2. 2 . The vacuum drying method for botulinum toxin according to claim 1 , wherein, in the step a), the upper limit of the pressure is 1.7 mmHg.
  3. 3 . The vacuum drying method for botulinum toxin according to claim 1 , wherein, in the step b), the upper limit of the pressure is 0.8 mmHg.
  4. 4 . The vacuum drying method for botulinum toxin according to claim 1 , wherein, in the step c), the upper limit of the pressure is 0.4 mmHg.
  5. 5 . The vacuum drying method for botulinum toxin according to claim 1 , wherein, in the step c), the upper limit of the pressure is 0.2 mmHg.
  6. 6 . The vacuum drying method for botulinum toxin according to claim 1 , wherein, in each of the steps a), b), and c), drying time is 30 minutes to 120 minutes.
  7. 7 . The vacuum drying method for botulinum toxin according to claim 1 , wherein, in the vacuum drying method for botulinum toxin, total drying time is 6 hours or less.
  8. 8 . The vacuum drying method for botulinum toxin according to claim 1 , wherein, in the vacuum drying method for botulinum toxin, total drying time is 5 hours or less.
  9. 9 . The vacuum drying method for botulinum toxin according to claim 1 , wherein, in the vacuum drying method for botulinum toxin, total drying time is 4 hours or less.
  10. 10 . The vacuum drying method for botulinum toxin according to claim 1 , wherein, the vacuum drying method for botulinum toxin achieves a titer recovery rate of 80% or more.
  11. 11 . The vacuum drying method for botulinum toxin according to claim 1 , wherein, the vacuum drying method for botulinum toxin achieves a titer recovery rate of 85% or more.
  12. 12 . The vacuum drying method for botulinum toxin according to claim 1 , wherein, the vacuum drying method for botulinum toxin achieves a titer recovery rate of 90% or more.
  13. 13 . The vacuum drying method for botulinum toxin according to claim 1 , wherein, the botulinum toxin in the step a) is one or more selected from the group consisting of botulinum toxin types A, B, C1, C2, D, E, F, and G and botulinum serotypes.
  14. 14 . The vacuum drying method for botulinum toxin according to claim 1 , wherein the solution containing botulinum toxin in the step a) includes one or more selected from i) the group consisting of an excipient, a stabilizer, a preservative, a buffer, a thickener, a suspending agent, an emulsifier, a flavoring agent, a coloring agent, and a solubilizing agent; ii) the group consisting of sodium chloride, calcium chloride, sodium phosphate, calcium phosphate, sodium acetate, ethanol, propylene glycol, polyethylene glycol, and aqueous solutions thereof; and iii) the group consisting of albumin, gelatin, sugar, and sugar alcohol.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a national stage application of PCT/KR2021/013828 filed 7 Oct. 2021 which claims priority to Korean Patent Application No. 10-2020-0129385 filed 7 Oct. 2020. The entire disclosures of each application are herein incorporated by reference. TECHNICAL FIELD The present invention relates to a drying process in a process of manufacturing a botulinum toxin preparation, and specifically to a vacuum drying method for botulinum toxin that dries by vacuum drying and not by conventional freeze drying, which exhibits improved yield, stability and manufacturing efficiency compared to conventional methods. BACKGROUND ART It is known that botulinum toxin is a neurotoxic protein produced by Clostridium botulinum and related species and has an effect of blocking the release of acetylcholine, a neurotransmitter secreted from the axon terminal of a neuromuscular junction. In addition, there are 8 types of serologically related natural botulinum toxin from type A to type H, and botulinum toxin has varying effects on the human body depending on the type, but is known to have a fatal effect on the human body as a whole. In the case of botulinum toxin type H, injection of only one over two billion of a gram into the body can be lethal, and botulinum toxin types A and B can cause diseases. Botulinum toxin type A has been used for strabismus correction after safety and efficacy were proven since 1978. Further, it was discovered that wrinkles in the glabellar area disappeared after injecting the toxin for the treatment of blepharospasm patients in 1987, and the toxin attracted interest as a possibility of a use for cosmetic purposes. In general, botulinum toxin types A and B are manufactured into medicine and medical supplies and injected intramuscularly as an injection to treat muscle spasms and diseases caused by muscle overactivity. Considering the effect on the human body according to the injection amount, guidelines for the use of botulinum toxin and guidelines for the approval of botulinum toxin have been prepared. Currently, there are problems such as instability of protein and loss of active ingredients in the process of preparing medicine with botulinum toxin, so a separate ingredient such as a stabilizer is required. In this regard, Korean Patent Registration No. 10-1087017 discloses a method for manufacturing a liquid composition by using polysorbate 20, methionine and/or isoleucine. Commercially available botulinum toxin preparations are distributed in powder form after freeze drying or vacuum drying for preventing decomposition of botulinum toxin preparations, facilitating handling of botulinum toxin preparations, and reducing transportation costs or the like and can be reconstituted by using a liquid carrier such as water or saline solution before use. However, in the case of freeze drying, which is a drying technique commonly used in the related art, there are disadvantages in that botulinum toxin is lost due to the instability thereof and that it takes a long period of time for freeze drying. Accordingly, the present inventors have diligently studied to improve a drying method for botulinum toxin and resultantly found a vacuum drying method, in which the loss of active materials is small and the required time is significantly shortened while properties of the product are excellent, by applying the vacuum drying according to the present invention consisting of specific steps, to complete the present invention. SUMMARY OF INVENTION Technical Problem The present invention is to provide a vacuum drying method for botulinum toxin in which yield, stability, manufacturing efficiency, and productivity are significantly improved by vacuum drying, in order to solve the problems in terms of production efficiency in that it takes a long period of time for drying and of yield problem after drying of the botulinum toxin when botulinum toxin is manufactured by a method for drying botulinum toxin by freeze drying in the related art. Solution to Problem In order to solve the problems described above, the present invention provides a vacuum drying method for botulinum toxin, comprising the steps of: a first drying of a solution containing botulinum toxin at a temperature of 5° C. to 30° C. under a pressure of 0.01 to 2 mmHg; b) second drying of the first-dried product obtained in step a) at a temperature of 5° C. to 20° C. under a pressure of 0.01 to 1 mmHg; and c) third drying of the second-dried product obtained in step b) at a temperature of 5° C. to 30° C. under a pressure of 0.01 to 0.5 mmHg. According to an aspect of the present invention, the step a) may be to perform first drying while the temperature is increased at 0.1° C./min to 2° C./min from an initial temperature of 5° C. or higher. According to an aspect of the present invention, in the step a), an upper limit of the pressure may be 1.7 mmHg. In addition, according to a specific aspect of the present invention,