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EP-4740957-A1 - BOTULINUM TOXIN PROTEIN COMPOSITION AND USE THEREOF

EP4740957A1EP 4740957 A1EP4740957 A1EP 4740957A1EP-4740957-A1

Abstract

Provided are a botulinum toxin protein composition and a use thereof, in particular a botulinum toxin protein composition containing L-carnitine or a structural analogue thereof. The botulinum toxin protein composition can be used as a liquid preparation in the fields of medicine and cosmetics. The composition has good stability, particularly long-term stability, and is beneficial to the storage of botulinum toxin proteins.

Inventors

  • YANG, WU
  • GONG, Hui

Assignees

  • Chongqing Claruvis Pharmaceutical Co., Ltd.

Dates

Publication Date
20260513
Application Date
20240704

Claims (10)

  1. A botulinum toxin protein composition, comprising: a botulinum toxin protein and L-carnitine or a derivative thereof or a salt of L-carnitine or of the derivative thereof, wherein preferably, the composition is a liquid composition, and more preferably, the composition further comprises a solvent, such as water for injection or 0.9% sodium chloride injection.
  2. The composition according to claim 1, wherein the L-carnitine or the derivative thereof or the salt thereof has a concentration of 1 mM to 50 mM, preferably 1 mM to 20 mM.
  3. The composition according to claim 1 or 2, wherein the derivative of the L-carnitine is alkanoyl L-camitine; preferably, the alkanoyl group has 2 to 26 carbon atoms; more preferably, the alkanoyl is acetyl, propionyl, butyryl, isobutyryl, valeryl or isovaleryl; more preferably, the derivative of the L-carnitine is O-acetyl-L-carnitine.
  4. The composition according to claim 1 or 2, wherein the salt of the L-carnitine or the derivative thereof is a pharmaceutically acceptable salt, preferably selected from tartrate, hydrochloride, citrate, succinate and fumarate, more preferably selected from tartrate or hydrochloride.
  5. The composition according to claim 1, further comprising a solubilizer, wherein preferably, a volume percentage concentration of the solubilizer is 0% to 0.1%; preferably, the solubilizer is selected from one or more of a Tween, a Span, sodium dodecyl sulfate and poloxamer; more preferably, the solubilizer is Tween 80.
  6. The composition according to claim 1, further comprising an osmotic pressure regulator, wherein preferably, the osmotic pressure regulator is selected from sodium chloride, glucose, glycerol, fructose, sorbitol, magnesium chloride, phosphate, sodium citrate and mannitol; more preferably, the osmotic pressure regulator is sodium chloride at a mass percentage concentration of 0.9% in the composition.
  7. The composition according to any one of claims 1 to 6, wherein the botulinum toxin protein is selected from any one of botulinum toxin protein type A, botulinum toxin protein type B, botulinum toxin protein type C1, botulinum toxin protein type C2, botulinum toxin protein type D, botulinum toxin protein type E, botulinum toxin protein type F or botulinum toxin protein type G, and is preferably botulinum toxin protein type A; preferably, the botulinum toxin is a recombinant botulinum toxin.
  8. The composition according to claim 7, comprising the botulinum toxin protein, the L-carnitine or the derivative thereof or a salt of L-carnitine or of the derivative thereof, the solubilizer, and the osmotic pressure regulator, wherein the L-carnitine or the derivative thereof or the salt thereof has a concentration of 1 mM to 50 mM, the solubilizer has a volume percentage concentration of 0% to 0.1%, and the osmotic pressure regulator is an isotonic regulator; preferably, the composition comprises the botulinum toxin protein, 2 mM to 10 mM of the L-carnitine or the derivative thereof or the salt thereof, 0% to 0.1% Tween 80, and 0.9% sodium chloride; more preferably, the composition comprises the botulinum toxin protein, 10 mM of the L-carnitine or the derivative thereof or the salt thereof, 0.1% Tween 80, and 0.9% sodium chloride.
  9. Use of the composition according to any one of claims 1 to 8 in preparing a medicament for preventing and/or treating a disease and a cosmetic product.
  10. The use according to claim 9, wherein the disease is selected from neuromuscular diseases, autonomic disorders, pain, neuropsychiatric disorders, skin diseases, dental diseases and cancer; preferably, the disease is selected from spasmodic dysphonia, spasmodic torticollis, laryngeal dystonia, oromandibular dysphonia, lingual dystonia, cervical dystonia, focal dystonia, blepharospasm, strabismus, hemifacial spasm, eyelid disorder, cerebral palsy, focal spasm and other language disorders, spastic colitis, neurogenic bladder, anismus, limb spasm, tics, tremor, bruxism, anal fissure, achalasia, dysphagia and other dystonias as well as other disorders characterized by muscle group involuntary movement, lacrimation, hyperhidrosis, excessive salivation, excessive gastrointestinal secretion, secretory disorders, pain due to muscle spasm, headache; psoriasis, allergy, hemophagocytic lymphohistiocytosis and alcoholic pancreatic disease; epilepsy, central sensitization chronic pain, post-stroke central pain, regional pain, phantom limb pain and demyelinating pain; schizophrenia, Alzheimer's disease, mania, anxiety disorder, depression; tension headache, migraine, sinus headache, post-operative pain, visceral pain, neuralgia and fibromyalgia; the cosmetic use is selected from wrinkle removal or prevention, facial slimming, scar repair, improvement or removal of pimples or acne, eyebrow shape modification, mouth corner lifting, body contouring, body odor removal, hair growth and hair retention.

Description

TECHNICAL FIELD The present disclosure relates to the field of pharmaceutical formulations, and in particular, to a botulinum toxin protein composition and use thereof, particularly a botulinum toxin protein composition comprising L-carnitine or a structural analog thereof. BACKGROUND Native botulinum neurotoxins (BoNTs) are toxin proteins produced by an anaerobic bacterium Clostridium botulinum. They cause muscle paralysis in mammals by blocking the presynaptic release of neurotransmitter acetylcholine at the neuromuscular junction. Currently, seven types of BoNTs have been identified, designated as BoNT/A through BoNT/G, respectively. BoNTs have rapidly become therapies for cholinergic hyperexcitability due to their unique pharmacological properties including high specificity for the nervous system, limited diffusion by local injection, and reversible effects, and possess broad applications in the fields of medicine and cosmetology. In general, therapeutically and pharmaceutically active proteins are prepared in solutions, in particular for injections. Therapeutically active proteins are generally prepared as compositions and commercialized as a ready-to-use solution or a lyophilized form for reconstitution into a solution. For example, commercial BoNT/A products are vacuum-dried or lyophilized solid formulations and require reconstitution by healthcare providers at the time of use, thus requiring precise control of the reconstitution volume. In addition, due to the differences in therapeutic purpose and individual dosage between patients, the volume required for each dose varies considerably. After reconstituting the commercial products to the volume specified by the manufacturer, clinicians often administer only a small portion of the content in the vial to the patient, and preserve the remainder in a refrigerator for later use. It has been estimated that the preservation of a reconstituted BoNT/A formulation in a refrigerator (about 4 °C) for 12 h may lead to a 44% or greater loss of efficacy. Thus in practice, it is generally recommended to use the product within 4 h after reconstitution, which results in a waste of medications and an unnecessary economic burden for the patient. In addition, due to the extremely low concentration of botulinum toxin in use, it is generally prepared with the addition of high concentrations of exogenous proteins to keep the stability of the botulinum toxin protein at the low concentration and avoid the adsorption of the active ingredient onto solid surfaces. In most botulinum toxin formulations, albumin or gelatin is used as the stabilizer, which not only causes immune responses, but also has the potential to introduce a source of contamination. SUMMARY To overcome the defects in the prior art, the present disclosure provides a botulinum toxin protein composition, a preparation method therefor, and use thereof. In a first aspect of the present disclosure, provided is a botulinum toxin protein composition comprising a botulinum toxin protein, and L-carnitine or a derivative thereof or a salt thereof. In one embodiment of the present disclosure, the composition is a liquid composition further comprising a solvent, such as water (particularly water for injection) and sodium chloride injection (e.g., 0.9% sodium chloride injection and compound sodium chloride injection). Specifically, the solvent is a sterile solvent, such as sterilized water for injection and 0.9% sodium chloride injection. Specifically, the L-carnitine or the derivative thereof or the salt thereof in the composition has a concentration of 1 mM to 50 mM (e.g., 1 mM, 2 mM, 3 mM, 4 mM, 4.5 mM, 4.8 mM, 4.9 mM, 5 mM, 6 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 14 mM, 15 mM, 20 mM, 20.1 mM, 20.2 mM, 20.5 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, or 50 mM), such as 1 mM to 4.9 mM, 2 mM to 4.5 mM, 1 mM to 20 mM, 20.1 mM to 50 mM, 20.5 mM to 40 mM, or 20.5 mM to 30 mM. In one embodiment of the present disclosure, the composition comprises botulinum toxin protein and L-camitine. In one embodiment of the present disclosure, the composition comprises the botulinum toxin protein and the salt of the L-camitine. In one embodiment of the present disclosure, the composition comprises the botulinum toxin protein and the derivative of the L-carnitine or the salt thereof. In the composition, the L-carnitine or the derivative thereof or the salt thereof is used as a protein stabilizer; in one embodiment, the protein stabilizer is the L-camitine; in another embodiment, the protein stabilizer is the salt of the L-camitine; in another embodiment, the protein stabilizer is the derivative of the L-camitine; in another embodiment, the protein stabilizer is the salt of the derivative of the L-camitine. In some embodiments of the present disclosure, the derivative of the L-carnitine is alkanoyl L-carnitine having a structural formula of wherein R represents alkanoyl, which may be saturated or unsaturated and linear or branched, and has 2 to