US20190183988A1 - Neurotoxin formulation - Google Patents

Neurotoxin formulation Download PDF

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Publication number
US20190183988A1
US20190183988A1 US16/304,986 US201716304986A US2019183988A1 US 20190183988 A1 US20190183988 A1 US 20190183988A1 US 201716304986 A US201716304986 A US 201716304986A US 2019183988 A1 US2019183988 A1 US 2019183988A1
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US
United States
Prior art keywords
liquid composition
botulinum neurotoxin
composition according
tryptophan
amino acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US16/304,986
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English (en)
Inventor
Anders Jarstad
Anna FRIIS
Ulf Stahl
Ann GURELL
Barbro AGREN
Emilia EDSTROM
Andrew Pickett
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ipsen Biopharm Ltd
Original Assignee
Nestle Skin Health SA
Ipsen Biopharm Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nestle Skin Health SA, Ipsen Biopharm Ltd filed Critical Nestle Skin Health SA
Publication of US20190183988A1 publication Critical patent/US20190183988A1/en
Assigned to NESTLE SKIN HEALTH SA, IPSEN BIOPHARM LIMITED reassignment NESTLE SKIN HEALTH SA ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FRIIS, Anna, EDSTROM, Emilia, AGREN, Barbro, GURELL, Ann, PICKETT, ANDREW, JARSTAD, ANDERS, STAHL, ULF
Assigned to IPSEN BIOPHARM LIMITED reassignment IPSEN BIOPHARM LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NESTLE SKIN HEALTH SA
Abandoned legal-status Critical Current

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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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    • A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
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Definitions

  • a further aspect of the present invention is the use of an amino acid selected from tryptophan and tyrosine to protect a proteinaceous neurotoxin from degradation in a liquid composition which is free of animal derived proteins.
  • Natural BoNTs are produced by Clostridium botulinum , and other Clostridial species such as C. butyricum, C. baratii and C. argentinense as part of multi-protein complexes that protect the neurotoxin from proteolytic degradation.
  • botulinum neurotoxin in complex form is meant a botulinum neurotoxin and one or more of the proteins which are part in nature of such multi-protein complexes (neurotoxin-associated proteins or “NAPs”).
  • NAPs include non-toxic non-hemagglutinin (NTNH) protein and hemagglutinin proteins (HA-17, HA-33, and HA-70).
  • high purity botulinum neurotoxin is meant a botulinum neurotoxin essentially free of NAPs.
  • Non-ionic surfactants include Polyoxyethylene glycol alkyl ethers, such as Octaethylene glycol monododecyl ether or Pentaethylene glycol monododecyl ether; Polyoxypropylene glycol alkyl ethers; Glucoside alkyl ethers, such as Decyl glucoside, Lauryl glucoside or Octyl glucoside; Polyoxyethylene glycol octylphenol ethers, such as Triton X-100; Polyoxyethylene glycol alkylphenol ethers, such as Nonoxynol-9; Glycerol alkyl esters, such as Glyceryl laurate; Polyoxyethylene glycol sorbitan alkyl esters, such as Polysorbates; Sorbitan alkyl esters, such as Spans; Cocamide MEA, cocamide DEA; Dodecyldimethylamine oxide; Block copolymers of polyethylene glycol and polypropylene glycol, such as Poloxa
  • the CMC is approximately 8 ⁇ 10 ⁇ 5 M at 21° C., i.e. approximately 0.01% w/v.
  • the sodium phosphate concentration is preferably from 1 to 100 mM, preferably from 2 to 50 mM, for example about 2, 5, 10, 20, 30, 40 or 50 mM.
  • the mouse LD50 (MLD50) unit for botulinum toxins is not a standardised unit. Indeed, assays used by different manufacturers of marketed toxins differ in particular in the choice of dilution buffer. For example the test used for Dysport® uses gelatine phosphate buffer, whereas the assay used for BOTOX® uses saline as a diluent. It is believed that gelatine buffers protect the toxin at the high dilutions used in LD50 assays. In contrast the use of saline as a diluent is thought to lead to some loss of potency. This could explain why when tested with the Dysport® assay, one BOTOX® unit is equivalent to approximately three units of Dysport (Straughan, D. W., 2006, ATLA 34(3), 305-313; Hambleton and Pickett, Hambleton, P., and A. M. Pickett., 1994, Journal of the Royal Society of Medicine 87.11: 719).
  • the liquid compositions according to the invention can be stored in sealed vials or syringes, for example glass vials or syringes, preferably type 1 (or “body neutral”) glass vials or syringes. Preferably there is no or very little oxygen in the vial or syringe.
  • the vials or syringes can for example be filled in an atmosphere with an oxygen below 100 ppm, preferably below 50 ppm, and nitrogen gas can be used as a protective atmosphere in the vials.
  • glass vials can for example be capped with chlorobutyl or bromobutyl rubber stoppers, which can be FluroTec® coated stoppers.
  • the liquid compositions according to the invention are stored in glass vials capped with FluroTec® coated stoppers.
  • a liquid composition according to the invention comprises or consists essentially of:
  • a liquid composition according to the invention comprises or consists essentially of:
  • a liquid composition according to the invention comprises or consists essentially of:
  • a liquid composition according to the invention comprises or consists essentially of:
  • a liquid composition according to the invention comprises or consists essentially of:
  • Liquid botulinum toxin preparations containing 350 ng/mL of highly purified BoNT/B, 15% v/v polysorbate 20, an amino acid selected from tyrosine (Tyr), tryptophan (Trp) and cysteine (Cys) or a mixture of methionine (Met), tyrosine (Tyr), tryptophan (Trp) and cysteine (Cys), and Phosphate Buffer Saline (PBS) at pH 7.4 were prepared, filtered using 0.22 ⁇ m filters and stored in siliconized 2 mL glass syringes for two weeks at 40° C., after which a potency test was performed for each preparation as described above.

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  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Birds (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Inorganic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Dermatology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Rheumatology (AREA)
  • Biochemistry (AREA)
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  • Gerontology & Geriatric Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
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  • Diabetes (AREA)
  • Urology & Nephrology (AREA)
  • Pain & Pain Management (AREA)
  • Ophthalmology & Optometry (AREA)
  • Neurosurgery (AREA)
  • Toxicology (AREA)
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US16/304,986 2016-05-27 2017-05-26 Neurotoxin formulation Abandoned US20190183988A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP2016062085 2016-05-27
EPPCT/EP2016/062085 2016-05-27
PCT/EP2017/062785 WO2017203038A1 (en) 2016-05-27 2017-05-26 Liquid neurotoxin formulation stabilized with tryptophan or tyrosine

Related Parent Applications (1)

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PCT/EP2017/062785 A-371-Of-International WO2017203038A1 (en) 2016-05-27 2017-05-26 Liquid neurotoxin formulation stabilized with tryptophan or tyrosine

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US17/304,888 Continuation US20230190892A9 (en) 2016-05-27 2021-06-28 Liquid neurotoxin formulation stabilized with tryptophan or tyrosine

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US20190183988A1 true US20190183988A1 (en) 2019-06-20

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Family Applications (4)

Application Number Title Priority Date Filing Date
US16/304,986 Abandoned US20190183988A1 (en) 2016-05-27 2017-05-26 Neurotoxin formulation
US17/304,888 Abandoned US20230190892A9 (en) 2016-05-27 2021-06-28 Liquid neurotoxin formulation stabilized with tryptophan or tyrosine
US18/173,991 Abandoned US20230181702A1 (en) 2016-05-27 2023-02-24 Liquid neurotoxin formulation stabilized with tryptophan or tyrosine
US18/476,731 Pending US20240050539A1 (en) 2016-05-27 2023-09-28 Liquid Neurotoxin Formulation Stabilized with Tryptophan or Tyrosine

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US17/304,888 Abandoned US20230190892A9 (en) 2016-05-27 2021-06-28 Liquid neurotoxin formulation stabilized with tryptophan or tyrosine
US18/173,991 Abandoned US20230181702A1 (en) 2016-05-27 2023-02-24 Liquid neurotoxin formulation stabilized with tryptophan or tyrosine
US18/476,731 Pending US20240050539A1 (en) 2016-05-27 2023-09-28 Liquid Neurotoxin Formulation Stabilized with Tryptophan or Tyrosine

Country Status (30)

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US (4) US20190183988A1 (ru)
EP (3) EP4026532A1 (ru)
JP (1) JP7053498B2 (ru)
KR (2) KR102399451B1 (ru)
CN (2) CN111701010B (ru)
AR (1) AR108631A1 (ru)
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