Botulinum toxin pre-filled injectable formulation that facilitates discharge rate control and is stable

Abstract

To provide a botulinum toxin pre-filled injectable formulation that facilitates discharge rate control and is stable.SOLUTION: Provided is a syringe formulation pre-filled with botulinum toxin, comprising: a syringe comprising a syringe barrel, a plunger rod, and a plunger stopper; and a botulinum toxin liquid preparation filled in the syringe, where an amount of increase of a force acting on an end of the plunger rod decreases as a rate of discharge of the botulinum toxin liquid preparation increases.SELECTED DRAWING: Figure 2

Description

[Technical field]

[0001] The present invention relates to a stable pre-filled syringe dosage form of botulinum toxin with easily adjustable delivery rate. [Background technology]

[0002] Botulinum toxin (BoNT) is one of the most potent toxins known, and acts by blocking acetylcholine release from peripheral cholinergic neurons. Botulinum toxin is administered to individuals in very small doses and has been used to reduce overactive muscles and exocrine glands. For example, botulinum toxin is used for cosmetic purposes as well as to treat neuromuscular disorders and overactive exocrine gland disorders.

[0003] The botulinum toxin is known to be inherently unstable, particularly at alkaline pH, and highly unstable and heat-labile. A medical dosage form that overcomes these shortcomings is the pre-filled syringe system, which has become increasingly more popular as a drug delivery device in recent years. However, when proteins are used as active ingredients, the limited stability of proteins has made it a particularly difficult task for formulation scientists to use the pre-filled syringe system, especially when applied to very dilute aqueous solutions of botulinum toxin.

[0004] To increase the stability of pharmaceutical botulinum toxin compositions, stabilizing proteins such as human serum albumin (HSA) are sometimes added, and it is also known to add non-proteinaceous stabilizers such as surfactants, polyvinylpyrrolidone (PVP), disaccharides, polyols, etc.

[0005] However, despite the above background art, a need remains for a stable pre-filled syringe dosage form of botulinum toxin with enhanced storage stability and easy control of delivery rate. Summary of the Invention [Problem to be solved by the invention]

[0006] One aspect is to provide a stable pre-filled syringe dosage form of botulinum toxin with easy to regulate syringe delivery rate. [Means for solving the problem]

[0007] One aspect provides a botulinum toxin pre-filled syringe dosage form comprising a syringe including a syringe barrel, a plunger rod, and a plunger stopper, and a botulinum toxin liquid formulation loaded within the syringe. The dosage form also reduces the amount of increase in force acting on the end of the plunger rod due to an increase in the rate at which the botulinum toxin liquid formulation is expelled.

[0008] The term "prefilled syringe" as used herein refers to a syringe having a partially or completely enclosed space that can be or is sealed and can also be used to contain, store and / or transport a liquid dosage form. The syringe refers to a closed or sealed container made of plastic, such as an organic polymer, or made partially or mainly of plastic.

[0009] The pre-filled syringe has two openings that are sealed to prevent leakage of the contents, a proximal end of the pre-filled syringe is sealed by a plunger stopper, and a distal end is sealed by a capping device.

[0010] The barrel also includes a proximal end and a distal end, and a generally cylindrical wall extending therebetween forming a barrel lumen. The barrel may have a distally projecting tip extending therethrough and having a fluid passageway in communication with the barrel lumen. The proximal end and the distal end have proximal end and distal end open outlets, respectively. The tip may also be of the same material as the remainder of the barrel.

[0011] The barrel is removably capped with a capping device (e.g., a "tip cap" that is removed prior to use and replaced with a needle, or in the case of pre-filled syringes having a removable or permanent needle, by a sealing means such as a needle shield) to sealingly close the distal end of the syringe after filling, and is closed at the proximal end by a plunger or any other means in fluid-tight communication with the inner wall of the barrel to contain the fluid. To use a pre-filled syringe, the tip cap, needle shield, or other type of capping device is removed, a needle is optionally attached (if not already present), the plunger tip or piston is advanced within the barrel, and the contents of the barrel, i.e., the botulinum toxin formulation, is injected into a patient.

[0012] The inner surface of the barrel may be coated or uncoated. The inner surface of the barrel is also coated with a barrier layer for lubrication purposes (hereinafter also referred to as "lubricant layer"). The lubricant layer must not only provide high lubricity to allow the plunger to easily glide through the barrel, but also be compatible with the botulinum toxin dosage form and ensure its shelf life. The lubricant layer may be a silicone-free lubricant layer or a silicone lubricant layer. The inner surface of the wall is also coated with silicone. That is, the barrier layer is also a silicone layer.

[0013] The silicone coating may also be manufactured by a siliconization method selected from a silicone oil-based method (e.g., spray-on siliconization or baked-on siliconization) and a deposition method (e.g., plasma-enhanced chemical vapor deposition (PECVD)). The silicone coating may also be formed by, for example, a spray-on siliconization coating or a baked-on siliconization coating. The silicone coating may also be a polydimethylsiloxane coating.

[0014] In the spray-on siliconization method, for example, a diving nozzle or a static nozzle can be used to spray silicone oil (e.g., DOW CORNING® 360 with a viscosity of 1,000 cSt) into a syringe, i.e., into a barrel, to generate a thin silicone oil layer. The bake-on siliconization method also includes applying silicone oil to a barrel with an emulsion, e.g., DOW CORNING® 365 siliconization emulsion, and then baking on a plastic surface at a specific temperature for a specific time. The bake-on siliconization method can produce fewer silicone oil particles that are invisible to the naked eye and silicone oil particles that are visible to the naked eye, compared to the spray-on siliconization method.

[0015] The material of the syringe barrel may include a plastic material. The material may be glass, a cycloolefin copolymer (COC), a cycloolefin polymer (COP), or a mixture thereof. The COP may have a silicone coating on its surface. COC is produced by polymerization of a cyclic monomer such as norbornene with ethane, while COP is also produced by ring-opening metathesis of the cyclic monomer followed by hydrogenation. COC, COP, and mixtures of COP and COC materials exhibit many desirable characteristics including high transparency, low density, excellent moisture barrier properties, and resistance to aqueous and polar organic media. Specific examples include Topas® COC and Daikyo Crystal Zenith®.

[0016] The tip of the barrel may also be integrally formed with the barrel. For example, the tip may be integrally molded with the barrel. The barrel may also include an integrally formed luer lock tip or luer slip tip. The tip may also include an integral passageway extending axially through the tip and communicating with a chamber for dispensing the contents of the barrel. The tip may have a substantially frusto-conical shape that converges from the distal outlet end of the barrel toward the outlet end of the tip.

[0017] The barrel may have an inner diameter calibrated to accommodate a fill volume of, for example, 0.5 ml, 1.0 ml, 1.5 ml, or 2.0 ml. The barrel may have graduated indicia indicating the volume of fluid in the syringe. The barrel may also include a flange-style interface. The flange design may be compatible with, for example, ISO 11040. The flange-style interface may be compatible with an optional tab.

[0018] The ratio of the length to the inner diameter of the syringe barrel may be from 10 to 22, from 12 to 20, or even from 14 to 16.

[0019] The syringe barrel has an inner diameter of 3 to 7 mm, 3.5 to 6.5 mm, 4 to 6 mm, or 4.5 to 5.5 mm, and a length of 30 to 130 mm, 50 to 110 mm, 60 to 100 mm, or 70 to 90 mm. The syringe has an inner diameter of 3.5 to 6.5 mm, and a length of 60 to 100 mm. The syringe has an inner diameter of 3 to 7 mm, and a length of 30 to 130 mm. The syringe has an inner diameter of 4 to 6 mm, and a length of 50 to 110 mm. The syringe has an inner diameter of 4.5 to 5.5 mm, and a length of 70 to 90 mm.

[0020] The plunger rod and plunger stopper can be coupled to form a plunger rod / plunger stopper assembly that also extends into the proximal end of the barrel. The assembly also includes a rod having a plunger stopper at its tip in sliding fluid-tight engagement with the cylindrical wall of the barrel lumen. The assembly forms a proximal seal and a dynamic seal that allows for extrusion of a botulinum toxin liquid formulation. The stopper contacts the botulinum toxin liquid formulation during storage and / or administration.

[0021] The stopper may also be made of an elastomeric polymeric material. The stopper may optionally have a coating on at least a portion thereof that contacts the botulinum toxin liquid formulation during storage and / or injection.

[0022] The elastomeric polymer may be isoprene rubber (IS), butadiene rubber (polybutadiene (BR)), butyl rubber (isobutylene and isoprene copolymer (IIR)), halogenated butyl rubber (e.g., chlorobutyl rubber (CIIR) and bromobutyl rubber (BIIR)), styrene-butadiene rubber (styrene and butadiene copolymer (SBR)), or a mixture thereof. In one embodiment, the stopper material may be butyl rubber, halogenated butyl rubber, or a mixture thereof. In one embodiment, the stopper material may be bromobutyl rubber or chlorobutyl rubber. The elastomeric polymer may also be reinforced with an inert mineral. The elastomeric polymer may also be cured, for example, with an organic peroxide, a phenolic resin, or the like.

[0023] The stopper may be coated or uncoated. The coating may typically be applied to at least the sealing surface, including the surface portion of the plunger stopper that faces the barrel lumen and that contacts the botulinum toxin dosage form during storage and / or use. The coating also provides good lubricity while minimizing interaction between the plunger stopper and the botulinum toxin liquid formulation.

[0024] Suitable coatings for the plunger stopper are generally made of materials that do not undesirably interfere with the botulinum toxin dosage form and exhibit low levels of extractables / leachables. Such coatings may include polypropylene, polyethylene, parylene (e.g., parylene N, parylene C, and parylene HT), cross-linked silicone, fluoropolymers, or mixtures thereof. Examples of cross-linked silicone coatings include B2-coating (Daiko Seiko) or XSi TM (Becton Dickinson).

[0025] The fluoropolymer coating may be a fluorinated ethylene-propylene copolymer (e.g., tetrafluoroethylene-hexafluoropropylene copolymer (FEP)), a fluorinated ethylene-ethylene copolymer (e.g., ethylene-tetrafluoroethylene copolymer (ETFE) (e.g., Flurotec®), PVA (a copolymer of tetrafluoroethylene (TFE) and perfluoropropyl vinyl ether (PPVE)), a tetrafluoroethylene-perfluoroethylene copolymer, polyvinylidene fluoride (PVDF), polyvinyl fluoride (PVF), polytetrafluoroethylene (PTFE) (Teflon®), or a mixture thereof. For example, the coating is made of ETFE, in particular a Flurotec® coating. In one embodiment, the plunger stopper is uncoated.

[0026] The design of the plunger stopper is not particularly limited, and may be a nested stopper or a bagged stopper. The interface to the rod may also be threaded to allow for rod installation after sterilization. Alternatively, the interface to the rod may be designed with a snap-on design. The rod, like the plunger stopper, is generally designed to withstand sterilization, but is not particularly limited by any particular method. The rod may also be made of plastic materials such as ethylene vinyl acetate (EVA) copolymer or polypropylene.

[0027] 1 is a diagram illustrating an example of a pre-filled syringe including a needle. The pre-filled syringe includes a barrel 10, a plunger 80 including a plunger rod 20 and a plunger stopper 30, a needle 50, and a botulinum toxin liquid formulation 40 contained in the lumen of the barrel 10.

[0028] The pre-filled syringe also includes a "capping device," which broadly refers to any means for closing and sealing the distal open outlet end of a syringe. In the present invention, the term "open outlet end" or "distal open outlet end" refers to any distal open end of a syringe that is in fluid communication with a barrel lumen. The capping device may generally comprise a channel having a closed end and an open end that is sized to receive and effectively seal the open outlet end of the syringe and prevent leakage.

[0029] In the case of pre-filled syringes without a pre-attached needle, the capping device is a capping means commonly known as a "tip cap". The tip cap forms a fluid-tight seal with the tip of the syringe, effectively closing the syringe barrel and preventing leakage of the contents of the syringe barrel. The tip cap is usually removably coupled to the syringe tip or luer collar. The luer collar surrounds the upper portion (e.g., the syringe tip) of the syringe barrel. The luer collar has an internal thread, and the tip cap also has an external thread complementary to the internal thread of the luer collar for coupling the tip cap to the syringe barrel. In the case of the pre-filled syringes of the present invention, the luer collar is typically formed integrally with the syringe barrel. Before use, the tip cap can be removed and then the needle cannula (needle assembly) can be securely coupled to the syringe tip.

[0030] 2 is a diagram illustrating an example of a pre-filled syringe including a tip cap. The pre-filled syringe includes a barrel 10, a plunger 80 including a plunger rod 20 and a plunger stopper 30, a tip 100 formed at the end of the barrel, a luer collar 110 having threads formed on the tip, a tip cap 120 secured to the tip by attachment to the luer collar, and a botulinum toxin liquid formulation 40 contained in the lumen of the barrel 10.

[0031] When a pre-filled syringe includes a removable or non-removable (i.e., permanent) cannula or needle cannula (also referred to as a "needle" or "needle assembly") that extends from the syringe tip to deliver the botulinum toxin formulation from the syringe, the capping device is also referred to as a "needle shield." The needle shield may generally have a channel with a closed end and an open end that is dimensioned to receive and couple with a cannula (needle) mounted on the tip of the syringe. Typically, the (sharp) end of the cannula can penetrate the closed end of the channel in the needle shield to seal the open end of the cannula.

[0032] 3 is a diagram illustrating an example of a pre-filled syringe including a needle assembly and a needle shield. The pre-filled syringe includes a barrel 10, a plunger 80 including a plunger rod 20 and a plunger stopper 30, a needle 50, a needle assembly 60, a needle shield 70, and a botulinum toxin liquid formulation 40 contained in the lumen of the barrel 10.

[0033] The capping device (e.g., tip cap or needle shield) may be a single piece or may typically be made of a flexible and resilient polymeric material (e.g., elastomeric) or may have an outer cap made of a material that includes or is made of an elastomeric polymer, such as a rigid plastic material coupled to a flexible and resilient inner cap, at least a portion of which contacts and seals the distal opening of the syringe. Typically, at least the outlet coupling portion that contacts the distal tip opening and forms a fluid-tight seal is made of a flexible and / or resilient material (e.g., elastomeric), which will contact the botulinum toxin formulation during storage and / or use. The outlet coupling portion is also made of a material that minimizes the possibility of undesirable extractables / leachables. The outlet coupling portion may have a coating thereon to further reduce the amount of extractables and / or leachables and increase compatibility with the botulinum toxin formulation.

[0034] Suitable flexible and / or resilient materials for the capping device, particularly the outlet coupling portion, may include elastomeric polymers that do not interfere with the aqueous botulinum toxin formulation and allow for long-term storage. In particular, the portion of the capping device that contacts or is configured to contact the botulinum toxin dosage form, e.g., the outlet coupling portion, should exhibit low extractable / leachable levels during long-term storage of the botulinum toxin formulation. As used herein, the term "elastomeric polymer" or "elastomeric polymeric material" also includes crosslinked thermoset rubbery polymers that are more readily deformable than plastics, but are approved for use with pharmaceutical grade fluids and do not readily exude or out-gas.

[0035] The elastomeric material may be isoprene rubber (IS), butadiene rubber (polybutadiene (BR)), butyl rubber (copolymer of isobutylene and isoprene (IIR)), halogenated butyl rubber (e.g. chlorobutyl rubber (CIIR) and bromobutyl rubber (BIIR)), styrene-butadiene rubber (copolymer of styrene and butadiene (SBR)), or a mixture thereof. For example, the elastomeric material may be butyl rubber or halogenated butyl rubber, in particular bromobutyl rubber or chlorobutyl rubber, or a mixture thereof. The elastomeric material may also be reinforced by an inert mineral. The elastomeric material may also be cured, for example, by organic peroxides, phenolic resins, etc.

[0036] Suitable coatings that may optionally be present on outlet coupling portions made from the aforementioned elastomeric polymeric materials are generally made from materials that do not undesirably interfere with the aqueous botulinum toxin formulation and also exhibit low levels of extractables / leachables. Coatings for use in the present invention also include polypropylene, polyethylene, parylene (e.g., parylene N, parylene C, and parylene HT), cross-linked silicone, or fluoropolymer coatings. Examples of suitable cross-linked silicone coatings include B2-coating (Daiko Seiko) or XSi TM (Becton Dickinson).

[0037] Fluoropolymer coatings may also include fluorinated ethylene-propylene copolymers (e.g., tetrafluoroethylene-hexafluoropropylene copolymer (FEP)), fluorinated ethylene-ethylene copolymers (e.g., ethylene-tetrafluoroethylene copolymer (ETFE), e.g., Flurotec), PVA (copolymer of tetrafluoroethylene (TFE) and perfluoropropyl vinyl ether (PPVE)), tetrafluoroethylene-perfluoroethylene copolymers, polyvinylidene fluoride (PVDF), polyvinyl fluoride (PVF), polytetrafluoroethylene (PTFE), or mixtures thereof. The coating may, for example, be made of ETFE, such as the Flurotec coating.

[0038] The botulinum toxin liquid formulation may be an aqueous formulation, which may include an aqueous suspension, an aqueous dispersion, an aqueous emulsion, or an aqueous solution.

[0039] The botulinum toxin liquid formulations have a botulinum toxin concentration of, for example, about 1 to about 3,000 U / mL, about 10 to about 1,000 U / mL, about 10 to about 400 U / mL, about 10 to about 200 U / mL, about 10 to about 100 U / mL, about 10 to about 70 U / mL, about 20 to about 60 U / mL, or about 40 U / mL.

[0040] The volume of the botulinum toxin liquid formulation can be 10 to 80, 10 to 50, 20 to 80, 20 to 60, 20 to 50, 30 to 80, 40 to 80, 20 to 40, or 25 to 35 units per syringe.

[0041] As used herein, the term "botulinum toxin" refers broadly to any form or type of botulinum toxin. More specifically, the botulinum toxin may be botulinum toxin type A, B, C1, C2, D, E, F, G, or a mixture thereof. For example, the botulinum toxin may be serotype A, B, or C1. The term "botulinum toxin" is also intended to include both the botulinum toxin complex ("toxin complex") and the "neurotoxic component" of the botulinum toxin or complex. As used herein, the term "botulinum toxin complex" refers to a high molecular weight complex that contains a neurotoxic component of approximately 150 kDa and non-toxic proteins of Clostridium botulinum, including hemagglutinin and non-hemagglutinin proteins. An example of the botulinum toxin serotype A complex is Medytoxin (Medytox Corporation).

[0042] As used herein, the term "neurotoxic component" refers to the neurotoxic polypeptide (the "150 kDa" polypeptide, typically in its di-chain form) of the toxin complex, free of any associated non-toxic proteins. A pure neurotoxic component is, for example, Coatoxinj (Medytox). For example, the term "botulinum toxin" refers to the neurotoxic component of a botulinum toxin complex of a given serotype (e.g., serotype A, B, or C1, particularly serotype A). In other words, the botulinum toxin dosage form contained in the pre-filled syringe contains only the neurotoxic component, and is also free of any other proteins of the Clostridium botulinum toxin complex.

[0043] The botulinum toxin includes an active (i.e., biologically active) isoform, homolog, ortholog, paralog, or fragment of a wild-type botulinum toxin that exhibits 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more sequence identity to the amino acid sequence of a neurotoxic component of wild-type botulinum toxin A or serotype A1 botulinum toxin deposited in the GenBank database under Accession No. AAA23262.

[0044] The sequence identity can be calculated by any algorithm suitable for calculating reliable results, for example, using the FASTA algorithm (WR Pearson & DJ Lipman, PNAS 85: 2444-2448, 1988). The sequence identity can also be calculated by comparing two domains, such as two polypeptides, or two LC domains or fragments thereof.

[0045] The botulinum toxins include modified botulinum toxins and recombinant botulinum toxins. The botulinum toxin liquid formulation may also contain other pharma- ceutically acceptable substances, such as salts (e.g., sodium chloride), stabilizing proteins (e.g., albumin, gelatin), sugars (e.g., glucose, fructose, galactose, trehalose, sucrose, and maltose), carbohydrate polymers (e.g., hyaluronic acid and polyvinylpyrrolidone (PVP)), polyols (e.g., sugar alcohols such as mannitol, inositol, lactitol, isomalt, xylitol, erythritol, sorbitol, and glycerol), amino acids, vitamins (e.g., vitamin C), zinc, magnesium, anesthetics (e.g., local anesthetics such as lidocaine), surfactants, tonicity modifiers, etc. As used herein, the term "pharma-ceutically acceptable" refers to a compound or substance that is suitable for contact with mammalian, and particularly human, tissue.

[0046] The botulinum toxin liquid formulation is also free of animal components. The botulinum toxin liquid formulation is also free of albumin. For example, the botulinum toxin liquid formulation includes a botulinum toxin, an amino acid, a surfactant, and a tonicity modifier in water. For example, the botulinum toxin liquid formulation includes 10 to 70 U / ml of botulinum toxin, 0.05 to 0.7 g / L of amino acid, 0.10 to 0.5 g / L of surfactant, and 0.10 to 1.0 g / L of NaCl in water. The botulinum toxin is botulinum toxin type A, B, C1, C2, D, E, F, G, or a mixture thereof. The amino acid may be glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, glutamic acid, a pharma- ceutically acceptable salt thereof, or a mixture thereof. The amino acid may be, for example, methionine, histidine, arginine, a pharma- ceutically acceptable salt thereof, or a mixture thereof. The surfactant may be a non-ionic surfactant. The non-ionic surfactant may be a polysorbate, a poloxamer, or a mixture thereof. The polysorbate may be polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a mixture thereof. The NaCl may be added at a physiologically acceptable concentration, for example, about 0.85 to 0.95 g / L, or about 0.9 g / L.

[0047] The botulinum toxin liquid formulation may further comprise a buffering agent that maintains a pH between about 5.5 and about 7.5. The buffering agent may be citrate, histidine, HEPES, arginine, acetate, phosphate, a salt thereof, or a mixture thereof.

[0048] The pH of the botulinum toxin formulation is also maintained during storage in the range of about 5.5 to about 7.5, about 6.0 to about 7.5, about 6.5 to about 7.5, about 6.1 to about 7.3, or about 6.2 to about 7.2.

[0049] The botulinum toxin liquid formulation exhibited an LD of 75 to 125%, 75 to 120%, or 80 to 125% of the initial value when stored for 2, 4, or 6 months at 25° C., which is an accelerated test condition. 50 It also indicates the titer recovery rate.

[0050] The botulinum toxin liquid formulations also exhibit protease activity recovery rates of 75 to 125%, 75 to 120%, or 80 to 125%, relative to the initial value, when stored for 2, 4, or 6 months at accelerated test conditions of 25°C.

[0051] The botulinum toxin liquid formulation also has a pH change within ±1.5, ±1.0, or ±0.5 of the initial value when stored for 2, 4, or 6 months at 25° C., which is an accelerated test condition.

[0052] One specific example is a botulinum toxin pre-filled syringe dosage form that includes a syringe including a syringe barrel, a plunger rod and a plunger stopper, and a botulinum toxin liquid formulation loaded within the syringe, wherein an increase in the rate at which the botulinum toxin liquid formulation is expelled reduces the amount of increase in force acting on the end of the plunger rod.

[0053] In the above embodiment, the ratio of the length to the inner diameter of the syringe barrel is 10 to 22. The inner diameter of the syringe barrel is 3.5 to 6.5 mm and the length is 60 to 100 mm. The material of the syringe barrel is glass, COC, or silicone-coated COP. The material of the syringe barrel is COC. The silicone coating is a spray-on silicone coating, a bake-on silicone coating, or a polydimethylsiloxane coating. The material of the plunger stopper is isoprene rubber (IS), butadiene rubber (BR), butyl rubber, halogenated butyl rubber, styrene-butadiene rubber, or a mixture thereof. The plunger stopper is uncoated. The volume of the botulinum toxin liquid formulation is 10 to 50 units / syringe. The botulinum toxin liquid formulation is albumin-free. The botulinum toxin liquid formulation is animal component-free. The botulinum toxin liquid formulation also includes a botulinum toxin, an amino acid, a surfactant, and an isotonicity agent. The amino acid is methionine. The surfactant is polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or poloxamer. The botulinum toxin liquid formulation also includes a buffer that maintains a pH of 5.5 to 7.5. The buffer is citrate, histidine, HEPES, arginine, acetate, phosphate, a salt thereof, or a mixture thereof. The botulinum toxin liquid formulation has an LD of 80 to 125% of the initial value when stored for 2, 4, or 6 months at 25° C., which is an accelerated test condition. 50 The botulinum toxin liquid formulation also exhibits a protease activity recovery rate of 80 to 125% compared to the initial value when stored for 2, 4 or 6 months at 25°C, which is an accelerated test condition. The botulinum toxin liquid formulation also exhibits a pH fluctuation of within ±1.0 compared to the initial value when stored for 2, 4 or 6 months at 25°C, which is an accelerated test condition.

[0054] Another specific example is a botulinum toxin pre-filled syringe dosage form that includes a syringe including a syringe barrel, a plunger rod, and a plunger stopper, and a botulinum toxin liquid formulation loaded into the syringe, wherein the material of the syringe barrel is glass, COC, or silicone-coated COP.

[0055] In the above embodiment, the material of the syringe barrel is COC. The silicone coating is a spray-on silicone coating, a bake-on silicone coating, or a polydimethylsiloxane coating. The material of the plunger stopper is isoprene rubber (IS), butadiene rubber (BR), butyl rubber, halogenated butyl rubber, styrene-butadiene rubber, or a mixture thereof. The plunger stopper is uncoated. An increase in the rate at which the botulinum toxin liquid formulation is expelled reduces an increase in the force acting on the end of the plunger rod. The ratio of the length to the inner diameter of the syringe barrel is 10 to 22. The inner diameter of the syringe barrel is 3.5 to 6.5 mm, and the length is 60 to 100 mm. The volume of the botulinum toxin liquid formulation is 10 to 50 units / syringe. The botulinum toxin liquid formulation is albumin-free. The botulinum toxin liquid formulation is animal component-free. The botulinum toxin liquid formulation also includes a botulinum toxin, an amino acid, a surfactant, and an isotonicity agent. The amino acid is methionine. The surfactant is polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or poloxamer. The botulinum toxin liquid formulation also includes a buffer that maintains a pH of 5.5 to 7.5. The buffer is citrate, histidine, HEPES, arginine, acetate, phosphate, a salt thereof, or a mixture thereof. The botulinum toxin liquid formulation has an LD of 80 to 125% of the initial value when stored for 2, 4, or 6 months at 25° C., which is an accelerated test condition. 50The botulinum toxin liquid formulation also exhibits a protease activity recovery rate of 80 to 125% compared to the initial value when stored for 2, 4 or 6 months at 25°C, which is an accelerated test condition. The botulinum toxin liquid formulation also exhibits a pH fluctuation of within ±1.0 compared to the initial value when stored for 2, 4 or 6 months at 25°C, which is an accelerated test condition.

[0056] Another embodiment includes a syringe including a syringe barrel, a plunger rod, and a plunger stopper, and a botulinum toxin liquid formulation loaded into the syringe, the botulinum toxin liquid formulation also being in the form of a botulinum toxin pre-filled syringe that does not contain albumin.

[0057] In the above embodiment, the present invention also includes a syringe including a syringe barrel, a plunger rod, and a plunger stopper, and a botulinum toxin liquid formulation loaded in the syringe, the botulinum toxin liquid formulation being free of animal components. The botulinum toxin liquid formulation also includes a botulinum toxin, an amino acid, a surfactant, and an isotonicity agent. The amino acid is methionine. The surfactant is polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a poloxamer. The botulinum toxin liquid formulation also includes a buffering agent that maintains a pH of 5.5 to 7.5. The buffering agent is citrate, histidine, HEPES, arginine, acetate, phosphate, a salt thereof, or a mixture thereof. The volume of the botulinum toxin liquid formulation is 10 to 50 units per syringe. The syringe barrel may be made of glass, COC, or silicone-coated COP. The syringe barrel may be made of COC. The silicone coating may be a spray-on silicone coating, a bake-on silicone coating, or a polydimethylsiloxane coating. The plunger stopper may be made of isoprene rubber (IS), butadiene rubber (BR), butyl rubber, halogenated butyl rubber, styrene-butadiene rubber, or a mixture thereof. The plunger stopper may be uncoated. The botulinum toxin pre-filled syringe dosage form may reduce the increase in force acting on the end of the plunger rod due to an increase in the rate at which the botulinum toxin liquid formulation is expelled. The ratio of the length to the inner diameter of the syringe barrel may be 10 to 22. The inner diameter of the syringe barrel may be 3.5 to 6.5 mm, and the length may be 60 to 100 mm. The liquid botulinum toxin formulation exhibited an LD of 80 to 125% of the initial value when stored for 2, 4, or 6 months at 25° C., which is an accelerated test condition. 50The botulinum toxin liquid formulation also exhibits a protease activity recovery rate of 80 to 125% compared to the initial value when stored for 2, 4 or 6 months at 25°C, which is an accelerated test condition. The botulinum toxin liquid formulation also exhibits a pH fluctuation of within ±1.0 compared to the initial value when stored for 2, 4 or 6 months at 25°C, which is an accelerated test condition. Effect of the Invention

[0058] According to one embodiment of the present invention, the botulinum toxin pre-filled syringe formulation exhibits an LD 200 mg / kg / day or ... 50 The potency, botulinum toxin endopeptidase potency and pH are also maintained stable. Additionally, the botulinum toxin pre-filled syringe formulation allows for easy delivery rate control. [Brief description of the drawings]

[0059] [Figure 1] FIG. 1 illustrates an example of a pre-filled syringe including a needle. [Diagram 2] FIG. 1 illustrates an example of a pre-filled syringe including a tip cap. [Diagram 3] 1A-1C illustrate examples of pre-filled syringes including a needle assembly and a needle shield. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0060] The present invention will be described in more detail below through examples. However, these examples are for illustrative purposes only and the scope of the present invention is not limited to these examples.

[0061] Example 1: Stability of Botulinum Toxin Prefilled Liquid Syringe Dosage Forms: Syringes with Barrels Made of COC or COP Materials 1. Production of Botulinum Toxin Prefilled Liquid Formulation In this example, a liquid botulinum toxin formulation was filled into a syringe for use with highly viscous drugs (HVD) (hereinafter also referred to as an "HVD syringe"), and the stability over storage time was measured. The HVD syringe had an inner diameter of 5.00 mm, an outer diameter of 9.40 mm, a barrel length of 80.0 mm, and a volume of the liquid formulation filled therein of 0.8 mL. For reference, an example of a conventionally known syringe is the TopPac syringe manufactured by SCHOTT. TM The syringe has an inner diameter of 6.50 mm, an outer diameter of 9.40 mm, a barrel length of 64.5 mm, and a volume filled with liquid formulation of 1 mL. TM Compared to a syringe, it has a smaller inner diameter but is longer. TM The syringe includes a barrel, a plunger, a plunger rod, and a tip cap, the barrel is made of COC material and has a luer lock. The barrel inner surface is siliconized with a reactive silicone compound and crosslinked by curing. The tip cap is made of rubber (Datwyler). The HVD syringe includes a COC material made of TOPAS 6015 material and has improved heat resistance.

[0062] The stability of the HVD syringe was also measured depending on the barrel material, the plunger stopper material, and the material used for coating thereof, as well as the composition of the aqueous liquid botulinum toxin formulation filled in the barrel. Here, the syringe includes a plastic syringe barrel, a capping device, and a plunger rod assembly. The barrel includes a proximal end and a distal end, and a generally cylindrical wall extending therebetween to form a barrel lumen. The barrel has a distally protruding tip extending therethrough and having a fluid passageway communicating with the barrel lumen, and the generally cylindrical wall has an interior surface selectively coated with a barrier layer. In this embodiment, the interior surface of the wall is coated with silicone, i.e., the barrier layer is a silicone layer. Also, in this embodiment, the barrel has a COC material or a COP material.

[0063] The capping device has an outlet coupling part that sealingly couples with and closes the open outlet of the distal end of the barrel. The capping device for the distal end of the barrel is composed of a cap and a rubber tip cap, the cap being made of a polycarbonate material and the rubber tip cap being made of the same material as the plunger. Here, the rubber tip cap corresponds to the outlet coupling part. The outlet coupling part is made of an elastomeric polymeric material having a selective coating on its surface. The outlet coupling part and the capping device are coupled in a luer lock form.

[0064] The plunger rod assembly extends into the proximal end of the barrel and includes a plunger stopper in sliding fluid-tight engagement with the cylindrical wall of the barrel lumen, the stopper being fabricated from an elastomeric polymeric material and optionally having a coating on at least a portion of the stopper that contacts an aqueous liquid botulinum toxin formulation during storage and / or injection. In this embodiment, the stopper material is bromobutyl rubber (BIIR) or chlorobutyl rubber (CIIR), which is optionally coated with Teflon.

[0065] Table 1 shows the botulinum toxin pre-filled syringe formulations used in this example, which were pre-filled with liquid botulinum toxin formulations in water. [Table 1]

[0066] In Table 1, COC stands for cyclic olefin copolymer, and COP stands for cyclic olefin polymer. BIIR and CIIR stand for bromochlorobutyl rubber (IIR) and chlorobutyl rubber (IIR), respectively. The material of the plunger stopper indicates the material of the rubber part. Here, butyl rubber (IRR) is a copolymer of isobutylene and isoprene. Teflon (registered trademark) coating indicates that the BIIR surface or CIIR surface is coated with FluroTec (R) film. L-Met, T20, NaCl, and toxin indicate the amount of L-methionine, polysorbate 20, NaCl, and botulinum toxin type A component dissolved in water, i.e., water for injection.

[0067] The formulation is inserted into the lumen of the barrel by fitting the plunger rod assembly, and the stopper of the plunger seals the liquid formulation while contacting the liquid formulation. The outlet coupling portion at the distal end of the barrel is sealingly coupled to the capping device to close the open outlet. The syringe and the capping device are integrated, and the capping device is removed immediately before use. At this time, the liquid comes into contact with the rubber tip cap inside the capping device. That is, the pre-filled syringe of the botulinum liquid formulation does not have a needle attached to it, but is attached to a capping device. As a result, the materials of the syringe barrel were selected according to COC and COP, the plunger stoppers were selected according to bromobutyl rubber, chlorobutyl rubber, and their Teflon (registered trademark) coating, and the concentrations of methionine and polysorbate 20 were varied in four types of syringes, to prepare a total of eight types of pre-filled syringe botulinum liquid formulations.

[0068] 2. Long-term stability testing of prefilled syringe dosage forms (1) Potency test The eight prepared formulations, i.e., formulations A to H, were stored at 4°C in a stability specimen storage room, and the median lethal dose (LD ) of mice was measured at 0, 3, 6, 9, 12, 18, and 24 months. 50 ) was measured.

[0069] The liquid samples of the eight dosage forms were serially diluted and then administered intraperitoneally to 4-week-old female ICR mice weighing 17 to 22 g. After administration, the lethality rate for each diluted sample was observed for 3 days, and the median lethal dose was calculated using the statistical program PROBIT. The median lethal dose at 0 months was set to 100%, and the tendency of the median lethal dose obtained at each time point to change was shown in %. Table 2 shows the median lethal dose for dosage forms A, B, C, D, E, F, G, and H according to the storage period. [Table 2]

[0070] As shown in Table 2, at 24 months, the recovered lethal dose values ​​of formulations A through F were measured to be 73% or more, while the recovered lethal dose values ​​of formulations G and H were not measured from 9 months. This indicates that the botulinum toxin is stable for 24 months when the barrel is made of COC material and is silicone coated, regardless of whether the plunger stopper material is BIIR or CIIR, or whether the surface of the plunger stopper is Teflon (registered trademark) coated or not. On the other hand, when the barrel material is COP, the recovered titer has not been measured in the syringe from 9 months.

[0071] (2) Botulinum toxin endopeptidase titer analysis The eight prefilled syringe formulations A through H described above were stored in a stability chamber and the activity of BoNTA / LC was measured at 0, 3, 6, 9, 12, 18, and 24 months. 100 μl of SNAP25 (self-produced) fragment consisting of a sequence of about 70 amino acids was added to each well of a 96-well plate and incubated at 2 to 8° C. for 16 hours. The SNAP25 fragment contains a sequence of 10 or more consecutive amino acids including the cleavage site between amino acids 197 and 198.

[0072] A BONTA sample was prepared as a standard sample for which a quantitative curve can be obtained using a BoNTA standard (Innotox (Medytox)). Test samples were prepared by diluting BONTA in a HEPES solution (Sigma) so that the results of the samples of formulations A to H were included in the quantitative curve range. The standard sample and test samples A to H were each placed in a well containing SNAP25 and reacted at room temperature for 1 hour. Next, anti-SNAP25 polyclonal antibody (self-produced) was added to each well and reacted at room temperature for 1 hour. After reacting the secondary antibody bound to HRP for 1 hour at room temperature, a coloring agent 3,3',5,5'-tetramethylbenzidine (TMB) was added and incubated to perform a coloring reaction.

[0073] The absorbance at 450 nm was measured using a plate reader (TECAN microplate reader) to quantify the degree of color development due to BoNT / LC activity, and a quantitative curve was created using the absorbance values ​​of the standard sample. The absorbance values ​​of samples A to H were substituted into the quantitative curve to calculate the BoNT / LC activity in each sample. The BoNT / LC activity at 0 months was set to 100%, and the tendency for the BoNT / LC activity obtained at each time point to change was shown in %. Table 3 shows the endopeptidase activity of BoNTA contained in dosage forms A to H according to the storage period. [Table 3]

[0074] As shown in Table 3, at 24 months, the recovered titers of dosage forms A to F were maintained at 111 to 141% compared to the initial values, whereas the recovered titers of dosage forms G and H had not been measured since the 9th month.

[0075] (3)pH stability At 0, 3, 6, 9, 12, 18, and 24 months, eight prefilled syringes of dosage forms A through H were filled into 15 mL single-use tubes to a volume of at least 3 mL, and the pH of each sample was measured using a pH meter (Mettler Toledo). Table 4 shows the change in pH of dosage forms A through H over storage time. [Table 4]

[0076] As shown in Table 4, the pH of Formulations A through F was maintained at 6.8 to 7.4 at 24 months, while Formulations G and H were maintained at pH 5.3 to 5.9 at 6 months, when activity was measured.

[0077] Example 2: Stability of Botulinum Toxin Prefilled Liquid Syringe Dosage Forms: Syringes with Barrels Made of Glass or COP Material 1. Production of Botulinum Toxin Prefilled Liquid Formulation The botulinum toxin prefilled liquid formulations in Table 5 below were prepared using a HVD syringe as described in Table 1, with an inner diameter of 5.00 mm, an outer diameter of 9.40 mm, a barrel length of 80.0 mm, and a volume of 0.8 mL filled with the liquid formulation. [Table 5]

[0078] In Table 5, the barrels of dosage forms I and J are products of POONGLIM Pharmatech Inc. (catalog number: Art.69, Korea), the barrels of dosage forms K and L are products of SiO2 Medical Products Inc. (catalog number: 850009-100-04, USA), and the barrels of dosage forms M and N are products of Terumo Corporation (catalog number: PJ-B1L9BFTF1, Japan). The botulinum toxin is BTX1301 (API arrangement number) of Medytox Co., Ltd. and BoNTA. In Table 5, COC indicates cyclic olefin copolymer, and COP indicates cyclic olefin polymer. BIIR and CIIR indicate bromobutyl rubber (IIR) and chlorobutyl rubber (IIR), respectively. Here, butyl rubber (IRR) is a copolymer of isobutylene and isoprene. L-Met, T20, NaCl, and Toxin indicate the amounts of L-methionine, polysorbate 20, NaCl, and botulinum toxin type A components dissolved in the water. The liquids containing these components had a pH between 6.0 and 7.0.

[0079] The formulation is fitted into the lumen of the barrel with the plunger rod assembly fitted so that the stopper of the plunger contacts the liquid formulation and seals the liquid formulation. Also, the outlet fitting portion of the distal end of the barrel is fitted in a sealing manner with the capping device to close the open outlet. That is, the pre-filled syringe of botulinum liquid formulation is fitted to the capping device without the injection needle.

[0080] As a result, the materials of the syringe barrel were selected from glass and COP, and the plunger stopper was selected from bromobutyl rubber and i-coating. The concentrations of methionine and polysorbate 20 in the three types of syringes were varied, and a total of six types of pre-filled syringe botulinum liquid formulations I to N were prepared.

[0081] 2. Stability Testing of Prefilled Syringe Dosage Forms I to N (1) Potency test The six prepared dosage forms, i.e., dosage forms I to N, were stored in a thermohygrostat (Binder) at 25°C for the accelerated test conditions. For the long-term storage test, the samples were stored in a stability specimen storage room at 4°C. After storage, the median lethal dose (LD) of mice was measured at 0, 2, 3, 4, and 6 months. 50 ) was measured.

[0082] The liquid samples of the six dosage forms were serially diluted and then administered intraperitoneally to 4-week-old female ICR mice weighing 17 to 22 g. After administration, the lethality rate for each diluted sample was observed for 3 days, and the median lethal dose was calculated using the statistical program PROBIT. The median lethal dose at 0 months was set to 100%, and the tendency of the median lethal dose obtained at each time point to change was shown in %. Table 6 shows the median lethal dose for dosage forms I, J, K, L, M, and N according to storage period. [Table 6]

[0083] As shown in Table 6, at 6 months, potencies of the six prefilled syringe dosage forms I through N were maintained in the range of 86 to 108% of the initial potency.

[0084] (2) Botulinum toxin endopeptidase titer analysis The six prefilled syringes, Forms I through N, were stored in a stability chamber and the activity of BoNTA / LC was measured at 0, 2, 3, 4, and 6 months.

[0085] 100 μl of SNAP25 (self-produced) fragment consisting of a sequence of about 70 amino acids was added to each well of a 96-well plate and incubated at 2 to 8° C. for 16 hours. The SNAP25 fragment contains a sequence of 10 or more consecutive amino acids including the cleavage site between amino acids 197 and 198.

[0086] A BoNTA standard (Innotox (Medytox)) was used to prepare a BONTA sample, which is a standard sample from which a quantitative curve can be obtained. Test samples were prepared by diluting the BoNTA in a HEPES solution (Sigma) so that the results of the samples in formulations A to H were within the quantitative curve range. The standard sample and test samples A to H were each placed in a well containing SNAP25 and reacted at room temperature for 1 hour. Next, anti-SNAP25 polyclonal antibody (self-produced) was added to each well and reacted at room temperature for 1 hour. After reacting the secondary antibody bound to HRP for 1 hour at room temperature, a color reagent 3,3',5,5'-tetramethylbenzidine (TMB) was added and incubated to perform a color reaction.

[0087] The absorbance was measured at 450 nm using a plate reader (TECAN), and the degree of color development due to BoNT / LC activity was quantified. A quantitative curve was then obtained using the absorbance values ​​of the standard samples. The absorbance values ​​of samples I to N were substituted into the quantitative curve to calculate the BoNT / LC activity of each sample. The BoNT / LC activity at 0 months was set to 100%, and the tendency of change in BoNT / LC activity obtained at each time point was shown in %. Table 7 shows the endopeptidase activity of BoNTA contained in dosage forms I to N according to the storage period. [Table 7] As shown in Table 7, at 6 months, the recovered titers of formulations I to N were maintained at 53 to 94% of the initial values.

[0088] (3)pH stability At a certain time point for six pre-filled syringes, dosage forms I to N, each sample was placed in a 15 mL single-use tube to a volume of 3 mL or more, and the pH of each sample was measured using a pH meter (Mettler Toledo). Table 8 shows the pH change of dosage forms I to N depending on the storage period. The time points were 0, 2, 4, and 6 months for the accelerated condition experiment, and 0, 3, and 6 months for the long-term storage experiment. [Table 8] As shown in Table 8, by month 6, the pH of Formulations I through N was maintained between 7.1 and 7.9.

[0089] Example 3: Stability of Botulinum Toxin Prefilled Liquid Syringe Dosage Forms: Effect of Albumin 1. Production of Botulinum Toxin Prefilled Liquid Formulation As shown in Table 9 below, a dosage form O containing human serum albumin but not containing L-Met and polysorbate 20, and a dosage form P not containing human serum albumin but containing L-Met and polysorbate 20 were prepared. In Table 9, the solvent was water, the toxin was a BoNTA type, and a product of Medytox was used. The O and P dosage forms were loaded into the HVD syringe, which was the B syringe in Table 1, with a barrel made of COC material and a plunger made of siliconized BIIR. [Table 9]

[0090] 2. Potency test: LD 50 (Accelerated testing) The syringe formulations, in which the O and P formulation samples were pre-filled in each syringe, were stored in a stability chamber, and the median lethal dose (LD) of mice was measured at 0, 2, 3, 7, 14, 28, and 56 days. 50 ) was measured.

[0091] Samples 1 and 2 were serially diluted with water and then administered intraperitoneally to 4-week-old female ICR mice weighing 17 to 22 g. After administration, the lethality rate for each diluted sample was observed for 3 days, and the median lethal dose was calculated using the statistical program PROBIT. The median lethal dose at 0 months was set to 100%, and the tendency of the median lethal dose obtained at each time point to change was shown in %. The shelf life was calculated using the Arrhenius equation (https: / / met.uk.com / medical-device-packaging-testing / 4a-medical-accelerated-ageing), which shows the relationship between the reaction rate constant and temperature.

[0092] Table 10 shows the storage stability of the albumin-containing dosage form O and the albumin-free dosage form P in terms of LD 50 This is a table showing the values. [Table 10]

[0093] In Table 10, STD is the standard sample, Medytoxin inj (Medytox Co., Ltd.), normalization indicates the relative potency when the data value on day 0 is set to 100, and N / A indicates that the test result was LD in the previous cycle. 50 The value was very low at the 20% level, so there was no point in proceeding with the test, and so it was not carried out. For the three formulations prepared, i.e., standard sample (STD), O and P formulations, the albumin formulation O lost its recovery titer on the 28th day of the test under accelerated conditions of 56 days, i.e., about 2 months, while the non-albumin formulation P maintained a recovery titer of 86% on the 28th day and 52% on the 56th day. The accelerated conditions were performed by storing the samples at 40°C and collecting samples at 0, 2, 5, 7, 14, 28 and 56 days.

[0094] 3. Injection force test Albumin dosage form O and albumin-free dosage form P described in Table 9 were loaded into a 1 ml SHOTT TopPac syringe described in Section 1 of Example 1 and an HVD syringe (i.e., syringe B in Table 1), respectively, to prepare a total of four pre-loaded syringe botulinum liquid formulations Q, R, S, and T, i.e., four dosage forms.

[0095] The plunger injection force of the four dosage forms was measured using a MultiTest 2.5 (Mecmesin, UK) tension and compression device as a function of the plunger movement speed of the syringe. The injection force is the average injection force.

[0096] Specifically, a 30G needle was attached to each of the syringes containing the four dosage forms. The syringes were then fixed to the jig of a tension compression machine, and the plunger rod was adjusted to be in the center of the load cell of the machine. The jig is the syringe fixing part of the machine.

[0097] After setting the measurement distance considering the length of each syringe, the speed value was input by the program built into the device, the start button was pressed, and the device was operated to carry out the test. The measurement distance was set so that the contents of the HVD syringe were filled to a height of about 40 mm when filled with 1 mL because of the small inner diameter and long length, and the contents of the TopPac syringe were filled to a height of about 30 mm when filled with 1 mL, and the measurement distance was set so that the plunger was pushed from 0 to 35 mm for the HVD syringe and from 0 to 25 mm for the TopPac syringe, with a margin of 5 mm for safety when measuring the injection force. The specimens for which the measurement was completed were removed from the jig, and the measurement was repeated three times for each specimen to obtain the injection force results. Table 11 shows the injection force according to the plunger movement speed. [Table 11]

[0098] As shown in Table 11, the injection force of the dosage forms R and T containing the HVD syringe was the same or stronger than that of the dosage forms Q and S containing the TopPac syringe at low plunger movement speeds of 10 and 50 mm / min, but was weaker than that of the dosage forms Q and S containing the TopPac syringe at high plunger movement speeds of 100 and 200 mm / min. This indicates that the plunger compression force of the dosage forms R and T containing the HVD syringe is stronger at slow plunger movement speeds and weaker at fast plunger movement speeds than that of the dosage forms Q and S containing the TopPac syringe. Therefore, the dosage forms containing the HVD syringe allow fine manipulation at low speeds and can be injected more easily at high speeds.

Claims

1. a syringe including a syringe barrel, a plunger rod, and a plunger stopper; and A liquid formulation of botulinum toxin is contained in the syringe, A botulinum toxin pre-filled syringe dosage form, wherein an increase in the rate at which the botulinum toxin liquid formulation is expelled reduces the amount of increase in force acting on the end of the plunger rod.

2. 2. The dosage form of claim 1, wherein the ratio of length to inner diameter of the syringe barrel is from 10 to 22.

3. 3. The dosage form of claim 2, wherein the syringe barrel has an inner diameter of 3.5 to 6.5 mm and a length of 60 to 100 mm.

4. 10. The dosage form of claim 1, wherein the syringe barrel material is glass, COC, or COP.

5. 2. The dosage form of claim 1, wherein the plunger stopper is made of isoprene rubber (IS), butadiene rubber (BR), butyl rubber, halogenated butyl rubber, styrene-butadiene rubber, or a mixture thereof.

6. 10. The dosage form of claim 1, wherein the liquid botulinum toxin formulation does not contain albumin.

7. 10. The dosage form of claim 1, wherein the liquid botulinum toxin formulation is free of animal components.

8. 8. The dosage form of claim 6 or 7, wherein the botulinum toxin liquid formulation comprises a botulinum toxin, an amino acid, a surfactant, and an isotonicity agent.

9. 9. The dosage form of claim 8, wherein the amino acid is methionine.

10. 9. The dosage form of claim 8, wherein the surfactant is polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 or a poloxamer.

11. 9. The dosage form of claim 6 or 8, wherein the liquid botulinum toxin formulation further comprises a buffering agent that maintains a pH between 5.5 and 7.

5.

12. 12. The dosage form of claim 11, wherein the buffering agent is citrate, histidine, HEPES, arginine, acetate, phosphate, a salt thereof, or a mixture thereof.

13. The botulinum toxin liquid preparation exhibited an LD of 80 to 125% of the initial value when stored for 2, 4, or 6 months at 25° C., which is an accelerated test condition. ５０ 9. A dosage form according to any one of claims 1 to 8, exhibiting a titer recovery.

14. The liquid botulinum toxin preparation according to any one of claims 1 to 8, wherein the liquid botulinum toxin preparation exhibits a protease activity recovery rate of 80 to 125% compared to the initial value when stored for 2, 4 or 6 months at 25°C, which is an accelerated test condition.

15. The liquid botulinum toxin preparation according to any one of claims 1 to 8, wherein the liquid botulinum toxin preparation has a pH change of within ±1.0 compared to the initial value when stored for 2, 4 or 6 months at 25°C under accelerated test conditions.

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