A botulinum toxin pre-filled syringe dosage form that is easy to control the discharge speed and is stable

Abstract

The present invention provides a pre-filled syringe dosage form of botulinum toxin that is easy to control the discharge speed and is stable.

Description

Technical Field

[0001] The present invention relates to a prefilled syringe dosage form of botulinum toxin that is easy to control the discharge speed and is stable. Background Art

[0002] Botulinum toxin (BoNT) is one of the most toxic known toxins and acts by blocking the release of acetylcholine from peripheral cholinergic neurons. Botulinum toxin is being used to reduce overactive muscles and exocrine glands by administering very small doses to an individual. For example, botulinum toxin is used not only for treating neuromuscular diseases and diseases of overactive exocrine glands, but also for cosmetic purposes.

[0003] Botulinum toxin is inherently unstable. In particular, it is known to be highly unstable at alkaline pH values and heat-labile. The prefilled syringe format is a form of drug administration that overcomes these drawbacks and has become increasingly popular in recent years as a drug delivery device. However, when a protein is used as the active ingredient, the limited stability of the protein makes it a particularly difficult task for formulation scientists to use the prefilled syringe format. In particular, this applies to very dilute aqueous solutions of botulinum toxin.

[0004] To increase the stability of botulinum toxin compositions in pharmacy, stabilizing proteins such as human serum albumin (HSA) are often added. In addition, non-protein stabilizers such as surfactants, polyvinylpyrrolidone (PVP), disaccharides, polyols, etc. are known.

[0005] However, despite the above background art, there is still a need for a prefilled syringe dosage form of botulinum toxin that has high storage stability, is easy to control the discharge speed, and is stable. Summary of the Invention

[0006] Technical Problem

[0007] One aspect of the present invention provides a prefilled syringe dosage form of botulinum toxin that is easy to control the discharge speed and is stable.

[0008] Technical Solution

[0009] One aspect of the present invention provides a prefilled syringe dosage form of botulinum toxin, which includes: a syringe including a syringe barrel, a plunger rod, and a plunger stopper; and a liquid preparation of botulinum toxin filled in the syringe.

[0010] In the dosage form, as the discharge speed of the liquid preparation of botulinum toxin increases, the increase amount of the force acting on the end of the plunger rod can be reduced.

[0011] As used herein, the term "prefilled syringe" refers to a sealed or sealable syringe that can be used to contain, store, and / or deliver a liquid dosage form and has a partially or fully enclosed space. The syringe refers to a closed or sealed container made of plastic such as an organic polymer, or partially or mainly made of plastic.

[0012] The prefilled syringe has two openings that are sealed to prevent leakage of the contents. In the prefilled syringe, the proximal end is sealed by a plunger stopper, and the distal end is sealed by a capping device.

[0013] The barrel may include a proximal end and a distal end, and a generally cylindrical wall that extends between the proximal end and the distal end and forms a barrel cavity. The barrel may have a tip that projects distally, wherein a fluid passage extends through the tip and communicates with the barrel cavity. The proximal end and the distal end have respective proximal open outlets and distal open outlets. The tip may be made of the same material as the rest of the barrel.

[0014] After filling, the barrel is removably capped by a capping device (e.g., a "tip cap" such as removed and replaced with a needle before use, or a sealing tool such as a needle shield in the case of a prefilled syringe with a detachable or permanent needle) that seals the distal end of the syringe in a sealed manner, and is sealed at the proximal end by a plunger or any other tool that is fluid-tightly combined with the inner wall of the barrel to receive the fluid. To use the prefilled syringe, remove the tip cap, needle shield, or other type of capping device, optionally attach a needle (if not already attached), and advance the plunger tip or piston within the barrel to inject the contents within the barrel, i.e., the botulinum toxin preparation, into a patient.

[0015] The inner surface of the barrel may or may not have a coating. The inner surface of the barrel may be coated with, for example, a barrier layer (hereinafter also referred to as a "lubricant layer") for lubrication purposes. The lubricant layer should not only provide high lubricity to allow the plunger to slide easily over 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-containing lubricant layer. The inner surface of the wall may be coated with silicone. That is, the barrier layer may be a silicone layer.

[0016] The silicone coating may be prepared by a silicification method selected from silicone oil-based methods (e.g., spray-on silicification or baked-on silicification) and deposition methods (e.g., plasma-enhanced chemical vapor deposition (PECVD)). The silicone coating may be formed by, for example, spray-on silicification or baked-on silicification coating. The silicone coating may be a polydimethylsiloxane coating.

[0017] In a spray silanization method, for example, silicone oil (e.g., DOW with a viscosity of 1000 cSt) can be sprayed into a syringe barrel using a diving or static nozzle to produce a thin layer of silicone oil. The baking silanization method can include: applying the silicone oil as an emulsion, such as DOW 360 silanization emulsion, to the barrel and then baking it on the plastic surface at a specific temperature for a specific time. Compared with the spray silanization method, the baking silanization method can produce fewer silicone oil particles invisible to the naked eye and visible silicone oil particles. The material of the syringe barrel can include plastic materials. The material can be glass, cyclo olefin copolymer, cyclo olefin polymer, or a mixture thereof. The COP can be coated with silicone on its surface. COC can be polymerized from cyclic monomers such as norbornene and ethane, while COP can be formed by hydrogenation after ring-opening metathesis of cyclic monomers. COC, COP, and the mixture materials of COP and COC exhibit many preferred properties, including high transparency, low density, significant moisture-proof ability, and tolerance to aqueous and polar organic media. Specific examples include

[0018] COC and Daikyo Crystal

[0019] The tip of the barrel can be integrally formed with the barrel. For example, the tip can be integrally molded with the barrel. The barrel can include a luer lock tip or a luer slip tip integrally formed. The tip can include an integral channel that axially extends through the tip and communicates with the chamber to dispense the contents of the barrel. The tip can have a generally frustoconical shape that converges from the distal outlet end of the barrel to the outlet end of the tip.

[0020] The barrel can have an inner diameter adjusted to accommodate a fill volume of, for example, 0.5 ml, 1.0 ml, 1.5 ml, or 2.0 ml. The barrel can have scale marks indicating the fluid volume in the syringe. Additionally, the barrel can include a flanged interface. The design of the flange can, for example, conform to ISO11040. The flanged interface can be compatible with an optional handle present.

[0021] The ratio of the length of the syringe barrel to the inner diameter can be 10 to 22, 12 to 20, or 14 to 16.

[0022] The inner diameter of the syringe barrel can be 3 mm to 7 mm, 3.5 mm to 6.5 mm, 4 mm to 6 mm, or 4.5 mm to 5.5 mm, and the length can be 30 mm to 130 mm, 50 mm to 110 mm, 60 mm to 100 mm, or 70 mm to 90 mm. The inner diameter of the syringe barrel can be 3.5 mm to 6.5 mm, and the length can be 60 mm to 100 mm. Additionally, the inner diameter of the syringe barrel can be 3 mm to 7 mm, and the length can be 30 mm to 130 mm. Additionally, the inner diameter of the syringe barrel can be 4 mm to 6 mm, and the length can be 50 mm to 110 mm. Furthermore, the inner diameter of the syringe barrel can be 4.5 mm to 5.5 mm, and the length can be 70 mm to 90 mm.

[0023] The plunger rod can be combined with the plunger plug to form a plunger rod and plunger plug assembly. The assembly can extend into the proximal end of the barrel. The assembly can include a rod that is slidably and fluid-tightly engaged with the cylindrical wall of the barrel cavity and has a plunger plug at its tip. The assembly forms a proximal seal and a dynamic seal, and the dynamic seal can extrude the botulinum toxin liquid formulation. The plug contacts the botulinum toxin liquid formulation during storage and / or administration.

[0024] The plug can be made of an elastomeric material. Optionally, the plug has a coating on at least a portion of it, and at least a portion of the plug contacts the botulinum toxin liquid formulation during storage and / or injection.

[0025] The elastomer can be isoprene rubber (IS), polybutadiene (BR), butyl rubber (a copolymer of isobutene and isoprene, IIR), halogenated butyl rubber (e.g., chlorinated butyl rubber, CIIR; and brominated butyl rubber, BIIR), styrene-butadiene rubber (a copolymer of styrene and butadiene, SBR), or a mixture thereof. In a specific embodiment, the plug material can be butyl rubber, halogenated butyl rubber, or a mixture thereof. In a specific embodiment, the plug material can be brominated butyl rubber or chlorinated butyl rubber. The elastomer can also be reinforced with inert minerals. Additionally, the elastomer, for example, can be cured by organic peroxides, phenolic resins, etc.

[0026] The plug can have a coating or not. The coating can generally be applied at least to the seal surface, which includes the surface portion of the plunger plug that faces the barrel cavity and contacts the botulinum toxin dosage form during storage and / or use. The coating can provide good lubricity while minimizing the interaction between the plunger plug and the botulinum toxin liquid formulation.

[0027] Suitable coatings for the plunger plug can generally be made of materials that do not preferably interfere with the botulinum toxin formulation and exhibit low levels of extractables / leachables. The coating can include polypropylene, polyethylene, parylene (e.g., parylene N, parylene C, and parylene HT), cross-linked silicone, fluoropolymer, or mixtures thereof. Examples of cross-linked silicone coatings include B2-coating (Daikyo Seiko) or XSiTM (Becton Dickinson).

[0028] The fluoropolymer coating can 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., ), 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 mixtures thereof. For example, the coating is made of ETFE, in particular, coating. In a specific embodiment, the plunger plug can be uncoated.

[0029] The design of the plunger plug is not particularly limited and can be a nested or bagged plug. Additionally, the interface for the rod can be formed with threads so that the rod can be installed after sterilization. Optionally, the interface for the rod can be designed as a snap-on design. The rod, such as the plunger plug, is generally designed to withstand sterilization, but is not limited in any particular way. The rod can be made of a plastic material, e.g., ethylene vinyl acetate (EVA) copolymer or polypropylene.

[0030] Figure 1 An example of a prefilled syringe including a needle is shown. The prefilled syringe includes a barrel 10, a plunger 80 including a plunger rod 20 and a plunger plug 30, a needle 50, and a botulinum toxin liquid formulation 40 included in the cavity of the barrel 10.

[0031] The prefilled syringe can include a "capping device". The capping device refers to any tool for closing and sealing the distal open outlet end of the syringe. As used herein, the term "open outlet end" or "distal open outlet end" refers to any distal open end of the syringe that is in fluid communication with the barrel cavity. The capping device can have a channel including a closed end and an open end, and the size of the channel is generally designed to accommodate and effectively seal the open outlet end of the syringe to prevent leakage.

[0032] For a prefilled syringe without a preinstalled needle, the capping device is a capping tool commonly known as a "tip cap". The tip cap forms a fluid-tight seal with the syringe tip to effectively enclose the syringe barrel and prevent leakage of the contents of the syringe barrel. The tip cap is typically removably coupled to the syringe tip or a luer collar. The luer collar surrounds the upper portion of the syringe barrel (e.g., the syringe tip). The luer collar may have internal threads, and the tip cap may have external threads complementary to the internal threads of the luer collar for coupling the tip cap to the syringe barrel. For the prefilled syringe of the present invention, the luer collar is typically integrally formed with the syringe barrel. Before use, the tip cap can be removed, and then a needle cannula (needle assembly) can be firmly coupled to the syringe tip.

[0033] Figure 2 An example of a prefilled syringe including a tip cap is shown. The prefilled syringe includes a barrel 10, a plunger 80 including a plunger rod 20 and a plunger stopper 30, a luer collar 110 having a tip 100 formed at the end of the barrel and threads formed on the tip, a tip cap 120 fixed to the tip by engagement with the luer collar, and a botulinum toxin liquid preparation 40 included in the cavity of the barrel 10.

[0034] When the prefilled syringe includes a removable or non-removable (i.e., permanent) cannula or needle cannula (also referred to as a "needle" or "needle assembly") extending from the syringe tip for delivering the botulinum toxin preparation from the syringe, the capping device can be referred to as a "needle shield". The needle shield may have a channel including a closed end and an open end, and the size of the channel is typically designed to accommodate and couple a cannula (needle) mounted on the syringe tip. Typically, the (sharp) end of the cannula can pass through the closed end of the inner channel of the needle shield to seal the open end of the cannula.

[0035] Figure 3 An example of a prefilled syringe including a needle assembly and a needle shield is shown. The prefilled 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 preparation 40 included in the cavity of the barrel 10.

[0036] A capping device (e.g., a tip cap or needle shield) can be a single piece, typically made of a flexible and elastic polymeric material (e.g., an elastomer), or can have an outer cap coupled to a flexible and elastic inner cap, the outer cap made of a rigid plastic material or of a material including or made of an elastomer, at least a portion of which contacts and seals the distal opening of the syringe. Generally, at least the outlet engaging portion of the seal that contacts the distal tip opening to form a fluid seal is made of a flexible and / or elastic material (e.g., an elastomer), and the engaging portion can contact the botulinum toxin formulation during storage and / or use. The outlet engaging portion can be made of a material that minimizes the likelihood of undesirable extractables / leachables. To further reduce the amount of extractables and / or leachables and increase compatibility with the botulinum toxin formulation, the outlet engaging portion can have a coating thereon.

[0037] Suitable flexible and / or elastic materials for the capping device, particularly the outlet engaging portion, can include elastomers that can be stored long-term without disturbing an aqueous botulinum toxin formulation. In particular, a portion of the sealing device that contacts or is configured to contact the botulinum toxin dosage form, such as the outlet engaging portion, should exhibit low levels of extractables / leachables during long-term storage of the botulinum toxin formulation. As used herein, the term "elastomeric polymer" or "elastomeric polymer material" can include crosslinked thermoset rubber-like polymers that are more deformable than plastics but are approved for use with pharmaceutical-grade fluids and do not readily exhibit leaching or gas migration.

[0038] The elastomeric material can be isoprene rubber (IS), polybutadiene (BR), butyl rubber (a copolymer of isobutene and isoprene, IIR), halogenated butyl rubber (e.g., chlorinated butyl rubber, CIIR; and brominated butyl rubber, BIIR), styrene-butadiene rubber (a copolymer of styrene and butadiene, SBR), or a mixture thereof. For example, the elastomeric material can be butyl rubber or halogenated butyl rubber, particularly brominated butyl rubber or chlorinated butyl rubber, or a mixture thereof. The elastomeric material can also be reinforced with inert minerals. Additionally, the elastomeric material, for example, can be cured by organic peroxides, phenolic resins, etc.

[0039] Suitable coatings that can optionally be present on the outlet engaging portion made of the above-described elastomeric material are generally made of materials that do not undesirably interfere with an aqueous botulinum toxin formulation and exhibit low levels of extractables / leachables. Coatings for use in the present invention can include polypropylene, polyethylene, parylene (e.g., parylene N, parylene C, and parylene HT), crosslinked silicone, or fluoropolymer coatings. Examples of suitable crosslinked silicone coatings include B2-coatings (Daikyo Seiko or XSiTM (Becton Dickinson).

[0040] The fluoropolymer coating can include fluorinated ethylene-propylene copolymer (e.g., tetrafluoroethylene-hexafluoropropylene copolymer (FEP)), fluorinated ethylene-ethylene copolymer (e.g., ethylene-tetrafluoroethylene copolymer (ETFE), e.g., ), PVA (copolymer of tetrafluoroethylene (TFE) and perfluoropropyl vinyl ether (PPVE)), tetrafluoroethylene-perfluoroethylene copolymer, polyvinylidene fluoride (PVDF), polyvinyl fluoride (PVF), polytetrafluoroethylene (PTFE) or mixtures thereof. The coating is made of ETFE, for example, and can be coating.

[0041] The botulinum toxin liquid formulation can be an aqueous formulation. The aqueous formulation can include an aqueous suspension, an aqueous dispersion, an aqueous emulsion or an aqueous solution.

[0042] In the botulinum toxin liquid formulation, the concentration of botulinum toxin can be, for example, about 1 U / mL to about 3000 U / mL, about 10 U / mL to about 1000 U / mL, about 10 U / mL to about 400 U / mL, about 10 U / mL to about 200 U / mL, about 10 U / mL to about 100 U / mL, about 10 U / mL to about 70 U / mL, about 20 U / mL to about 60 U / mL or about 40 U / mL.

[0043] Based on units / syringe, the dose 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.

[0044] As used herein, the term "botulinum toxin" generally refers to any form or type of botulinum toxin. More specifically, the botulinum toxin can be botulinum toxin type A, B, C1, C2, D, E, F, G or mixtures thereof. For example, the botulinum toxin can be serotype A, B or C1.

[0045] In addition, the term "botulinum toxin" is intended to include both botulinum toxin complex ("toxin complex") and the "neurotoxic component" of botulinum toxin or complex. As used herein, the term "botulinum toxin complex" refers to a high molecular weight complex that includes a neurotoxic component of about 150 kDa and non-toxic proteins of Clostridium botulinum including hemagglutinin and non-hemagglutinin proteins. The botulinum toxin serotype A complex can be Meditoxin (Medytox Inc.), for example.

[0046] As used herein, the term "neurotoxic component" refers to the neurotoxic polypeptide of the toxin complex ("150 kDa" polypeptide; usually its double-stranded form), which does not contain any associated non-toxic proteins. A pure neurotoxic component can be, for example, Coretox (Medytox Inc.). For example, the term "botulinum toxin" refers to the neurotoxic component of the botulinum toxin complex of a given serotype (e.g., serotype A, B, or C1, especially serotype A). In other words, the botulinum toxin formulation contained in a pre-filled syringe can contain only the neurotoxic component and no other proteins of the Clostridium botulinum toxin complex.

[0047] The botulinum toxin includes wild-type botulinum toxin, for example, a functional (i.e., biologically active) isoform, homolog, ortholog, paralog, and fragment of botulinum toxin that shows 50% or higher, 60% or higher, 70% or higher, 80% or higher, or 90% or higher sequence identity with the amino acid sequence of the neurotoxic component of the wild-type botulinum toxin A or botulinum toxin of serotype A1 deposited in the GenBank database under accession number AAA23262.

[0048] Sequence identity can be calculated by any algorithm suitable for producing reliable results, for example, using the FASTA algorithm (document [WR Pearson & DJ Lipman, PNAS 85:2444 - 2448, 1988]). Sequence identity can be calculated by comparing two domains, such as two polypeptides, or two LC domains or fragments thereof.

[0049] The botulinum toxin includes modified and recombinant botulinum toxins.

[0050] The botulinum toxin liquid formulation can include other pharmaceutically 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., glycerol and sugar alcohols such as mannitol, inositol, lactitol, isomaltulose, xylitol, erythritol, sorbitol), 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 "pharmaceutically acceptable" refers to a compound or substance suitable for contact with mammalian, especially human, tissues.

[0051] The botulinum toxin liquid preparation may be free of animal components. The botulinum toxin liquid preparation may be free of albumin. For example, the botulinum toxin liquid preparation may include botulinum toxin, amino acids, a surfactant, and a tonicity regulator in water. The botulinum toxin liquid preparation may, for example, include 10 U / ml to 70 U / ml of botulinum toxin, 0.05 g / L to 0.7 g / L of amino acids, 0.10 g / L to 0.5 g / L of surfactant, and an aqueous sodium chloride solution of 0.10 g / L to 1.0 g / L in water. The botulinum toxin may be botulinum toxin type A, B, C1, C2, D, E, F, G, or a mixture thereof. The amino acids may be glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, glutamic acid, their pharmaceutically acceptable salts, or a mixture thereof. The amino acids may, for example, be methionine, histidine, arginine, their pharmaceutically acceptable salts, or a mixture thereof. The surfactant may be a nonionic surfactant. The nonionic surfactant may be polysorbate, poloxamer, or a mixture thereof. The polysorbate may be polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a mixture thereof. The sodium chloride may be added at a physiologically acceptable concentration, for example, about 0.85 g / L to 0.95 g / L, or about 0.9 g / L.

[0052] The botulinum toxin liquid preparation may further include a buffer to maintain the pH at about 5.5 to about 7.5. The buffer may be citrate, histidine, HEPES, arginine, acetic acid, phosphoric acid, their salts, or a mixture thereof.

[0053] The pH of the botulinum toxin preparation may be maintained within 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 during storage.

[0054] When the botulinum toxin liquid preparation is stored for 2 months, 4 months, or 6 months under accelerated test conditions at 25 °C, compared to the initial value, it may show an LD 50 titer recovery of 75% to 125%, 75% to 120%, or 80% to 125%.

[0055] When the botulinum toxin liquid preparation is stored for 2 months, 4 months, or 6 months under accelerated test conditions at 25 °C, compared to the initial value, it may show a protease activity recovery of 75% to 125%, 75% to 120%, or 80% to 125%.

[0056] When the botulinum toxin liquid preparation is stored for 2 months, 4 months or 6 months under the accelerated test conditions at 25°C, compared with the initial value, the pH fluctuation can be within ±1.5, ±1.0 or ±0.5.

[0057] A specific embodiment can be a pre-filled syringe dosage form of botulinum toxin, which includes a syringe barrel, a syringe including a plunger rod and a plunger plug, and a botulinum toxin liquid preparation filled in the syringe. As the discharge speed of the botulinum toxin liquid preparation increases, the increase amount of the force acting on the end of the plunger rod decreases.

[0058] In the specific embodiment, the ratio of the length to the inner diameter of the syringe barrel can be 10 to 22. The inner diameter of the syringe barrel can be 3.5 mm to 6.5 mm, and the length can be 60 mm to 100 mm. The material of the syringe barrel can be glass, COC or COP with a silicone coating. The material of the syringe barrel can be COC. The silicone coating can be a sprayed silicone coating, a baked silicone coating or a polydimethylsiloxane coating. The material of the plunger plug can be isoprene rubber (IS), cis-butadiene rubber (BR), butyl rubber, halogenated butyl rubber, styrene-butadiene rubber or a mixture thereof. The plunger plug can have no coating. The dose of the botulinum toxin liquid preparation can be 10 units / syringe to 50 units / syringe. The botulinum toxin liquid preparation can be albumin-free. The botulinum toxin liquid preparation can be animal ingredient-free. The botulinum toxin liquid preparation can include botulinum toxin, amino acids, surfactants and isotonic agents. The amino acid can be methionine. The surfactant can be polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 or poloxamer. The botulinum toxin liquid preparation can also include a buffer to maintain the pH at 5.5 to 7.5. The buffer can be citrate, histidine, HEPES, arginine, acetic acid, phosphoric acid, their salts or a mixture thereof. When the botulinum toxin liquid preparation is stored for 2 months, 4 months or 6 months under the accelerated test conditions at 25°C, compared with the initial value, it can show an LD 50 titer recovery rate of 80% to 125%. When the botulinum toxin liquid preparation is stored for 2 months, 4 months or 6 months under the accelerated test conditions at 25°C, compared with the initial value, it can show a protease activity recovery rate of 80% to 125%. When the botulinum toxin liquid preparation is stored for 2 months, 4 months or 6 months under the accelerated test conditions at 25°C, compared with the initial value, the pH fluctuation can be within ±1.0.

[0059] Another specific embodiment may be a pre-filled syringe dosage form of botulinum toxin, which includes a syringe barrel, a syringe including a plunger rod and a plunger stopper, and a liquid preparation of botulinum toxin filled in the syringe. The material of the syringe barrel is glass, COC or COP with a silicone coating.

[0060] In the specific embodiment, the material of the syringe barrel may be COC. The silicone coating may be a sprayed silicone coating, a baked silicone coating or a polydimethylsiloxane coating. The material of the plunger stopper may be isoprene rubber (IS), cis-butadiene rubber (BR), butyl rubber, halogenated butyl rubber, styrene-butadiene rubber or a mixture thereof. The plunger stopper may have no coating. As the discharge rate of the botulinum toxin liquid preparation increases, the increase in the force acting on the end of the plunger rod may decrease. The ratio of the length of the syringe barrel to the inner diameter may be 10 to 22. The inner diameter of the syringe barrel may be 3.5 mm to 6.5 mm, and the length may be 60 mm to 100 mm. The dose of the botulinum toxin liquid preparation may be 10 units / syringe to 50 units / syringe. The botulinum toxin liquid preparation may not contain albumin. The botulinum toxin liquid preparation may not contain animal components. The botulinum toxin liquid preparation may include botulinum toxin, amino acids, surfactants and isotonic agents. The amino acid may be methionine. The surfactant may be polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 or poloxamer. The botulinum toxin liquid preparation may further include a buffer to maintain the pH at 5.5 to 7.5. The buffer may be citrate, histidine, HEPES, arginine, acetic acid, phosphoric acid, their salts or a mixture thereof. When the botulinum toxin liquid preparation is stored for 2 months, 4 months or 6 months under accelerated test conditions at 25 °C, compared with the initial value, it may show an LD 50 titer recovery rate of 80% to 125%. When the botulinum toxin liquid preparation is stored for 2 months, 4 months or 6 months under accelerated test conditions at 25 °C, compared with the initial value, it may show a protease activity recovery rate of 80% to 125%. When the botulinum toxin liquid preparation is stored for 2 months, 4 months or 6 months under accelerated test conditions at 25 °C, compared with the initial value, its pH fluctuation may be within ±1.0.

[0061] Another specific embodiment may be a pre-filled syringe dosage form of botulinum toxin, which includes a syringe barrel, a syringe including a plunger rod and a plunger stopper, and a liquid preparation of botulinum toxin filled in the syringe. The botulinum toxin liquid preparation does not contain albumin.

[0062] The specific embodiment may be a pre-filled syringe dosage form of botulinum toxin, which includes a syringe barrel, a syringe including a plunger rod and a plunger plug, and a liquid preparation of botulinum toxin filled in the syringe. The botulinum toxin liquid preparation does not contain animal components. The botulinum toxin liquid preparation may include botulinum toxin, amino acids, surfactants, and isotonic agents. The amino acid may be methionine. The surfactant may be polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or poloxamer. The botulinum toxin liquid preparation may further include a buffer to maintain the pH at 5.5 to 7.5. The buffer may be citrate, histidine, HEPES, arginine, acetic acid, phosphoric acid, their salts, or a mixture thereof. The dose of the botulinum toxin liquid preparation may be 10 units / syringe to 50 units / syringe. The material of the syringe barrel may be glass, COC, or COP with a silicone coating. The material of the syringe barrel may be COC. The silicone coating may be a spray silicone coating, a baked silicone coating, or a polydimethylsiloxane coating. The material of the plunger plug may be isoprene rubber (IS), cis-butadiene rubber (BR), butyl rubber, halogenated butyl rubber, styrene-butadiene rubber, or a mixture thereof. The plunger plug may have no coating. In the pre-filled syringe dosage form of botulinum toxin, as the discharge rate of the botulinum toxin liquid preparation increases, the increase in the force acting on the end of the plunger rod may decrease. The ratio of the length of the syringe barrel to the inner diameter may be 10 to 22. The inner diameter of the syringe barrel may be 3.5 mm to 6.5 mm, and the length may be 60 mm to 100 mm. When the botulinum toxin liquid preparation is stored for 2 months, 4 months, or 6 months under accelerated test conditions at 25 °C, compared with the initial value, it may show an LD 50 titer recovery rate. When the botulinum toxin liquid preparation is stored for 2 months, 4 months, or 6 months under accelerated test conditions at 25 °C, compared with the initial value, it may show a protease activity recovery rate of 80% to 125%. When the botulinum toxin liquid preparation is stored for 2 months, 4 months, or 6 months under accelerated test conditions at 25 °C, compared with the initial value, its pH fluctuation may be within ±1.0.

[0063] Beneficial effects

[0064] According to the pre-filled syringe dosage form of botulinum toxin of one aspect, when stored for 2 months, 4 months, or 6 months under accelerated test conditions at 25 °C, compared with the initial value, LD 50 titer, botulinum toxin endopeptidase titer, and pH value can all be maintained stable. In addition, according to the pre-filled syringe dosage form of botulinum toxin, it is easy to control the discharge rate. Description of the drawings

[0065] Figure 1 An example of a prefilled syringe including a needle is shown.

[0066] Figure 2 An example of a prefilled syringe including a tip cap is shown.

[0067] Figure 3 An example of a prefilled syringe including a needle assembly and a needle shield is shown. DETAILED DESCRIPTION

[0068] The present invention will be described in more detail below with reference to embodiments. However, these embodiments are only for exemplarily describing the present invention, and the scope of the present invention is not limited to these embodiments.

[0069] Example 1: Stability of a prefilled liquid syringe dosage form of botulinum toxin: A syringe having a barrel made of COC or COP material

[0070] 1. Preparation of a liquid formulation prefilled with botulinum toxin

[0071] In this example, a liquid botulinum toxin formulation was filled in a syringe for highly viscous drugs (hereinafter referred to as "HVD syringe"), and the stability according to the storage period was measured. The HVD syringe has an inner diameter of 5.00 mm, an outer diameter of 9.40 mm, a barrel length of 80.0 mm, and a liquid formulation filling volume of 0.8 mL. For reference, as an example of a known syringe, the TopPac TM syringe of SCHOTT company has an inner diameter of 6.50 mm, an outer diameter of 9.40 mm, a barrel length of 64.5 mm, and a liquid formulation filling volume of 1 mL. That is, compared with the TopPacTM syringe, the HVD syringe has a smaller inner diameter and a longer length. The TopPacTM syringe includes a barrel, a plunger, a plunger rod, and a tip cap. The barrel is made of COC material and is formed with a Luer Lock. The inner surface of the barrel is silanized with a reactive silicone mixture and then crosslinked by curing. The tip cap is made of rubber (Datwyler company). The HVD syringe includes a COC material made of TOPAS 6015 material and has higher heat resistance.

[0072] In addition, in the HVD syringe, stability is measured based on the material of the barrel, the material of the plunger stopper, the material for its coating, and the composition of the aqueous liquid botulinum toxin preparation filled in the barrel. Among them, 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 between the proximal end and the distal end and forming a barrel cavity. The barrel has a tip protruding distally, where a fluid passage extends through the tip and communicates with the barrel cavity. The generally cylindrical wall has an inner surface optionally coated with a barrier layer. In this embodiment, the inner surface of the wall is coated with silicone, that is, the barrier layer is a silicone layer. In addition, in this embodiment, the barrel has a COC or COP material.

[0073] The capping device has an outlet coupling portion that sealingly couples and closes the open outlet at the distal end of the barrel. The capping device for the distal end of the barrel consists of a cap and a rubber tip cap. The cap is made of polycarbonate material, and the rubber tip cap is made of the same material as the plunger. Among them, the rubber tip cap corresponds to the outlet coupling portion. The outlet coupling portion is made of an elastomeric material optionally having a coating on the surface. The outlet coupling portion and the capping device are coupled in a Luer lock form.

[0074] The plunger rod assembly extends into the proximal end of the barrel and includes a plunger stopper that slidably fluid-sealingly engages with the cylindrical wall of the barrel cavity. The stopper is made of an elastomeric material and optionally has a coating on at least a portion of the stopper that contacts the aqueous liquid botulinum toxin preparation during storage and / or injection. In this embodiment, the material of the stopper is bromobutyl rubber (BIIR) or chlorobutyl rubber (CIIR) and is optionally coated with Teflon.

[0075] Table 1 shows the botulinum toxin pre-filled syringe preparation of the pre-filled liquid botulinum toxin preparation in water used in this embodiment.

[0076]

Table 1

[0077]

[0078]

[0079] In Table 1, COC represents cyclic olefin copolymer, and COP represents cyclic olefin polymer. BIIR and CIIR represent brominated and chlorinated butyl rubber (IIR), respectively. The material of the plunger stopper represents the material of the rubber part. Among them, butyl rubber (IRR) is a copolymer of isobutene and isoprene. The Teflon coating means coating the surface of BIIR or CIIR with a FluroTecR film. L-Met, T20, sodium chloride, and toxin represent the amounts of L-methionine, polysorbate 20, sodium chloride, and botulinum toxin type A components dissolved in water, i.e., water for injection.

[0080] The preparation combines the plunger rod assembly into the cavity of the barrel so that the stopper of the plunger seals the liquid preparation when it contacts the liquid preparation. In addition, the outlet joint part at the distal end of the barrel is sealingly combined with the capping device to close the open outlet. The syringe is integrally formed with the capping device, and the capping device is removed before use. At this time, the liquid contacts the rubber tip cap inside the capping device.

[0081] That is, the pre-filled syringe botulinum liquid preparation is in a state where the syringe is connected to the capping device and no injection needle is connected to it.

[0082] Therefore, a total of 8 pre-filled syringe botulinum liquid preparations were prepared by adding 2 different concentrations of methionine and polysorbate 20 to 4 syringes. Among them, the materials of the syringe barrels were COC and COP, and the stoppers of the plungers were brominated butyl rubber, chlorinated butyl rubber, and their Teflon coatings.

[0083] 2. Long-term stability test of pre-filled syringe dosage form

[0084] (1) Titre test

[0085] The 8 dosage forms prepared, namely dosage forms A to H, were stored in a stability sample storage room at 4°C, and the median lethal dose (LD 50 ) of mice was measured at the 0th month, 3rd month, 6th month, 9th month, 12th month, 18th month, and 24th month.

[0086] After serial dilution of the liquid samples of 8 dosage forms, 4-week-old female ICR mice weighing 17 g to 22 g were intraperitoneally administered. The lethality of each diluted sample was observed 3 days after administration, and the median lethal dose was calculated using the statistical program PROBIT. The median lethal dose at month 0 was set as 100%, and the changing trend of the median lethal dose obtained at each time point was expressed as a percentage. Table 2 is a table showing the median lethal doses according to the storage periods of dosage forms A, B, C, D, E, F, G, and H.

[0087]

Table 2

[0088]

[0089] As shown in Table 2, the recovered lethal dose values measured for dosage forms A to F at month 24 were 73% or greater, but for dosage forms G and H, no recovered lethal dose values were measured starting from month 9. This indicates that botulinum toxin can remain stable for 24 months when the barrel is made of COC material and silicone-coated, regardless of whether the plunger stopper material is BIIR or CIIR, or whether the surface of the plunger stopper is coated with Teflon. On the other hand, when the barrel material is COP, no recovered titer was measured in this syringe starting from month 9.

[0090] (2) Analysis of botulinum toxin endopeptidase titer

[0091] The 8 prefilled syringe dosage forms A to H were stored in a stability chamber, and the activity of BoNTA / LC was measured at month 0, month 3, month 6, month 9, month 12, month 18, and month 24.

[0092] 100 ul of the SNAP25 (self-made) fragment consisting of about 70 amino acid sequences was placed in each well of a 96-well plate and incubated at 2 °C to 8 °C for 16 hours. The SNAP25 fragment includes 10 or more consecutive amino acid sequences, which include the cleavage site between amino acids 197 and 198.

[0093] Prepare a standard sample, i.e., the BoNTA sample, that can obtain a quantitative curve using the BoNTA standard product (Innotox, Medytox Inc.). Prepare test samples by diluting BoNTA in HEPES solution (Sigma Inc.) so that the result values of samples A to H of the dosage form can be included within the range of the quantitative curve. Place each of the standard sample and test samples A to H into wells containing SNAP25 and react at room temperature for 1 hour. Next, add the anti-SNAP25 polyclonal antibody (self-made) to each well and react at room temperature for 1 hour. After the HRP-conjugated secondary antibody reacts at room temperature for 1 hour, add the chromogenic reagent 3,3',5,5'-tetramethylbenzidine (3,3',5,5'-Tetramethylbenzidine: TMB), and incubate for color development.

[0094] Measure the absorbance at 450 nm using a microplate reader (TECAN Inc.), quantify the degree of color development according to the activity of BoNT / LC, and obtain a quantitative curve using the absorbance values of the standard sample. Calculate the BoNT / LC activity of each sample by substituting the absorbance values of samples A to H into the quantitative curve. Set the activity of BoNT / LC at month 0 to 100%, and express the change trend of the BoNT / LC activity obtained at each time point as a percentage. Table 3 is a table showing the endopeptidase activity of BoNTA contained in dosage forms A to H according to the storage period.

[0095]

Table 3

[0096]

[0097]

[0098] As shown in Table 3, the recovery titers of dosage forms A to F at month 24 were maintained at 111% to 141% compared to the initial stage, but the recovery titers of dosage forms G and H were not measured starting from month 9.

[0099] (3) pH stability

[0100] Place each sample of the 8 pre-filled syringe dosage forms A to H at month 0, month 3, month 6, month 9, month 12, month 18, and month 24 into a 15 mL disposable test tube to a volume of more than 3 mL, and measure the pH of each sample using a pH meter (Mettler Toledo Inc.). Table 4 is a table showing the change in pH of dosage forms A to H according to the storage period.

[0101]

Table 4

[0102]

[0103]

[0104] As shown in Table 4, the pH of Formulations A to F remained between 6.8 and 7.4 at the 24th month, while the pH of Formulations G and H remained between 5.3 and 5.9 at the 6th month when the activity was measured.

[0105] Example 2: Stability of a prefilled liquid syringe formulation of botulinum toxin: A syringe having a barrel made of glass or COP material

[0106] 1. Preparation of a liquid formulation prefilled with botulinum toxin

[0107] Prepare the botulinum toxin prefilled liquid formulations in Table 5 below. At this time, the syringe is the HVD syringe described in Table 1, which has an inner diameter of 5.00 mm, an outer diameter of 9.40 mm, a barrel length of 80.0 mm, and a liquid formulation filling volume of 0.8 mL.

[0108] [Table 5]

[0109]

[0110]

[0111] The barrels of Formulations I and J in Table 5 are products of POONGLIM Pharmatech Inc. (article number, Art.69, Korea), the barrels of Formulations K and L are products of SiO2 Medical Products Inc. (article number, 850009-100-04, USA), and the barrels of Formulations M and N are products of TERUMO Corporation (article number, PJ-B1L9BFTF1, Japan). The botulinum toxin is BTX1301 (API batch number) of Medytox Inc., i.e., BoNTA. In Table 5, COC represents cyclic olefin copolymer, and COP represents cyclic olefin polymer. BIIR and CIIR represent brominated and chlorinated isobutylene-isoprene rubber (IIR), respectively. Among them, isobutylene rubber (IRR) is a copolymer of isobutylene and isoprene. L-Met, T20, sodium chloride, and toxin represent the amounts of L-methionine, polysorbate 20, sodium chloride, and botulinum toxin type A components dissolved in water. The pH of the liquid containing these components is 6.0 to 7.0.

[0112] The preparation combines the plunger rod assembly into the cavity of the barrel to seal the liquid preparation when the stopper of the plunger contacts the liquid preparation. Additionally, the outlet joint portion at the distal end of the barrel is sealingly combined with the capping device to close the open outlet. That is, the pre-filled syringe botulinum liquid preparation is in a state where the syringe is connected to the capping device without an injection needle connected thereto.

[0113] Therefore, a total of six pre-filled syringe botulinum liquid preparations I to N were prepared by adding two different concentrations of methionine and polysorbate 20 to three syringes, where the material of the syringe barrel was selected as glass and COP, and the plunger stopper was selected as bromobutyl rubber and i-coating.

[0114] 2. Stability tests of pre-filled syringe dosage forms I to N

[0115] (1) Titration test

[0116] The six prepared dosage forms, namely samples of dosage forms I to N, were stored in a thermo-hygrostat (Binder) at 25 °C for experiments under accelerated test conditions. For the long-term storage test, the samples were stored in a stability sample storage room at 4 °C. The median lethal dose (LD 50 ) of mice was measured at the 0th, 2nd, 3rd, 4th, and 6th months after storage.

[0117] After serial dilution of the liquid samples of the six dosage forms, 4-week-old female ICR mice weighing 17 g to 22 g were intraperitoneally administered. The lethality of each diluted sample was observed 3 days after administration, and the median lethal dose was calculated using the statistical program PROBIT. The median lethal dose at the 0th month was set as 100%, and the change trend of the median lethal dose obtained at each time point was expressed as a percentage. Table 6 is a table showing the median lethal doses according to the storage periods of dosage forms I, J, K, L, M, and N.

[0118]

Table 6

[0119]

[0120] As shown in Table 6, at the 6th month, the titers of the six pre-filled syringe dosage forms I to N remained in the range of 86% to 108% compared with the initial titer.

[0121] (2) Analysis of botulinum toxin endopeptidase titer

[0122] The six pre-filled syringe dosage forms I to N were stored in a stability chamber, and the activities of BoNTA / LC were measured at the 0th, 2nd, 3rd, 4th, and 6th months.

[0123] Put 100 μl of the self-made SNAP25 fragment consisting of about 70 amino acid sequences into each well of a 96-well plate and incubate at 2 °C to 8 °C for 16 hours. The SNAP25 fragment includes 10 or more consecutive amino acid sequences, which include a cleavage site between amino acids 197 and 198.

[0124] Prepare a standard sample, i.e., the BoNTA sample, that can obtain a quantitative curve using a BoNTA standard (Innotox, Medytox Inc.). Prepare test samples by diluting BoNTA in a HEPES solution (Sigma Inc.) so that the result values of samples A to H of the dosage form can be included within the range of the quantitative curve. Put each of the standard sample and test samples A to H into the wells containing SNAP25 and react at room temperature for 1 hour. Next, add the anti-SNAP25 polyclonal antibody (self-made) to each well and react at room temperature for 1 hour. After the HRP-conjugated secondary antibody reacts at room temperature for 1 hour, add the chromogenic reagent 3,3',5,5'-tetramethylbenzidine (3,3',5,5'-Tetramethylbenzidine: TMB) and incubate for color development.

[0125] Measure the absorbance at 450 nm in a microplate reader (TECAN Inc.), quantify the degree of color development according to the activity of BoNT / LC, and obtain a quantitative curve using the absorbance values of the standard sample. Calculate the BoNT / LC activity of each sample by substituting the absorbance values of samples I to N into the quantitative curve. Set the activity of BoNT / LC at the 0th month as 100%, and represent the change trend of the BoNT / LC activity obtained at each time point as a percentage. Table 7 is a table showing the endopeptidase activity of BoNTA contained in dosage forms I to N according to the storage period.

[0126]

Table 7

[0127]

[0128]

[0129] As shown in Table 7, compared with the initial value, the recovery titers of dosage forms I to N at the 6th month remained at 53% to 94%.

[0130] (3) pH stability

[0131] Samples of six pre-filled syringe dosage forms I to N at certain time points were placed in 15 mL disposable test tubes to a volume of more than 3 mL, and the pH of each sample was measured using a pH meter (Mettler Toledo). Table 8 is a table showing the change in pH of dosage forms I to N over the storage period. The time points for the accelerated condition experiment were the 0th month, 2nd month, 4th month, and 6th month, and the time points for the long-term storage experiment were the 0th month, 3rd month, and 6th month.

[0132]

Table 8

[0133]

[0134] As shown in Table 8, the pH of dosage forms I to N remained between 7.1 and 7.9 until the 6th month.

[0135] Example 3: Stability of Botulinum Toxin Pre-filled Liquid Syringe Dosage Forms: Effect of Albumin

[0136] 1. Preparation of Liquid Formulations Pre-filled with Botulinum Toxin

[0137] As shown in Table 9 below, dosage form O containing human serum albumin but not containing L-Met and polysorbate 20 and dosage form P containing L-Met and polysorbate 20 but not containing human serum albumin were prepared. In Table 9, the solvent was water and the toxin was the BoNTA type product produced by Medytox.

[0138] Dosage forms O and P were filled into the HVD syringes. Among them, the HVD syringe was syringe B in Table 1, the barrel was made of COC material, and the plunger was made of silanized BIIR material.

[0139]

Table 9

[0140]

[0141] 2. Titer Test: LD 50 (Accelerated Test)

[0142] Two prepared samples, namely dosage forms O and P, were pre-filled in each syringe. The syringe dosage forms were stored in a stability chamber, and the median lethal dose (LD 50 ) of mice was measured on the 0th day, 2nd day, 3rd day, 7th day, 14th day, 28th day, and 56th day.

[0143] Samples 1 and 2 were serially diluted with water and then intraperitoneally administered to 4-week-old female ICR mice weighing 17 g to 22 g. The lethality of each diluted sample was observed 3 days after administration, and the median lethal dose was calculated using the statistical program PROBIT. The median lethal dose at month 0 was set to 100%, and the change trend of the median lethal dose obtained at each time point was expressed as a percentage. The shelf life was calculated using the Arrhenius equation (https: / / met.uk.com / medical-device-packaging-testing / 4a-medical-accelerated-ageing), which represents the relationship between the reaction rate constant and temperature.

[0144] Table 10 shows the storage stability of albumin-containing formulation O and albumin-free formulation P as LD 50 values in a table.

[0145]

Table 10

[0146]

[0147] In Table 10, STD is Meditoxin (Medytox Inc.) as a standard sample, normalization represents the relative titer when the data value on day 0 is set to 100, and N / A indicates that no test was performed because the LD 50 value in the previous cycle of the test was as low as about 20%, so it was meaningless to conduct the test. For the three prepared formulations, namely the standard sample (STD), formulation O, and formulation P, under accelerated conditions for 56 days, i.e., about 2 months, the albumin-containing formulation O lost the recovered titer on day 28 of the test, but the albumin-free formulation P maintained 86% of the recovered titer on day 28 and 52% of the recovered titer on day 56. For the accelerated conditions, the samples were stored at 40 °C, and the samples were recovered on day 0, day 2, day 5, day 7, day 14, day 28, and day 56 for experiments.

[0148] 3. Injection Force Test

[0149] The albumin-containing formulation O and albumin-free formulation P described in Table 9 were respectively filled into the SHOTT TopPac syringe 1 ml and HVD syringe described in Section 1 of Example 1, i.e., syringe B in Table 1, to prepare a total of 4 pre-filled syringe botulinum liquid preparations Q, R, S, and T, i.e., 4 formulations.

[0150] For the four dosage forms, the plunger injection force according to the movement speed of the syringe plunger was measured using a MultiTest 2.5 (Mecmesin, UK) tensile compression device. The injection force was the average injection force.

[0151] Specifically, first, 30G needles were respectively attached to the syringes filled with the four dosage forms. Then, the syringes were fixed to the fixture of the tensile compression device, and the plunger rod was adjusted to be centered on the load cell of the device. The fixture was the syringe fixing part of the device.

[0152] After setting the measurement distance considering the length of each syringe, the speed value was input into the program built into the device, and the device was started by pressing the start button to conduct the test. For the measurement distance, since the HVD syringe has a small inner diameter and a large length, when filling 1 mL, the content fills to a height of approximately 40 mm, while the TopPac syringe fills to a height of approximately 30 mm when filling 1 mL. When measuring the injection force, for safety reasons, with a 5 - mm margin left, the measurement distance was set to push the plunger of the HVD syringe from 0 mm to 35 mm and the plunger of the TopPac syringe from 0 mm to 25 mm. After the measurement, the samples were removed from the fixture, and each sample was measured 3 times to obtain the injection force results. Table 11 is a table showing the injection force according to the plunger movement speed.

[0153]

Table 11

[0154]

[0155] As shown in Table 11, compared with dosage forms Q and S including the TopPac syringe, dosage forms R and T including the HVD syringe had the same or higher injection force at low plunger movement speeds of 10 mm / min and 50 mm / min, but had a lower injection force at high plunger movement speeds of 100 mm / min and 200 mm / min compared with dosage forms Q and S including the TopPac syringe. This indicates that compared with dosage forms Q and S including the TopPac syringe, dosage forms R and T including the HVD syringe have a higher plunger compression force at low plunger movement speeds and a lower plunger compression force at high plunger movement speeds. Therefore, the dosage forms including the HVD syringe can be finely operated at low speeds and can be more easily injected at high speeds.

Claims

1. A pre-filled syringe dosage form of botulinum toxin, comprising: a syringe, It includes a syringe barrel, a plunger rod and a plunger stopper; and a botulinum toxin liquid preparation filled in the syringe, wherein, the inner diameter of the syringe barrel is 4.5 mm to 5.5 mm, and the length of the syringe barrel is 70 mm to 90 mm, and wherein, as the discharge rate of the botulinum toxin liquid preparation increases, the increase amount of the force acting on the end of the plunger rod decreases.

2. The syringe dosage form according to claim 1, wherein, The material of the syringe barrel is glass or cycloolefin polymer.

3. The syringe dosage form according to claim 1, wherein The material of the syringe barrel is cycloolefin copolymer.

4. The syringe dosage form according to claim 1, wherein The material of the plunger stopper is isoprene rubber, cis-butadiene rubber, butyl rubber, halogenated butyl rubber, styrene-butadiene rubber or a mixture thereof.

5. The syringe dosage form according to claim 1, wherein, The botulinum toxin liquid preparation includes botulinum toxin, amino acid, surfactant and isotonic agent.

6. The syringe dosage form according to claim 5, wherein The amino acid is methionine, and the surfactant is polysorbate or poloxamer.

7. The syringe dosage form according to claim 5, wherein, The botulinum toxin liquid preparation does not contain animal components.

8. The syringe dosage form according to claim 7, wherein The botulinum toxin liquid preparation does not contain albumin.

9. The syringe dosage form according to claim 5, wherein The botulinum toxin liquid preparation further includes a buffer to maintain the pH at 5.5 to 7.

5.

10. The syringe dosage form according to claim 9, wherein The buffer is citrate, histidine, histidine salt, N-(2-hydroxyethyl)piperazine-N'-ethanesulfonic acid, N-(2-hydroxyethyl)piperazine-N'-ethanesulfonic acid salt, arginine, arginine salt, acetic acid, acetate, phosphoric acid, phosphate, or a mixture thereof.

11. The syringe dosage form according to any one of claims 5 and 7 to 10, wherein, When the botulinum toxin liquid preparation is stored for 2 months, 4 months or 6 months under accelerated test conditions at 25 °C, it shows an LD 50 titer recovery rate of 80% to 125% compared with the initial value.

12. The syringe dosage form according to any one of claims 5 and 7 to 10, wherein, When the botulinum toxin liquid preparation is stored for 2 months, 4 months or 6 months under the accelerated test conditions at 25 °C, compared with the initial value, it shows a protease activity recovery rate of 80% to 125%.

13. The syringe dosage form according to any one of claims 5 and 7 to 10, wherein, When the botulinum toxin liquid preparation is stored for 2 months, 4 months or 6 months under the accelerated test conditions at 25 °C, compared with the initial value, its pH fluctuates within ±1.

0.

14. The syringe dosage form according to claim 1, wherein, The botulinum toxin liquid preparation includes a stabilizing protein and sugar.

15. The syringe dosage form according to claim 14, wherein, The stabilizing protein is albumin.

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