Stable botulinum toxin pre-filled syringe dosage form capable of easily controlling discharge speed

Abstract

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

Description

[0001] Cross Reference to Related Applications

[0002] This application is a divisional application of Chinese Patent Application No. 202180026182.8, filed on September 29, 2022, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0003] The present invention relates to a botulinum toxin pre-filled syringe dosage form which is easy to control the discharge speed and stable. BACKGROUND

[0004] Botulinum toxin (BoNT) is one of the most toxic toxins known, which 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 a very small dose to an individual. For example, botulinum toxin is not only used for the treatment of neuromuscular diseases and overactive exocrine gland diseases, but also for cosmetic purposes.

[0005] Botulinum toxin is inherently unstable, in particular, it is known to be highly unstable at alkaline pH and heat-labile. The pre-filled syringe system is a drug administration form that overcomes these disadvantages, which has been increasingly popular as a drug delivery device in recent years. However, when a protein is used as an active ingredient, the limited stability of the protein makes it a particularly difficult task for formulating scientists to use the pre-filled syringe system. In particular, this applies to very dilute aqueous solutions of botulinum toxin.

[0006] In order to increase the stability of the pharmaceutical botulinum toxin composition, a stable protein such as human serum albumin (HSA) is often added. In addition, it is known to add non-protein stabilizers such as surfactants, polyvinylpyrrolidone (PVP), disaccharides, polyols, etc.

[0007] However, despite the above background art, there is still a need for a botulinum toxin pre-filled syringe dosage form which has high storage stability, is easy to control the discharge speed and is stable. SUMMARY

[0008] TECHNICAL PROBLEM

[0009] An aspect of the present invention provides a botulinum toxin pre-filled syringe dosage form which is easy to control the discharge speed and stable.

[0010] TECHNICAL SOLUTION

[0011] An aspect of the present invention provides a botulinum toxin pre-filled syringe dosage form, which comprises: a syringe including a syringe barrel, a plunger rod, and a plunger stopper; and a botulinum toxin liquid preparation filled in the syringe.

[0012] In the dosage form, the amount of force increase acting on the end of the plunger rod can be reduced as the speed of the botulinum toxin liquid formulation discharge increases.

[0013] 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 completely closed space. The syringe refers to a closed or sealed container made of plastic, such as organic polymer, or partially or mainly made of plastic.

[0014] The prefilled syringe has two openings, which 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 cap device.

[0015] The barrel can include 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 can have a tip projecting distally, in which 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 can have the same material as the rest of the barrel.

[0016] After filling, the barrel is used to seal the cap device (for example, a "tip cap" such as removed and replaced with a needle before use, or a sealing means 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 closed at the proximal end by a plunger or any other means that is fluidly sealed to the inner wall of the barrel to receive fluid. To use the prefilled syringe, the tip cap, needle shield or other type of cap device is removed, a needle is optionally attached (if not already), and the plunger tip or piston is advanced within the barrel to inject the contents within the barrel, i.e. the botulinum toxin formulation, into the patient.

[0017] The inner surface of the barrel can or can not have a coating. The inner surface of the barrel can be coated with a barrier layer (also referred to as "lubricant layer" below) for lubrication purposes, for example. The lubricant layer should not only provide high lubricity for the plunger to slide easily through the barrel, but also be compatible with the botulinum toxin dosage form and ensure its shelf life. The lubricant layer can be silicone-free or silicone-containing. The inner surface of the wall can be coated with silicone. That is, the barrier layer can be a silicone layer.

[0018] The silicone coating can be prepared by a siliconization method selected from the group consisting of a silicone oil based method (e.g., spray-on siliconization or baked-on siliconization) and a deposition method (e.g., plasma enhanced chemical deposition (PECVD)). The silicone coating can be formed by, for example, spray-on siliconization or baked-on siliconization coating. The silicone coating can be a polydimethylsiloxane coating.

[0019] In a spray-on siliconization method, for example, a diving or static nozzle can be used to spray silicone oil (e.g., DOW CORNING® 200® 360 Fluid, viscosity 1000 cSt) into a syringe barrel to create a thin layer of silicone oil. A baked-on siliconization method can include applying silicone oil as an emulsion, for example, DOW CORNING® 200® 360 Siliconization Emulsion, to the barrel and then baking at a specific temperature on the plastic surface for a specific time. The baked-on siliconization method can produce fewer naked-eye invisible silicone oil particles and naked-eye visible silicone oil particles compared to the spray-on siliconization method. 360) into a syringe barrel to create a thin layer of silicone oil. A baked-on siliconization method can include applying silicone oil as an emulsion, for example, DOW CORNING® 200® 360 Siliconization Emulsion, to the barrel and then baking at a specific temperature on the plastic surface for a specific time. The baked-on siliconization method can produce fewer naked-eye invisible silicone oil particles and naked-eye visible silicone oil particles compared to the spray-on siliconization method. 360) into a syringe barrel to create a thin layer of silicone oil. A baked-on siliconization method can include applying silicone oil as an emulsion, for example, DOW CORNING® 200® 360 Siliconization Emulsion, to the barrel and then baking at a specific temperature on the plastic surface for a specific time. The baked-on siliconization method can produce fewer naked-eye invisible silicone oil particles and naked-eye visible silicone oil particles compared to the spray-on siliconization method.

[0020] The material of the syringe barrel can include a plastic material. The material can be glass, cyclo olefin copolymer (COC), cyclo olefin polymer (COP), or a mixture thereof. The COP can be coated with silicone on its surface. COC can be made by polymerization of cyclic monomers such as norbornene with ethane, while COP can be made by ring-opening metathesis followed by hydrogenation of cyclic monomers. COC, COP, and mixtures of COP and COC materials exhibit a number of preferred properties, including high clarity, low density, significant moisture barrier capability, and resistance to aqueous and polar organic media. Specific examples include COC and Daikyo Crystal

[0021] The tip of the barrel can be integrally formed with the barrel. For example, the tip can be integrally formed with the barrel. The barrel can include an integrally formed luer lock tip or a luer slip tip. The tip can include an integral channel that extends axially 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.

[0022] 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 graduated markings that indicate the volume of fluid in the syringe. Additionally, the barrel can include a flanged interface. The design of the flange can conform to ISO 11040, for example. The flanged interface can be compatible with an optionally present handle.

[0023] The ratio of the length to the inner diameter of the syringe barrel can be 10 to 22, 12 to 20, or 14 to 16.

[0024] 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. Further, 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.

[0025] The plunger rod can be combined with a plunger stopper to form a plunger rod and plunger stopper assembly. The assembly can extend into the proximal end of the barrel. The assembly can include a rod that is in sliding, fluid-tight engagement with the cylindrical wall of the barrel cavity and has a plunger stopper at its tip. The assembly forms a proximal seal and a dynamic seal that can express the botulinum toxin liquid formulation. The stopper is in contact with the botulinum toxin liquid formulation during storage and / or administration.

[0026] The stopper can be made of an elastomeric material. The stopper optionally has a coating on at least a portion of it that is in contact with the botulinum toxin liquid formulation during storage and / or injection.

[0027] The elastomer can be isoprene rubber (IS), polybutadiene (BR), butyl rubber (copolymer of isobutylene and isoprene, IIR), halogenated butyl rubber (e.g., chlorinated butyl rubber, CIIR; and brominated butyl rubber, BIIR), styrene-butadiene rubber (copolymer of styrene and butadiene, SBR), or mixtures thereof. In a particular embodiment, the stopper material can be butyl rubber, halogenated butyl rubber, or mixtures thereof. In a particular embodiment, the stopper 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, phenol resins, and the like.

[0028] The stopper can have a coating or no coating. The coating can be applied at least to the sealing portion surface, which includes the surface portion of the plunger stopper facing the barrel cavity and in contact with the botulinum toxin formulation during storage and / or use. The coating can provide good lubricity while minimizing the interaction between the plunger stopper and the botulinum toxin liquid formulation.

[0029] A suitable coating for the plunger stopper can generally be made from a material that does not undesirably interfere with the botulinum toxin formulation and exhibits 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 XSi TM (Becton Dickinson).

[0030] 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), such as, ), PFA (a copolymer of tetrafluoroethylene (TFE) and perfluoroalkyl vinyl ether (PPVE)), tetrafluoroethylene-perfluoroalkyl ethylene copolymer, polyvinylidene fluoride (PVDF), polyvinyl fluoride (PVF), polytetrafluoroethylene (PTFE) (Teflon), or mixtures thereof. For example, the coating is made from ETFE, in particular, coating. In a particular embodiment, the plunger stopper can have no coating.

[0031] The design of the plunger stopper is not particularly limited and can be a nested or bagged stopper. Additionally, the interface for the rod can be threaded so that the rod can be installed after sterilization. Alternatively, the interface for the rod can be designed as a snap-on design. The rod, such as the plunger stopper, is generally designed to withstand sterilization, but is not limited in any particular way. The rod can be made from a plastic material, such as an ethylene vinyl acetate (EVA) copolymer or polypropylene.

[0032] Figure 1 An example of a pre-filled syringe including a needle is shown. 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 included in the cavity of the barrel 10.

[0033] The prefilled syringe can include a "capping device." The capping device refers to any means 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 passageway comprising a closed end and an open end, the passageway typically sized to receive and effectively seal the open outlet end of the syringe to prevent leakage.

[0034] For prefilled syringes without a pre-attached needle, the capping device is a capping means commonly known as a "tip cap." The tip cap forms a seal with the syringe tip that is fluid tight to effectively close 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 luer collar. The luer collar surrounds the upper portion of the syringe barrel (e.g., the syringe tip). The luer collar can have internal threads and the tip cap can have external threads that are complementary to the internal threads of the luer collar for coupling the tip cap to the syringe barrel. For the prefilled syringes of the present invention, the luer collar is typically integrally formed with the syringe barrel. Prior to use, the tip cap can be removed and then a needle cannula (needle assembly) can be securely coupled to the syringe tip.

[0035] 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 threads formed at the tip of the barrel 100 and a tip cap 120 secured to the tip by engagement with the luer collar, and a botulinum toxin liquid formulation 40 included in the cavity of the barrel 10.

[0036] 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 to deliver the botulinum toxin formulation from the syringe, the capping device can be referred to as a "needle shield." The needle shield can have a passageway comprising a closed end and an open end, the passageway typically sized to receive and couple the cannula (needle) mounted on the syringe tip. Typically, the (sharp) end of the cannula can pass through the closed end of the passageway in the needle shield to seal the open end of the cannula.

[0037] 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 formulation 40 included in the cavity of the barrel 10.

[0038] The closure device (e.g., tip cap or needle shield) can be a single component, typically can be made of a flexible and elastic polymeric material (e.g., elastomer), or can have an outer cap that is joined to a flexible and elastic inner cap, the outer cap being made of a rigid plastic material or of a material that includes or is made of, for example, an elastomer, at least a portion of which is in contact with and seals the distal opening of the syringe. Typically, at least the outlet junction portion of the sealing portion that is in contact with the distal tip opening to form a fluid seal is made of a flexible and / or elastic material (e.g., elastomer), the junction portion can be in contact with the botulinum toxin formulation during storage and / or use. The outlet junction portion can be made of a material that minimizes the potential for undesirable extractables / leachables. To further reduce the amount of extractables and / or leachables and increase compatibility with the botulinum toxin formulation, the outlet junction portion can have a coating thereon.

[0039] Suitable flexible and / or elastic materials for the closure device, particularly the outlet junction portion, can include elastomers that are capable of long-term storage without interfering with aqueous botulinum toxin formulations. In particular, the portion of the sealing device that is in contact with or configured to come into contact with the botulinum toxin dosage form, such as the outlet junction 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" can include cross-linked thermoset rubbery polymers that are more easily deformed than plastics but are approved for use with pharmaceutical grade fluids and are not prone to leaching or gas migration.

[0040] The elastomeric material can be isoprene rubber (IS), polybutadiene (BR), butyl rubber (copolymer of isobutylene and isoprene, IIR), halogenated butyl rubber (e.g., chlorinated butyl rubber, CIIR; and brominated butyl rubber, BIIR), styrene-butadiene rubber (copolymer of styrene and butadiene, SBR), or mixtures thereof. For example, the elastomeric material can be butyl rubber or halogenated butyl rubber, particularly brominated butyl rubber or chlorinated butyl rubber, or mixtures 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, and the like.

[0041] Suitable coatings optionally present on the outlet junctions made of the above-mentioned elastomeric materials can generally be made of materials that do not unpreferably interfere with aqueous botulinum toxin formulations and exhibit low levels of extractables / leachables. Coatings for use in the present application can 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 (Daikyo Seiko or XSi TM (Becton Dickinson).

[0042] Fluoropolymer coatings can include fluorinated ethylene-propylene copolymer (e.g., tetrafluoroethylene-hexafluoropropylene copolymer (FEP)), fluorinated ethylene-ethylene copolymer (e.g., ethylene-tetrafluoroethylene copolymer (ETFE), e.g., ), PFA (copolymer of tetrafluoroethylene (TFE) and perfluoropropyl vinyl ether (PPVE)), tetrafluoroethylene-perfluoroalkyl ethylene copolymer, polyvinylidene fluoride (PVDF), polyvinyl fluoride (PVF), polytetrafluoroethylene (PTFE), or mixtures thereof. The coating is made of, for example, ETFE, and can be coated.

[0043] 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.

[0044] 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.

[0045] 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 units / syringe.

[0046] As used herein, the term "botulinum toxin" refers broadly to any form or type of botulinum toxin. More specifically, the botulinum toxin can be botulinum toxin type A, B, CI, C2, D, E, F, G, or mixtures thereof. For example, the botulinum toxin can be serotype A, B, or CI.

[0047] In addition, the term "botulinum toxin" is intended to include both botulinum toxin complexes ("toxin complexes") and the "neurotoxic component" of botulinum toxin or complexes. As used herein, the term "botulinum toxin complex" refers to a high molecular weight complex comprising a neurotoxic component of about 150 kDa and non-toxic proteins of Clostridium botulinum comprising hemagglutinin and non-hemagglutinin proteins. A botulinum toxin serotype A complex may, for example, be Meditoxin (Medytox Inc.).

[0048] As used herein, the term "neurotoxic component" relates to the neurotoxic polypeptide of the toxin complex ("150 kDa" polypeptide; typically in its di-chain form) which is free of any associated non-toxic proteins. A pure neurotoxic component may, for example, be Coretox (Medytox Inc.). 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 Cl, in particular serotype A). In other words, the botulinum toxin dosage form contained in the prefilled syringe can contain only the neurotoxic component and not any other proteins of the Clostridium botulinum toxin complex.

[0049] The botulinum toxin includes wild-type botulinum toxin, e.g., functional (i.e., biologically active) isoforms, homologs, orthologs, paralogs, and fragments of botulinum toxin that exhibit 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more sequence identity to the amino acid sequence of the neurotoxic component of wild-type botulinum toxin A or serotype Al botulinum toxin deposited with the GenBank database under accession number AAA23262.

[0050] Sequence identity can be calculated by any algorithm suitable to yield reliable results, e.g., using the FASTA algorithm (file

WR Pearson & DJ Lipman, PNAS 85:2444-2448, 1988

[0051] The botulinum toxin includes modified and recombinant botulinum toxin.

[0052] The botulinum toxin liquid formulation can include other pharmaceutically acceptable substances, for example, a salt (e.g., sodium chloride), a stabilizing protein (e.g., albumin, gelatin), a sugar (e.g., glucose, fructose, galactose, trehalose, sucrose, and maltose), a carbohydrate polymer (e.g., hyaluronic acid and polyvinylpyrrolidone (PVP)), a polyol (e.g., glycerol and sugar alcohols such as mannitol, inositol, lactitol, isomaltitol, xylitol, erythritol, sorbitol), an amino acid, a vitamin (e.g., vitamin C), zinc, magnesium, an anesthetic (e.g., a local anesthetic such as lidocaine), a surfactant, a tonicity modifier, and the like. As used herein, the term "pharmaceutically acceptable" refers to a compound or material that is suitable for contact with the tissues of a mammal, particularly a human, without an adverse effect.

[0053] The botulinum toxin liquid formulation can be free of animal-derived ingredients. The botulinum toxin liquid formulation can be free of albumin. For example, the botulinum toxin liquid formulation can include, in water, a botulinum toxin, an amino acid, a surfactant, and a tonicity modifier. The botulinum toxin liquid formulation may, for example, include, in water, 10 U / ml to 70 U / ml of a botulinum toxin, 0.05 g / L to 0.7 g / L of an amino acid, 0.10 g / L to 0.5 g / L of a surfactant, and 0.10 g / L to 1.0 g / L of a sodium chloride aqueous solution. The botulinum toxin can be botulinum toxin type A, B, CI, C2, D, E, F, G, or a mixture thereof. The amino acid can be glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, glutamic acid, a pharmaceutically acceptable salt thereof, or a mixture thereof. The amino acid may, for example, be methionine, histidine, arginine, a pharmaceutically acceptable salt thereof, or a mixture thereof. The surfactant can be a non-ionic surfactant. The non-ionic surfactant can be a polysorbate, a poloxamer, or a mixture thereof. The polysorbate can be polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a mixture thereof. The sodium chloride can 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.

[0054] The botulinum toxin liquid formulation can further include a buffer to maintain the pH at about 5.5 to about 7.5. The buffer can be citrate, histidine, HEPES, arginine, acetic acid, phosphoric acid, a salt thereof, or a mixture thereof.

[0055] The pH of the botulinum toxin preparation can remain 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 during storage.

[0056] The botulinum toxin liquid preparation can exhibit a recovery of LD50 titers of 75% to 125%, 75% to 120%, or 80% to 125% compared to the initial value when stored at 25°C under accelerated test conditions for 2 months, 4 months, or 6 months. 50 titer recovery.

[0057] The botulinum toxin liquid preparation can exhibit a recovery of LD50 titers of 75% to 125%, 75% to 120%, or 80% to 125% compared to the initial value when stored at 25°C under accelerated test conditions for 2 months, 4 months, or 6 months.

[0058] The botulinum toxin liquid preparation can exhibit a pH fluctuation of ±1.5, ±1.0, or ±0.5 or less compared to the initial value when stored at 25°C under accelerated test conditions for 2 months, 4 months, or 6 months.

[0059] One embodiment can be a botulinum toxin pre-filled syringe dosage form including a syringe barrel, a syringe including a plunger rod and a plunger stopper, and a botulinum toxin liquid preparation filled in the syringe, wherein an increase in force acting on the end of the plunger rod decreases as the speed of the botulinum toxin liquid preparation being expelled increases.

[0060] In the specific embodiments, 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 silicone-coated COP. The material of the syringe barrel can be COC. The silicone coating can be a spray silicone coating, a baked silicone coating, or a polydimethylsiloxane coating. The material of the plunger stopper can be isoprene rubber (IS), butadiene rubber (BR), butyl rubber, halogenated butyl rubber, styrene-butadiene rubber, or a mixture thereof. The plunger stopper can be free of coating. The dose of the botulinum toxin liquid formulation can be 10 units / syringe to 50 units / syringe. The botulinum toxin liquid formulation can be free of albumin. The botulinum toxin liquid formulation can be free of animal-derived ingredients. The botulinum toxin liquid formulation can include botulinum toxin, an amino acid, a surfactant, and an isotonic agent. The amino acid can be methionine. The surfactant can be polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or poloxamer. The botulinum toxin liquid formulation can further 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, a salt thereof, or a mixture thereof. The botulinum toxin liquid formulation can show a recovery rate of LD50titer of 80% to 125% compared to the initial value when stored for 2 months, 4 months, or 6 months under accelerated test conditions at 25°C. The botulinum toxin liquid formulation can show a pH fluctuation of ±1.0 or less compared to the initial value when stored for 2 months, 4 months, or 6 months under accelerated test conditions at 25°C. 50 The botulinum toxin liquid formulation can show a recovery rate of LD50titer of 80% to 125% compared to the initial value when stored for 2 months, 4 months, or 6 months under accelerated test conditions at 25°C. The botulinum toxin liquid formulation can show a pH fluctuation of ±1.0 or less compared to the initial value when stored for 2 months, 4 months, or 6 months under accelerated test conditions at 25°C.

[0061] Another specific embodiment can be a botulinum toxin pre-filled syringe dosage form including a syringe barrel, a syringe including a plunger rod and a plunger stopper, and a liquid formulation of botulinum toxin filled in the syringe, the material of the syringe barrel being glass, COC, or silicone-coated COP.

[0062] In the specific embodiments, the material of the syringe barrel can be COC. The silicone coating can be a spray-on silicone coating, a baked-on silicone coating, or a polydimethylsiloxane coating. The material of the plunger stopper can be isoprene rubber (IS), butadiene rubber (BR), butyl rubber, halogenated butyl rubber, styrene-butadiene rubber, or a mixture thereof. The plunger stopper can be free of a coating. The amount of force acting on the end of the plunger rod can decrease as the rate of the botulinum toxin liquid formulation being expelled increases. 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 dose of the botulinum toxin liquid formulation can be 10 units / syringe to 50 units / syringe. The botulinum toxin liquid formulation can be free of albumin. The botulinum toxin liquid formulation can be free of animal-derived ingredients. The botulinum toxin liquid formulation can include botulinum toxin, an amino acid, a surfactant, and an isotonic agent. The amino acid can be methionine. The surfactant can be polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or poloxamer. The botulinum toxin liquid formulation can further 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, a salt thereof, or a mixture thereof. The botulinum toxin liquid formulation can exhibit an LD50titer recovery of 80% to 125% compared to the initial value when stored at 25°C under accelerated testing conditions for 2 months, 4 months, or 6 months. 50 The botulinum toxin liquid formulation can exhibit an LD50titer recovery of 80% to 125% compared to the initial value when stored at 25°C under accelerated testing conditions for 2 months, 4 months, or 6 months. The botulinum toxin liquid formulation can exhibit a pH fluctuation of within ±1.0 compared to the initial value when stored at 25°C under accelerated testing conditions for 2 months, 4 months, or 6 months.

[0063] Another specific embodiment can be a botulinum toxin prefilled syringe dosage form including a syringe barrel, a syringe including a plunger rod and a plunger stopper, and a botulinum toxin liquid formulation filled in the syringe, the botulinum toxin liquid formulation being free of albumin.

[0064] The specific embodiments can be a botulinum toxin pre-filled syringe dosage form including 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 being free of animal-derived ingredients. The botulinum toxin liquid preparation can include botulinum toxin, an amino acid, a surfactant, and an isotonic agent. 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 further 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, a salt thereof, or a mixture thereof. The dose of the botulinum toxin liquid preparation can be 10 units / syringe to 50 units / syringe. The material of the syringe barrel can be glass, COC, or silicone-coated COP. The material of the syringe barrel can be COC. The silicone coating can be a spray silicone coating, a baked silicone coating, or a polydimethylsiloxane coating. The material of the plunger stopper can be isoprene rubber (IS), cis-butadiene rubber (BR), butyl rubber, halogenated butyl rubber, styrene-butadiene rubber, or a mixture thereof. The plunger stopper can have no coating. In the botulinum toxin pre-filled syringe dosage form, as the speed of discharge of the botulinum toxin liquid preparation increases, the amount of increase in the force acting on the end of the plunger rod can be reduced. 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 botulinum toxin liquid preparation can show a recovery rate of LD 50 titer of 80% to 125% compared to the initial value when stored for 2 months, 4 months, or 6 months under accelerated test conditions at 25°C. The botulinum toxin liquid preparation can show a recovery rate of protease activity of 80% to 125% compared to the initial value when stored for 2 months, 4 months, or 6 months under accelerated test conditions at 25°C. The pH fluctuation of the botulinum toxin liquid preparation can be within ±1.0 compared to the initial value when stored for 2 months, 4 months, or 6 months under accelerated test conditions at 25°C.

[0065] Advantageous Effects

[0066] The botulinum toxin pre-filled syringe dosage form according to an aspect can show a recovery rate of LD 50 The titer, the endopeptidase titer of botulinum toxin, and the pH value can be maintained stable. In addition, according to the botulinum toxin pre-filled syringe dosage form, it is easy to control the discharge speed. BRIEF DESCRIPTION OF DRAWINGS

[0067] Figure 1 An example of a prefilled syringe including a needle is shown.

[0068] Figure 2 An example of a prefilled syringe including a tip cap is shown.

[0069] Figure 3 An example of a prefilled syringe including a needle assembly and a needle shield is shown. DETAILED DESCRIPTION

[0070] The present application will be described in greater detail by reference to the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present application.

[0071] Example 1: Stability of botulinum toxin prefilled liquid syringe formulations: syringes with barrel made of COC or COP material

[0072] 1. Preparation of prefilled liquid botulinum toxin formulation

[0073] In this example, a liquid botulinum toxin formulation was filled in a syringe for highly viscous drugs (hereinafter "HVD syringe") and the stability according to the storage period 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 liquid formulation filling volume of 0.8 mL. For reference, as an example of a prior known syringe, TopPac TM The syringe had 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 to the TopPac TM The HVD syringe had a smaller inner diameter and a longer length than the TopPac TM The syringe included a barrel made of COC material and formed with a Luer Lock, a plunger, a plunger rod, and a tip cap. The inner surface of the barrel was silicified with a reactive silicone mixture and then crosslinked by curing. The tip cap was made of rubber (Datwyler). The HVD syringe included COC material made of TOPAS 6015 material and had higher heat resistance.

[0074] Further, in the HVD syringe, the stability is measured in terms of the material of the barrel, the material of the plunger stopper and the material used for its coating, and the composition of the aqueous liquid botulinum toxin preparation filled in the barrel. Wherein, the syringe comprises a plastic syringe barrel, a closure device and a plunger rod assembly. The barrel comprises a proximal end and a distal end, and a substantially cylindrical wall extending between the proximal end and the distal end and forming a barrel cavity. The barrel has a distally projecting tip with a fluid passage extending through the tip and in communication with the barrel cavity, the substantially cylindrical wall having an inner surface optionally coated with a barrier layer. In the present embodiment, the inner surface of the wall is coated with silicone, i.e. the barrier layer is a silicone layer. Further, in the present embodiment, the barrel has a COC or COP material.

[0075] The closure device has an outlet joining portion sealingly joining and closing the open outlet of the barrel distal end. The closure device for the barrel distal end consists of a cap made of polycarbonate material and a rubber tip cap made of the same material as the plunger. Wherein the rubber tip cap corresponds to the outlet joining portion. The outlet joining portion is made of an elastomeric material optionally having a coating on the surface. The outlet joining portion and the closure device are joined in the form of a luer lock.

[0076] The plunger rod assembly extends into the proximal end of the barrel and comprises a plunger stopper slidingly fluid-tightly joined with the cylindrical wall of the barrel cavity, the stopper being made of an elastomeric material, optionally having a coating on at least a portion of the stopper in contact with the aqueous liquid botulinum toxin preparation during storage and / or injection. In the present embodiment, the material of the stopper is bromobutyl rubber (BIIR) or chlorobutyl rubber (CIIR), optionally coated with Teflon.

[0077] Table 1 shows the botulinum toxin pre-filled syringe formulation of the pre-filled liquid botulinum toxin preparation in water used in the present embodiment.

[0078]

Table 1

[0079]

[0080]

[0081] In Table 1, COC represents a cyclic olefin copolymer, COP represents a 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 portion. Among them, butyl rubber (IIR) is a copolymer of isobutylene and isoprene. Teflon coating refers to coating a FluroTecR film on the surface of BIIR or CIIR. L-Met, T20, sodium chloride, and toxin represent the amount of L-methionine, polysorbate 20, sodium chloride, and botulinum toxin type A component dissolved in water, i.e., water for injection.

[0082] The formulation incorporates the plunger rod assembly into the cavity of the barrel so that the stopper of the plunger seals the liquid formulation when in contact with the liquid formulation. In addition, the outlet incorporating portion of the distal end of the barrel is sealingly incorporated with the cap device to close the open outlet. The syringe is integrally formed with the cap device, and the cap device is removed before use. At this time, the liquid comes into contact with the rubber tip cap inside the cap device.

[0083] That is, the prefilled syringe botulinum liquid formulation is in a state in which the syringe is connected to the cap device without the injection needle being connected thereto.

[0084] Therefore, by adding two different concentrations of methionine and polysorbate 20 to four syringes, a total of eight prefilled syringe botulinum liquid formulations were prepared, in which the material of the syringe barrel was selected from COC and COP, and the stopper of the plunger was selected from brominated butyl rubber and chlorinated butyl rubber and Teflon coating thereof.

[0085] 2. Long-term stability test of prefilled syringe dosage form

[0086] (1) Titer test

[0087] The prepared eight dosage forms, i.e., A dosage form to H dosage form, were stored in a stability sample storage room at 4°C, and the median lethal dose (LD 50 ) of mice was measured at 0 months, 3 months, 6 months, 9 months, 12 months, 18 months, and 24 months.

[0088] After performing a graded dilution on liquid samples of 8 dosage forms, 4-week-old female ICR mice with a body weight of 17 g to 22 g were administered intraperitoneally. Three days after administration, the lethality of each diluted sample was observed, and the half-lethal dose was calculated using the statistical program PROBIT. The half-lethal dose of the 0th month was set to 100%, and the change trend of the half-lethal dose obtained at each time point was expressed in percentage. Table 2 is a table showing the half-lethal dose according to the storage period of dosage forms A, B, C, D, E, F, G, and H.

[0089] [Table 2]

[0090]

[0091] As shown in Table 2, the recovered lethal dose values of dosage forms A to F measured at the 24th month were 73% or more, but for dosage forms G and H, the recovered lethal dose values were not measured from the 9th month. This indicates that, regardless of whether the plunger stopper material is BIIR or CIIR, or whether the surface of the plunger stopper is coated with Teflon, when the barrel is made of a COC material and a silicone coating, the botulinum toxin can remain stable for 24 months. On the other hand, when the barrel material is COP, the recovered titer was not measured in the syringe from the 9th month.

[0092] (2) Botulinum neurotoxin endopeptidase titer analysis

[0093] The 8 pre-filled syringe dosage forms A to H were stored in a stable room, and the activity of BoNTA / LC was measured at the 0th month, the 3rd month, the 6th month, the 9th month, the 12th month, the 18th month, and the 24th month.

[0094] 100 ul of a SNAP25 (self-made) fragment consisting of a sequence of about 70 amino acids 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 a sequence of 10 or more consecutive amino acids including a cleavage site between amino acids 197 and 198.

[0095] A standard sample, which is a BONTA sample, for which a quantitative curve can be obtained, was prepared using a BoNTA standard (Innotox, Medytox Co.), and test samples A to H were prepared by diluting the BONTA in a HEPES solution (Sigma Co.) so that the result values of the samples A to H could be included in the range of the quantitative curve. Each of the standard sample and the test samples A to H was put into a well containing SNAP25 and reacted for 1 hour at room temperature. Next, an anti-SNAP25 polyclonal antibody (self-made) was added to each well and reacted for 1 hour at room temperature. After an HRP-conjugated secondary antibody was reacted for 1 hour at room temperature, a color developing reagent 3,3',5,5'-Tetramethylbenzidine (TMB) was added, and color development was incubated.

[0096] The absorbance at 450 nm was measured in a microplate reader (TECAN Co.), the degree of color development was quantified according to the activity of the BoNT / LC, and a quantitative curve was obtained using the absorbance values of the standard sample. By substituting the absorbance values of the samples A to H into the quantitative curve, the BoNT / LC activity possessed by each sample was calculated. The activity of the BoNT / LC at the 0th month was set to 100%, and the activity change trend of the BoNT / LC obtained at each time point was expressed in percentage. Table 3 is a table showing the endopeptidase activity of the BoNTA contained in the dosage forms A to H according to the storage period.

[0097]

Table 3

[0098]

[0099]

[0100] As shown in Table 3, the recovery titers of the dosage forms A to F at the 24th month were maintained at 111% to 141% compared to the initial stage, but the recovery titers of the dosage forms G and H were not measured from the 9th month.

[0101] (3) pH stability

[0102] Each sample of the 8 pre-filled syringe dosage forms A to H at the 0th month, the 3rd month, the 6th month, the 9th month, the 12th month, the 18th month, and the 24th month was put into a 15 mL disposable test tube to 3 mL or more, and the pH of each sample was measured with a pH meter (Mettler Toledo Co.). Table 4 is a table showing the change in the pH of the dosage forms A to H according to the storage period.

[0103]

Table 4

[0104]

[0105]

[0106] As shown in Table 4, the pH of the dosage forms A to F remained between 6.8 and 7.4 at the 24th month, but the pH of the dosage forms G and H remained between 5.3 and 5.9 at the 6th month when the activity was measured.

[0107] Example 2: Stability of botulinum toxin pre-filled liquid syringe dosage forms: syringes having barrels made of glass or COP materials

[0108] 1. Preparation of a pre-filled botulinum toxin liquid formulation

[0109] Botulinum toxin pre-filled liquid formulations in the following Table 5 were prepared. At this time, the syringes were HVD syringes described in Table 1, which had 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.

[0110]

Table 5

[0111]

[0112]

[0113] The barrels of the dosage forms I and J in Table 5 were products of POONGLIM Pharmatech Inc. (catalog number, Art. 69, Republic of Korea), the barrels of the dosage forms K and L were products of SiO2 Medical Products Inc. (catalog number, 850009-100-04, USA), and the barrels of the dosage forms M and N were products of TERUMO Corporation (catalog number, PJ-B1L9BFTF1, Japan). The botulinum toxin was BTX1301 (API batch number) of Medytox Corporation, which is a BoNTA. In Table 5, COC indicates a cyclic olefin copolymer, and COP indicates a clyclic olefin polymer. BIIR and CIIR indicate brominated and chlorinated butyl rubber (IIR), respectively. Among them, butyl rubber (IIR) is a copolymer of isobutylene and isoprene. L-Met, T20, sodium chloride, and toxin indicate the amounts of L-methionine, polysorbate 20, sodium chloride, and botulinum toxin type A ingredients dissolved in water. The pH of the liquid containing these ingredients was 6.0 to 7.0.

[0114] The formulation combines the plunger rod assembly into the cavity of the barrel such that the stopper of the plunger seals the liquid formulation when in contact with the liquid formulation. In addition, the outlet coupling portion of the distal end of the barrel is sealingly coupled to the closure device to close the open outlet. That is, the prefilled syringe botulinum liquid formulation is in a state where the syringe is connected to the closure device without a syringe needle connected thereto.

[0115] Thus, by adding 2 different concentrations of methionine and polysorbate 20 to 3 syringes, a total of 6 prefilled syringe botulinum liquid formulations I to N were prepared, in which the material of the syringe barrel was selected from glass and COP, and the plunger stopper was selected from bromobutyl rubber and i-coating.

[0116] 2. Stability test of prefilled syringe formulations I to N

[0117] (1) Titer test

[0118] The prepared 6 formulations, i.e., the I to N formulation samples, were stored in a constant temperature and humidity chamber (Binder Co.) at 25°C for use in experiments under accelerated test conditions. To perform a 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 month, 2nd month, 3rd month, 4th month, and 6th month after storage.

[0119] After performing a graded dilution of the liquid samples of the 6 formulations, 4-week-old female ICR mice weighing 17 to 22 g were administered intraperitoneally. The mortality rate 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 of the 0th month was set to 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 dose according to the storage period of the formulations I, J, K, L, M, and N.

[0120]

Table 6

[0121]

[0122] As shown in Table 6, at the 6th month, the titers of the 6 prefilled syringe formulations I to N were maintained in the range of 86% to 108% compared to the initial titer.

[0123] (2) Botulinum toxin endopeptidase titer analysis

[0124] The 6 prefilled syringe formulations I to N were stored in a stability chamber, and the activity of BoNTA / LC was measured at the 0th month, 2nd month, 3rd month, 4th month, and 6th month.

[0125] 100ul of a SNAP25 (self-made) fragment consisting of about 70 amino acid sequences was put into each well of a 96-well plate and incubated at 2 to 8°C for 16 hours. The SNAP25 fragment included 10 or more consecutive amino acid sequences including a cleavage site between amino acids 197 and 198.

[0126] A standard sample, i.e., a BONTA sample, from which a quantitative curve was obtained, was prepared using a BoNTA standard (Innotox, Medytox Corporation), and test samples A to H were prepared by diluting BONTA in a HEPES solution (Sigma Corporation) so that the result values of the dosage forms A to H samples could be included in the range of the quantitative curve. Each of the standard sample and the test samples A to H was put into a well containing SNAP25 and reacted at room temperature for 1 hour. Next, an anti-SNAP25 polyclonal antibody (self-made) was added to each well and reacted at room temperature for 1 hour. After an HRP-conjugated secondary antibody was reacted at room temperature for 1 hour, a color developing reagent 3,3',5,5'-Tetramethylbenzidine (TMB) was added, and color development was incubated.

[0127] The absorbance at 450 nm was measured in a microplate reader (TECAN Corporation), the degree of color development was quantified according to the activity of BoNT / LC, and a quantitative curve was obtained using the absorbance values of the standard sample. By substituting the absorbance values of the samples I to N into the quantitative curve, the BoNT / LC activity possessed by each sample was calculated. The activity of BoNT / LC at the 0th month was set to 100%, and the activity change trend of BoNT / LC obtained at each time point was expressed in percentage. Table 7 is a table showing the endopeptidase activity of BoNTA contained in the dosage forms I to N according to the storage period.

[0128]

Table 7

[0129]

[0130]

[0131] As shown in Table 7, the recovery titers of the dosage forms I to N at the 6th month were maintained at 53 to 94% compared to the initial values.

[0132] (3) pH stability

[0133] Each sample of the six pre-filled syringe dosage forms I to N at a certain time point was put into a 15 mL disposable test tube to 3 mL or more, and the pH of each sample was measured with a pH meter (Mettler Toledo). Table 8 is a table showing the change in the pH of dosage forms I to N with the storage period. The time points of the accelerated condition experiment were the 0th month, 2nd month, 4th month, and 6th month, and the time points of the long-term storage experiment were the 0th month, 3rd month, and 6th month.

[0134] [Table 8]

[0135]

[0136] As shown in Table 8, the pH of dosage forms I to N was maintained at 7.1 to 7.9 until the 6th month.

[0137] Example 3: Stability of botulinum toxin pre-filled liquid syringe dosage form: effect of albumin 1, preparation of pre-filled liquid botulinum toxin formulation

[0138] As shown in Table 9 below, dosage form O containing human serum albumin without L-Met and polysorbate 20 and dosage form P containing L-Met and polysorbate 20 without human serum albumin were prepared. In Table 9, the solvent is water, and the toxin is a BoNT / A product manufactured by Medytox.

[0139] Dosage forms O and P were filled into the HVD syringes. Among them, the HVD syringes were B syringes of Table 1, the barrel was made of COC material, and the plunger was made of siliconized BIIR material.

[0140] [Table 9]

[0141]

[0142] 2, titer test: LD 50 (Accelerated test)

[0143] The prepared two, i.e., dosage forms O and P samples were pre-filled in each syringe, and the syringe dosage forms were stored in a stability chamber, and the LD 50 ) of mice was measured on the 0th day, 2nd day, 3rd day, 7th day, 14th day, 28th day, and 56th day.

[0144] Samples 1 and 2 were diluted with water in stages, 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 half-lethal dose was calculated using the statistical program PROBIT. The half-lethal dose of the 0th month was set to 100%, and the change trend of the half-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 speed constant and the temperature.

[0145] Table 10 is a table showing the storage stability of the albumin-containing formulation O and the non-albumin-containing formulation P as LD 50 values.

[0146]

Table 10

[0147]

[0148] In Table 10, STD is Meditoxin (Medytox Co.) as a standard sample, normalization indicates the relative titer when the data value of the 0th day is set to 100, and N / A indicates that the test was not performed because the test result of the previous cycle was LD 50 values were as low as about 20%, so it was meaningless to perform the test. The three formulations prepared, i.e., the standard sample (STD), the formulation O, and the formulation P, under the accelerated condition of 56 days, i.e., about 2 months, the albumin-containing formulation O lost the recovery titer on the 28th day of the test, but the non-albumin-containing formulation P maintained the recovery titer of 86% on the 28th day and the recovery titer of 52% on the 56th day. For the accelerated condition, the samples were stored at 40°C, and the samples were recovered on the 0th day, the 2nd day, the 5th day, the 7th day, the 14th day, the 28th day, and the 56th day to perform the experiment.

[0149] 3. Injection force test

[0150] The albumin-containing formulation O and the non-albumin-containing formulation P described in Table 9 were each filled into the SHOTT TopPac syringe 1 ml and the HVD syringe described in Section 1 of Example 1, i.e., the B syringe of Table 1, to prepare a total of 4 pre-filled syringe botulinum liquid formulations Q, R, S, and T, i.e., 4 formulations.

[0151] For the 4 formulations, the plunger injection force according to the speed of the plunger movement of the syringe plunger was measured using a MultiTest 2.5 (Mecmesin, UK) tensile compression device. The injection force was the average injection force.

[0152] Specifically, first, a 30G needle was attached to each of the syringes filled with the 4 formulations, respectively. Next, the syringes were fixed to the clamps of the tensile compression device, and the plunger rod was adjusted to be centered on the load cell of the device. The clamps were the syringe fixing parts of the device.

[0153] 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 test was performed by starting the device by pressing the start button. For the measurement distance, since the HVD syringe has a small inner diameter and a large length, the contents were filled to a height of about 40 mm when 1 mL was filled, and the TopPac syringe was filled to a height of about 30 mm when 1 mL was filled, and in measuring the injection force, in order to be safe, the measurement distance was set to push the plunger of the HVD syringe to 0 mm to 35 mm and the plunger of the TopPac syringe to 0 mm to 25 mm, leaving a margin of 5 mm. After the measurement was completed, the samples were removed from the clamps, and the injection force results were obtained by repeating the measurement 3 times for each sample. Table 11 is a table showing the injection force according to the speed of the plunger movement.

[0154]

Table 11

[0155]

[0156] As shown in Table 11, the formulations 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 compared to the formulations Q and S including the TopPac syringe, but had lower injection force at high plunger movement speeds of 100 mm / min and 200 mm / min compared to the formulations Q and S including the TopPac syringe. This indicates that the formulations R and T including the HVD syringe have higher plunger compression force at low plunger movement speeds and lower plunger compression force at high plunger movement speeds compared to the formulations Q and S including the TopPac syringe. Accordingly, the formulations including the HVD syringe can be finely operated at low speed, and injection can be more easily performed at high speed.

Claims

1. A botulinum toxin pre-filled syringe dosage form comprising: a syringe, comprising a syringe barrel, a plunger rod, and a plunger stopper; and a botulinum toxin liquid preparation filled in the syringe, wherein the material of the syringe barrel comprises cyclic olefin copolymer; and The botulinum toxin liquid preparation does not contain albumin.

2. The dosage form according to claim 1, wherein the material of the plunger stopper comprises at least one of isoprene rubber, butadiene rubber, butyl rubber, halogenated butyl rubber and styrene-butadiene rubber.

3. The dosage form of claim 1, wherein the botulinum toxin liquid preparation does not contain animal ingredients.

4. The dosage form according to claim 1, wherein the botulinum toxin liquid preparation comprises botulinum toxin, an amino acid, a surfactant, and an isotonicity agent.

5. The dosage form of claim 4, wherein the amino acid comprises methionine.

6. The dosage form of claim 4, wherein the surfactant comprises at least one of a polysorbate and a poloxamer.

7. The dosage form of claim 4, wherein the botulinum toxin liquid formulation further comprises a buffer to maintain the pH at 5.5 to 7.

5.

8. The dosage form according to claim 1, wherein when the botulinum toxin liquid preparation is stored under accelerated test conditions at 25°C for 2 months, 4 months or 6 months, it shows an LD of 80% to 125% compared to the initial value. 50 Titer recovery rate.

9. The dosage form of claim 1, wherein when the botulinum toxin liquid formulation is stored under accelerated test conditions at 25° C. for 2 months, 4 months, or 6 months, it exhibits a protease activity recovery rate of 80% to 125% compared to the initial value; or, the pH fluctuation is within ±1.0 compared to the initial value.

10. A botulinum toxin pre-filled syringe dosage form comprising: a syringe, comprising a syringe barrel, a plunger rod, and a plunger stopper; and a botulinum toxin liquid preparation filled in the syringe, wherein the material of the syringe barrel comprises glass or cycloolefin polymer; and The botulinum toxin liquid preparation does not contain albumin.

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