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CA-3020897-C - BOTULINUM TOXIN PREFILLED SYRINGE SYSTEM

CA3020897CCA 3020897 CCA3020897 CCA 3020897CCA-3020897-C

Abstract

The present invention relates a botulinum toxin prefilled syringe system with desirable injection force characteristics, in particular low gliding force and low break loose force, comprising a syringe barrel of glass containing a liquid botulinum toxin composition, a plunger stopper and a closure device such as a tip cap or a needle shield. In addition, the present invention relates to a kit comprising the botulinum toxin prefilled syringe system, and optionally instructions for use, and to the use of the botulinum toxin prefilled syringe system in therapeutic and cosmetic applications.

Inventors

  • Markus Vogt

Assignees

  • MERZ PHARMA GMBH & CO. KGAA

Dates

Publication Date
20260505
Application Date
20170620
Priority Date
20160622

Claims (16)

  1. Claims 1. A botulinum toxin prefilled syringe system comprising: a syringe barrel of glass, the syringe barrel including an inner surface defining a chamber containing a liquid botulinum toxin formulation, having a proximal end and a distal end, and having a label attached to its outside surface; a plunger stopper slidably positioned inside the syringe barrel and providing a fluid-tight seal of the proximal end of the syringe barrel; a closure device attached to the distal end of the syringe barrel, the closure device having an outlet engaging portion sealingly engaging and closing a distal open outlet end of the syringe system to prevent leakage of the liquid botulinum toxin formulation; wherein the plunger stopper has a plurality of annular ribs providing multiple discrete contact areas with the inner surface of the syringe barrel, wherein the plurality of annular ribs of the plunger stopper is three to five annular ribs, and wherein the botulinum toxin prefilled syringe system has a normalized maximum gliding force of 20 N or less, as measured at a temperature of 20°C and using a 32Gx1/2" needle and a displacement speed of 100 mm/min, wherein the normalized maximum gliding force is defined as follows: GFmax = GFmeasured X (dbarre1}2/(Dbarre1}2 wherein: GFmax is the normalized maximal gliding force in N, GFmeasured is the measured highest gliding force in N before the plunger stopper finishes its course at the distal end of the syringe barrel, dbarre1 is the barrel inner diameter of a reference syringe and is 6.35 mm, and Dbarre1 is the inner barrel diameter in mm of the prefilled syringe system, wherein the annular ribs extend outward radially from an axis of the plunger stopper, and wherein the annular rib located adjacent to the distal end of the plunger stopper has a greater Full Width at Half Maximum (FWHM) than the other annular ribs of the plunger Date Re9ue/Date Received 2024-01-25 stopper, wherein the FWHM is herein defined as the width in the axial direction of the plunger stopper between those two points on the surface of an annular rib, which are half the maximum height in perpendicular direction to the axis of the plunger stopper, wherein the distance between any two proximal adjacent annular ribs, except the most distal annular rib, in the axial direction of the plunger stopper is at least two times the sum of the full width at half maximum (FWHM) of the two adjacent annular ribs, wherein the inner surface of the syringe barrel is siliconized, wherein the plunger stopper is of an elastomeric material and has a coating on at least a portion of the plunger stopper such that the liquid botulinum toxin formulation contacts only said coating during storage or injection or during storage and injection, and wherein said coating is a fluoropolymer coating, a crosslinked silicone coating, or a coating consisting of an outer crosslinked silicone coating layered on a fluoropolymer coating.
  2. 2. The botulinum toxin prefilled syringe system of claim 1, wherein the botulinum toxin prefilled syringe system has a normalized break loose force of 15 N or less, as measured at a temperature of 20 °C using a 32Gx1/2" needle and a displacement speed of 100 mm/min, wherein the normalized break loose force is defined as follows: BLFnorm = BLFmeasured X (dbarre1)2/(Dbarre1}2 wherein: BLFnorm is the normalized break loose force in N, BLFmeasured is the measured break loose force in N and is defined as the highest force between 0 and 2 mm plunger displacement distance, dbarre1 is the barrel inner diameter of a reference syringe and is 6.35 mm, and Dbarre1 is the inner barrel diameter in mm of the prefilled syringe system.
  3. 3. The botulinum toxin prefilled syringe system of claim 1 or 2, wherein the normalized break loose force is lower than the maximum gliding force. Date Re9ue/Date Received 2024-01-25
  4. 4. The botulinum toxin prefilled syringe system of any one of claims 1 to 3, wherein the botulinum toxin prefilled syringe system has a normalized dynamic gliding force of 15 N or less, as measured at a temperature of 20°c using a 32Gx1/2" needle and a displacement speed of 100 mm/min, wherein the normalized dynamic gliding force is defined as follows: DGFnorm = DGFmeasured X (dbarre1}2/(Dbarre1}2 wherein: DGFnorm is the normalized dynamic gliding force in N, DGFmeasured is the mean gliding force calculated from the measured gliding forces at 1/3 and 2/3 of the total plunger displacement distance in N, dbarre1 is the barrel inner diameter of a reference syringe and is 6.35 mm, and Dbarre1 is the inner barrel diameter in mm of the prefilled syringe system.
  5. 5. The botulinum toxin prefilled syringe system of any one of claims 1 to 4, wherein (i) the normalized maximum gliding force (GFmax) is determined without storage or after storage for 12 months at 2 to 8°C or 25°C or (ii) the normalized break loose force (BLFnorm) is determined without storage or after storage for 12 months at 2 to 8°C or 25 °C or (iii) the normalized dynamic gliding force (DGFnorm) is determined without storage or after storage for 12 months at 2 to 8 °C or 25 °C, or (iv) GFmax and BLFnorm, or GFmax and DGFnorm, or BLFnorm and DGFnorm, or GFmax, BLFnorm and DGFnorm are determined according to (i) to (iii).
  6. 6. The botulinum toxin prefilled syringe system of any one of claims 1 to 5, wherein the plurality of annular ribs of the plunger stopper is three to four or four to five.
  7. 7. The botulinum toxin prefilled syringe system of any one of claims 1 to 6, wherein (i) the plunger stopper has a normalized total contact area with the inner surface of the syringe barrel of 70 mm2 or less, wherein the normalized total contact area is calculated as follows: TCAnorm = TCAcalc X (dbarre1}2/(Dbarre1}2 Date Re9ue/Date Received 2024-01-25 wherein: TCAnorm is the normalized total contact area in mm2, TCAca1c is the calculated total contact area in mm2 and is defined as the sum of the contact surfaces (CTrib) of each annular rib in mm2, wherein CTrib = 2nrh, with r being the greatest distance perpendicular to the axis of the plunger stopper between a point on the surface of the annular rib and the axis of the plunger stopper in mm, and h being the full width at half maximum (FWHM) of the annular rib in mm, the FWHM being defined as the width in the axial direction of the plunger stopper between those two points on the surface of the annular rib which are half the maximum height of the annular rib in perpendicular direction to the axis of the plunger stopper, dbarre1 is the barrel inner diameter of a reference syringe and is 6.35 mm, and Dbarre1 is the inner barrel diameter in mm of the prefilled syringe system, and/or (ii) the percentage of the calculated total contact area of the plunger stopper with the inner surface of the syringe barrel to the total side face area of the plunger stopper is 50% or less, wherein the calculated total contact area (TCAca1c) is defined as in (i) and the total side face area of the plunger stopper is defined as follows: TSFA = 21trmaxH wherein: TSFA is the total side face area of the plunger stopper in mm2, rmax is the greatest distance perpendicular to the axis of the plunger stopper between a point on the surface of any annular rib and the axis of the plunger stopper in mm, and His the total length of the plunger stopper in axial direction in mm.
  8. 8. The botulinum toxin prefilled syringe system of any one of claims 1 to 7, wherein the inner surface of the syringe barrel is spray-siliconized or baked-on siliconized.
  9. 9. The botulinum toxin prefilled syringe system of any one of claims 1 to 8, wherein Date Re9ue/Date Received 2024-01-25 the elastomeric material of the plunger stopper is a synthetic rubber, which is an isoprene rubber, a neoprene rubber, a butadiene rubber, a butyl rubber, a styrene-butadiene copolymer, a acrylonitrile-butadiene copolymer, a polysulfide elastomer, a urethane rubber, or an ethylene-propylene elastomer.
  10. 10. The botulinum toxin prefilled syringe system of claim 9, wherein the elastomeric material of the plunger stopper is a halogenated butyl rubber.
  11. 11. The botulinum toxin prefilled syringe system of any one of claims 1 to 10, wherein the outlet engaging portion of the closure device is of an elastomeric material or wherein the outlet engaging portion of the closure device is of an elastomeric material having a coating on an outer surface thereof such that the liquid botulinum toxin formulation contacts only said coating during storage or injection or during storage and injection.
  12. 12. The botulinum toxin prefilled syringe system of claim 11, wherein (i) the elastomeric material is a synthetic rubber, which is an isoprene rubber, a neoprene rubber, a butadiene rubber, a butyl rubber, a butyl rubber-isoprene rubber blend, a halogenated butyl rubber, a styrene-butadiene copolymer, an acrylonitrile-butadiene copolymer, a polysulfide elastomer, a urethane rubber, or an ethylene-propylene elastomer, (ii) the coating is a fluoropolymer coating, a crosslinked silicone coating, or a coating consisting of an outer crosslinked silicone coating layered on a fluoropolymer coating, or (iii) the elastomeric material is defined as in (i) and the coating is defined as in (ii).
  13. 13. The botulinum toxin prefilled syringe system of any one of claims 1 to 12, wherein the toxin activity is not reduced by more than 25%, relative to the initial toxin Date Re9ue/Date Received 2024-01-25 activity, upon storage of the botulinum toxin prefilled syringe system for 12 months at 5 °C or 25 °C.
  14. 14. A kit comprising a botulinum toxin prefilled syringe system according to any one of claims 1 to 13 and instructions for use of said botulinum toxin prefilled syringe system.
  15. 15. A botulinum toxin prefilled syringe system of any one of claims 1 to 13 for use in therapy.
  16. 16. Use of a botulinum toxin prefilled syringe system of any one of claims 1 to 13 in cosmetic applications. 2595358.1 Date Re9ue/Date Received 2024-01-25

Description

BOTULINUM TOXIN PREFILLED SYRINGE SYSTEM FIELD OF THE INVENTION [0001] The present invention relates a botulinum toxin prefilled syringe system with desirable injection force characteristics, in particular low gliding force and low break loose force, comprising a syringe barrel of glass containing a liquid botulinum toxin composition, a plunger stopper and a closure device such as a tip cap or a needle shield. In addition, the present invention relates to a kit comprising the botulinum toxin prefilled syringe system, and optionally instructions for use, and to the use of the botulinum toxin prefilled syringe system in therapeutic and cosmetic applications. BACKGROUND OF THE INVENTION [0002] Prefilled syringes (PFS) are increasingly used as a drug delivery device because of the range of compelling benefits, such as patient safety, convenience, dosing accuracy, reliability, and reduced amount of drug waste, over conventional delivery systems like vials and ampoules. Nowadays, prefilled syringes are considered to be the presentation of choice for numerous injectable drugs across a broad range of applications. [0003] The presentation of highly sensitive biological drugs like protein-based drugs in a prefilled syringe format is, however, often a key challenge for pharmaceutical companies. One reason is that the stability of protein-based drugs is frequently limited due to their high sensitivity to pH, temperature, ionic strength, specific chemical substances (e.g., free silicone particles) and other factors. Proteinbased drugs also generally have a high tendency to adsorb on syringe surfaces and are prone to aggregation and denaturation. Furthermore, the interaction of the liquid 1 Date Re9ue/Date Received 2024-01-25 protein formulation with the syringe materials during storage generally leads to the release of substances (so-called "extractables" and "leachables") which have the potential to exert an adverse effect on protein stability and activity. [0004] Another major concern for developers of prefilled syringes for highly sensitive protein-based drugs is the syringe functionality over time. For example, the sliding force may be too high to ensure the desired convenience, precision and accuracy of injection. Furthermore, the break loose force, especially after long-term storage of the prefilled syringe, may be inacceptable high leading to the risk of overdosing. It is therefore essential that the plunger moves freely when required to do so, and does not become stuck to the barrel even after long-time storage. However, syringe materials that might provide the desired syringe functionality, are frequently incompatible with sensitive protein-based drugs because of the release of extractables/leachables and other substances that may destabilize protein-based drugs. Therefore, it is in many cases a major challenge to obtain the desired syringe functionality. [0005] Botulinum toxin is an example of the above-mentioned sensitive proteinbased drugs. It is a highly potent neurotoxin and is produced by Clostridium botulinum and related Clostridium spp. Today, it is used in the treatment of a wide range of debilitating neuromuscular diseases (e.g., cervical dystonia, blepharospasm, spasticity, and hyperhidrosis) as well as in aesthetic medicine (e.g., treatment of facial wrinkles). The active principle of botulinum toxin, which naturally exists as a complex with other non-toxic clostridial proteins, is the neurotoxic polypeptide (also referred to as the "neurotoxic component"). The neurotoxic component exists in different serotypes (serotypes A to G) and consists of a heavy chain of about 100 kDa and a light chain of about 50 kDa. 2 Date Re9ue/Date Received 2024-01-25 [0006] Due to its inherent instability, botulinum toxin is commonly marketed as a lyophilized formulation for reconstitution with physiological saline prior to use, such as Botox® (Allergan Inc., Irvine, CA), Dysport® (Ipsen, France), and Xeomin® (Merz Pharma GmbH & Co. KGaA, Germany). The use of such lyophilized products, however, suffers from a number of drawbacks like inconvenience of use, sterility issues, inaccurate dosing, solubilizing/dilution problems, wasting of expensive reconstituted toxin, and limited storage time of the toxin formulation after reconstitution. [0007] Therefore, there is a strong demand in the art for a botulinum toxin prefilled syringe which provides sufficient toxin stability but also has the desired functionality in terms of suitable injection force characteristics. In particular, there is a great interest in a botulinum toxin syringe having a low gliding force to allow accurate administration of a given dose, even if low amounts of toxin are to be injected and/or the toxin is to be administered by multiple injections. Furthermore, there is also a great interest in a botulinum toxin syringe having a low break loose force to allow for repeated precise toxin injection and to mitigate the risk of toxin overdosing. OBJECTIVE OF T