Botulinum toxin prefilled syringe system

Patent metadata

Field	Value
Publication number	US-2019201630-A1
Application number	US-201716311728-A
Country	US
Kind code	A1
Filing date	Jun 20, 2017
Priority date	Jun 22, 2016
Publication date	Jul 4, 2019
Grant date	—

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.

First claim

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 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 32G×½″ needle and a displacement speed of 100 mm/min, wherein the normalized maximum gliding force is defined as follows:
GF max =GF measured ×( d barrel ) 2 /( D barrel ) 2

wherein: GF max is the normalized maximal gliding force in N, GF measured is the measured highest gliding force in N before the plunger stopper finishes its course at the distal end of the syringe barrel, d barrel is the barrel inner diameter of a reference syringe and is 6.35 mm, and D barrel is the inner barrel diameter in mm of the prefilled syringe system.

2 . The botulinum toxin prefilled syringe system of claim 1 , wherein the normalized break loose force is 15 N or less, and optionally lower than the maximum gliding force, as measured at a temperature of 20° C. using a 32G×½″ needle and a displacement speed of 100 mm/min, wherein the normalized break loose force is defined as follows:
BLF norm =BLF measured ×( d barrel ) 2 /( D barrel ) 2

wherein:
BLF norm is the normalized break loose force in N,
BLF measured is the measured break loose force in N and is defined as the highest force between 0 and 2 mm plunger displacement distance,
d barrel is the barrel inner diameter of a reference syringe and is 6.35 mm, and
D barrel is the inner barrel diameter in mm of the prefilled syringe system.

3 . The botulinum toxin prefilled syringe system of claim 1 , wherein the normalized dynamic gliding force is 15 N or less, as measured at a temperature of 20° C. using a 32G×½″ needle and a displacement speed of 100 mm/min, wherein the normalized dynamic gliding force is defined as follows:
DGF norm =DGF measured ×( d barrel ) 2 /( D barrel ) 2

wherein:
DGF norm is the normalized dynamic gliding force in N,
DGF measured is the mean gliding force calculated from the measured gliding forces at ⅓ and ⅔ of the total plunger displacement distance in N,
d barrel is the barrel inner diameter of a reference syringe and is 6.35 mm, and
D barrel is the inner barrel diameter in mm of the prefilled syringe system.

4 . The botulinum toxin prefilled syringe system of claim 1 , wherein (i) the normalized maximum gliding force (GF max ) 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 (BLF norm ) 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 (DGF norm ) is determined within storage or after storage for 12 months at 2 to 8° C. or 25° C., or (iv) GF max and BLF norm , or GF max and DGF norm , or BLF norm and DGF norm , or GF max , BLF norm and DGF norm are determined according to (i) to (iii).

5 . The botulinum toxin prefilled syringe system of claim 1 , wherein the plunger stopper has a plurality of annular ribs providing multiple contact areas with the inner surface of the syringe barrel, wherein the number of annular ribs of the plunger stopper is optionally two to six, optionally two to five or three to four.

6 . The botulinum toxin prefilled syringe system of claim 1 , wherein
(i) the plunger stopper has a normalized total contact area with the inner surface of the syringe barrel of 70 mm 2 or less, wherein the normalized total contact area is calculated as follows:
TCA norm =TCA calc ×( d barrel ) 2 /( D barrel ) 2

wherein: TCA norm is the normalized total contact area in mm 2 , TCA calc is the calculated total contact area in mm 2 and is defined as the sum of the contact surfaces (CT rib ) of each annular rib in mm 2 , wherein CT rib =2πrh, 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, d barrel is the barrel inner diameter of a reference syringe and is 6.35 mm, and D band 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 (TCA calc ) is defined as in (i) and the total side face area of the plunger stopper is defined as follows:
TSFA=2π r max H

wherein: TSFA is the total side face area of the plunger stopper in mm 2 , r max 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 H is the total length of the plunger stopper in axial direction in mm.

7 . The botulinum toxin prefilled syringe system of claim 1 , wherein the inner surface of the syringe barrel is siliconized, optionally spray-siliconized or baked-on siliconized.

8 . The botulinum toxin prefilled syringe system of claim 1 , wherein the plunger stopper is of an elastomeric material and optionally 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 and/or injection.

9 . The botulinum toxin prefilled syringe system of claim 8 , wherein
(i) the elastomeric material is a synthetic rubber selected from the group consisting of isoprene rubber, neoprene rubber, butadiene rubber, butyl rubber, styrene-butadiene copolymer, acrylonitrile-butadiene copolymer, polysulfide elastomers, urethane rubbers, and ethylene-propylene elastomers, and wherein the elastomeric material is optionally a butyl rubber optionally a halogenated butyl rubber, or (ii) the coating on at least a portion of the plunger stopper 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).

10 . The botulinum toxin prefilled syringe system of claim 1 , wherein the outlet engaging portion of the closure device is of an elastomeric material optionally having a coating on an outer surface thereof such that the liquid botulinum toxin formulation contacts only said coating during storage and/or injection.

11 . The botulinum toxin prefilled syringe system of claim 10 , wherein
(i) the elastomeric material is a synthetic rubber selected from the group consisting of isoprene rubber, neoprene rubber, butadiene rubber, butyl rubber, styrene-butadiene copolymer, acrylonitrile-butadiene copolymer, polysulfide elasto

Assignees

• Merz Pharma Gmbh & Co Kgaa

Inventors

• Vogt Markus

Classifications

• A61M5/31513 Primary

  Piston constructions to improve sealing or sliding · CPC title

• A61K38/4893

  Botulinum neurotoxin (3.4.24.69) · CPC title

• A61M2005/312

  comprising sealing means, e.g. severable caps, to be removed prior to injection by, e.g. tearing or twisting · CPC title

• A61M5/3158

  performed by axially moving actuator operated by user, e.g. an injection button · CPC title

• A61M5/488

  Limiting injection pressure · CPC title