Injection spring for aged prefilled syringe and auto injector

Abstract

An auto injector apparatus includes a syringe and an auto injector. The syringe includes a barrel holding a therapeutic fluid including an anti-calcitonin gene-related peptide (anti-CGRP) antibody. The syringe also includes a stopper disposed within the barrel and the stopper moves axially within the barrel between a first position and a second position to expel at least some of the therapeutic fluid from the syringe. The auto injector includes a rod that abuts the stopper and an injection spring that drives the rod to apply a dispensing force through the rod to the stopper. The dispensing force includes a first dispensing force of between 20 N and 40 N and a second dispensing force of between 12 N and 20 N. The injection spring initially applies the first dispensing force and then applies the second dispensing force to move the stopper to the second position.

What is claimed is: 
     
         1 . An auto injector apparatus comprising:
 a syringe comprising:
 a barrel; 
 a therapeutic fluid held within the barrel, the therapeutic fluid comprising an anti-calcitonin gene-related peptide (anti-CGRP) antibody; and 
 a stopper disposed within the barrel, the stopper being configured to move axially within the barrel between a first position and a second position to expel at least some of the therapeutic fluid from the syringe; and 
   an auto injector configured to hold the syringe, the auto injector comprising:
 a rod configured to abut the stopper; and 
 an injection spring configured drive the rod to apply a dispensing force through the rod to the stopper, the dispensing force comprising a first dispensing force of between 20 N and 40 N and a second dispensing force of between 12 N and 20 N, 
   wherein, upon an actuation of the auto injector, the injection spring applies the first dispensing force through the rod to the stopper to move the stopper from the first position, and   wherein, after the stopper moves from the first position, the injection spring applies the second dispensing force through the rod to the stopper to move the stopper to the second position.   
     
     
         2 . The auto injector apparatus of  claim 1 , wherein the anti-CGRP antibody comprises a heavy chain variable region that is at least 90% identical in amino acid sequence to SEQ ID NO: 1 and a light chain variable region that is at least 90% identical in amino acid sequence to SEQ ID NO: 2. 
     
     
         3 . The auto injector apparatus of  claim 2 , wherein the heavy chain variable region is at least 95% identical in amino acid sequence to SEQ ID NO: 1 and the light chain variable region is at least 95% identical in amino acid sequence to SEQ ID NO: 2. 
     
     
         4 . The auto injector apparatus of  claim 3 , wherein the heavy chain variable region is 100% identical in amino acid sequence to SEQ ID NO: 1 and the light chain variable region is 100% identical in amino acid sequence to SEQ ID NO: 2. 
     
     
         5 . The auto injector apparatus of  claim 2 , wherein the anti-CGRP antibody is formulated at 150 mg/mL nominal concentration in 16 mM histidine; 6.6% sucrose; 0.136 mg/mL disodium ethylenediaminetetraacetic acid dihydrate (EDTA); and 1.2 mg/mL polysorbate-80, having a pH of 5.5. 
     
     
         6 . The auto injector apparatus of  claim 1 , wherein the therapeutic fluid comprises a liquid pharmaceutical composition, the liquid pharmaceutical composition comprising:
 about 225 mg of the anti-CGRP antibody, the anti-CGRP antibody comprising a heavy chain variable region that is 100% identical in amino acid sequence to SEQ ID NO: 1 and a light chain variable region that is 100% identical in amino acid sequence to SEQ ID NO: 2;   about 0.204 mg disodium ethylenediaminetetraacetic acid dihydrate (EDTA);   about 0.815 mg L-histidine;   about 3.93 mg L-histidine hydrochloride monohydrate;   about 0.3 mg polysorbate-80;   about 99 mg sucrose; and   water,   wherein liquid pharmaceutical composition for injection has a pH of 5.5.   
     
     
         7 . The auto injector apparatus of  claim 1 , wherein the first dispensing force is between 20 N and 30 N. 
     
     
         8 . The auto injector apparatus of  claim 1 , wherein the second dispensing force is at least 12.5 N or at least 14 N. 
     
     
         9 . The auto injector apparatus of  claim 1 , wherein the second dispensing force is between 15 N and 18 N. 
     
     
         10 . The auto injector apparatus of  claim 1 , wherein the therapeutic fluid has an accelerated age of at least 24 months. 
     
     
         11 . The auto injector apparatus of  claim 1 , wherein, before the actuation of the auto injector, the injection spring has a stored energy of between about 0.9 J and about 2 J. 
     
     
         12 . The auto injector apparatus of  claim 11 , wherein, before the actuation of the auto injector, the injection spring has a stored spring constant of between 0.2 N/mm and 0.4 N/mm and a compressed length of between 50 mm and 100 mm. 
     
     
         13 . The auto injector apparatus of  claim 12 , wherein the stored spring constant is between 0.28 N/mm and 0.32 N/mm and the compressed length is between 75 mm and 95 mm. 
     
     
         14 . The auto injector apparatus of  claim 13 , wherein, upon the actuation of the auto injector, the injection spring is configured to apply the dispensing force through the rod to the stopper to move the stopper from the first position to the second position in a period of between 5 seconds and 19 seconds. 
     
     
         15 . The auto injector apparatus of  claim 1 , wherein:
 the therapeutic fluid is unaged,   the barrel comprises an inner surface comprising glass, and   the syringe comprises an oil on the inner surface.   
     
     
         16 . The auto injector apparatus of  claim 1 , wherein the stopper is coated with a first coating comprising ethylene tetrafluoroethylene and a second coating comprising silicone, and
 the first coating coats a first portion of the stopper and the second coating coats a second portion of the stopper that is different from the first portion of the stopper.   
     
     
         17 . An auto injector apparatus comprising:
 a syringe comprising a stopper and a therapeutic fluid comprising an anti-calcitonin gene-related peptide (anti-CGRP) antibody; and   an auto injector comprising an injection spring and a rod,   wherein, upon an actuation of the auto injector, the injection spring is configured to provide, via the rod, a first dispensing force of between 20 N and 40 N to the stopper when the stopper is positioned at a first position and is configured to provide, via the rod, a second dispensing force of between 12 N and 20 N to the stopper to move the stopper to a second position.   
     
     
         18 . The auto injector apparatus of  claim 17 , wherein the anti-CGRP antibody comprises a heavy chain variable region that is at least 90% identical in amino acid sequence to SEQ ID NO: 1 and a light chain variable region that is at least 90% identical in amino acid sequence to SEQ ID NO: 2. 
     
     
         19 . The auto injector apparatus of  claim 18 , wherein the heavy chain variable region is at least 95% identical in amino acid sequence to SEQ ID NO: 1 and the light chain variable region is at least 95% identical in amino acid sequence to SEQ ID NO: 2. 
     
     
         20 . The auto injector apparatus of  claim 19 , wherein the heavy chain variable region is 100% identical in amino acid sequence to SEQ ID NO: 1 and the light chain variable region is 100% identical in amino acid sequence to SEQ ID NO: 2. 
     
     
         21 . The auto injector apparatus of  claim 18 , wherein the anti-CGRP antibody is formulated at 150 mg/mL nominal concentration in 16 mM histidine; 6.6% sucrose; 0.136 mg/mL disodium ethylenediaminetetraacetic acid dihydrate (EDTA); and 1.2 mg/mL polysorbate-80, having a pH of 5.5. 
     
     
         22 . The auto injector apparatus of  claim 17 , wherein the therapeutic fluid comprises a liquid pharmaceutical composition, the liquid pharmaceutical composition comprising:
 about 225 mg of the anti-CGRP antibody, the anti-CGRP antibody comprising a heavy chain variable region that is 100% identical in amino acid sequence to SEQ ID NO: 1 and a light chain variable region that is 100% identical in amino acid sequence to SEQ ID NO: 2;   about 0.204 mg disodium ethylenediaminetetraacetic acid dihydrate (EDTA);   about 0.815 mg L-histidine;   about 3.93 mg L-histidine hydrochloride monohydrate;   about 0.3 mg polysorbate-80;   about 99 mg sucrose; and   water,   wherein liquid pharmaceutical composition for injection has a pH of 5.5.   
     
     
         23 . The auto injector apparatus of  claim 17 , wherein a distance between the first position and the second position corresponds to one dose of the therapeutic fluid. 
     
     
         24 . The auto injector apparatus of  claim 17 , wherein the injection spring is configured to provide the first dispensing force and the second dispensing force, via the rod, to the stopper to move the stopper from the first position to the second position within a period of 19 seconds or less. 
     
     
         25 . The auto injector apparatus of  claim 17 , wherein the first dispensing force is between 20 N and 30 N. 
     
     
         26 . The auto injector apparatus of  claim 17 , wherein the second dispensing force is at least 12.5 N or at least 14 N. 
     
     
         27 . The auto injector apparatus of  claim 17 , wherein the second dispensing force is between 15 N and 18 N. 
     
     
         28 . The auto injector apparatus of  claim 17 , wherein, before the actuation of the auto injector, the injection spring has a stored energy of between about 0.9 J and about 2 J. 
     
     
         29 . The auto injector apparatus of  claim 28 , wherein, before the actuation of the auto injector, the injection spring has a stored spring constant of between 0.2 N/mm and 0.4 N/mm and a compressed length of between 50 mm and 100 mm. 
     
     
         30 . The auto injector apparatus of  claim 29 , wherein the stored spring constant is between 0.28 N/mm and 0.32 N/mm and the compressed length is between 75 mm and 95 mm.