AU2015271924A1 - Syringe - Google Patents

Abstract

The present invention relates to a syringe, particularly to a small volume syringe such as a syringe suitable for ophthalmic injections.

Description

SYRINGE TECH NICAL FELD The present invention relates to a syringe, particularly to a small volume svnne such as a syringe suitable for ophtharnic tnjectiona 5 BACKGROUND ART maiv medicaments are delivered to a patient in a single front which the u'r can dispense the predicament, eiaeii eiee oapteti yig itiV often ltoeurlel the patient. or a caregiver, to inject the mediuCaenL It is important for patient safety and nedicament integrity that the syringe and the contents of that svringe are sufficiently sterile to avoid 0 infection. or other risks tor patients. Sterilisation can be achieved b terminal sterilisationi in which the assembled product, typically already in its associated packaging, is sterilised using, heat or a steriliing gas. [or small volume syrns- for example those for injections into the eye in which t i i intended that about 0.1ml or less of liquid is to be injected the sterilisation can pose difficulties that are 5 not necessarily associated with larger syringes Changes in pressure. internal or enematol the syringe, can cause parts of the syringe to move unpredictably, which nay alter sealing charcterisfics and potentially compromise sterility, incorrect handling of the sninge can atso pose risks to product steri Furthermore. certain therapeutics suich- as,, blcic molecules-,ire particularly sensitive to 10 :'terihisation, be it cold gas,- steriIisi tioll, therml striain r raito hs aeu balancig act is required to ensure that while a suitable levet of sterisation is carried out, the syringre remains suitably sealed, such that the therapeutic is not compromised. Of course. the syrngae must also remain easy to use in that the force required to depress the ph ger to administer the medicament iust not be too high. 25 There is therefore a need for a new syrinCe constructwhich provides a robust seal for its conten t , buthich maintains ease of use. DISCLOSURE OF THE INVENTION The present invention provides a prefilled syrincge the syringe comping a body a stopperand a plunger the body comprising an outlet at an outlet end and the stopper being arranged within 30 the body such that a front surface of the stopper and the body define a variable, volume chamber 95157 frol which a fluid can be expelled though the outlet, the plunger comprising a plunger contact surface at a first end and a rod extending between the plunger contact surface and a rear portion, he' 'phnger contact surface arranged to contact the stopper such that the be used to force the stopper towards the outlet end of the body, reducing the volurne of the variable volume 5 chamber, characterised in that the fluid comprises al ophthalmic solution. In one embodimen the ophthalmic solution comprises a VEG antagonist In one embodimilent, the syringe: is statable for oplhtilmi injections, more particulaly intravitreal injections, and as, uch has a suitably small volume, The svringe may also be silicone oil free, or substantially silicone oil free or may comprise a lowlevel of silicone oil as lubricant. 0 In one embodiment, despite the low silicone oil level, the stopper break loose and slide force is less than 201N, For ophthalmic injections, it is particulary important for the ophthalmic solution to have particularly loAw particle content, in one embodiment, the syringe meets US Pharmacopeia standard 789 (USP789) * t Sringe The body of the syringe may be a substantially cylindrical shell, or may include a substantially cylindrical bore with a non circular outer shape he outlet end of the body includes an outlet through which a fluid housed within the variable volume chamber can be expelled as the volume of said chamber is reduced. The out uty comprise a projection trom the outlet end through :0 which extends a channel having a smaller diameter than that of the variable volume chamber. The outlet may be adapted. for example via a luer lock type connection, for connection to a needle or other accessory such as a sealing deve which is able to seal the variable volume chamber, but can be operated, or removed, to unseal the variable volume chamber and allow connection of the syringe to another accessory, such as a needle. Such a connection may be 25 made directly between the syringe and accessory; via tie sailing device. The body extends along a first axis from the outlet end to a rear end Thle body may be made from a plastic material (eg a cyclic oletin polymer) or rom glass and may include indicia on a surface thereotf to act as an injection guide, In one embodiment the body may comprise a priming mark. This allows the phlsician to align a pre-determined part of 30 tile stopper (such as the tip of the front surface or one ofbe crcumferential ribs, discussed later) or plunger with the mark thus expelling excess ophthalmic solution and any air bubbles from the -- 0- 55157 syringe. The priming process ensures that an exact. pre-deteortined dosage is administered to the patient. The stopper may be made from rubber. silicone or other suitable resiliently deformable material, The stopper may be substantially cylindrical and the stopper may include one or more S cicmeetAis around an outer surface of the sutoper. the stpper anud rbs heing dimnensioned such that the -ribs, tormn a substa ntially J.'uid tiin seal -with an internal surface of the syringe body. The front surface of the stopper may be any suitable shape, for example substantially planar, substantially conical or of a domed shape. The rear surface of the stopper may include a substantially central recess. Such a central recess could be used to connect a 0 plunger to the stopper using a snap fit feature or thread connection in a known manner The stopper rmay be substantially rotationally metic about an axis ough te stopper. The plunger comprises a plunger contact surthee and extending from that a rod extends from the uner contact surface to a roar portion, The rear portion may include a user contaCt portion adapted to be contacted by a user during an injection event, The user Contact portion may S comprise a substanially disc shaped portion, the radius of the disc extending, substantially perpendicuhar to the axis alone which the rod extends. The user contact portion could be any suitable shape, The axis along which the rod exends may be the first axis. or ay be substantially parallel with the first axis. The syringe may include a backstop arranged at a rear portion of the body. The backstop may be 0 removable from ifthe syringe body includes at the end opposite the outlet end the backstop may be configured to substantially sandwich terminal flanges of the body as this prevent mrovemecnt of the backstop in a dir;ction parallel to the first axis. The rod may comprise at least one rod shoulder directed away from the outlet end and the backstop may inchide a backstop shoulder dieted towards the outlet end to cooperate with the 25 rod shoulder to substantially preven moeent of the rod away from the outlet end when the backstop shoulder and rod shoulder are in contact. Restriction of the movement of the rod away from the outet end can hep to maintain sterility during terminal sterilisation operations or other operations in which the pressure within the ariable volume chamber or outside the chamber may change. During such operations any gas trapped within the variable volune chamber, or .0 bubbles that may form in a liquid therein may change in volume and thereby cause the stopper to move. Movement of the stopper away front the outit could result in the broaching of a sterility zone created by the stopper. This is particularly iniportint for low vlumune syringes 55 157 where there are much lower tolerances in the component sizes and less flexibility in the stopper. The term sterility zone as used herein is used to refer to the area within the syringe that is sealed by the stopper f1omm access from either end of the spring. This may be the area betweer a seal of te stopper. for example a circunferemial rib, closest to the outlet and a seal of the stopper, 5 for example a circurnerential rib, furthest from the outlet The distance between these two seals defnes the sterility zone of the stopper since the stopper is installed into the syringe barrel in a steri le environment. To further assist in maintaining sterility during the operations noted above the stopper may comprise at a front Circumferential rib and a rear circumferential rib and those ribs may be 0 separated in a direction along the first axis by at least 3mm, by at least 3.5 tnrn by at least 3375mm or by 4mm or niore. One or more additional ribs (for example 2. 3, 4 or 5 additional ribs, or between 1 10, 2-8.3-6 or 4-5 additional ribs) may be arranged between the front and rear ribs, In one enbodiment there are a total of three ciremferential ribs. A stopper with such an enhanced sterility zone can also provide protection for the injectable 5 medicament during a terminal sterilisation process. More ribs on the stopper or a greater distance between the front and rear ribs can reduce the potential exposure of the medicament to the sterilising agent, However, increasing the number of ribs can increase the friction between the stopper and syringe body, reducing ease of use. While this may be overcome by increasing the siliconisation of the syringe such an increase in silicone oil levels is particularly undesirable A) for syringes for ophthalmic use The rod shoulder may be arranged within the external diameter of the rod, or may be arranged outside the external diameter of the rod. By providing a shoulder that extends beyond the extermi dianieter of the rod, but still fits within the body. the boulder can help to stabilise the movement of the rod within the body by reducing niovemeit of ihe rod perpendicular to the first 25 axis. The rod shoulder may comprise alny suitable shoulder fonnng elements on the rod, but in one embodiment the rod shoulder comprses a substantial disc shaped portion on the rod. Inone embodiment of the syringe when arranged wiIth the plunger contact surface in contact with the stopper and the variable volume chamber is at is intended namnu volume there is a clearance of no more than about 2mm between the rod shoulder and. backstop shoulder. In some 30 embodiments there is a clearance of less than about 1m.5 nm and in someless than about inm. I'his distance is selected to substantially limit or prevent excessive rearward (away from the outlet end) inovemient 0 f.tie stopper.

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5157 In one embodiment the variable volume chamber has an interal diameter greater than -5tii or 6mm, or less than 3nm or 4mm. The internal diameter may be between 3mlm and 6mln or between 4mm and 5mn In another embodiment the syrnge is dimensoned so as to have a nominal maxnium fill volume 5 of between about 0.im] and about I15ml. In certain embodiments the nominal maximma fill volume is between about O3mT and about Imi, In certain embodiments the norninal maximum fil volne is about 0(Xml or about Iml, or about 1 5ml. The length of the body of the syringe may be less than 70mm, less than 60mm or less than 50mm in one embodiment the length of the syringe body is between 45mm and 5hnrn 0 In one embodiment the syringe is filled with between about O. lml and about 1.SmI (for example between about 0,05ml and about lnl. between about IOinil and about 0.5m] between about 0.511Smi and about 01 7i5ml) of a VEGF antagonist solution. In one embodiment, the syringe is filed with 0 165mi of a VEGF antagonist solution. Of course, typically a singe 1s filled with more than the desired dose to be administered to the patient, to take into account 5 wastage due to dead space" within the syringe and needle, There may also be a certain amount of wastage when the syringe is primed by the physician so that it is ready to inject the patient. TFhus. in, one embodiment, the syrTinge is tilled wiha dosage volume (e.the volume of niedicaincent intended for deliery to the patent) of betw, een about. 0.0t.mil and about 1,.Snil (e~g. between about 005ml aimd about 1im. between about 0. il and about 0.5ml) of a VEGF !0 antagonist solution, In one embodiment, the dosage volume is between about 0,03ml and about 0.05m1. For example, for Lucentis, the dosage volume is 0.051m or 0.03ml (0.5mg or 031ng) of a 10ng/ml injectable medicanent solution; for Eylea; the dosage volume is 0.05m of a 40mg/ml injectable medicament solution. Although unapprm ved for ophthalnic indications, bevacitmab is used offlabel in such ophthalmic indicatOns at a concenration of 25mg/mltypically at a 25 dosage volume of (X50ml (I 25mg In one embodiment, the extractable volume from the syringe (tha is the amount of product obtainablefom the syringe flowing filling, taking into account loss due to dead space in the syringe and needle) is about 009ml. In one embodinment the length of the syringe body is between about 45mm and about 50mm, the integral diameter is between about 4mm and about 5mnthe fill volume is between about 0.2 0 and about 03n and the dosage volume is between about 053Om and about 0.05mL 5515"7 As the fringe contains a medicament solution the outlet may be reversibly sealed to maintain sterility of the rnedicamen. hisseaing may be achieved through the use of a sealing device as is known i the art. For exaple the OVS 5 system which is available froi. Vetter Pharna International am bR. 5 It is typical to siliconise the syringe in order to allow ease of use, i.e to apply silicone oil to the inside of the barrel, which decreases the force required to move the stopper. However. for ophthalmic use, it is desirable to decrease the likelihood of silicone oil droplets being injected into the eye, With nuhiple injections, the amount of silicone droplets can build up in the eye, Causing potential adverse effects, including "floaters" and an increase in intra-ocular pressure. 0 Furthermore, silicone oil can cause proteins to aggregate. A typical Iml syringe comprises 100 80(tg silicone oil in the barrel, though a survey of manufacturers reported that 500-1 00pg was typically used in pre-filled syringes (Badkar et aL 2011 A A P S PharmnaSciTech 12i2):564-572.) Thus. in one embodiment, a syringe aCCording to the invention comprises less than about OOW ije.. about Iess than about 5 0 0 pgj less than about 300pg, less than about 20 0 pg less than about 5 10(t; less than about 7$ ttg, less than about, $Opg, les than about 24.less than about 1$ pg, than about lOpg) siionee in the barrel. If the syringes comprises a lowlevel of silicone oill this ma be more than about I more than about 3pg, rnore than about rg more than about 7g or more than about 0 Opg silicone oil in the barrel. Thus,, in one emnbodimern. the syringe may comprise about I ige-about 500pg about 3pgeabout 20pg about Sigabout 100pig U or about ig-about 50pg silicone oil in the barrel. Methods for measuring the amount of silicone oil in such a syringe barrel are known in the art and include, for example, differential weighing metods and - ard-spctrocop of the. oil diluted in a sufitable solvent. Various types of silicone oil are available, but typically either DC360 (Dow Coming: with a viscosity of 1000eP) or D365 enuision (Dow Corning"; DC360 oil with a viscosity of 25 300) are, used for syringe sihconisation. in one etnbodiment the preilled syringe of the in mention comprises DC3 6e5nulsion. during testing it wassurprisingly found that, for syringes having small dimensions such as those discussed above, and particularly those described in conjunction with the Figures below, the break loose arid sliding forces for the stopper within the syringe are substantially ttnaffcted by 30 reducing the siliconisation levels far belm the current standard to the levels discussed here. This is in contrast to conventional thinking that would suggest that if you decrease the silicone oil level, the forces required would increase see eg. Schoe nknecht., AAPS National Biotechnology Conference 2007 Abstract no, NBC07-000488. which indicates that while 400pg silicone oil is

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55157 acceptable. usability improves when increased to 800pg). Having too great a force required to moe the stopper can cause problems during use for soc users, fraurate dose setting or smooth dose delivery may be made more difficult if significant strength is required to move, and/or keep in motion, the stopper. Smooth adninistration is particularly important in 5 sensitive tissues such as the eye, where movement of the s_ ringe during administration could cause local tissue damage Break loose and slide forces for pro-fIled syringes known in the art are typically in the region of less than 20N, but where the pre-filled syringes contain about 100pngabout 800g silicone oil. In one embodiment the glide/slide force for the stopper within the pre-tilled syringe is less than about I N or less than 9N, less than 7N. less than 5N or 0 between about 3N to 5N, In one embodiment the break loose toree is less than about 1 IN or less than 9N less than 7N, less than 5N or between about 2 N to 5N. Note that such measurements are for a filled syringe rather than an empty syringe, The forces are typically measured at a stopper travelling speed of 190 /mn.n In one embodiment, the forces are measured with a 300 x 0.5 inch needle attached to the syringe. In one embodiment, thesvyringe has a nominal maximal fill 5 volume of between about 0AmK and mL. contains less than about 100pg silicone oil and has a break loose force between about 2N to 5N, In one embodiment the syringe barrel has an internal coating of silicone oil that has an average thickness of about 450nrtn or less (i.e 400nn or less 350nm or les.30n or less 20nm or less 100arn or less, 50nin or less, 20in or less), Methods to measure the thickness of silicone oil 0 in a syringe are known in the art and include the rapJDl layer Explorer@ Application, whic can also be used to ineasure the mass of silicone oil inside a svringe barrel in one emrnbodimient. the syringe is silcone oil free, or substantially silicone oil tree. Such low silicone oil levels can be achieved by using uncoated syringe barrels and/or by avoiding the use of silicone: oil as a lubricant for product contacting machine parts or pumps in the syringe 25 assembly and fill line. A further way to reduce silicone oil and inorganic silica levels in a pro filled syringe is to avoid the use of silone tubing in filling lines, fbr example between storage tanks and pmnps The syringe according to the invention may also meet certain requirements for particulate content In one embodin ents.the ophthalmic solution comprises no more than 2particies 50pm 30 in diameter per ml in one embodiment, the ophthalmic solution eonmises no more than 5 particles t25pm in dianieter per ml In one embodiment, the ophthalmic soluion comprises no more than 5) particles -10pm in diameter per ml. In one embodiment, the ophthalmic solution -7 55157 comnprises no more, than 2 particles in diameter per ml no more than p 5 artiles >25pm in diameter per ml and no more than Si0 particles >1pm i diameter per ml In one embodiment a syrInge according to the invention neetsSP789 (United States Pharmacopoeia: Partilte Matter in Ophthalmic Solutions). In one embodiment the syringe has low levels of silicone oil 5 suffIcient for the syringe to meet )SP789, L EG.F Anttagatnists Anfibody 1E~t anaigOnifss VEGF is a well-characterised signal protein which stimulats angiogenesis. Two antibody VEIF antagonists have been approved for human ue namely ranabitumab (Lucentis@) and 0 bevacizumab (Avastin@) N'on.Antibody 15EGF antagonius In One aspect of the invention, the non-antibody VEX$ antagonist is an hmfmiiirloadhesint One such 'imuoadhesin is aflibercept tEylea . WhiCh has been approved for human use and is also known as VEGF-rap (Inlash ei al (2002) NAS USA 99:11393-98 Riely & Miller 5 (2007) Cilin Cancer R 13:46237s). Atlibercept is the prefeed nonatibody VEOF antagonist for use with the invention Aflibercept is a recombinant human soluble VEGE receptor fusion protein consisting of portions of human VEGF receptors I and 2 extracellular dominns fused to the FC portion of human IgOI It is a diteric glycoprotein with a protein molecular weight of97 kilodaltons (kDa and contains gycoslat ion, constitutng an additional 15% of the total '0 molecular mass, resulting in a total molecular weight of I15 kDa. t is convenieyproduced as a lycproen expression in recombinant ClIO K1 cells. Each monomer can have the : acid sequence (SEQ ID NO: 1}; $:DTG> TFMSFIT-E IPIMrEDSRKKIXSNATY iKE ICVLLC EATVNGH~LYiKTNLTET . IDVVZS PSHG~I ELSVGEIKLVNCPJQRPSELNP2IDENNEP$ 25 siKUongt vatKit.- jsas5E:Mxsi5ts rV1iEGvTRsoQGLYTC as St ru.NsTSvavatur:4'reerec YRVVSVLTVLiQDWLNGKEYKCiKXSNKAL ARKIKWFRP9~aSDETNVICV GersDAV~e~aPENYITPVus SL'bK~vkSR WQGiNV$SV4YtNCAL{NBY'TOYSL .50 and disud$ide hridges can be formed between residues 30I9, 124-185. 246-306 and 352-410 within each monomer, nd between residues 211211 and 214-214 between the nmonomers.

Another nonanti body VEOGF antagonist iUnoadhesin currently in pre-chnical developinent is a recombinant human Solhble VEGF receptor fusion protein similar to VEGP-trap containing extraceiitdar ligand-binding domains 3 and 4 from VEiFR2/KDR and domain 2 from VEGFR IFit- these domains are fused to a human iG Fe protein fragment (Li et al 2011 5 MoWecar Vision 17197803). This antagonist binds to isoforms VEOF-A EOFB and VEGF C The moiecul is prepared using two different production proCesses resuing in different glycosylation pattems on the final proteins The two glycoforms are referred to as KH902 (coibercept) and KI-906, The fusion protein can have the folowing amino acid sequence (SEQ 11) NO.2%. 0 MVSYW&TGVLLCALLSCXLLTGSSSGGORPFVEMYSCPEI2 T rEGR~EjKPsOR~vSP N'TVTKKPLDT LI&PDGKRIIWDSRKGFIISNTYKEIG .TCEAVNGM YTNY. EROTNIo'vLSPSHGIELVGE Iiic'rTARTIlNVG;1nFNWEYPSSK{QH.KKnVNRDiKTQ CSGSEMvt$eT~ruVRSQGIYTCA$$ LCTYKNSTFvRREKPFVAGSGMESLVEATVGERVRLIPAKYLGYPSPP.1 KWKNG I PLESNHTIKAG~hVL I V$N 4GYVTV1L4PNISK KS a!&vSLV V tPUGPDKTHT4CPALNLGGPSFP PEDT 15 IkiMSRTPEVTCYDVSHEDPEyKFNtVDUEVENAKTKPREEQYNSTERVVSETVLHQD iGKe KVSNKALPAPIE5TISKAKGKPEPQVTPPSRONNVSLTCLVKGFYPSDIAVENNQiENK and, like VEG,-trapc be present as a dimer. This -fsion protein and related molecules are further characterized in [P 1767546, ~0Other no-nioyVEOF aaconis-ts include antibody minleties (c.,2. Af~flbodv®,k molecules. aflins, affitins, anticalins avimers Kunitz domain peptides and monobxdies) with VEOF antagonist activity, This includes recomibinant indng poteins comprising an ankyrin repeat domain that binds VEiF-A and prevents it from binding to VE GFR-2. One example fot suc a molecule is DARPin@ MP0 11. The ankrin finding domain inay have the tollowing 1mino 25 acid sequence (SEQ ID NO: 3): GSDOLGKXLt.AARAGQDDtEVRlTAMANCADYNTADSTGWPTMILAP>GilLTVEVLLKYCADYNKFC Or!PIxAge&A.GHN-Nv tRNADVN±\QDK..G..A7...IS IDNGNEDLAPEI LQKAA. Recombinant binding proins c ps an kyrin repeat domain that binds VEGV-A and prevents it from binding to VEFIR-2 are described in more detail in WO2010/060748 and 30 WO201 1/135067 Further specific antibody mmetics with V E(iF antagonist activi ty are the 40 kD peg lated antcain RPRS-050 and the inonobody angiocept (CT-22) ..5157 The afore-mentioned non-anibody VEGF m antagonism may be modified to further improve their phanacokinetie properties or bioavailability For example. a non-antibody VEGF antagonit m ay be chemically modified (eg. pegylated) to extend its in va half-life. Alternative or in addition, it may be modified by flycosylation or the addition of further glycosylation sites not 5 present in the protein sequence of the natural protein from which the VEGl antagonist was derived, Variants of the above-specified V F antagonists that have improved characteristic.s for the desired application may be produced by the addition or deletion of amino acids. Ordinarily, these amino aid sequence variants wl have an amino acid sequence havingat least 60%a.mmo acid 0 sequence identity with the amino acid sequences of SEQ ID NO: I SEQ ID NO: 2 or SEQ I) NO: 3, preferably at least 80% more preferably at least 85%. more preferably at least 90% and most preferably at least 95%, including for example, 80%, 81% 82% 83% 84% 85% 86% 87%, 8% 89%, 90% 91% 92%, 93%, 94% 95% 96% 97% 98%, 99%. and 100% Identity or omlo wth respect to this sequence is defined herein as the percentage of ainino acid 5 residues in the candidate sequence that are identical wil SIQ ID NO: I, SEQ 11) NO: 2 or SF0Q ID NO: 3 after aligning the sequences and introducing gaps, necessary, to achieve the rnaxrunn percent sequence identity, and not considering any conservatiye substitutions as part of the sequence identity. Sequence identity can be determined by standard methods that are commonly used to compare 0 the similarity in position of the amino acids of two polypeptides. Using a computer program such as BLAST or FASTA, two polypeptides are aligned for optimal. matching of their respective amino acids (either along the full length of one or both sequences or along a pre determined portion of one or both sequences), The programs provide a default opening penalty and a default ggp penalty, and a scoring matrix such as PAM 250 [a standard scorig matrix;ee 25 Dayhoff et al, in Atlas of Protein Sequence and Structure, vol 5. supp 3 (1978)}can be used in conjunction with the computer program. For example, the percent identity can then he calculated as the total number of identical matches muhiplied by 100 and then divided by the sum of the length of the longer sequence within the matched span and the number of gaps introduced into the longer sequences in order to align the two sequences. 30 Preferably, the non-antibody VECF antagonist of the invention binds toVFOP via one or more protein domnain(s) thnt are not derived from t110 domain ofan a o. e non -In_- 55157 antibody \F [ antagonist of the invention are preferably proteinaceous, but may include modifications that are non-proteinaceous g nation), Therapy '[he syringe of the invention may be used to treat an ocular disease including but not limited to 5 choroidal neovascularisation. age--related macular degeneration (both wet and dry fornis) macular edema secondary to retinal vein occlusion (RVO) including both branch RVO (bRVO) and central RVO (eRVO), choroidal neovasularisation secondary to pathologic myopia (PM) di abetic macular edenia (DIE), diabetic retnopathy, and prolierativ retinopathy Thus the invention provides a inethod of treating a patient suffering from of an ocular disease 0 selected from choroidal neovascularisation, vet age-relaed macular degeneration. macular edema secondary to retinal vein occlusion (RVO) including both branch RV) (hRVD) and central RVO (cRAVO) choroidal neoascularisation secondary to pathologic myopia (PN) diabetic macular edema (DMI) diabetic retinopathy, and proliferative retinopathy comprising the step of administe'ring an ophthalnic solution to the parent using a pre-filled syringe of the 5 invention. This method preferably further compares an initial priming step in which the physician depresses the plunger of the pre filled syringe to align the pre-detennined part of the stopper with the priming mark. In one embodiment, theinention provides a method of treating an ocular disease selected from choroidal neovasc ularisation wet ageriated macular degeneration mactdar edema secondary to .) retinal vein occlusion (RVO) including both branch RVO (bRVO) and central RVO (cRVO). choroidal neovascudarisation secondary to pathologic myopi a (PM), diabetic macuilar edema (DME diabetic retinopathy, and proliirative retinopathy. comprsig adninistering a non antibody VAGF antagonist with a pretlled syringe of the invenion, wherein the patient has previously received treatment with an antibody YEOF antagonist 25 AtU Also provided are kits comprising the pre~Olled syringes of the inventin. In one embodiment. such a kit comprises a prea-tilled syringe of the invention in a blister pack. 1 he blister pack tmay itself be sterile on the inside, in one embodiment syringes according to the invention may be placed inside such blister packs prior to undergoing sterlisationS for example terminal 30 terilisalion, 55i57 Such a kit may further comprise a needle for administration of the VEF antagonist If the \?1W1X antagonist is to be administered intravitrealy, it is typical to use a 30gauge x inch needle, though 31-gauge and 32-gauge needles may be used. For intravitreai administration. 33-gauge or 34-gauge needles could alternatively be used, Such kits may further comprise 5 instructions for use, In one embodiment. the invention provides a carton containing a pre-filled syringe according to the invention contained within a blister pack, a needle and optionally instructions for admiunstration.

Sterilisa/io H As noted above, a terminal sterilisation pres nay be used to serihse the syringe and such a 0 process may use a known process such as an ethylene oxide (EtO) or a hydrogen peroxide (1-2sterilisation process, Needles to be used with the syringe may be sterilised by the same method, as may kits according to the invention. The package is exposed to the steriising gas until the outside of the syringe is sterile. Following such a process ihe outer surface of the syringe nay remain sterile (whilst in in blister pack) for 5 up to 6 months. 9 months, 12 months. 15 months, 18 months, 24 months or longer Thus. in one embodiment, a syringe according to the invention (whilst in its blister pack) may have a shelfli-fe of up to 6 months, 9 months. 12 months, 15 months, 1 8 months24 mths or longer In one embodiment. less than one syringe in a million has detectable microbial presence on the outside of the syringe after 18 months of storage, In one enibodiment the pre-filled syringe has been !0 sterilized using RIO With a SterilityAsranCe Level of at. least 1 t i one emhodhment, the pre fitled syringe has been sterilised using hydrogen peroxide with a Sterility Assurance Level of at least i01 Of course.i is a requeLdent that significant amounts of lie sterilisingeas should not enter the variable volume chamber of the syringe. The term "significant amounts as used herein refers to an amount of geas that would cause unacceptable modieation of the ophthalmic 25 sahion within the variable volume chamber. In one ernbodimnent the sterilisation process causes 0 (preferably <5%. <3 1%) alkylation of the VEF antagnist In one embodiment, the Sre-filled syringe has been sterlsed usingi:0O but the outer surface of the syne hi s <1 ppm preferably <0.2ppm EtO residue. In one embodiment the pre-filled syringe has been sterilised using hydrogen peroxide. but the outer surface ofthe syringe has Ippm. preferably 0A2ppm 30 hydrogen peroxide residue in another embodiment, the prefidled syringe has been sterilized using EDO and the total lit) residue found on the outside of the syringe and inside of the blister pack is . 1img. In another embodiment the pre-filled svrine has been sterfiised using hydrogen A fl 55157 peroxide. and the total hvdrogen peroxide residue found on the outside of the syringe and inside of the blister pack is Umg General The term "comprising Ieans "mcluding" as well as "consisting" eg a composition S 4cmprising" X may consist exclusively of X or may includesomething additional e g X + . The term about in relaion to a numerical value x means, for examples X+10% References to a percentage sequence identity between two amino acid sequences means that, when aligned, that percentage of amino acids are the same in comparing the two sequences This alignment and the percent homology or sequence identity can be determined using software 0 programs known in the art for example those described in section ,718 of Current Ptocos in Aoaecudr Bioogy (FM Ausubel e! -. , edt 1987) Supplement 30 A preferred alignment is detennined by the Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of.2., BLOSUM matrix of 62, The Smith Waterman homology search algorithm is disclosed in Smith & Waterman (1981 Adv. AppL 5 M.Jto& 2: 482-489 BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows a side view of a syringe Figure 2 shows a cross section of a top down vew of a syringe 20 Figure 3 stows a vieW of a plunger Figure 4 shows a cross secion though a plunger ure 5 shows a steppe 55157 MODES FOR CARRYING OUT THE INVENTION The invention will nw be farther described, byw ay of example only, with reference to the drawings. Figure I shows a viey from a side of a syringe I comprising a body 2, plunger 4, backstop 6 and a 5 sealing device 8. Figure 2 shows a cross section through the syringe I of Figure I from above. The syringe I is suitable for use in an ophthlmic inmectiort The yrirg I comprises a body a stopper 10 and a plunger 4. The syringe I extends along a first axis - The body 2 comprises an outlet 12 at ar outlet end 14 and the stopper 10 is arranged within the body 2 such that a front surfae 16 of the 0 stopper 10 and the body .2 define a variable volume chamber 1$ The variable volume chaner 18 contains an injectable medicament 20 comprising an ophthahnic solution comprising a VEGF antagonist such as ranibizumab. The injectable fhud 20 can be expelled though the outlet 12 by movement of the stopper 10 towards the outlet end 14 thereby reducing the volume of the variable volume chamber 18- The plmger 4 comprises a plnger contact surl7ee 22 at a frst end 24 and a 5 rod 26 extending between the plunger contact surface 22 and a rear portion 25. The plunger contact surface 22 is arranged to contact the stopper 10, such that the plunger 4 can be used to move the stopper 10 towards the outlet end 14 of the body 2. Such movement reduces the volume of the variable volume chamber 18 and causes fluid therein to be expeelld though the outlet The backstop 6 is attached to the body 2 by coupling to a terminal flange 28 of he ody 2 The 0 backstop 6 includes sandwich portion 30 which is adapted to substantially sandwich at least some of thle temnlflange.28 of the body 2. The baktpli dpe o be oupled to the body 2) f0mm the side by leaving one side of the backstop 6 open so that the backstop 6 can be fitted to the syringe The body 2 defines a substantially cylindrical bore 6 whieh has a bore radius. The rod 26 25 comprises a rod shoulder 32 directed away froU the outlet end 14. The rod shoulder 32 extends from to a rod shoulder radius from the first axis A which isuch that it is slightly less than the bore radius so that thesho\lder fits whin the bore 36. The backstop 6 includes a backstop shoulder 34 directed towards the outlet end 14. The shoulders 32. 34 are configured to cooperate to substantially prevent movement of the rod 26 away from the outlet end 14 when the backstop 30 shoulder 34 and rod shoulder 32 are in contact: The backstop shoulder 34 extends from outside te bore radius to a radius less than the rod shoulder radius so that the rod shoulder 32 cannot pass the

"AA-

55137 backstop shoulder -34 by mnovinit alono the first axis:\. rIn this case the rod shoulder 32 is substantially disc. of ring shaped and the backstop shoulder 34 in mfudes ar around a rea end 38 of the body 2, The backstop 6 also includes two finger projections 40 which extend in opposite directions away 5 from the body 2 substantially perpendicular to the first axis A to facilitate manual handling of the syringe I dunni use. In this example the syringe comprises a .5m. body 2 filled wi between about 0. 1 and 03 ml of an injectable medicament 20 comprising a 10mg/ml injectable solution comprising ranibizumab The syringe body 2 has an internal diameter of about between about 4.3mm and 48mm, a length of 0 between about 45mm and 50mnm The plunger 4 and stopper 10 will be described in more detail wih reference to later figures. Figure 3 shows a perspective viewof the plunger 4 of Figure I showing the plunger contact surface 22 at the first end 24 of the plunger 4. The rod 26 extends frn the first end 24 to the rear portion 25 The rear portion 25 includes a disc shaped flange 42 to facilitate user handling of the device' 5 The flaange 4.2 provides a later surface area for contact by the user than a bare end of the rod 26. Figure 4 shoWs a cross section though a syringe body 2 and rod 26. The rod 26 includes four longitudinal ribs 44 and the angle between the ribs is 90", Figure 5 shows a detailed view of a stopper 10 showing a conical shaped frout surtee l16 and three circumferential ribs 52456 around a substantially cylindrical body '8. The axial gap between the 20 first rib 52 and the last rib 56 is about 3mm. The rear surface 60 of the stopper 10 includes a substantially central recess 62. The central recess 62 includes an initial bore 64 having a first diameter. The initial bore 64 leading from the rear surface 60 into the stopper 10 to an inner recess 66 having a second diameter, the second diameter being larger than the tirst diameter. 25 Stopper movement forces 0.Sml syringes siliconised with <100pg silicone oil, filed with l..ucentcis, comprising one of two different stopper designs were tested for mnaxim and average break out and slide force. Prior to testing, 300 x 0.5 needles were attached to the sringes. 'The testing was carried out at a sopper speed of I9rmnrmin over travel length of I0.mm Stopper design 2 had a 43, increase in the 30 distance between the front circumferential rib and rear circumferential rib, 55157 topper topper desgn 2 .reak loose Averae N 2 N 2 N 25N force f synoges ~~~~~--- ------------------ --------- ----------.... kn Ma indwidutil 2iN E26N 2 ,7Nm Slidi force Averace ot0 3J N 2N 3 N 4 I\ 4.6N swfinges Mix i -xandv 'dal NN 6-tN 4 N 4. 8N For both stopper designs, average and maximn break out fore remained beloW 3 For both stopper designs, average and maximum sliding force remained belw SN It will be understood that the invention has been described by way of example only and S mnodificatirons may be made whist remaining within the scope and spirit of the invenin,

Claims (15)

1. A prefilled syringe, the syringe comprising a glass body, a stopper and a plunger the body comprising an outlet at an outlet end and the stopper being arranged within the body such that a front surface of the stopper and the body defne a variable volume Chamber froi which a fluid 5 can be expelled though the outlet the phiunger comprising a Inplunger contact swfac at a first end and a rod extending between the plunger contact surface and a reair porn the pkm6ge.r Contact sufe rranged to contact the stopper., such th at the phunger w'Inn! usedJ to fth"re theo stopper towards the outlue end of the body, reducing the volue of the Variable volume chamber. characterised in that the fluid is an ophthalmic solution which comprises a VEGFantagonist 0 wherein (a) the syrmgle has a o inaximnum tiL olm ofbewen bot ladaothi ()the syirnge is filled a dosage volume of between about OA)Thd and about 0.05ml of said VEC anutagonist solution, (c) the syrnge barrel comprises less than about 500pg silicone oil, and 5 (d) the VEGF antagonist solution comprises no nore than 2 particles :50Lm in diameter per ml,

2. A preilled syringe according to claim Wvwherein the syringe is filled with betWveen about 0 15m and about 0 I175ml of a VEGP antagonist solution.

3. A pre-filled syringe according to claim 1 or claim 2. wherein the syringe is filled with about 0. 16ini olf s-d N [ (mlantaaornist Solution. 20 4, A pre-fldled sringe according to any previous claim, wherein the syringe is filled with dosage volume of about 0,05en oIa JGF antagonit solution. 5 A pre-lilled syringe according to any previous claim, in which the dosagie volume is detern md by the volume of' the variable volume chamber when a predeueirnined part of the stopper is aligned with a priing mark on the syringe. 25 6. A pireflled synge cording to any previous claim, wherein the singe barreI has an internal coamng of siemone oil that has An avenge thickness of about 450am or less, preferably 400nm or less, preferably 350nn or less, preferably 300nm mr less, preferably 20Qam o les. preferably 100nm or less, preferably 50ni or less, preferably 2onm or less. ..17.. 157 7 pre-filled syringe aCCOrding to any previous claim, Wherein the syrige barrel as an) internal coating of less than about SQOpg silicone oil, preferably less thm about 100pg slicone oil, preferably less than about 50pg silicone oil, prekrabiyess than about 25pg silicone oil, preferably less than about 10 (p silicone oil. 5 8 A prc-filled syringe according to any previous claim, where the i barrla an internal coating of more than about 1 pg, more than about 3pg more than about 51g. more than about. 7g or muore than about I O silicone oil.

9. A pre-filled syringe according to any previous claim, wherein i the syringe barrel has an integral coating of about Ipg-about 50 0 pg. about 3 pg-about 200pg.about 5pg-about 1OOpg or 0 about 10pg-about 50pg silicone oil. i, A pre-hlled syn e according to aym- devious clain, where, the silicone on is Uocf3Z5 emulsion i -A.preilled syringe actooding to any one of clahis - wherein the syringe is silicone oil free, 5 12. A pre-filled syringe according to any previous claim, wherein the VEGF antagonist solution further comprises one or more of (i) no more than 5 particles :25pm in diameter per i. and (ii) no more than 50 particles> 1pm in diameter per i

13. A pr-dilled syrnge according to any previous aim, wherein the VEIGF antagonist solution meets U SP)789 20 14, A gre-filled syringe according to any previous claim, wherein the VEGF antagonist is an ani- VEGF antibody, 15, A pre-flled syringe according to claim 14, wherein the anti-VEF antibody is ranibizumab

16. Apie-ld syringe according to claim 15, wherein the ranibizumab is at a concntration of IS n- rngni I. ith EFana

17. A pre-iled syri ccrdng to any one of claims 1-13 werein the VEG antagonistis a non-antibody VEGF antagonist

18. A pre filled syringe according to claim 17, wherin the non-antibody V 13GF antagaont is alibercept or conbercept. $5157 19, A pre-tilled syringe according to claim 18, wherein the non-antibody VEF antagonist is afiberrept at a concentration of 40n g/m

20. A pre-filled syringe aCCOrding to any previous claim, Wherein the syringe has a stopper break loose force of less than about Il N 5 21l A pro- filled s-yringe according to clai-m 20, wherein thfying as a stperbreak loose force of less than about SN 22, A prc-lilled sydge according to any previous claim, wherein the syringe has a stopper slide force of less than about I IN

23. A pre-filled syringe according to claim 22, wherein the syringe has a stopper slide force of 0 less than about 5N.

24. A pre-filled syringe according to any of claims 20-23, whterin the stopper break loose force or stopper slide force is measured using a filled saying at a stopper travelling speed of I90mnin, with a 300 x 0.S inch needle attached to the syrmge

25. A blister pack comprisng a pc-filled syringc according to any previous clain, wherein the 5 syringe has been steriised using IO 2 or Etc 26 A blister pack comprising a pve-filled syringe according to claim 25. wherein the outer surface of the syringe has _lpp EtO or 1 2 0bfesidue 27 A blister pack comprising a predilled syringe according to claim 25, wherein the syringe has been sterilised using EO or I2JAN and the total B/O or 1O2 residue fond on the outside of the 20 syrirge and inside ofthe blister pack is 0.Img.

28. A blster pack comprising a pre-filled syringe according to any one of claims 25-27, wherein 5% of the VF antagonist is alkyite 29,.A blister pack comprising a preiled syringe according to any of caims 25-2K wherein the syringe has been sterilised using 110 or 122 vith a Serility Asurance level of at least 1 0$ 25 30 A blister pack according to any of claims 25~09, wherein the pre-filled syringe has a shelf life of up to 6 months, 9 months, 12 months, 15 months, 18 months, 24 months or longer -10- 515'7 3 A kit comprising, (i) a pre-tiled syringe according to any one of claims 1-24. or a blister pack comprising a pre-filled syringe according to any one of clairns 2 0, (ii) a needle, and optionally (iii) insitrtions for admninstration.

32. A kit according to claims 31 whe.rein the needle is a 30-gauge x incedle y3 A according to ay oneo claims 1-24 for use il therapy

334. A pre-filled syringe according to anly one of Claims .1-24 for us e in the treatment of artocular disease selected from choroidal weovasOilaisation Wet age-related macular degeneration. macular edema secondary to retinal vein occlusion (RVO) Including both branch RVO (bRVO) and central iRVQ (cRVCY) choroidal neovascularisation secondary to pathologic myopia (PM), 0 diabetic macular edema (DMB) diabetic reiopathy and proleratve retinopathy. 35. A method of treating a patient suffering from of an ocular disease selected from choroidal neoasulristin.wet ac-related Tnacuflar degeneration, rmcular edemna secondaryin. 10l retinal vein occlusion (RVO) including both branch RVO (bRVO) aid central RVO (cRVO m cboroidal neovascularsation secondary to pathologic myopia (PM), diabetic macular edema (DM 5 diabetic retinopathy, and proliferative retinopathy corising the step of administering an ophthalhic solution to the patient using a pre-filed syrnge according to any one ofclaxms I 24. 36. [hei method of claim '35, further comprisin anIT tnitial Priming step in which the physician depresses the plunger of the pre-filled syringe to align the pre-detennined part of the stopper with the priming mark, M0 37, A method according to claim 35 or 36, wherein the VEGF antagonist administered is a non antibody VEGE antagonist and wherein the patient has previously received treatment with an antibody VEOF antagonist.