DE202012011260U1 - Ranibizumab Injection - Google Patents

Abstract

A prefilled syringe, wherein the syringe comprises a body, a stopper and a piston, the body includes an outlet at an outlet end, and the stopper is disposed within the body such that a frontal surface of the stopper and the body describe a variable volume chamber, from which a liquid can be forced through the outlet, the piston comprises a piston contacting surface at a first end and a rod extending between the piston contacting surface and a rear part, the piston contacting surface being arranged to contact the stopper so that the piston can be used to push the stopper towards the outlet end of the body, reducing the volume of the variable volume chamber, characterized in that the fluid is an ophthalmic solution comprising a VEGF antagonist, wherein (a) the syringe is a nominal one maximum filling volume of between about 0.5 ml and et wa 1 ml, (b) the syringe with between about ...

Description

TECHNICAL AREA

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

STATE OF THE ART

Patients are given many medications using a syringe that allows the user to apply the medication. When administering a drug to a patient in a syringe, this is often done to allow the patient or caregiver to inject the drug themselves. For patient safety and the integrity of the drug, it is important that the syringe and its contents are sufficiently sterile to prevent infection and other risks to the patient. Sterilization can be achieved by a final sterilization in which the assembled product, which is typically already in the associated packaging, is sterilized with the aid of heat or a sterilizing gas.

In the case of small volume syringes, for example those for injections into the eye intended to inject about 0.1 ml or less of the liquid, sterilization can lead to problems not necessarily encountered with larger syringes. Pressure changes inside or outside the syringe may cause parts of the syringe to move unpredictably, altering density characteristics and possibly compromising sterility.

In addition, certain therapeutics, such as biological molecules, are particularly susceptible to sterilization, be it cold gas sterilization, thermal sterilization or irradiation. Therefore, a careful balancing act is necessary to ensure that, while a suitable degree of sterilization is achieved, the syringe will continue to be adequately sealed so that the therapeutic is not compromised.

Therefore, there is a need for a new syringe design that provides a stable seal for its contents but maintains easy handling.

DISCLOSURE OF THE INVENTION

The present invention provides a prefilled syringe, the syringe comprising a body, a stopper and a piston, the body comprising an outlet at an outlet end and the stopper disposed in the body such that the frontal surface of the stopper and the body Describe a variable volume chamber from which a liquid is forced through the outlet, the piston includes a piston contact surface at a first end and a rod extending between the piston contact surface and a rear portion, the piston contact surface is arranged to contact the stopper so that the piston can be used to push the stopper towards the outlet end of the body, thereby reducing the volume of the variable volume chamber, characterized in that the fluid comprises an ophthalmic solution. In one embodiment, the ophthalmic solution comprises a VEGF antagonist.

In one embodiment, the syringe is suitable for ophthalmic injections, especially intravitreal injections, and therefore has a suitably low volume. The syringe may also be free of silicone oil or nearly free of silicone oil, or may contain a small amount of silicone oil as a lubricant.

In the case of ophthalmic injections, it is of considerable importance for the ophthalmic solution to have a particularly low particle content. In one embodiment, the syringe conforms to the requirement of the US Pharmacopeia Standard 789 (USP789).

syringe

The body of the syringe may be substantially a cylindrical shell or may substantially enclose a cylindrical bore having a non-circular outer shape. The outlet end of the body includes an outlet through which a liquid located within the variable volume chamber can be forced out while reducing the volume of said chamber. Of the Outlet may include a projection from the outlet end, through which a channel extends with a smaller diameter than the diameter of the variable volume chamber. The outlet may be designed, for example via a luer-lock connection, for connection to a needle or other accessory, such as a sealing device that can seal the variable volume chamber, but it may be used or removed around the variable volume chamber to unseal and allows a connection of the syringe with other accessories, such as a needle. Such a connection can be made directly between the syringe and the accessory, or with the aid of the sealing device. The body extends along a first axis from the outlet end to the rear end.

The body may be made of plastic (e.g., a cyclic olefin polymer) or glass and may include traces thereof on a surface to act as an injection guide. In one embodiment, the syringe body may have a fill mark. This allows the practitioner to align a predetermined portion of the stopper (such as the tip of the anterior surface or one of the circumferential fins, which will be discussed later) on the marker, thereby forcing excess ophthalmic solution or any air bubbles out of the syringe. The filling process ensures that the patient is given a precise predetermined dose.

The stopper may be made of rubber, silicone or other suitable elastically deformable material. In essence, the stopper may have a cylindrical shape, and the stopper may include one or more circumferential louvers around an outer surface of the stopper, the stopper and the louvers are designed so that the louvers with an inner surface of the syringe body for a substantially ensure a liquid-tight seal. The frontal surface of the stopper may be any suitable shape, for example substantially planar, substantially conical or domed. The rear surface of the stopper may have a central recess. Such a recess could be used to connect a piston to the stopper using a snap device or threaded connection in a known manner. The stopper may be substantially rotationally symmetric to an axis through the stopper.

The piston includes a piston-contacting surface and, starting therefrom, a rod extends from the piston-contacting surface to a rear part. The rear part may have a contact part for a user that is designed to be touched by a user during an injection. The contact portion for a user may comprise a substantially disc-shaped portion, the radius of the disc extending substantially perpendicular to the axis along which the rod extends. The contact part for a user could have any suitable shape. The axis along which the rod extends may be the first axis or may be substantially parallel to the first axis.

The syringe may have a rear barrier located at the rear end of the syringe body. The rear barrier may be removable from the syringe. When the syringe body has terminal arms at the end opposite the outlet end, the rear barrier can be configured to substantially surround the terminal arms of the body as this prevents movement of the rear barrier in a direction parallel to the first axis.

The rod may have at least one rod shoulder facing away from the outlet end and the rear barrier may have a shoulder of the rear barrier aligned towards the outlet end to substantially prevent the rod from interfering with the shoulder of the rod The outlet end is removed when the shoulder of the rear barrier and the rod shoulder touch. Restricting the movement of the rod away from the outlet end may help maintain sterility during the final steps of the sterilization procedure or other operations where the pressure within the variable volume chamber and outside the variable chamber may vary. During such operations, any gas trapped in the variable volume chamber, or bubbles that may form in a liquid therein, may change in volume causing the stopper to move. The movement of the stopper away from the outlet could result in the breakage of a sterility area established by the stopper. This is particularly important for small-volume syringes, where the tolerances on the component sizes are much tighter and the stopper has less flexibility. As used herein, the term sterility range is used to refer to an area in the syringe that is sealed by the stopper against the ingress of both ends of the syringe. This may be the area between a seal of the stopper, for example a revolving louver closest to the outlet, and a seal of the stopper, for example a revolving louver furthest from the outlet is removed. The distance between these two seals determines the sterility range of the stopper because the stopper is placed in the syringe barrel in a sterile environment.

To further maintain the sterility of the above operations, the stopper may include a forward circumferential louver and a rear circumferential louver, and these louvers may be spaced in a direction along the first axis by a minimum distance of 3mm, 3.5mm, 3, 75 mm, 4 mm or more apart. One or more additional sipes (for example 2, 3, 4 or 5 additional sipes, or between 1-10, 2-8, 3-6 or 4-5 additional sipes) may be placed between the front and rear sipes. According to one embodiment, there are a total of three circumferential lamellae.

A stopper with such an improved sterility range may also provide protection for the injectable drug during a final sterilization procedure. Further lamellae at the stopper or a greater distance between the anterior and posterior lamellae may reduce the potential exposure of the drug to the sterilant. However, the increasing number of lamellas can increase the friction between the stopper and the syringe body and thus reduce the handling. While this can be overcome by increasing the syringes siliconization, such an increase in silicone oil levels in syringes is particularly undesirable for ophthalmic use.

The bar shoulder can be located within the outside diameter of the bar or outside the outside diameter of the bar. By providing a shoulder which extends beyond the outer diameter of the rod but still fits into the body, the shoulder can help stabilize the movement of the rod in the body by reducing the movement of the rod perpendicular to the first axis. The bar shoulder may comprise any suitable member for forming a shoulder on the bar, but in one embodiment, the bar shoulder comprises a substantially disc-shaped portion on the bar.

In one embodiment of the syringe in which the piston contact surface contacts the stopper and the variable volume chamber has its intended maximum volume, there is a gap of no more than 2 mm between the rod shoulder and the shoulder of the rear barrier. In some embodiments, the gap is less than about 1.5 mm, and in some less than 1 mm. This distance is chosen to substantially reduce or prevent excessive backward movement (away from the outlet end) of the stopper.

In one embodiment, the variable volume chamber has an inside diameter of more than 5 mm or 6 mm, or less than 3 mm or 4 mm. The inner diameter can be between 3 mm and 6 mm, or between 4 mm and 5 mm.

In another embodiment, the syringe is dimensioned to have a nominal maximum fill volume between about 0.1 ml and about 1.5 ml. In certain embodiments, the nominal maximum fill volume is about 0.5 ml and about 1 ml. In certain embodiments, the nominal maximum fill volume is about 0.5 ml, or about 1 ml, or about 1.5 ml.

The length of the syringe body may be less than 70 mm, less than 60 mm or less than 50 mm. In one embodiment, the length of the syringe body is between 45 mm and 50 mm.

In one embodiment, the syringe is between about 0.01 ml and about 1.5 ml (for example, between about 0.05 ml and about 1 ml, between about 0.1 ml and about 0.5 ml, between about 0, 15 ml and about 0.175 ml) of a VEGF antagonist solution. In one embodiment, the syringe is filled with 0.165 ml of a VEGF antagonist solution. Of course, a syringe is typically filled with more than the desired dose to be administered to the patient to account for the loss due to "dead space" in the syringe and the needle. There may also be some loss when the syringe is filled by the practitioner to be available for administration to the patient.

Thus, in one embodiment, the syringe having a dosing volume (ie, the volume of drug provided for delivery to the patient) is between about 0.01 ml and about 1.5 ml (eg, between about 0.05 ml and about 1 ml). between about 0.1 ml and about 0.5 ml) of a VEGF antagonist solution. In one embodiment, the dosing volume is between about 0.03 ml and about 0.05 ml. For Lucentis, for example, the dosing volume is 0.05 ml or 0.03 ml (0.5 mg or 0.3 mg) of a 10 mg / ml. ml injectable Drug solution; for Eylea, the dosing volume is 0.05 ml of a 40 mg / ml injectable drug solution.

In one embodiment, the syringe body is between about 45 mm and about 50 mm long, the inner diameter is between about 4 mm and about 5 mm, the filling volume is between about 0.12 and about 0.3 ml and the dosing volume is between about 0, 03 ml and about 0.05 ml.

Since the syringe contains a drug solution, the outlet can be reversibly sealed to maintain sterility of the drug. This seal can be achieved by the use of a sealing device, as known in the art. For example, the OVS ^TM system available from Vetter Pharma International GmbH.

Typically, the syringe is siliconized to allow easy handling, ie, applying silicone oil to the inside of the cylinder, which reduces the force that must be applied to move the stopper. For ophthalmic use, however, it is desirable to reduce the likelihood that silicone oil drops will be injected into the eye. In addition, silicone oil can lead to the aggregation of proteins. A typical 1 ml syringe contains 100-800 μg silicone oil in the cylinder. Thus, in one embodiment, a syringe according to the invention contains less than about 800 μg (ie, less than about 500 μg, less than about 300 μg, less than about 200 μg, less than about 100 μg, less than about 75 μg, less than about 50 μg, less than about 25 μg, less than about 15 μg, less than about 10 μg) silicone oil in the barrel. Methods for measuring the amount of silicone oil in such a syringe barrel are already known in the art and include, for example, different weighing methods and quantification by infrared spectroscopy of the oil diluted with a suitable solvent. Various types of silicone oil are available, but typically is either DC360 (Dow Corning ^®; with a viscosity of 1000 cps) or an emulsion DC365 (Dow Corning ^®; DC360 oil with a viscosity of 350 cP) was used for the Spritzensilikonisierung. In one embodiment, the prefilled syringe according to the invention contains a DC365 emulsion.

In experiments it has been found that in the case of small size syringes such as those mentioned above, and especially those described in connection with the figures below, the breakaway and sliding forces for the stopper in the syringe remain largely unaffected by a reduction in the degree of siliconation far below the current standard levels to the levels mentioned here. This is in contrast to the usual way of thinking, which would lead to the assumption that in case of a reduction of the silicone oil level, the required forces would increase. Excessive force required to move the stopper may cause problems for some users during use, for example, exact dose adjustment or smooth administration of the dose may be hampered if much force is needed to stop it To set stopper in motion and / or to keep it moving. The breakaway and sliding forces in pre-filled syringes known in the art are typically on the order of less than 20 N, but prefilled syringes contain from about 100 μg to about 800 μg of silicone oil. In one embodiment, the sliding / slipping force for the stopper in the prefilled syringe is less than about 11 N or less than 9 N, less than 7 N, less than 5 N or between about 3 N to 5 N. In one embodiment, the Breakout force less than about 11 N or less than 9 N, less than 7 N, less than 5 N, or between about 2 N to 5 N. It should be noted that such measurements are for a filled syringe rather than an empty syringe. The forces are typically measured on a stopper moving at a speed of 190 mm / min. In one embodiment, the syringe has a nominal maximum fill volume between about 0.5 ml and 1 ml, contains less than about 100 μg of silicone oil, and the breakout force is between about 2 N to 5 N.

In one embodiment, the syringe barrel has a silicone inner coating having an average thickness of about 450 nm or less (ie 400 nm or less, 350 nm or less, 300 nm or less, 200 nm or less, 100 nm or less, 50 nm or less, 20 nm or less). Methods for measuring the thickness of the silicone oil layer in a syringe are known in the art and include the "rap. ID Layer Explorer ^® "application, which can also be used to determine the amount of silicone oil in a syringe barrel.

In one embodiment, the spray is free or nearly free of silicone oil. Such low silicone oil levels can be achieved by using uncoated syringe barrels and / or avoiding silicone oil as a lubricant in a product that contacts components or machine parts, or pumps in syringe assembly and filling.

The syringe according to the invention can also meet certain particle content requirements. In one embodiment, the ophthalmic solution comprises no more than 2 particles of ≥ 50 μm in diameter per ml. In one embodiment, the ophthalmic solution comprises no more than 5 particles of ≥ 25 μm in diameter per ml. In one embodiment, the ophthalmic solution does not comprise more than 50 particles of ≥ 10 μm in diameter per ml. In one embodiment, the ophthalmic solution comprises no more than 2 particles of ≥ 50 μm in diameter per ml, no more than 5 particles of ≥ 25 μm in diameter per ml and not more as 50 particles of ≥ 10 μm in diameter per ml. In one embodiment, a syringe according to the invention corresponds to USP789. In one embodiment, the syringe has a low silicone oil level sufficient for the syringe to meet the requirements of USP789.

VEGF antagonists

VEGF antibody antagonists

VEGF is a well-described signaling protein that promotes angiogenesis. Two VEGF antibody antagonists have been approved for use in humans, namely Ranibizumab (Lucentis ^®) and bevacizumab (Avastin ^®).

Non-antibody VEGF antagonists

und Disulfidbrücken können zwischen den Resten 30-79, 124-185, 246-306 und 352-410 innerhalb jedes Monomers, und zwischen den Resten 211-211 und 214-214 zwischen den Monomeren gebildet werden.In one aspect of the invention, a non-antibody-like VEGF antagonist is an immunoadhesin. Such an immunoadhesin is aflibercept (Eylea ^®), which was recently approved for use in humans and the (also known as VEGF Trap Holash et al. (2002) PNAS USA 99: 11393-98 ; Riely & Miller (2007) Clin Cancer Res 13: 4623-7s ) is known. Aflibercept is the preferred non-antibody VEGF antagonist for use with the invention. Aflibercept is a recombinant, human soluble VEGF receptor fusion protein consisting of portions of the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of human IgG1. It is a dimeric glycoprotein with a protein molecular weight of 97 kilodaltons (kDA) and contains glycosylations, which add up to 15% of the total molecular mass, resulting in a total molecular weight of 115 kDa. It is usually produced as a glycoprotein by expression in recombinant CHO K1 cells. Each monomer may have the following amino acid sequence (SEQ ID NO: 1):

and disulfide bridges can be formed between residues 30-79, 124-185, 246-306 and 352-410 within each monomer, and between residues 211-211 and 214-214 between the monomers.

und wie VEGF-Trap als ein Dimer vorkommen. Dieses Fusionsprotein und damit verwandte Moleküle werden in EP1767546 genauer beschrieben.Another non-antibody VEGF antagonist immunoadhesin currently in preclinical development is a recombinant human soluble VEGF receptor fusion protein, similar to VEGF-Trap, extracellular ligand binding domains 3 and 4 from VEGFR2 / KDR and domain 2 from VEGFR1 / FIt-1; these domains are fused with a protein fragment of the human IgG Fc ( Li et al., 2011 Molecular Vision 17: 797-803 ). This antagonist binds to the isoforms VEGF-A, VEGF-B and VEGF-C. The molecule is created by using two different production methods that lead to different glycosylation patterns in the finished protein. The two glycoforms are referred to as KH902 (Conbercept) and KH906. The fusion protein may have the following amino acid sequence (SEQ ID NO: 2):

and how VEGF trap occurs as a dimer. This fusion protein and related molecules are in EP1767546 described in more detail.

Other non-antibody-like VEGF antagonists include antibodies mimics (z. B. Affibody ^® molecules, affilines, Affitine, anticalins, Avimere, Kunitz domain peptides and Mono body) with VEGF-antagonist activity. This includes recombinant binding proteins comprising an ankyrin repeat domain that binds VEGF-A and prevents it from binding to VEGFR-2. An example of such a molecule is DARPin ^® MP0112. The ankyrin binding domain may have the following amino acid sequence (SEQ ID NO: 3):

Recombinant binding proteins comprising an ankyrin repeat domain which binds VEGF-A and prevents it from binding to VEGFR-2 are disclosed in U.S. Pat WO2010 / 060748 and WO2011 / 135067 described in more detail.

Other specific antibody mimetics with VEGF antagonist activity are the 40 kD pegylated anticalin PRS-050 and the monoclonal angiocept (CT-322).

The aforementioned non-antibody VEGF antagonist may be modified to further improve its pharmacokinetic properties or bioavailability. For example, a non-antibody-like VEGF antagonist may be chemically modified (e.g., pegylated) to prolong its in vivo half-life. Alternatively or additionally, it may be modified by glycosylation or the addition of additional glycosylation sites that are not present in the protein sequence of the natural protein from which the VEGF antagonist was derived.

Variants of the VEGF antagonist described above which have improved properties for the desired application can be prepared by the addition or deletion of amino acids. Usually, these amino acid sequence variants will have an amino acid sequence having at least 60% amino acid sequence identity with the amino acid sequence SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3, preferably at least 80%, more preferably at least 85%, more preferably at least 90% and most preferably at least 95%, wherein z. 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% and 100% are included. Identity or homology to this sequence is defined herein as the percentage of amino acid residues in the candidate sequence that are identical to SEQ ID 1, SEQ ID 2 or SEG ID NO 3, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percentage of sequence identity, disregarding any conservative substitutions as part of sequence identity.

Sequence identity can be determined by standard methods commonly used to compare the similarity of the position of amino acids of two polypeptides. When using In a computer program such as BLAST or FASTA, two polypeptides are aligned by alignment to achieve optimal mating of the corresponding amino acids (either along the full length of one or both sequences or along a predetermined portion of one or both sequences). By default, the programs provide an opening parameter and defaults to a gap penalty parameter, and a scoring die such as PAM 250 [a standard scoring die; See Dayhoff et al., Atlas of Protein Sequence and Structure, Vol. 5, Supplement 3 (1978)], may be used in conjunction with the computer program. For example, the percent identity can then be calculated: the total number of identical pairings multiplied by 100 and then divided by the sum of the length of the longer sequence within the paired range and the number of blanks introduced in the longer sequences by the two sequences to arrange by an alignment.

Preferably, the non-antibody-like VEGF antagonist of the invention binds to VEGF via one or more protein domains that are not derived from the antigen-binding domain of an antibody. The non-antibody-like VEGF antagonist according to the invention is preferably proteinaceous, but may include modifications that are not proteinaceous (eg, pegylation, glycosylation).

therapy

The syringe of the present invention may be used to treat an ocular condition that has choroidal neovascularization, age-related macular degeneration (both wet and dry forms), macular edema secondary to retinal vein occlusion (RVO) , including a branched RVO (bRVO) and a central RVO (cRVO), a choroidal neovascularization secondary to pathological myopia (PM), a diabetic macular edema (DME), includes but is not limited to diabetic retinopathy and proliferative retinopathy.

Thus, the invention provides a method for treating a patient suffering from an eye disease selected from choroidal neovascularization, wet age-related macular degeneration, macular edema secondary to retinal vascular occlusion (RVO), including a branched RVO ( BRVO) and central RVO (cRVO), a choroidal neovascularization secondary to pathological myopia (PM), diabetic macular edema (DME), diabetic retinopathy, and proliferative retinopathy, comprising the step of administering an ophthalmic solution the patient using a prefilled syringe according to the invention. This method preferably further comprises an initial loading step wherein the practitioner presses the plunger of the prefilled syringe to align the predetermined portion of the stopper with the fill mark.

In one embodiment, the invention provides a method of treating an eye disease selected from choroidal neovascularization, wet age-related macular degeneration, macular edema secondary to retinal vascular occlusion (RVO), including a branched RVO (bRVO) and a central RVO (cRVO), a choroidal neovascularization secondary to pathological myopia (PM), diabetic macular edema (DME), diabetic retinopathy, and proliferative retinopathy, comprising administering a non-antibody VEGF antagonist with a prefilled syringe according to the invention, wherein the patient has previously received treatment with a VEGF antibody antagonist.

Kits

Also provided are kits comprising the prefilled syringes according to the invention. In one embodiment, such a kit comprises a prefilled syringe according to the invention in a blister pack. The blister pack can be sterile even on the inside. In one embodiment, syringes according to the invention may be placed within such blister packs to undergo sterilization, e.g. B. a final sterilization.

Such a kit may further comprise a needle for administering the VEGF antagonist. If the VEGF antagonist is to be administered intravitreally, it is typical to use a 30 gauge x ½ inch needle, although 31 gauge and 32 gauge needles may be used. For intravitreal administration, 33-gauge or 34-gauge needles could alternatively be used. Such kits may further include instructions for use. In one embodiment, the invention provides a box which includes a prefilled syringe according to the invention contained within a blister pack, a needle, and optionally instructions for administration.

sterilization

As noted above, a final sterilization process can be used to sterilize the syringe, and for such a process, a known method can be used, such as an ethylene oxide or a hydrogen peroxide sterilization process. Needles to be used with the syringe, as well as kits according to the invention, can be sterilized by the same method.

The pack is exposed to the sterilizing gas until the outside of the syringe is sterile. Following such a procedure, the outer surface of the syringe (while in its blister pack) may remain sterile for up to 6 months, 9 months, 12 months, 15 months, 18 months or longer. In one embodiment, less than one million syringes have detectable microbes on the outside of the syringe after 18 months of storage. In one embodiment, the prefilled syringe has been sterilized using EtO with a sterility level of at least 10 ^-6 . In one embodiment, the prefilled syringe has been sterilized using hydrogen peroxide having a sterility level of at least 10 ^-6 . Of course, it is a requirement that significant quantities of the sterilizing gas should not enter the variable volume chamber of the syringe. The term "significant amounts" as used herein refers to an amount of gas that would cause an unacceptable change in the ophthalmic solution within the variable volume chamber. In one embodiment, the sterilization procedure causes ≤10% (preferably ≤5%, ≤3%, ≤1%) alkylation of the VEGF antagonist. In one embodiment, the prefilled syringe has been sterilized using EtO but the outer surface of the syringe has ≦ 1 ppm, preferably ≦ 0.2 ppm EtO remainder. In one embodiment, the prefilled syringe has been sterilized using hydrogen peroxide, but the outer surface of the syringe has a hydrogen peroxide residue of ≦ 1 ppm, preferably ≦ 0.2 ppm. In another embodiment, the prefilled syringe has been sterilized using EtO and the total EtO remainder found on the outside of the syringe and the inside of the blister pack is ≤ 0.1 mg. In another embodiment, the prefilled syringe has been sterilized using hydrogen peroxide, and all the hydrogen peroxide residue found on the outside of the syringe and the inside of the blister pack is ≤ 0.1 mg.

General

The term "comprising" means "including" as well as "consisting of," e.g. For example, a composition "comprising" X may consist solely of X, or it may include something additional, e.g. B. X + Y.

The term "about" with respect to a numerical value x means z. Eg x ± 10%.

A reference to a percent sequence identity between two amino acid sequences means that in an alignment arrangement, this percentage of the amino acids is the same in comparing the two sequences. This alignment arrangement and percent homology or sequence identity may be determined using software programs known in the art, for example those described in Section 7.7.18 of the Current Protocols in Molecular Biology ( FM Ausubel et al., Eds., 1987 ) Supplementary band 30 are described. A preferred alignment arrangement is determined by the Smith-Waterman homology search algorithm using an affine space search with a gap open penalty parameter of 12 and a gap extension penalty parameter of 2, a BLOSUM template of 62. The Smith-Waterman homology search algorithm is described in Smith & Waterman (1981) Adv. Appl. Math. 2: 482-489 disclosed.

BRIEF DESCRIPTION OF THE FIGURES

1 shows a side view of a syringe.

2 shows a cross section of a syringe in a top-down view.

3 shows a view of a piston.

4 shows a cross section through a piston.

5 shows a stopper.

MODES FOR CARRYING OUT THE INVENTION

The invention will now be further described by way of example only with reference to the drawings.

1 shows a view from one side of a syringe 1 comprising a body 2 , a piston 4 , a rear barrier 6 and a sealing device 8th ,

2 shows a cross section through the syringe 1 from 1 from above. The syringe 1 is suitable for use with ophthalmic injection. The syringe 1 includes a body 2 , a stopper 10 and a piston 4 , The syringe 1 extends along a first axis A. The body 2 includes an outlet 12 at an outlet end 14 and the stopper 10 is so within body 2 arranged that a frontal surface 16 of the stopper 10 and the body 2 a variable volume chamber 18 define. The variable volume chamber 18 contains an injectable drug 20 containing an ophthalmic solution comprising a VEGF antagonist, such as ranibizumab. The injectable solution 20 can through the outlet 12 by means of a movement of the stopper 10 on the outlet end 14 pushed out, causing the volume of the variable volume chamber 18 reduced. The piston 4 includes a piston contact surface 22 at a first end 24 and a staff 26 that extends between the piston contact surface 22 and a back part 25 extends. The piston contact surface 22 is arranged such that it the stopper 10 touched, so the piston 4 can be used to stopper 10 on the outlet end 14 of the body 2 to move. Such movement reduces the volume of the variable volume chamber 18 and causes the liquid in it to be forced out through the outlet.

The rear barrier 6 joins the body 2 by coupling to a terminal cantilever 28 of the body 2 , The rear barrier 6 closes a composite part 30 configured to substantially cover at least a portion of the terminal cantilever 28 of the body 2 to surround. The rear barrier 6 is designed to be attached to the body 2 to be docked by the side by one side of the rear barrier 6 remains open, leaving the rear barrier 6 at the syringe 2 can be attached.

The body 2 defines a substantially cylindrical bore 36 having a bore radius. The rod 26 includes a bar shoulder 32 coming from the outlet end 14 points away. The staff shoulder 32 extends to a rod shoulder radius of the first axis A, which is formed so that it is slightly smaller than the bore radius, so that the shoulder into the bore 36 fits. The rear barrier 6 close one shoulder 34 the rear lock on the exhaust end 14 is aligned. Shoulders 32 . 34 are configured such that together they essentially move the rod 26 away from the outlet end 14 prevent when the shoulder 34 the rear barrier and the rod shoulder 32 touch. The shoulder 34 the rearward barrier extends from outside the bore radius to a radius less than the radius of the rod shoulder, such that the rod shoulder 32 the shoulder 34 the rear barrier can not pass by a movement along the first axis A. In this case, the bar shoulder is 32 essentially disc or annular, and the shoulder 34 the rear barrier closes around the rear end 38 of the body 2 one.

The rear barrier 6 also includes two finger-shaped projections 40 one that is in opposite directions away from the body 2 extend substantially perpendicular to the first axis A, to a manual handling of the syringe 1 to facilitate during use.

In this example, the tip comprises a 0.5 ml body 2 containing between about 0.1 and 0.3 ml of an injectable drug 20 which comprises a 10 mg / ml injectable solution comprising ranibizumab. The syringe body 2 has an inner diameter of between about 4.5 mm and 4.8 mm, a length of between about 45 mm and 50 mm.

The piston 4 and stoppers 10 will be described in more detail with reference to the following figures.

3 shows a perspective view of the piston 4 from 1 wherein the piston contact surface 22 at the first end 24 of the piston 4 is shown. The rod 26 extends from the first end 24 the rear part 25 , The back part 25 closes a disc-shaped boom 42 a to the handling of Facilitate device by the user. The boom 42 provides a greater surface area for user touch than a bare end of the wand 26 ,

4 shows a cross section through a syringe body 2 and a staff 26 , The rod 26 closes four longitudinal slats 44 on, and the angle between the slats is 90 °.

5 shows a detailed view of a stopper 10 , where a conical shaped frontal surface 16 and three circumferential slats 52 . 54 . 56 around a substantially cylindrical body 58 are shown. The axial gap between the first lamella 52 and the last lamella 56 is about 3 mm. The back surface 60 of the stopper 10 includes a substantially central recess 62 one. The central recess 62 shoots a starting hole 64 with a first diameter. The initial drilling 64 leads from the back surface 60 in the stopper 10 to an inner recess 66 with a second diameter, the second diameter is larger than the first diameter.

stopper forces

0.5 ml syringes siliconized with <100 μg silicone oil filled with Lucentis, which comprise one of two different stopper designs, were tested for their maximum breakaway and sliding force. Prior to testing, 30 G x 0.5 "needles were attached to the syringes. Testing was performed at a stopper speed of 190 mm / min over a path length of 10.9 mm. Stopper design 1 Stopper design 2 Batch A Batch B Lot C Batch D Batch E Breakaway force of syringes Mean of 10 syringes 2.2 N 2.3 N 1.9 N 2.1 N 2.5 N Maximum single value 2.5 N 2.5 N 2.3 N 2.6 N 2.7 N sliding force Mean of 10 syringes 3.1 N 3.2 N 3.1 N 4.1 N 4.6 N Maximum single value 3.5 N 3.5 N 3.6 N 4.7 N 4.8 N

For both stopper designs, the average and maximum breakout forces remained below 3 N. For both stopper designs, the average and maximum slip forces remained below 5 N.

It should be understood that the invention has been described by way of example only and modifications may be made which remain within the scope and spirit of the invention.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• EP 1767546 [0033]
• WO 2010/060748 [0035]
• WO 2011/135067 [0035]

Cited non-patent literature

• Holash et al. (2002) PNAS USA 99: 11393-98 [0032]
• Riely & Miller (2007) Clin Cancer Res 13: 4623-7s [0032]
• Li et al., 2011 Molecular Vision 17: 797-803 [0033]
• FM Ausubel et al., Eds., 1987 [0050]
• Smith & Waterman (1981) Adv. Appl. Math. 2: 482-489 [0050]

Claims (23)

A prefilled syringe, wherein the syringe comprises a body, a stopper and a piston, the body includes an outlet at an outlet end, and the stopper is disposed within the body such that a frontal surface of the stopper and the body describe a variable volume chamber, from which a liquid can be forced through the outlet, the piston comprises a piston contacting surface at a first end and a rod extending between the piston contacting surface and a rear part, the piston contacting surface being arranged to contact the stopper so that the piston can be used to push the stopper towards the outlet end of the body, reducing the volume of the variable volume chamber, characterized in that the fluid is an ophthalmic solution comprising a VEGF antagonist, wherein (a) the syringe is a nominal one maximum filling volume of between about 0.5 ml and e (b) the syringe is filled with between about 0.15 ml and about 0.175 ml of the VEGF antagonist solution comprising a dosing volume of about 0.05 ml of the VEGF antagonist solution, (c) the syringe barrel comprises less than about 500 μg of silicone oil, (d) the VEGF antagonist solution comprises no more than two particles of ≥ 50 μm in diameter per milliliter, and (e) the VEGF antagonist is the VEGF antibody antagonist ranibizumab , A prefilled syringe, wherein the syringe comprises a body, a stopper and a piston, the body includes an outlet at an outlet end, and the stopper is disposed within the body such that a frontal surface of the stopper and the body describe a variable volume chamber, from which a liquid can be forced through the outlet, the piston comprises a piston contacting surface at a first end and a rod extending between the piston contacting surface and a rear part, the piston contacting surface being arranged to contact the stopper so that the piston can be used to push the stopper towards the outlet end of the body, reducing the volume of the variable volume chamber, characterized in that the fluid is an ophthalmic solution comprising a VEGF antagonist, wherein (a) the syringe has a nominal maximum filling volume of between about 0.5 ml and about 1 ml, (b) the syringe is filled with between about 0.15 ml and about 0.175 ml of the VEGF antagonist solution comprising a dosing volume of about 0.05 ml of the VEGF antagonist solution, (c) the syringe barrel comprises less than about 500 μg of silicone oil, (d) the VEGF antagonist solution comprises no more than two particles of ≥ 50 μm in diameter per milliliter, and (e) the VEGR antagonist is the VEGF antibody antagonist ranibizumab at a concentration of 10 mg / ml. A prefilled syringe according to claim 1 or 2, wherein the syringe is filled with about 0.165 ml of the VEGF antagonist solution. A prefilled syringe according to any one of the preceding claims, wherein the syringe barrel has an inner coating of silicone oil having an average thickness of about 450 mm or less. A prefilled syringe according to any one of the preceding claims, wherein the syringe barrel has an inner coating of less than about 500 micrograms of silicone oil, preferably less than about 100 micrograms of silicone oil, preferably less than about 50 micrograms of silicone oil, preferably less than about 25 micrograms of silicone oil. A prefilled syringe according to any one of the preceding claims, wherein the silicone oil is a GC 365 emulsion. A prefilled syringe according to any one of the preceding claims, wherein the syringe is free of silicone oil. A prefilled syringe according to any one of the preceding claims, wherein the VEGF antagonist solution further comprises one or more of (i) not more than 5 particles of ≥25 μg in diameter per ml and (ii) not more than 50 particles of ≥10 μg in diameter per ml. A prefilled syringe according to any one of the preceding claims wherein the VEGF antagonist solution is USP 789. A prefilled syringe according to any one of the preceding claims, wherein the syringe has a stopper break-out force of less than about 11N. A prefilled syringe according to claim 10, wherein the syringe has a stopper breakage force of less than about 5N. A prefilled syringe according to any one of the preceding claims, wherein the syringe has a Stoppergleitkraft of less than about 11 N. A prefilled syringe according to claim 12, wherein the syringe has a Stoppergleitkraft of less than about 5 N. A prefilled syringe according to any one of the preceding claims, wherein the metering volume is determined by the volume of the variable volume chamber when a predetermined portion of the stopper or piston is aligned with a filling mark on the syringe. A blister pack comprising a prefilled syringe according to any one of the preceding claims, wherein the syringe has been sterilized using H ₂ O ₂ or EtO. A blister pack comprising a prefilled syringe according to claim 15, wherein the outer surface of the syringe has an EtO or H ₂ O ₂ residue of ≤ 1 ppm. A blister pack comprising a prefilled syringe according to claim 15, wherein the syringe has been sterilized using EtO or H ₂ O ₂ and all the EtO or H ₂ O ₂ residue found on the outside of the syringe and inside of the blister pack ≤ 0.1 mg. A blister pack comprising a prefilled syringe according to any one of claims 15 to 17, wherein ≤ 5% of the VEGF antagonist is alkylated. A blister pack comprising a prefilled syringe according to any one of claims 15 to 18, wherein the syringe has been sterilized using EtO or H ₂ O ₂ having a sterility level of at least 10 ^-6 . A kit comprising: (i) a prefilled syringe according to any one of claims 1 to 14 or a blister pack comprising a prefilled syringe according to any one of claims 15 to 19, (ii) a needle, and optionally (iii) instructions for administration. A kit according to claim 20, wherein the needle is a 30 gauge x 1/2 inch needle. A prefilled syringe according to any one of claims 1 to 14 for use in therapy. A prefilled syringe according to any one of claims 1 to 14 for use in the treatment of an ocular disease selected from choroidal neovascularization, wet age-related macular degeneration, macular edema secondary to retinal vascular occlusion (RVO), including a branched RVO (bRVO) and a central RVO ( cRVO), choroidal neovascularization, secondary to pathological myopia (PM), diabetic macular edema (DME), diabetic retinopathy and proliferative retinopathy.

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