SYRINGE

Abstract

Syringe (11) comprising: a reservoir (12) filled with X mL of a formulation of omalizumab at 150 mg / mL, a stopper (15), and a needle (13) having a length of 12.7 mm, being of gauge 27, having a minimum internal diameter of 0.277 mm, and having 5 bevels on its distal surface; and the syringe (11) being configured to expel the formulation contained in the reservoir (12) through the needle (13) when a force is applied to the stopper (15), one of the following conditions being met when a constant force of 10 N is applied to the stopper (15): when X is equal to 2, the syringe (11) is configured to expel the formulation through the needle (13) in less than 16 seconds; when X is equal to 1, the syringe (11) is configured to expel the formulation through the needle (13) in less than 7.5 seconds; when X is equal to 0.5, the syringe (11) is configured to expel the formulation through the needle (13) in less than 4 seconds.Figure 3 accompanies the summary.

Description

Title of the invention: SYRINGE

[0001] This application claims the benefit of European patent applications 23188544.3 filed on July 28, 2023 and 24171754.5 filed on April 22, 2024.

[0002] This disclosure relates to methods for treating a patient with one or more of the following: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids. The method comprises administering a 150 mg / ml formulation of omalizumab to the patient, which formulation of omalizumab is administered subcutaneously using a syringe. This disclosure also relates to a 150 mg / ml formulation of omalizumab for use in accordance with the methods described herein. This disclosure also relates to syringes comprising a reservoir filled with a 150 mg / ml formulation of omalizumab and configured to carry out the methods described herein.This presentation also relates to the use of a 150 mg / ml formulation of omalizumab for the manufacture of a drug for any of the treatment methods disclosed herein. Background of the invention

[0003] Omalizumab is a humanized IgGlk monoclonal antibody derived from recombinant DNA that selectively binds to human immunoglobulin E (IgE) and is used to treat allergic asthma, chronic urticaria and nasal polyps, IgE-mediated food allergy, and chronic spontaneous urticaria.

[0004] When omalizumab first came onto the market in 2003, it was available only as a lyophilized dry powder (XOLAIR® lyophilized powder). To administer XOLAIR® to the patient, it was necessary to reconstitute the powder with sterile water and then inject the resulting solution. The procedure for reconstituting XOLAIR® lyophilized powder involves adding 0.9 or 1.4 mL of water for injection to a vial containing 75 or 150 mg of lyophilized powder, respectively, and swirling the vial for approximately 5 to 10 seconds every 5 minutes for approximately 15 to 20 minutes to allow the powder to dissolve completely. Because this procedure is lengthy and complex, XOLAIR® lyophilized powder can only be administered by a healthcare professional, which limits ease of use and the patient experience.As described in document US2002 / 0045571, this reconstituted formulation is approximately 80 times more viscous than water at 25°C.

[0005] Following its initial approval, omalizumab (XOLAIR®) became available as a 75 mg / 0.5 mL or 150 mg / 1 mL solution in a pre-filled, single-dose syringe for subcutaneous administration, the syringe having a 26-gauge needle. This eliminated the need for reconstitution immediately before administration, greatly improving ease of use, the patient experience, and ultimately, patient acceptance and outcomes. Furthermore, XOLAIR® was approved for self-injection, which further enhanced ease of use.

[0006] Subcutaneous injection of a 150 mg / ml formulation of omalizumab offers several advantages (Shi et al. Subcutaneous Injection Performance in Yucatan Miniature Pigs with and without Human Hyaluronidase and Auto-injector Tolerability in Humans. AAPS PharmSciTech. January 2021; 22(1): 39). First, it allows for self-administration, thus reducing the need for patients to visit healthcare providers to receive treatment. Second, subcutaneous injections are typically less painful than other injections, such as intravenous and intramuscular injections. As a result, subcutaneous injection is often the preferred route of delivery for both patients and healthcare professionals.

[0007] However, there are still difficulties associated with current dosing regimens and methods of administration of omalizumab. First, omalizumab is usually administered at a dose of 150 mg to 375 mg subcutaneously every 2 to 4 weeks, but only 15% to 20% of patients can receive their XOLAIR® treatment with a single injection using the currently available doses of 75 mg / 0.5 ml and 150 mg / 1 ml. Second, omalizumab formulations are highly viscous, and therefore subcutaneous injection using currently available pre-filled syringes requires high injection force and a long injection time. As a result, patients and caregivers may not be able to perform omalizumab injections with confidence.Third, omalizumab injections can cause injection site reactions—in fact, in asthmatic patients, injection site reactions of all severity occur at a rate of 45%, and severe injection site reactions occur at a rate of 12%. This problem is exacerbated by the need to administer each injection at a new injection site, and by the fact that 80% to 85% of patients must administer the contents of several syringes to reach their prescribed dose. Each of these difficulties negatively impacts the patient experience and convenience, and therefore negatively impacts patient adherence to omalizumab therapy. In the case of chronic diseases such as those treated with omalizumab, non-adherence is estimated at around 50% (Baryakova et al. 'Overcoming barriers to patient adherence: the case for developing omalizumab.'). 'Innovative Drug Delivery Systems'. Nature Reviews Drug Discovery. March 2023; volume 22, pages 387-409). Therefore, the above difficulties need to be resolved to improve ease of use and the patient experience, thereby improving patient adherence and outcomes. Summary of the invention

[0008] Omalizumab is currently proposed for use in the treatment of one or more of the following: allergic asthma; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids. The antibody is administered to the patient subcutaneously as a 150 mg / ml formulation of omalizumab, using a syringe with a reservoir filled with 0.5 ml or 1 ml of the 150 mg / ml formulation of omalizumab.

[0009] An object of the invention is to make available new uses for omalizumab, new syringes, and new administration / dosing regimens for omalizumab that can overcome the above obstacles in order to improve ease of use, patient experience, patient adherence, and outcomes when using omalizumab. In particular, an object of the invention is to make available new uses that reduce the number of individual injections required per treatment, reduce the time and injection forces required to deliver the omalizumab formulation subcutaneously, and reduce the risk of injection site reactions. Another object of the invention is to achieve these improvements without loss of antibody stability and purity, and while maintaining bioequivalence with known syringes.

[0010] However, there are significant difficulties in proposing a method of administration of omalizumab that achieves these objectives, because omalizumab is abnormally viscous in solution, particularly at the high concentration required for a dose of 150 mg / ml. These difficulties are described in more detail below.

[0011] The formulation of XOLAIR® is 150 mg / ml of antibody with 42.1 mg / ml of L-arginine hydrochloride, 1.37 mg / ml of L-histidine, 2.34 mg / ml of L-histidine hydrochloride monohydrate, and 0.4 mg / ml of polysorbate 20 as an aqueous solution (in sterile water for injection (USP)). Omalizumab Xolair® 75 mg / 0.5 ml, 150 mg / 1 ml, and 300 mg / 2 ml all have the same formulation, with a high antibody concentration of 150 mg / ml. The viscosity of omalizumab XOLAIR® is 12 to 14 mPa·s at room temperature. In one experiment, the viscosity measured at a shear rate of 200 s⁻¹ was: 24.7 ± 0.5 mPa·s 5.0 ± 0.2°C, 15.3 ± 0.5 mPa.s at 15.0 ± 0.2°C, 11.4 ± 0.5 mPa.s at 25.0 ± 0.2°C and 7.2 ± 1.2 mPa.s at 40.0 ± 0.2°C.

[0012] The high viscosity of omalizumab formulations presents several difficulties in obtaining the object of the invention.

[0013] In general, the higher the viscosity of a fluid, the more force and time are required to inject it using a syringe. Patients may have difficulty applying high injection forces to syringes and therefore may fail to push the stoppers to their terminal positions in the syringe to administer a full dose. Furthermore, high injection forces increase the risk of syringe breakage.

[0014] Long injection times significantly reduce patient experience and compliance. It is generally accepted that patients can comfortably hold a syringe in place for a maximum of 20 seconds. Therefore, when using syringes that inject medication for a duration approaching 20 seconds, there is an increased risk of incomplete administration because patients prematurely remove the syringe from the injection site due to discomfort.

[0015] These problems of high injection forces and long injection times are also exacerbated when administering larger volumes of omalizumab (> 1 ml) because the larger the volume of fluid to be injected, the more force and time are required to inject it. Furthermore, larger administration volumes also result in higher pressures at the injection site, leading to a greater likelihood of injection site reactions and associated injection errors.

[0016] Lubricants can be incorporated inside a syringe (for example, by silicone coating) to reduce the force and duration of injection, but they can cause protein aggregation, which reduces the purity and efficacy of the omalizumab solution. Furthermore, protein aggregation can cause blockages, requiring more force to inject the solution, thus reducing ease of use. Finally, it is necessary to bear in mind that regulatory and international standards must be met when making any improvements to currently available pre-filled omalizumab syringes.

[0017] Studies have been conducted to investigate the impact of viscosity, volume, and flow rate on the patient's experience of subcutaneous injection; see: 1) Rini et al. Enabling faster subcutaneous delivery of larger volume, high viscosity fluids. Expert Opinion on Drug Delivery. 2022, Vol. 19, No. 9, 1165-1176; 2) Roberts et al. Novel cannula design improves large volume auto-injection rates for high viscosity solutions. Drug Delivery, 29: 143-51; and 3) Berteau et al. Evaluation of the impact ofviscosity, injection volume, and injection flow rate on subcutaneous injection tolerance. Medical Devices: Evidence and Research 2015: 8, 473-484. However, some of these studies were conducted on non-biological solutions, and therefore the applicability of the findings to the uses of romalizumab is limited. Berteau et al. (2015) and Rini et al. (2022) clearly demonstrate that it is difficult to accurately predict the behavior of any biological agent when administered subcutaneously because the unique characteristics of each drug will impact its behavior. These unique characteristics include particle size, shape, sedimentation / resuspension characteristics, aggregation / agglomeration potential, and viscoelastic flow behavior. Berteau et al.(2015) conclude that each drug delivery device for high-speed, large-volume subcutaneous injection must be designed specifically for each drug in order to optimize ease of use, patient experience, patient adherence, and outcomes.

[0018] The inventors have overcome the difficulties stated above to make available new uses for romalizumab and treatment methods that address the various problems involved. According to one aspect of the invention, a treatment method is made available for a patient with one or more of the following: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps;moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient X ml of a 150 mg / ml formulation of omalizumab, where X is 2, and which X ml of the 150 mg / ml formulation of omalizumab are administered subcutaneously by means of a syringe, the syringe comprising: a reservoir filled with X ml of a 150 mg / ml formulation of omalizumab, which X ml of the 150 mg / ml formulation of omalizumab have 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter > 25 pm; and the syringe further comprising: a stopper, and a 27 gauge needle; and the syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper.

[0019] Providing a syringe containing 2 ml of a 150 mg / ml omalizumab formulation reduces the number of individual injections required per treatment for patients prescribed a dose greater than 150 mg of omalizumab. Reduced administration frequency improves patient adherence and experience. (Baryakova et al. 2023). Furthermore, a small number of injections leads to a reduced risk of injection site reaction, further improving patient adherence and experience. In this way, the present invention improves ease of use, patient experience, patient adherence, and outcomes when using omalizumab.

[0020] As will be demonstrated below, providing a syringe containing a 27-gauge needle reduces the time required to deliver romalizumab, compared to currently available syringes. In this way, the present invention reduces the injection time required to administer the dose. Furthermore, since the needle gauge is larger than that of the prior art, the needle of the present invention has a smaller outer diameter, which reduces pain during needle insertion. Thus, the present invention improves ease of use, patient experience, patient adherence, and outcomes when using romalizumab.

[0021] In some embodiments, the needle has one of the following: a) a minimum internal diameter of 0.277 mm; b) a minimum internal diameter of 0.191 mm; c) a minimum internal diameter of 0.184 mm; and d) a minimum internal diameter of 0.241 mm.

[0022] Larger minimum internal diameters further reduce the injection time required to administer romalizumab.

[0023] According to a second aspect of the invention, a method is made available for treating a patient with one or more of the following: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient X ml of a 150 mg / ml formulation of omalizumab, where X is 2, 1, or 0.5, and which X ml of the 150 mg / ml formulation of omalizumab are administered subcutaneously by means of a syringe, the syringe comprising: a reservoir filled with X ml of a 150 mg / ml omalizumab formulation, where X ml of the 150 mg / ml omalizumab formulation has 6000 or fewer particles with a diameter >10 pm and / or 600 or fewer particles with a diameter >25 pm; and the syringe further comprising: a stopper, and a needle from gauge 25 to gauge 29; and the syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper, and wherein one of the following options is satisfied when a constant force of 10 N is applied to the stopper, a) when X equals 2, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 16 seconds; b) when X equals 1, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 5 seconds; and c) when X equals 0.5, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 4 seconds.

[0024] Systems for measuring the duration of syringe injection and methods for configuring said systems are well known in the art.

[0025] The invention reduces the required injection forces, improving ease of use and making it more likely that a full dose will be administered. Thus, the present invention improves ease of use, patient experience, patient adherence, and outcomes when using omalizumab.

[0026] In certain embodiments of the invention in which X is 2, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in one or more of the following ways: a) less than 8.5 seconds when a constant force of 17 N is applied to the stopper; and b) less than 5 seconds when a constant force of 30 N is applied to the stopper.

[0027] In certain embodiments in which X is 2, the syringe is configured to expel X ml of the omalizumab formulation contained in the reservoir through the needle in one or more of the following ways: a) approximately 16 seconds to approximately 14 seconds when a constant force of 10 N is applied to the stopper; b) approximately 8.5 seconds to approximately 6 seconds when a constant force of 17 N is applied to the stopper; and c) approximately 5 seconds to approximately 4 seconds when a constant force of 30 N is applied to the cap.

[0028] In certain embodiments in which X is 1, the syringe is configured to expel X ml of the 150 mg / ml omalizumab formulation through the needle in one or more of the following: a) less than 5 seconds, less than 4.75 seconds, less than 4.5 seconds, less than 4.25 seconds, or about 4 seconds when a constant force of 10 N is applied to the cap; b) less than 3 seconds when a constant force of 17 N is applied to the stopper; and c) less than 2 seconds when a constant force of 30 N is applied to the stopper.

[0029] In certain embodiments in which X is 1, the syringe is configured to expel X ml of the 150 mg / ml omalizumab formulation through the needle in one or more of the following: a) less than 5 seconds to about 4 seconds, less than 4.75 seconds to about 4 seconds, less than 4.5 seconds to about 4 seconds, less than 4.25 seconds to about 4 seconds, or about 4 seconds when a constant force of 10 N is applied to the cap; b) less than 3.5 seconds to approximately 2 seconds when a constant force of 17 N is applied to the stopper; and c) less than 2 seconds to about 1 second when a constant force of 30 N is applied to the cap.

[0030] In certain embodiments in which X is 0.5, the syringe is intended to expel X ml of the 150 mg / ml omalizumab formulation through the needle in one or more of the following: a) less than 2 seconds when a constant force of 17 N is applied to the cap; and b) less than 1 second when a constant force of 30 N is applied to the stopper.

[0031] In certain embodiments in which X is 0.5, the syringe is intended to expel X ml of the 150 mg / ml omalizumab formulation through the needle in one or more of the following: a) less than 4 seconds to about 2 seconds when a constant force of 10 N is applied to the cap; b) less than 2 seconds to approximately 1 second when a constant force of 17 N is applied to the stopper; and c) less than 1 second to about 0.5 seconds when a constant force of 30 N is applied to the cap.

[0032] In certain embodiments of the invention, the syringe contains: a) at least 76% of the main charge variant of omalizumab, measured by ion-exchange chromatography after it has been filled with a 150 mg / ml omalizumab solution stored at 5°C ± 3°C; and / or b) at least 77% of the main charge variant of romalizumab, measured by ion-exchange chromatography after it has been filled with a 150 mg / ml solution of romalizumab and then stored at 5°C ± 3°C for 2.5 months.

[0033] In some embodiments, the percentage of the main charge variant of omalizumab in the syringe, measured by exchange chromatography of ions, is reduced by 2% or less after the syringe has been stored at 5°C ± 3°C for 2.5 months (e.g. measured from filling).

[0034] In certain embodiments of the invention, the proportion of the first peak of the syringe, measured by hydrophobic chromatography, is at least: a) 62% after filling with a 150 mg / ml omalizumab solution stored at 5°C ± 3°C; and / or b) 62% after it was filled with a 150 mg / ml omalizumab solution and then stored at 5°C ± 3°C for 2.5 months.

[0035] In certain embodiments of the invention, the proportion of the first peak of the syringe, measured by means of hydrophobic chromatography, is reduced by 0.4% or less after the syringe has been stored at 5°C ± 3°C for 2.5 months.

[0036] In some embodiments of the invention, the syringe contains at least 0.4 mg / ml of polysorbate 20 after filling with a 150 mg / ml omalizumab solution stored at 5°C ± 3°C.

[0037] In some embodiments of the invention, the syringe contains at least 69% of the main charge variant of romalizumab, measured by means of ion-exchange chromatography, after it has been filled with a 150 mg / ml solution of romalizumab and then stored at 25°C ± 3°C for 1.5 months.

[0038] In certain embodiments of the invention, the proportion of the first peak of the syringe, measured by means of hydrophobic chromatography, is at least: a) 56% for the syringe after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 3°C for 1.5 months; and / or b) 51% for the syringe after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 3°C for 2.5 months.

[0039] In some embodiments, the syringe contains: a) at least 0.4 mg / ml of polysorbate 20 after it has been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 3°C for 1.5 months; and / or b) at least 0.3 mg / ml of polysorbate 20 after it has been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 3°C for 6 months.

[0040] The percentages of the main charge variant of romalizumab, the peak by hydrophobic chromatography, and the polysorbate 20 content are measures of the purity and stability of romalizumab. As will be demonstrated below, the present invention preserves the purity and stability of romalizumab in a manner similar to that of current uses.

[0041] In certain embodiments of the invention, the needle has one gauge among one of: gauge 23, gauge 24, gauge 25, gauge 26, gauge 27, gauge 28, gauge 29, gauge 30, gauge 31, and gauge 32.

[0042] In certain embodiments of the invention, the needle has one gauge among a: a) gauge 23 defining a minimum internal diameter of 0.370 mm, b) gauge 23 defining a minimum internal diameter of 0.317 mm, c) gauge 24 defining a minimum internal diameter of 0.343 mm, d) gauge 24 defining a minimum internal diameter of 0.280 mm, e) gauge 25 defining a minimum internal diameter of 0.292 mm, f) gauge 25 defining a minimum internal diameter of 0.232 mm, g) gauge 26 defining a minimum internal diameter of 0.292 mm, h) gauge 26 defining a minimum internal diameter of 0.232 mm, i) gauge 27 defining a minimum internal diameter of 0.277 mm, j) gauge 27 defining a minimum internal diameter of 0.191 mm, k) gauge 27 defining a minimum internal diameter of 0.184 mm, l) gauge 27 defining a minimum internal diameter of 0.241 mm, m) gauge 28 defining a minimum internal diameter of 0.133 mm, n) gauge 28 defining a minimum internal diameter of 0.190 mm, o) gauge 29 defining a minimum internal diameter of 0.265 mm,p) gauge 29 defining a minimum internal diameter of 0.240 mm, q) gauge 29 defining a minimum internal diameter of 0.190 mm, r) gauge 29 defining a minimum internal diameter of 0.133 mm, s) gauge 30 defining a minimum internal diameter of 0.240 mm, t) gauge 30 defining a minimum internal diameter of 0.190 mm, u) gauge 30 defining a minimum internal diameter of 0.165 mm, v) gauge 30 defining a minimum internal diameter of 0.133 mm, w) gauge 31 defining a minimum internal diameter of 0.176 mm, x) gauge 31 defining a minimum internal diameter of 0.146 mm, y) gauge 31 defining a minimum internal diameter of 0.125 mm, z) gauge 31 defining a minimum internal diameter of 0.114 mm, aa) gauge 32 defining a minimum internal diameter of 0.146 mm, bb) gauge 32 defining a minimum internal diameter of 0.125 mm, ce) gauge 32 defining a minimum internal diameter of 0.105 mm, and dd) gauge 32 defining a minimum internal diameter of 0.089 mm.

[0043] In some embodiments of the invention, the needle is of gauge 25 to gauge 29, preferably of gauge 26 to gauge 28, especially of gauge 27.

[0044] In certain embodiments, when the needle is 25 gauge, the needle has one of the following: a) a minimum internal diameter of 0.292 mm, and b) a minimum internal diameter of 0.232 mm.

[0045] In certain embodiments, when the needle is 26 gauge, the needle has one of the following: a) a minimum internal diameter of 0.292 mm, and b) a minimum internal diameter of 0.232 mm.

[0046] In certain embodiments, when the needle is 27 gauge, the needle has one of the following: a) a minimum internal diameter of 0.277 mm; b) a minimum internal diameter of 0.191 mm; c) a minimum internal diameter of 0.184 mm; and d) a minimum internal diameter of 0.241 mm.

[0047] In certain embodiments, when the needle is 28 gauge, the needle has one of the following: a) a minimum internal diameter of 0.133 mm; and b) a minimum internal diameter of 0.190 mm.

[0048] In certain embodiments, when the needle is 29 gauge, the needle has one of the following: a) a minimum internal diameter of 0.265 mm; b) a minimum internal diameter of 0.240 mm; c) a minimum internal diameter of 0.190 mm; and d) a minimum internal diameter of 0.133 mm; Preferably the needle has a minimum internal diameter of 0.240 mm or 0.265 mm.

[0049] In another preferred embodiment of the invention, the needle is 29 gauge. In another preferred embodiment of the invention, the needle is 29 gauge and has a minimum internal diameter of 0.240 mm. In another preferred embodiment of the invention, the needle is 29 gauge and has a minimum internal diameter of 0.265 mm.

[0050] In certain embodiments of the invention, the stopper has a fluorinated resin on the side that comes into contact with the product or a layering of ethylene-tetrafluoroethylene (ETFE) barrier film. The layering of the stopper reduces friction, thereby reducing injection forces, shortening the injection time, and making it more likely that a full dose will be administered. In this way, the present invention improves ease of use, patient experience, patient adherence, and outcomes when using omalizumab.Furthermore, stratification helps prevent contamination between the stopper material and romalizumab, preserving the stability and purity of romalizumab.

[0051] In certain embodiments of the invention, the stopper has a UV-cured B2-40 lubricating coating or is lubricated with a 1000 cSt silicone oil. The stopper coating reduces friction, thereby reducing injection forces and the duration of the injection, and making it more likely that a full dose will be administered. In this way, the present invention improves ease of use, patient experience, patient adherence, and outcomes during the use of omalizumab. In addition, the cap coating helps prevent contamination between the cap material and omalizumab, preserving the stability and purity of omalizumab.

[0052] In certain embodiments of the invention, the syringe has an internal coating of between 0.3 and 1.0 mg (for example, 0.4 ± 0.2 mg or 0.7 ± 0.2 mg) of polydimethylsiloxane. The internal coating of the syringe reduces friction, thereby reducing injection forces, shortening the injection time, and making it more likely that a full dose will be administered. In this way, the present invention improves ease of use, patient experience, patient adherence, and outcomes when using omalizumab. Furthermore, the internal coating of the syringe helps to preserve the stability and purity of omalizumab.

[0053] In certain embodiments of the invention, the needle has 3 bevels on its distal surface or 5 bevels on its distal surface. The beveled distal surface reduces pain during needle insertion, improving the patient experience and thus patient adherence and outcomes.

[0054] In certain embodiments of the invention, the apparent viscosity of the 150 mg / ml formulation of omalizumab at a shear rate of 200 s⁻¹ is: 24.7 ± 0.5 mPa.s at 5.0 ± 0.2°C, 15.3 ± 0.5 mPa.s at 15.0 ± 0.2°C, 11.4 ± 0.5 mPa.s at 25.0 ± 0.2°C or 7.2 ± 1.2 mPa.s at 40.0 ± 0.2°C.

[0055] In certain embodiments of the invention, the syringe has a latex-free needle protector. The latex-free needle protector reduces the risk of reaction at the injection site, improving the patient experience and therefore patient adherence and outcomes.

[0056] In certain embodiments of the invention, the syringe has a round collar at one proximal end of the reservoir. In certain embodiments of the invention, the round collar has a maximum diameter of 11 ± 0.25 mm or 14.7 ± 0.25 mm. The round collar helps the syringe to better withstand significant injection forces, reducing the risk of syringe breakage and improving the patient experience. This is particularly advantageous when the syringe of the present invention is used in combination with an auto-injector that retains the syringe by the collar.

[0057] In certain embodiments of the invention, when X is 1 or 0.5, the syringe has a length of 54.0 ± 0.5 mm and an internal diameter of 6.35 mm ± 0.05 mm.

[0058] In certain embodiments of the invention, when X is 1 or 0.5, when the cap is not inserted in the reservoir, it has one of the following: a) a maximum external diameter of 6.67 mm to 7.10 mm and / or a length of 7.85 ± 0.4 mm; and b) a maximum external diameter of 6.70 ± 0.15 mm and / or a length of 7.85 ± 0.4 mm.

[0059] In certain embodiments of the invention, when X is 1 or 0.5, the stopper has at least one circumferential rib having an outer diameter of 6.60 ±0.15 mm. The circumferential ribs help to reduce contact between the stopper and the syringe, minimizing friction and thus reducing the force and duration of the injection. In this way, the present invention improves patient experience, adherence, and outcomes.

[0060] In certain embodiments of the invention, when X equals 2, the syringe has a length of 54.0 ± 0.5 mm and an internal diameter of 8.65 mm ± 0.05 mm.

[0061] In certain embodiments of the invention, when X is 2, the cap has a maximum external diameter of 9.05 ± 0.15 mm and / or a length of 7.70 ± 0.4 mm when it is not inserted into the reservoir.

[0062] In certain embodiments of the invention, when X equals 2, the stopper has at least one circumferential rib having an outside diameter of 9.00 ±0.15 mm. The ribs help to reduce contact between the stopper and the syringe, minimizing friction and thus reducing the force and duration of the injection. In this way, the present invention improves the patient experience, adherence, and outcomes. In certain embodiments of the invention, the dislodging force required to move the stopper of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of the following: a) approximately 2 N to approximately 4 N after storage at 5°C ± 3°C for 2.5 months after filling; b) approximately 2 N to approximately 4 N after storage at 5°C ± 3°C for 6 months after filling.

[0063] In certain embodiments of the invention, the dislodging force required to move the plug of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of the following: a) approximately 2 N to approximately 3.5 N at 25°C ± 3°C after filling; b) approximately 2 N to approximately 4.5 N after storage at 25°C ± 3°C for 1.5 months after filling; c) approximately 2.5 N to approximately 5 N after storage at 25°C ± 3°C for 2.5 months after filling; and / or d) approximately 2.5 N to approximately 5.5 N after storage at 25°C ± 3°C for 6 months after filling.

[0064] In certain embodiments of the invention, the dislodging force required to move the plug of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of the following: a) approximately 3 N to approximately 4.5 N after storage at 40°C ± 3°C for 1.5 months after filling; and b) about 3 N to about 5 N after storage at 40°C ± 3°C for 2.5 months after filling.

[0065] The syringes of the present invention require less force to release the syringes than those of the prior art, thereby reducing both the force and the duration of the injection. Furthermore, the release forces of the syringes of the present invention are less variable than those of the prior art. Syringe reliability has been shown to be an important factor in reducing injection errors (Menzella et al. Self-administration of omalizumab: why not? A literature review and expert opinion. Expert Opinion on Biological Therapy; Vol. 21, 2021 - 4th publication, pages 499-507). In this way, the present invention reduces the risk of injection errors, thereby improving the patient experience, patient adherence, and outcomes.

[0066] Needle phobia reduces patient adherence (Baryakova et al.). The needle protection device of the present invention covers the needle to improve the experience of patients with needle phobia, thereby improving patient adherence and outcomes.

[0067] In certain embodiments of the invention, the syringe is supplied in a needle protection device comprising a needle sleeve and a piston; and wherein a manual force can be applied to the piston to expel the 150 mg / ml formulation of omalizumab and unlock the needle sleeve so that the needle sleeve can cover the needle after injection.

[0068] In certain embodiments of the invention, the syringe is manufactured by a process comprising: aseptic filling of the reservoir with the 150 mg / ml formulation of omalizumab; and sealing the tank with the cap.

[0069] In certain embodiments of the invention, aseptic filling is carried out using a peristaltic pump or a stainless steel piston pump.

[0070] In certain embodiments of the invention, before aseptic filling, the reservoir and the needle are sterilized by treatment with gaseous ethylene oxide, electron beam (e-beam) and / or steam sterilization in an autoclave.

[0071] Although the present claims relate to a treatment method in which the 150 mg / ml formulation of omalizumab is administered subcutaneously by means of a syringe, it will be understood that the syringes of the present invention can be offered alone, or in combination with an auto-injector, and that the present invention also encompasses new dosing regimens of omalizumab using the syringe of the present invention. Therefore, additional clauses covering the syringe of the present invention are set forth below.

[0072] The invention has been described in relation to the treatment of: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids. More particularly, it can be used for one or more of the following: moderate to severe persistent asthma in adults and pediatric patients aged 6 years and older with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids; chronic rhinosinusitis with nasal polyps (CRSwNP) in adult patients aged 18 years and older with an inadequate response to nasal corticosteroids, as adjunctive maintenance therapy; IgE-mediated food allergy in adults and pediatric patients aged 1 year and older for the reduction of allergic reactions (type I), including anaphylaxis, that may occur upon accidental exposure to one or more foods (and can be used in conjunction with food allergen avoidance); and / or Chronic spontaneous urticaria (CSU) in adults and adolescents aged 12 years and older who remain symptomatic despite antihistamine treatment. Brief description of the patterns

[0073] [Fig.1] Fig.1 is a schematic diagram of a syringe for subcutaneous delivery according to the prior art.

[0074] [Fig.2] Fig.2 shows the dosage regimens currently used to administer a 150 mg / ml formulation of omalizumab.

[0075] [Fig.3] The [Fig.3] is a schematic diagram of a syringe for subcutaneous delivery according to an embodiment of the invention.

[0076] [Fig.4] The [Fig.4] is a schematic diagram of a syringe for subcutaneous delivery according to an embodiment of the invention.

[0077] [Fig.5] The [Fig.5] is a schematic diagram of a syringe for subcutaneous delivery according to an embodiment of the invention.

[0078] [Fig.6] The [Fig.6] is a schematic diagram of a syringe for subcutaneous delivery according to an embodiment of the invention.

[0079] [Fig.7] Fig.7 shows the experimental results of the injection time as a function of the constant force for the syringe of the prior art and the syringes of the present invention.

[0080] [Fig.8] Fig.8 shows the experimental results of the detachment force as a function of the duration and temperature of storage for the syringe of the prior art and the syringes of the present invention.

[0081] [Fig.9] Fig.9 shows the percentage of main charge variant of romalizumab, measured by means of ion-exchange chromatography, for the syringe of the prior art and the syringes of the present invention.

[0082] [Fig. 10] Fig. 10 shows the proportion of the first HIC peak (obtained by hydrophobic chromatography) for the syringe of the prior art and the syringes of the present invention.

[0083] [Fig. 11] Fig. 11 shows the proportion of the second HIC peak for the syringe of the prior art and the syringes of the present invention.

[0084] [Fig. 12] The [Fig. 12] shows the proportion of the third peak of HIC for the syringe of the prior art and the syringes of the present invention.

[0085] [Fig. 13] The [Fig. 13] shows the polysorbate 20 (PS20) content of the syringe of the prior art and of the syringes of the present invention.

[0086] [Fig.14A] Figures 14A and 14B show schematic diagrams of a pre-filled syringe with a needle protection device.

[0087] [Fig.14B] Figures 14A and 14B show schematic diagrams of a pre-filled syringe with a needle protection device.

[0088] [Fig. 15] The [Fig. 15] is a schematic diagram of a pre-filled syringe inside an auto-injector.

[0089] [Fig. 16] The [Fig. 16] shows the time measured to expel the 150 mg / ml formulation of omalizumab out of the reservoir and through the needle by using an auto-injector when combined with syringes of the invention.

[0090] [Fig. 17] The [Fig. 17] shows new dosage regimens of 150 mg / ml formulation of omalizumab according to the present invention. Detailed description

[0091] The present invention provides new uses for romalizumab, new syringes, and new administration regimens that improve ease of use, patient experience, patient adherence, and outcomes when using omalizumab. In particular, the present invention provides new uses for romalizumab, new syringes, and new administration regimens that reduce the number of individual injections required per treatment, reduce the duration and injection forces required to deliver the omalizumab formulation subcutaneously, and reduce the risk of injection site reactions.

[0092] A detailed description of the present invention and its advantages and improvements over current uses of omalizumab, current syringes, and current administration regimens is given below. The detailed description of the present invention is structured as follows. First, the syringe currently used for subcutaneous administration of omalizumab is described with reference to [Fig. 1]. The manufacturing process for the syringe of [Fig. 1] is also described. Second, seven embodiments of the syringes of the present invention, together with manufacturing processes, are described with reference to Figures 3 to 6. Third, the experimental results of tests performed on syringes of the prior art and five embodiments of syringes of the present invention are described with reference to Figures 7 to 13.

[0093] As will be explained in detail below, the experimental results of tests carried out on the syringe of the prior art and five embodiments of syringes of the invention highlight the following points. i) The syringes of the present invention expel omalizumab in less time than the syringes of the prior art when forces are applied to the stopper (see [Fig.7] and the associated description). (ii) Multiple features of the syringes of the present invention contribute to the reduced injection time referred to in point (i), including, but not limited to: the needle gauge, the minimum internal diameter of the needle, the stopper stratification, the stopper coating, the number of bevels on the distal surface of the needle, the syringe collar, the maximum internal diameter of the stopper and the diameter of the outer rib on the stopper (see [Fig.7] and the associated description). iii) The syringes of the present invention require a lower breakaway force than the syringe of the prior art (see [Fig.8] and the associated description). (iv) The syringes of the present invention preserve the purity and stability of omalizumab and therefore improve the bioavailability of omalizumab (see Figures 9 to 13 and the associated description).

[0094] As a result, experimental results demonstrate that the inventors have made available syringes which reduce the time and injection forces required to deliver the omalizumab formulation subcutaneously and reduce the risk of injection site reactions.

[0095] In particular, according to one aspect of the present invention, a method is made available for treating a patient with one or more of the following: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient X ml of a 150 mg / ml formulation of omalizumab, where X is 2, 1, or 0.5, and which X ml of the 150 mg / ml formulation of omalizumab are administered subcutaneously by means of a syringe, the syringe comprising: a reservoir filled with X ml of a 150 mg / ml omalizumab formulation, wherein X ml of the 150 mg / ml omalizumab formulation have 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter >25 pm; and the syringe further comprising: a stopper, and a needle; and the syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper, wherein one of the following options is satisfied when a constant force of 10 N is applied to the stopper, a) When X equals 2, the syringe is configured to expel the omalizumab formulation from the reservoir through the needle in less than 16 seconds; b) when X equals 1, the syringe is configured to expel the omalizumab formulation from the reservoir through the needle in less than 5 seconds; and c) when X equals 0.5, the syringe is configured to expel the omalizumab formulation from the reservoir through the needle in less than 4 seconds.

[0096] As indicated in point (ii) above, multiple features of the syringes of the present invention contribute to the reduced injection time achieved in one aspect of the invention. However, as demonstrated in Figures 7 and 8 and the accompanying description, a 27-gauge needle is particularly advantageous for achieving the reduced injection time.Therefore, in accordance with one aspect of the invention, the present invention makes available a method for treating a patient with one or more of the following: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 2 ml of a 150 mg / ml formulation of omalizumab, in . in which the omalizumab formulation is administered subcutaneously using a syringe, the syringe comprising: a reservoir filled with X ml of a 150 mg / ml omalizumab formulation, where X ml of the 150 mg / ml omalizumab formulation has 6000 or fewer particles with a diameter >10 pm and / or 600 or fewer particles with a diameter >25 pm; and the syringe further comprising: a stopper, and a 27 gauge needle; and the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper.

[0097] As will be demonstrated with reference to Figures 7 and 8, for syringes that administer 0.5 ml or 1 ml of omalizumab, the syringe of the present invention that administers omalizumab most rapidly is the syringe described with reference to [Fig. 5]. Therefore, a preferred embodiment of the invention is a syringe according to the first or second aspect above, wherein one or more of the following are satisfied. a) The syringe is configured to expel 1 ml of 150 mg / ml omalizumab formulation in one or more of the following: 4.64 ± 0.22 seconds when a constant force of 10 N is applied to the stopper, 2.54 ± 0.11 seconds when a constant force of 17 N is applied to the stopper, and 1.39 ± 0.04 seconds when a constant force of 30 N is applied to the stopper. b) The syringe has an internal coating of 0.4 ± 0.2 mg of polydimethylsiloxane (PDMS). c) The syringe has a 27 gauge needle defining a minimum internal diameter 1D N of 0.277 mm. d) The stopper, when not inserted into the syringe reservoir, has a maximum external diameter D s of 6.70 ± 0.15 mm and a length L s of 7.85 ± 0.4 mm. e) The stopper has a distal surface of conical shape and at least one circumferential rib having an outside diameter R s of 6.60 ±0.15 mm. f) The stopper is formed of a bromobutyl elastomer and has a barrier film layer of ethylene-tetrafluoroethylene (ETFE). g) The cap has a UV-cured B2-40 lubricating coating.

[0098] Finally, since the syringes of the present invention achieve a reduced injection time and reduced detachment force compared with the syringes of the prior art, while maintaining comparable purity, stability and bioavailability of romalizumab, the syringes of the invention can be used to administer larger volumes of romalizumab than those of the syringes of the previous technique, i.e. greater than 0.5 ml or 1 ml of omalizumab at 150 mg / ml.

[0099] TERMINOLOGY USED IN THE DETAILED DESCRIPTION

[0100] The term "distal" refers to a location that is relatively closer to an injection site, and the term "proximal" refers to a location that is relatively farther from the injection site. The term "approximately," in relation to a numerical value x, is optional and means x ± 5%.

[0101] Filling volume

[0102] It is necessary to fill the syringes to account for the remaining residue and to ensure that the recommended dose is dispensed. Therefore, in this application, references to syringes filled with 0.5 ml of the 150 mg / ml omalizumab formulation should be understood as 0.520 ml ± 5%. References to syringes filled with 1 ml of the 150 mg / ml omalizumab formulation should be understood as 1.020 ml ± 2.5%. References to syringes filled with 2 ml of the 150 mg / ml omalizumab formulation should be understood as 2.040 ml ± 2.75%.

[0103] Extractable volume

[0104] When a 150 mg / ml formulation of omalizumab is dispensed from a syringe, a certain amount of residue will remain. In this application, references to syringes dispensing 0.5 ml should be understood as 0.5 ml ± 5%. References to syringes dispensing 1 ml should be understood as 1 ml ± 5%. References to syringes dispensing 2 ml should be understood as 2 ml ± 5%.

[0105] Formulation of omalizumab

[0106] Containers with a nominal content of less than 100 mL of a 150 mg / mL omalizumab formulation (150 mg / mL antibody with 42.1 mg / mL L-arginine hydrochloride, 1.37 mg / mL L-histidine, 2.34 mg / mL L-histidine hydrochloride monohydrate, 0.4 mg / mL polysorbate 20 as an aqueous solution (in sterile water for injection (USP)) have 6000 or fewer particles with a diameter >10 µm and / or 600 or fewer particles with a diameter >25 µm. The number of particles with a diameter >10 µm and / or 25 µm may be measured by a light-occulting particle count test or a microscopic particle count test as set forth in the United States Pharmacopeia, Chapter 788.

[0107] Omalizumab formulations used according to the invention may contain a histidine buffer, arginine hydrochloride, and a polysorbate (such as polysorbate 20). They may have a pH in the range of 5.5 at 6.5. A useful formulation for omalizumab at 150 mg / ml has 42.1 mg / ml of arginine hydrochloride, 1.37 mg / ml of histidine, 2.34 mg / ml of histidine hydrochloride monohydrate, and 0.4 mg / ml of polysorbate 20.

[0108] CURRENT USES OF OMALIZUMAB

[0109] Current syringe (also called prior art syringe)

[0110] Figure 1 shows a schematic diagram of a syringe 1 currently used to deliver a 150 mg / ml omalizumab (XOLAIR®) solution. The syringe has a reservoir 2 with a length 1R of 54 ± 0.5 mm and an internal diameter dR of 6.35 ± 0.1 mm, filled with 0.5 ml or 1 ml of a 150 mg / ml omalizumab (XOLAIR®) solution. The length 1R of the syringe is the maximum internal length of the syringe reservoir. The syringe is made of borosilicate glass and the inner surface of the syringe has an internal coating of < 1.0 mg of polydimethylsiloxane (PDMS) having a kinematic viscosity of approximately 1000 cSt. Needle 3 has a 1N length of 12.7 ± 0.2 mm extending outside the syringe, a GN gauge of 26 defining a minimum internal diameter ID N of 0.232 mm (inset 3' shows a close-up view of the internal diameter ID N) and 3 bevels on its distal surface.Needle 3 has an internal polydimethylsiloxane (PDMS) coating with a kinematic viscosity of approximately 12,500 cSt. Needle 3 is captive, meaning it is inserted into the syringe and secured in place with adhesive; the IP fluid path length between the distal end of the reservoir and the proximal end of the portion of needle 3 extending from the syringe is approximately 8 mm. A collar 4, shaped like a cut collar, is located at the proximal end of the reservoir.

[0111] The syringe also includes a stopper 5 which, when not inserted into the syringe reservoir 2, has a maximum external diameter Ds of 6.67 mm to 7.10 mm and a length Ls of 7.85 ± 0.4 mm. The stopper has a conical distal surface 5a and at least three circumferential ribs 5b having an external diameter Rs of 6.60 ± 0.1 mm. The inset labeled 5' shows a close-up view of the stopper. The stopper is formed of a bromobutyl elastomer and has a fluorinated resin on the side in contact with the product. The stopper is lubricated with DC360 Medical Fluid silicone oil of 1000 cSt.

[0112] Before use, the needle is enclosed in a rubber needle protector (not shown) to maintain the needle's sterility. The rubber needle protector is made of styrene-butadiene rubber, which is composed of epoxypyrene, a derivative of natural rubber latex. The rubber needle protector is enclosed by a rigid polypropylene outer cap.

[0113] Syringe 1 is a 1 ml BD Hypak™ pre-filled glass syringe with a captive needle fitted with a stopper 5, which is a BD (West) 4023 / 50 FluroTec® stopper. The 1 ml BD Hypak™ pre-filled glass syringe with a captive needle is manufactured by Becton Dickinson. The bromobutyl elastomer formulation is 4023 / 50, and the fluorinated resin is a FluroTec® coating. The stopper 5 is manufactured by West Pharmaceutical Services and supplied by Becton Dickinson. The rubber needle protector is an FM27 / 0 rubber component and is enclosed by a rigid polypropylene cap; the rubber needle protector is manufactured by AptarGroup.

[0114] Method for manufacturing the syringe of the prior art

[0115] The manufacturing process of the syringe of the prior art presented and described with reference to [Fig.1] is stated below.

[0116] The first step is the thawing and homogenization of a preformulated frozen 15% omalizumab drug substance. Thawing can be carried out by circulating a heat transfer fluid through a jacketed container containing the 15% omalizumab drug substance. Homogenization can be carried out by recirculating the thawed 15% omalizumab drug substance through a recirculation loop in the jacketed container.

[0117] The second step is filtration and mixing of the 15% omalizumab drug substance. Filtration can be carried out by passing the 15% omalizumab drug substance through a nominal 0.2 µm membrane filter made of poly(vinylidene fluoride). Mixing can be carried out with a magnetically coupled stirrer inside a jacketed storage container containing the 15% omalizumab drug substance. The 15% omalizumab drug substance may optionally be pooled and refrozen during this second step.

[0118] The third step is a sterile inline filtration of the 15% omalizumab drug substance. The inline filtration can be carried out by passing the 15% omalizumab drug substance through a nominal 0.2 µm membrane filter made of poly(vinylidene fluoride).

[0119] The fourth step is aseptic filling of reservoir 2 with the captive needle 3 as shown and described with reference to [Fig. 1]. Reservoir 2 is filled with 1 mL or 0.5 mL of the omalizumab formulation using a stainless steel piston pump. Dosage accuracy can be monitored offline by determining the extractable volume. Before aseptic filling, the following treatments are performed: a) the reservoir 2 and the captive needle 3 are washed with water for injection (WFI) and the internal coating of < 1.0 mg of polydimethylsiloxane (PDMS) having a kinematic viscosity of about 1000 cSt is sprayed onto the reservoir body using a submerged nozzle; (b) The rubber needle protector and the outer rigid polypropylene cap are assembled with the reservoir 2 and the captive needle 3 so that they enclose the captive needle 3; and c) the reservoir 2, the captive needle 3, the rubber needle protector and the rigid outer polypropylene cap, assembled, undergo steam sterilization in an autoclave.

[0120] The fifth step is capping the syringe, i.e., placing the stopper 5 in the reservoir 2. The stopper can be placed in the appropriate position in the reservoir 2 using a tube-based stopper placement technology. Before capping the syringe, the stopper 5 is steam-sterilized in an autoclave.

[0121] Current dosing regimens of romalizumab

[0122] Figure 2 shows currently used dosing regimens for the administration of a 150 mg / ml formulation of omalizumab. The 150 mg / ml formulation of omalizumab is administered in doses of 75 mg to 600 mg by subcutaneous injection every 2 or 4 weeks. The 150 mg / ml formulation of omalizumab is currently available in syringes containing either 0.5 ml or 1 ml of the 150 mg / ml formulation of omalizumab. Therefore, as shown in Figure 2, if a patient requires a 225 mg dose of omalizumab, the dose should be administered using one syringe containing 1 ml of the 150 mg / ml formulation of omalizumab and one syringe containing 0.5 ml of the 150 mg / ml formulation of omalizumab. If a patient requires a 300 mg dose of omalizumab, the dose should be administered using two syringes, each containing 1 ml of the 150 mg / ml omalizumab formulation.If a patient requires a 375 mg dose of omalizumab, the dose should be administered using three syringes: two syringes, each containing 1 ml of the 150 mg / ml omalizumab formulation, and one syringe, each containing 0.5 ml of the 150 mg / ml omalizumab formulation. If a patient requires a 450 mg dose of omalizumab, the dose should be administered using three syringes, each containing 1 ml of the 150 mg / ml omalizumab formulation. If a patient requires a 525 mg dose of omalizumab, the dose should be administered using four syringes: three syringes, each containing 1 ml of the 150 mg / ml omalizumab formulation, and one syringe, each containing 0.5 ml of the 150 mg / ml omalizumab formulation. If a patient requires a 600 mg dose of omalizumab, the dose should be administered using four syringes, each containing 1 ml of the 150 mg / ml omalizumab formulation.

[0123] Difficulties related to current uses of romalizumab

[0124] The difficulties associated with current uses of omalizumab have been described in detail above. In summary, the syringe 1 currently used to deliver a 150 mg / ml formulation of omalizumab is unsuitable for use with volumes greater than 1 ml. Due to the high viscosity of the 150 mg / ml omalizumab solution, significant injection forces are required to inject more than 1 ml of the 150 mg / ml omalizumab formulation within an injection time acceptable to patients. As a result, patients may struggle to apply the necessary injection forces and thus may fail to push the stopper 5 to its terminal position inside the syringe 1 to administer a full dose.Furthermore, even when syringe 1 is used to deliver 0.5 ml or 1 ml of the 150 mg / ml omalizumab formulation, it would be advantageous to reduce the required injection force and duration, and any risk of injection site reaction.

[0125] NEW USES OF OMALIZUMAB

[0126] Figures 3 to 6 show syringes which are part of the invention.

[0127] First and second embodiments of the invention

[0128] Figure 3 shows a syringe 11 according to the invention. The syringe has a reservoir 12 having a length 1R of 54.0 ± 0.5 mm and an internal diameter dR of 6.35 mm ± 0.05 mm and is filled with 0.5 ml (in a first embodiment) or 1 ml (in a second embodiment) of a 150 mg / ml omalizumab solution (XOLAIR®). The syringe 11 is made of borosilicate glass and the inner surface of the syringe has an internal coating of 0.4 ± 0.2 mg of polydimethylsiloxane (PDMS). The syringe has a round collar 14 having a maximum diameter of 11 ± 0.25 mm.The syringe includes a captive needle 13 with a length 1N of 12.7 mm extending outside the syringe, and is 27 gauge, defining a minimum internal diameter 1D N of 0.277 mm (inset 13' shows a close-up view of the internal diameter 1D N). The needle 13 is captive, meaning it is inserted into the syringe and secured in place with adhesive; the fluid path length 1P between the distal end of the reservoir and the proximal end of the portion of the needle 13 extending from the syringe is approximately 8 mm. The needle has 5 bevels on its distal surface. Before use, the needle 13 is enclosed by an elastomeric needle protector (not shown) to maintain needle sterility. The elastomeric needle protector may include an outer rigid polypropylene cap. The needle protector is latex-free.

[0129] The syringe also includes a stopper 15 which, when not inserted into the syringe reservoir 12, has a maximum external diameter Ds of 6.67 mm to 7.10 mm and a length Ls of 7.85 ± 0.4 mm. The stopper has a conical distal surface 15a and at least three circumferential ribs 15b having an external diameter 6.60 ±0.1 mm. The inset labeled 15' shows a close-up view of the stopper. The stopper is made of a bromobutyl elastomer and has a fluorinated resin on the side that comes into contact with the product. The stopper is lubricated with DC360 Medical Fluid silicone oil at 1000 cSt.

[0130] Syringe 11 is a long, pre-filled glass syringe for 1 ml of BD Neopak™ with a captive needle fitted with a stopper 15, which is a BD (West) 4023 / 50 FluroTec® stopper. The long, pre-filled glass syringe for 1 ml of BD Neopak™ with a captive needle is manufactured by Becton Dickinson. The bromobutyl elastomer formulation is 4023 / 50, and the fluorinated resin is a FluroTec® coating. The stopper 15 is manufactured by West Pharmaceutical Services and supplied by Becton Dickinson.

[0131] Third and fourth embodiments of the invention

[0132] Figure 4 shows a syringe 21 according to the invention. The syringe 21 has a reservoir 22 having a length 1R of 54 ± 0.5 mm and an internal diameter dR of 6.35 mm ± 0.05 mm and is filled with 0.5 ml (in a third embodiment) or 1 ml (in a fourth embodiment) of a 150 mg / ml omalizumab solution (XOLAIR®). The syringe is made of borosilicate glass and the inner surface of the syringe has an internal silicone oil coating. The syringe has a round collar 24 having a maximum diameter of 11 ± 0.25 mm.The syringe includes a needle with a length 1N of 12.7 mm extending outside the syringe, and is 27 gauge, defining a minimum internal diameter 1D N of 0.191 mm (Inset 23' shows a close-up view of the internal diameter 1D N). The needle 23 is captive, meaning it is inserted into the syringe and secured in place with adhesive; the fluid path length 1P between the distal end of the reservoir and the proximal end of the portion of the needle 23 extending from the syringe is approximately 8 mm. Before use, the needle 23 is enclosed by an elastomeric needle protector (not shown) to maintain needle sterility. The elastomeric needle protector may include a rigid outer polypropylene cap. The needle protector is latex-free.

[0133] The syringe also includes a stopper 25 which, when not inserted into the syringe reservoir 22, has a maximum external diameter Ds of 6.70 ± 0.15 mm and a length Ls of 7.85 ± 0.4 mm. The stopper has a conical distal surface 25a and at least one circumferential rib 25b having an external diameter Rs of 6.60 ± 0.15 mm. The inset labeled 25' shows a close-up view of the stopper. The stopper is formed of a bromobutyl elastomer and has an ethylene-tetrafluoroethylene (ETFE) barrier film lamination. The stopper has a lubricating coating of B2-40 UV cured; this is a coating in which PDMS is sprayed onto the cap, heated and UV cured on the surface of the cap.

[0134] Syringe 21 is a 1 ml long, pre-filled glass syringe of Nexa® with a captive needle fitted with a stopper 25, which is a 1 ml long, West NovaPure® stopper. The 1 ml Nexa® pre-filled glass syringe with a captive needle is manufactured by Ompi, a brand of the Stevanato Group. The bromobutyl elastomer formulation is 4023 / 50, and the ethylene-tetrafluoroethylene (ETFE) barrier film lamination is a FluroTec® coating. The stopper 25 is manufactured and supplied by West Pharmaceutical Services.

[0135] Fifth and sixth embodiments of the invention

[0136] Figure 5 shows a syringe 31 according to the invention. The syringe has a reservoir 32 having a length 1R of 54.0 ± 0.5 mm and an internal diameter dR of 6.35 mm ± 0.05 mm and is filled with 0.5 ml (in a fifth embodiment) or 1 ml (in a sixth embodiment) of a 150 mg / ml omalizumab solution (XOLAIR®). The syringe 31 is made of borosilicate glass and the inner surface of the syringe has an internal coating of 0.4 ± 0.2 mg of polydimethylsiloxane (PDMS). The syringe has a round collar 34 having a maximum diameter of 11 ± 0.25 mm.The syringe includes a needle 33 having a length 1N of 12.7 mm extending outside the syringe, and is 27 gauge, defining a minimum internal diameter 1D N of 0.277 mm (inset 33' shows a close-up view of the internal diameter 1D N). The needle 33 is captive, meaning it is inserted into the syringe and secured in place with adhesive; the fluid path length 1P between the distal end of the reservoir and the proximal end of the portion of the needle 33 extending from the syringe is approximately 8 mm. The needle has 5 bevels on its distal surface. Before use, the needle 33 is enclosed by an elastomeric needle protector (not shown) to maintain needle sterility. The elastomeric needle protector may include an outer rigid polypropylene cap. The needle protector is Latex-free.

[0137] The syringe also includes a stopper 35 which, when not inserted into the syringe reservoir 32, has a maximum external diameter Ds of 6.70 ± 0.15 mm and a length Ls of 7.85 ± 0.4 mm. The stopper has a conical distal surface 35a and at least one circumferential rib 35b having an external diameter Rs of 6.60 ± 0.15 mm. The inset labeled 35' shows a close-up view of the stopper. The stopper is made of a bromobutyl elastomer and has an ethylene-tetrafluoroethylene (ETFE) barrier film lamination. The stopper has a UV-cured B2-40 lubrication coating; this coating consists of PDMS sprayed onto the stopper, heated, and UV-cured on the stopper surface.

[0138] Syringe 31 is a 1 ml long glass pre-fillable syringe of BD Neopak™ with a captive needle fitted with a stopper 35, which is a 1 ml long West NovaPure® stopper. The 1 ml long glass pre-fillable syringe of BD Neopak™ with a captive needle is manufactured by Becton Dickinson. The bromobutyl elastomer formulation is 4023 / 50, and the ethylene-tetrafluoroethylene (ETFE) barrier film lamination is a FluroTec® coating. The stopper 35 is manufactured and supplied by West Pharmaceutical Services.

[0139] Seventh embodiment of the invention

[0140] Figure 6 shows a syringe 41 according to a seventh embodiment of the present invention. The syringe has a reservoir 42 having a length 1R of 54.5 ± 0.4 mm and an internal diameter dR of 8.65 mm ± 0.1 mm and is filled with 2 ml of a 150 mg / ml omalizumab solution (XOLAIR®). The syringe is made of borosilicate glass and the inner surface of the syringe has an internal coating of 0.7 ± 0.2 mg of polydimethylsiloxane (PDMS). The syringe has a round collar 44 having a maximum diameter of 14.7 ± 0.25 mm.The syringe includes a needle with a length 1N of 12.7 mm extending outside the syringe, and is 27 gauge, defining a minimum internal diameter 1D N of 0.277 mm (inset 43' shows a close-up view of the internal diameter 1D N). The needle 43 is captive, meaning it is inserted into the syringe and secured in place with adhesive; the fluid path length 1P between the distal end of the reservoir and the proximal end of the portion of the needle 43 extending from the syringe is approximately 8 mm. The needle has 5 bevels on its distal surface. Before use, the needle 43 is enclosed in a thermoplastic elastomer needle protector to maintain needle sterility. The needle protector may include a rigid polypropylene outer cap. The needle protector is latex-free.

[0141] The syringe also includes a stopper 45 which, when not inserted into the syringe, has a maximum external diameter Ds of 9.05 ± 0.15 mm and a length Ls of 7.70 ± 0.4 mm. The stopper has a conical distal surface 45a and includes at least one circumferential rib 45b having an external diameter Rs of 9.00 ± 0.15 mm. The inset labeled 45' shows a close-up view of the stopper. The stopper is formed of a bromobutyl elastomer and has an ethylene-tetrafluoroethylene (ETFE) barrier film lamination. The stopper has a UV-cured B2-40 lubricating coating; this coating consists of PDMS sprayed onto the stopper, heated, and UV-cured on the stopper surface.

[0142] Syringe 41 is a pre-filled glass syringe for 2.25 ml BD Neopak™ with a captive needle fitted with a stopper 45, which is a West NovaPure® stopper for 1-3 ml. The pre-filled glass syringe for 2.25 ml BD Neopak™ with a captive needle is manufactured by Becton Dickinson. The bromobutyl elastomer formulation is 4023 / 50, and the ethylene-tetrafluoroethylene (ETFE) barrier film lamination is a FluroTec® coating. The 45 cap is manufactured and supplied by West Pharmaceutical Services.

[0143] According to the invention, each of the syringes in Figures 3 to 6 can be used to administer a 150 mg / ml formulation of omalizumab subcutaneously.

[0144] Methods for manufacturing syringes according to the present invention

[0145] A method for manufacturing syringes according to the present invention is stated below.

[0146] The first step is the thawing and homogenization of a preformulated frozen 15% omalizumab drug substance. Thawing can be carried out by circulating a heat transfer fluid through a jacketed container containing the 15% omalizumab drug substance. Homogenization can be carried out by recirculating the thawed 15% omalizumab drug substance through a recirculation loop in the jacketed container.

[0147] The second step is filtration and mixing of the 15% omalizumab drug substance. Filtration can be carried out by passing the 15% omalizumab drug substance through a nominal 0.2 µm membrane filter made of poly(vinylidene fluoride). Mixing can be carried out with a magnetically coupled stirrer inside a jacketed storage container containing the 15% omalizumab drug substance. The 15% omalizumab drug substance may optionally be repacked and refrozen during this second step.

[0148] The third step is a sterile inline filtration of the 15% omalizumab drug substance. The inline filtration can be carried out by passing the 15% omalizumab drug substance through a nominal 0.2 µm membrane filter made of poly(vinylidene fluoride).

[0149] The fourth step is aseptic filling of a reservoir 12, 22, 32, 42 with a captive needle 13, 23, 33, 43 as shown and described with reference to any one of Figures 3 to 6. The reservoir 12, 22, 32, 42 is filled with 0.5 mL, 1 mL, or 2 mL of the omalizumab formulation using a peristaltic pump. Dosage accuracy can be monitored by automated weighing of the syringes before and after filling.

[0150] Aseptic filling using a peristaltic pump has advantages over aseptic filling using stainless steel piston pumps. First, peristaltic pumps exert less stress on the proteins than stainless steel piston pumps. Secondly, unlike stainless steel piston pumps, peristaltic pumps do not require cleaning when used for single-use dispensing. In this way, the peristaltic pump reduces the likelihood of cross-contamination. Thirdly, peristaltic pumps are faster to set up and calibrate than stainless steel piston pumps.

[0151] Before aseptic filling, the following treatments are carried out: a) the reservoir 12, 22, 32, 42 and the captive needle 13, 23, 33, 43 are washed with water for injection (WFI) and the internal coating of 0.4 ± 0.2 mg of polydimethylsiloxane (PDMS) having a kinematic viscosity of about 1000 cSt is sprayed onto the reservoir body using a submerged nozzle; (b) The elastomer needle protector and the outer rigid polypropylene cap are assembled with the reservoir 12, 22, 32, 42 and the captive needle 3 so that they enclose the captive needle 13, 23, 33, 43; and c) the reservoir 12, 22, 32, 42, the captive needle 13, 23, 33, 43, the elastomer needle protector and the outer rigid polypropylene cap, assembled, are sterilized by treatment with gaseous ethylene oxide.

[0152] The fifth step is capping the syringe, i.e., placing the stopper 15, 25, 35, 45 in the reservoir 12, 22, 32, 42. The stopper 15, 25, 35, 45 can be placed in the appropriate position in the reservoir 12, 22, 32, 42 using a tube-based stopper placement technology. Before capping the syringe, the stopper 15, 25, 35, 45 is sterilized. Sterilization can be achieved by steam sterilization in an autoclave, electron beam (e-beam), and / or treatment with gaseous ethylene oxide.

[0153] Accordingly, the present invention provides a method for treating a patient with one or more of the following: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient X ml of a 150 mg / ml formulation of omalizumab, where X is 2, 1, or 0.5, and which X ml of the 150 mg / ml formulation of omalizumab are administered subcutaneously by means of a syringe, wherein the syringe is manufactured by a process comprising: aseptic filling of the reservoir with the 150 mg / ml formulation of omalizumab; and sealing the tank with the cap.

[0154] In another embodiment, the present invention provides X ml of 150 mg / ml omalizumab formulation, in which aseptic filling is carried out by means of a peristaltic pump or a stainless steel piston pump.

[0155] In another embodiment, the present invention provides X ml of 150 mg / ml omalizumab formulation, in which, prior to aseptic filling, the reservoir and needle are sterilized by treatment with gaseous ethylene oxide, electron beam (e-beam) and / or steam sterilization in an autoclave.

[0156] New romalizumab dosing regimens

[0157] Figure 17 shows new dosing regimens of the present invention. Figure 17 shows dosing regimens that include the use of an auto-injector equipped with a syringe of the present invention filled with 0.5 ml, 1 ml, or 2 ml of the 150 mg / ml omalizumab formulation. However, the use of an auto-injector is optional, and the dosing regimens shown can also be implemented using syringes of the invention when they are not inserted into a device and / or when they are inserted into a needle-protective device.

[0158] Advantageously, the syringes of the present invention configured to administer 2 ml of omalizumab at 150 mg / ml reduce the number of injections required compared with current administration regimens shown in [Fig. 2]. For example, as shown in [Fig. 17], if a patient requires a 300 mg dose of omalizumab, the dose can be administered using a single syringe of the invention containing 2 ml of the 150 mg / ml omalizumab formulation. If a patient requires a 375 mg dose of omalizumab, the dose can be administered using two syringes—one syringe of the invention filled with 2 ml of the 150 mg / ml omalizumab formulation and one syringe filled with 0.5 ml of the 150 mg / ml omalizumab formulation.If a patient requires a 450 mg dose, it can be administered using two syringes: one syringe of the invention filled with 2 ml of the 150 mg / ml omalizumab formulation and one syringe filled with 1 ml of the 150 mg / ml omalizumab formulation. If a patient requires a 525 mg dose, it can be administered using three syringes: one syringe of the invention filled with 2 ml of the 150 mg / ml omalizumab formulation, one syringe filled with 0.5 ml of the 150 mg / ml omalizumab formulation, and one syringe filled with 1 mg of the 150 mg / ml omalizumab formulation. If a patient requires a 600 mg dose, it can be administered using two syringes of the invention, each filled with 2 ml of the 150 mg / ml omalizumab formulation. The syringes filled with 0.5 ml of omalizumab 150 mg / ml formulation and 1 ml of omalizumab 150 mg / ml formulation may be syringes of the present invention or current syringes.

[0159] The syringes can be offered alone, in an auto-injector such as the auto-injector described with reference to [Fig. 15], and / or in a needle protective device such as the needle protective device described with reference to Figures 14A and 14B. In this way, the present invention improves patient convenience and the risk of reaction at the injection site, and thus improves patient acceptance.

[0160] It is further noted that larger volumes of highly viscous drugs are more likely to be deposited deeper into the subcutaneous layer than smaller volumes, and are therefore less likely to leak into the intradermal layer, resulting in leakage from the injection site and a reaction at the injection site. Consequently, the availability of a treatment method comprising the administration of 2 ml of the 150 mg / ml omalizumab formulation according to the invention will result in less leakage and a reduced risk of injection site reaction compared with current treatment methods comprising the administration of 0.5 ml and 1 ml of 150 mg / ml omalizumab.

[0161] Furthermore, as described previously, the syringes of the present invention filled with 0.5 ml of omalizumab 150 mg / ml and 1 ml of the omalizumab 150 mg / ml formulation reduce the force and / or time required for injection compared with current syringes, improving ease of use and making it more likely that a full dose will be administered. Thus, the present invention improves ease of use, patient experience, patient adherence, and outcomes when using omalizumab.

[0162] Consequently, new dosing regimens are also made available that are similar to those illustrated in [Fig. 2] but that use the syringes of the present invention filled with 0.5 ml of omalizumab 150 mg / ml and / or 1 ml of the 150 mg / ml omalizumab formulation. If a patient requires a 75 mg dose, the dose can be administered using a single syringe of the present invention filled with 1 ml of the 150 mg / ml omalizumab formulation. If a patient requires a 150 mg dose, the dose can be administered using a single syringe of the present invention filled with 1 ml of the 150 mg / ml omalizumab formulation. If a patient requires a dose of 225 mg, the dose may be administered using a syringe filled with 0.5 ml of omalizumab 150 mg / ml and a syringe filled with 1 ml of the 150 mg / ml formulation of omalizumab; of which one or both of the syringes are syringes of the present invention.If a patient requires a 300 mg dose, the dose can be administered using two syringes filled with 1 ml of a 150 mg / ml omalizumab formulation; one or both of which may be syringes of the present invention. If a patient requires a 375 mg dose, the dose can be administered using three syringes—one syringe filled with 0.5 ml of 150 mg / ml omalizumab and two other syringes filled with 0.5 ml of the 150 mg / ml formulation. of 1 ml of a 150 mg / ml omalizumab formulation; of which at least one of the syringes is a syringe of the present invention. If a patient requires a 450 mg dose, the dose can be administered using three syringes, all three syringes being filled with 1 ml of a 150 mg / ml omalizumab formulation; of which at least one of the syringes is a syringe of the present invention. If a patient requires a 525 mg dose, the dose can be administered using four syringes—one syringe filled with 0.5 ml of 150 mg / ml omalizumab and three syringes filled with 1 ml of a 150 mg / ml omalizumab formulation; of which at least one of the syringes is a syringe of the present invention.If a patient requires a dose of 600 mg, the dose can be administered using four syringes, all four syringes being filled with 1 ml of a 150 mg / ml formulation of omalizumab; of which at least one of the syringes is a syringe of the present invention.

[0163] In the new dosing regimens of the present invention, the syringes can be offered alone, in an auto-injector such as the auto-injector described with reference to [Fig. 15], and / or in a needle protective device such as the needle protective device described with reference to Figures 14A and 14B.

[0164] Therefore, the invention makes available the following new treatment methods.

[0165] A method for treating a patient with one or more of the following: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 225 mg of an omalizumab formulation; which method comprises one of the following: a) the implementation of a method of the invention in which X is 0.5; and the implementation of a method of the invention in which X is 1; b) the implementation of a method of the invention in which X is 0.5; and the administration of 1 ml of a 150 mg / ml omalizumab formulation subcutaneously using a syringe; and c) the implementation of a method of the invention in which X equals 1; and the administration of 0.5 ml of a 150 mg / ml formulation of omalizumab subcutaneously using a syringe.

[0166] A method of treating a patient with one or more of the following: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; persistent asthma moderate to severe in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 300 mg of an omalizumab formulation; which method comprises administering 1 ml of a 150 mg / ml omalizumab formulation subcutaneously using a syringe and implementing a method of the invention wherein X is 1.

[0167] A method for treating a patient with one or more of the following: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 375 mg of an omalizumab formulation; which method comprises administering 0.5 ml of a 150 mg / ml omalizumab formulation subcutaneously using a syringe; and one of the following: a) the implementation of a method of the invention comprising administering to the patient 2 ml of a 150 mg / ml formulation of omalizumab; and b) the implementation of a method of the invention in which X is 1 and the administration of 1 ml of 150 mg / ml omalizumab formulation subcutaneously using a syringe.

[0168] A method for treating a patient with one or more of the following: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 450 mg of an omalizumab formulation; which method comprises administering 1 ml of a 150 mg / ml omalizumab formulation subcutaneously using a syringe; and one of the following: a) the implementation of a method of the invention comprising administering to the patient 2 ml of a 150 mg / ml formulation of omalizumab; and b) the implementation of a method of the invention in which X is 1 and the administration of 1 ml of 150 mg / ml omalizumab formulation subcutaneously using a syringe.

[0169] A method of treating a patient with one or more of the following: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; persistent asthma moderate to severe in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 525 mg of an omalizumab formulation; which method comprises administering 1 ml of a 150 mg / ml omalizumab formulation subcutaneously using a syringe; and administering 0.5 ml of a 150 mg / ml omalizumab formulation subcutaneously using a syringe; and one of: a) implementing a method of the invention comprising administering to the patient 2 ml of a 150 mg / ml omalizumab formulation; and b) the implementation of a method of the invention in which X is 1 and the administration of 1 ml of 150 mg / ml omalizumab formulation subcutaneously using a syringe.

[0170] A method for treating a patient with one or more of the following: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 600 mg of omalizumab formulation; which method comprises: a) the implementation of a method of the invention comprising administering to the patient 2 ml of omalizumab formulation 150 mg / ml and the implementation of a method of the invention comprising administering to the patient 2 ml of omalizumab formulation 150 mg / ml; or b) the implementation of a method of the invention in which X is 1, the administration of 1 ml of 150 mg / ml omalizumab formulation subcutaneously using a syringe, and the administration of 1 ml of 150 mg / ml omalizumab formulation subcutaneously using a syringe.

[0171] In any one of these methods: (A) one of the steps requiring the subcutaneous administration of 0.5 ml of omalizumab 150 mg / ml formulation using a syringe may include the implementation of a method of the invention in which X is 0.5; and (B) one of the steps requiring the subcutaneous administration of 1 ml of omalizumab 150 mg / ml formulation using a syringe may include the implementation of a method of the invention in which X is 1.

[0172] Other embodiments of the invention

[0173] In certain embodiments of the present invention in which X is 2, the syringe can be configured to expel the omalizumab formulation contained in the reservoir through the needle in one or more of the following ways: a) less than 8.5 seconds when a constant force of 17 N is applied to the stopper; and b) less than 5 seconds when a constant force of 30 N is applied to the stopper.

[0174] Furthermore, in certain embodiments in which X is 2, the syringe can be configured to expel X ml of the omalizumab formulation contained in the reservoir through the needle in one or more of the following ways: a) approximately 16 seconds to approximately 14 seconds when a constant force of 10 N is applied to the stopper; b) approximately 8.5 seconds to approximately 6 seconds when a constant force of 17 N is applied to the stopper; and c) approximately 5 seconds to approximately 4 seconds when a constant force of 30 N is applied to the cap.

[0175] In certain embodiments in which X is 1, the syringe can be configured to expel X ml of the 150 mg / ml omalizumab formulation through the needle in one or more of the following ways: a) less than 5 seconds, less than 4.75 seconds, less than 4.5 seconds, less than 4.25 seconds, or about 4 seconds when a constant force of 10 N is applied to the cap; b) less than 3 seconds when a constant force of 17 N is applied to the stopper; and c) less than 2 seconds when a constant force of 30 N is applied to the stopper.

[0176] In certain embodiments in which X is 1, the syringe may be configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of the following: a) less than 5 seconds to about 4 seconds, less than 4.75 seconds to about 4 seconds, less than 4.5 seconds to about 4 seconds, less than 4.25 seconds to about 4 seconds, or about 4 seconds when a constant force of 10 N is applied to the cap; b) less than 3.5 seconds to approximately 2 seconds when a constant force of 17 N is applied to the stopper; and c) less than 2 seconds to about 1 second when a constant force of 30 N is applied to the cap.

[0177] In certain embodiments in which X is 0.5, the syringe can be configured to expel X ml of the 150 mg / ml omalizumab formulation through the needle in one or more of the following ways: a) less than 2 seconds when a constant force of 17 N is applied to the cap; and b) less than 1 second when a constant force of 30 N is applied to the cap.

[0178] In certain embodiments in which X is 0.5, the syringe can be configured to expel X ml of the 150 mg / ml omalizumab formulation through the needle in one or more of the following ways: a) less than 4 seconds to about 2 seconds when a constant force of 10 N is applied to the cap; b) less than 2 seconds to approximately 1 second when a constant force of 17 N is applied to the stopper; and c) less than 1 second to about 0.5 seconds when a constant force of 30 N is applied to the cap.

[0179] In some embodiments of the invention, the needle is of gauge 25 to gauge 29, preferably of gauge 26 to gauge 28, especially of gauge 27.

[0180] In certain embodiments where the needle is 25 gauge, the needle has one of the following: a) a minimum internal diameter of 0.292 mm, and b) a minimum internal diameter of 0.232 mm.

[0181] In certain embodiments where the needle is 26 gauge, the needle has one of the following: a) a minimum internal diameter of 0.292 mm, and b) a minimum internal diameter of 0.232 mm.

[0182] In certain embodiments where the needle is 27 gauge, the needle has one of the following: a) a minimum internal diameter of 0.277 mm; b) a minimum internal diameter of 0.191 mm; c) a minimum internal diameter of 0.184 mm; and d) a minimum internal diameter of 0.241 mm.

[0183] In certain embodiments where the needle is 28 gauge, the needle has one of the following: a) a minimum internal diameter of 0.133 mm; and b) a minimum internal diameter of 0.190 mm.

[0184] In certain embodiments where the needle is 29 gauge, the needle has one of the following: a) a minimum internal diameter of 0.265 mm; b) a minimum internal diameter of 0.240 mm; c) a minimum internal diameter of 0.190 mm; and d) a minimum internal diameter of 0.133 mm; preferably the needle has a minimum internal diameter of 0.240 mm or 0.265 mm.

[0185] In some embodiments of the invention, the needle may include 3 bevels on its distal surface or 5 bevels on its distal surface.

[0186] In some embodiments, the cap may have a fluorinated resin on the side coming into contact with the product or a barrier film lamination of ethylene-tetrafluoroethylene (ETFE).

[0187] In some embodiments, the cap may have a UV-cured B2-40 lubricating coating or is lubricated with a 1000 cSt silicone oil.

[0188] In some embodiments, the syringe may have an internal coating of 0.4 ± 0.2 mg or 0.7 ± 0.2 mg of polydimethylsiloxane.

[0189] In some embodiments, the syringe may have a latex-free needle protector.

[0190] In some embodiments, the syringe may have a round collar at a proximal end of the reservoir; in other embodiments, the round collar has a maximum diameter of 11 ± 0.25 mm or 14.7 ± 0.25 mm.

[0191] In embodiments where X is 1 or 0.5, the syringe may have a length of 54.0 ± 0.5 mm and an internal diameter of 6.35 mm ± 0.05 mm.

[0192] In embodiments where X is 1 or 0.5, when the cap is not inserted in the reservoir, it may have one of the following: a) a maximum external diameter of 6.67 mm to 7.10 mm and / or a length of 7.85 ± 0.4 mm; and b) a maximum external diameter of 6.70 ± 0.15 mm and / or a length of 7.85 ± 0.4 mm.

[0193] In some embodiments, when X is 1 or 0.5, the cap may have at least one circumferential rib having an outside diameter of 6.60 ±0.15 mm.

[0194] In some embodiments where X is 2, the syringe may have a length of 54.0 ± 0.5 mm and an internal diameter of 8.65 mm ± 0.05 mm.

[0195] In certain embodiments where X is 2, when the stopper is not inserted into the reservoir, the stopper may have a maximum external diameter of 9.05 ±0.15 mm and / or a length of 7.70 ± 0.4 mm when it is not inserted into the reservoir.

[0196] In certain embodiments where X is 2, the cap may have at least one circumferential rib having an outside diameter of 9.00 ±0.15 mm.

[0197] In some embodiments, the apparent viscosity of the 150 mg / ml formulation of omalizumab at a shear rate of 200 s⁻¹ is: 24.7 ± 0.5 mPa.s at 5.0 ± 0.2°C, 15.3 ± 0.5 mPa.s at 15.0 ± 0.2°C, 11.4 ± 0.5 mPa.s at 25.0 ± 0.2°C or 7.2 ± 1.2 mPa.s at 40.0 ± 0.2°C.

[0198] Although the above aspects relate to a treatment method comprising administering to the patient a formulation of omalizumab, which formulation of omalizumab is administered subcutaneously by means of a syringe, it will be understood that the syringes of the present invention can be offered alone or in combination with a needle protection device or an auto-injector. Therefore, the present invention provides syringes containing a 150 mg / ml formulation of omalizumab that are usable with auto-injectors in that the syringes of the present invention expel the 150 mg / ml formulation of omalizumab in less time than syringes of the prior art when forces are applied to the stopper.

[0199] The present invention provides a syringe comprising: a reservoir filled with 1 ml of a 150 mg / ml formulation of omalizumab, a stopper, and a needle; and which is configured to expel 1 ml of 150 mg / ml omalizumab formulation through the needle in one or more of the following: less than 8 seconds when a constant force of 10 N is applied to the cap; less than 4 seconds when a constant force of 17 N is applied to the cap; and less than 2 seconds when a constant force of 30 N is applied to the cap.

[0200] In some embodiments, the syringe is configured to expel 1 ml of 150 mg / ml omalizumab formulation through the needle in one or more of the following: less than 8 seconds to about 4 seconds when a constant force of 10 N is applied to the stopper; less than 4 seconds to approximately 2 seconds when a constant force of 17 N is applied to the cap; and less than 2 seconds to about 1 second when a constant force of 30 N is applied to the cap.

[0201] In some embodiments, the syringe is configured to expel 1 ml of 150 mg / ml omalizumab formulation through the needle in less than 5 seconds, less than 4.75 seconds, less than 4.5 seconds, less than 4.25 seconds, or about 4 seconds when a constant force of 10 N is applied to the stopper.

[0202] In some embodiments, the syringe is configured to expel 1 ml of 150 mg / ml omalizumab formulation through the needle in less than 7.5 seconds to about 4 seconds, less than 5 seconds to about 4 seconds, less than 4.75 seconds to about 4 seconds, less than 4.5 seconds to about 4 seconds, less than 4.25 seconds to about 4 seconds, or about 4 seconds when a constant force of 10 N is applied to the stopper.

[0203] The present invention also provides a syringe for subcutaneous injection, the syringe comprising: a reservoir filled with 0.5 ml of omalizumab 150 mg / ml formulation, a stopper, and a needle; and the syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper, which syringe being configured to expel 0.5 ml of 150 mg / ml omalizumab formulation through the needle in one or more of the following: less than 4 seconds when a constant force of 10 N is applied to the stopper; less than 2 seconds when a constant force of 17 N is applied to the stopper; and less than 1 second when a constant force of 30 N is applied to the stopper.

[0204] In some embodiments, the syringe is configured to expel 0.5 ml of 150 mg / ml omalizumab formulation through the needle in one or more of the following: less than 4 seconds to about 2 seconds when a constant force of 10 N is applied to the stopper; less than 2 seconds to approximately 1 second when a constant force of 17 N is applied to the cap; and less than 1 second to about 0.5 seconds when a constant force of 30 N is applied to the cap.

[0205] The present invention also provides a subcutaneous injection syringe, the syringe comprising a reservoir filled with 2 ml of 150 mg / ml omalizumab formulation, a stopper, and a needle, the syringe being configured to expel 2 ml of the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper.

[0206] In some embodiments, the syringe is configured to expel 2 ml of omalizumab formulation 150 mg / ml from the reservoir and through the needle in one or more of the following ways: less than 16 seconds when a constant force of 10 N is applied to the cork; less than 9 seconds when a constant force of 17 N is applied to the cork; and less than 4 seconds when a constant force of 30 N is applied to the cork.

[0207] In some embodiments, the syringe is configured to expel 2 ml of omalizumab formulation 150 mg / ml from the reservoir through the needle in one or more of the following: less than 16 seconds to about 8 seconds when a constant force of 10 N is applied to the stopper; less than 9 seconds to approximately 4 seconds when a constant force of 17 N is applied to the cap; and less than 4 seconds to about 2 seconds when a constant force of 30 N is applied to the cap. Experimental results

[0208] Figures 7 to 13 show experimental results obtained with the syringe of the prior art (described with reference to [Fig. 1]) and five syringes of the present invention (described with reference to Figures 3 to 6). Table 1 summarizes the syringes used in the experiments. [Table 1] Table 1 - Syringes used in the experiments ABCDEF Syringe Described with reference to Figure 3 Figure 5 Figure 5 Figure 6 Figure 4 Figure 1 Filling volume (1 50 mg / ml omalizumab) 1 ml 0.5 ml 1 ml 2 ml 1 ml 1 ml

[0209] TIME TO EXPEL A 150 MG / ML FORMULATION WITH CONSTANT FORCE ([Fig.7])

[0210] According to the present invention, the 150 mg / ml formulation of omalizumab is expelled from a syringe in less time than from syringes of the prior art when forces are applied to the stopper. Figure 7 shows the time measured to expel the 150 mg / ml formulation of omalizumab from syringes that are part of the present invention (syringes A, C, D, and E) and from the syringe of the prior art (syringe F) when a constant force of 10 N, 17 N, or 30 N is applied to the stopper.

[0211] A motorized test bench was used to apply a constant force to each syringe filled with the relevant volume of the 150 mg / ml omalizumab formulation, and the time taken to move the stopper from its proximal to its distal position, expelling the syringe contents into the air, was measured. The constant force was applied to a piston which, in turn, applied a force to the stopper. Ten syringe samples were tested for each constant force measurement, and the average was calculated. These tests were performed at room temperature. This test method can be used to determine the performance of syringes according to the invention.

[0212] The syringe samples were tested immediately after filling (a moment referred to as time point 0 in the technique).

[0213] Under the experimental conditions, the prior art syringe (syringe F) is configured to expel 1 mL of the 150 mg / mL omalizumab formulation through the needle in 8.53 ± 0.45 seconds when a constant force of 10 N is applied to the stopper, 4.32 ± 0.20 seconds when a constant force of 17 N is applied to the stopper, and 2.14 ± 0.09 seconds when a constant force of 30 N is applied to the stopper. In other words, the prior art syringe is configured to expel a 150 mg / ml formulation of omalizumab through the needle in 0.85 ± 0.4 seconds per ml and per N of constant force applied.

[0214] Syringe A is configured to expel 1 mL of a 150 mg / mL omalizumab formulation through the needle in 6.73 ± 0.51 seconds when a constant force of 10 N is applied to the stopper, 3.27 ± 0.11 seconds when a constant force of 17 N is applied to the stopper, and 1.57 ± 0.10 seconds when a constant force of 30 N is applied to the stopper. In other words, syringe A is configured to expel a 150 mg / mL omalizumab formulation through the needle in less than 0.67 ± 0.5 seconds per mL and per N of constant force applied.

[0215] Syringe E is configured to expel 1 ml of a 150 mg / ml omalizumab formulation through the needle in 5.40 ± 0.23 seconds when a constant force of 10 N is applied to the stopper, 2.84 ± 0.12 seconds when a constant force of 17 N is applied to the stopper, and 1.67 ± 0.15 seconds when a constant force of 30 N is applied to the stopper. In other words, syringe E is configured to expel a 150 mg / ml omalizumab formulation through the needle in less than 0.54 ± 0.2 seconds per ml and per N of constant force applied.

[0216] Syringe C is configured to expel 1 mL of a 150 mg / mL omalizumab formulation through the needle in 4.64 ± 0.22 seconds when a constant force of 10 N is applied to the stopper, 2.54 ± 0.11 seconds when a constant force of 17 N is applied to the stopper, and 1.39 ± 0.04 seconds when a constant force of 30 N is applied to the stopper. In other words, syringe C is configured to expel a 150 mg / mL omalizumab formulation through the needle in less than 0.4 ± 0.5 seconds per mL and per N of constant force applied.

[0217] Syringe D is configured to expel 2 mL of a 150 mg / mL omalizumab formulation through the needle in 15.14 ± 0.51 seconds when a constant force of 10 N is applied to the stopper, 8.30 ± 0.20 seconds when a constant force of 17 N is applied to the stopper, and 4.75 ± 0.23 seconds when a constant force of 30 N is applied to the stopper. In other words, syringe D is configured to expel a 150 mg / mL omalizumab formulation through the needle in less than 0.75 ± 0.5 seconds per mL and per N of constant force applied.

[0218] Fig. 7 demonstrates that the syringes of the present invention (syringes A, C and E) are configured to expel 1 ml of 150 mg / ml omalizumab formulation from the reservoir and through the needle in less time than the syringe of the prior art (syringe F).

[0219] Therefore, the present invention provides a method for treating a patient with one or more of the following: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients presenting with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient X ml of a 150 mg / ml formulation of omalizumab, where X is 2, 1 or 0.5, and which X ml of the 150 mg / ml formulation of omalizumab are administered subcutaneously by means of a syringe, the syringe comprising: a reservoir filled with X ml of a 150 mg / ml formulation of omalizumab, which X ml of the 150 mg / ml formulation of omalizumab have 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter > 25 pm; and the syringe further comprising: a stopper, and a 25 gauge to 29 gauge needle; and the syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper, wherein one or more of the following options are fulfilled when a constant force of 10 N is applied to the stopper, a) when X is 2, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 16 seconds; b) when X equals 1, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 5 seconds;and c) when X equals 0.5, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 4 seconds.

[0220] Furthermore, [Fig. 7] demonstrates that the various components of the syringes of the present invention each contribute to a shorter injection time for the syringes of the present invention. The stopper 5 of syringe F (prior art syringe) is identical to the stopper of syringe A, but the reservoir 2 and the needle 3 of syringe F are different from the reservoir 12 and the needle 13 of syringe A. Therefore, since [Fig. 7] shows that syringe A is configured to expel 1 ml of the 150 mg / ml omalizumab formulation from the reservoir and through the needle in less time than syringe F, the characteristics of both the needle 13 and the reservoir 12 of syringe A contribute to a shorter injection time for syringe A.Similarly, reservoir 12 and needle 13 of syringe A are identical to reservoir 32 and needle 33 of syringe C, but stopper 15 of syringe A is different from stopper 35 of syringe C. Therefore, as [Fig. 7] shows that syringe C is configured to expel 1 ml of the 150 mg / ml omalizumab formulation from the reservoir and through the needle in less time than syringe A, the characteristics of stopper 35 of syringe C contribute to the shorter injection time of syringe C. Finally, the stopper 35 of syringe C. C is identical to the stopper 25 of syringe E, but the reservoir 32 and needle 33 of syringe C are different from the reservoir 22 and needle 23 of syringe E. As [Fig. 7] shows that syringe E is configured to expel 1 ml of 150 mg / ml omalizumab formulation from the reservoir and through the needle in less time than syringe C, the characteristics of the reservoir 22 and needle 23 of syringe E contribute to the shorter injection time of syringe E.

[0221] In view of this, it will be understood that the syringes of the present invention (syringes A, B, C, D, and E) have been described by way of example only, and that modifications may be made while remaining within the scope of the invention. For example, it will be understood that the stopper 15 can be combined with the syringe reservoir 22 and the needle 33, 23, or 13 to form a syringe that forms part of the invention.Furthermore, any of the features of the syringes, needles and stoppers of the present invention can be combined to form a syringe according to the invention, including, but not limited to, needle gauges suitable for subcutaneous injection (i.e. from gauge 23 to gauge 32), minimum internal diameter of the needle, stopper layering, stopper coating, number of bevels on the distal surface of the needle, syringe collar, maximum internal diameter of the stopper and diameter of the outer circumferential rib on the stopper.

[0222] Therefore, the present invention provides a method for treating a patient with one or more of the following: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps;moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient X ml of a 150 mg / ml formulation of omalizumab, where X is 1, and which X ml of the 150 mg / ml formulation of omalizumab are administered subcutaneously by means of a syringe, the syringe comprising: a reservoir filled with X ml of a 150 mg / ml formulation of omalizumab, which X ml of the 150 mg / ml formulation of omalizumab have 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter > 25 pm; and the syringe further comprising: a stopper, and a 25 gauge to 29 gauge needle;and the syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper, wherein, when a constant force of 10 N is applied to the stopper, the syringe is; configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 5 seconds, less than 4.75 seconds, less than 4.5 seconds, less than 4.25 seconds, or approximately 4 seconds.

[0223] In addition, [Fig.7] demonstrates that 27 gauge needles are particularly advantageous in contributing to a shorter injection time of the syringes of the present invention compared with the prior art because each of the syringes A, C and E includes a 27 gauge needle while syringe F includes a 26 gauge needle.

[0224] Accordingly, the present invention provides a method for treating a patient with one or more of the following: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 2 ml of a 150 mg / ml formulation of omalizumab, wherein the omalizumab formulation is administered subcutaneously using a syringe, the syringe comprising: a reservoir filled with X ml of a 150 mg / ml omalizumab formulation, where X ml of the 150 mg / ml omalizumab formulation has 6000 or fewer particles with a diameter >10 pm and / or 600 or fewer particles with a diameter >25 pm; and the syringe further comprising: a stopper, and a 27 gauge needle; and the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper.

[0225] In some embodiments, the needle has one of: a) a minimum internal diameter of 0.277 mm; b) a minimum internal diameter of 0.191 mm; c) a minimum internal diameter of 0.184 mm; and d) a minimum internal diameter of 0.241 mm.

[0226] Finally, the results of syringe D on [Fig.7] demonstrate that the syringes of the present invention can be used to administer larger volumes of omalizumab than those of the syringes of the prior art, i.e. greater than 0.5 ml and 1 ml of omalizumab formulation.

[0227] SEPARATION FORCE ([Fig.8])

[0228] As demonstrated with reference to [Fig. 8], the shorter injection times of the syringes of the present invention are due in part to the fact that the syringes of the present invention require a lower release force than the syringe of the prior art. Fig. 8 shows the measured uncoupling force required to move the stopper of the syringes of the present invention (syringes A, C, D and E) and of the syringe of the prior art (syringe F) from an initial fixed point at a speed of 190 mm / min.

[0229] Syringes A, C, D, E, and F were filled with the 150 mg / mL omalizumab formulation as required and stored at 5°C ± 3°C, 25°C ± 3°C, or 40°C ± 3°C. The peel strength of syringe samples stored at 5°C ± 3°C was tested 2.5 and 6 months post-filling. The peel strength of syringe samples stored at 25°C ± 3°C was tested immediately post-filling and 1.5, 2.5, and 6 months post-filling. The peel strength of syringe samples stored at 40°C ± 3°C was tested 1.5 and 2.5 months post-filling.

[0230] A motorized test bench was used to apply a force to the plug and measure the applied force, and the instrument was adjusted to move the plug at a speed of 190 mm / min.

[0231] Under the experimental conditions, the dislodging force required to move the stopper of the prior art syringe (syringe F) from an initial fixed point at a speed of 190 mm / min is one or more of: about 4 N to about 6 N after storage at 5°C ± 3°C for 2.5 months after filling; approximately 4.5 N to approximately 6 N after storage at 5°C ± 3°C for 6 months after filling.

[0232] Under the experimental conditions, the dislodging force required to move the stopper of the prior art syringe (syringe F) from an initial fixed point at a speed of 190 mm / min is one or more of: about 4 N to about 4.5 N at 25°C ± 3°C after filling; approximately 5.5 N to approximately 7 N after storage at 25°C ± 3°C for 1.5 months after filling; approximately 4.5 N to approximately 7.5 N after storage at 25°C ± 3°C for 2.5 months after filling; and / or approximately 7 N to approximately 10 N after storage at 25 °C ± 3 °C for 6 months after filling.

[0233] Under the experimental conditions, the dislodging force required to move the stopper of the prior art syringe (syringe F) from an initial fixed point at a speed of 190 mm / min is one or more of: about 6 N to about 10 N after storage at 40°C ± 3°C for 1.5 months after filling; and about 8 N to about 10 N after storage at 25°C ± 3°C for 2.5 months after filling.

[0234] Fig. 8 demonstrates that the detachment force required to move the stopper of the syringes of the present invention from an initial fixed point at a speed of 190 mm / min is much lower and much less variable than that for the prior art.

[0235] The dislodging force required to move the stopper of the syringes of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of the following: approximately 2 N to approximately 4 N after storage at 5°C ± 3°C for 2.5 months after filling; approximately 2 N to approximately 4 N after storage at 5°C ± 3°C for 6 months after filling.

[0236] The dislodging force required to move the stopper of the syringes of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of the following: approximately 2 N to approximately 3.5 N at 25°C ± 3°C after filling; approximately 2 N to approximately 4.5 N after storage at 25°C ± 3°C for 1.5 months after filling; approximately 2.5 N to approximately 5 N after storage at 25°C ± 3°C for 2.5 months after filling; and / or approximately 2.5 N to approximately 5.5 N after storage at 25°C ± 3°C for 6 months after filling.

[0237] The dislodging force required to move the stopper of the syringes of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of the following: approximately 3 N to approximately 4.5 N after storage at 40°C ± 3°C for 1.5 months after filling; and approximately 3 N to approximately 5 N after storage at 40°C ± 3°C for 2.5 months after filling.

[0238] PURITY & STABILITY MEASURED BY ION EXCHANGE CHROMATOGRAPHY (IEC) ([Fig.9])

[0239] As demonstrated with reference to [Fig.9], the syringes of the present invention preserve the purity and stability of romalizumab in a manner comparable to current syringes.

[0240] Figure 9 shows the percentage of the main charge variant of romalizumab, measured by ion-exchange chromatography, for the prior art syringe (syringe F) and the syringes of the present invention (syringes A, B, C, D and E).

[0241] Syringe samples were filled with the 150 mg / ml formulation of omalizumab and stored at 5°C ± 3°C or 25°C ± 3°C. The percentage of romalizumab main loading variant after storage at 5°C ± 3°C was measured by ACE inhibitor after filling, after 2.5 months of storage, and after 6 months of storage. The percentage of romalizumab main loading variant after storage at 25°C ± 3°C was measured by ACE inhibitor after 1.5 months of storage and after 2.5 months of storage. Table 2 shows the test results. [Table 2] Table 2 - By-products and degradation products by IEC, % of main variant Storage temperature Storage duration (months) Syringe A Syringe B Syringe C Syringe D Syringe E Syringe F 5°C ± 3°C 0 76.43 76.25 76.26 76.04 76.3 75.08 2.5 77.45 77.74 77.59 77.32 77.13 76.26 6 77.47 77.97 78.12 77.57 77.96 77.27 25°C ± 3°C 1.5 69.28 68.99 69.18 69.26 69.28 68.87 2.5 68.18 68.14 68.12 68.13 68.14 68.23

[0242] As shown in Table 2 and [Fig.9], the syringes of the present invention (syringes A, B, C, D and E) preserve the purity and stability of romalizumab in a similar manner to the syringe of the prior art (syringe F).

[0243] The syringes of the present invention contain at least 76% of the main charge variant of omalizumab, measured by ion-exchange chromatography, after filling with a 150 mg / ml omalizumab solution stored at 5°C ± 3°C. This demonstrates that the syringes of the present invention preserve the purity of omalizumab in a manner comparable to the syringe of the prior art (syringe F), which contained only 75.08% of the main charge variant of omalizumab, measured by ion-exchange chromatography, after filling with 1 ml of a 150 mg / ml omalizumab solution stored at 5°C ± 3°C.

[0244] The syringes of the present invention also preserve the stability of omalizumab in a manner similar to the syringe of the prior art. The syringes of the present invention contain at least 77% of the main charge variant of omalizumab, measured by ion-exchange chromatography, after being filled with a 150 mg / ml solution of omalizumab and then stored at 5°C ± 3°C for 2.5 months, compared to 76% for the syringe of the prior art prior under the same conditions. In addition, the syringes of the present invention contain at least 69% of the main loading variant of omalizumab after being filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 3°C for 1.5 months.

[0245] PURITY & STABILITY MEASURED BY HYDROPHOBIC CHROMATOGRAPHY (HIC) (Figures 10 to 12)

[0246] As demonstrated with reference to [Fig. 10], the syringes of the present invention preserve the purity and stability of romalizumab in a manner similar to the syringes of the prior art in a manner similar to the current syringe.

[0247] Figure 10 shows the proportion of the first HIC peak for the syringe of the prior art (syringe F) and the syringes of the present invention (syringes A, B, C, D, and E). Figure 11 shows the proportion of the second HIC peak for the syringe of the prior art and the syringes of the present invention. Figure 12 shows the proportion of the third HIC peak for the syringe of the prior art and the syringes of the present invention.

[0248] Samples of syringes were filled with the 150 mg / ml formulation of omalizumab and stored at 5°C ± 3°C or 25°C ± 3°C. The proportions of the first, second, and third HIC peaks of syringes stored at 5°C ± 3°C were measured after filling, after 2.5 months of storage, and after 6 months of storage. The proportions of the first, second, and third HIC peaks of syringes stored at 25°C ± 3°C were measured after 1.5 months of storage and after 2.5 months of storage. Tables 3, 4, and 5 show the test results. [Table 3] Table 3 - By-products and degradation products by HIC, Peak 1% Storage temperature Storage duration (months) Syringe A Syringe B Syringe C Syringe D Syringe E Syringe F 5°C ± 3°C 0 62.8 62.7 62.8 62.8 62.8 60.2 2.5 62.3 62.4 62.3 62.3 62.4 59.7 6 65.6 65.7 65.6 65.7 65.4 63.1 25°C ± 3°C 1.5 56.1 56.0 56.2 56.2 56.2 53.8 2.5 51.2 51.3 51.3 51.3 51.3 49.9 [Table 4] Table 4 - By-products and degradation products by HIC, Peak 2% Storage temperature Storage duration (months) Syringe A Syringe B Syringe C Syringe D Syringe E Syringe F 5°C ± 3°C 0 27.6 27.7 27.6 27.6 27.6 28.2 2.5 27.0 27.0 26.9 26.9 27.0 27.6 6 22.5 22.7 22.5 22.6 22.9 23.5 25°C ± 3°C 1.5 24.3 24.2 24.3 24.3 24.3 25.1 2.5 22.6 22.5 22.5 22.5 22.6 23.3 [Table 5] Table 5 - By-products and degradation products by HIC, Peak 3% Storage temperature Storage duration (months) Syringe A Syringe B Syringe C Syringe D Syringe E Syringe F 5°C ± 3°C 0 6.3 6.2 6.3 6.3 6.3 7.7 2.5 7.1 6.9 7.0 7.0 6.9 8.3 6 8.0 7.8 7.9 7.9 7.9 9.1 25°C ± 3°C 1.5 12.1 12.1 11.9 12.0 12.1 13.1 2.5 17.2 17.1 17.1 17.2 17.2 17.9

[0249] As demonstrated in Table 3 and [Fig. 10], the syringes of the present invention (syringes A, B, C, D and E) preserve the purity and stability of romalizumab in a manner comparable to the syringe of the prior art (syringe F).

[0250] The proportion of the first HIC peak is at least 62% for the syringes of the present invention after filling with a 150 mg / ml omalizumab solution stored at 5°C ± 3°C. This demonstrates that the syringes of the present invention preserve the purity of omalizumab in a manner comparable to the syringe of the prior art (syringe F), which had a first HIC peak of 60.2% after filling with a 150 mg / ml omalizumab solution stored at 5°C ± 3°C.

[0251] The syringes of the present invention also preserve the stability of romalizumab. The proportion of the first HIC peak is at least 62% for the syringes of the present invention after they have been filled with a 150 mg / ml omalizumab solution and then stored at 5°C ± 3°C for 2.5 months, compared to 59% for the syringe of the prior art under the same conditions. The proportion of The first HIC peak is at least 56% for syringes of the present invention after they have been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 3°C for 1.5 months, compared to 53.8% for the syringe of the prior art under the same conditions. The proportion of the first HIC peak is at least 51% for syringes of the present invention after they have been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 3°C for 2.5 months, compared to 49.9% for the syringe of the prior art under the same conditions.

[0252] Therefore, in certain embodiments of the invention, the proportion of the first peak of the syringe, measured by hydrophobic chromatography, is at least: a) 62% after filling with a 150 mg / ml omalizumab solution stored at 5°C ± 3°C; and / or b) 62% after it was filled with a 150 mg / ml omalizumab solution and then stored at 5°C ± 3°C for 2.5 months.

[0253] In some embodiments of the invention, the proportion of the first peak of the syringe, measured by hydrophobic chromatography, is reduced by 0.4% or less after the syringe has been stored at 5°C ± 3°C for 2.5 months.

[0254] In certain embodiments of the invention, the proportion of the first syringe peak, measured by hydrophobic chromatography, is at least: a) 56% for the syringe after it has been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 3°C for 1.5 months; and / or b) 51% for the syringe after it was filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 3°C for 2.5 months.

[0255] POLYSORBATE 20 CONTENT ([Fig. 13])

[0256] As demonstrated with reference to [Fig. 13], the syringes of the present invention preserve the purity and stability of romalizumab in a manner similar to current syringes.

[0257] Fig. 13 shows the polysorbate 20 (PS20) content of the syringe of the prior art and of syringes of the present invention.

[0258] Syringe samples were filled with the 150 mg / ml omalizumab formulation and stored at 5°C ± 3°C or 25°C ± 3°C. The polysorbate 20 content was measured for each sample after filling, after 2.5 months of storage, and after 6 months of storage. Table 6 shows the test results. [Table 6] Table 6 - Dosage of PS20 excipient by HPLC (mg / ml) Storage temperature Storage duration (months) Syringe A Syringe B Syringe C Syringe D Syringe E Syringe F 5°C ± 3°C 0 0.429 0.425 0.428 0.427 0.422 0.392 2.5 0.462 0.472 0.484 0.496 0.475 0.428 6 0.440 0.449 0.450 0.455 0.445 0.398 25°C ± 3°C 1.5 0.40- 0.404 0.413 0.402 0.401 0.360 2.5 0.420 0.414 0.421 0.432 0.423 0.363 6 0.353 0.347 0.353 0.355 0.351 0.289

[0259] As demonstrated in Table 6 and [Fig. 13], the syringes of the present invention (syringes A, B, C, D and E) preserve the purity and stability of romalizumab in a manner comparable to the syringe of the prior art (syringe F).

[0260] The polysorbate 20 content of the syringes of the present invention is at least 0.4 mg / ml after filling with a 150 mg / ml omalizumab solution stored at 5°C ± 3°C. This demonstrates that the syringes of the present invention preserve the purity of the 150 mg / ml omalizumab solution in a manner comparable to the syringe of the prior art (syringe F), which contains a polysorbate 20 content of 0.392 mg / ml under the same conditions.

[0261] The syringes of the present invention also preserve the stability of omalizumab. The polysorbate 20 content of the syringes of the present invention is at least 0.4 mg / ml after they have been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 3°C for 1.5 months, compared to 0.360 mg / ml for the syringe of the prior art under the same conditions. The polysorbate 20 content of the syringes of the present invention is at least 0.3 mg / ml after they have been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 3°C for 6 months, compared to 0.289 mg / ml for the syringe of the prior art under the same conditions.

[0262] Therefore, in some embodiments, the syringe contains at least 0.4 mg / ml of polysorbate 20 after filling with a 150 mg / ml omalizumab solution stored at 5°C ± 3°C.

[0263] In some embodiments, the syringe contains: a) at least 0.4 mg / ml of polysorbate 20 after it has been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 3°C for 1.5 months; and / or b) at least 0.3 mg ml of polysorbate 20 after it has been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 3°C for 6 months.

[0264] NEEDLE PROTECTION DEVICES

[0265] Although the present application describes a treatment method in which a 150 mg / ml formulation of omalizumab is administered subcutaneously by means of a syringe, it will be understood that the syringes of the present invention may be supplied alone, or in combination with a needle-protective device.

[0266] Figures 14A and 14B show schematic diagrams of a pre-filled syringe 50 according to the present invention with a needle protective device 60. [Fig.14A] shows a configuration before use and [Fig.14B] shows a configuration in use.

[0267] A piston 51 is present and includes a piston rod 53 and a piston head 52. A user can apply manual force to the piston head 52 in a distal direction to manually expel the fluid contained in the reservoir through the needle. When the piston reaches the end of its distal movement, it can unlock needle protector retaining arms 54 located inside the needle protector device, releasing a needle sleeve 55. When the needle protector device is removed from an injection site, the needle sleeve 55 can extend under the constraint of the needle protector spring 56 to cover the needle, as shown in [Fig. 14B].

[0268] Accordingly, in certain embodiments of the present invention, the syringe is supplied in a needle protective device comprising a needle sleeve and a piston; and wherein a manual force can be applied to the piston to expel the 150 mg / ml formulation of omalizumab and unlock the needle sleeve so that the needle sleeve can cover the needle after injection.

[0269] AUTO-INJECTORS

[0270] Although the present application describes a treatment method in which a 150 mg / ml formulation of omalizumab is administered subcutaneously using a syringe, it will be understood that the syringes of the present invention may be supplied alone or in combination with an auto-injector. Therefore, in certain embodiments of the invention, the syringe is supplied in an auto-injector.

[0271] Figure 15 is a schematic diagram of a pre-filled syringe 111 inside an auto-injector 100. The auto-injector comprises a housing 101 configured to hold the syringe 111 and a drive mechanism 102 configured to apply a force to the stopper in a distal direction and expel fluid from the syringe through the needle. A trigger mechanism 103 is arranged to actuate the drive mechanism. In the example shown in [Fig. 15], the trigger 103 is moved in the direction of the arrow, away from the pre-filled syringe.

[0272] The syringe comprises a reservoir filled with a 150 mg / ml formulation of omalizumab, a stopper, and a needle. As will be appreciated, the 100 auto-injector can also be combined with any of the syringes of the invention—further details on the syringes of the invention and the filling volume are described with reference to Figures 3 to 6.

[0273] The drive mechanism 102 is configured to apply a force to the stopper to drive the stopper through the reservoir towards the needle to expel the 150 mg / ml formulation of omalizumab out of the reservoir and through the needle.

[0274] A triggering mechanism 103 is present and is movable from a holding position, in which the drive mechanism is held in a rest position, to a release position, in which the drive mechanism is released, as a consequence of which the drive mechanism drives the stopper through the reservoir towards the needle to expel the 150 mg / ml formulation of omalizumab out of the reservoir and through the needle in about 1 second to about 17 seconds.

[0275] In the embodiment shown in [Fig. 15], the drive mechanism is configured to expel the 150 mg / ml omalizumab formulation from the reservoir and through the needle in approximately 1 to 17 seconds by applying an average force of at least 10 N to the stopper over the period of time during which the 150 mg / ml omalizumab formulation is expelled. In some embodiments, the drive mechanism is configured to apply an average force of at least 11 N to the stopper, at least 12 N, at least 13 N, at least 14 N, at least 15 N, at least 16 N, at least 17 N, at least 18 N, at least 19 N, at least 20 N, at least 21 N, at least 22 N, at least 23 N, at least 24 N, at least 25 N, at least 26 N, at least 27 N, at least 28 N, at least 29 N, at least 30 N, at least 31 N, at least 32 N, at least 33 N, at least 34 N, at least 35 N, at least 36 N, at least 37 N, at least 38 N, at least 39 N or at least 40 N.

[0276] In the embodiment shown in [Fig. 15], the drive mechanism comprises a helical spring configured to apply an average force of 25 N to the stopper. The average force can be calculated by determining the force applied to the stopper at the beginning of the injection (when the drive mechanism is released) and the force applied to the stopper at the end of the injection (when the stopper has been driven through the reservoir until it engages with the distal end of the reservoir and can no longer be driven), and calculating the average of the two. forces. As a person skilled in the art will understand, Hooke's law can be used to calculate the force applied by a given spring to a given extension.

[0277] Although the drive mechanism of the auto-injector shown in [Fig. 15] includes a helical drive spring, the invention is not limited to such a drive mechanism. Other types of drive mechanisms may be used to apply an average force of at least 10 N to the stopper to expel the 150 mg / ml omalizumab formulation from the reservoir and through the needle in a period of less than 17 seconds in accordance with the present invention. For example, a drive mechanism comprising a torsion spring or an electromechanical drive may be used.

[0278] The auto-injector further includes an auto-injector cap (not shown). The auto-injector cap is configured to be permanently engaged with the syringe needle protector (described in more detail with reference to Figures 3 and 6) and releasably engaged with the auto-injector housing. When the auto-injector cap is disengaged from the housing, it removes the needle protector from the syringe, thus allowing access to the needle.

[0279] TIME FOR EXPELTING THE OMALIZUMAB FORMULATION BY MEANS OF AN AUTO-INJECTOR COMBINED WITH SYRINGES OF THE PRESENT INVENTION ([Fig. 16])

[0280] Fig. 16 shows the time measured to expel the 150 mg / ml formulation of omalizumab from the reservoir and through the needle by using an auto-injector when combined with syringes of the invention.

[0281] Four auto-injectors, as shown and described with reference to [Fig. 15], were tested. The first auto-injector was fitted with syringe A. The second auto-injector was fitted with syringe E. The third auto-injector was fitted with syringe C. The fourth auto-injector was fitted with syringe D. The triggering mechanism of each auto-injector was moved from the holding position to the release position, and the time for the stopper to be drawn through the reservoir until it engaged with the distal end of the reservoir was measured. The test was repeated 20 times for each auto-injector embodiment.

[0282] Each tested auto-injector expelled the 150 mg / ml formulation of omalizumab from the reservoir and through the needle in approximately 1 second to approximately 17 seconds. The drive mechanism of each tested auto-injector included a helical spring configured to apply an average force of 25 N to the stopper.

[0283] The first auto-injector expelled 1 ml of 150 mg / ml omalizumab solution from the reservoir and through the needle in approximately 3 to 5 seconds.

[0284] The second auto-injector expelled 1 ml of 150 mg / ml omalizumab solution from the reservoir and through the needle in approximately 4 to 6 seconds.

[0285] The third auto-injector expelled 1 ml of 150 mg / ml omalizumab solution from the reservoir and through the needle in approximately 3 to 4 seconds. In one test, the third auto-injector expelled 1 ml of 150 mg / ml omalizumab solution from the reservoir and through the needle in approximately 9 seconds – this test result was found to be an error.

[0286] The fourth auto-injector expelled 2 ml of 150 mg / ml omalizumab solution from the reservoir and through the needle in approximately 6 to 7 seconds.

[0287] As demonstrated in [Fig. 16], the present invention further provides an auto-injector filled with a 150 mg / ml omalizumab formulation, which is configured to expel the 150 mg / ml omalizumab formulation from the reservoir and through the needle in a time period of less than 17 seconds. This time period of less than 17 seconds is acceptable to patients.

[0288] Although [Fig. 16] shows only test results for auto-injectors with syringes filled with 1 ml or 2 ml of the 150 mg / ml omalizumab formulation, it will be understood that auto-injectors with syringes filled with 0.5 ml of the 150 mg / ml omalizumab formulation can also be supplied according to the invention. Furthermore, [Fig. 16] does not show the test results of an auto-injector equipped with the prior art syringe (syringe F), because the prior art syringe is not usable with auto-injectors. The prior art syringe is not usable with auto-injectors because it cannot reliably withstand the high injection forces required for the administration of omalizumab within an acceptable timeframe.

[0289] Accordingly, in one aspect, an auto-injector is described comprising: a syringe according to the invention, for example a syringe comprising a reservoir filled with 0.5 ml, 1 ml or 2 ml of 150 mg / ml omalizumab formulation, a stopper, and a needle; a drive mechanism configured to apply a force to the stopper to drive the stopper through the reservoir towards the needle to expel the 150 mg / ml omalizumab formulation from the reservoir and through the needle; a housing configured to contain the syringe and the drive mechanism; and a trigger mechanism movable from a holding position, in which the drive mechanism is held in a rest position in which it does not apply force to the stopper, to a release position, in which the drive mechanism is released, as a result of which the drive mechanism applies a force to the stopper to drive the stopper through the reservoir towards the needle to expel the 150 mg / ml omalizumab formulation from the reservoir and through the needle in a period of time of less than 17 seconds.

[0290] The syringe can be filled with 0.5 ml of omalizumab 150 mg / ml formulation, in which case the drive mechanism is configured to expel the 0.5 ml of omalizumab 150 mg / ml formulation from the reservoir and through the needle in a time period of approximately 1 second to approximately 17 seconds, approximately 1 second to approximately 16 seconds, approximately 1 second to approximately 15 seconds, and approximately 1 second to approximately 14 seconds. seconds, from approximately 1 second to approximately 13 seconds, from approximately 1 second to approximately 12 seconds, from approximately 1 second to approximately 11 seconds, from approximately 1 second to approximately 10 seconds, from approximately 1 second to approximately 9 seconds, from approximately 1 second to approximately 8 seconds, from approximately 1 second to approximately 7 seconds, from approximately 1 second to approximately 6 seconds, from approximately 1 second to approximately 5 seconds, from approximately 1 second to approximately 4 seconds, from about 1 second to about 2 seconds; or about 1 second.

[0291] The syringe can be filled with 1 ml of omalizumab 150 mg / ml formulation, and the drive mechanism is configured to expel the 1 ml of omalizumab 150 mg / ml formulation from the reservoir and through the needle in a time period of approximately 3 seconds to approximately 17 seconds, approximately 3 seconds to approximately 16 seconds, approximately 3 seconds to approximately 15 seconds, approximately 3 seconds to approximately 14 seconds, approximately 3 seconds to approximately 13 seconds, approximately 3 seconds to approximately 12 seconds, approximately 3 seconds to approximately 11 seconds, approximately 3 seconds to approximately 10 seconds, approximately 3 seconds to approximately 9 seconds, and approximately 3 seconds. at approximately 8 seconds, from approximately 3 seconds to approximately 7 seconds, from approximately 3 seconds at approximately 6 seconds, from approximately 3 seconds to approximately 5 seconds, from approximately 3 seconds at approximately 4 seconds; or approximately 3 seconds.

[0292] The syringe can be filled with 2 ml of 150 mg / ml omalizumab formulation, and the drive mechanism is configured to expel the 2 ml of 150 mg / ml omalizumab formulation from the reservoir and through the needle in a time period of approximately 6 to 17 seconds, approximately 6 to approximately 16 seconds, approximately 6 to approximately 15 seconds, approximately 6 to approximately 14 seconds, approximately 6 to approximately 13 seconds, approximately 6 to approximately 12 seconds, approximately 6 to approximately 11 seconds, approximately 6 to approximately 10 seconds, approximately 6 to approximately 9 seconds, approximately 6 to approximately 8 seconds, approximately 6 to approximately 7 seconds, or approximately 6 seconds.

[0293] The drive mechanism can be configured to apply an average force of at least 10 N to the stopper over the period of time during which the 150 mg / ml omalizumab formulation is expelled. It can be configured to apply an average force to the stopper over the period of time during which the 150 mg / ml omalizumab formulation is expelled of at least 11 N, at least 12 N, at least 13 N, at least 14 N, at least 15 N, at least 16 N, at least 17 N, at least 18 N, of at least 19 N, of at least 20 N, of at least 21 N, of at least 22 N, of at least 23 N, of at least 24 N, of at least 25 N, of at least 26 N, of at least 27 N, of at least 28 N, of at least 29 N, of at least 30 N, of at least 31 N, of at least 32 N, of at least 33 N, of at least 34 N, of at least 35 N, of at least 36 N, of at least 37 N, of at least 38 N, of at least 39 N or at least 40 N.

[0294] The drive mechanism may include a helical spring, a torsion spring and / or an electromechanical drive.

[0295] In some aspects, the syringe is filled with 0.5 ml of 150 mg / ml omalizumab formulation and the drive is configured to expel the 0.5 ml of 150 mg / ml formulation from the reservoir and through the needle in a time period of approximately 1 second to approximately 17 seconds, approximately 1 second to approximately 16 seconds, approximately 1 from one second to approximately 15 seconds, from approximately 1 second to approximately 14 seconds, from approximately 1 from one second to approximately 13 seconds, from approximately 1 second to approximately 12 seconds, from approximately 1 from one second to approximately 11 seconds, from approximately 1 second to approximately 10 seconds, from approximately from 1 second to approximately 9 seconds, from approximately 1 second to approximately 8 seconds, from approximately from 1 second to approximately 7 seconds, from approximately 1 second to approximately 6 seconds, from approximately from 1 second to approximately 5 seconds, from approximately 1 second to approximately 4 seconds, from approximately 1 one to approximately 2 seconds; or approximately 1 second.

[0296] In certain aspects, the syringe is filled with 1 ml of omalizumab 150 mg / ml formulation, and the drive is configured to expel the 1 ml of omalizumab 150 mg / ml formulation from the reservoir and through the needle in a time period of approximately 3 seconds to approximately 17 seconds, approximately 3 seconds to approximately 16 seconds, approximately 3 seconds to approximately 15 seconds, approximately 3 seconds to approximately 14 seconds, approximately 3 seconds to approximately 13 seconds, approximately 3 seconds to approximately 12 seconds, approximately 3 seconds to approximately 11 seconds, approximately 3 seconds to approximately 10 seconds, approximately 3 seconds to approximately 9 seconds, approximately 3 seconds to approximately 8 seconds, approximately 3 seconds to approximately 7 seconds, approximately 3 seconds to approximately 6 seconds, approximately 3 seconds to approximately 5 seconds, and approximately 3 seconds to approximately 4 seconds; or about 3 seconds.

[0297] In some aspects, the syringe is filled with 2 ml of 150 mg / ml omalizumab formulation, and the drive is configured to expel the 2 ml of 150 mg / ml omalizumab formulation from the reservoir and through the needle in a time period of approximately 6 seconds to 17 seconds, or approximately 6 seconds to approximately 16 seconds; which time period is possibly one of: approximately 6 seconds to approximately 15 seconds, approximately 6 seconds to approximately 14 seconds, approximately 6 seconds to approximately 13 seconds, approximately 6 seconds to approximately 12 seconds, approximately 6 seconds to approximately 11 seconds, approximately 6 seconds to approximately 10 seconds, or approximately 6 seconds to about 9 seconds, about 6 seconds to about 8 seconds, about 6 seconds to about 7 seconds, or about 6 seconds.

[0298] A kit is also made available including a syringe according to the present invention and optionally: an auto-injector, a needle protection device, and / or instructions for administration.

[0299] In one aspect of the invention, the injection of a highly viscous 150 mg / ml formulation of omalizumab using an auto-injector is made available for the first time. In particular, one aspect allows the injection of a highly viscous 150 mg / ml formulation of omalizumab in a time period of 1 to 17 seconds—this time period is acceptable to patients and thus improves ease of use and patient acceptance.

[0300] Furthermore, as shown in [Fig. 16], the auto-injectors comprise a syringe filled with 1 ml of omalizumab 150 mg / ml formulation and comprising a drive mechanism configured to expel the 1 ml of omalizumab 150 mg / ml formulation from the reservoir and through the needle in a time period of approximately 3 to 6 seconds. This injection time is considerably shorter than the injection time of comparable self-administered antibody formulations such as the Fasenra 30 mg / 1 ml (benzalizumab) auto-injector (injection time period of up to 15 seconds) and the Nucala 100 mg / 1 ml (mepolizumab) auto-injector (injection time period of up to 15 seconds).

[0301] This shorter injection time facilitates the injection of high doses of omalizumab that were not previously available to patients, such as 2 ml of the 300 mg / 2 ml omalizumab formulation, in a single syringe. As shown in [Fig. 16], the present invention provides an auto-injector comprising a syringe filled with 2 ml of the 150 mg / ml omalizumab formulation and a drive mechanism configured to expel the 2 ml of the 150 mg / ml formulation from the reservoir and through the needle in a period of approximately 6 to 7 seconds. This injection time is significantly shorter than the injection time of comparable antibody formulations of similar volume; for example, the Dupixent 300 mg / ml (dupilumab) auto-injector (injection time of up to 20 seconds).

[0302] As demonstrated with reference to [Fig. 7], the shorter injection times of the auto-injectors of the present invention are due in part to the fact that the syringes of the present invention expel the 150 mg / ml formulation of omalizumab more rapidly than the syringes of the prior art when constant forces are applied to the stopper. Furthermore, as demonstrated with reference to [Fig. 8], the shorter injection times of the auto-injectors of the present invention are due in part to the fact that the syringes of the present invention require a lower release force than the syringe of the prior art.

[0303] Surprisingly, as demonstrated with reference to Figures 9 to 13, the syringes of the present invention better preserve the purity and stability of romalizumab. The improved purity and stability of romalizumab also contribute to the shorter injection time of the syringes and auto-injectors of the present invention because they reduce aggregation and thus limit increases in fluid viscosity.

[0304] BIOEQUIVALENCE DATA

[0305] It has been demonstrated that new treatment methods including the administration of omalizumab, described in this application, are bioequivalent to previously approved treatment methods including the administration of omalizumab, see Sangana et al. Bioequialvence between a new omalizumab prefilled syringe with an autoinjector or with a needle safety device compared with the current prefilled syringe: a randomized controlled trial in healthy volunteers, Clinical Pharmacology. 2024, 0 (0) 1-10.

[0306] Sangana et al. demonstrated the bioequivalence of omalizumab between: (1) the new 300 mg / 2 ml pre-filled syringe in an auto-injector (new PFS-AI), i.e. the auto-injector 100 described with reference to [Fig. 15] fitted with syringe D described with reference to [Fig. 6] and two of the current 150 mg / 1 ml pre-filled syringes in a needle protector (current PFS-NSD), i.e. the needle protector 60 described with reference to Figures 14A and 14B fitted with syringe F described with reference to [Fig. 1]; (2) the new 300 mg / 2 ml pre-filled syringe in a needle protective device (new PFS-NSD), i.e., needle protective device 60 described with reference to Figures 14A and 14B with syringe D described with reference to [Fig. 6], and two of the current 150 mg / 1 ml pre-filled syringes in a needle protective device (current PFS-NSD), i.e., needle protective device 60 described with reference to Figures 14A and 14B with syringe F described with reference to [Fig. 1]; and (3) the new 300 mg / 2 ml pre-filled syringe in an auto-injector (new PFS-AI), i.e. the auto-injector 100 described with reference to [Fig. 15] fitted with syringe D described with reference to [Fig. 6] and the new 300 mg / 2 ml pre-filled syringe in a needle protector device (new PFS-NSD), i.e. the needle protector device 60 described with reference to Figures 14A and 14B fitted with syringe D described with reference to [Fig. 6].

[0307] For the bioequivalence comparison, pharmacokinetic parameters transformed to the natural logarithm (Cmax, AUCiast, AUCinf) were analyzed by a An analysis of covariance model (ANCOVA) was performed with treatment group strata, body area of ​​injection, and body weight as fixed effects, and baseline IgE as a covariate. Cmax is the maximum observed serum concentration, AUCiast is the area under the serum concentration-time curve calculated at the last quantifiable concentration point, and AUCinf is the area under the serum concentration-time curve extrapolated to infinity. Based on the ANCOVA model, point estimates and corresponding 95% and 90% confidence limits were calculated for the difference between each novel omalizumab configuration (new PSF-AI, new PFS-NSD) and the control intervention (current PFS-NSD).These point estimates and confidence limits were exponentialized to obtain point estimates with 95% and 90% confidence intervals (Cis) for the proportions of geometric means on the original scale. Bioequivalence claims were made for each comparison if and only if Cmax, AUCiast, and AUCinf were declared equivalent (i.e., the Cis values ​​for all proportions were within 80% and 125%), based on the progressive Bonferroni-Holm method for multiple comparisons.

[0308] Statistical comparisons of serum pharmacokinetic parameter values ​​of romalizumab for the new PFS-AI, the new PFS-NSD and the current PFS-NSD are summarized below. [Paintings?] Parameter (1) New PSF-AI vs. Current PFS-NSD (2) New PFS-NSD vs. Current PFS-NSD (3) New PFS-AI vs. New PFS-NSD GMR (%) [95% CI]a GMR (%) [95% CI]b GMR (%) [90% CI]c Cmax (pg / ml) 108.5 [99.6-118.1] 100.6 [92.3-109.6] 107.8 [100.4-115.8] AUClast (pg*h / ml) 109.3 [99.7-119.9] 101.6 [92.5-111.6] 107.6 [99.6-116.3] AUCinf (pg*h / ml) 110.0 [100.1-120.9] 102.7 [93.3-113.0] 107.2 [99.0-116.0] a In comparing each new configuration with the current configuration, bioequivalence was established on the basis of 95% Cis in accordance with the B onferroni-Holm procedure b In comparing the new configurations with each other, another bioequivalence was established on the basis of Cis at 90%. AUCinf, area under the curve from time 0 to infinity; AUClast, area under the curve from time 0 to the last sampling time of measurable concentration; CI, confidence interval; Cmax, maximum (peak) observed drug concentration after administration of a single dose; GMR, geometric mean ratio; PFS-AI, pre-filled syringe assembled with an auto-injector; PFS-NSD, pre-filled syringe with a needle safety device.

[0309] Formal bioequivalence was established between: (1) the new PFS-AI and the current PFS-NSD (95% CI or 90% CI, based on the Bonferroni-Holm procedure); (2) the new PFS-NSD and the current PFS-NSD (95% CI or 90% CI, based on the Bonferroni-Holm procedure); and (3) the new PFS-AI and the new PFS-NSD (90% CI); the CI for each treatment contrast being contained within the range of 80% to 125% for Cmax, AUCiast and AUCinf after a single dose of omalizumab.

[0310] Some numbered examples relating to the invention are described below. Example 1

[0311] X ml of a 150 mg / ml omalizumab formulation for use in a method of treatment of one or more of the following: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, where X is 2, and which X ml of 150 mg / ml omalizumab formulation are administered subcutaneously by means of a syringe, the syringe comprising: a reservoir filled with X ml of a 150 mg / ml omalizumab formulation, which X ml of 150 mg / ml omalizumab formulation have 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter > 25 pm;and the syringe further comprising: a stopper, and a needle, the syringe being configured to expel X ml of the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper. Example 2

[0312] X ml of a 150 mg / ml omalizumab formulation for use in a method of treatment of one or more of the following: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, where X is 2, 1, or 0.5, and X ml of a 150 mg / ml omalizumab formulation are administered subcutaneously using a syringe, the syringe comprising: a reservoir filled with X ml of a 150 mg / ml omalizumab formulation, where X ml of the 150 mg / ml omalizumab formulation has 6000 or fewer particles with a diameter >10 pm and / or 600 or fewer particles with a diameter >25 pm; and the syringe further comprising: a stopper, and a 27 gauge needle; and the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper. Example 3

[0313] X ml of 150 mg / ml omalizumab formulation for use according to Example 2, wherein the needle has one of: a) a minimum internal diameter of 0.277 mm; b) a minimum internal diameter of 0.191 mm; c) a minimum internal diameter of 0.184 mm; and d) a minimum internal diameter of 0.241 mm. Example 4

[0314] X ml of a 150 mg / ml omalizumab formulation for use in a method of treatment of one or more of the following: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, where X is 2, 1 or 0.5, and which X ml of 150 mg / ml omalizumab formulation are administered subcutaneously by means of a syringe, the syringe comprising: a reservoir filled with X ml of a 150 mg / ml omalizumab formulation, which X ml of 150 mg / ml omalizumab formulation have 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter > 25 pm; and the syringe further comprising: a stopper, and a needle;and the syringe being configured to expel the 150 mg / ml formulation of omalizumab contained in the reservoir through the needle when a force is applied to the stopper, the syringe being configured to expel the omalizumab formulation through the needle in less than 0.8 seconds per ml per N of constant force applied to the stopper. ;

[0315] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 4, in which X is 2, in which the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 0.75 ± 0.5 seconds per ml and per N of constant force applied. Example 6

[0316] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 5, where X is 2, wherein the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in one or more of the following: a) less than 16 seconds when a constant force of 10 N is applied to the stopper; b) less than 8.5 seconds when a constant force of 17 N is applied to the stopper; and c) less than 5 seconds when a constant force of 30 N is applied to the cap. Example 7

[0317] X ml of 150 mg / ml omalizumab formulation for use according to Example 6, wherein the syringe is configured to expel X ml of the omalizumab formulation contained in the reservoir through the needle in one or more of: a) about 16 seconds to about 14 seconds when a constant force of 10 N is applied to the stopper; b) approximately 8.5 seconds to approximately 6 seconds when a constant force of 17 N is applied to the stopper; and c) approximately 5 seconds to approximately 4 seconds when a constant force of 30 N is applied to the cap. Example 8

[0318] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 2 to 4, wherein X is 1 or 0.5, wherein the syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in less than 0.67 ± 0.5 seconds per ml and per N of constant force applied, possibly less than 0.54 ± 0.2 seconds per ml and per N of constant force applied, again possibly less than 0.4 ± 0.5 seconds per ml and per N of constant force applied. Example 9

[0319] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 2 to 4 and 8, where X is 1, and where the syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of the following: a) less than 7.5 seconds when a constant force of 10 N is applied to the stopper; b) less than 3 seconds when a constant force of 17 N is applied to the stopper; and c) less than 2 seconds when a constant force of 30 N is applied to the cap. Example 10

[0320] X ml of 150 mg / ml omalizumab formulation for use according to Example 9, wherein the syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of the following: a) less than 7.5 seconds to about 4 seconds when a constant force of 10 N is applied to the cap; b) less than 3.5 seconds to approximately 2 seconds when a constant force of 17 N is applied to the stopper; and c) less than 2 seconds to about 1 second when a constant force of 30 N is applied to the cap. Example 11

[0321] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 2 to 4 and 8, in which X is 0.5, and in which the syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of the following: a) less than 4 seconds when a constant force of 10 N is applied to the stopper; b) less than 2 seconds when a constant force of 17 N is applied to the stopper; and c) less than 1 second when a constant force of 30 N is applied to the cap. Example 12

[0322] X ml of 150 mg / ml omalizumab formulation for use according to Example 11, wherein the syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of the following: a) less than 4 seconds to about 2 seconds when a constant force of 10 N is applied to the cap; b) less than 2 seconds to approximately 1 second when a constant force of 17 N is applied to the stopper; and c) less than 1 second to about 0.5 seconds when a constant force of 30 N is applied to the cap. Example 13

[0323] X ml of omalizumab 150 mg / ml formulation for use according to any one of Examples 1 to 12, wherein the syringe contains: a) at least 76% of the main charge variant of omalizumab, measured by ion-exchange chromatography, after filling with a 150 mg / ml omalizumab solution stored at 5°C ± 1°C; and / or b) at least 77% of the main charge variant of omalizumab, measured by ion-exchange chromatography, after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 5°C ± 1°C for 2.5 months. Example 14

[0324] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 12, wherein the percentage of main charge variant of omalizumab in the syringe, measured by ion-exchange chromatography, is reduced by 2% or less after the syringe has been stored at 5°C ± 1°C for 2.5 months. Example 15

[0325] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 14, wherein the proportion of the first syringe peak, measured by hydrophobic chromatography, is at least: a) 62% after filling with a 150 mg / ml omalizumab solution stored at 5°C ± 1°C; and / or b) 62% after it was filled with a 150 mg / ml omalizumab solution and then stored at 5°C ± 1°C for 2.5 months. Example 16

[0326] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 15, wherein the proportion of the first syringe peak, measured by hydrophobic chromatography, is reduced by 0.4% or less after the syringe has been stored at 5°C ± 1°C for 2.5 months. Example 17

[0327] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 16, wherein the syringe contains at least 0.4 mg / ml of polysorbate 20 after filling with a 150 mg / ml omalizumab solution stored at 5°C ± 1°C. Example 18

[0328] X ml of 150 mg / ml omalizumab formulation for use according to any of Examples 1 to 12, wherein the syringe contains at least 69% of the main charge variant of omalizumab, as measured by ion-exchange chromatography, after it has been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 1°C for 1.5 months.

[0329] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 12 and 18, wherein the proportion of the first peak of the syringe, measured by hydrophobic chromatography, is at least: a) 56% for the syringe after it has been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 1°C for 1.5 months; and / or b) 51% after it has been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 1°C for 2.5 months. Example 20

[0330] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 12, 18 and 19, wherein the syringe contains: a) at least 0.4 mg / ml of polysorbate 20 after it has been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 1°C for 1.5 months; and / or b) at least 0.3 mg / ml of polysorbate 20 after it has been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 1°C for 6 months. Example 21

[0331] X mL of a 150 mg / mL omalizumab formulation for use in any one of Examples 1 to 4 and 20 when not dependent on Example 2 or Example 3, wherein the needle is of one of the following gauges: 23, 24, 25, 26, 27, 28, 29, 30, 31, and 32. Example 22

[0332] X ml of a 150 mg / ml omalizumab formulation for use in any one of Examples 1 to 4 and 20 when they do not depend on Example 2 or Example 3, wherein the needle is one of the following: a) gauge 23 defining a minimum internal diameter of 0.370 mm; b) gauge 23 defining a minimum internal diameter of 0.317 mm; c) gauge 24 defining a minimum internal diameter of 0.343 mm; d) gauge 24 defining a minimum internal diameter of 0.280 mm; e) gauge 25 defining a minimum internal diameter of 0.292 mm; f) gauge 25 defining a minimum internal diameter of 0.232 mm; g) gauge 26 defining a minimum internal diameter of 0.292 mm; h) gauge 26 defining a minimum internal diameter of 0.232 mm; i) gauge 27 defining a minimum internal diameter of 0.277 mm; j) gauge 27 defining a minimum internal diameter of 0.191 mm; k) gauge 27 defining a minimum internal diameter of 0.184 mm; 1) gauge 27 defining a minimum internal diameter of 0.241 mm; m) gauge 28 defining a minimum internal diameter of 0.133 mm; n) gauge 28 defining a minimum internal diameter of 0.190 mm; o) gauge 29 defining a minimum internal diameter of 0.265 mm; p) gauge 29 defining a minimum internal diameter of 0.240 mm; q) gauge 29 defining a minimum internal diameter of 0.190 mm; r) gauge 29 defining a minimum internal diameter of 0.133 mm; s) gauge 30 defining a minimum internal diameter of 0.240 mm; t) gauge 30 defining a minimum internal diameter of 0.190 mm; u) gauge 30 defining a minimum internal diameter of 0.165 mm; v) gauge 30 defining a minimum internal diameter of 0.133 mm; w) gauge 31 defining a minimum internal diameter of 0.176 mm; x) gauge 31 defining a minimum internal diameter of 0.146 mm; y) gauge 31 defining a minimum internal diameter of 0.125 mm; z) gauge 31 defining a minimum internal diameter of 0.114 mm; aa) gauge 32 defining a minimum internal diameter of 0.146 mm; bb) gauge 32 defining a minimum internal diameter of 0.125 mm; ce) gauge 32 defining a minimum internal diameter of 0.105 mm; and dd) gauge 32 defining a minimum internal diameter of 0.089 mm. Example 23

[0333] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 22, wherein the stopper has a fluorinated resin on the product-contacting side or an ethylene-tetrafluoroethylene (ETFE) barrier film lamination. Example 24

[0334] X ml of 150 mg / ml omalizumab formulation for use according to any of Examples 1 to 23, wherein the cap has a UV-cured B2-40 lubricating coating or is lubricated with 1000 cSt silicone oil. Example 25

[0335] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 24, wherein the syringe has an internal coating of 0.4 ± 0.2 mg polydimethylsiloxane. Example 26

[0336] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 25, wherein the needle has 3 bevels on its distal surface or 5 bevels on its distal surface. Example 27

[0337] X ml of a 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 25, wherein the apparent viscosity of the formulation at 150 mg / ml of omalizumab at a shear rate of 200 s 1 is: 24.7 ± 0.5 mPa.s at 5.0 ± 0.2°C, 15.3 ± 0.5 mPa.s at 15.0 ± 0.2°C, 11.4 ± 0.5 mPa.s at 25.0 ± 0.2°C or 7.2 ± 1.2 mPa.s at 40.0 ± 0.2°C. Example 28

[0338] X ml of 150 mg / ml omalizumab formulation for use according to any of Examples 1 to 27, wherein the syringe has a latex-free needle protector. Example 29

[0339] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 28, in which the syringe has a round collar; optionally in which the round collar has a maximum diameter of 11 ± 0.25 mm or 14.7 ± 0.25 mm. Example 30

[0340] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 2 to 4 and 8 to 29 where X is 1 or 0.5, wherein the syringe has a length of 54.0 ± 0.5 mm and an internal diameter of 6.35 mm ± 0.05 mm. Example 31

[0341] X ml of a 150 mg / ml omalizumab formulation for use according to any one of Examples 2 to 4 and 8 to 30 where X is 1 or 0.5, wherein, when the cap is not inserted in the reservoir, it has one of: a) a maximum external diameter of 6.67 mm to 7.10 mm and / or a length of 7.85 ± 0.4 mm; and b) a maximum external diameter of 6.70 ± 0.15 mm and / or a length of 7.85 ± 0.4 mm. Example 32

[0342] X ml of a 150 mg / ml omalizumab formulation for use according to any one of Examples 2 to 4 and 8 to 31 where X is 1 or 0.5, wherein the stopper has at least one rib having an outside diameter of 6.60 ± 0.15 mm. Example 33

[0343] X ml of 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 7 and 13 to 29 where X equals 2, wherein the syringe has a length of 54.0 ± 0.5 mm and an internal diameter of 8.65 mm ± 0.05 mm. Example 34

[0344] X ml of a 150 mg / ml omalizumab formulation for use in any one of Examples 1 to 7, 13 to 29, and 33 where X is 2, wherein the The cap has a maximum external diameter of 9.05 ± 0.15 mm and / or a length of 7.70 ± 0.4 mm when not inserted in the reservoir. Example 35

[0345] X ml of a 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 7, 13 to 29, 33 and 34 where X is 2, wherein the stopper has at least one rib having an outside diameter of 9.00 ±0.15 mm. Example 36

[0346] X ml of a 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 17 and 21 to 35 when they do not depend on Examples 18 to 20, wherein the dislodging force configured to move the stopper of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of: a) approximately 2 N to approximately 4 N after storage at 5°C ± 1°C for 2.5 months; b) approximately 2 N to approximately 4 N after storage at 5°C ± 1°C for 6 months. Example 37

[0347] X ml of a 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 12 and 18 to 35 when they do not depend on Examples 12 to 17, wherein the dislodging force configured to move the stopper of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of: a) approximately 2 N to approximately 3.5 N at 25°C ± 1°C after filling; b) approximately 2 N to approximately 4.5 N after storage at 25°C ± 1°C for 1.5 months; c) about 2.5 N to about 5 N after storage at 25°C ± 1°C for 2.5 months; and / or d) about 2.5 N to about 5.5 N after storage at 25°C ± 1°C for 6 months. Example 38

[0348] X ml of a 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 12 and 21 to 35 when they do not depend on Examples 13 to 20, wherein the dislodging force configured to move the stopper of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of: a) about 3 N to about 4.5 N after storage at 40°C ± 1°C for 1.5 months; and b) about 3 N to about 5 N after storage at 40°C ± 1°C for 2.5 months. Example 39

[0349] X ml of a 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 38, wherein the syringe is supplied in a needle-protective device comprising a needle sleeve and a plunger; and wherein manual force can be applied to the plunger to expel the formulation to 150 mg / ml of omalizumab and unlock the needle sleeve so that the needle sleeve can cover the needle after injection. Example 40

[0350] X ml of a 150 mg / ml omalizumab formulation for use according to any one of Examples 1 to 39, wherein the syringe is manufactured by a process comprising: aseptic filling of the reservoir with the 150 mg / ml formulation of omalizumab; and sealing the tank with the cap. Example 41

[0351] X ml of 150 mg / ml omalizumab formulation for use according to Example 40, wherein aseptic filling is performed using a peristaltic pump or a stainless steel piston pump. Example 42

[0352] X ml of 150 mg / ml omalizumab formulation for use according to Example 40 or 41, wherein, prior to aseptic filling, the reservoir and needle are sterilized by gaseous ethylene oxide treatment, beam-e and / or steam sterilization in an autoclave. Example 43

[0353] A syringe containing: a reservoir filled with X ml of a 150 mg / ml formulation of omalizumab, which X ml of the 150 mg / ml formulation of omalizumab have 6000 or fewer particles having a diameter >10 pm and / or 600 or fewer particles having a diameter > 25 pm; and the syringe further comprising: a stopper, and a needle, the syringe being configured to expel X ml of the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper. Example 44

[0354] A syringe containing: a reservoir filled with X ml of a 150 mg / ml omalizumab formulation, where X ml of the 150 mg / ml omalizumab formulation has 6000 or fewer particles with a diameter >10 pm and / or 600 or fewer particles with a diameter >25 pm; and the syringe further comprising: a stopper, and a 27 gauge needle; and the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper. Example 45

[0355] A syringe containing: a reservoir filled with X ml of a 150 mg / ml omalizumab formulation, where X ml of the 150 mg / ml omalizumab formulation has 6000 or fewer particles with a diameter >10 pm and / or 600 or fewer particles with a diameter >25 pm; where X is 2; and the syringe further comprising: a cork, and a needle, the syringe being configured to expel X ml of the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper. Example 46

[0356] A syringe containing: a reservoir filled with X ml of a 150 mg / ml omalizumab formulation, where X ml of the 150 mg / ml omalizumab formulation has 6000 or fewer particles with a diameter >10 pm and / or 600 or fewer particles with a diameter >25 pm; where X is 0.5, 1, or 2; and the syringe further comprising: a cork, and a 27 gauge needle; and the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper. Example 47

[0357] The syringe of Example 46, in which the needle has one of: a) a minimum internal diameter of 0.277 mm; b) a minimum internal diameter of 0.191 mm; c) a minimum internal diameter of 0.184 mm; and d) a minimum internal diameter of 0.241 mm. Example 48

[0358] A syringe containing: a reservoir filled with X ml of a 150 mg / ml omalizumab formulation, where X ml of the 150 mg / ml omalizumab formulation has 6000 or fewer particles with a diameter >10 pm and / or 600 or fewer particles with a diameter >25 pm; where X is 0.5, 1, or 2; and the syringe further comprising: a cork, and a needle; and the syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper, the syringe being configured to expel the 150 mg / ml formulation of omalizumab through the needle in less than 0.8 seconds per ml per N of constant force applied to the stopper. Example 49

[0359] The syringe according to any one of Examples 45 to 48, in which X is 2, which syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 0.75 ± 0.5 seconds per ml and per N of constant force applied. Example 50

[0360] The syringe according to any one of Examples 45 to 49, in which X is 2, which syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in one or more of the following: a) less than 16 seconds when a constant force of 10 N is applied to the stopper; b) less than 8.5 seconds when a constant force of 17 N is applied to the stopper; and c) less than 5 seconds when a constant force of 30 N is applied to the cap. Example 51

[0361] The syringe according to Example 50, which syringe is configured to expel X ml of the omalizumab formulation contained in the reservoir through the needle in one or more of the following: a) approximately 16 seconds to approximately 14 seconds when a constant force of 10 N is applied to the stopper; b) approximately 8.5 seconds to approximately 6 seconds when a constant force of 17 N is applied to the stopper; and c) approximately 5 seconds to approximately 4 seconds when a constant force of 30 N is applied to the cap. Example 52

[0362] The syringe according to any one of Examples 46 to 48, in which X is 1 or 0.5, which syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in less than 0.67 ± 0.5 seconds per ml and per N of constant force applied, optionally less than 0.54 ± 0.2 seconds per ml and per N of constant force applied, again optionally less than 0.4 ± 0.5 seconds per ml and per N of constant force applied. Example 53

[0363] The syringe according to any one of Examples 46 to 48 and 52, in which X is 1, which syringe is intended to expel X ml of omalizumab 150 mg / ml formulation through the needle in one or more of the following: a) less than 7.5 seconds when a constant force of 10 N is applied to the stopper; b) less than 3 seconds when a constant force of 17 N is applied to the stopper; and c) less than 2 seconds when a constant force of 30 N is applied to the cap. Example 54

[0364] The syringe according to Example 53, which syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of the following: a) less than 7.5 seconds to about 4 seconds when a constant force of 10 N is applied to the cap; b) less than 3.5 seconds to approximately 2 seconds when a constant force of 17 N is applied to the stopper; and c) less than 2 seconds to about 1 second when a constant force of 30 N is applied to the cap. Example 55

[0365] The syringe according to any one of Examples 46 to 48 and 52, in which X is 0.5, which syringe is intended to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of the following: a) less than 4 seconds when a constant force of 10 N is applied to the stopper; b) less than 2 seconds when a constant force of 17 N is applied to the stopper; and c) less than 1 second when a constant force of 30 N is applied to the cap. Example 56

[0366] The syringe according to Example 55, which syringe is intended to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of: a) less than 4 seconds to about 2 seconds when a constant force of 10 N is applied to the stopper; b) less than 2 seconds to approximately 1 second when a constant force of 17 N is applied to the stopper; and c) less than 1 second to about 0.5 seconds when a constant force of 30 N is applied to the cap. Example 57

[0367] The syringe according to any one of Examples 45 to 56, which syringe contains: a) at least 76% of the main charge variant of omalizumab, measured by ion-exchange chromatography, after filling with a 150 mg / ml omalizumab solution stored at 5°C ± 1°C; and / or b) at least 77% of the main charge variant of omalizumab, measured by ion-exchange chromatography, after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 5°C ± 1°C for 2.5 months. Example 58

[0368] The syringe according to any one of Examples 45 to 56, wherein the percentage of main charge variant of omalizumab in the syringe, measured by means of ion-exchange chromatography, is reduced by 2% or less after the syringe has been stored at 5°C ± 1°C for 2.5 months. Example 59

[0369] The syringe according to any one of Examples 45 to 58, in which the proportion of the first peak of the syringe, measured by hydrophobic chromatography, is at least: a) 62% after filling with a 150 mg / ml omalizumab solution stored at 5°C ± 1°C; and / or b) 62% after it was filled with a 150 mg / ml omalizumab solution and then stored at 5°C ± 1°C for 2.5 months. Example 60

[0370] The syringe according to any one of Examples 45 to 59, wherein the proportion of the first peak of the syringe, measured by means of hydrophobic chromatography, is reduced by 0.4% or less after the syringe has been stored at 5°C ± 1°C for 2.5 months. Example 61

[0371] The syringe according to any one of Examples 45 to 60, which syringe contains at least 0.4 mg / ml of polysorbate 20 after filling with a 150 mg / ml omalizumab solution stored at 5°C ± 1°C. Example 62

[0372] The syringe according to any one of Examples 45 to 56, which syringe contains at least 69% of the main charge variant of omalizumab, as measured by ion-exchange chromatography, after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 1°C for 1.5 months. Example 63

[0373] The syringe according to any one of Examples 45 to 56 and 62, in which the proportion of the first peak of the syringe, measured by hydrophobic chromatography, is at least: a) 56% for the syringe after it has been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 1°C for 1.5 months; and / or b) 51% for the syringe after it was filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 1°C for 2.5 months. Example 64

[0374] The syringe according to any one of Examples 45 to 56, 62 and 63, which syringe contains: a) at least 0.4 mg / ml of polysorbate 20 after it has been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 1°C for 1.5 months; and / or b) at least 0.3 mg / ml of polysorbate 20 after it has been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 1°C for 6 months. Example 65

[0375] The syringe according to any one of Examples 45 and 48 to 64 when they do not depend on Example 2 or Example 3, which needle has one of: gauge 23, gauge 24, gauge 25, gauge 26, gauge 27, gauge 28, gauge 29, gauge 30, gauge 31, and gauge 32. Example 66

[0376] The syringe according to any one of Examples 45 and 48 to 64 when they do not depend on Example 2 or Example 3, which needle has one of the following: a) the 23 gauge defining a minimum internal diameter of 0.370 mm; b) gauge 23 defining a minimum internal diameter of 0.317 mm; c) the 24 gauge defining a minimum internal diameter of 0.343 mm; d) the 24 gauge defining a minimum internal diameter of 0.280 mm; e) gauge 25 defining a minimum internal diameter of 0.292 mm; f) gauge 25 defining a minimum internal diameter of 0.232 mm; g) gauge 26 defining a minimum internal diameter of 0.292 mm; h) gauge 27 defining a minimum internal diameter of 0.232 mm; i) gauge 27 defining a minimum internal diameter of 0.277 mm; j) gauge 27 defining a minimum internal diameter of 0.191 mm; k) gauge 27 defining a minimum internal diameter of 0.184 mm; 1) the 27 gauge defining a minimum internal diameter of 0.241 mm; m) the 28 gauge defining a minimum internal diameter of 0.133 mm; n) the 28 gauge defining a minimum internal diameter of 0.190 mm; o) gauge 29 defining a minimum internal diameter of 0.265 mm; p) gauge 29 defining a minimum internal diameter of 0.240 mm; q) gauge 29 defining a minimum internal diameter of 0.190 mm; r) gauge 29 defining a minimum internal diameter of 0.133 mm; s) the 30 gauge defining a minimum internal diameter of 0.240 mm; t) the 30 gauge defining a minimum internal diameter of 0.190 mm; u) the 30 gauge defining a minimum internal diameter of 0.165 mm; v) the 30 gauge defining a minimum internal diameter of 0.133 mm; w) gauge 31 defining a minimum internal diameter of 0.176 mm; x) gauge 31 defining a minimum internal diameter of 0.146 mm; y) gauge 31 defining a minimum internal diameter of 0.125 mm; z) gauge 31 defining a minimum internal diameter of 0.114 mm; aa) the 32 gauge defining a minimum internal diameter of 0.146 mm; bb) gauge 32 defining a minimum internal diameter of 0.125 mm; ce) gauge 32 defining a minimum internal diameter of 0.105 mm; and dd) gauge 32 defining a minimum internal diameter of 0.089 mm. Example 67

[0377] The syringe according to any one of Examples 45 to 66, wherein the stopper has a fluorinated resin on the side coming into contact with the product or a barrier film lamination of ethylene-tetrafluoroethylene (ETFE). Example 68

[0378] The syringe according to any one of Examples 45 to 67, wherein the stopper has a UV-cured B2-40 lubricating coating or is lubricated with a 1000 cSt silicone oil. Example 69

[0379] The syringe according to any one of Examples 45 to 68, which syringe has an internal coating of 0.4 ± 0.2 mg of polydimethylsiloxane. Example 70

[0380] The syringe according to any one of Examples 45 to 69, in which the needle has 3 bevels on its distal surface or 5 bevels on its distal surface. Example 71

[0381] The syringe according to any one of Examples 45 to 70, in which the apparent viscosity of the 150 mg / ml formulation of omalizumab at a shear rate of 200 s 1 is: 24.7 ± 0.5 mPa.s at 5.0 ± 0.2°C, 15.3 ± 0.5 mPa.s at 15.0 ± 0.2°C, 11.4 ± 0.5 mPa.s at 25.0 ± 0.2°C or 7.2 ± 1.2 mPa.s at 40.0 ± 0.2°C. Example 72

[0382] The syringe according to any one of Examples 45 to 71, which syringe has a latex-free needle protector. Example 73

[0383] The syringe according to any one of Examples 45 to 72, which syringe has a round collar; optionally in which the round collar has a maximum diameter of 11 ± 0.25 mm or 14.7 ± 0.25 mm. Example 74

[0384] The syringe according to any one of Examples 46 to 48 and 52 to 73 when X is 1 or 0.5, which syringe has a length of 54.0 ± 0.5 mm and an internal diameter of 6.35 mm ± 0.05 mm. Example 75

[0385] The syringe according to any one of Examples 46 to 48 and 52 to 74 when X equals 1 or 0.5, in which, when the cap is not inserted into the tank, it has one of the following: a) a maximum external diameter of 6.67 mm to 7.10 mm and / or a length of 7.85 ± 0.4 mm; and b) a maximum external diameter of 6.70 ± 0.15 mm and / or a length of 7.85 ± 0.4 mm. Example 76

[0386] The syringe according to any one of Examples 46 to 48 and 52 to 74 when X is 1 or 0.5, in which the stopper has at least one rib having an outside diameter of 6.60 ±0.15 mm. Example 77

[0387] The syringe according to any one of Examples 45 to 51 and 57 to 73 when X equals 2, which syringe has a length of 54.0 ± 0.5 mm and an internal diameter of 8.65 mm ± 0.05 mm. Example 78

[0388] The syringe according to any one of Examples 45 to 51, 57 to 73 and 77 when X equals 2, in which the stopper has a maximum external diameter of 9.05 ±0.15 mm and / or a length of 7.70 ± 0.4 mm when not inserted in the reservoir. Example 79

[0389] The syringe according to any one of Examples 45 to 51, 57 to 73, 77 and 78 when X equals 2, in which the stopper has at least one rib having an outside diameter of 9.00 ±0.15 mm. Example 80

[0390] The syringe according to any one of Examples 45 to 61 and 65 to 79 when they do not depend on Examples 62 to 64, wherein the dislodging force configured to move the stopper of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of: a) approximately 2 N to approximately 4 N after storage at 5°C ± 1°C for 2.5 months; b) approximately 2 N to approximately 4 N after storage at 5°C ± 1°C for 6 months. Example 81

[0391] The syringe according to any one of Examples 45 to 56 and 62 to 79 when they do not depend on Examples 52 to 61, wherein the dislodging force configured to move the stopper of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of: a) approximately 2 N to approximately 3.5 N at 25°C ± 1°C after filling; b) approximately 2 N to approximately 4.5 N after storage at 25°C ± 1°C for 1.5 months; c) about 2.5 N to about 5 N after storage at 25°C ± 1°C for 2.5 months; and / or d) about 2.5 N to about 5.5 N after storage at 25°C ± 1°C for 6 months. Example 82

[0392] The syringe according to any one of Examples 45 to 56 and 65 to 79 when they do not depend on Examples 57 to 64, wherein the dislodging force configured to move the stopper of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of: a) about 3 N to about 4.5 N after storage at 40°C ± 1°C for 1.5 months; and b) about 3 N to about 5 N after storage at 40°C ± 1°C for 2.5 months. Example 83

[0393] The syringe according to any one of Examples 45 to 82, which syringe is supplied in a needle protective device comprising a needle sleeve and a plunger; and wherein manual force can be applied to the plunger to expel the 150 mg / ml formulation of omalizumab and unlock the needle sleeve so that the needle sleeve can cover the needle after injection. Example 84

[0394] The syringe according to any one of Examples 45 to 83, which syringe is manufactured by a process comprising: aseptic filling of the reservoir with the 150 mg / ml formulation of omalizumab; and sealing the tank with the cap. Example 85

[0395] The syringe according to Example 84, in which aseptic filling is carried out by means of a peristaltic pump or a stainless steel piston pump. Example 86

[0396] The syringe according to Example 84 or 85, in which, prior to aseptic filling, the reservoir and the needle are sterilized by treatment with gaseous ethylene oxide, beam-e and / or steam sterilization in an autoclave. Example 87

[0397] The syringe according to Examples 45 to 86, which is usable with an auto-injector. Example 88

[0398] A method for treating a patient with one or more of the following: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 2 ml of a 150 mg / ml formulation of omalizumab, wherein the omalizumab formulation is administered subcutaneously using a syringe, the syringe comprising: a reservoir filled with 2 ml of a 150 mg / ml omalizumab formulation, whereby 2 ml of the 150 mg / ml omalizumab formulation has 6000 or fewer particles having a diameter greater than or equal to 10 µm and / or 600 or fewer particles having a diameter greater than or equal to 25 µm; and the syringe further comprising: a stopper, and a 27 gauge needle; and the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper. Example 89

[0399] The method according to Example 88, wherein the needle has one of: a) a minimum internal diameter of 0.277 mm; b) a minimum internal diameter of 0.191 mm; c) a minimum internal diameter of 0.184 mm; and d) a minimum internal diameter of 0.241 mm. Example 90

[0400] A method for treating a patient with one or more of the following: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient X ml of a 150 mg / ml formulation of omalizumab, where X is 2, 1, or 0.5, and wherein the X ml of the 150 mg / ml formulation of omalizumab are administered subcutaneously using a syringe, the syringe comprising: a reservoir filled with X ml of a 150 mg / ml omalizumab formulation, which X ml of the 150 mg / ml omalizumab formulation have 6000 particles or fewer having a diameter >10 µm and / or 600 particles or fewer having a diameter > 25 µm; and the syringe further comprising: a cork, and a needle from gauge 25 to gauge 29; and the syringe being configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper, wherein one of the following options is satisfied when a constant force of 10 N is applied to the stopper, a) when X equals 2, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 16 seconds; b) when X equals 1, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 5 seconds; and c) when X equals 0.5, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 4 seconds. Example 91

[0401] The method of Example 88 or 90, wherein X is 2, wherein the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in one or more of the following: a) less than 8.5 seconds when a constant force of 17 N is applied to the stopper; and b) less than 5 seconds when a constant force of 30 N is applied to the cap. Example 92

[0402] The method of Example 91, wherein the syringe is configured to expel X ml of the omalizumab formulation contained in the reservoir through the needle in one or more of the following: a) approximately 16 seconds to approximately 14 seconds when a constant force of 10 N is applied to the stopper; b) approximately 8.5 seconds to approximately 6 seconds when a constant force of 17 N is applied to the stopper; and c) approximately 5 seconds to approximately 4 seconds when a constant force of 30 N is applied to the cap. Example 93

[0403] The method of Example 90, wherein X is 1, and wherein the syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of the following: a) less than 5 seconds, less than 4.75 seconds, less than 4.5 seconds, less than 4.25 seconds, or about 4 seconds when a constant force of 10 N is applied to the cap; b) less than 3 seconds when a constant force of 17 N is applied to the stopper; and c) less than 2 seconds when a constant force of 30 N is applied to the cap. Example 94

[0404] The method of Example 93, wherein the syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of the following: a) less than 5 seconds to about 4 seconds, less than 4.75 seconds to about 4 seconds, less than 4.5 seconds to about 4 seconds, less than 4.25 seconds to about 4 seconds, or about 4 seconds when a constant force of 10 N is applied to the cap; b) less than 3.5 seconds to approximately 2 seconds when a constant force of 17 N is applied to the stopper; and c) less than 2 seconds to about 1 second when a constant force of 30 N is applied to the cap. Example 95

[0405] The method of Example 90, wherein X is 0.5, and wherein the syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of the following: a) less than 2 seconds when a constant force of 17 N is applied to the cap; and b) less than 1 second when a constant force of 30 N is applied to the cap. Example 96

[0406] The method of Example 95, wherein the syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of the following: a) less than 4 seconds to about 2 seconds when a constant force of 10 N is applied to the cap; b) less than 2 seconds to approximately 1 second when a constant force of 17 N is applied to the stopper; and c) less than 1 second to about 0.5 seconds when a constant force of 30 N is applied to the cap. Example 97

[0407] The method of Example 88 or Example 90, in which the syringe contains: a) at least 76% of the main charge variant of omalizumab, measured by ion-exchange chromatography, after it has been filled with a 150 mg / ml omalizumab solution stored at 5°C ± 1°C; and / or b) at least 77% of the main charge variant of omalizumab, measured by ion-exchange chromatography, after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 5°C ± 1°C for 2.5 months. Example 98

[0408] The method of Example 88 or Example 90, wherein the percentage of main charge variant of omalizumab in the syringe, measured by means of ion-exchange chromatography, is reduced by 2% or less after the syringe has been stored at 5°C ± 1°C for 2.5 months measured from filling. Example 99

[0409] The method of Example 88 or Example 90, wherein the proportion of the first syringe peak, measured by hydrophobic chromatography, is at least: a) 62% after filling with a 150 mg / ml omalizumab solution stored at 5°C ± 1°C; and / or b) 62% after it was filled with a 150 mg / ml omalizumab solution and then stored at 5°C ± 1°C for 2.5 months. Example 100

[0410] The method of Example 88 or Example 90, wherein the proportion of the first peak of the syringe, measured by means of hydrophobic chromatography, is reduced by 0.4% or less after the syringe has been stored at 5°C ± 1°C for 2.5 months. Example 101

[0411] The method of Example 88 or Example 90, wherein the syringe contains at least 0.4 mg / ml of polysorbate 20 after filling with a 150 mg / ml omalizumab solution stored at 5°C ± 1°C. Example 102

[0412] The method of Example 88 or Example 90, wherein the syringe contains at least 69% of the main charge variant of omalizumab, measured by ion-exchange chromatography, after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 1°C for 1.5 months. Example 103

[0413] The method of Example 88 or Example 90, wherein the proportion of the first syringe peak, measured by hydrophobic chromatography, is at least: a) 56% for the syringe after it has been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 1°C for 1.5 months; and / or b) 51% for the syringe after it was filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 1°C for 2.5 months. Example 104

[0414] The method of Example 88 or Example 90, wherein the syringe contains: a) at least 0.4 mg / ml of polysorbate 20 after it has been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 1°C for 1.5 months; and / or b) at least 0.3 mg / ml of polysorbate 20 after it has been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 1°C for 6 months. Example 105

[0415] The method of Example 90, in which the needle has a gauge of 26 gauge to 29 gauge, especially 27 gauge. Example 106

[0416] The method of Example 105, in which, when the needle is of gauge 25, the needle has one of: a) a minimum internal diameter of 0.292 mm, and b) a minimum internal diameter of 0.232 mm. Example 107

[0417] The method of Example 105, in which, when the needle is of gauge 26, the needle has one of: a) a minimum internal diameter of 0.292 mm, and b) a minimum internal diameter of 0.232 mm. Example 108

[0418] The method of Example 105, in which, when the needle is of gauge 27, the needle has one of: a) a minimum internal diameter of 0.277 mm; b) a minimum internal diameter of 0.191 mm; c) a minimum internal diameter of 0.184 mm; and d) a minimum internal diameter of 0.241 mm. Example 109

[0419] The method of Example 105, in which, when the needle is 28 gauge, the needle has one of: a) a minimum internal diameter of 0.133 mm; and b) a minimum internal diameter of 0.190 mm. Example 110

[0420] The method of Example 105, in which, when the needle is of gauge 29, the needle has one of: a) a minimum internal diameter of 0.265 mm; b) a minimum internal diameter of 0.240 mm; c) a minimum internal diameter of 0.190 mm; and d) a minimum internal diameter of 0.133 mm; preferably the needle has a minimum internal diameter of 0.240 mm or 0.265 mm. Example 111

[0421] The method of Example 88 or Example 90, wherein the stopper has a fluorinated resin on the side coming into contact with the product or a barrier film lamination of ethylene-tetrafluoroethylene (ETFE). Example 112

[0422] The method of Example 88 or Example 90, wherein the stopper has a UV-cured B2-40 lubricating coating or is lubricated with a 1000 cSt silicone oil. Example 113

[0423] The method of Example 88 or Example 90 when X equals 2, wherein the syringe has an internal coating of 0.7 ± 0.2 mg of polydimethylsiloxane. Example 114

[0424] The method of Example 90, when X is 1 or 0.5, wherein the syringe has an internal coating of 0.4 ± 0.2 mg of polydimethylsiloxane. Example 115

[0425] The method of Example 88 or Example 90, in which the needle has 3 bevels on its distal surface or 5 bevels on its distal surface. Example 116

[0426] The method of Example 88 or Example 90, in which the apparent viscosity of the 150 mg / ml formulation of omalizumab is 12 to 14 mPa.s or, when measured at a shear rate of 200 s 1 is: 24.7 ± 0.5 mPa.s at 5.0 ± 0.2°C, 15.3 ± 0.5 mPa.s at 15.0 ± 0.2°C, 11.4 ± 0.5 mPa.s at 25.0 ± 0.2°C or 7.2 ± 1.2 mPa.s at 40.0 ± 0.2°C. Example 117

[0427] The method of Example 88 or Example 90, in which the syringe has a latex-free needle protector. Example 118

[0428] The method of Example 88 or Example 90, in which the syringe has a round collar at a proximal end of the reservoir; possibly in which the round collar has a maximum diameter of 11 ± 0.25 mm or 14.7 ± 0.25 mm. Example 119

[0429] The method of Example 90 when X is 1 or 0.5, in which the syringe has a length of 54.0 ± 0.5 mm and an internal diameter of 6.35 mm ± 0.05 mm. Example 120

[0430] The method of Example 90 in which, when the cap is not inserted into the reservoir, it has one of the following: a) a maximum external diameter of 6.67 mm to 7.10 mm and / or a length of 7.85 ± 0.4 mm; and b) a maximum external diameter of 6.70 ± 0.15 mm and / or a length of 7.85 ± 0.4 mm. Example 121

[0431] The method of Example 90 when X is 1 or 0.5, wherein the stopper has at least one circumferential rib having an outside diameter of 6.60 ±0.15 mm. Example 122

[0432] The method of Example 88 or Example 90 when X equals 2, in which the syringe has a length of 54.0 ± 0.5 mm and an internal diameter of 8.65 mm ± 0.05 mm. Example 123

[0433] The method of Example 88 or Example 90 when X equals 2, in which the stopper has a maximum external diameter of 9.05 ± 0.15 mm and / or a length of 7.70 ± 0.4 mm when not inserted in the reservoir. Example 124

[0434] The method of Example 88 or Example 90 when X equals 2, wherein the stopper has at least one rib having an outside diameter of 9.00 ±0.15 mm. Example 125

[0435] The method of Example 88 or Example 90, wherein the release force configured to move the stopper of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of: a) about 2 N to about 4 N after storage at 5°C ± 1°C for 2.5 months after filling; b) about 2 N to about 4 N after storage at 5°C ± 1°C for 6 months after filling. Example 126

[0436] The method of Example 88 or Example 90, wherein the release force configured to move the plug of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of: a) about 2 N to about 3.5 N at 25°C ± 1°C after filling; b) approximately 2 N to approximately 4.5 N after storage at 25°C ± 1°C for 1.5 months after filling; c) approximately 2.5 N to approximately 5 N after storage at 25°C ± 1°C for 2.5 months after filling; and / or d) approximately 2.5 N to approximately 5.5 N after storage at 25°C ± 1°C for 6 months after filling. Example 127

[0437] The method of Example 88 or Example 90, wherein the dislodging force configured to move the stopper of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of: a) about 3 N to about 4.5 N after storage at 40°C ± 1°C for 1.5 months after filling; and b) about 3 N to about 5 N after storage at 40°C ± 1°C for 2.5 months after filling. Example 128

[0438] The method of Example 88 or Example 90, wherein the syringe is supplied in a needle protective device comprising a needle sleeve and a plunger; and wherein manual force can be applied to the plunger to expel the 150 mg / ml formulation of omalizumab and unlock the needle sleeve so that the needle sleeve can cover the needle after injection. Example 129

[0439] The method of Example 88 or Example 90, wherein the syringe is manufactured by a process comprising: aseptic filling of the reservoir with the 150 mg / ml formulation of omalizumab; and sealing the tank with the cap. Example 130

[0440] The method of Example 129, in which aseptic filling is carried out using a peristaltic pump or a stainless steel piston pump. Example 131

[0441] The method of Example 129, wherein, prior to aseptic filling, the reservoir and the needle are sterilized by treatment with gaseous ethylene oxide, electron beam and / or steam sterilization in an autoclave. Example 132

[0442] A syringe containing: a reservoir filled with X ml of a 150 mg / ml omalizumab formulation, where X is 2, 1, or 0.5, which X ml of the 150 mg / ml omalizumab formulation have 6000 or fewer particles with a diameter >10 µm and / or 600 or fewer particles with a diameter >25 µm; and the syringe further comprising: a stopper, and a 25-gauge to 29-gauge needle, the syringe being configured to expel X ml of the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper, wherein one of the following options is satisfied when a constant force of 10 N is applied to the stopper: a) when X equals 2, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 16 seconds; b) when X equals 1, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 5 seconds; and c) when X equals 0.5, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 4 seconds. Example 133

[0443] The syringe of Example 132, in which X is 1, which syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in less than 5 seconds to about 4 seconds, less than 4.75 seconds to about 4 seconds, less than 4.5 seconds to about 4 seconds, less than 4.25 seconds to about 4 seconds, or about 4 seconds, when a constant force of 10 N is applied to the stopper. Example 134

[0444] A syringe containing: a reservoir filled with X ml of a 150 mg / ml omalizumab formulation, where X is 2, which X ml of the 150 mg / ml omalizumab formulation have 6000 or fewer particles with a diameter >10 pm and / or 600 or fewer particles with a diameter >25 pm; and the syringe further comprising: a stopper, and a 27 gauge needle; and the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper.

[0445] The method of Example 88 or Example 90, or the syringe according to Example 132 or 134, wherein the 150 mg / ml formulation of omalizumab consists of 150 mg / ml of antibody with 42.1 mg / ml of L-arginine hydrochloride, 1.37 mg / ml of L-histidine, 2.34 mg / ml of L-histidine hydrochloride monohydrate, 0.4 mg / ml of polysorbate 20 as an aqueous solution. Example 136

[0446] A method for treating a patient with one or more of the following: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 300 mg of an omalizumab formulation, which method comprises administering 2 ml of 150 mg / ml omalizumab formulation subcutaneously using a single syringe filled with 2 ml of 150 mg / ml omalizumab formulation. Example 137

[0447] A method for treating a patient with one or more of the following: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 375 mg of an omalizumab formulation, which method comprises: administering 2 ml of 150 mg / ml omalizumab formulation subcutaneously using a single syringe filled with 2 ml of 150 mg / ml omalizumab formulation; and the administration of 0.5 ml of 150 mg / ml omalizumab formulation subcutaneously using a single syringe filled with 0.5 ml of 150 mg / ml omalizumab formulation. Example 138

[0448] A method of treating a patient with one or more of the following: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising the administration to the patient of 450 mg of an omalizumab formulation, which method comprises: the administration of 2 ml of a 150 mg / ml omalizumab formulation subcutaneously using a single syringe filled with 2 ml of a 150 mg / ml omalizumab formulation; and administration of 1 ml of 150 mg / ml omalizumab formulation subcutaneously using a single syringe filled with 1 ml of 150 mg / ml omalizumab formulation. Example 139

[0449] A method for treating a patient with one or more of the following: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 525 mg of an omalizumab formulation, which method comprises: administering 2 ml of 150 mg / ml omalizumab formulation subcutaneously using a single syringe filled with 2 ml of 150 mg / ml omalizumab formulation; the administration of 1 ml of the 150 mg / ml omalizumab formulation subcutaneously using a single syringe filled with 1 ml of the 150 mg / ml omalizumab formulation; and administration of 0.5 ml of 150 mg / ml omalizumab formulation subcutaneously using a single syringe filled with 0.5 ml of 150 mg / ml omalizumab formulation. Example 140

[0450] A method for treating a patient with one or more of the following: allergic asthma; food allergy; chronic rhinosinusitis with nasal polyps; chronic spontaneous urticaria; nasal polyps; moderate to severe persistent asthma in patients with a positive skin test or in vitro reactivity to a perennial airborne allergen and symptoms that are inadequately controlled by inhaled corticosteroids, the method comprising administering to the patient 600 mg of an omalizumab formulation, which method comprises: administering 2 ml of a 150 mg / ml omalizumab formulation subcutaneously using a single syringe filled with 2 ml of a 150 mg / ml omalizumab formulation; and administration of 2 ml of 150 mg / ml omalizumab formulation subcutaneously using a single syringe filled with 2 ml of 150 mg / ml omalizumab formulation. Example 141

[0451] The method of any of Examples 136 to 140, wherein any one of the steps requiring the subcutaneous administration of 2 ml of omalizumab 150 mg / ml formulation using a single syringe filled with 2 ml of omalizumab 150 mg / ml formulation, includes the implementation of the method of Example 88 or Example 90 in which X is 2. Example 142

[0452] The method of any one of Examples 137 and 139, wherein any one of the steps requiring the subcutaneous administration of 0.5 ml of 150 mg / ml omalizumab formulation using a single syringe filled with 0.5 ml of 150 mg / ml omalizumab formulation, includes the implementation of the method of Example 90 in which X is 0.5. Example 143

[0453] The method of any one of Examples 138 and 139, wherein any one of the steps requiring the subcutaneous administration of 1 ml of omalizumab 150 mg / ml formulation using a single syringe filled with 1 ml of omalizumab 150 mg / ml formulation, includes the implementation of the method of Example 90 in which X is 1. Example 144

[0454] A syringe containing: a reservoir filled with 2 ml of a 150 mg / ml omalizumab formulation, whereby 2 ml of the 150 mg / ml omalizumab formulation has 6000 or fewer particles having a diameter greater than or equal to 10 µm and / or 600 or fewer particles having a diameter greater than or equal to 25 µm; and the syringe further comprising: a stopper, and a 27 gauge needle; and the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper. Example 145

[0455] The syringe of Example 144, in which the needle has one of: a) a minimum internal diameter of 0.277 mm; b) a minimum internal diameter of 0.191 mm; c) a minimum internal diameter of 0.184 mm; and d) a minimum internal diameter of 0.241 mm. Example 146

[0456] A syringe containing: a reservoir filled with X ml of a 150 mg / ml omalizumab formulation, where X is 2, 1, or 0.5, which X ml of the 150 mg / ml omalizumab formulation have 6000 or fewer particles with a diameter >10 µm and / or 600 or fewer particles with a diameter >25 µm; and the syringe further comprising: a stopper, and a needle from gauge 25 to gauge 29; and which syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper, wherein one of the following options is satisfied when a constant force of 10 N is applied to the stopper, a) when X equals 2, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 16 seconds; b) when X equals 1, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 5 seconds; and c) when X equals 0.5, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in less than 4 seconds. Example 147

[0457] The syringe of Example 144 or 3, wherein X is 2, which syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in one or more of the following: a) less than 8.5 seconds when a constant force of 17 N is applied to the stopper; and b) less than 5 seconds when a constant force of 30 N is applied to the cap. Example 148

[0458] The syringe of Example 147, which syringe is configured to expel X ml of the omalizumab formulation contained in the reservoir through the needle in one or more of the following: a) approximately 16 seconds to approximately 14 seconds when a constant force of 10 N is applied to the stopper; b) approximately 8.5 seconds to approximately 6 seconds when a constant force of 17 N is applied to the stopper; and c) approximately 5 seconds to approximately 4 seconds when a constant force of 30 N is applied to the cap.

[0459] The syringe of Example 146, in which X is 1, which syringe is configured to expel X ml of omalizumab 150 mg / ml formulation through the needle in one or more of the following: a) less than 5 seconds, less than 4.75 seconds, less than 4.5 seconds, less than 4.25 seconds, or about 4 seconds when a constant force of 10 N is applied to the cap; b) less than 3 seconds when a constant force of 17 N is applied to the stopper; and c) less than 2 seconds when a constant force of 30 N is applied to the cap. Example 150

[0460] The syringe of Example 149, which syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of: a) less than 5 seconds to about 4 seconds, less than 4.75 seconds to about 4 seconds, less than 4.5 seconds to about 4 seconds, less than 4.25 seconds to about 4 seconds, or about 4 seconds when a constant force of 10 N is applied to the stopper; b) less than 3.5 seconds to approximately 2 seconds when a constant force of 17 N is applied to the stopper; and c) less than 2 seconds to about 1 second when a constant force of 30 N is applied to the cap. Example 151

[0461] The syringe of Example 146, in which X is 0.5, which syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of the following: a) less than 2 seconds when a constant force of 17 N is applied to the cap; and b) less than 1 second when a constant force of 30 N is applied to the cap. Example 152

[0462] The syringe of Example 151, which syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in one or more of: a) less than 4 seconds to about 2 seconds when a constant force of 10 N is applied to the stopper; b) less than 2 seconds to approximately 1 second when a constant force of 17 N is applied to the stopper; and c) less than 1 second to about 0.5 seconds when a constant force of 30 N is applied to the cap.

[0463] The syringe of Example 144 or Example 146, which syringe contains: a) at least 76% of the main charge variant of omalizumab, as measured by ion-exchange chromatography, after it has been filled with a 150 mg / ml solution of omalizumab stored at 5°C ± 1°C; and / or b) at least 77% of the main charge variant of omalizumab, measured by ion-exchange chromatography, after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 5°C ± 1°C for 2.5 months. Example 154

[0464] The syringe of Example 144 or Example 146, wherein the percentage of omalizumab main charge variant in the syringe, measured by ion-exchange chromatography, is reduced by 2% or less after the syringe has been stored at 5°C ± 1°C for 2.5 months measured from filling. Example 155

[0465] The syringe of Example 144 or Example 146, in which the proportion of the first peak of the syringe, measured by hydrophobic chromatography, is at least: a) 62% after filling with a 150 mg / ml omalizumab solution stored at 5°C ± 1°C; and / or b) 62% after it was filled with a 150 mg / ml omalizumab solution and then stored at 5°C ± 1°C for 2.5 months. Example 156

[0466] The syringe of Example 144 or Example 146, wherein the proportion of the first peak of the syringe, measured by means of hydrophobic chromatography, is reduced by 0.4% or less after the syringe has been stored at 5°C ± 1°C for 2.5 months. Example 157

[0467] The syringe of Example 144 or Example 146, which syringe contains at least 0.4 mg / ml of polysorbate 20 after filling with a 150 mg / ml omalizumab solution stored at 5°C ± 1°C. Example 158

[0468] The syringe of Example 144 or Example 146, which syringe contains at least 69% of the main charge variant of omalizumab, as measured by ion-exchange chromatography, after it has been filled with a 150 mg / ml solution of omalizumab and then stored at 25°C ± 1°C for 1.5 months.

[0469] The syringe of Example 144 or Example 146, in which the proportion of the first peak of the syringe, measured by hydrophobic chromatography, is at least: a) 56% for the syringe after it has been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 1°C for 1.5 months; and / or b) 51% for the syringe after it was filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 1°C for 2.5 months. Example 160

[0470] The syringe of Example 144 or Example 146, which syringe contains: a) at least 0.4 mg / ml of polysorbate 20 after it has been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 1°C for 1.5 months; and / or b) at least 0.3 mg / ml of polysorbate 20 after it has been filled with a 150 mg / ml omalizumab solution and then stored at 25°C ± 1°C for 6 months. Example 161

[0471] The syringe of Example 146, in which the needle has a gauge of 26 gauge to 29 gauge, preferably 27 gauge. Example 162

[0472] The syringe of Example 161, in which, when the needle is 25 gauge, the needle has one of: a) a minimum internal diameter of 0.292 mm, and b) a minimum internal diameter of 0.232 mm. Example 163

[0473] The syringe of Example 161, in which, when the needle is 26 gauge, the needle has one of: a) a minimum internal diameter of 0.292 mm, and b) a minimum internal diameter of 0.232 mm. Example 164

[0474] The syringe of Example 161, in which, when the needle is 27 gauge, the needle has one of: a) a minimum internal diameter of 0.277 mm; b) a minimum internal diameter of 0.191 mm; c) a minimum internal diameter of 0.184 mm; and d) a minimum internal diameter of 0.241 mm. Example 165

[0475] The syringe of Example 161, in which, when the needle is 28 gauge, the needle has one of: a) a minimum internal diameter of 0.133 mm; and b) a minimum internal diameter of 0.190 mm. Example 166

[0476] The syringe of Example 161, in which, when the needle is 29 gauge, the needle has one of: a) a minimum internal diameter of 0.265 mm; b) a minimum internal diameter of 0.240 mm; c) a minimum internal diameter of 0.190 mm; and d) a minimum internal diameter of 0.133 mm; preferably the needle has a minimum internal diameter of 0.240 mm or 0.265 mm. Example 167

[0477] The syringe of Example 144 or Example 146, wherein the stopper has a fluorinated resin on the side coming into contact with the product or a barrier film lamination of ethylene-tetrafluoroethylene (ETFE). Example 168

[0478] The syringe of Example 144 or Example 146, wherein the stopper has a UV-cured B2-40 lubricating coating or is lubricated with a 1000 cSt silicone oil. Example 169

[0479] The syringe of Example 144 or of Example 146 when X is 2, wherein the syringe has an internal coating of 0.7 ± 0.2 mg of polydimethylsiloxane. Example 170

[0480] The syringe of Example 146, when X is 1 or 0.5, which syringe has an internal coating of 0.4 ± 0.2 mg of polydimethylsiloxane. Example 171

[0481] The syringe of Example 144 or Example 146, wherein the needle has 3 bevels on its distal surface or 5 bevels on its distal surface. Example 172

[0482] The syringe of Example 144 or Example 146, in which the apparent viscosity of the 150 mg / ml formulation of omalizumab is 12 to 14 mPa.s or, when measured at a shear rate of 200 s 1 is: 24.7 ± 0.5 mPa.s at 5.0 ± 0.2°C, 15.3 ± 0.5 mPa.s at 15.0 ± 0.2°C, 11.4 ± 0.5 mPa.s at 25.0 ± 0.2°C or 7.2 ± 1.2 mPa.s at 40.0 ± 0.2°C. Example 173

[0483] The syringe of Example 144 or of Example 146, which syringe has a latex-free needle protector. Example 174

[0484] The syringe of Example 144 or Example 146, which syringe has a round collar at a proximal end of the reservoir; optionally wherein the round collar has a maximum diameter of 11 ± 0.25 mm or 14.7 ± 0.25 mm. Example 175

[0485] The syringe of Example 146 when X is 1 or 0.5, which syringe has a length of 54.0 ± 0.5 mm and an internal diameter of 6.35 mm ± 0.05 mm. Example 176

[0486] The syringe of Example 146, in which, when the stopper is not inserted into the reservoir, it has one of: a) a maximum external diameter of 6.67 mm to 7.10 mm and / or a length of 7.85 ± 0.4 mm; and b) a maximum external diameter of 6.70 ± 0.15 mm and / or a length of 7.85 ± 0.4 mm. Example 177

[0487] The syringe of Example 146 when X is 1 or 0.5, wherein the stopper has at least one circumferential rib having an outside diameter of 6.60 ±0.15 mm. Example 178

[0488] The syringe of Example 144 or of Example 146 when X equals 2, which syringe has a length of 54.0 ± 0.5 mm and an internal diameter of 8.65 mm ± 0.05 mm. Example 179

[0489] The syringe of Example 144 or Example 146 when X is 2, in which the stopper has a maximum external diameter of 9.05 ± 0.15 mm and / or a length of 7.70 ± 0.4 mm when not inserted in the reservoir. Example 180

[0490] The syringe of Example 144 or of Example 146 when X equals 2, in which the stopper has at least one rib having an outside diameter of 9.00 ±0.15 mm. Example 181

[0491] The syringe of Example 144 or Example 146, wherein the release force configured to move the stopper of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of: a) about 2 N to about 4 N after storage at 5°C ± 1°C for 2.5 months after filling; b) about 2 N to about 4 N after storage at 5°C ± 1°C for 6 months after filling. Example 182

[0492] The syringe of Example 144 or Example 146, wherein the dislodging force configured to move the stopper of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of: a) about 2 N to about 3.5 N at 25°C ± 1°C after filling; b) approximately 2 N to approximately 4.5 N after storage at 25°C ± 1°C for 1.5 months after filling; c) approximately 2.5 N to approximately 5 N after storage at 25°C ± 1°C for 2.5 months after filling; and / or d) approximately 2.5 N to approximately 5.5 N after storage at 25°C ± 1°C for 6 months after filling. Example 183

[0493] The syringe of Example 144 or Example 146, wherein the dislodging force configured to displace the stopper of the present invention from an initial fixed point at a speed of 190 mm / min is one or more of: a) about 3 N to about 4.5 N after storage at 40°C ± 1°C for 1.5 months after filling; and b) about 3 N to about 5 N after storage at 40°C ± 1°C for 2.5 months after filling. Example 184

[0494] The syringe of Example 144 or Example 146, which syringe is supplied in a needle protective device comprising a needle sleeve and a plunger; and wherein manual force can be applied to the plunger to expel the 150 mg / ml formulation of omalizumab and unlock the needle sleeve so that the needle sleeve can cover the needle after injection. Example 185

[0495] The syringe of Example 144 or Example 146, which syringe is manufactured by a process comprising: aseptic filling of the reservoir with the 150 mg / ml formulation of omalizumab; and sealing the tank with the cap. Example 186

[0496] The syringe of Example 185, in which aseptic filling is carried out by means of a peristaltic pump or a stainless steel piston pump. Example 187

[0497] The syringe of Example 185, in which, prior to aseptic filling, the reservoir and the needle are sterilized by treatment with gaseous ethylene oxide, electron beam and / or steam sterilization in an autoclave. Example 188

[0498] The syringe of Example 146, in which X is 1, which syringe is configured to expel X ml of 150 mg / ml omalizumab formulation through the needle in less than 5 seconds to about 4 seconds, less than 4.75 seconds to about 4 seconds, less than 4.5 seconds to about 4 seconds, less than 4.25 seconds to about 4 seconds, or about 4 seconds, when a constant force of 10 N is applied to the stopper. Example 189

[0499] The syringe of Example 144 or Example 146, wherein the 150 mg / ml formulation of omalizumab consists of 150 mg / ml of antibody with 42.1 mg / ml of L-arginine hydrochloride, 1.37 mg / ml of L-histidine, 2.34 mg / ml of L-histidine hydrochloride monohydrate, 0.4 mg / ml of polysorbate 20 as an aqueous solution.

Claims

Demands

1. Syringe (11, 21, 31, 41) comprising: a reservoir (12, 22, 32, 42) filled with X mL of a 150 mg / mL omalizumab formulation, with X equal to 2, 1 or 0.5, the formulation containing 150 mg / mL of antibody with 42.1 mg / mL of L-arginine hydrochloride, 1.37 mg / mL of L-histidine, 2.34 mg / mL of L-histidine hydrochloride monohydrate, 0.4 mg / mL of polysorbate 20 in aqueous solution; and the formulation having 6000 or fewer particles of a diameter greater than or equal to 10 pm and / or 600 or fewer particles of a diameter greater than or equal to 25 pm; the syringe (11, 21, 31, 41) further comprising: a stopper (15, 25, 35, 45), and a needle (13, 23, 33, 43) having a length of 12.7 mm, being of gauge 27, having a minimum internal diameter of 0.277 mm, and having 5 bevels on its distal surface;and the syringe (11, 21, 31, 41) being configured to expel the formulation contained in the reservoir (12, 22, 32, 42) through the needle (13, 23, 33, 43) when a force is applied to the stopper (15, 25, 35, 45), one of the following conditions being met when a constant force of 10 N is applied to the stopper (15, 25, 35, 45): a. when X is equal to 2, the syringe (11, 21, 31, 41) is configured to expel the formulation through the needle (13, 23, 33, 43) in less than 16 seconds; b. when X is equal to 1, the syringe (11, 21, 31, 41) is configured to expel the formulation through the needle (13, 23, 33, 43) in less than 7.5 seconds; c. when X is equal to 0.5, the syringe (11, 21, 31, 41) is configured to expel the formulation through the needle (13, 23, 33, 43) in less than 4 seconds.

2. Syringe according to claim 1, wherein X is equal to 2, and the syringe (11, 21, 31, 41) is configured to expel the formulation contained in the reservoir (12, 22, 32, 42) through the needle (13, 23, 33, 43) according to one or more of the following options: a. in less than 8.5 seconds when a constant force of 17 N is applied to the cap (15, 25, 35, 45); and b. in less than 5 seconds when a constant force of 30 N is applied to the cap (15, 25, 35, 45).

3. Syringe according to claim 2, further configured to expel the formulation contained in the reservoir (12, 22, 32, 42) through the needle (13, 23, 33, 43) according to one or more of the following options: a. between approximately 16 seconds and approximately 14 seconds when a constant force of 10 N is applied to the cap (15, 25, 35, 45); b. between approximately 8.5 seconds and approximately 6 seconds when a constant force of 17 N is applied to the cap (15, 25, 35, 45); and c. between about 5 seconds and about 4 seconds when a constant force of 30 N is applied to the cap (15, 25, 35, 45).

4. Syringe according to claim 1, wherein X is equal to 1, and the syringe (11, 21, 31, 41) is configured to expel the formulation through the needle (13, 23, 33, 43) according to one or more of the following options: a) in less than 3 seconds when a constant force of 17 N is applied to the cap (15, 25, 35, 45); and b) in less than 2 seconds when a constant force of 30 N is applied to the cap (15, 25, 35, 45).

5. Syringe according to claim 4, further configured to expel the formulation through the needle (13, 23, 33, 43) according to one or more of the following options: a) between less than 7.5 seconds and about 4 seconds when a constant force of 10 N is applied to the cap (15, 25, 35, 45); b) between less than 3.5 seconds and about 2 seconds when a constant force of 17 N is applied to the cap (15, 25, 35, 45); and c) between less than 2 seconds and about 1 second when a constant force of 30 N is applied to the cap (15, 25, 35, 45).

6. Syringe according to claim 1, wherein X is equal to 0.5, and the syringe (11, 21, 31, 41) is configured to expel the formulation through the needle (13, 23, 33, 43) according to one or more of the following options: a. in less than 2 seconds when a constant force of 17 N is applied to the cap (15, 25, 35, 45); and b. in less than 1 second when a constant force of 30 N is applied to the cap (15, 25, 35, 45).

7. Syringe according to claim 6, further configured to expel the formulation through the needle (13, 23, 33, 43) according to one or more of the following options: a. between less than 4 seconds and about 2 seconds when a constant force of 10 N is applied to the cap (15, 25, 35, 45); b. between less than 2 seconds and about 1 second when a constant force of 17 N is applied to the cap (15, 25, 35, 45); and c. between less than 1 second and about 0.5 seconds when a constant force of 30 N is applied to the cap (15, 25, 35, 45).

8. Syringe according to any one of claims 1 to 7, wherein the syringe (11, 21, 31, 41) contains: a. at least 76% of the main charge variant of omalizumab, as measured by ion-exchange chromatography after filling with a 150 mg / mL omalizumab solution and storage at 5 °C ± 1 °C; and / or b. at least 77% of the main charge variant of omalizumab, as measured by ion-exchange chromatography after filling with a 150 mg / mL omalizumab solution and then storage at 5 °C ± 1 °C for 2.5 months.

9. Syringe according to any one of claims 1 to 7, wherein the percentage of main charge variant of romalizumab in the syringe (11, 21, 31, 41), measured by ion-exchange chromatography, decreases by 2% or less after storage at 5°C ± 1°C for 2.5 months.

10. Syringe according to any one of claims 1 to 9, wherein the proportion of the first peak of the syringe (11,21,31,41), measured by hydrophobic chromatography, is at least: a. 62% after filling with a 150 mg / mL omalizumab solution stored at 5 °C ± 1 °C; and / or b. 62% after filling with a 150 mg / mL omalizumab solution, then stored at 5 °C ± 1 °C for 2.5 months.

11. Syringe according to any one of claims 1 to 10, wherein the proportion of the first peak of the syringe (11,21,31,41), measured by hydrophobic chromatography, decreases by 0.4% or less after storage at 5°C ± 1°C for 2.5 months.

12. Syringe according to any one of claims 1 to 11, wherein the syringe (11,21,31,41) contains at least 0.4 mg / mL of polysorbate 20 after filling with a 150 mg / mL omalizumab solution stored at 5 °C ± 1 °C.

13. Syringe according to any one of claims 1 to 8, wherein the syringe (11, 21, 31, 41) contains at least 69% of the main loading variant of romalizumab, as measured by ion-exchange chromatography after filling with a 150 mg / mL omalizumab solution and then storage at 25 °C ± 1 °C for 1.5 months.

14. Syringe according to any one of claims 1 to 8 and 13, wherein the proportion of the first peak of the syringe (11,21,31,41), measured by hydrophobic chromatography, is at least: a. 56% after filling with a 150 mg / mL omalizumab solution, then stored at 25 °C ± 1 °C for 1.5 months; and / or b. 51% after filling with a 150 mg / mL omalizumab solution, then stored at 25 °C ± 1 °C for 2.5 months.

15. Syringe according to any one of claims 1 to 8, 13 and 14, wherein the syringe contains: a. at least 0.4 mg / mL of polysorbate 20 after filling with a 150 mg / mL omalizumab solution, then stored at 25 °C ± 1 °C for 1.5 months; and / or b. at least 0.3 mg / mL of polysorbate 20 after filling with a 150 mg / mL omalizumab solution, then stored at 25 °C ± 1 °C for 6 months.

16. Syringe according to any one of claims 1 to 15, wherein the stopper (15, 25, 35, 45) has a fluorinated resin on the side coming into contact with the product or a barrier film lamination of ethylene-tetrafluoroethylene (ETFE).

17. Syringe according to any one of claims 1 to 16, wherein the stopper (15, 25, 35, 45) has a UV-cured B2-40 lubricating coating or is lubricated with a 1000 cSt silicone oil.

18. Syringe according to any one of claims 1 to 3 and 8 to 17, wherein X is equal to 2, and the syringe has an internal coating of 0.7 ± 0.2 mg of polydimethylsiloxane.

19. Syringe according to any one of claims 1 to 17, wherein the syringe has an internal coating of 0.4 ± 0.2 mg of polydimethylsiloxane.

20. Syringe according to any one of claims 1 to 19, wherein the apparent viscosity of the omalizumab formulation at 150 mg / mL at a shear rate of 200 S-1 is: 24.7 ± 0.5 mPa-s at 5.0 ± 0.2 °C, 15.3 ± 0.5 mPa-s at 15.0 ± 0.2 °C, 11.4 ± 0.5 mPa-s at 25.0 ± 0.2 °C, or 7.2 ± 1.2 mPa-s at 40.0 ± 0.2 °C.

21. Syringe according to any one of claims 1 to 20, wherein the syringe (11, 21, 31, 41) has a latex-free needle protector (60).

22. Syringe according to any one of claims 1 to 21, wherein the syringe (11, 21, 31, 41) has a round collar (14, 24, 34, 44) preferably having a maximum diameter of 11 ± 0.25 mm or 14.7 ± 0.25 mm.

23. Syringe according to any one of claims 1, 4 to 17 and 19 to 22, wherein, when X is equal to 1 or 0.5, the syringe (11, 21, 31, 41) has a length of 54.0 ± 0.5 mm and an internal diameter of 6.35 ± 0.05 mm.

24. Syringe according to any one of claims 1, 4 to 17 and 19 to 22, wherein, when X is equal to 1 or 0.5, the stopper (15, 25, 35, 45), when not inserted into the reservoir (12, 22, 32, 42), has one of: a maximum external diameter of 6.67 mm to 7.10 mm and / or a length of 7.85 ± 0.4 mm; and a maximum external diameter of 6.70 ± 0.15 mm and / or a length of 7.85 ± 0.4 mm.

25. Syringe according to any one of claims 1, 4 to 17 and 19 to 22, wherein, when X is equal to 1 or 0.5, the stopper (15, 25, 35, 45) has at least one rib with an external diameter of 6.60 ±0.15 mm.

26. Syringe according to any one of claims 1 to 3 and 8 to 23, wherein, when X equals 2, the syringe has a length of 54.0 ± 0.5 mm and an internal diameter of 8.65 ± 0.05 mm.

27. ​​Syringe according to any one of claims 1 to 3, 8 to 22 and 26, wherein, when X equals 2, the stopper (15, 25, 35, 45) has a maximum external diameter of 9.05 ±0.15 mm and / or a length of 7.70 ± 0.4 mm when not inserted into the reservoir.

28. Syringe according to any one of claims 1 to 3, 8 to 22 and 26 to 27, wherein, when X equals 2, the stopper (15, 25, 35, 45) has at least one rib with an external diameter of 9.00 ± 0.15 mm.

29. Syringe according to any one of claims 1 to 12 and 16 to 28, when not dependent on claims 13 to 15, wherein the dislodgement force configured to move the stopper (15, 25, 35, 45) from an initial fixed point up to a velocity of 190 mm / min is at least one of: about 2 N to about 4 N after storage at 5 °C ± 1 °C for 2.5 months; about 2 N to about 4 N after storage at 5 °C ± 1 °C for 6 months.

30. Syringe according to any one of claims 1 to 7 and 13 to 19, when it does not depend on claims 8 to 12, wherein the dislodging force configured to move the stopper (15, 25, 35, 45) at a speed of 190 mm / min is at least one of: about 2 N to about 3.5 N at 25 °C ± 1 °C after filling; about 2 N to about 4.5 N after storage at 25 °C ± 1 °C for 1.5 months; about 2.5 N to about 5 N after storage at 25 °C ± 1 °C for 2.5 months; and / or about 2.5 N to about 5.5 N after storage at 25 °C ± 1 °C for 6 months.

31. Syringe according to any one of claims 1 to 7 and 16 to 28, when not dependent on claims 8 to 15, wherein the dislodgement force configured to dislodge the stopper (15, 25, 35, 45) at a speed of 190 mm / min is at least one of: about 3 N to about 4.5 N after storage at 40 °C ± 1 °C for 1.5 months; and about 3 N to about 5 N after storage at 40 °C ± 1 °C for 2.5 months.

32. Syringe according to any one of claims 1 to 31, wherein the syringe (11, 21, 31, 41) is provided in a needle protective device (60) comprising a needle sleeve (55) and a piston (51); and wherein a manual force can be applied to the piston (51) to expel the formulation and release the needle sleeve (55) so that it can cover the needle (13, 23, 33, 43) after injection.

33. Syringe according to any one of claims 1 to 32, wherein the syringe (11, 21, 31, 41) is manufactured according to a process comprising: - aseptic filling of the reservoir (12, 22, 32, 42) with the formulation of omalizumab at 150 mg / mL; and - capping of the reservoir (12, 22, 32, 42) using the stopper (15, 25, 35, 45).

34. Syringe according to claim 33, wherein aseptic filling is carried out using a peristaltic pump or a stainless steel piston pump.

35. Syringe according to claim 33 or 34, wherein, prior to aseptic filling, the reservoir (12, 22, 32, 42) and the needle (13, 23, 33, 43) are sterilized by treatment with ethylene oxide gas, by electron beam and / or by steam sterilization in an autoclave.

Images