EP4683947A1 - Neue verwendungen von omalizumab - Google Patents

Neue verwendungen von omalizumab

Info

Publication number
EP4683947A1
EP4683947A1 EP24748362.1A EP24748362A EP4683947A1 EP 4683947 A1 EP4683947 A1 EP 4683947A1 EP 24748362 A EP24748362 A EP 24748362A EP 4683947 A1 EP4683947 A1 EP 4683947A1
Authority
EP
European Patent Office
Prior art keywords
omalizumab
formulation
syringe
seconds
needle
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24748362.1A
Other languages
English (en)
French (fr)
Inventor
Maria Chaikou
Mathieu Paul-Léon Rigollet
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Genentech Inc
Original Assignee
Novartis AG
Genentech Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from EP24183812.7A external-priority patent/EP4497758A1/de
Application filed by Novartis AG, Genentech Inc filed Critical Novartis AG
Publication of EP4683947A1 publication Critical patent/EP4683947A1/de
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/42—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against immunoglobulins
    • C07K16/4283—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an allotypic or isotypic determinant on Ig
    • C07K16/4291—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an allotypic or isotypic determinant on Ig against IgE
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Definitions

  • the present disclosure relates to methods of treating a patient with one or more 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids, the method comprising administering 150mg/mL omalizumab formulation to the patient, wherein the omalizumab formulation is administered subcutaneously by a syringe.
  • the present disclosure also relates to 150mg/mL omalizumab formulation for use according to the methods described herein.
  • Omalizumab is a recombinant DNA-derived humanized lgG1k monoclonal antibody that selectively binds to human immunoglobulin E (IgE) and is used to treat allergic asthma, chronic hives and nasal polyps, IgE-mediated food allergy, and chronic spontaneous urticaria.
  • IgE immunoglobulin E
  • XOLAIR® lyophilized powder When omalizumab first entered the market in 2003, it was available only as a dry lyophilized powder (XOLAIR® lyophilized powder). To administer XOLAIR® to a patient, it was necessary to reconstitute the powder with sterile water and then inject the resulting solution.
  • the process for reconstituting XOLAIR® lyophilized powder comprises introducing 0.9 or 1 ,4mL water for injection to a vial of 75 or 150mg lyophilized powder, respectively, and swirling the vial for 5 to 10 seconds approximately every 5 minutes over the course of around 15 to 20 minutes to allow the powder to dissolve completely.
  • XOLAIR® lyophilized powder can be administered only by a healthcare professional, limiting ease of use and patient experience.
  • this reconstituted formulation is about 80 fold more viscous than water at 25 °C.
  • omalizumab After initial authorization omalizumab (XOLAIR®) became available as a 75mg/0.5mL and 150mg/1 mL solution in a single-dose prefilled syringe for subcutaneous delivery, the syringe having a needle of gauge 26. This eliminated the need for reconstitution immediately before administration, greatly improving ease of use, patient experience and, ultimately, patient compliance and outcomes. Furthermore, XOLAIR® was approved for self-injection, further improving ease of use. Subcutaneous injection of 150mg/mL omalizumab formulation offers advantages (Shi et al. Subcutaneous Injection Performance in Yucatan Miniature Pigs with and without Human Hyaluronidase and Auto-injector Tolerability in Humans. AAPS PharmSciTech.
  • 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 patients and healthcare professionals alike.
  • omalizumab is usually administered in a dosage of 150mg to 375mg subcutaneously every 2 to 4 weeks but only 15% to 20% of patients can receive their XOLAIR® treatment with one single injection using the currently available 75mg/0.5mL and 150mg/1 mL doses.
  • omalizumab formulations are highly viscous and so subcutaneous injection using the currently available prefilled syringes requires high injection forces and long injection times. As a result, patients and caregivers can lack the ability to complete injections of omalizumab with confidence.
  • omalizumab injections can cause injection site reactions - indeed, in patients with asthma, injection site reactions of any severity occur at a rate of 45% and severe injection site reactions occur at a rate of 12%. This problem is exacerbated by the requirement to administer each injection at a new injection site and that 80% to 85% of patients must administer the contents of multiple syringes to achieve their prescribed dose.
  • Each of these difficulties negatively impact patient experience and convenience and so negatively impact patient adherence to omalizumab treatment.
  • chronic illnesses such as those treated by omalizumab, non-adherence is estimated at around 50% (Baryakova et al. ‘Overcoming barriers to patient adherence: the case for developing innovative drug delivery systems’. Nature Reviews Drug Discovery. March 2023; volume 22, pages 387-409) . Therefore, there is a need to address the above difficulties to improve ease of use and patient experience and so improve patient adherence and outcomes.
  • omalizumab for use in treating of one or more of: 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids.
  • the antibody is subcutaneously administered as a 150mg/mL omalizumab formulation to the patient, by a syringe having a reservoir filled with 0.5mL or 1mL of 150mg/mL omalizumab formulation.
  • the XOLAIR® formulation is 150mg/mL antibody with 42.1 mg/mL L-arginine hydrochloride, 1.37mg/mL L-histidine, 2.34mg/mL L-histidine hydrochloride monohydrate, 0.4mg/mL polysorbate 20 as an aqueous solution (in sterile water for injection (USP)).
  • Omalizumab XOLAIR® 75mg/0.5mL, 150mg/1mL and 300mg/2mL all have the same formulation, with the high 150mg/mL antibody concentration.
  • the viscosity of omalizumab XOLAIR® is 12 to 14 mPa-s at room temperature.
  • viscosity measured at a shear rate of 200s _1 was: 24.7 ⁇ 0.5 mPa-s at of 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.
  • X mL of 150mg/mL omalizumab formulation for use in a method of treatment of one or more 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids, wherein X is 2 and wherein the X mL 150mg/mL omalizumab formulation is administered subcutaneously by a syringe, the syringe comprising: a reservoir filled with X mL of 150mg/mL omalizumab formulation, wherein the X mL 150mg/mL omalizumab formulation has
  • Providing a syringe containing 2mL of 150mg/mL omalizumab formulation reduces the number of individual injections required per treatment for patients who are prescribed a dose larger than 150mg omalizumab. Reduced dosing frequency improves patient adherence and experience (Baryakova et al. 2023). In addition, a lower number of injections leads to 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 using omalizumab.
  • providing a syringe containing a needle of gauge 27 reduces the time required to deliver the omalizumab as compared to the currently available syringes. In this way, the present invention reduces the injection time required to administer the dose.
  • the needle gauge is larger than in the prior art, the needle of the present invention has a smaller outer diameter, reducing pain during needle insertion.
  • the present invention improves ease of use, patient experience, patient adherence and outcomes using omalizumab.
  • the needle has one of: a) a minimum internal diameter of 0.277mm; b) a minimum internal diameter of 0.191mm; c) a minimum internal diameter of 0.184mm; and d) a minimum internal diameter of 0.241mm.
  • the invention reduces the injection forces required, improving ease of use and making it more likely that a complete dose will be administered. Hence, the present invention improves ease of use, patient experience, patient adherence and outcomes using omalizumab.
  • the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in one or more of: a) less than 8.5 seconds when a constant force of 17N is applied to the stopper; and b) less than 5 seconds when a constant force of 30N is applied to the stopper.
  • 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 10N is applied to the stopper; b) about 8.5 seconds to about 6 seconds when a constant force of 17N is applied to the stopper; and c) about 5 seconds to about 4 seconds when a constant force of 30N is applied to the stopper.
  • the syringe is to expel X mL of 150mg/ml omalizumab formulation through the needle in one or more of: a) less than 3 seconds when a constant force of 17N is applied to the stopper; and b) less than 2 seconds when a constant force of 30N is applied to the stopper.
  • the syringe is configured to expel X mL of 150mg/ml omalizumab formulation through the needle in one or more of: a) less than 7.5 seconds to about 4 seconds when a constant force of 10N is applied to the stopper; b) less than 3.5 seconds to about 2 seconds when a constant force of 17N is applied to the stopper; and c) less than 2 seconds to about 1 second when a constant force of 30N is applied to the stopper.
  • the syringe is configured to expel X mL of 150mg/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 in about 4 seconds when a constant force of 10N is applied to the stopper.
  • the syringe is configured to expel X mL of 150mg/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 in about 4 seconds when a constant force of 10N is applied to the stopper.
  • the syringe is to expel X mL of 150mg/ml omalizumab formulation through the needle in one or more of: a) less than 2 seconds when a constant force of 17N is applied to the stopper; and b) less than 1 second when a constant force of 30N is applied to the stopper.
  • the syringe is to expel X mL of 150mg/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 10N is applied to the stopper; b) less than 2 seconds to about 1 second when a constant force of 17N is applied to the stopper; and c) less than 1 second to about 0.5 seconds when a constant force of 30N is applied to the stopper.
  • the syringe contains: a) at least 76% main omalizumab charge variant measured by ion exchange chromatography after being filled with 150mg/mL omalizumab solution stored at 5°C ⁇ 3°C; and/or b) at least 77% main omalizumab charge variant measured by ion exchange chromatography after being filled with 150mg/mL omalizumab solution and then stored at 5°C ⁇ 3°C for 2.5 months.
  • the percentage of main omalizumab charge variant in the syringe measured by ion exchange chromatography reduces by 2% or less after the syringe is stored at 5°C ⁇ 3°C for 2.5 months (e.g.measured from filling).
  • the proportion of the first peak of the syringe measured by hydrophobic interaction chromatography is at least: a) 62% after filling with 150mg/mL omalizumab solution stored at 5°C ⁇ 3°C; and/or b) 62% after being filled with 150mg/mL omalizumab solution and then stored at 5°C ⁇ 3°C for 2.5 months.
  • the proportion of the first peak of the syringe measured by hydrophobic interaction chromatography reduces by 0.4% or less after the syringe is stored at 5°C ⁇ 3°C for 2.5 months.
  • the syringe contains at least 0.4 mg/mL polysorbate 20 after filling with 150mg/mL omalizumab solution stored at 5°C ⁇ 3°C.
  • the syringe contains at least 69% main omalizumab charge variant measured by ion exchange chromatography after being filled with 150mg/mL omalizumab solution and then stored at 25°C ⁇ 3°C for 1.5 months.
  • the proportion of the first peak of the syringe measured by hydrophobic interaction chromatography is at least: a) 56% for the syringe after being filled with 150mg/mL omalizumab solution and then stored at 25°C ⁇ 3°C for 1 .5 months; and/or b) 51% for the syringe after being filled with 150mg/mL omalizumab solution and then stored at 25°C ⁇ 3°C for 2.5 months.
  • the syringe contains: a) at least 0.4mg/mL polysorbate 20 after being filled with 150mg/mL omalizumab solution and then stored at 25°C ⁇ 3°C for 1.5 months; and/or b) at least 0.3mg/mL polysorbate 20 after being filled with 150mg/mL omalizumab solution and then stored at 25°C ⁇ 3°C for 6 months.
  • Percentage of main omalizumab charge variant, hydrophobic interaction chromatography peak, and polysorbate 20 content are measures of omalizumab purity and stability. As will be demonstrated below, the present invention preserves the purity and stability of omalizumab similarly to current uses.
  • the 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.
  • the needle has one of: a) gauge 23 defining a minimum internal diameter of 0.370mm, b) gauge 23 defining a minimum internal diameter of 0.317mm, c) gauge 24 defining a minimum internal diameter of 0.343mm, d) gauge 24 defining a minimum internal diameter of 0.280mm, e) gauge 25 defining a minimum internal diameter of 0.292mm, f) gauge 25 defining a minimum internal diameter of 0.232mm, g) gauge 26 defining a minimum internal diameter of 0.292mm, h) gauge 26 defining a minimum internal diameter of 0.232mm, i) gauge 27 defining a minimum internal diameter of 0.277mm; j) gauge 27 defining a minimum internal diameter of 0.191 mm; k) gauge 27 defining a minimum internal diameter of 0.184mm; l) gauge 27 defining a minimum internal diameter of 0.241 mm; m) gauge 28 defining a minimum internal diameter of 0.133mm, n) gauge 28 defining a minimum internal diameter of 0.370mm,
  • the needle has a gauge of gauge 25 to gauge 29, preferably gauge 26 to gauge 28, most preferably gauge 27.
  • the needle when the needle has a gauge of 25, the needle has one of: a) a minimum internal diameter of 0.292mm, and b) a minimum internal diameter of 0.232mm.
  • the needle when the needle has a gauge of 26, the needle has one of: a) a minimum internal diameter of 0.292mm; and b) a minimum internal diameter of 0.232mm.
  • the needle when the needle has a gauge of 27, the needle has one of: a) a minimum internal diameter of 0.277mm; b) a minimum internal diameter of 0.191mm; c) a minimum internal diameter of 0.184mm; and d) a minimum internal diameter of 0.241mm. In some embodiments when the needle has a gauge of 28, the needle has one of: a) a minimum internal diameter of 0.133mm; and b) a minimum internal diameter of 0.190mm.
  • the needle when the needle has a gauge of 29, the needle has one of: a) a minimum internal diameter of 0.265mm; b) a minimum internal diameter of 0.240mm; c) a minimum internal diameter of 0.190mm; and d) a minimum internal diameter of 0.133mm; preferably wherein the needle has a minimum internal diameter of 0.240mm or 0.265mm.
  • the needle has a gauge of 29. In another preferred embodiment of the invention, the needle has a gauge of 29 and a minimum internal diameter of 0.240mm. In another preferred embodiment of the invention, the needle has a gauge of 29 and a minimum internal diameter of 0.265mm.
  • the stopper has a fluoro-resin on the product contacting side or an ethylene tetrafluoroethylene (ETFE) barrier film lamination.
  • EFE ethylene tetrafluoroethylene
  • the lamination of the stopper reduces friction, reducing injection forces, reducing injection time and making it more likely that a complete dose will be administered. In this way, the present invention improves ease of use, patient experience, patient adherence and outcomes using omalizumab.
  • the lamination helps to prevent contamination between the material of the stopper and omalizumab, preserving the stability and purity of the omalizumab.
  • the stopper has a B2-40 UV cured lubrication coating or is lubricated with 1000cSt silicone oil.
  • the coating of the stopper reduces friction, reducing injection forces and reducing injection time and making it more likely that a complete dose will be administered. In this way, the present invention improves ease of use, patient experience, patient adherence and outcomes using omalizumab.
  • the coating of the stopper helps to prevent contamination between the material of the stopper and omalizumab, preserving the stability and purity of the omalizumab.
  • the syringe has an internal coating of between 0.3-1.0 mg (e.g. 0.4 ⁇ 0.2mg or 0.7 ⁇ 0.2mg) of polydimethylsiloxane.
  • the internal coating of the syringe reduces friction, reducing injection forces, reducing injection time and making it more likely that a complete dose will be administered. In this way, the present invention improves ease of use, patient experience, patient adherence and outcomes using omalizumab.
  • the internal coating of the syringe helps to preserve the stability and purity of the omalizumab.
  • the needle has 3 bevels on its distal surface or 5 bevels on its distal surface.
  • the bevelled distal surface reduces needle insertion pain, improving patient experience and so patient adherence and outcomes.
  • the apparent viscosity of the 150mg/mL omalizumab formulation at a shear rate of 200s -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.
  • the syringe has a latex-free needle shield.
  • the latex-free needle shield reduces risk of injection site reaction, improving patient experience and so patient adherence and outcomes.
  • the syringe has a round flange at a proximal end of the reservoir.
  • the round flange has a maximum diameter of 11 ⁇ 0.25mm or 14.7 ⁇ 0.25mm. The round flange helps the syringe to better withstand high injection forces, reducing the risk of syringe breakage and improving patient experience. This is particularly advantageous when the syringe of the present invention is used in combination with an autoinjector which holds syringe by the flange.
  • the syringe when X is 1 or 0.5, has a length of 54.0 ⁇ 0.5mm and an internal diameter of 6.35mm ⁇ 0.05mm.
  • X when X is 1 or 0.5, when the stopper is not inserted into the reservoir, it has one of: a) a maximum external diameter of 6.67mm to 7.10mm and/or a length of 7.85 ⁇ 0.4 mm; and b) a maximum external diameter of 6.70 ⁇ 0.15mm and/or a length of 7.85 ⁇ 0.4 mm.
  • the stopper when X is 1 or 0.5, has at least one circumferential rib of outer diameter 6.60 ⁇ 0.15 mm.
  • the circumferential ribs help to reduce contact between the stopper and the syringe, minimising friction and so reducing injection force and time. In this way, the present invention improves patient experience, adherence and outcomes.
  • the syringe when X is 2, has a length of 54.0 ⁇ 0.5mm and an internal diameter of 8.65mm ⁇ 0.05mm.
  • the stopper when X is 2, has a maximum external diameter 9.05 ⁇ 0.15mm and/or length 7.70 ⁇ 0.4 mm when not inserted into the reservoir.
  • the stopper when X is 2, has at least one circumferential rib of outer diameter 9.00 ⁇ 0.15 mm.
  • the ribs help to reduce contact between the stopper and the syringe, minimising friction and so reducing injection force and time. In this way, the present invention improves patient experience, adherence and outcomes.
  • a break loose force configured to move the stopper of the present invention from an initial stationary point to a velocity of 190mm/min is one or more of: a) about 2N to about 4N after storage at 5°C ⁇ 3 °C for 2.5 months after filling; b) about 2N to about 4N after storage at 5°C ⁇ 3 °C for 6 months after filling.
  • a break loose force configured to move the stopper of the present invention from an initial stationary point to a velocity of 190mm/min is one or more of: a) about 2N to about 3.5N at 25°C ⁇ 3 °C after filling; b) about 2N to about 4.5N after storage at 25°C ⁇ 3 °C for 1.5 months after filling; c) about 2.5N to about 5N after storage at 25°C ⁇ 3 °C for 2.5 months after filling; and/or d) about 2.5N to about 5.5N after storage at 25°C ⁇ 3 °C for 6 months after filling.
  • a break loose force configured to move the stopper of the present invention from an initial stationary point to a velocity of 190mm/min is one or more of: a) about 3N to about 4.5N after storage at 40°C ⁇ 3 °C for 1.5 months after filling; and b) about 3N to about 5N after storage at 40°C ⁇ 3 °C for 2.5 months after filling.
  • the syringes of the present invention require a lower break loose force than the prior art syringes, reducing injection force and time.
  • the break loose forces of the syringes of the present invention are less variable than in prior art syringes. It has been shown that reliability of syringes is 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 - Issue 4, pgs 499-507). In this way, the present invention reduces risk of injection errors, improving patient experience, patient adherence and outcomes.
  • Needle phobia reduces patient adherence (Baryakova et al.).
  • the needle shield device of the present invention covers the needle to improve the experience of patients with needle phobia, improving patient adherence and outcomes.
  • the syringe is provided in needle shield device comprising a needle sleeve and a plunger; and wherein a manual force can be applied to the plunger to expel the 150mg/mL omalizumab formulation and unlatch needle sleeve so that the needle sleeve can cover the needle after injection.
  • the syringe is manufactured by a method comprising: aseptic filling of the reservoir with the 150mg/mL omalizumab formulation; and stoppering the reservoir with the stopper.
  • the reservoir and needle prior to the aseptic filling, are sterilised by ethylene oxide gas treatment, electron beam (e-beam) and/or steam sterilisation by autoclave.
  • ethylene oxide gas treatment electron beam (e-beam) and/or steam sterilisation by autoclave.
  • e-beam electron beam
  • steam sterilisation by autoclave.
  • 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids. More particularly, it can be used for one or more of:
  • IgE-mediated food allergy in adult and pediatric patients aged 1 year and older for the reduction of allergic reactions (Type I), including anaphylaxis, that may occur with accidental exposure to one or more foods (and can be used in conjunction with food allergen avoidance); and/or
  • CSU chronic spontaneous urticaria
  • Figure 2 shows dosing regimens currently used to administer 150mg/mL omalizumab formulation.
  • Figure 6 is a schematic diagram of a syringe for subcutaneous delivery according to an embodiment of the invention.
  • Figure 7 shows experimental results of injection time vs constant force for the prior art syringe and syringes of the present invention.
  • Figure 8 shows experimental results of break loose force vs storage duration and temperature for the prior art syringe and syringes of the present invention.
  • Figure 9 shows the percentage of the main omalizumab charge variant measured by ion exchange chromatography for the prior art syringe and syringes of the present invention.
  • Figure 13 shows the polysorbate 20 (PS20) content of the prior art syringe and syringes of the present invention.
  • Figure 15 is a schematic diagram of a prefilled syringe within an autoinjector.
  • Figure 16 shows the measured time to expel the 150mg/mL omalizumab formulation out of the reservoir and through the needle using an autoinjector when combined with syringes of the invention.
  • Figure 17 shows new dosing regimens of 150mg/mL omalizumab formulation in accordance with the present invention.
  • the present invention provides new uses of omalizumab, new syringes and new administration regimens which improve ease of use, patient experience, patient adherence and outcomes using omalizumab.
  • the present invention provides new uses of omalizumab, new syringes and new administration regimens which 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.
  • the syringes of the present invention expel omalizumab in less time than prior art syringes when forces are applied to the stopper see Figure 7 and related description).
  • Multiple characteristics of the syringes of the present invention contribute to the reduced injection time referenced in point (i), including but not limited to: needle gauge, needle minimum internal diameter, stopper lamination, stopper coating, number of bevels on the needle distal surface, syringe flange, stopper maximum internal diameter and diameter of outer rib on the stopper (see Figure 7 and related description).
  • the syringes of the present invention require a lower break loose force than the prior art syringe (see Figure 8 and related description).
  • the syringes of the present invention preserve the purity and stability of omalizumab and thus improve the bioavailability of omalizumab (see Figures 9 to 13 and related description).
  • X mL of 150mg/mL omalizumab formulation for use in a method of treatment of one or more 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids, wherein X is 2, 1 or 0.5 and wherein the X mL 150mg/mL omalizumab formulation is administered subcutaneously by a syringe, the syringe comprising: a reservoir filled with X mL of 150mg/mL omalizumab formulation, wherein the X mL 150mg/mL omalizumab formulation has 6000 or fewer particles of diameter > 10pm and/or 600 or fewer particles of diameter > 25pm; and
  • a needle gauge of 27 is particularly advantageous in achieving the reduced injection time.
  • the present invention provides X mL of 150mg/mL omalizumab formulation for use in a method of treatment of one or more 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids, wherein X is 2, wherein the omalizumab formulation is administered subcutaneously by a syringe, the syringe comprising: a reservoir filled with X mL of 150mg/mL omalizumab formulation, wherein the X mL 150mg/mL omalizumab formulation has 6000 or fewer particles of diameter > 10pm and/or 600 or fewer particles of diameter > 25pm; and the syringe further comprising: a stopper, and
  • one preferred embodiment of the invention is a syringe according to the first or second aspects above, wherein one or more of the following is provided.
  • the syringe is configured to expel 1mL 150mg/mL omalizumab formulation in one or more of: 4.64 ⁇ 0.22 seconds when a constant force of 10N is applied to the stopper, 2.54 ⁇ 0.11 seconds when constant force of 17N is applied to the stopper, and 1.39 ⁇ 0.04 seconds when a constant force of 30N is applied to the stopper.
  • the syringe has an internal coating of 0.4 ⁇ 0.2mg of polydimethylsiloxane (PDMS).
  • PDMS polydimethylsiloxane
  • the syringe has a needle of gauge 27 defining a minimum internal diameter ID N of 0.277mm.
  • the stopper when it is not inserted into the syringe reservoir, has a maximum external diameter Ds6.70 ⁇ 0.15mm and length Ls 7.85 ⁇ 0.4 mm.
  • the stopper has a conically shaped distal surface and at least one circumferential rib of outer diameter Rs 6.60 ⁇ 0.15 mm.
  • the stopper is formed from bromobutyl elastomer and has an ethylene tetrafluoroethylene (ETFE) barrier film lamination.
  • the stopper has a B2-40 UV cured lubrication coating.
  • the syringes of the present invention achieve reduced injection time, reduced break loose force as compared to syringes of the prior art, while maintaining comparable purity, stability and bioavailability of omalizumab, the syringes of the invention can be used to administer larger volumes of omalizumab than prior art syringes, i.e. larger than 0.5mL or 1 mL 150mg/mL omalizumab.
  • distal refers to a location that is relatively closer to a site of injection
  • proximal refers to a location that is relatively further away from the injection site.
  • the term ‘about’ in relation to a numerical value x is optional and means x + 5%.
  • syringes are referred to as being filled with 0.5mL of 150mg/mL omalizumab formulation, this should be understood as 0.520mL ⁇ 5%.
  • syringes are referred to as being filled with 1 mL of 150mg/mL omalizumab formulation, this should be understood as 1.020mL ⁇ 2.5%.
  • syringes are referred to as being filled with 2mL of 150mg/mL omalizumab formulation in this application, this should be understood as 2.040mL ⁇ 2.75%.
  • Containers with a nominal content of less than 100mL of 150mg/mL omalizumab formulation 150mg/mL antibody with 42.1 mg/mL L-arginine hydrochloride, 1.37mg/mL L-histidine, 2.34mg/mL L-histidine hydrochloride monohydrate, 0.4mg/mL polysorbate 20 as an aqueous solution (in sterile water for injection (USP)) have 6000 or fewer particles of diameter > 10pm and/or 600 or fewer particles of diameter > 25pm. The number of particles of diameter > 10pm and/or 25pm can be measured by a light obscuration particle count test or a microscopic particle count test as set out in United States Pharmacopeia, Chapter 788
  • Omalizumab formulations used according to the invention can include a histidine buffer, arginine hydrochloride, and a polysorbate (such as polysorbate 20). They can have a pH in the range of 5.5-6.5.
  • One useful formulation for 150mg/mL omalizumab has 42.1 mg/mL arginine hydrochloride, 1.37mg/mL histidine, 2.34mg/mL histidine hydrochloride monohydrate, and 0.4mg/mL polysorbate 20.
  • Figure 1 shows a schematic diagram of a syringe 1 currently used to provide 150mg/mL omalizumab (XOLAIR®) solution.
  • the syringe has reservoir 2 length IR 54 ⁇ 0.5mm and an internal diameter dp of 6.35 ⁇ 0.1mm filled with 0.5mL or 1 mL 150mg/mL omalizumab (XOLAIR®) solution.
  • the length IR of the syringe is the maximum internal length of the syringe reservoir.
  • the syringe is formed from borosilicate glass and the inner surface of the syringe has an internal coating of ⁇ 1.0 mg of polydimethylsiloxane (PDMS) with a kinematic viscosity of about 1000cSt.
  • PDMS polydimethylsiloxane
  • a needle 3 has a length l N of 12.7 ⁇ 0.2mm extending outside of the syringe, a gauge G w of 26 defining a minimum internal diameter ID N of 0.232mm (inset 3’ shows close up view of internal diameter IDN and 3 bevels on its distal surface.
  • the needle 3 has an internal coating of polydimethylsiloxane (PDMS) with a kinematic viscosity of about 12500cSt.
  • the needle 3 is staked meaning that it is inserted into the syringe and secured in place with adhesive; the length of the fluid path IP between the distal end of the reservoir and the proximal end of the part of the needle 3 extending from the syringe is about 8mm.
  • a flange 4 At a proximal end of the reservoir is a flange 4 in the form of a cut flange.
  • the syringe also comprises a stopper 5 which, when it is not inserted into the syringe reservoir 2, has a maximum external diameter Ds of 6.67mm to 7.10mm and length Ls of 7.85 ⁇ 0.4 mm.
  • the stopper has a conically shaped distal surface 5a and at least three circumeferential ribs 5b of outer diameter Rs 6.60 ⁇ 0.1 mm. A close up of the stopper is shown inset, labelled 5’.
  • the stopper is formed from bromobutyl elastomer and has a fluoro-resin on the product contacting side.
  • the stopper is lubricated with DC360 Medical Fluid 1000cSt silicone oil.
  • the syringe 1 is a BD HypakTM 1 mL glass prefillable syringe with staked needle fitted with a stopper 5 which is a BD (West) 4023/50 FluroTec® stopper.
  • the BD HypakTM 1mL glass prefillable syringe with staked needle is manufactured by Becton Dickinson.
  • the elastomeric formulation of the bromobutyl elastomer is 4023/50 and the fluoro-resin is a FluroTec® coating.
  • the stopper 5 is manufactured by West Pharmaceutical Services and supplied by Becton Dickinson.
  • the rubber needle shield is a FM27/0 rubber component and is enclosed by outer rigid polypropylene cap; the rubber needle shield is manufactured by AptarGroup.
  • the first step is thawing and homogenizing frozen pre-formulated omalizumab 15% drug substance.
  • Thawing can be achieved by circulating heat transfer fluid through a jacketed vessel containing the omalizumab 15% drug substance.
  • Homogenization can be achieved by recirculating the thawed omalizumab 15% drug substance through a recirculation loop of the jacketed vessel.
  • the second step is filtering and mixing the omalizumab 15% drug substance.
  • Filtering can be achieved by passing the omalizumab 15% drug substance through a 0.2pm rated membrane filter made from polyvinylidene fluoride.
  • Mixing can be achieved with a magnetically coupled stirrer within a jacketed storage vessel holding the omalizumab 15% drug substance.
  • the omalizumab 15% drug substance can be pooled and refrozen during this second step.
  • the third step is in-line sterile filtration of the omalizumab 15% drug substance.
  • In-line filtration can be achieved by passing the omalizumab 15% drug substance through a 0.2pm rated membrane filter made from polyvinylidene fluoride.
  • the fourth step is aseptic filling of a reservoir 2 with staked needle 3 as shown in and described with reference to Figure 1.
  • the reservoir 2 is filled with 1mL or 0.5mL omalizumab formulation by a stainless steel piston pump. Dosing accuracy can be monitored off-line by determination of extractable volume.
  • Figure 2 shows dosing regimens currently used to administer 150mg/mL omalizumab formulation.
  • 150mg/mL omalizumab formulation is administered in doses of 75mg to 600mg by subcutaneous injection every 2 or 4 weeks.
  • 150mg/mL omalizumab formulation is currently provided in syringes containing 0.5mL or 1 mL 150mg/mL omalizumab formulation.
  • a patient requires a dose of 225mg omalizumab
  • the dose must be administered using one syringe containing 1mL 150mg/mL omalizumab formulation and one syringe containing 0.5mL 150mg/mL omalizumab formulation.
  • the dose must be administered using two syringes, each containing 1 mL 150mg/mL omalizumab formulation.
  • a patient requires a dose of 375mg omalizumab
  • the dose must be administered using three syringes - two syringes each containing 1mL 150mg/mL omalizumab formulation and one syringe containing 0.5mL 150mg/mL omalizumab formulation.
  • the dose must be administered using three syringes each containing 1mL 150mg/mL omalizumab formulation.
  • a patient requires a dose of 525mg omalizumab
  • the dose must be administered using four syringes - three syringes each containing 1 mL 150mg/mL omalizumab formulation and one syringe containing 0.5mL 150mg/mL omalizumab formulation.
  • the dose must be administered using four syringes, each containing 1mL 150mg/mL omalizumab formulation.
  • Figures 3 to 6 show syringes which are part of the invention.
  • FIG. 3 shows a syringe 11 according to the invention.
  • the syringe has a reservoir 12 of length IR of 54.0 ⁇ 0.5mm and an internal diameter dp of 6.35mm ⁇ 0.05mm filled with 0.5mL (in a first embodiment) or 1 mL (in a second embodiment) 150mg/mL omalizumab (XOLAIR®) solution.
  • the syringe 11 is formed from borosilicate glass and the inner surface of the syringe has an internal coating of 0.4 ⁇ 0.2mg of polydimethylsiloxane (PDMS).
  • PDMS polydimethylsiloxane
  • the syringe has a round flange 14 of maximum diameter 11 ⁇ 0.25mm.
  • the syringe comprises a staked needle 13 having a length IN 12.7mm extending outside of the syringe and a gauge 27 defining a minimum internal diameter IDN of 0.277mm (inset 13’ shows close up view of internal diameter /£) «).
  • the needle 13 is staked meaning that it is inserted into the syringe and secured in place with adhesive; the length of the fluid path IR between the distal end of the reservoir and the proximal end of the part of the needle 13 extending from the syringe is about 8mm.
  • the needle has 5 bevels on its distal surface.
  • the needle 13 is enclosed by an elastomer needle shield to maintain needle sterility (not shown).
  • the elastomer needle shield can comprise an outer rigid polypropylene cap.
  • the needle shield is latex free.
  • the syringe also comprises a stopper 15 which, when it is not inserted into the syringe reservoir 12, has a maximum external diameter Ds 6.67mm to 7.10mm and length Ls 7.85 ⁇ 0.4 mm.
  • the stopper has a conically shaped distal surface 15a and at least one circumferential rib 15b of outer diameter 6.60 ⁇ 0.1 mm. A close up of the stopper is shown inset, labelled 15’.
  • the stopper is formed from bromobutyl elastomer and has a fluoro-resin on the product contacting side.
  • the stopper is lubricated with DC360 Medical Fluid 1000cSt silicone oil.
  • the syringe 11 is a BD NeopakTM 1mL long glass prefillable syringe with staked needle fitted with a stopper 15 which is a BD (West) 4023/50 FluroTec® stopper.
  • the BD NeopakTM 1mL long glass prefillable syringe with staked needle is manufactured by Becton Dickinson.
  • the elastomeric formulation of the bromobutyl elastomer is 4023/50 and the fluoro-resin is a FluroTec® coating.
  • the stopper 15 is manufactured by West Pharmaceutical Services and supplied by Becton Dickinson.
  • FIG. 4 shows a syringe 21 according to the invention.
  • the syringe 21 has a reservoir 22 of length IR of 54 ⁇ 0.5mm and an internal diameter dp of 6.35mm ⁇ 0.05mm filled with 0.5mL (in a third embodiment) or 1 mL (in a fourth embodiment) 150mg/mL omalizumab (XOLAIR®) solution.
  • the syringe is formed from borosilicate glass and the inner surface of the syringe has an internal coating of silicone oil.
  • the syringe has a round flange 24 of maximum diameter 11 ⁇ 0.25mm.
  • the syringe comprises a needle having a length l N 12.7mm extending outside of the syringe and a gauge 27 defining a minimum internal diameter ID N of 0.191 mm (inset 23’ shows close up view of internal diameter /D w ).
  • the needle 23 is staked meaning that it is inserted into the syringe and secured in place with adhesive; the length of the fluid path IP between the distal end of the reservoir and the proximal end of the part of the needle 23 extending from the syringe is about 8mm.
  • the needle 23 is enclosed by an elastomer needle shield to maintain needle sterility (not shown).
  • the elastomer needle shield can comprise an outer rigid polypropylene cap.
  • the needle shield is latex free.
  • the syringe also comprises a stopper 25 which, when it is not inserted into the syringe reservoir 22, has a maximum external diameter Ds6.70 ⁇ 0.15mm and length Ls 7.85 ⁇ 0.4 mm.
  • the stopper has a conically shaped distal surface 25a and at least one circumferential rib 25b of outer diameter Rs 6.60 ⁇ 0.15 mm. A close up of the stopper is shown inset, labelled 25’.
  • the stopper is formed from bromobutyl elastomer and has an ethylene tetrafluoroethylene (ETFE) barrier film lamination.
  • the stopper has a B2-40 UV cured lubrication coating; this is a coating in which PDMS is sprayed onto the stopper, heated and UV cured to the surface of the stopper.
  • the syringe 21 is a Nexa® 1mL long glass prefillable syringe with staked needle fitted with a stopper 25 which is a West NovaPure® 1 mL long stopper.
  • the Nexa® 1 mL glass prefillable syringe with staked needle is manufactured by Ompi, a Stevanato Group Brand.
  • the elastomeric formulation of the bromobutyl elastomer 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.
  • Figure 5 shows a syringe 31 according the invention.
  • the syringe has a reservoir 32 of length IR of 54.0 ⁇ 0.5mm and an internal diameter dp of 6.35mm ⁇ 0.05mm filled with 0.5mL (in a fifth embodiment) or 1 mL (in a sixth embodiment) 150mg/mL omalizumab (XOLAIR®) solution.
  • the syringe 31 is formed from borosilicate glass and the inner surface of the syringe has an internal coating of 0.4 ⁇ 0.2mg of polydimethylsiloxane (PDMS).
  • PDMS polydimethylsiloxane
  • the syringe has a round flange 34 of maximum diameter 11 ⁇ 0.25mm.
  • the syringe comprises a needle 33 having a length IN 12.7mm extending outside of the syringe and a gauge 27 defining a minimum internal diameter IDN of 0.277mm (inset 33’ shows close up view of internal diameter IDN .
  • the needle 33 is staked meaning that it is inserted into the syringe and secured in place with adhesive; the length of the fluid path Ip between the distal end of the reservoir and the proximal end of the part of the needle 33 extending from the syringe is about 8mm.
  • the needle has 5 bevels on its distal surface.
  • the needle 33 is enclosed by an elastomer needle shield to maintain needle sterility (not shown).
  • the elastomer needle shield can comprise an outer rigid polypropylene cap.
  • the needle shield is latex free.
  • the syringe also comprises a stopper 35 which, when it is not inserted into the syringe reservoir 32, has a maximum external diameter Ds 6.70 ⁇ 0.15mm and length Ls 7.85 ⁇ 0.4 mm.
  • the stopper has a conically shaped distal surface 35a and at least one circumferential rib 35b of outer diameter Rs 6.60 ⁇ 0.15 mm. A close up of the stopper is shown inset, labelled 35’.
  • the stopper is formed from bromobutyl elastomer and has an ethylene tetrafluoroethylene (ETFE) barrier film lamination.
  • the stopper has a B2-40 UV cured lubrication coating; this is a coating in which PDMS is sprayed onto the stopper, heated and UV cured to the surface of the stopper.
  • the syringe 31 is a BD NeopakTM 1mL long glass prefillable syringe with staked needle fitted with a stopper 35 which is a West NovaPure® 1mL long stopper.
  • the BD NeopakTM 1mL long glass prefillable syringe with staked needle is manufactured by Becton Dickinson.
  • the elastomeric formulation of the bromobutyl elastomer 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.
  • FIG. 6 shows a syringe 41 according to a seventh embodiment of the present invention.
  • the syringe has a reservoir 42 of length l R of 54.5 ⁇ 0.4mm and an internal diameter d R of 8.65mm ⁇ 0.1mm filled with 2mL 150mg/mL omalizumab (XOLAIR®) solution.
  • the syringe is formed from borosilicate glass and the inner surface of the syringe has an internal coating of 0.7 ⁇ 0.2mg polydimethylsiloxane (PDMS).
  • PDMS polydimethylsiloxane
  • the syringe has a round flange 44 of maximum diameter 14.7 ⁇ 0.25mm.
  • the syringe comprises a needle having a length IN 12.7mm extending outside of the syringe and a gauge 27 defining a minimum internal diameter IDN of 0.277mm (inset 43’ shows close up view of internal diameter ID N .
  • the needle 43 is staked meaning that it is inserted into the syringe and secured in place with adhesive; the length of the fluid path IP between the distal end of the reservoir and the proximal end of the part of the needle 43 extending from the syringe is about 8mm.
  • the needle has 5 bevels on its distal surface.
  • the needle 43 is enclosed by a thermoplastic elastomer needle shield to maintain needle sterility.
  • the needle shield can comprise an outer rigid polypropylene cap.
  • the needle shield is latex free.
  • the syringe also comprises a stopper 45 which, when it is not inserted into the syringe, has a maximum external diameter Ds 9.05 ⁇ 0.15mm and length Ls 7.70 ⁇ 0.4 mm.
  • the stopper has a conically shaped distal surface 45a, and comprises at least one circumferential rib 45b of outer diameter Rs 9.00 ⁇ 0.15 mm. A close up of the stopper is shown inset, labelled 45’.
  • the stopper is formed from bromobutyl elastomer and has an ethylene tetrafluoroethylene barrier film lamination.
  • the stopper has a B2-40 UV cured lubrication coating; this is a coating in which PDMS is sprayed onto the stopper, heated and UV cured to the surface of the stopper.
  • the syringe 41 is a BD NeopakTM 2.25mL glass prefillable syringe with staked needle fitted with a stopper 45 which is a West NovaPure® 1-3mL stopper.
  • the BD NeopakTM 2.25mL glass prefillable syringe with staked needle is manufactured by Becton Dickinson.
  • the elastomeric formulation of the bromobutyl elastomer is 4023/50 and the ethylene tetrafluoroethylene (ETFE) barrier film lamination is a FluroTec® coating.
  • the stopper 45 is manufactured and supplied by West Pharmaceutical Services.
  • each of the syringes of Figures 3 to 6 can be used to administer 150mg/mL omalizumab formulation subcutaneously.
  • a method of manufacturing the syringes according the present invention is set out below.
  • the first step is thawing and homogenizing frozen pre-formulated omalizumab 15% drug substance.
  • Thawing can be achieved by circulating heat transfer fluid through a jacketed vessel containing the omalizumab 15% drug substance.
  • Homogenization can be achieved by recirculating the thawed omalizumab 15% drug substance through a recirculation loop of the jacketed vessel.
  • the second step is filtering and mixing the omalizumab 15% drug substance.
  • Filtering can be achieved by passing the omalizumab 15% drug substance through a 0.2pm rated membrane filter made from polyvinylidene fluoride.
  • Mixing can be achieved with a magnetically coupled stirrer within a jacketed storage vessel holding the omalizumab 15% drug substance.
  • the omalizumab 15% drug substance can be pooled and refrozen during this second step.
  • the third step is in-line sterile filtration of the omalizumab 15% drug substance.
  • In-line filtration can be achieved by passing the omalizumab 15% drug substance through a 0.2pm rated membrane filter made from polyvinylidene fluoride.
  • the fourth step is aseptic filling of a reservoir 12, 22, 32, 42 with staked needle 13, 23, 33, 43 as shown in and described with reference to any one of Figures 3 to 6.
  • the reservoir 12, 22, 32, 42 is filled with 0.5mL, 1 mL or 2mL omalizumab formulation by a peristaltic pump. Dosing accuracy can be monitored by automated weighing of syringes before and after filing.
  • Aseptic filling by peristaltic pump has advantages over aseptic filling by stainless steel piston pumps. Firstly, peristaltic pumps exert less stress on protein 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 chance of crosscontamination. Thirdly, peristaltic pumps are faster to set up and calibrate than stainless steel piston pumps.
  • the following processes are carried out: a) the reservoir 12, 22, 32, 42 and staked needle 13, 23, 33, 43 are washed with water for injection (WFI) and the internal coating of 0.4 ⁇ 0.2mg of polydimethylsiloxane (PDMS) with a kinematic viscosity of about 1000cSt is sprayed onto the reservoir body with a diving nozzle; b) the elastomer needle shield and outer rigid polypropylene cap are assembled with the reservoir 12, 22, 32, 42 and staked needle 3 so that they enclose the staked needle 13, 23, 33, 43; and c) the assembled reservoir 12, 22, 32, 42, staked needle 13, 23, 33, 43, elastomer needle shield and outer rigid polypropylene cap are sterilised by ethylene oxide gas treatment.
  • WFI water for injection
  • PDMS polydimethylsiloxane
  • the fifth step is syringe stoppering i.e. the placement of the stopper 15, 25, 35, 45 into the reservoir 12, 22, 32, 42.
  • the stopper 15, 25, 35, 45 can be placed into the appropriate position in the reservoir 12, 22, 32, 42 by stopper placement tube technology.
  • the stopper 15, 25, 35, 45 is sterilized. This sterilisation can be achieved by steam sterilisation by autoclave, electron beam (e-beam) and/or ethylene oxide gas treatment.
  • the present invention provides X mL of 150mg/mL omalizumab formulation for use in a method of treatment of one or more 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids, wherein X is 2, 1 or 0.5 and wherein the X mL 150mg/mL omalizumab formulation is administered subcutaneously by a syringe according to the present invention, wherein the syringe is manufactured by a method comprising: aseptic filling of the reservoir with the 150mg/mL omalizumab formulation; and stoppering the reservoir with the stopper.
  • the present invention provides X mL of 150mg/mL omalizumab formulation, wherein the aseptic filling is performed by a peristaltic pump or stainless steel piston pump.
  • the present invention provides X mL of 150mg/mL omalizumab formulation wherein, prior to the aseptic filling, the reservoir and needle are sterilised by ethylene oxide gas treatment, electron beam (e-beam) and/or steam sterilisation by autoclave.
  • Figure 17 shows new dosing regimens of the present invention.
  • Figure 17 depicts dosing regimens which include the use of an autoinjector fitted with a syringe of the present invention filled with 0.5mL, 1mL or 2mL 150mg/mL omalizumab formulation.
  • the use of an autoinjector is optional and the dosing regimens depicted can also be performed using syringes of the invention when not fitted into a device and/or when fitted into a needle shield device.
  • the syringes of the present invention configured to administer 2mL of 150mg/mL omalziumab reduce the number of injections required as compared to current dosing regimens shown in Figure 2.
  • the dose can be administered using only one syringe of the invention containing 2mL 150mg/mL omalizumab formulation.
  • the dose can be administered using two syringes - one syringe of the invention filled with 2mL 150mg/mL omalizumab formulation and one syringe filled with 0.5mL 150mg/mL omalizumab formulation.
  • the dose can be administered using two syringes - one syringe of the invention filled with 2mL 150mg/mL omalizumab formulation and one syringe filled with 1mL 150mg/mL omalizumab formulation.
  • the dose can be administered using three syringes - one syringe of the invention filled with 2mL 150mg/mL omalizumab formulation, one syringe filled with 0.5mL 150mg/mL omalizumab formulation and one syringe filled with 1mL 150mg/mL omalizumab formulation. If a patient requires a dose of 600mg, the dose can be administered using two syringes of the invention filled with 2mL 150mg/mL omalizumab formulation.
  • the syringes filled with 0.5ml 150mg/mL omalizumab formulation and 1mL 150mg/mL omalizumab formulation can be syringes of the present invention or the current syringes.
  • the syringes may be provided alone, in an autoinjector such as the autoinjector described with reference to Figure 15 and/or in a needle shield device such as the needle shield device described with reference to Figures 14A and 14Bin this way, the present invention improves patient convenience and risk of injection site reaction and so improves patient compliance.
  • the syringes of the present invention filled with 0.5mL 150mg/mL omalizumab and 1 mL 150mg/mL omalizumab formulation reduce the injection forces and/or time required as compared to current syringes, improving ease of use and making it more likely that a complete dose will be administered.
  • the present invention improves ease of use, patient experience, patient adherence and outcomes using omalizumab.
  • new dosing regimens which are similar to those illustrated in Figure 2 but which use the syringes of the present invention filled with 0.5mL 150mg/mL omalizumab and/or 1 mL 150mg/mL omalizumab formulation. If a patient requires a dose of 75mg, the dose can be administered using one syringe of the present invention filled with 0.5ml 150mg/mL omalizumab formulation. If a patient requires a dose of 150mg, the dose can be administered using one syringe of the present invention filled with 1 ml 150mg/mL omalizumab formulation.
  • the dose can be administered using one syringe filled with 0.5ml 150mg/mL omalizumab and one syringe filled with 1ml 150mg/mL omalizumab formulation; wherein one or both of the syringes is a syringe of the present invention.
  • the dose can be administered using two syringes filled with 1ml 150mg/mL omalizumab formulation; wherein one or both of the syringes is a syringe of the present invention.
  • the dose can be administered using three syringes - one syringe filled with 0.5ml 150mg/mL omalizumab and two syringes filled with 1 ml 150mg/mL omalizumab formulation; wherein at least one of the syringes is a syringe of the present invention.
  • the dose can be administered using three syringes, all three syringes filled with 1ml 150mg/mL omalizumab formulation; wherein at least one of the syringes is a syringe of the present invention.
  • the dose can be administered using four syringes - one syringe filled with 0.5ml 150mg/mL omalizumab and three syringes filled with 1ml 150mg/mL omalizumab formulation; wherein at least one of the syringes is a syringe of the present invention.
  • the dose can be administered using four syringes, all four syringes filled with 1ml 150mg/mL omalizumab formulation; wherein at least one of the syringes is a syringe of the present invention.
  • the syringes may be provided alone, in an autoinjector such as the autoinjector described with reference to Figure 15 and/or in a needle shield device such as the needle shield device described with reference to Figures 14A & 14B.
  • the invention provides the following new methods of treatment.
  • a method of treating a patient with one or more 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids comprising administering 300mg omalizumab formulation to the patient; wherein the method comprises administering 1 mL 150mg/mL omalizumab formulation subcutaneously by a syringe and performing a method of the invention wherein X is 1.
  • a method of treating a patient with one or more 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids comprising administering 375mg omalizumab formulation to the patient; wherein the method comprises administering 0.5mL 150mg/mL omalizumab formulation subcutaneously by a syringe; and one of: a) performing a method of the invention comprising administering 2 mL of 150mg/mL omalizumab formulation to the patient; and b) performing a method of the invention wherein X is 1 and administering 1 mL 150mg/mL omalizumab formulation subcutaneously by a syringe.
  • a method of treating a patient with one or more 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids comprising administering 450mg omalizumab formulation to the patient; wherein the method comprises administering 1 mL 150mg/mL omalizumab formulation subcutaneously by a syringe; and one of: a) performing a method of the invention comprising administering 2 mL of 150mg/mL omalizumab formulation to the patient; and b) performing a method of the invention wherein X is 1 and administering 1 mL 150mg/mL omalizumab formulation subcutaneously by a syringe.
  • a method of treating a patient with one or more 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids comprising administering 525mg omalizumab formulation to the patient; wherein the method comprises administering 1 mL 150mg/mL omalizumab formulation subcutaneously by a syringe and administering 0.5mL 150mg/mL omalizumab formulation subcutaneously by a syringe; and one of: a) performing a method of the invention comprising administering 2 mL of 150mg/mL omalizumab formulation to the patient; and b) performing a method of the invention wherein X is 1 and administering 1 mL 150mg/mL omalizumab
  • one of the steps requiring administering 0.5mL 150mg/mL omalizumab formulation subcutaneously by a syringe may comprise performing a method of the invention wherein X is 0.5; and/or (B) one of the steps requiring administering 1mL 150mg/mL omalizumab formulation subcutaneously by a syringe may comprise performing a method of the invention wherein X is 1.
  • the syringe may be configured to expel the omalizumab formulation contained in the reservoir through the needle in one or more of: a) less than 8.5 seconds when a constant force of 17N is applied to the stopper; and b) less than 5 seconds when a constant force of 30N is applied to the stopper.
  • the syringe may be 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 10N is applied to the stopper; b) about 8.5 seconds to about 6 seconds when a constant force of 17N is applied to the stopper; and c) about 5 seconds to about 4 seconds when a constant force of 30N is applied to the stopper.
  • the syringe may be configured to expel X mL of 150mg/ml omalizumab formulation through the needle in one or more of: a) less than 3 seconds when a constant force of 17N is applied to the stopper; and b) less than 2 seconds when a constant force of 30N is applied to the stopper.
  • the syringe may be configured to expel X mL of 150mg/ml omalizumab formulation through the needle in one or more of: a) less than 7.5 seconds to about 4 seconds when a constant force of 10N is applied to the stopper; b) less than 3.5 seconds to about 2 seconds when a constant force of 17N is applied to the stopper; and c) less than 2 seconds to about 1 second when a constant force of 30N is applied to the stopper.
  • the syringe may be configured to expel X mL of 150mg/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 in about 4 seconds when a constant force of 10N is applied to the stopper.
  • the syringe may be configured to expel X mL of 150mg/ml omalizumab formulation through the needle in less than 5 seconds to about 4 seconds, less than 4.75 seconds to about 4 seconds, in less than 4.5 seconds to about 4 seconds, in less than 4.25 seconds to about 4 seconds or in about 4 seconds when a constant force of 10N is applied to the stopper.
  • the syringe may be configured to expel X mL of 150mg/ml omalizumab formulation through the needle in one or more of: a) less than 2 seconds when a constant force of 17N is applied to the stopper; and b) less than 1 second when a constant force of 30N is applied to the stopper.
  • the syringe may be configured to expel X mL of 150mg/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 10N is applied to the stopper; b) less than 2 seconds to about 1 second when a constant force of 17N is applied to the stopper; and c) less than 1 second to about 0.5 seconds when a constant force of 30N is applied to the stopper.
  • the needle has one of: a) a minimum internal diameter of 0.292mm, and b) a minimum internal diameter of 0.232mm.
  • the needle has one of: a) a minimum internal diameter of 0.292mm; and b) a minimum internal diameter of 0.232mm.
  • the needle has one of: a) a minimum internal diameter of 0.277mm; b) a minimum internal diameter of 0.191mm; c) a minimum internal diameter of 0.184mm; and d) a minimum internal diameter of 0.241mm.
  • the needle has one of: a) a minimum internal diameter of 0.133mm; and b) a minimum internal diameter of 0.190mm.
  • the needle has one of: a) a minimum internal diameter of 0.265mm; b) a minimum internal diameter of 0.240mm; c) a minimum internal diameter of 0.190mm; and d) a minimum internal diameter of 0.133mm, preferably wherein the needle has a minimum internal diameter of 0.240mm or 0.265mm.
  • the needle can comprise 3 bevels on its distal surface or 5 bevels on its distal surface.
  • the stopper may a fluoro-resin on the product contacting side or an ethylene tetrafluoroethylene (ETFE) barrier film lamination.
  • ETFE ethylene tetrafluoroethylene
  • the stopper may have a B2-40 UV cured lubrication coating or is lubricated with 1000cSt silicone oil.
  • the syringe may have an internal coating of 0.4 ⁇ 0.2mg or 0.7 ⁇ 0.2mg of polydimethylsiloxane.
  • the syringe may have a latex-free needle shield.
  • the syringe may have round flange at a proximal end of the reservoir; in further embodiments, the round flange has a maximum diameter of 11 ⁇ 0.25mm or 14.7 ⁇ 0.25mm.
  • the syringe may have a length of 54.0 ⁇ 0.5mm and an internal diameter of 6.35mm ⁇ 0.05mm.
  • the stopper when it is not inserted into the reservoir, it may have has one of: a) a maximum external diameter of 6.67mm to 7.10mm and/or a length of 7.85 ⁇ 0.4 mm; and b) a maximum external diameter of 6.70 ⁇ 0.15mm and/or a length of 7.85 ⁇ 0.4 mm.
  • the syringe may have a length of 54.0 ⁇ 0.5mm and an internal diameter of 8.65mm ⁇ 0.05mm.
  • syringes of the present invention can be provided alone or in combination with a needle shield device or autoinjector. Accordingly, the present invention provides syringes containing 150mg/mL omalizumab formulation which are suitable to be used with autoinjectors in that the syringes of the present invention expel 150mg/mL omalizumab formulation in less time than prior art syringes when forces are applied to the stopper.
  • the present invention provides a syringe comprising: a reservoir filled with 1 mL of 150mg/mL omalizumab formulation, a stopper, and a needle; and which is configured to expel 1 mL of 150mg/ml omalizumab formulation through the needle in one or more of: less than 8 seconds when a constant force of 10N is applied to the stopper; less than 4 seconds when a constant force of 17N is applied to the stopper; and less than 2 seconds when a constant force of 30N is applied to the stopper.
  • the syringe is configured to expel 1mL of 150mg/ml omalizumab formulation through the needle in one or more of: less than 8 seconds to about 4 seconds when a constant force of 10N is applied to the stopper; less than 4 seconds to about 2 seconds when a constant force of 17N is applied to the stopper; and less than 2 seconds to about 1 second when a constant force of 30N is applied to the stopper.
  • the syringe is configured to expel 1mL of 150mg/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 in about 4 seconds when a constant force of 10N is applied to the stopper.
  • the syringe is configured to expel 1mL of 150mg/ml omalizumab formulation through the needle in less than 7.5 seconds to about 4 seconds, in less than 5 seconds to about 4 seconds, in less than 4.75 seconds to about 4 seconds, in less than 4.5 seconds to about 4 seconds, in less than 4.25 seconds to about 4 seconds or in about 4 seconds when a constant force of 10N is applied to the stopper.
  • the present invention also provides a syringe for subcutaneous injection, the syringe comprising: a reservoir filled with 0.5mL of 150mg/mL omalizumab 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, the syringe being configured to expel 0.5mL of 150mg/ml omalizumab formulation through the needle in one or more of: less than 4 seconds when a constant force of 10N is applied to the stopper; less than 2 seconds when a constant force of 17N is applied to the stopper; and less than 1 second when a constant force of 30N is applied to the stopper.
  • the syringe is configured to expel 0.5mL of 150mg/ml omalizumab formulation through the needle in one or more of: less than 4 seconds to about 2 seconds when a constant force of 10N is applied to the stopper; less than 2 seconds to about 1 second when a constant force of 17N is applied to the stopper; and less than 1 seconds to about 0.5 seconds when a constant force of 30N is applied to the stopper.
  • the present invention also provides a syringe for subcutaneous injection, the syringe comprising a reservoir filled with 2mL of 150mg/mL omalizumab formulation, a stopper, and a needle, the syringe being configured to expel 2mL of the omalizumab formulation contained in the reservoir through the needle when a force is applied to the stopper.
  • the syringe is configured to expel 2mL of 150mg/mL omalizumab formulation out of the reservoir and through the needle in one or more of: less than 16 seconds when a constant force of 10N is applied to the stopper; less than 9 seconds when a constant force of 17N is applied to the stopper; and less than 4 seconds when a constant force of 30N is applied to the stopper.
  • the syringe is configured to expel 2mL of 150mg/mL omalizumab formulation out of the reservoir through the needle in one or more of: less than 16 seconds to about 8 seconds when a constant force of 10N is applied to the stopper; less than 9 seconds to about 4 seconds when a constant force of 17N is applied to the stopper; and less than 4 seconds to about 2 seconds when a constant force of 30N is applied to the stopper.
  • Figures 7 to 13 show experimental results carried out on the prior art syringe (described with reference to Figure 1) and five syringes of the present invention (described with reference to Figures 3 to 6). Table 1 summarises the syringes used in the experiments.
  • the 150mg/mL omalizumab formulation is expelled from a syringe in less time than from prior art syringes when forces are applied to the stopper.
  • Figure 7 shows the measured time to expel the 150mg/ml omalizumab formulation from syringes which form part of the present invention (Syringes A, C, D and E) and the prior art syringe (Syringe F) when a constant force of 10N, 17N or 30N is applied to the stopper.
  • a motorized test stand was used to apply a constant force to each syringe filled with the relevant volume of 150mg/ml omalizumab formulation and the time taken to move the stopper from its proximal position to its distal position, expelling the contents of the syringe into air was measured.
  • the constant force was applied to a plunger which, in turn, applied force to the stopper.
  • Ten syringe samples were tested for each constant force measurement and the mean was calculated. These tests were performed at room temperature. This test method can be used for determining the performance of syringes according to the invention.
  • the syringe samples were tested immediately after filling (known as time point 0 in the art).
  • the prior art syringe (Syringe F) is configured to expel 1mL of 150mg/mL omalizumab formulation through the needle in 8.53 ⁇ 0.45 seconds when a constant force of 10N is applied to the stopper, 4.32 ⁇ 0.20 seconds when a constant force of 17N is applied to the stopper and 2.14 ⁇ 0.09 seconds when a constant force of 30N is applied to the stopper.
  • the prior art syringe is configured to expel 150mg/mL omalizumab formulation through the needle in 0.85 ⁇ 0.4 seconds per mL, per N of constant force applied.
  • Syringe A is configured to expel 1mL of 150mg/mL omalizumab formulation through the needle in 6.73 ⁇ 0.51 seconds when a constant force of 10N is applied to the stopper, 3.27 ⁇ 0.11 seconds when a constant force of 17N is applied to the stopper and 1.57 ⁇ 0.10 seconds when a constant force of 30N is applied to the stopper.
  • syringe A is configured to expel 150mg/mL omalizumab formulation through the needle in less than 0.67 ⁇ 0.5 seconds per mL, per N of constant force applied.
  • Syringe E is configured to expel 1mL of 150mg/mL omalizumab formulation through the needle in 5.40 ⁇ 0.23 seconds when a constant force of 10N is applied to the stopper, 2.84 ⁇ 0.12 seconds when a constant force of 17N is applied to the stopper and 1.67 ⁇ 0.15 seconds when a constant force of 30N is applied to the stopper.
  • syringe E is configured to expel 150mg/mL omalizumab formulation through the needle in less than 0.54 ⁇ 0.2 seconds per mL, per N of constant force applied.
  • Syringe C is configured to expel 1 mL of 150mg/mL omalizumab formulation through the needle in 4.64 ⁇ 0.22 seconds when a constant force of 10N is applied to the stopper, 2.54 ⁇ 0.11 seconds when a constant force of 17N is applied to the stopper and 1 .39 ⁇ 0.04 seconds when a constant force of 30N is applied to the stopper.
  • syringe C is configured to expel 150mg/mL omalizumab formulation through the needle in less than 0.4 ⁇ 0.5 seconds per mL, per N of constant force applied.
  • Syringe D is configured to expel 2mL of 150mg/mL omalizumab formulation through the needle in 15.14 ⁇ 0.51 seconds when a constant force of 10N is applied to the stopper, 8.30 ⁇ 0.20 seconds when a constant force of 17N is applied to the stopper and 4.75 ⁇ 0.23 seconds when a constant force of 30N is applied to the stopper.
  • syringe D is configured to expel 150mg/mL omalizumab formulation through the needle in less than 0.75 ⁇ 0.5 seconds per mL, per N of constant force applied.
  • Figure 7 demonstrates that syringes of the present invention (Syringes A, C and E) are configured to expel 1 mL 150ml/mL omalizumab formation out of the reservoir and through the needle in less time than the syringe of the prior art (Syringe F).
  • the present invention provides X mL of 150mg/mL omalizumab formulation for use in a method of treatment of one or more 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids, wherein X is 2, 1 or 0.5 and wherein the X mL 150mg/mL omalizumab formulation is administered subcutaneously by a syringe, the syringe comprising: a reservoir filled with X mL of 150mg/mL omalizumab formulation, wherein the X mL 150mg/mL omalizumab formulation has 6000 or fewer particles of diameter > 10pm and/or 600 or fewer particles of diameter > 25pm; and the syringe further comprising
  • Figure 7 demonstrates that different components of the syringes of the present invention each contribute to the quicker injection time of the syringes of the present invention.
  • the stopper 5 of Syringe F (prior art syringe) is the same as the stopper in Syringe A but the reservoir 2 and needle 3 of Syringe F are different to the reservoir 12 and needle 13 of Syringe A. Therefore, since Figure 7 shows that Syringe A is configured to expel 1ml 150ml/mL omalizumab formation out of the reservoir and through the needle in less time than Syringe F, the characteristics of the needle 13 and reservoir 12 of Syringe A both contribute to the quicker injection time of Syringe A.
  • the reservoir 12 and needle 13 of Syringe A are the same as the reservoir 32 and needle 33 of Syringe C but the stopper 15 of Syringe A is different to the stopper 35 of Syringe C. Therefore, since Figure 7 shows that Syringe C is configured to expel 1 ml 150ml/mL omalizumab formation out of the reservoir and through the needle in less time than Syringe A, the characteristics of the stopper 35 of Syringe C contribute to the faster injection time of Syringe C. Finally, the stopper 35 of Syringe C is the same as the stopper 25 in Syringe E but the reservoir 32 and needle 33 of Syringe C are different to the reservoir 22 and needle 23 of Syringe E.
  • syringes of the present invention have been described by way of example only and modifications may be made whilst remaining within the scope of the invention.
  • stopper 15 can be combined with syringe reservoir 22 and needle 33, 23 or 13 to provide a syringe which forms part of the invention.
  • any of the characteristics of the syringes, needles and stoppers of the present invention can be combined to provide a syringe according to the invention, including but not limited to needle gauges suitable for subcutaneous injection (i.e. gauge 23 to 32), needle minimum internal diameter, stopper lamination, stopper coating number of bevels on the needle distal surface, syringe flange, stopper maximum internal diameter and diameter of outer circumferential rib on the stopper.
  • the present invention provides XmL of 150mg/mL omalizumab formulation for use in a method of treatment of one or more 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids, wherein X is 1 and wherein the X mL 150mg/mL omalizumab formulation is administered subcutaneously by a syringe, the syringe comprising: a reservoir filled with X mL of 150mg/mL omalizumab formulation, wherein the X mL 150mg/mL omalizumab formulation has 6000 or fewer particles of diameter > 10pm and/or 600 or fewer particles of diameter > 25pm; and the syringe further comprising: a stop
  • the needle can have a gauge of gauge 25 to gauge 29.
  • the syringe can be configured to 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 in about 4 seconds when a constant force of 10N is applied to the stopper.
  • Figure 7 demonstrates that needles of gauge 27 are particularly advantageous in contributing to the quicker injection time of the syringes of the present invention as compared to the prior art because each of Syringes A, C and E comprise a needle of gauge 27 whereas Syringe F comprises a needle of gauge 26.
  • the present invention provides XmL of 150mg/mL omalizumab formulation for use in a method of treatment one or more 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids, wherein X is 2, wherein the omalizumab formulation is administered subcutaneously by a syringe, the syringe comprising: a reservoir filled with X mL of 150mg/mL omalizumab formulation, wherein the X mL 150mg/mL omalizumab formulation has 6000 or fewer particles of diameter > 10pm and/or 600 or fewer particles of diameter > 25pm; and the syringe further comprising: a stopper, and a needle having a gauge of 27;
  • the needle has one of: a) a minimum internal diameter of 0.277mm; b) a minimum internal diameter of 0.191mm; c) a minimum internal diameter of 0.184mm; and d) a minimum internal diameter of 0.241mm.
  • Syringe D in Figure 7 demonstrates that the syringes of the present invention can be used to administer larger volumes of omalizumab than prior art syringes, i.e. larger than 0.5mL and 1mL omalizumab formulation.
  • Figure 8 shows the measured break loose force required to move the stopper of the syringes of the present invention (Syringes A, C, D and E) and the prior art syringe (Syringe F) from an initial stationary point to a velocity of 190mm/min.
  • Syringes A, C, D, E and F were filled with 150mg/ml omalizumab formulation as required and placed into storage at 5°C ⁇ 3 °C, 25°C ⁇ 3 °C or 40°C ⁇ 3 °C.
  • the break loose force of syringe samples stored at 5°C ⁇ 3 °C was tested at 2.5 and 6 months after filling.
  • the break loose force of syringe samples stored at 25°C ⁇ 3 °C was tested at time points after filling, and 1.5, 2.5 and 6 months after filling.
  • the break loose force of syringe samples stored at 40°C ⁇ 3 °C was tested 1.5 and 2.5 months after filling.
  • a motorized test stand was used to apply force to the stopper and measure the applied force and the instrument was adjusted to move the stopper at a velocity of 190mm/min.
  • the break loose force required to move the stopper of the prior art syringe (Syringe F) from an initial stationary point to a velocity of 190mm/min is one or more of: about 4N to about 6N after storage at 5°C ⁇ 3 °C for 2.5 months after filling; about 4.5N to about 6N after storage at 5°C ⁇ 3 °C for 6 months after filling.
  • the break loose force required to move the stopper of the prior art syringe (Syringe F) from an initial stationary point to a velocity of 190mm/min is one or more of: about 4N to about 4.5N at 25°C ⁇ 3 °C after filling; about 5.5N to about 7N after storage at 25°C ⁇ 3 °C for 1.5 months after filling; about 4.5N to about 7.5N after storage at 25°C ⁇ 3 °C for 2.5 months after filling; and/or about 7N to about 10N after storage at 25°C ⁇ 3 °C for 6 months after filling.
  • the break loose force required to move the stopper of the prior art syringe (Syringe F) from an initial stationary point to a velocity of 190mm/min is one or more of: about 6N to about 10N after storage at 40°C ⁇ 3 °C for 1 .5 months after filling; and about 8N to about 10N after storage at 25°C ⁇ 3 °C for 2.5 months after filling.
  • Figure 8 demonstrates that the break loose force required to move the stopper of the syringes of the present invention from an initial stationary point to a velocity of 190mm/min is much lower and much less variable as compared to the prior art.
  • the break loose force required to move the stopper of the syringes of the present invention from an initial stationary point to a velocity of 190mm/min is one or more of: About 2N to about 4N after storage at 5°C ⁇ 3 °C for 2.5 months after filling; about 2N to about 4N after storage at 5°C ⁇ 3 °C for 6 months after filling.
  • the break loose force required to move the stopper of the syringes of the present invention from an initial stationary point to a velocity of 190mm/min is one or more of: about 2N to about 3.5N at 25°C ⁇ 3 °C after filling; about 2N to about 4.5N after storage at 25°C ⁇ 3 °C for 1.5 months after filling; about 2.5N to about 5N after storage at 25°C ⁇ 3 °C for 2.5 months after filling; and/or about 2.5N to about 5.5N after storage at 25°C ⁇ 3 °C for 6 months after filling.
  • the break loose force required to move the stopper of the syringes of the present invention from an initial stationary point to a velocity of 190mm/min is: about 3N to about 4.5N after storage at 40°C ⁇ 3 °C for 1.5 months after filling; and about 3N to about 5N after storage at 40°C ⁇ 3 °C for 2.5 months after filling.
  • the syringes of the present invention preserve the purity and stability of omalizumab comparably with the current syringes.
  • Figure 9 shows the percentage of the main omalizumab charge variant measured by ion exchange chromatography for the prior art syringe (Syringe F) and syringes of the present invention (Syringes A, B, C, D and E).
  • Syringe samples were filled with 150mg/mL omalizumab formulation and placed into storage at 5°C ⁇ 3 °C or 25°C ⁇ 3 °C.
  • the percentage of the main omalizumab charge variant after storage at 5°C ⁇ 3 °C was measured by IEC after filling, after 2.5 months in storage and after 6 months in storage.
  • the percentage of the main variant after storage at 25°C ⁇ 3 °C was measured by IEC after 1 .5 months in storage and after 2.5 months in storage. Table 1 shows the test results.
  • the syringes of the present invention preserve the purity and stability of omalizumab similarly to the prior art syringe (syringe F).
  • the syringes of the present invention contain at least 76% main omalizumab charge variant measured by ion exchange chromatography after filling with 150mg/mL omalizumab solution stored at 5°C ⁇ 3°C.
  • the syringes of the present invention also preserve the stability of omalizumab similarly to the prior art syringe.
  • the syringes of the present invention contain at least 77% main omalizumab charge variant measured by ion exchange chromatography after being filled with 150mg/mL omalizumab solution and then stored at 5°C ⁇ 3°C for 2.5 months, compared to 76% for the prior art syringe under the same conditions.
  • the syringes of the present invention contain at least 69% main omalizumab charge variant after being filled with 150mg/mL omalizumab solution and then stored at 25°C ⁇ 3°C for 1.5 months.
  • Figure 10 shows the proportion of the first HIC peak for the prior art syringe (Syringe F) and syringes of the present invention (Syringes A, B, C, D and E).
  • Figure 11 shows the proportion of the second HIC peak for the prior art syringe and syringes present invention.
  • Figure 12 shows the proportion of the third HIC peak for the prior art syringe and syringes of the present invention.
  • the proportion of the first HIC peak is at least 62% for the syringes of the present invention after filling with 150mg/mL omalizumab solution stored at 5°C ⁇ 3°C.
  • the syringes of the present invention also preserve the stability of omalizumab.
  • the proportion of the first HIC peak is at least 62% for the syringes of the present invention after being filled with 150mg/mL omalizumab solution and then stored at 5°C ⁇ 3°C for 2.5 months, compared to 59% for the prior art syringe under the same conditions.
  • the proportion of the first HIC peak is at least 56% for the syringes of the present invention after being filled with 150mg/mL omalizumab solution and then stored at 25°C ⁇ 3°C for 1.5 months, compared to 53.8% for the prior art syringe under the same conditions.
  • the proportion of the first HIC peak is at least 51 % for the syringes of the present invention after being filled with 150mg/mL omalizumab solution and then stored at 25°C ⁇ 3°C for 2.5 months, compared to 49.9% for the prior art syringe under the same conditions.
  • the proportion of the first peak of the syringe measured by hydrophobic interaction chromatography is at least: a) 62% after filling with 150mg/mL omalizumab solution stored at 5°C ⁇ 3°C; and/or b) 62% after being filled with 150mg/mL omalizumab solution and then stored at 5°C ⁇ 3°C for 2.5 months.
  • the proportion of the first peak of the syringe measured by hydrophobic interaction chromatography reduces by 0.4% or less after the syringe is stored at 5°C ⁇ 3°C for 2.5 months.
  • the proportion of the first peak of the syringe measured by hydrophobic interaction chromatography is at least: a) 56% for the syringe after being filled with 150mg/mL omalizumab solution and then stored at 25°C ⁇ 3°C for 1 .5 months; and/or b) 51 % for the syringe after being filled with 150mg/mL omalizumab solution and then stored at 25°C ⁇ 3°C for 2.5 months.
  • the syringes of the present invention preserve the purity and stability of omalizumab similarly to current syringes.
  • Figure 13 shows the polysorbate 20 (PS20) content of the prior art syringe and syringes of the present invention.
  • Syringe samples were filled with 150mg/ml omalizumab formulation and placed into storage 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 in storage and after 6 months in storage. Table 6 shows the test results.
  • the syringes of the present invention preserve the purity and stability of omalizumab comparably with the prior art syringe (Syringe F).
  • the polysorbate 20 content of the syringes of the present invention is at least 0.4mg/mL after filling with 150mg/mL omalizumab solution stored at 5°C ⁇ 3°C. This demonstrates that the syringes of the present invention preserve purity of the 150mg/mL omalizumab solution comparably with the prior art syringe (syringe F), which contains 0.392mg/mL polysorbate 20 content under the same conditions.
  • 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 0.4mg/mL for the syringes of the present invention after being filled with 150mg/mL omalizumab solution and then stored at 25°C ⁇ 3°C for 1.5 months, compared to 0.360mg/mL for the prior art syringe under the same conditions.
  • the polysorbate 20 content of the syringes of the present invention is at least 0.3mg/mL for the syringes of the present invention after being filled with 150mg/mL omalizumab solution and then stored at 25°C ⁇ 3°C for 6 months, compared to 0.289mg/mL for the prior art syringe under the same conditions.
  • the syringe contains at least 0.4 mg/mL polysorbate 20 after filling with 150mg/mL omalizumab solution stored at 5°C ⁇ 3°C.
  • the syringe contains: a) at least 0.4mg/mL polysorbate 20 after being filled with 150mg/mL omalizumab solution and then stored at 25°C ⁇ 3°C for 1.5 months; and/or b) at least 0.3mg/mL polysorbate 20 after being filled with 150mg/mL omalizumab solution and then stored at 25°C ⁇ 3°C for 6 months.
  • syringes of the present invention can be provided alone, or in combination with a needle shield device.
  • Figures 14A and 14B show schematic diagrams of a prefilled syringe 50 in accordance with the present invention with a needle shield device 60.
  • Figure 14A shows a pre-use configuration and
  • Figure 14B shows a used configuration.
  • the syringe is provided in needle shield device comprising a needle sleeve and a plunger; and wherein a manual force can be applied to the plunger to expel the 150mg/mL omalizumab formulation and unlatch needle sleeve so that the needle sleeve can cover the needle after injection.
  • the present application describes 150mg/mL omalizumab formulation for use in a method of treatment, wherein 150mg/mL omalizumab formulation is administered subcutaneously by a syringe
  • the syringes of the present invention can be provided alone, or in combination with an autoinjector. Accordingly, in some embodiments of the invention, the syringe is provided in an autoinjector.
  • FIG 15 is a schematic diagram of a prefilled syringe 111 within an autoinjector 100.
  • the autoinjector comprises a housing 101 configured to contain the syringe 111 and a drive mechanism 102 configured to apply force to the stopper in a distal direction and expel fluid from the syringe through the needle.
  • a trigger mechanism 103 is provided to actuate the drive mechanism. In the example shown in Figure 15, the trigger 103 is moved in the direction of the arrow, away from the prefilled syringe.
  • the syringe comprises a reservoir filled with 150mg/mL omalizumab formulation, a stopper and a needle.
  • the autoinjector 100 can also be combined with any of the syringes of the invention - further details of the syringes of the invention and the fill volume are described with reference to Figures 3 to 6.
  • 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 150mg/mL omalizumab formulation out of the reservoir and through the needle.
  • a trigger mechanism 103 is provided which is movable from a hold position, in which the drive mechanism is held in a rest position, to a release position, in which the drive mechanism is released, causing the drive mechanism to drive the stopper through the reservoir towards the needle to expel the 150mg/mL omalizumab formulation out of the reservoir and through the needle in about 1 second to about 17 seconds.
  • the drive mechanism comprises a helical spring configured to apply a mean force of 25N to the stopper.
  • the mean 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 is engaged with the distal end of reservoir and cannot be driven any further) and calculating the mean of the two forces.
  • Hooke’s law can be used to calculate the force applied by a given spring at a given extension.
  • the drive mechanism of the autoinjector shown in Figure 15 comprises a helical drive spring
  • the invention is not limited to such a drive mechanism.
  • Other types of drive mechanism can be used to apply a mean average force of at least 10N to the stopper to expel the 150mg/mL omalizumab formulation out of the reservoir and through the needle in a time period of less than 17s in accordance with the present invention.
  • a drive mechanism comprising a torsion spring or an electromechanical drive can be used.
  • the autoinjector further comprises an autoinjector cap (not shown).
  • the autoinjector cap is configured to permanently engage with the syringe needle shield (described in more detail with reference to Figures 3 to 6) and removably engage with the autoinjector housing. When the autoinjector cap is disengaged from the housing, it removes the needle shield from the syringe, thus allowing access to the needle.
  • Figure 16 shows the measured time to expel the 150mg/mL omalizumab formulation out of the reservoir and through the needle using an autoinjector when combined with syringes of the invention.
  • the first autoinjector was fitted with Syringe A.
  • the second autoinjector was fitted with Syringe E.
  • the third autoinjector was fitted with Syringe C.
  • the fourth autoinjector was fitted Syringe D.
  • the trigger mechanism of each autoinjector was moved from the hold position to the release position and the time for the stopper to be driven through the reservoir until it engaged with the distal end of reservoir was measured. The test was repeated 20 times for each autoinjector embodiment.
  • Each autoinjector tested expelled the 150mg/mL omalizumab formulation out of the reservoir and through the needle in about 1 second to about 17 seconds.
  • the drive mechanism of each autoinjector that was tested included a helical spring configured to apply a mean average force of 25N to the stopper.
  • the first autoinjector expelled 1 ml of 150mg/mL omalizumab solution out of the reservoir and through the needle in about 3 to 5 seconds.
  • the second autoinjector expelled 1 ml of 150mg/mL omalizumab solution out of the reservoir and through the needle in about 4 to 6 seconds.
  • the third autoinjector expelled 1 ml of 150mg/mL omalizumab solution out of the reservoir and through the needle in about 3 to 4 seconds.
  • the third autoinjector expelled 1 ml of 150mg/mL omalizumab solution out of the reservoir and through the needle in about 9 seconds - this test result appears to be an error.
  • the fourth autoinjector embodiment expelled 2 ml of 150mg/mL omalizumab solution out of the reservoir and through the needle in about 6 to 7 seconds.
  • the present invention further provides an autoinjector filled with 150mg/mL omalizumab formulation which is configured to needle to expel the 150mg/mL omalizumab formulation out of the reservoir and through the needle in a time period of less than 17s. This time period of less than 17s is acceptable to patients.
  • Figure 16 only shows test results of autoinjectors with syringes filled with 1 mL or 2mL 150mg/mL omalizumab formulation, it will be understood that autoinjectors with syringes filled with 0.5mL 150mg/mL omalizumab formulation can also be provided in accordance with the invention.
  • Figure 16 does not show test results of an autoinjector fitted with the prior art syringe (syringe F) because the prior art syringe is not suitable for use with autoinjectors.
  • the prior art syringe is not suitable for use with autoinjectors because it cannot reliably withstand the high injection forces required to administer the omalizumab within an acceptable time period.
  • an autoinjector comprising: a syringe according to the invention, e.g. a syringe comprising a reservoir filled with 0.5mL, 1 mL or 2mL of 150mg/mL omalizumab formulation, a stopper, and a needle; a drive mechanism configured to apply force to the stopper to drive the stopper through the reservoir towards the needle to expel the 150mg/mL omalizumab formulation out of the reservoir and through the needle; a housing configured to contain the syringe and the drive mechanism; and a trigger mechanism movable from a hold position, in which the drive mechanism is held in a rest position in which it does not apply a force to the stopper, to a release position, in which the drive mechanism is released, causing the drive mechanism to apply a force to the stopper to drive the stopper through the reservoir towards the needle to expel the 150mg/mL omalizumab formulation out of the
  • the syringe can be filled with 0.5mL of 150mg/mL omalizumab formulation and wherein the drive mechanism is configured to expel the 0.5mL of 150mg/mL out of the reservoir and through the needle in a time period of about 1 second to about 17 seconds, about 1 second to about 16 seconds, about 1 second to about 15 seconds, about 1 second to about 14 seconds, about 1 second to about 13 seconds, about 1 second to about 12 seconds, about 1 second to about 11 seconds, about 1 second to about 10 seconds, about 1 second to about 9 seconds, about 1 second to about 8 seconds, about 1 second to about 7 seconds, about 1 seconds to about 6 seconds, about 1 second to about 5 seconds, about 1 second to about 4 seconds, about 1 second to about 2 seconds; or about 1 second.
  • the syringe can be filled with 1 mL of 150mg/mL omalizumab formulation, and the drive mechanism is configured to expel the 1 mL of 150mg/mL out of the reservoir and through the needle in a time period of about 3 seconds to about 17 seconds, about 3 seconds to about 16 seconds, about 3 seconds to about 15 seconds, about 3 seconds to about 14 seconds, about 3 seconds to about 13 seconds, about 3 seconds to about 12 seconds, about 3 seconds to about 11 seconds, about 3 seconds to about 10 seconds, about 3 seconds to about 9 seconds, about 3 seconds to about 8 seconds, about 3 seconds to about 7 seconds, about 3 seconds to about 6 seconds, about 3 seconds to about 5 seconds, about 3 seconds to about 4 seconds; or about 3 seconds.
  • the syringe be filled with 2mL of 150mg/mL omalizumab formulation
  • the drive is configured to expel the 2mL of 150mg/mL omalizumab formulation out of the reservoir and through the needle in a time period of about 6 seconds to 17 seconds, about 6 seconds to about 16 seconds, about 6 seconds to about 15 seconds, about 6 seconds to about 14 seconds, about 6 seconds to about 13 seconds, about 6 seconds to about 12 seconds, about 6 seconds to about 11 seconds, about 6 seconds to about 10 seconds, about 6 seconds to about 9 seconds, about 6 seconds to about 8 seconds, about 6 seconds to about 7 seconds, or about 6 seconds
  • the drive mechanism can be configured to apply a mean average force of at least 10N to the stopper over the time period in which the 150mg/mL omalizumab formulation is expelled. It can be configured to apply a mean average force to the stopper over the time period in which the 150mg/mL omalizumab formulation is expelled of at least 11 N, at least 12N, at least 13N, at least
  • 21 N at least 22N, at least 23N, at least 24N, at least 25N, at least 26N, at least 27N, at least
  • 28N at least 29N, at least 30N, at least 31 N, at least 32N, at least 33N, at least 34N, at least
  • 35N at least 36N, at least 37N, at least 38N, at least 39N or at least 40N.
  • the drive mechanism can comprise a helical spring, a torsion spring and/or an electromechanical drive.
  • the syringe is filled with 0.5mL of 150mg/mL omalizumab formulation and the drive is configured to expel the 0.5mL of 150mg/mL out of the reservoir and through the needle in a time period of about 1 second to about 17 seconds, about 1 second to about 16 seconds, about 1 second to about 15 seconds, about 1 second to about 14 seconds, about 1 second to about 13 seconds, about 1 second to about 12 seconds, about 1 second to about 11 seconds, about 1 second to about 10 seconds, about 1 second to about 9 seconds, about 1 second to about 8 seconds, about 1 second to about 7 seconds, about 1 seconds to about 6 seconds, about 1 second to about 5 seconds, about 1 second to about 4 seconds, about 1 second to about 2 seconds; or about 1 second.
  • the syringe is filled with 1 mL of 150mg/mL omalizumab formulation
  • the drive is configured to expel the 1mL of 150mg/mL out of the reservoir and through the needle in a time period of about 3 seconds to about 17 seconds, about 3 seconds to about 16 seconds, about 3 seconds to about 15 seconds, about 3 seconds to about 14 seconds, about 3 seconds to about 13 seconds, about 3 seconds to about 12 seconds, about 3 seconds to about 11 seconds, about 3 seconds to about 10 seconds, about 3 seconds to about 9 seconds, about 3 seconds to about 8 seconds, about 3 seconds to about 7 seconds, about 3 seconds to about 6 seconds, about 3 seconds to about 5 seconds, about 3 seconds to about 4 seconds; or about 3 seconds.
  • the syringe is filled with 2mL of 150mg/mL omalizumab formulation and the drive is configured to expel the 2mL of 150mg/mL omalizumab formulation out of the reservoir and through the needle in a time period of about 6 seconds to 17 seconds, about 6 seconds to about 16 seconds; optionally wherein the time period is one of: about 6 seconds to about 15 seconds, about 6 seconds to about 14 seconds, about 6 seconds to about 13 seconds, about 6 seconds to about 12 seconds, about 6 seconds to about 11 seconds, about 6 seconds to about 10 seconds, about 6 seconds to about 9 seconds, about 6 seconds to about 8 seconds, about 6 seconds to about 7 seconds, or about 6 seconds.
  • kit comprising a syringe according to the present invention and optionally: an autoinjector, a needle shield device, and/or instructions for administration.
  • one aspect of the invention there is provided, for the first time, injection of highly viscous 150mg/mL omalizumab formulation by an autoinjector.
  • one aspect provides for injection of highly viscous 150mg/mL omalizumab formulation in a time period of 1 second to 17 seconds - this time period is acceptable to patients and so improves ease of use and patient compliance.
  • the autoinjectors comprise a syringe filled with 1mL of 150mg/mL omalizumab formulation and comprising a drive mechanism configured to expel the 1mL of 150mg/mL out of the reservoir and through the needle in a time period of about 3 seconds to 6 seconds.
  • This injection time is much faster than the injection time of comparable selfadministered antibody formulations such as the 30mg/1mL Fasenra (benralizumab) autoinjector (injection time period of up to 15 seconds) and the 100mg/1 mL Nucala (mepolizumab) autoinjector (injection time period of up to 15 seconds).
  • the present invention provides an autoinjector comprising a syringe filled with 2mL of 150mg/mL omalizumab formulation and comprising a drive mechanism configured to expel the 2mL of 150mg/mL out of the reservoir and through the needle in a time period of about 6 seconds to 7 seconds.
  • This injection time is much faster than the injection time of comparable antibody formulations of similar volume; for example the 300mg/mL Dupixent (dupilumab) autoinjector (injection time of up to 20 seconds).
  • the faster injection times of autoinjectors of the present invention are, in part, because the syringes of the present invention expel 150mg/mL omalizumab formulation at faster times than prior art syringes when constant forces are applied are applied to the stopper.
  • the faster injection times of the autoinjectors of the present invention are, in part, because the syringes of the present invention require a lower break loose force than the prior art syringe.
  • the syringes of the present invention better preserve the purity and stability of omalizumab.
  • the better preserved purity and stability of omalizumab also contributes to the faster injection time of the syringes and autoinjectors of the present invention because it reduces aggregation and so limits increases in fluid viscosity.
  • C ma x is the maximum observed serum concentration
  • AUCiast is the area under the serum concentration-time curve calculated to last quantifiable concentration point
  • AUCint is the area under the serum concentration-time curve extrapolated to infinity.
  • AllCinf area under curve from time 0 to infinity; AUCiast, area under curve from time 0 to last measurable concentration sampling time; Cl, confidence interval; C ma x, maximum (peak) observed drug concentration after single dose administration; GMR, geometric mean ratio; PFS- AI, prefilled syringe assembled with an autoinjector; PFS-NSD, prefilled syringe with a needle safety device.
  • X mL of 150mg/mL omalizumab formulation for use in a method of treatment of one or more 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids, wherein X is 2, and wherein the X mL 150mg/mL omalizumab formulation is administered subcutaneously by a syringe, the syringe comprising: a reservoir filled with X mL of 150mg/mL omalizumab formulation, wherein the X mL of 150mg/mL omalizumab formulation has 6000 or fewer particles of diameters 10pm and/or 600 or fewer particles of diameter > 25pm; and the syringe further comprising: a stopper, and
  • X mL of 150mg/mL omalizumab formulation for use in a method of treatment of one or more 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids, wherein X is 2, 1 or 0.5 and wherein the X mL 150mg/mL omalizumab formulation is administered subcutaneously by a syringe, the syringe comprising: a reservoir filled with X mL of 150mg/mL omalizumab formulation, wherein the X mL 150mg/mL omalizumab formulation has 6000 or fewer particles of diameters 10pm and/or 600 or fewer particles of diameter > 25pm; and the syringe further comprising: a stopper
  • X mL of 150mg/mL omalizumab formulation for use in a method of treatment of one or more 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids, wherein X is 2, 1 or 0.5 and wherein the X mL 150mg/mL omalizumab formulation is administered subcutaneously by a syringe, the syringe comprising: a reservoir filled with X mL of 150mg/mL omalizumab formulation, wherein the X mL 150mg/mL omalizumab formulation has 6000 or fewer particles of diameters 10pm and/or 600 or fewer particles of diameter > 25pm; and the syringe further comprising: a stopper
  • X mL of 150mg/mL omalizumab formulation for use according to clause 9, wherein the syringe is configured to expel X mL of 150mg/ml omalizumab formulation through the needle in one or more of: a) less than 7.5 seconds to about 4 seconds when a constant force of 10N is applied to the stopper; b) less than 3.5 seconds to about 2 seconds when a constant force of 17N is applied to the stopper; and c) less than 2 seconds to about 1 second when a constant force of 30N is applied to the stopper.
  • X mL of 150mg/mL omalizumab formulation for use according to any one of clauses 2 to 4 and 8, wherein X is 0.5, wherein the syringe is to expel X mL of 150mg/ml omalizumab formulation through the needle in one or more of: a) less than 4 seconds when a constant force of 10N is applied to the stopper; b) less than 2 seconds when a constant force of 17N is applied to the stopper; and c) less than 1 second when a constant force of 30N is applied to the stopper.
  • X mL of 150mg/mL omalizumab formulation for use according to clause 11 , wherein the syringe is to expel X mL of 150mg/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 10N is applied to the stopper; b) less than 2 seconds to about 1 second when a constant force of 17N is applied to the stopper; and c) less than 1 second to about 0.5 seconds when a constant force of 30N is applied to the stopper.
  • X mL of 150mg/mL omalizumab formulation for use according to any one of clauses 1 to 16 wherein the syringe contains at least 0.4 mg/mL polysorbate 20 after filling with 150mg/mL omalizumab solution stored at 5°C ⁇ 1°C.
  • X mL of 150mg/mL omalizumab formulation for use according to any one of clauses 1 to 17 and 21 to 35 when not dependent on clauses 18 to 20, wherein a break loose force configured to move the stopper of the present invention from an initial stationary point to a velocity of 190mm/min is one or more of: a) about 2N to about 4N after storage at 5°C ⁇ 1 °C for 2.5 months; b) about 2N to about 4N after storage at 5°C ⁇ 1 °C for 6 months.
  • X mL of 150mg/mL omalizumab formulation for use according to any one of clauses 1 to 12 and 18 to 35 when not dependent on clauses 13 to 17, wherein a break loose force configured to move the stopper of the present invention from an initial stationary point to a velocity of 190mm/min is one or more of: a) about 2N to about 3.5N at 25°C ⁇ 1 °C after filling; b) about 2N to about 4.5N after storage at 25°C ⁇ 1 °C for 1 .5 months; c) about 2.5N to about 5N after storage at 25°C ⁇ 1 °C for 2.5 months; and/or d) about 2.5N to about 5.5N after storage at 25°C ⁇ 1 °C for 6 months.
  • X mL of 150mg/mL omalizumab formulation for use according to any one of clauses 1 to 12 and 21 to 35 when not dependent on clauses 13 to 20, wherein a break loose force configured to move the stopper of the present invention from an initial stationary point to a velocity of 190mm/min is one or more of: a) about 3N to about 4.5N after storage at 40°C ⁇ 1 °C for 1 .5 months; and b) about 3N to about 5N after storage at 40°C ⁇ 1 °C for 2.5 months.
  • X mL of 150mg/mL omalizumab formulation for use according to any one of clauses 1 to 38, wherein the syringe is provided in needle shield device comprising a needle sleeve and a plunger; and wherein a manual force can be applied to the plunger to expel the 150mg/mL omalizumab formulation and unlatch needle sleeve so that the needle sleeve can cover the needle after injection.
  • syringe comprising: a reservoir filled with X mL of 150mg/mL omalizumab formulation, wherein the X mL of 150mg/mL omalizumab formulation has 6000 or fewer particles of diameters 10pm and/or 600 or fewer particles of diameter > 25pm; 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.
  • syringe comprising: a reservoir filled with X mL of 150mg/mL omalizumab formulation, wherein the X mL 150mg/mL omalizumab formulation has 6000 or fewer particles of diameters 10pm and/or 600 or fewer particles of diameter s 25pm; and the syringe further comprising: a stopper, and a needle having a gauge of 27; 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.
  • syringe comprising: a reservoir filled with X mL of 150mg/mL omalizumab formulation, wherein the X mL of 150mg/mL omalizumab formulation has 6000 or fewer particles of diameters 10pm and/or 600 or fewer particles of diameter s 25pm, wherein X is 2; 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.
  • syringe comprising: a reservoir filled with X mL of 150mg/mL omalizumab formulation, wherein the X mL 150mg/mL omalizumab formulation has 6000 or fewer particles of diameter s 10pm and/or 600 or fewer particles of diameter s 25pm, wherein X is 0.5, 1 or 2; and the syringe further comprising: a stopper, and a needle having a gauge of 27; 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 of clause 46 the needle has one of: a) a minimum internal diameter of 0.277mm; b) a minimum internal diameter of 0.191mm; c) a minimum internal diameter of 0.184mm; and d) a minimum internal diameter of 0.241mm.
  • a syringe comprising: a reservoir filled with X mL of 150mg/mL omalizumab formulation, wherein the X mL 150mg/mL omalizumab formulation has 6000 or fewer particles of diameters 10pm and/or 600 or fewer particles of diameter > 25pm, wherein X is 0.5, 1 or 2; 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, the syringe being configured to expel 150mg/mL omalizumab formulation through the needle in less than 0.8 seconds per mL per N of constant force applied to the stopper.
  • 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 10N is applied to the stopper; b) about 8.5 seconds to about 6 seconds when a constant force of 17N is applied to the stopper; and c) about 5 seconds to about 4 seconds when a constant force of 30N is applied to the stopper.
  • X is 1 or 0.5
  • the syringe is configured to expel X mL of 150mg/ml omalizumab formulation through the needle in less than 0.67 ⁇ 0.5 seconds per mL, per N of constant force applied, optionally less than 0.54 ⁇ 0.2 seconds per mL, per N of constant force applied, further optionally less than 0.4 ⁇ 0.5 seconds per mL, per N of constant force applied.
  • the syringe according to clause 53 wherein the syringe is configured to expel X mL of 150mg/ml omalizumab formulation through the needle in one or more of: a) less than 7.5 seconds to about 4 seconds when a constant force of 10N is applied to the stopper; b) less than 3.5 seconds to about 2 seconds when a constant force of 17N is applied to the stopper; and c) less than 2 seconds to about 1 second when a constant force of 30N is applied to the stopper.
  • X is 0.5
  • the syringe is to expel X mL of 150mg/ml omalizumab formulation through the needle in one or more of: a) less than 4 seconds when a constant force of 10N is applied to the stopper; b) less than 2 seconds when a constant force of 17N is applied to the stopper; and c) less than 1 second when a constant force of 30N is applied to the stopper.
  • the syringe according to clause 55 wherein the syringe is to expel X mL of 150mg/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 10N is applied to the stopper; b) less than 2 seconds to about 1 second when a constant force of 17N is applied to the stopper; and c) less than 1 second to about 0.5 seconds when a constant force of 30N is applied to the stopper.
  • a break loose force configured to move the stopper of the present invention from an initial stationary point to a velocity of 190mm/min is one or more of: a) about 2N to about 3.5N at 25°C ⁇ 1 °C after filling; b) about 2N to about 4.5N after storage at 25°C ⁇ 1 °C for 1.5 months; c) about 2.5N to about 5N after storage at 25°C ⁇ 1 °C for 2.5 months; and/or d) about 2.5N to about 5.5N after storage at 25°C ⁇ 1 °C for 6 months.
  • a method of treating a patient with one or more 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids comprising administering 2 mL of 150mg/mL omalizumab formulation to the patient, wherein the omalizumab formulation is administered subcutaneously by a syringe, the syringe comprising: a reservoir filled with 2 mL of 150mg/mL omalizumab formulation, wherein the 2 mL 150mg/mL omalizumab formulation has 6000 or fewer particles of diameter > 10pm and/or 600 or fewer particles of diameter > 25pm; and the
  • the needle has one of: a) a minimum internal diameter of 0.277mm; b) a minimum internal diameter of 0.191mm; c) a minimum internal diameter of 0.184mm; and d) a minimum internal diameter of 0.241mm.
  • a method of treating a patient with of one or more 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids comprising administering X mL of 150mg/mL omalizumab formulation to the patient, wherein X is 2, 1 or 0.5 and wherein the X mL 150mg/mL omalizumab formulation is administered subcutaneously by a syringe, the syringe comprising: a reservoir filled with X mL of 150mg/mL omalizumab formulation, wherein the X mL 150mg/mL omalizumab formulation has 6000 or fewer particles of diameter > 10pm and/or 600 or fewer particles of diameter > 25pm; and the syring
  • 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 10N is applied to the stopper; b) about 8.5 seconds to about 6 seconds when a constant force of 17N is applied to the stopper; and c) about 5 seconds to about 4 seconds when a constant force of 30N is applied to the stopper.
  • the syringe is configured to expel X mL of 150mg/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 in about 4 seconds when a constant force of 10N is applied to the stopper; b) less than 3.5 seconds to about 2 seconds when a constant force of 17N is applied to the stopper; and c) less than 2 seconds to about 1 second when a constant force of 30N is applied to the stopper.
  • the syringe is to expel X mL of 150mg/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 10N is applied to the stopper; b) less than 2 seconds to about 1 second when a constant force of 17N is applied to the stopper; and c) less than 1 second to about 0.5 seconds when a constant force of 30N is applied to the stopper.
  • the syringe contains: a) at least 76% main omalizumab charge variant measured by ion exchange chromatography after being filled with 150mg/mL omalizumab solution stored at 5°C ⁇ 1 °C; and/or b) at least 77% main omalizumab charge variant measured by ion exchange chromatography after being filled with 150mg/mL omalizumab solution and then stored at 5°C ⁇ 1 °C for 2.5 months.
  • the syringe contains: a) at least 0.4mg/mL polysorbate 20 after being filled with 150mg/mL omalizumab solution and then stored at 25°C ⁇ 1 °C for 1 .5 months; and/or b) at least 0.3mg/mL polysorbate 20 after being filled with 150mg/mL omalizumab solution and then stored at 25°C ⁇ 1 °C for 6 months.
  • the needle has a gauge of gauge 26 to gauge 29, most preferably gauge 27. .
  • a break loose force configured to move the stopper of the present invention from an initial stationary point to a velocity of 190mm/min is one or more of: a) about 2N to about 4N after storage at 5°C ⁇ 1 °C for 2.5 months after filling; b) about 2N to about 4N after storage at 5°C ⁇ 1 °C for 6 months after filling. .
  • a break loose force configured to move the stopper of the present invention from an initial stationary point to a velocity of 190mm/min is one or more of: a) about 2N to about 3.5N at 25°C ⁇ 1 °C after filling; b) about 2N to about 4.5N after storage at 25°C ⁇ 1 °C for 1.5 months after filling; c) about 2.5N to about 5N after storage at 25°C ⁇ 1 °C for 2.5 months after filling; and/or d) about 2.5N to about 5.5N after storage at 25°C ⁇ 1 °C for 6 months after filling.
  • a break loose force configured to move the stopper of the present invention from an initial stationary point to a velocity of 190mm/min is one or more of: a) about 3N to about 4.5N after storage at 40°C ⁇ 1 °C for 1.5 months after filling; and b) about 3N to about 5N after storage at 40°C ⁇ 1 °C for 2.5 months after filling. .
  • the method of claim 129 wherein the aseptic filling is performed by a peristaltic pump or stainless steel piston pump. .
  • the method of claim 129 wherein, prior to the aseptic filling, the reservoir and needle are sterilised by ethylene oxide gas treatment, electron beam and/or steam sterilisation by autoclave. .
  • a syringe comprising: a reservoir filled with X mL of 150mg/mL omalizumab formulation, wherein X is 2, 1 or 0.5, wherein the X mL of 150mg/mL omalizumab formulation has 6000 or fewer particles of diameter > 10pm and/or 600 or fewer particles of diameter > 25pm; and the syringe further comprising: a stopper, and a needle having a gauge of gauge 25 to gauge 29, 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 fulfilled when a constant force of 10N 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 is 1 , the syringe is configured to ex
  • a syringe comprising: a reservoir filled with X mL of 150mg/mL omalizumab formulation, wherein X is 2, the X mL 150mg/mL omalizumab formulation has 6000 or fewer particles of diameter s 10pm and/or 600 or fewer particles of diameter > 25pm; and the syringe further comprising: a stopper, and a needle having a gauge of 27; 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. .
  • a method of treating a patient with one or more 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids comprising administering 300mg omalizumab formulation to the patient, wherein the method comprises administering 2mL of 150mg/mL omalizumab formulation subcutaneously by one syringe filled with 2mL 150mg/mL omalizumab formulation.
  • a method of treating a patient with one or more 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids comprising administering 450mg omalizumab formulation to the patient, wherein the method comprises: administering 2mL of 150mg/mL omalizumab formulation subcutaneously by one syringe filled with 2mL 150mg/mL omalizumab formulation; and administering 1mL of 150mg/mL omalizumab formulation subcutaneously by one syringe filled with 1mL 150mg/mL omalizumab formulation.
  • a method of treating a patient with one or more 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids comprising administering 525mg omalizumab formulation to the patient, wherein the method comprises: administering 2mL of 150mg/mL omalizumab formulation subcutaneously by one syringe filled with 2mL 150mg/mL omalizumab formulation; administering 1mL of 150mg/mL omalizumab formulation subcutaneously by one syringe filled with 1mL 150mg/mL omalizumab formulation; and administering 0.5mL of 150mg/mL omalizumab formulation subcutaneously by one syringe filled with 0.5m
  • a method of treating a patient with one or more 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids comprising administering 600mg omalizumab formulation to the patient, wherein the method comprises: administering 2mL of 150mg/mL omalizumab formulation subcutaneously by one syringe filled with 2mL 150mg/mL omalizumab formulation; and administering 2mL of 150mg/mL omalizumab formulation subcutaneously by one syringe filled with 2mL 150mg/mL omalizumab formulation.
  • any one of the steps requiring administering 2mL of 150mg/mL omalizumab formulation subcutaneously by one syringe filled with 2mL 150mg/mL omalizumab formulation comprises performing the method of clause 88, or clause 90 wherein X is 2.
  • the method of any one of clauses 137 and 139, wherein any one of the steps requiring administering 0.5mL 150mg/mL omalizumab formulation subcutaneously by one syringe filled with 0.5mL 150mg/mL omalizumab formulation comprises performing the method of clause 90 wherein X is 0.5. .
  • any one of the steps requiring administering 1mL 150mg/mL omalizumab formulation subcutaneously by one syringe filled with 1 mL 150mg/mL omalizumab formulation comprises performing the method of clause 90 wherein X is 1. .
  • a syringe comprising: a reservoir filled with 2 mL of 150mg/mL omalizumab formulation, wherein the 2 mL 150mg/mL omalizumab formulation has 6000 or fewer particles of diameter > 10pm and/or 600 or fewer particles of diameter > 25pm; and the syringe further comprises: a stopper, and a needle having a gauge of 27; 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. .
  • a syringe comprising: a reservoir filled with X mL of 150mg/mL omalizumab formulation, wherein X is 2, 1 or 0.5, wherein the X mL 150mg/mL omalizumab formulation has 6000 or fewer particles of diameter > 10pm and/or 600 or fewer particles of diameter > 25pm; and the syringe further comprises: a stopper, and a needle having a gauge of gauge 25 to gauge 29; 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, wherein one of the following options is fulfilled when a constant force of 10N 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 is 1 , the syringe is configured to expel the omali
  • the syringe of clause 147 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 10N is applied to the stopper; b) about 8.5 seconds to about 6 seconds when a constant force of 17N is applied to the stopper; and c) about 5 seconds to about 4 seconds when a constant force of 30N is applied to the stopper. .
  • the syringe of clause 149 wherein the syringe is configured to expel X mL of 150mg/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 in about 4 seconds when a constant force of 10N is applied to the stopper; b) less than 3.5 seconds to about 2 seconds when a constant force of 17N is applied to the stopper; and c) less than 2 seconds to about 1 second when a constant force of 30N is applied to the stopper. .
  • the syringe of clause 151 wherein the syringe is to expel X mL of 150mg/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 10N is applied to the stopper; b) less than 2 seconds to about 1 second when a constant force of 17N is applied to the stopper; and c) less than 1 second to about 0.5 seconds when a constant force of 30N is applied to the stopper. .
  • the syringe of clause 144 or clause 146, wherein the proportion of the first peak of the syringe measured by hydrophobic interaction chromatography is at least: a) 62% after filling with 150mg/mL omalizumab solution stored at 5°C ⁇ 1°C; and/or b) 62% after being filled with 150mg/mL omalizumab solution and then stored at 5°C ⁇ 1 °C for 2.5 months. .
  • the syringe of clause 144 or clause 146, wherein the proportion of the first peak of the syringe measured by hydrophobic interaction chromatography reduces by 0.4% or less after the syringe is stored at 5°C ⁇ 1°C for 2.5 months. .
  • the syringe of clause 144 or clause 146 wherein the syringe contains: a) at least 0.4mg/mL polysorbate 20 after being filled with 150mg/mL omalizumab solution and then stored at 25°C ⁇ 1 °C for 1 .5 months; and/or b) at least 0.3mg/mL polysorbate 20 after being filled with 150mg/mL omalizumab solution and then stored at 25°C ⁇ 1 °C for 6 months. .
  • the syringe of clause 161 wherein when the needle has a gauge of 27, the needle has one of: a) a minimum internal diameter of 0.277mm; b) a minimum internal diameter of 0.191mm; c) a minimum internal diameter of 0.184mm; and d) a minimum internal diameter of 0.241mm. .
  • the syringe of clause 161 wherein when the needle has a gauge of 28, the needle has one of: a) a minimum internal diameter of 0.133mm; and b) a minimum internal diameter of 0.190mm. .
  • the syringe of clause 161 wherein when the needle has a gauge of 29, the needle has one of: a) a minimum internal diameter of 0.265mm; b) a minimum internal diameter of 0.240mm; c) a minimum internal diameter of 0.190mm; and d) a minimum internal diameter of 0.133mm; preferably wherein the needle has a minimum internal diameter of 0.240mm or 0.265mm.
  • ETFE ethylene tetrafluoroethylene
  • the syringe of clause 146 wherein when the stopper is not inserted into the reservoir, it has one of: a) a maximum external diameter of 6.67mm to 7.10mm and/or a length of 7.85 ⁇ 0.4 mm; and b) a maximum external diameter of 6.70 ⁇ 0.15mm and/or a length of 7.85 ⁇ 0.4 mm..
  • a break loose force configured to move the stopper of the present invention from an initial stationary point to a velocity of 190mm/min is one or more of: a) about 2N to about 3.5N at 25°C ⁇ 1 °C after filling; b) about 2N to about 4.5N after storage at 25°C ⁇ 1 °C for 1.5 months after filling; c) about 2.5N to about 5N after storage at 25°C ⁇ 1 °C for 2.5 months after filling; and/or d) about 2.5N to about 5.5N after storage at 25°C ⁇ 1 °C for 6 months after filling.
  • a break loose force configured to move the stopper of the present invention from an initial stationary point to a velocity of 190mm/min is one or more of: a) about 3N to about 4.5N after storage at 40°C ⁇ 1 °C for 1.5 months after filling; and b) about 3N to about 5N after storage at 40°C ⁇ 1 °C for 2.5 months after filling. .
  • the syringe of clause 144 or clause 146 wherein the syringe is provided in a needle shield device comprising a needle sleeve and a plunger; and wherein a manual force can be applied to the plunger to expel the 150mg/mL omalizumab formulation and unlatch needle sleeve so that the needle sleeve can cover the needle after injection.
  • the syringe of clause 185 wherein the aseptic filling is performed by a peristaltic pump or stainless steel piston pump. .
  • the syringe of clause 185 wherein, prior to the aseptic filling, the reservoir and needle are sterilised by ethylene oxide gas treatment, electron beam and/or steam sterilisation by autoclave. .
  • a method of treating a patient with one or more 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids comprising administering 300mg omalizumab formulation to the patient; wherein the method comprises administering 1mL 150mg/mL omalizumab formulation subcutaneously by a syringe and performing the method of clause 90 wherein X is 1 . .
  • a method of treating a patient with one or more 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids comprising administering 375mg omalizumab formulation to the patient; wherein the method comprises administering 0.5mL 150mg/mL omalizumab formulation subcutaneously by a syringe; and one of: a) performing the method of clause 88 or clause 90 wherein X is 2; and b) performing the method of clause 90 wherein X is 1 and administering 1mL 150mg/mL omalizumab formulation subcutaneously by a syringe.
  • a method of treating a patient with one or more 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids comprising administering 450mg omalizumab formulation to the patient; wherein the method comprises administering 1mL 150mg/mL omalizumab formulation subcutaneously by a syringe; and one of: a) performing the method of clause 88 or clause 90 wherein X is 2; and b) performing the method of clause 90 wherein X is 1 and administering 1mL 150mg/mL omalizumab formulation subcutaneously by a syringe.
  • a method of treating a patient with one or more 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids comprising administering 525mg omalizumab formulation to the patient; wherein the method comprises administering 1mL 150mg/mL omalizumab formulation subcutaneously by a syringe and administering 0.5mL 150mg/mL omalizumab formulation subcutaneously by a syringe; and one of: a) performing the method of clause 88 or clause 90 wherein X is 2; b) performing the method of clause 90 wherein X is 1 and administering 1mL 150mg/mL omalizumab formulation subcutaneously by a syringe.
  • a method of treating a patient with one or more 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 aeroallergen and symptoms that are inadequately controlled with inhaled corticosteroids comprising administering 600mg omalizumab formulation to the patient; wherein the method comprises administering 1mL 150mg/mL omalizumab formulation subcutaneously by a syringe, administering 1 mL 150mg/mL omalizumab formulation subcutaneously by a syringe administering 1mL 150mg/mL omalizumab formulation subcutaneously by a syringe; and performing the method of clause 90 wherein X is 1 .
  • any one of the steps requiring administering 0.5mL 150mg/mL omalizumab formulation subcutaneously by a syringe comprises performing the method of clause 90 wherein X is 0.5.
  • the method of any one of claims 190 to 194 and 196, wherein any one of the steps requiring administering 1mL 150mg/mL omalizumab formulation subcutaneously by a syringe comprises performing the method of clause wherein X is 1 . .

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  • Infusion, Injection, And Reservoir Apparatuses (AREA)
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  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
EP24748362.1A 2023-07-28 2024-07-23 Neue verwendungen von omalizumab Pending EP4683947A1 (de)

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EP23188544 2023-07-28
EP24171754 2024-04-22
EP24183812.7A EP4497758A1 (de) 2023-07-28 2024-06-21 Neue verwendungen von omalizumab
PCT/EP2024/070864 WO2025026821A1 (en) 2023-07-28 2024-07-23 New uses of omalizumab

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