Patent Application
20250034281
This application claims the benefit of European patent application 23188544.3 filed Jul. 28, 2023, the complete contents of which are incorporated herein by reference for all purposes.
Omalizumab is a recombinant DNA-derived humanized IgG1k 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.
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 1.4 mL water for injection to a vial of 75 or 150 mg 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. As this process is lengthy and complex, XOLAIR® lyophilized powder can be administered only by a healthcare professional, limiting ease of use and patient experience. As described in US2002/0045571, this reconstituted formulation is about 80 fold more viscous than water at 25° C.
After initial authorization omalizumab (XOLAIR®) became available as a 75 mg/0.5 mL and 150 mg/l 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 150 mg/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. 2021 January; 22(1): 39). Firstly, it provides the possibility of self-administration, limiting the need for patients to visit healthcare providers to receive treatment. Secondly, 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.
However, there are still difficulties associated with current dosage regimes and modes of administration of omalizumab. Firstly, omalizumab is usually administered in a dosage of 150 mg to 375 mg subcutaneously every 2 to 4 weeks but only 15% to 20% of patients can receive their XOLAIR® treatment with one single injection using the currently available 75 mg/0.5 mL and 150 mg/l mL doses. Secondly, 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. Thirdly, 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. In 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.
Currently, omalizumab is provided 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 150 mg/mL omalizumab formulation to the patient, by a syringe having a reservoir filled with 0.5 mL or 1 mL of 150 mg/mL omalizumab formulation.
It is an object of the invention to provide new uses of omalizumab, new syringes, and new omalizumab administration/dosage regimens which can overcome the above obstacles to improve ease of use, patient experience, patient adherence and outcomes using omalizumab. In particular, it is an object of the invention to provide new uses which reduce the number of individual injections required per treatment, reduce the time and injection forces required to deliver the omalizumab formulation subcutaneously and to reduce the risk of injection site reactions. It is also an object of the invention to achieve these improvements without loss of antibody stability and purity, and while achieving bioequivalence with the known syringes.
However, there are significant difficulties in providing a mode of administration of omalizumab which achieves these objects because omalizumab is unusually viscous in solution, particularly at the high concentration which is required for a 150 mg/ml dosage. These difficulties are described in more detail below.
The XOLAIR® formulation is 150 mg/mL antibody with 42.1 mg/mL L-arginine hydrochloride, 1.37 mg/mL L-histidine, 2.34 mg/mL L-histidine hydrochloride monohydrate, 0.4 mg/mL polysorbate 20 as an aqueous solution (in sterile water for injection (USP)). Omalizumab XOLAIR® 75 mg/0.5 mL, 150 mg/l mL and 300 mg/2 ml all have the same formulation, with the high 150 mg/mL antibody concentration. The viscosity of omalizumab XOLAIR® is 12 to 14 mPa·s at room temperature. In one experiment, viscosity measured at a shear rate of 200 s−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.
The high viscosity of omalizumab formulations presents several difficulties in achieving the object of the invention.
In general, the higher the viscosity a fluid has, the more force and time are required to inject it using a syringe. Patients can struggle to apply high injection forces to syringes and so can fail to push syringe stoppers to their terminal positions within the syringe to administer a complete dose. Furthermore, high injection forces increase the risk of syringe breakage.
Long injection times greatly reduce patient experience and compliance. In general, it is accepted that patients can comfortably hold a syringe in place for a maximum of 20 seconds. Therefore, when using syringes which inject drugs in a time approaching 20 seconds, there is an increased risk of incomplete dosage because patients prematurely remove the syringe from the injection site due to discomfort.
These issues of high injection forces and long injection times are also exacerbated when administering larger volumes of omalizumab (>1 mL) because the higher the volume of fluid that must be injected, the more force and time are required to inject it. In addition, higher dosing volumes also result in higher pressures at the injection site, leading to higher chance of reaction at the injection site and associated injection errors.
Lubricants can be included within a syringe (e.g. siliconisation) to reduce injection force and times, but they can cause protein aggregation, reducing the purity and effectiveness of the omalizumab solution. In addition, the protein aggregation can cause blockages, thus requiring more force to inject the solution, reducing ease of use. Finally, it is necessary to bear in mind that regulatory and international standards must be met when making any improvements to currently available omalizumab prefilled syringes.
Studies have been conducted to investigate the impact of viscosity, volume and flow rate on patient experience of subcutaneous injection, see: 1) Rini et al. Enabling faster subcutaneous delivery of larger volume, high viscosity fluids. Expert Opinion on Drug Delivery. 2022, Vol. 19, No. 9, 1165-1176, 2) Roberts et al. Novel cannula design improves large volume auto-injection rates for high viscosity solutions. Drug Delivery, 29:1 43-51 and 3) Berteau et al. Evaluation of the impact of viscosity, injection volume, and injection flow rate on subcutaneous injection tolerance. Medical Devices: Evidence and Research 2015:8 473-484. However, some of these studies have been conducted on non-biologic solutions and so the applicability of the findings to uses of omalizumab is limited. Berteau et al. (2015) and Rini et al. (2022) make clear that it is difficult to accurately predict the behaviour of any biologic when it is administered subcutaneously because the unique characteristics of each drug will have an impact on its behaviour. These unique characteristics include particle size, shape, settling/resuspension characteristics and aggregation/agglomeration potential and viscoelastic flow behaviour. Berteau et al. (2015) concludes that each drug delivery device for high-volume, high-speed subcutaneous injection must be specifically designed for each drug in order to optimise ease of use, patient experience, patient adherence and outcomes.
The inventors have overcome the difficulties set out above to provide new uses of omalizumab and methods of treatment which address the various issues at hand. According to an aspect of the invention, there is provided 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, the method comprising administering X mL of 150 mg/mL omalizumab formulation to the patient, wherein X is 2 and wherein the X mL 150 mg/ml omalizumab formulation is administered subcutaneously by a syringe, the syringe comprising:
Providing a syringe containing 2 mL of 150 mg/mL omalizumab formulation reduces the number of individual injections required per treatment for patients who are prescribed a dose larger than 150 mg 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.
As will be demonstrated below, 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. In addition, since 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. Hence, the present invention improves ease of use, patient experience, patient adherence and outcomes using omalizumab.
In some embodiments of the invention, the needle has one of:
Larger minimum internal diameters further reduce the injection time required to administer omalizumab.
According to a second aspect of the invention, there is provided 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, the method comprising administering X mL of 150 mg/mL omalizumab formulation to the patient, wherein X is 2, 1 or 0.5 and wherein the X mL 150 mg/ml omalizumab formulation is administered subcutaneously by a syringe, the syringe comprising:
a reservoir filled with X mL of 150 mg/mL omalizumab formulation, wherein the X mL 150 mg/mL omalizumab formulation has 6000 or fewer particles of diameter≥10 μm and/or 600 or fewer particles of diameter≥25 μm; and the syringe further comprising:
Systems for measuring injection time of syringes and methods of setting up said systems are well known in the art.
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.
In some embodiments of the invention wherein X is 2, the syringe is configured to expel the omalizumab formulation contained in the reservoir through the needle in one or more of:
In some embodiments of the invention wherein X is 2, the syringe is configured to expel X mL of the omalizumab formulation contained in the reservoir through the needle in one or more of:
In some embodiments of the invention wherein X is 1, the syringe is to expel X mL of 150 mg/ml omalizumab formulation through the needle in one or more of:
In some embodiments of the invention wherein X is 1, the syringe is configured to expel X mL of 150 mg/ml omalizumab formulation through the needle in one or more of:
In some embodiments of the invention wherein X is 0.5, the syringe is to expel X mL of 150 mg/ml omalizumab formulation through the needle in one or more of:
In some embodiments of the invention wherein X is 0.5, the syringe is to expel X mL of 150 mg/ml omalizumab formulation through the needle in one or more of:
In some embodiments of the invention, the syringe contains:
In some embodiments of the invention, 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).
In some embodiments of the invention, the proportion of the first peak of the syringe measured by hydrophobic interaction chromatography is at least:
In some embodiments of the invention, 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.
In some embodiments of the invention, the syringe contains at least 0.4 mg/mL polysorbate 20 after filling with 150 mg/mL omalizumab solution stored at 5° C.±3° C.
In some embodiments of the invention, the syringe contains at least 69% main omalizumab charge variant measured by ion exchange chromatography after being filled with 150 mg/mL omalizumab solution and then stored at 25° C.±3° C. for 1.5 months.
In some embodiments of the invention, the proportion of the first peak of the syringe measured by hydrophobic interaction chromatography is at least:
In some embodiments of the invention, the syringe contains:
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.
In some embodiments of the invention, 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.
In some embodiments of the invention, the needle has one of:
In some embodiments of the invention, the needle has a gauge of gauge 25 to gauge 29, preferably gauge 26 to gauge 28, most preferably gauge 27.
In some embodiments when the needle has a gauge of 25, the needle has one of:
In some embodiments when the needle has a gauge of 26, the needle has one of:
In some embodiments when the needle has a gauge of 27, the needle has one of:
In some embodiments when the needle has a gauge of 28, the needle has one of:
In some embodiments when the needle has a gauge of 29, the needle has one of:
In another preferred embodiment of the invention, 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 0.240 mm. In another preferred embodiment of the invention, the needle has a gauge of 29 and a minimum internal diameter of 0.265 mm.
In some embodiments of the invention, the stopper has a fluoro-resin on the product contacting side or an ethylene tetrafluoroethylene (ETFE) barrier film lamination. 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. In addition, the lamination helps to prevent contamination between the material of the stopper and omalizumab, preserving the stability and purity of the omalizumab.
In some embodiments of the invention, the stopper has a B2-40 UV cured lubrication coating or is lubricated with 1000 cSt 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. In addition, 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.
In some embodiments of the invention, the syringe has an internal coating of between 0.3-1.0 mg (e.g. 0.4±0.2 mg or 0.7±0.2 mg) 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. In addition, the internal coating of the syringe helps to preserve the stability and purity of the omalizumab.
In some embodiments of the invention, 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.
In some embodiments of the invention, the apparent viscosity of the 150 mg/ml omalizumab formulation at a shear rate of 200 s−1 is: 24.7±0.5 mPa·s at 5.0±0.2° C., 15.3±0.5 mPa·s at 15.0±0.2° C., 11.4±0.5 mPa·s at 25.0±0.2° C., or 7.2±1.2 mPa·s at 40.0±0.2° C.
In some embodiments of the invention, 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.
In some embodiments of the invention, the syringe has a round flange at a proximal end of the reservoir. In some embodiments of the invention the round flange has a maximum diameter of 11±0.25 mm or 14.7±0.25 mm. 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.
In some embodiments of the invention, when X is 1 or 0.5, the syringe has a length of 54.0±0.5 mm and an internal diameter of 6.35 mm±0.05 mm.
In some embodiments of the invention, when X is 1 or 0.5, when the stopper is not inserted into the reservoir, it has one of:
In some embodiments of the invention when X is 1 or 0.5, the stopper 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.
In some embodiments of the invention when X is 2, the syringe has a length of 54.0±0.5 mm and an internal diameter of 8.65 mm±0.05 mm.
In some embodiments of the invention when X is 2, the stopper has a maximum external diameter 9.05±0.15 mm and/or length 7.70±0.4 mm when not inserted into the reservoir.
In some embodiments of the invention, when X is 2, the stopper 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.
In some embodiments of the invention, a break loose force configured to move the stopper of the present invention from an initial stationary point to a velocity of 190 mm/min is one or more of:
In some embodiments of the invention, a break loose force configured to move the stopper of the present invention from an initial stationary point to a velocity of 190 mm/min is one or more of:
In some embodiments of the invention, a break loose force configured to move the stopper of the present invention from an initial stationary point to a velocity of 190 mm/min is one or more of:
The syringes of the present invention require a lower break loose force than the prior art syringes, reducing injection force and time. In addition, 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. In some embodiments of the invention, the syringe is provided in needle shield device comprising a needle sleeve and a plunger; and wherein
In some embodiments of the invention, the syringe is manufactured by a method comprising:
In some embodiments of the invention, the aseptic filling is performed by a peristaltic pump or stainless steel piston pump.
In some embodiments of the invention, 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.
While the claims herein relate to a method of treatment, wherein the 150 mg/ml omalizumab formulation is administered subcutaneously by a syringe, it will be understood that the syringes of the present invention can be provided alone, or in combination with an autoinjector and that the present invention also encompasses new omalizumab dosing regimens using the syringe of the present invention. Accordingly, additional clauses covering the syringe of the present invention are set out below.
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:
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. In particular, 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.
Below is a detailed description of the present invention and its advantages and improvements over the current uses of omalizumab, current syringes and current administration regimens. The detailed description of the present invention is structured as follows. Firstly, the syringe currently used to administer omalizumab subcutaneously is described with reference to
As will be explained in detail below, the experimental results of tests conducted on the prior art syringe and five embodiments of syringes of the invention demonstrate the following points.
As a result, the experimental results demonstrate that the inventors have provided syringes which reduce the time and injection forces required to deliver the omalizumab formulation subcutaneously and reduce the risk of injection site reactions.
In particular, according to one aspect of the present invention, there is provided 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, the method comprising administering X mL of 150 mg/mL omalizumab formulation to the patient, wherein X is 2, 1 or 0.5 and wherein the X mL 150 mg/mL omalizumab formulation is administered subcutaneously by a syringe, the syringe comprising:
a reservoir filled with X mL of 150 mg/mL omalizumab formulation, wherein the X mL 150 mg/mL omalizumab formulation has 6000 or fewer particles of diameter≥ 10 μm and/or 600 or fewer particles of diameter≥25 μm; and the syringe further comprising:
As indicated in point (ii) above, multiple characteristics of the syringes of the present invention contribute to the reduced injection time achieved in the one aspect of the invention. However, as demonstrated in
a reservoir filled with X mL of 150 mg/mL omalizumab formulation, wherein the X mL 150 mg/mL omalizumab formulation has 6000 or fewer particles of diameter≥ 10 μm and/or 600 or fewer particles of diameter≥25 μm; and the syringe further comprising:
As will be demonstrated with respect to
Finally, since 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 0.5 mL or 1 mL 150 mg/mL omalizumab.
The term ‘distal’ refers to a location that is relatively closer to a site of injection, and the term ‘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%.
It is necessary to fill syringes in order to account for residue left in the syringe and ensure that the recommended dose is expelled from the syringe. Accordingly, in this application, where syringes are referred to as being filled with 0.5 mL of 150 mg/ml omalizumab formulation, this should be understood as 0.520 mL±5%. Where syringes are referred to as being filled with 1 mL of 150 mg/mL omalizumab formulation, this should be understood as 1.020 mL±2.5%. Where syringes are referred to as being filled with 2 mL of 150 mg/mL omalizumab formulation in this application, this should be understood as 2.040 ml±2.75%.
When 150 mg/mL omalizumab formulation is expelled from a syringe, some residue will be left behind. In this application, where syringes are referred to as expelling 0.5 mL, this should be understood as 0.5 mL±5%. Where syringes are referred to as expelling 1 mL, this should be understood as 1 ml±5%. Where syringes are referred to as expelling 2 mL, this should be understood as 2 ml±5%.
Containers with a nominal content of less than 100 ml of 150 mg/mL omalizumab formulation (150 mg/mL antibody with 42.1 mg/mL L-arginine hydrochloride, 1.37 mg/mL L-histidine, 2.34 mg/mL L-histidine hydrochloride monohydrate, 0.4 mg/mL polysorbate 20 as an aqueous solution (in sterile water for injection (USP)) have 6000 or fewer particles of diameter≥10 μm and/or 600 or fewer particles of diameter≥ 25 μm. The number of particles of diameter≥10 μm and/or 25 μm 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 150 mg/mL omalizumab has 42.1 mg/mL arginine hydrochloride, 1.37 mg/mL histidine, 2.34 mg/mL histidine hydrochloride monohydrate, and 0.4 mg/mL polysorbate 20.
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 6.67 mm to 7.10 mm 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 1000 cSt silicone oil.
Before use, the needle is enclosed by a rubber needle shield (not shown) to maintain needle sterility. The rubber needle shield is formed from styrene butadiene rubber which is made with epoxypyrene, derived from natural rubber latex. The rubber needle shield is enclosed by an outer rigid polypropylene cap.
The syringe 1 is a BD Hypak™ 1 mL glass prefillable syringe with staked needle fitted with a stopper 5 which is a BD (West) 4023/50 FluroTec® stopper. The BD Hypak™ 1 mL 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 method of manufacturing the prior art syringe shown in and described with reference to
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 0.2 μm 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. Optionally, 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 0.2 μm 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
The fifth step is syringe stoppering i.e. the placement of the stopper 5 into the reservoir 2. The stopper 5 can be placed into the appropriate position in the reservoir 2 by stopper placement tube technology. Prior to syringe stoppering, the stopper 5 is steam sterilized by autoclave.
Difficulties with Current Uses of Omalizumab
The difficulties with current uses of omalizumab were set out in detail above. To summarise, the syringe 1 currently used to provide 150 mg/mL omalizumab formulation is unsuitable for use with volumes greater than 1 mL. Due to the high viscosity of the 150 mg/mL omalizumab solution, high injection forces are required to inject more than 1 mL of 150 mg/mL omalizumab formulation in an injection time which is acceptable for patients. As a result, patients can struggle to apply the necessary injection forces and so can fail to push stopper 5 to its terminal position within the syringe 1 to administer a complete dose. Furthermore, even when the syringe 1 is used to provide 0.5 mL or 1 mL 150 mg/mL omalizumab formulation, it would be advantageous to reduce the injection forces and time required, and any risk of injection site reaction.
The syringe also comprises a stopper 15 which, when it is not inserted into the syringe reservoir 12, has a maximum external diameter DS 6.67 mm to 7.10 mm 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 1000 cSt silicone oil.
The syringe 11 is a BD Neopak™ 1 mL long glass prefillable syringe with staked needle fitted with a stopper 15 which is a BD (West) 4023/50 FluroTec® stopper. The BD Neopak™ 1 mL 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.
The syringe also comprises a stopper 25 which, when it is not inserted into the syringe reservoir 22, has a maximum external diameter DS 6.70±0.15 mm 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® 1 mL 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 Fluro Tec® coating. The stopper 25 is manufactured and supplied by West Pharmaceutical Services.
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±0.15 mm 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 Neopak™ 1 mL long glass prefillable syringe with staked needle fitted with a stopper 35 which is a West NovaPure® 1 mL long stopper. The BD Neopak™ 1 mL 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.
The syringe also comprises a stopper 45 which, when it is not inserted into the syringe, has a maximum external diameter DS 9.05±0.15 mm 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 Neopak™ 2.25 mL glass prefillable syringe with staked needle fitted with a stopper 45 which is a West NovaPure® 1-3 mL stopper. The BD Neopak™ 2.25 mL 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.
According to the invention, each of the syringes of
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 0.2 μm 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. Optionally, 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 0.2 μm 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
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 cross-contamination. Thirdly, peristaltic pumps are faster to set up and calibrate than stainless steel piston pumps.
Prior to aseptic filling, the following processes are carried out:
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. Prior to syringe stoppering, 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.
Accordingly, the present invention provides a method of treating a patient 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 150 mg/mL omalizumab formulation to the patient, wherein X is 2, 1 or 0.5 and wherein the X mL 150 mg/mL omalizumab formulation is administered subcutaneously by a syringe according to the present invention, wherein the syringe is manufactured by a method comprising:
In a further embodiment, the present invention provides X mL of 150 mg/ml omalizumab formulation, wherein the aseptic filling is performed by a peristaltic pump or stainless steel piston pump.
In a further embodiment, the present invention provides X mL of 150 mg/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.
Advantageously, the syringes of the present invention configured to administer 2 mL of 150 mg/mL omalziumab reduce the number of injections required as compared to current dosing regimens shown in
The syringes may be provided alone, in an autoinjector such as the autoinjector described with reference to
In addition, it is indicated that larger volumes of highly viscous drugs are more likely to be deposited deeper in the subcutaneous layer than smaller volumes and so are less likely to leak into the intradermal layer, resulting in site leakage and injection site reaction. Therefore, the provision of a method of treatment comprising administering 2 mL 150 mg/mL omalizumab formulation according to the invention will result less site leakage and reduced risk of injection site reaction than the currently methods of treatment comprising administering 0.5 mL and 1 mL 150 mg/mL omalizumab.
Furthermore, as described previously, the syringes of the present invention filled with 0.5 mL 150 mg/mL omalizumab and 1 mL 150 mg/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. Hence, the present invention improves ease of use, patient experience, patient adherence and outcomes using omalizumab.
Accordingly, there are also provided new dosing regimens which are similar to those illustrated in
wherein at least one of the syringes is a syringe of the present invention. If a patient requires a dose of 450 mg, the dose can be administered using three syringes, all three syringes filled with 1 ml 150 mg/mL omalizumab formulation; wherein at least one of the syringes is a syringe of the present invention. If a patient requires a dose of 525 mg, the dose can be administered using four syringes-one syringe filled with 0.5 ml 150 mg/mL omalizumab and three syringes filled with 1 ml 150 mg/mL omalizumab formulation; wherein at least one of the syringes is a syringe of the present invention. If a patient requires a dose of 600 mg, the dose can be administered using four syringes, all four syringes filled with 1 ml 150 mg/mL omalizumab formulation; wherein at least one of the syringes is a syringe of the present invention.
In the new dosing regiments of the present invention, the syringes may be provided alone, in an autoinjector such as the autoinjector described with reference to
Accordingly, 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, the method comprising administering 225 mg omalizumab formulation to the patient; wherein the method comprises one of:
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, the method comprising administering 300 mg omalizumab formulation to the patient; wherein the method comprises administering 1 mL 150 mg/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, the method comprising administering 375 mg omalizumab formulation to the patient; wherein the method comprises administering 0.5 mL 150 mg/mL omalizumab formulation subcutaneously by a syringe; and one of:
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, the method comprising administering 450 mg omalizumab formulation to the patient; wherein the method comprises administering 1 mL 150 mg/mL omalizumab formulation subcutaneously by a syringe; and one of:
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, the method comprising administering 525 mg omalizumab formulation to the patient; wherein the method comprises administering 1 mL 150 mg/mL omalizumab formulation subcutaneously by a syringe and administering 0.5 mL 150 mg/mL omalizumab formulation subcutaneously by a syringe; and one of:
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, the method comprising administering 600 mg omalizumab formulation to the patient; wherein the method comprises:
In any of these methods: (A) one of the steps requiring administering 0.5 mL 150 mg/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 1 mL 150 mg/mL omalizumab formulation subcutaneously by a syringe may comprise performing a method of the invention wherein X is 1.
In some embodiments of the present invention wherein X is 2, the syringe may be configured to expel the omalizumab formulation contained in the reservoir through the needle in one or more of:
Furthermore, in some embodiments of the present invention wherein X is 2, 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:
In some embodiments of the present invention wherein X is 1, the syringe may be configured to expel X mL of 150 mg/ml omalizumab formulation through the needle in one or more of:
In some embodiments of the present invention wherein X is 1, the syringe may be configured to expel X mL of 150 mg/ml omalizumab formulation through the needle in one or more of:
In some embodiments of the present invention wherein X is 0.5, the syringe may be configured to expel X mL of 150 mg/ml omalizumab formulation through the needle in one or more of:
In some embodiments of the present invention wherein X is 0.5, the syringe may be configured to expel X mL of 150 mg/ml omalizumab formulation through the needle in one or more of:
In some embodiments of the invention, the needle has a gauge of gauge 25 to gauge 29, preferably gauge 26 to gauge 28, most preferably gauge 27.
In some embodiments where the needle has a gauge of 25, the needle has one of:
In some embodiments where the needle has a gauge of 26, the needle has one of:
In some embodiments where the needle has a gauge of 27, the needle has one of:
In some embodiments where the needle has a gauge of 28, the needle has one of:
In some embodiments where the needle has a gauge of 29, the needle has one of:
In some embodiments, the needle can comprise 3 bevels on its distal surface or 5 bevels on its distal surface.
In some embodiments, the stopper may a fluoro-resin on the product contacting side or an ethylene tetrafluoroethylene (ETFE) barrier film lamination.
In some embodiments, the stopper may have a B2-40 UV cured lubrication coating or is lubricated with 1000 cSt silicone oil.
In some embodiments, the syringe may have an internal coating of 0.4±0.2 mg or 0.7±0.2 mg of polydimethylsiloxane.
In some embodiments, the syringe may have a latex-free needle shield.
In some embodiments, 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±0.25 mm or 14.7±0.25 mm.
In embodiments where X is 1 or 0.5, the syringe may have a length of 54.0±0.5 mm and an internal diameter of 6.35 mm±0.05 mm.
In embodiments where X is 1 or 0.5, when the stopper is not inserted into the reservoir, it may have has one of:
In some embodiments when X is 1 or 0.5, the stopper has at least one circumferential rib of outer diameter 6.60±0.15 mm.
In some embodiments where X is 2, the syringe may have a length of 54.0±0.5 mm and an internal diameter of 8.65 mm±0.05 mm.
In some embodiments where X is 2, when the stopper is not inserted into the reservoir, the stopper may have a maximum external diameter 9.05±0.15 mm and/or length 7.70±0.4 mm when not inserted into the reservoir.
In some embodiments where X is 2, the stopper may have least one circumferential rib of outer diameter 9.00±0.15 mm.
In some embodiments, the apparent viscosity of the 150 mg/mL omalizumab formulation at a shear rate of 200 s−1 is: 24.7±0.5 mPa·s at 5.0±0.2° C., 15.3±0.5 mPa·s at 15.0±0.2° C., 11.4±0.5 mPa·s at 25.0±0.2° C., or 7.2±1.2 mPa·s at 40.0±0.2° C.
While the above aspects related to a method of treatment comprising administering omalizumab formulation to the patient, wherein the omalizumab formulation is administered subcutaneously by a syringe, it will be understood that 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 150 mg/mL omalizumab formulation which are suitable to be used with autoinjectors in that the syringes of the present invention expel 150 mg/mL omalizumab formulation in less time than prior art syringes when forces are applied to the stopper.
The present invention provides a syringe comprising:
In some embodiments, the syringe is configured to expel 1 ml of 150 mg/ml omalizumab formulation through the needle in one or more of:
In some embodiments, the syringe is configured to expel 1 mL of 150 mg/ml omalizumab formulation through the needle in less than 5 seconds, less than 4.75 seconds, less than 4.5 seconds, less than 4.25 seconds, or in about 4 seconds when a constant force of 10N is applied to the stopper.
In some embodiments, the syringe is configured to expel 1 ml of 150 mg/ml omalizumab formulation through the needle in less than 7.5 seconds to about 4 seconds, 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:
In some embodiments, the syringe is configured to expel 0.5 mL of 150 mg/ml omalizumab formulation through the needle in one or more of:
The present invention also provides a syringe for subcutaneous injection, the syringe comprising a reservoir filled with 2 mL of 150 mg/mL omalizumab formulation,
In some embodiments, the syringe is configured to expel 2 mL of 150 mg/ml omalizumab formulation out of the reservoir and through the needle in one or more of:
In some embodiments, the syringe is configured to expel 2 ml of 150 mg/ml omalizumab formulation out of the reservoir through the needle in one or more of:
According to the present invention, the 150 mg/mL omalizumab formulation is expelled from a syringe in less time than from prior art syringes when forces are applied to the stopper.
A motorized test stand was used to apply a constant force to each syringe filled with the relevant volume of 150 mg/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).
Under the conditions in the experiment, the prior art syringe (Syringe F) is configured to expel 1 mL of 150 mg/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. In other words, the prior art syringe is configured to expel 150 mg/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 1 mL of 150 mg/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. In other words, syringe A is configured to expel 150 mg/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 1 mL of 150 mg/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. In other words, syringe E is configured to expel 150 mg/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 150 mg/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. In other words, syringe C is configured to expel 150 mg/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 2 mL of 150 mg/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. In other words, syringe D is configured to expel 150 mg/mL omalizumab formulation through the needle in less than 0.75±0.5 seconds per mL, per N of constant force applied.
Accordingly, the present invention provides 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, the method comprising administering X mL of 150 mg/mL omalizumab formulation to the patient, wherein X is 2, 1 or 0.5 and wherein the X mL 150 mg/mL omalizumab formulation is administered subcutaneously by a syringe, the syringe comprising:
In addition,
In view of this, it will be understood that the syringes of the present invention (Syringes A, B, C, D and E) have been described by way of example only and modifications may be made whilst remaining within the scope of the invention. For example, it will be understood that 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. In addition, 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.
Accordingly, the present invention provides 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, the method comprising administering X mL of 150 mg/mL omalizumab formulation to the patient, wherein X is 1 and wherein the X mL 150 mg/mL omalizumab formulation is administered subcutaneously by a syringe, the syringe comprising:
Furthermore,
Accordingly, the present invention provides 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, the method comprising administering 2 mL of 150 mg/mL omalizumab formulation to the patient wherein the omalizumab formulation is administered subcutaneously by a syringe, the syringe comprising:
a reservoir filled with X mL of 150 mg/mL omalizumab formulation, wherein the X mL 150 mg/mL omalizumab formulation has 6000 or fewer particles of diameter≥ 10 μm and/or 600 or fewer particles of diameter≥25 μm; and the syringe further comprising:
In some embodiments, the needle has one of:
Finally, the results of Syringe D in
As demonstrated with respect to
Syringes A, C, D, E and F were filled with 150 mg/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 190 mm/min.
Under the conditions in the experiment, 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 190 mm/min is one or more of:
Under the conditions in the experiment, 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 190 mm/min is one or more of:
Under the conditions in the experiment, 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 190 mm/min is one or more of:
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 190 mm/min is one or more of:
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 190 mm/min is one or more of:
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 190 mm/min is:
As demonstrated with respect to
Syringe samples were filled with 150 mg/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.
As demonstrated in Table 2 and
The syringes of the present invention contain at least 76% main omalizumab charge variant measured by ion exchange chromatography after filling with 150 mg/ml omalizumab solution stored at 5° C.±3° C. This demonstrates that syringes of the present invention preserve purity of omalizumab comparably with the prior art syringe (syringe F), which only contained 75.08% main omalizumab charge variant measured by ion exchange chromatography after filling with 1 mL 150 mg/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 150 mg/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. Furthermore, the syringes of the present invention contain at least 69% main omalizumab charge variant after being filled with 150 mg/mL omalizumab solution and then stored at 25° C.±3° C. for 1.5 months.
As demonstrated with respect to
Syringe samples were filled with 150 mg/mL omalizumab formulation and placed into storage at 5° C.±3° C. or 25° C.±3° C. The proportion of the first, second and third HIC peaks of the syringes stored at 5° C.±3° C. were measured after filling, after 2.5 months in storage and after 6 months in storage. The proportion of the first, second and third HIC peaks of the syringes stored at 25° C.±3° C. were measured after 1.5 months in storage and after 2.5 months in storage. Tables 3, 4 and 5 shows the test results.
As demonstrated in Table 3 and
The proportion of the first HIC peak is at least 62% for the syringes of the present invention after filling with 150 mg/mL omalizumab solution stored at 5° C.±3° C. This demonstrates that syringes of the present invention preserve purity of omalizumab comparably with the prior art syringe (syringe F), which has first HIC peak of 60.2% after filling with 150 mg/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 150 mg/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 150 mg/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 150 mg/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.
Accordingly, in some embodiments of the invention, the proportion of the first peak of the syringe measured by hydrophobic interaction chromatography is at least:
In some embodiments of the invention, 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.
In some embodiments of the invention, the proportion of the first peak of the syringe measured by hydrophobic interaction chromatography is at least:
As demonstrated with respect to
Syringe samples were filled with 150 mg/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.
As demonstrated in Table 6 and
The polysorbate 20 content of the syringes of the present invention is at least 0.4 mg/mL after filling with 150 mg/mL omalizumab solution stored at 5° C.±3° C. This demonstrates that the syringes of the present invention preserve purity of the 150 mg/mL omalizumab solution comparably with the prior art syringe (syringe F), which contains 0.392 mg/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 0.4 mg/ml for the syringes of the present invention after being filled with 150 mg/mL omalizumab solution and then stored at 25° C.±3° C. for 1.5 months, compared to 0.360 mg/mL for the prior art syringe under the same conditions. The polysorbate 20 content of the syringes of the present invention is at least 0.3 mg/mL for the syringes of the present invention after being filled with 150 mg/mL omalizumab solution and then stored at 25° C.±3° C. for 6 months, compared to 0.289 mg/mL for the prior art syringe under the same conditions.
Accordingly, in some embodiments of the invention, the syringe contains at least 0.4 mg/mL polysorbate 20 after filling with 150 mg/mL omalizumab solution stored at 5° C.±3° C.
In some embodiments of the invention, the syringe contains:
While the present application describes a method of treatment, wherein 150 mg/ml omalizumab formulation is administered subcutaneously by a syringe, it will be understood that the syringes of the present invention can be provided alone, or in combination with a needle shield device.
A plunger 51 is provided comprising a plunger rod 53 and thumb pad 52. A user can apply manual force to the thumb pad 22 in a distal direction to manually expel the fluid contained in the reservoir through the needle. As the plunger reaches the end of its distal movement, it can unlatch needle shield retaining arms 54 provided within the needle shield device, releasing a needle sleeve 55. When the needle shield device is removed from an injection site, the needle sleeve 15 can extend under the bias of the needle shield spring 56 to cover the needle, as shown in
Accordingly, in some embodiments of the present invention, 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 150 mg/mL omalizumab formulation and unlatch needle sleeve so that the needle sleeve can cover the needle after injection.
While the present application describes a method of treatment, wherein 150 mg/ml omalizumab formulation is administered subcutaneously by a syringe, it will be understood that 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.
The syringe comprises a reservoir filled with 150 mg/mL omalizumab formulation, a stopper and a needle. As will be appreciated, 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
The drive mechanism 102 is configured to apply a force to the stopper to drive the stopper through the reservoir towards the needle to expel the 150 mg/ml 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 150 mg/mL omalizumab formulation out of the reservoir and through the needle in about 1 second to about 17 seconds.
In the embodiment shown in
In the embodiment shown in
While the drive mechanism of the autoinjector shown in
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
Time to Expel Omalizumab Formulation Using an Autoinjector Combined with Syringes of the Present Invention (
Four autoinjectors as shown and described with reference to
Each autoinjector tested expelled the 150 mg/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 150 mg/mL omalizumab solution out of the reservoir and through the needle in about 3 to 5 seconds.
The second autoinjector expelled 1 ml of 150 mg/mL omalizumab solution out of the reservoir and through the needle in about 4 to 6 seconds.
The third autoinjector expelled 1 ml of 150 mg/mL omalizumab solution out of the reservoir and through the needle in about 3 to 4 seconds. In one test, the third autoinjector expelled 1 ml of 150 mg/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 150 mg/mL omalizumab solution out of the reservoir and through the needle in about 6 to 7 seconds.
As demonstrated in
While
Accordingly, in one aspect, there is described an autoinjector comprising:
The syringe can be filled with 0.5 mL of 150 mg/mL omalizumab formulation and wherein the drive mechanism is configured to expel the 0.5 mL of 150 mg/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 150 mg/mL omalizumab formulation, and the drive mechanism is configured to expel the 1 mL of 150 mg/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 2 mL of 150 mg/mL omalizumab formulation, and the drive is configured to expel the 2 mL of 150 mg/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 150 mg/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 150 mg/mL omalizumab formulation is expelled of at least 11N, at least 12N, at least 13N, at least 14N, at least 15N, at least 16N, at least 17N, at least 18N, at least 19N, at least 20N, at least 21N, 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 31N, 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.
In some aspects, the syringe is filled with 0.5 mL of 150 mg/mL omalizumab formulation and the drive is configured to expel the 0.5 mL of 150 mg/mL 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.
In some aspects, the syringe is filled with 1 mL of 150 mg/mL omalizumab formulation, and the drive is configured to expel the 1 mL of 150 mg/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.
In some aspects, the syringe is filled with 2 mL of 150 mg/mL omalizumab formulation and the drive is configured to expel the 2 mL of 150 mg/mL omalizumab formulation 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.
There is also provided a kit comprising a syringe according to the present invention and optionally: an autoinjector, a needle shield device, and/or instructions for administration.
In one aspect of the invention, there is provided, for the first time, injection of highly viscous 150 mg/mL omalizumab formulation by an autoinjector. In particular, one aspect provides for injection of highly viscous 150 mg/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.
Furthermore, as shown in
This faster injection time facilitates the injection of high doses of omalizumab which have not yet been available to patients, such as 2 mL of 300 mg/2 mL omalizumab formulation in a single syringe. As shown in
As demonstrated with respect to
Surprisingly, as demonstrated with respect to
It has been demonstrated that new methods of treatment comprising administering omalizumab described in this application are bioequivalent to the previously approved methods of treatment comprising administering omalizumab, see Sangana et al. Bioequialvence between a new omalizumab prefilled syringe with an autoinjector or with a needle safety device compared with the current prefilled syringe: a randomized controlled trial in healthy volunteers, Clinical Pharmacology. 2024, 0(0) 1-10.
Sangana et al. demonstrated the bioequivalence of omalizumab between:
For the bioequivalence comparison, natural log-transformed pharmacokinetic parameters (Cmax, AUClast, AUCint) were analyzed by an analysis of covariance (ANCOVA) model with treatment group, body area of injection and body weight strata as fixed effects and baseline IgE as a covariate. Cmax is the maximum observed serum concentration, AUClast is the area under the serum concentration-time curve calculated to last quantifiable concentration point and AUCinf. is the area under the serum concentration-time curve extrapolated to infinity. Based on the ANCOVA model, point estimates and the corresponding 95% and 90% confidence limits were calculated for the difference between each new omalizumab configuration (new PFS-AI, new PFS-NSD) and the control intervention (current PFS-NSD). These point estimates and confidence limits were exponentiated to obtain the point estimates with 95% and 90% confidence intervals (Cis) for the ratios of geometric means on the original scale. Bioequiavalence claims were made for each comparison if and only if Cmax, AUClast, and AUCinf were declared equivalent (ie, the Cis for all ratios were contained between 80% and 125%) based on the stepwise Bonferroni-Holm method for multiple comparisons.
The statistical comparisons of omalizumab serum pharmacokinetic parameter values for the new PFS-AI, new PFS-NSD and current PFS-NSD are summarised below.
aIn the comparison of each new configuration versus the current configuration bioequivalence was established based on the 95% Cis according to the Bonferroni-Holm procedure
bIn the comparison of the new configurations to each other bioequivalence was established based on the 90% Cis.
Formal bioequivalence was established between: (1) new PFS-AI and current PFS-NSD (95% CI or 90% CI, based on Bonferroni-Holm procedure); (2) new PFS-NSD and current PFS-NSD (95% CI or 90% CI, based on Bonferroni-Holm procedure); and (3) new PFS-Al and new PFS-NSD (90% CI); with the CI for each treatment contrast contained within the 80%-125% range for Cmax, AUClast, and AUCint following a single dose of omalizumab.
| Number | Date | Country | Kind |
|---|---|---|---|
| 23188544.3 | Jul 2023 | EP | regional |
| 24171754.5 | Apr 2024 | EP | regional |
