CN116761626A - Formulations for multi-purpose applications - Google Patents
Formulations for multi-purpose applications Download PDFInfo
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- CN116761626A CN116761626A CN202180079516.8A CN202180079516A CN116761626A CN 116761626 A CN116761626 A CN 116761626A CN 202180079516 A CN202180079516 A CN 202180079516A CN 116761626 A CN116761626 A CN 116761626A
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Abstract
The present invention relates generally to formulations of antibodies and antigen binding fragments thereof. To address the need for formulations for new antibodies that can be administered by different routes and at low and high doses, a formulation comprising an antibody or antigen binding fragment thereof is provided, as well as uses of the formulation and methods involving the formulation.
Description
Technical Field
The present invention is in the field of formulations for biomolecules. The present invention provides formulations for antibodies and antigen binding fragments thereof, as well as uses thereof and methods involving the formulations.
Disclosure of Invention
The present invention relates generally to formulations of antibodies and antigen binding fragments thereof.
There is provided a formulation comprising or consisting of: an antibody or antigen binding fragment thereof at a concentration of 1-200mg/mL in aqueous solution, 5-50mM acetate or histidine, 120-260mM glycine, 15-120mM trehalose, 0.1-1.0g/L polysorbate 20, and a pH of 4.5-6.5; as well as uses thereof and methods for treating patients with said formulations.
Drawings
Fig. 1: stability data for mAb1 in formulations F5-F8 under storage conditions at 5 ℃, with the percentage of high molecular weight species (HMW (%)) shown in a and the percentage of monomers (monomer (%)) shown in B.
Fig. 2: stability data for mAb1 in formulations F5-F8 under storage conditions at 25 ℃, with the percentage of high molecular weight species (HMW (%)) shown in a and the percentage of monomers (monomer (%)) shown in B.
Fig. 3: stability data for mAb1 in formulation F5 of different vial sizes under storage conditions at 5 ℃, with the percentage of high molecular weight species (HMW (%)) shown in a and the percentage of monomers (monomer (%)) shown in B.
Fig. 4: stability data for mAb1 in formulation F5 of different vial sizes under storage conditions at 25 ℃, with the percentage of high molecular weight species (HMW (%)) shown in a and the percentage of monomers (monomer (%)) shown in B.
Fig. 5: stability data for different concentrations of mAb1 in formulations F3 (10 mg/mL mAb 1) to F4 (150 mg/mL mAb 1) and F5 (50 mg/mL mAb 1) under storage conditions at 5 ℃ were shown with the percentage of high molecular weight species (HMW (%)) in a and the percentage of monomers (monomer (%)) in B.
Fig. 6: stability data for different concentrations of mAb1 in formulations F3 (10 mg/mL mAb 1) to F4 (150 mg/mL mAb 1) and F5 (50 mg/mL mAb 1) under storage conditions at 25 ℃, with the percentage of high molecular weight species (HMW (%)) shown in a and the percentage of monomers (monomer (%)) shown in B.
Fig. 7: loading of SARS-CoV-2 in nasopharyngeal swabs of animals pre-treated with mAb1 or vehicle prior to infection; LOD is the limit of detection.
Fig. 8: the loading of SARS-CoV-2 in bronchoalveolar lavage (BAL) of animals pre-treated with mAb1 or vehicle prior to infection; LOD is the limit of detection.
Fig. 9: the storage stability of mAb1 to mAb5 in formulation F5 under planned storage conditions (5 ℃) is shown in a, with the percentage of high molecular weight species (HMW (%)) and the percentage of monomers (monomer (%)) shown in B.
Fig. 10: the storage stability of mAb1 to mAb5 in formulation F5 under accelerated storage conditions (25 ℃) is shown in a with the percentage of high molecular weight species (HMW (%)) and the percentage of monomers (monomer (%)) in B.
Fig. 11: the storage stability of mAb1 in formulations F1, F2, F5 and F6 at 5 ℃ is shown in a for the percentage of high molecular weight species (HMW (%)) and B for the percentage of monomers (monomer (%)).
Fig. 12: the storage stability of mAb2 in formulations F1, F2, F5 and F6 at 5 ℃ is shown in a for the percentage of high molecular weight species (HMW (%)) and B for the percentage of monomers (monomer (%)).
Fig. 13: the storage stability of mAb3 in formulations F1, F2, F5 and F6 at 5 ℃ is shown in a for the percentage of high molecular weight species (HMW (%)) and B for the percentage of monomers (monomer (%)).
Fig. 14: the storage stability of mAb4 in formulations F1, F2, F5 and F6 at 5 ℃ is shown in a for the percentage of high molecular weight species (HMW (%)) and B for the percentage of monomers (monomer (%)).
Fig. 15: the storage stability of mAb5 in formulations F1, F2, F5 and F6 at 5 ℃ is shown in a for the percentage of high molecular weight species (HMW (%)) and B for the percentage of monomers (monomer (%)).
Fig. 16: the storage stability of mAb1 in formulations F1, F2, F5 and F6 at 25 ℃ with the percentage of high molecular weight species (HMW (%)) shown in a and the percentage of monomers (monomer (%)) shown in B.
Fig. 17: the storage stability of mAb2 in formulations F1, F2, F5 and F6 at 25 ℃ with the percentage of high molecular weight species (HMW (%)) shown in a and the percentage of monomers (monomer (%)) shown in B.
Fig. 18: the storage stability of mAb3 in formulations F1, F2, F5 and F6 at 25 ℃ is shown in a for the percentage of high molecular weight species (HMW (%)) and B for the percentage of monomers (monomer (%)).
Fig. 19: the storage stability of mAb4 in formulations F1, F2, F5 and F6 at 25 ℃ with the percentage of high molecular weight species (HMW (%)) shown in a and the percentage of monomers (monomer (%)) shown in B.
Fig. 20: the storage stability of mAb5 in formulations F1, F2, F5 and F6 at 25 ℃ with the percentage of high molecular weight species (HMW (%)) shown in a and the percentage of monomers (monomer (%)) shown in B.
Fig. 21: storage stability data for Low Concentration Liquid Formulations (LCLF) and High Concentration Liquid Formulations (HCLF) at planned storage conditions (5 ℃) for mAb1, mAb2, and mAb3, with the percentage of high molecular weight species (HMW (%)) shown in a and the percentage of monomers (monomer (%)) shown in B.
Fig. 22: storage stability data for Low Concentration Liquid Formulations (LCLF) and High Concentration Liquid Formulations (HCLF) under accelerated storage conditions (25 ℃) for mAb1, mAb2, and mAb3, with the percentage of high molecular weight species (HMW (%)) shown in a and the percentage of monomers (monomer (%)) shown in B.
Background
Antibodies and antigen binding fragments of such antibodies have become very important in the pharmaceutical field over the last few decades. Particularly in the case of pandemic, it has been demonstrated that antibodies can be the source of specific therapies, while other drug therapies remain under evaluation.
However, one challenge in providing antibodies or antigen binding fragments thereof as Active Pharmaceutical Ingredients (APIs) is the possible storage and route of administration considering the excipients that must be present in the formulation. Most formulations of antibodies or antigen binding fragments thereof are specifically designed for one particular route of administration and/or one particular concentration of API.
In drug development, particularly in the case of pandemic, there is a need to quickly adapt to certain needs in the following areas: formulations for novel antibodies are provided that can be administered by different routes and at low and high doses.
Detailed Description
To address the above-mentioned needs, formulations were developed that have several advantages: importantly, it represents a solution that can be used for a number of purposes such as for intravenous (i.v.) injection administration, subcutaneous (s.c.) administration, and oral inhalation and nasal inhalation (inh.) administration. Furthermore, it can be used for pediatric use. In particular, it can be used for both injection and inhalation presentation, for example by means of a jet atomizer or a mesh atomizer.
Furthermore, the formulation is particularly suitable for high dose administration (> 1 g/patient/day) required for pandemic situations or immunology, oncology, where the usual excipients typically exceed the maximum daily exposure limit level of the patient, reaching critical toxicological levels. Furthermore, sugars and polyols are commonly used to maintain osmolality of solutions known to be necessary for, for example, subcutaneous (s.c.) injection, and encompass most commonly used formulations used in clinical/commercial products. However, for high dose administration, the sugar or polyol will typically exceed the maximum daily exposure level of the patient or the osmolality of the solution cannot be maintained.
The specific combination of excipients used in the formulation satisfies both the maximum daily exposure level for the patient and the osmolality of the solution evaluated for high dose administration up to 5 g/patient/day (even if 100kg patient population is considered).
Accordingly, provided herein generally are pharmaceutical compositions or formulations comprising or consisting of: an antibody or antigen binding fragment thereof at a concentration of 1-200mg/mL in aqueous solution, 5-50mM acetate or histidine, 120-260mM glycine, 15-120mM trehalose, 0.1-1.0g/L polysorbate 20, and a pH of 4.5-6.5.
Unexpectedly, the formulation can be administered to a patient via injection (including subcutaneous (s.c.), intravenous (i.v.), and intradermal), via inhalation (including oral inhalation, nasal inhalation, and combination (with a mask covering the mouth and nose)), without any adjustments to the formulation for the route of administration. The formulations can be readily used as Low Concentrated Liquid Formulations (LCLF) and Highly Concentrated Liquid Formulations (HCLF) and stabilize different antibodies over a wide range of concentrations and surface/volume ratios. Thus, the formulation additionally provides for administration of low doses as well as high doses for patients.
The formulation is suitable for a variety of purposes due to its applicability over a wider range of API concentrations, its ability to stabilize APIs within that range, and its availability for a variety of different routes of administration to patients.
In one embodiment, a formulation is provided, the formulation comprising or consisting of: the provided formulations proved to be effective for different antibodies at a concentration of 10-260mg/mL of antibody or antigen binding fragment thereof, 10-25mM acetate or histidine, 172.7-259.1mM glycine, 17.3-25.9mM trehalose, 0.2-0.6g/L polysorbate 20 (polyoxyethylene (20) -sorbitan-monolaurate) in aqueous solution, and pH of 5.2-5.8.
In one embodiment, a pharmaceutical composition or formulation is provided, comprising or consisting of: an antibody concentration of 10-260mg/mL in aqueous solution, 10-25mM acetate, 172.7-259.1mM glycine, 17.3-25.9mM trehalose, 0.2-0.6g/L polysorbate 20 (polyoxyethylene (20) -sorbitan monolaurate), and pH 5.2-5.8.
In another embodiment, a formulation is provided, the formulation comprising or consisting of: an antibody or antigen binding fragment thereof at a concentration of 10 to 150mg/mL in aqueous solution, 20mM acetate or histidine, 220mM glycine, 20mM trehalose, 0.4g/L polysorbate 20, ph 5.5.
In another embodiment, a pharmaceutical composition or formulation is provided comprising 50mg/mL of an antibody or antigen binding fragment thereof in 20mM acetate, 220mM glycine, 20mM trehalose, 0.4g/L polysorbate 20, pH 5.5.
The formulation stabilizes all classes of antibodies, including IgGl, igG2, igG3, igG4, igA, igD, igE, and IgM. In particular, it is very suitable for stabilizing antibodies of the IgG1 type.
In one embodiment, the osmolality of the formulation is 220 to 380mOsmol/kg, preferably 240 to 360mOsmol/kg, more preferably 240 to 340mOsmol/kg, even more preferably 260 to 320mOsmol/kg.
The osmolality of the formulation is particularly affected by the nature (i.e., molecular weight) and concentration of the antibody or antigen binding fragment thereof.
The formulation proved suitable for Highly Concentrated Liquid Formulations (HCLF), necessary for high dose administration to patients, adapted for subcutaneous injection using a syringe in a fairly low volume (max 2.0 mL).
The formulation buffer (i.e., the above-described solution without the active ingredient (antibody or antigen binding fragment thereof)) may be used as a special diluent, a diluting solvent, and a placebo. It has further been demonstrated to be compatible with commercial clinical dilution media.
In particular, aqueous solutions having 5-50mM acetate or histidine, 120-260mM glycine, 15-120mM trehalose, 0.1-1.0g/L polysorbate 20 and pH 4.5-6.5 may be used as special diluents, dilution solvents, placebo or diluents compatible with other clinical dilution media.
In another embodiment, an aqueous solution having 10-25mM acetate or histidine, 172.7-259.1mM glycine, 17.3-25.9mM trehalose, 0.2-0.6g/L polysorbate 20 (polyoxyethylene (20) -sorbitan-monolaurate) and pH 5.2-5.8 is used as a special diluent, diluent solvent, placebo or diluent compatible with other clinical dilution media.
In another embodiment, an aqueous solution of 20mM acetate or histidine, 220mM glycine, 20mM trehalose, 0.4g/L polysorbate 20 and pH 5.5 is used as a special diluent, diluent solvent, placebo or diluent compatible with other clinical dilution media.
In yet another embodiment, an aqueous solution having 20mM acetate, 220mM glycine, 20mM trehalose, 0.4g/L polysorbate 20 and pH 5.5 is used as a special diluent, diluent solvent, placebo or diluent compatible with other clinical dilution media.
In one embodiment, the formulation is diluted with a clinical dilution medium (such as isotonic saline, lactated ringer's solution, or isotonic dextrose solution).
In one embodiment, the formulation comprises two or more, preferably two antibodies or antigen binding fragments thereof.
In one embodiment, the formulation is combined with another formulation comprising an antibody or antigen binding fragment thereof.
In one embodiment, the pharmaceutical formulation is administered to the patient at a dose of 10 to 50mg/kg body weight, preferably 30 to 50mg/kg body weight of the antibody or antigen binding fragment thereof. The pharmaceutical formulation according to the invention is suitable for daily administration of up to 5g of an antibody or antigen binding fragment thereof to a patient (even when considering patients in a patient population of 100kg body weight), wherein the excipient does not exceed the maximum daily exposure level of the patient while satisfying the osmolality of the solution evaluated for high dose administration.
The antibody or antigen-binding fragment thereof may be administered intravenously at a dose of about 2.5mg/kg, about 10mg/kg, or about 40mg/kg body weight by intravenous infusion diluted in a formulation buffer. Thus, the high dose administration ranges from 1 to 10mg/kg body weight, while the low dose administration ranges from 10 to 50mg/kg body weight, preferably from 30 to 50mg/kg body weight.
The pharmaceutical compositions or formulations of the present invention are formulated to be compatible with their intended route of administration. Examples of routes of administration include, but are not limited to, parenteral, such as intravenous, intradermal, subcutaneous, transdermal, and intranasal, via inhalation (e.g., nasal inhalation and oral inhalation), transmucosal, via rectal administration, among others.
In one embodiment, the pharmaceutical formulation is for administering an antibody or antigen binding fragment thereof to a patient, wherein the pharmaceutical formulation is administered by one or more of the following routes: injections, including intravenous, intradermal, and subcutaneous; inhalation, including oral inhalation, nasal inhalation, and mask inhalation; external use, including transdermal, transmucosal and rectal, preferably, the pharmaceutical formulation is administered intravenously, inhaled (including oral inhalation, nasal inhalation and mask inhalation) and/or subcutaneously.
In a particular embodiment, the pharmaceutical composition is formulated according to conventional procedures into a pharmaceutical composition suitable for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to a human. Typically, the pharmaceutical composition for intravenous administration is a solution in a sterile isotonic aqueous buffer. If desired, the pharmaceutical composition may also contain a solubilizing agent and a local anesthetic (e.g., lidocaine) to reduce pain at the injection site.
In one embodiment, the formulation is nebulizable at a concentration of the antibody or antigen-binding fragment thereof of 1 to 150mg/mL, preferably 10 to 80mg/mL, more preferably 10 to 60mg/mL, most preferably 10 to 50mg/mL.
In one embodiment, the pharmaceutical composition or formulation is administered by at least two different routes selected from intravenous, inhalation (including oral inhalation, nasal inhalation, and mask inhalation) and/or subcutaneous.
In one embodiment, the formulation is administered to a patient via at least two different routes, and the concentration of the antibody or antigen binding fragment thereof within the formulation administered by a first of the at least two different routes contains at least twice the concentration of the antibody or antigen binding fragment thereof as compared to the concentration of the antibody or antigen binding fragment thereof within the formulation administered by a second of the at least two different routes.
In one embodiment of the invention, the pharmaceutical formulation is administered to a patient by inhalation, wherein the concentration of the antibody or antigen binding fragment thereof in the formulation is from 1 to 150mg/mL, preferably 10 to 80mg/mL, more preferably 10 to 60mg/mL, most preferably 10 to 50mg/mL.
The formulations according to the invention can be easily applied by inhalation using different atomizers, including mesh atomizers, jet atomizers and ultrasonic atomizers.
In one embodiment, a method for treating a patient is provided, wherein a pharmaceutical formulation is administered to the patient by one or more of the following routes: injections, including intravenous, intradermal, and subcutaneous; inhalation, including oral inhalation, nasal inhalation, and mask inhalation; topical, including transdermal, transmucosal, and rectal, preferably the pharmaceutical formulation is administered intravenously, inhaled (including oral inhalation, nasal inhalation, and mask inhalation), and/or subcutaneously.
In one embodiment, a method for treating a patient is provided wherein the pharmaceutical formulation is administered by at least two different routes selected from intravenous, inhalation (including oral inhalation, nasal inhalation, and mask inhalation) and/or subcutaneous.
A single intravenous infusion may be performed after a single inhalation.
In one embodiment, a method for treating a patient is provided, wherein an antibody or antigen binding fragment thereof within the formulation is administered to the patient by at least two different routes, and the concentration of the antibody or antigen binding fragment thereof within the formulation administered by a first of the at least two different routes contains at least twice the concentration of the antibody or antigen binding fragment thereof as the concentration of the antibody or antigen binding fragment thereof within the formulation administered by a second of the at least two different routes.
In one embodiment of the invention, a method for treating a patient is provided, wherein the formulation is administered to the patient by inhalation and the concentration of the antibody or antigen binding fragment thereof is from 10 to 150mg/mL, preferably 10 to 80mg/mL, more preferably 10 to 60mg/mL, most preferably 10 to 50mg/mL.
The pharmaceutical compositions or formulations as described may prove effective in stabilizing mAb1 and other antibodies for inhalation administration using: (i) different nebulizer systems (e.g. mesh nebulizer, jet nebulizer), (ii) diluted and undiluted formulations (different API concentrations), and (iii) different masks or adapters of the inhaler (mouth and nose).
The methods of the invention may include pulmonary administration of pharmaceutical compositions formulated with nebulizers, for example, by use of an inhaler or nebulizer. See, for example, U.S. patent nos. 6,019,968, 5,985,320, 5,985,309, 5,934,272, 5,874,064, 5,855,913, 5,290,540 and 4,880,078; and PCT publications WO 92/19244, WO 97/32572, WO 97/44013, WO 98/31346 and WO 99/66903, each of which is incorporated herein by reference in its entirety. In a particular embodiment, the antibody or antigen-binding fragment thereof, combination therapy and/or pharmaceutical composition is administered with Alkermes Pulmonary drug delivery techniques (Alkermes, inc., cambridge, ma). In another specific embodiment, the antibody or antigen binding fragment thereof, the combination therapy and/or the pharmaceutical composition is administered Aerogen->Pulmonary drug delivery technology (Aerogen GmbH, latin root, germany).
For inhalation administration, the individual may be treated by a mouthpiece (mouthpiece) at a dose of, for example, 50mg, 100mg or 250mg per treatment after aerosol generation using a mesh nebulizer or jet nebulizer. The formulation may be diluted to a suitable volume with a formulation buffer.
The formulations proved to stabilize the drug in different container closure systems, i.e. 20R (20 mL) and 6R (6 mL) type vials, covering a wide range of technical parameters, such as surface/volume ratio.
The methods of the invention may also include administering a pharmaceutical composition formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion, including subcutaneous, intravenous, intramuscular injection, among others).
The pharmaceutical formulations of the present invention may be provided in liquid form or may be provided in lyophilized form.
Terminology and definitions
Terms not explicitly defined herein should be given their meaning to those skilled in the art in light of the present disclosure and context. The general embodiment "comprising" or "comprises" encompasses the more specific embodiment "consisting of … …".
Furthermore, the singular and plural forms are not used in a limiting manner. Thus, as used herein, the singular forms "a," "an," "one," and "the" refer to both the singular and the plural, unless otherwise indicated or clear from the context.
However, unless the contrary is stated, the following terms used in the specification have the indicated meanings and follow the following convention. The terms used in the process of the present invention have the following meanings.
The terms "pharmaceutical composition" and "formulation" as used herein are intended to be interchangeable. The terms "pharmaceutical composition" and "formulation" refer to a mixture of substances including a therapeutically active substance (i.e. an Active Pharmaceutical Ingredient (API)) for pharmaceutical use, respectively. In the context of the present invention, the term "formulation" or "pharmaceutical composition" refers to a composition comprising an antibody or antigen-binding fragment thereof (also referred to as an active drug or biological ingredient) together with one or more additional components.
The therapeutically active substance for pharmaceutical use herein is an antibody or antigen binding fragment thereof.
"antibodies and antigen-binding fragments thereof" are monoclonal antibodies, multispecific antibodies (e.g., bispecific antibodies and multispecific antibodies), and antibody fragments. The antibodies include antibody conjugates and molecules, such as chimeric molecules, comprising the antibodies. Thus, antibodies include, but are not limited to, full length and natural antibodies, and fragments or portions thereof that retain their binding specificity, such as any specific binding portion thereof, including those having any number of immunoglobulin classes and/or isotypes (e.g., igGl, igG2, igG3, igG4, igA, igD, igE, and IgM); and biologically relevant (antigen binding) fragments or specific binding portions thereof, including but not limited to Fab, F (ab') 2, fv, and scFv (single chain or related entities). Monoclonal antibodies are typically antibodies within a composition of substantially homogeneous antibodies; thus, any individual antibody contained within a monoclonal antibody composition is identical, except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies may comprise human IgG1 constant regions. Monoclonal antibodies may comprise human IgG4 constant regions.
The term "antibody, i.e. antigen binding fragment thereof", is used herein in its broadest sense and includes polyclonal and monoclonal antibodies, including whole antibodies and functional (antigen binding) antibody fragments thereof, including the following fragments: antigen binding (Fab) fragments, F (ab ') 2 fragments, fab' fragments, fv fragments, recombinant IgG (IgG) fragments, single chain antibody fragments (including single chain variable fragments (sFv or scFv)), and single domain antibody (e.g., sdAb, sdFv, nanobody) fragments. The term encompasses genetically engineered and/or otherwise modified forms of immunoglobulins, such as endosomes, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, and heteroconjugated antibodies, multispecific (e.g., bispecific) antibodies, diabodies, triabodies, and tetrabodies, tandem diabodies, tandem triabodies. Unless otherwise indicated, the term "antibody and antigen-binding fragments thereof" is to be understood as encompassing whole or full-length antibodies, including antibodies of any class or subclass (including IgG and subclasses thereof, igM, igE, igA and IgD), as well as functional antibody fragments of the foregoing antibodies. The antibody may comprise a human IgG1 constant region. The antibody may comprise a human IgG4 constant region.
The pharmaceutical composition or formulation according to the invention may comprise a buffer. Buffers include, but are not limited to, citric acid, HEPES, histidine, potassium acetate, potassium citrate, potassium phosphate (KH) 2 PO 4 ) Sodium acetate, sodium bicarbonate, sodium citrate, sodium phosphate (NAH) 2 PO 4 ) Tris base and Tris-HCl.
As used herein, the term "buffer providing a pH of about 5.0 to about 7.0" refers to an agent that resists a change in pH by the action of the acid/base conjugate components of the agent to a solution comprising the agent. The pH of the buffer used in the formulation according to the invention may range from about 5.5 to about 7.5 or from about 5.8 to about 7.0. In one embodiment, the pH is about 6.0. In one embodiment, the pH is about 7.0. Examples of buffers that control the pH within this range include acetate, succinate, gluconate, histidine, citrate, glycylglycine and other organic acid buffers.
The pharmaceutical composition or formulation according to the invention may comprise a tonicity agent. Tonicity agents include, but are not limited to, glycine, trehalose, dextrose, glycerol, mannitol, potassium chloride and sodium chloride.
"osmolality" means the concentration of the formulation in terms of osmolality of solute per kilogram of solvent (i.e., water in the aqueous solution).
By "isotonic" is meant that the formulation has substantially the same osmotic pressure as human blood. Isotonic formulations will typically have an osmotic pressure of from about 250 to 350 mOsmol/kg. Isotonicity can be measured using a vapor pressure or freezing point depression osmometer.
In certain embodiments, the pharmaceutical composition or formulation according to the invention comprises a stabilizer. Stabilizers include, but are not limited to, human serum albumin (hsa), bovine serum albumin (bsa), alpha-casein, globulin, alpha-lactalbumin, LDH, lysozyme, myoglobin, ovalbumin, and RNase A. Stabilizers also include amino acids and their metabolites such as glycine, alanine (alpha-alanine, beta-alanine), arginine, betaine, leucine, lysine, glutamic acid, aspartic acid, proline, 4-hydroxyproline, sarcosine, gamma-aminobutyric acid (GABA), opines (alanine), octopine, glycine (strombine), and trimethylamine N-oxide (TMAO).
In certain embodiments, a pharmaceutical composition or formulation according to the present invention may comprise a nonionic surfactant. Nonionic surfactants include, but are not limited to, polyoxyethylene sorbitan fatty acid esters (such as polysorbate 20 and polysorbate 80), polyethylene-polypropylene copolymers, polyethylene-polypropylene glycols, polyoxyethylene-stearates, polyoxyethylene alkyl ethers (such as polyoxyethylene monolauryl ether), alkylphenyl polyoxyethylene ethers (Triton-X), polyoxyethylene-polyoxypropylene copolymers (poloxamers, pluronic), sodium Dodecyl Sulfate (SDS). In one embodiment, the nonionic surfactant is polysorbate 20 or polysorbate 80. In one embodiment, the polysorbate concentration is about 0.005% to 0.02% (w/v).
The term "nebulizable" refers to the ability of an article to form soluble aerosol droplets characterized as a nebulized solution according to the combination of EMA/CHMP/QWP/49313"Guideline on the pharmaceutical quality of inhalation and nasal products" and european pharmacopoeia 2.9.44 and the combination of FDA industry guidelines "Nasal Spray and Inhalation Solution, suspend, and Spray Drug Products-Chemistry Manufacturing, and Controls Documentation" and USP <1601 >. The contents of each of these files are incorporated by reference in their entirety.
Thus, to determine whether a formulation is "nebulizable" in the sense of being used herein, the following parameters describing aerodynamic properties were studied:
active Substance Delivery Rate (ASDR)/drug delivery Rate (DSDR)
Total Active Substance Delivered (TASD)/total drug delivered (TDSD)
Aerodynamic evaluation of the nebulized aerosol:
the particle size distribution is chosen so that,
mass Median Aerodynamic Diameter (MMAD)
-Geometric Standard Deviation (GSD)
Fraction of fine particles (< 5.0 μm) (FPF)
The device used to investigate whether the formulation was "nebulizable" was a CE-marked sieve mesh or jet nebulizer and had a 510k clearance. These are intended for delivering an atomized solution. For the devices used herein, in Solo System instruction manual R20-3604, -/->Suitability for delivering solutions for nebulization is confirmed in Go instruction manual R20-4198 and Aero Eclipse x II breath-driven nebulizer (BAN) instruction manual R20-4199. These devices apply to the comparability of the results.
For evaluation of the complete delivery profile of the product for clinical trials, ASDR/DSDR and TASD/TDSD (i.e. total dose delivered to the patient) were determined according to the procedure described in european pharmacopoeia 2.9.44 and USP <1601>, except that separate experiments were performed to measure these two parameters. ASDR/DSDR and TASD/TDSD were studied using a filter-based approach that included an artificial lung (ASL 5000,Ingmar Medical, pittsburgh, pa, usa; 500mL inhaled volume, tidal breathing, 15 breaths per minute, sinusoidal, 1:1 inhaled/exhaled ratio) as a breathing simulator.
The particle size distribution of the liquid aerosol droplets produced by the atomizer was evaluated using a Next Generation Impactor (NGI). Mass Median Aerodynamic Diameter (MMAD), geometric Standard Deviation (GSD) and fine particle fraction (FPF <5.0 μm) were calculated from the impactor measurements.
The Mass Median Aerodynamic Diameter (MMAD) aerodynamic diameter of the droplets or particles is equal to the diameter of a sphere having a density of 1g/mL with the same sedimentation velocity. In addition to geometric diameter, the density and shape of the particles can also affect aerodynamic properties. Typically, MMAD values between 1 and 5 μm are considered optimal for lung deposition. Smaller particles are exhaled and larger particles are deposited in the mouth, nose or trachea.
The Geometric Standard Deviation (GSD) is a measure of the dispersion of the deviation from the mean value of the particle size distribution (MMAD). It is a dimensionless number. Smaller values represent a narrow particle size distribution, which is preferred for pulmonary applications, since if the MMAD is located in this region more droplets or particles should be in the desired range between 1 and 5 μm.
The Fine Particle Fraction (FPF) is the proportion of particles or droplets in the aerosol having a diameter below 5.0 μm. This portion reaches the deeper lungs after inhalation.
Ultra-efficient size exclusion chromatography (UP-SEC) was used to determine the High Molecular Weight (HMW) and monomer content before and after nebulization in order to evaluate the integrity of the antibodies.
Surface Plasmon Resonance (SPR) is used to evaluate binding activity and thus whether an antibody retains function after nebulization.
UV-Vis, UP-SEC and SPR were used to assess the integrity, function and product quality of the antibodies.
By "nasal inhalation" is meant inhalation through the nose only using, for example, a nasal mask (nasal cast), thereby completely covering the nose and aerosol droplets entering the respiratory tract via the nose.
By "oral inhalation" is meant inhalation through the mouth using, for example, only the respiratory mouth, thereby causing liquid aerosol droplets to enter the respiratory tract via the mouth/throat.
Mask inhalation means inhalation through the nose and mouth simultaneously, whereby the mask covers both the nose and mouth. The ingestion of liquid aerosol droplets is delivered to the respiratory tract through the nose and mouth/throat.
Examples
In order to show the effect of the formulation, different monoclonal antibodies have been used.
Antibody 1 (mAb 1) is a monoclonal antibody described as DZIF-10c in patent applications EP20213562.0 and PCT/EP 2021064326. The antibody is of the IgG1 type.
mAb2 is a monoclonal antibody of the IgG4 type. Antibodies mAb3 to mAb5 are also all monoclonal antibodies of the IgG1 type.
Example 1.1 formulation of mAb1 and other antibodies
mAb1 may be provided as a disposable sterile solution at a concentration of 50 mg/mL. mAb1 drug per vial may contain 20mL of buffer solution consisting of acetic acid, sodium acetate, glycine, trehalose, and polysorbate 20 (see table 1).
Table 1:
| component (A) | Concentration [ mg/mL ]] |
| mAb1 | 50.00 |
| Glacial acetic acid | 0.25 |
| Sodium acetate trihydrate | 2.15 |
| Glycine (Gly) | 16.52 |
| Trehalose dihydrate | 7.57 |
| Polysorbate 20 | 0.40 |
| Water for injection (WFI) | Ad 1mL |
In one embodiment, mAb1 is formulated at about 50mg/mL in about 20mM acetate, about 220mM glycine, about 20mM trehalose, about 0.4g/L polysorbate 20, pH about 5.5.
mAb1 may be administered by intravenous infusion or by inhalation administration after nebulization using a nebulizer.
In clinical studies, mAb1 was administered intravenously to patients (results not shown here) via intravenous infusion in formulated buffer at a dose of about 2.5mg/kg, about 10mg/kg, or about 40mg/kg using a 0.2 μm nylon line filter for 60 minutes (+/-10 minutes). The formulations exemplified above may be diluted to the appropriate volume with a formulation buffer (i.e., the above formulation without antibody mAb 1).
For inhalation administration, the individual may be treated by a mouthpiece at a dose of, for example, 50mg, 100mg or 250mg per treatment, after aerosol generation using a mesh nebulizer or a jet nebulizer. The formulations exemplified above may be diluted to a suitable volume with a formulation buffer.
A single intravenous infusion may be performed after a single inhalation.
In table 2 below, different formulations for antibodies are provided, part of which are according to the invention and part of which are comparative formulations. Formulation F5 corresponds to the formulation in table 1.
Table 2: exemplary formulations
| Annotating | Buffer solution | pH | Excipient 1 | Excipient 2 | PS20 | API concentration |
| F1 | 20mM phosphate | 7.5 | - | 240mM trehalose | 0.4g/L | 50mg/mL |
| F2 | 20mM acetate | 5.5 | 150mM NaCl | - | 0.4g/L | 50mg/mL |
| F3 | 20mM acetate | 5.5 | 220mM glycine | 20mM trehalose | 0.4g/L | 10mg/mL |
| F4 | 20mM acetate | 5.5 | 220mM glycine | 20mM trehalose | 0.4g/L | 150mg/mL |
| F5 | 20mM acetate | 5.5 | 220mM glycine | 20mM trehalose | 0.4g/L | 50mg/mL |
| F6 | 20mM citrate | 6.5 | 220mM glycine | 20mM trehalose | 0.4g/L | 50mg/mL |
| F7 | 20mM histidine | 6.0 | 220mM glycine | 20mM trehalose | 0.4g/L | 50mg/mL |
| F8 | 20mM histidine | 6.0 | - | 180mM trehalose | 0.4g/L | 50mg/mL |
| F9 | 20mM acetate | 5.5 | 220mM glycine | 20mM trehalose | 0.4g/L | 100mg/mL |
API means "active pharmaceutical ingredient" and reflects the amount of antibody added.
Formulations F3 to F5 and F9 are according to the invention, comprising different amounts of antibodies. Formulation F7 also comprises histidine instead of acetate according to the invention. All other formulations are comparative examples. The comparative examples are generally for commercially available antibodies, such as formulations F1, F2 and F8.
Example 1.2 comparison of different formulations of mAb1 with respect to stability
Stability data for formulations F5 to F8 with mAb1 under planned (5 ℃) and accelerated (25 ℃) storage conditions were measured via the percentage of high molecular weight species (HMW (%)) or via the percentage of monomers (monomer (%)) over a storage time of up to 12 months. The results of these measurements are shown in fig. 1 and 2 (for storage conditions of 5 ℃ and 25 ℃ respectively), with the percentage of HMW shown in a and the percentage of monomer shown in B. Monomers represent the active form of the antibody.
Formulation F5 with mAb1 proved to be stable in different container closure systems, namely 20R (20 mL) and 6R (6 mL), covering a wide range of technical parameters (e.g. surface/volume ratio). In the experiments, type I glass vials were used. This data is shown in fig. 3 and 4 (representing storage conditions at 5 ℃ and 25 ℃ respectively), with the percentage of HMW shown in a and the percentage of monomer shown in B.
Other data in fig. 5 and 6 show good stability of mAb1 in formulations according to the invention over a wide range of antibody concentrations (i.e. in formulations F4, F5 and F9), with a concentration of F9 of 100mg/mL mAb1, a concentration of F4 of 150mg/mL mAb1 (both representing Highly Concentrated Liquid Formulations (HCLF)), and a concentration of F5 of 50mg/mL mAb1. Data have been obtained over twelve weeks of storage time. In each figure, the percentage of HMW is shown in a and the percentage of monomer is shown in B.
Example 1.3-mAb1 in formulation F5 was nebulizable with a mesh nebulizerSolo assessed the aerosolization characteristics of mAb1 in F5. Determination of respective MMAD, GSD and FPF using NGI<5.0 μm. Size limitations of 5.0 μm particle size are specified in the european pharmacopoeia 2.9.18; it is generally believed that particles with aerodynamic diameters less than 5.0 μm can be assumed to reach the lower respiratory tract (deeper lung regions).
Table 3: by usingAerodynamic evaluation of 50mg/mL mAb1 in F5 by Solo three separately prepared batches were studied
The particle size distribution of the liquid aerosol droplets produced by the atomizer was evaluated using a Next Generation Impactor (NGI). Thus, NGI was pre-cooled at about 5 ℃ prior to use and measured beginning within 5 minutes after removal from the refrigerator. The impactor was operated at a flow rate of 15L/min. The mesh nebulizer uses a fill volume of 1mL and continues to nebulize until aerosol generation is complete.
Mass Median Aerodynamic Diameter (MMAD), geometric Standard Deviation (GSD) and fine particle fraction (FPF <5.0 μm) were calculated from the impactor measurements.
Table 3 provides the passageMMAD, GSD and FPF of Solo-generated liquid aerosol droplets<Calculated 5.0 μm. In Table 3Provides information about the overall suitability of F5 for inhalation. Furthermore, it shows three independently prepared mAb1 formulated in the F5 batch with the corresponding +.>Variability between measurements made with the Solo atomizer combination. The test in this setting corresponds to a single +.>Solo nebulizer, while nebulization experiments for individual mAb1 batches were performed in triplicate. In summary, three separately prepared mAb batches were each run on three different occasions Each of the atomizers atomizes.
In summary, all three parameters were comparable for the tested batches and nebulizers, showing consistency and robustness in aerodynamic assessment of nebulization of mAb in F5.
The corresponding FPF <5.0 μm for all mAb1 batches was close to 60%, which means that approximately 60% of mAb1 entered the lower respiratory tract (deeper lung regions) and demonstrated particularly good nebulization performance in the aerodynamic parameters obtained.
In summary, the F5 atomizer solution is suitable for useThe Solo system was administered to the patient by full inhalation (see Table 3). Example 1.4 comparison of different nebulizers for nebulization of mAb1
For all evaluations, mAb1 formulated in F5 was subjected to three independent replicates, with one nebulizer per test batch. Different atomizers are used in separate batches.
Formulation F5 showed a stabilizing effect when tested in different commercially available atomizer systems (mesh and jet atomizer), see table 4.
Table 4: product quality parameters after nebulization of mAb1 formulated in F5 using different mesh and jet nebulizers
N/a corresponds to unanalyzed measurements using Surface Plasmon Resonance (SPR)
Osmolality was determined after atomization. When using a jet atomizer, a higher osmolality is observed.
In summary, the integrity of mAb1 was shown to be unaffected by nebulization using different nebulizer devices.
Comparison of different formulations of 5-mAb1 with respect to nebulization
In AerogenThe different formulations according to table 2 (table 5) were tested in a nebulizer (i.e. in a mesh nebulizer). The same measurements were made with an API concentration of 10mg/mL (Table 6). To obtain a lower concentration of 10mg/mL mAb1, formulations F5, F6, F7 and F8 have been diluted with formulation buffer, whereby for each sample the same composition as the formulation but without API was used as diluent.
Table 5: results for undiluted formulation (50 mg/mL mAb 1)
N/a corresponds to unanalyzed measurements using Surface Plasmon Resonance (SPR)
Table 6: results for 1:5 diluted formulation (10 mg/mL mAb 1)
N/a corresponds to unanalyzed measurements using Surface Plasmon Resonance (SPR)
# mAb1 was included at 10mg/ml instead of 50mg/ml as indicated in Table 2 for formulations F5, F6, F7 and F8
In the above table HMW refers to high molecular weight particles, LMW refers to low molecular weight particles, and monomer refers to intact antibodies like this.
Measurement has been performed using CGE (i.e., capillary gel electrophoresis), UP-SEC, ultra-high performance size exclusion chromatography, and SPR (i.e., surface plasmon resonance).
The results indicate that mAb1 was prone to aerosolization in both F5 and F7, while antibody mAb1 was stable in these formulations.
Suitability of mAb1 in examples 1.6-F5 for inhalation via the nose and mouth
To show the suitability of the formulation for nasal and oral inhalation, measurements have been made using an artificial respiratory model.
For evaluation of the complete delivery profile of the product for clinical trials, ASDR/DSDR and TASD/TDSD (i.e. total dose delivered to the patient) were determined according to the procedure described in european pharmacopoeia 2.9.44 and USP <1601>, except that separate experiments were performed to measure these two parameters. ASDR/DSDR and TASD/TDSD were studied using a filter-based approach that included artificial lungs (ASL 5000,Ingmar Medical, pittsburgh, pa, usa; 500mL inhaled volume, tidal breathing, 15 breaths per minute, sinusoidal, 1:1 inhalation/exhalation ratio) as breathing simulators.
ASDR/DSDR was assessed to investigate the amount of mAb1 delivered to patients within one minute. All measurements were made using a respiratory mouth adapter.
Table 7 shows the results of three separate experiments and the mean value of the nebulizer for each of them tested for mAb1 formulated in F5 at 50 mg/mL. For use ofCharacterization of nebulization by Solo, an additional 10mg/mL mAb1 formulation (corresponding to F3) was used.
Table 7: ASDR/DSDR of mAb1 at 50mg/mL and 10mg/mL
The result is rounded to three significant digits
To collect enough active substances for analytical testing, 10mg/mL solution was atomized for a period of time [ ]Solo) was extended to 300 seconds. The rate of delivery of active per minute increases with increasing mAb1 concentration. F5 and F3 show overall good delivery rates, independent of the nebulizer used.
To assess the total amount of mAb1 inhaled by the patient and estimate the aerosol loss within the nebulization system itself and during exhalation, TASD/TDSD was determined. The measurement is performed bySolo nebulizer configurations are performed using a respiratory adapter or using a mask provided with the nebulizer.
The amount of total mAb1 deposited on the inhalation filter and in individual compartments of the oral or nasal mask was analyzed. The TASD/TDSD alone test values and their average for mAb1 are shown in table 8 (for mask and mouth breathing) and table 9 (for mask and nose breathing).
Table 8: TASD/TDSD (n=3) of 50mg/mL mAb1 using mask in combination with oral model; oral respiration
The atomization times for a test 1, test 2 and test 3 were 18:52, 18:10 and 18:06 minutes, respectively.
b dose of mAb1 filled into nebulizer
Table 9: TASD/TDSD (n=3) of 50mg/mL mAb1 using mask in combination with nasal model; nasal breathing
The atomization times for a test 1, test 2 and test 3 were 16:12, 15:40 and 16:47 minutes, respectively.
b dose of mAb1 filled into nebulizer
TDSD (total drug delivered) is the total amount of formulation deposited in the lungs during inhalation.
The metered dose% is the amount of drug recovered during the nebulization experiment compared to the dose used (i.e., the dose of mAb1 filled into the nebulizer).
For Ultra room and face maskSolo was tested. For the mask and nasal breathing setup (table 9), a lower average TASD/TDSD of 89.1mg was obtained. The TASD/TDSD is the sum of the average mAb1 amounts of 11.1mg in the nasal cavity, 6.5mg in the throat/trachea and 71.4mg on the filter representing the lung in this application model.
Since only partial deposition (i.e., deposition of particles with larger MMAD) can be expected for the aerosol portion of the filter that enters the nasal die but does not reach the end of the nasal die, a reduction in TASD/TDSD using nasal breathing is expected. Then, during the exhalation phase, the portion of the particles not deposited will be lost via the mask outlet valve.
From the TASD/TDSD of oral breathing of 119.6mg (lung filter) and 122.4mg (mask), the lung dose can be estimated by multiplying it with approximately 60% of the average FPF <5.0 μm (see table 3).
These data indicate that the formulations of the present invention are suitable for oral inhalation and nasal inhalation.
The pharmaceutical composition or formulation as described may prove effective in stabilizing all antibodies for inhaled administration using: (i) different nebulizer systems (e.g., mesh nebulizer, jet nebulizer), (ii) diluted and undiluted formulations (different API concentrations), and (iii) different masks (oral and nasal).
Example 1.7: evaluation of antiviral efficacy of two preventative nebulizations of mAb1 in cynomolgus monkeys
Two preventive nebulized antiviral efficacy of antibody mAb1 was evaluated in 6 cynomolgus monkeys prior to infection with SARS-CoV-2. For the study, 6 cynomolgus monkeys (Macaca fascicularis) were divided into two treatment groups: the 4 animals were included in the treatment group that received antibodies prior to infection, and both animals received vehicle only prior to infection.
Animals in the treatment group received two applications of 10mL mAb1 (50 mg/mL in 20mM acetate, 220mM glycine, 20mM trehalose, 0,04% (w/v) polysorbate 20, pH 5, 5) 4 (D-4) and 2 (D-2) days prior to infection. The application is using a sieve mesh atomizer, aerogen Nebulizers (Aerogen GmbH, latina root, germany) and suitable masks (Laerdal Medical GmbH, poheimer, germany, size S).
On the day of infection (D0), the infection was performed by using a micro-nebulizer device (model IA-1B,) Intranasal (IN) application of 500. Mu.L/nostril and by using a micro-nebulizer device (model IA-1B, pennCentury TM ) Intratracheal (IT) infection by spraying 1mL of inoculum in the trachea, all animals were treated with 10 7 TCID 50 SARS-CoV-2 strain hCoV-19/French/OCC-NRC 02765/2020 (accession number GISAID "EPI_ISL_640002, spike replacement D614G, K1073N) was inoculated.
Daily blood and saliva samples were collected for analysis, nasopharyngeal swabs and oropharyngeal swabs. Bronchoalveolar lavage was performed at D2, D4 and D6. Clinical monitoring includes body temperature, food intake and body weight. Cadaveric examinations of D6 included histopathology of the lungs and viral load determinations of the lungs, nasal mucosa, oropharynx and kidneys.
In nasopharyngeal swabs and bronchoalveolar lavage (BAL), copies of the virus can be found in both control animals after infection. In contrast, the treated animals showed results below the limit of detection (LOD) or levels several log lower than the control animals. The results of the nasopharyngeal swabs analysis of all animals are shown in fig. 7 and the bronchoalveolar lavage results are shown in fig. 8.
Body temperature: both control animals showed significant and prolonged hyperthermia after infection with SARS-CoV-2. Prophylactic treatment with mAb1 delayed the onset of hyperthermia, shortened the duration of hyperthermia and reduced the intensity of hyperthermia, or prevented the onset of hyperthermia altogether.
Macroscopic and microscopic observations of the lung: the lungs of both control animals showed a hardened dark red region, similar to that described in the main publication as lung metaplasia. The lungs of the four treated animals appeared healthy with no signs of lung injury. All these observations were confirmed by microscopic observation: there was a significant, extensive, subacute bronchointerstitial inflammation in most slides of both control animals, and there was very limited or no bronchointerstitial inflammation in the group of 2 animals.
Taken together, these results demonstrate that prophylactic treatment with mAb1 by inhalation application reduced viral load, reduced or prevented clinical symptoms (hyperthermia) and prevented lung pathology in terms of viral copy and infectious virus.
In the following examples, different formulations with mAb1, mAb2, mAb3, mAb4 and mAb5 were studied.
EXAMPLE 2.1 stability of different antibodies in different formulations
The formulations according to the invention show excellent stability compared to the other formulations studied.
The formulations shown in table 2 below were used with different antibodies.
Stability of mAb1, mAb2, mAb3, mAb4 and mAb5 have been tested in formulation F5 (see table 2). The formulation according to the invention shows very high stability of different antibodies at both 5 ℃ and 25 ℃. The 5 ℃ corresponds to the normal storage conditions (planned storage conditions) expected to be used for the biomolecules. 25 ℃ represents an accelerated storage condition, which is expected to be used only for a short period of time (e.g., prior to administration of the formulation to a subject/patient).
The results of these tests are shown in FIG. 9 (5 ℃) and FIG. 10 (25 ℃) where the percent of high molecular weight species (HMW (%)) is shown in A and the percent of monomers (monomer (%)) is shown in B.
In fig. 11 to 15, the storage stability at 5 ℃ of mAb1 (fig. 11), mAb2 (fig. 12), mAb3 (fig. 13), mAb4 (fig. 14) and mAb5 (fig. 15) are shown, each in formulation F5 and not formulations F1, F2 and F6 according to the invention. The formulations are described in table 2. In each figure, the percentage of high molecular weight species (HMW (%)) is shown in a, and the percentage of monomers (%)) is shown in B.
Figures 16 to 20 show the storage stability at 25 ℃ of mAb1 (figure 16), mAb2 (figure 17), mAb3 (figure 18), mAb4 (figure 19) and mAb5 (figure 20), each in formulations F5, F1, F2 and F6 (see table 2). The percentage of high molecular weight species (HMW (%)) is shown in a and the percentage of monomers (monomer (%)) is shown in B.
The high stability of all antibodies studied in F5 can be demonstrated.
EXAMPLE 2.2 stability of different antibodies at different concentrations
Since the pharmaceutical formulations according to the invention are intended for use in a wide concentration range of antibodies or antigen binding fragments thereof, the stability of mAb1, mAb2 and mAb3 has been determined at concentrations of 10mg/mL, 50mg/mL and 150mg/mL and under storage conditions of 5 ℃ and 25 ℃, respectively.
The results are shown in fig. 21 and 22, where the data points for mAb1, mAb2, and mAb3 are depicted as circles (∈), triangles (Δ), and squares (∈), respectively. mAb2 and mAb3 concentrations were evaluated: 10mg/mL, 50mg/mL and 150mg/mL, expressed as hollow, semi-solid and solid forms. For mAb1, only 50mg/ml and 150mg/ml concentrations were measured. The percentage of high molecular weight species (HMW (%)) is shown in a and the percentage of monomers (monomer (%)) is shown in B.
EXAMPLE 2.3 nebulization of different antibodies
Nebulization of antibodies mAb1, mAb2, mAb3, mAb4, and mAb5 has been performed using a 5mL sample volume of formulation F5 for each of these antibodies (i.e., an antibody concentration of 50 mg/mL). For atomization, aerogen was usedAn inhaler.
Aerodynamic characterization and product quality assessment were performed during and after atomization. All tests were performed in triplicate. The average of three independent tests is listed in table 10 below.
Table 10: using AerogenNebulization of mAb1 to mAb5 at an API concentration of 50mg/mL in F5 ≡>
* Each mAb (25 mg dose) was nebulized by technology in a sample volume of 0.5mL per individual measurement. The accumulated atomization time is considered to be available for AerogenThe maximum sample volume (5 mL) for mesh nebulizer nebulization was inferred and would correspond to the maximum inhaled dose of 250 mg.
The Mass Median Aerodynamic Diameter (MMAD) aerodynamic diameter of the droplets or particles is equal to the diameter of a sphere having a density of 1g/mL with the same sedimentation velocity. In addition to geometric diameter, the density and shape of the particles can also affect aerodynamic properties. Typically, MMAD values between 1 and 5 μm are considered optimal for lung deposition. Smaller particles are exhaled and larger particles are deposited in the mouth, nose or trachea.
The Geometric Standard Deviation (GSD) is a measure of the dispersion of the deviation from the mean value of the particle size distribution (MMAD). It is a dimensionless number. Smaller values represent a narrow particle size distribution, which is preferred for pulmonary applications, since if the MMAD is located in this region more droplets or particles should be in the desired range between 1 and 5 μm.
The Fine Particle Fraction (FPF) is the proportion of particles or droplets in the aerosol having a diameter below 5.0 μm. This portion reaches the deeper lungs after inhalation.
Ultra-efficient size exclusion chromatography (UP-SEC) was used to determine the High Molecular Weight (HMW) and monomer content before and after nebulization in order to evaluate the integrity of the antibodies.
Surface Plasmon Resonance (SPR) is used to evaluate binding activity and thus whether an antibody retains function after nebulization.
In general, UV-Vis, UP-SEC and SPR were used to evaluate the presence of AerogenThe mesh nebulizer provides integrity, function and product quality of the antibodies before and after nebulization.
mAb1 to mAb5 were used with AerogenThe sieve pore atomizer atomizes. When nebulized in F5, all mabs showed very good nebulization performance. Table 10 shows that mAb1 to mAb5 can be nebulized in F5 while FPF<5.0 μm reflects that all aerosol droplets of mAb enter the deep lung while maintaining its integrity, function and overall product quality. However, from mAb1 to mAb5, differences were observed in the nebulization time and aggregate formation after nebulization (increase in HMW) and monomer content (decrease in monomer). / >
Claims (15)
1. A formulation comprising or consisting of: an antibody or antigen binding fragment thereof at a concentration of 1-200mg/mL in aqueous solution, 5-50mM acetate or histidine, 120-260mM glycine, 15-120mM trehalose, 0.1-1.0g/L polysorbate 20, and a pH of 4.5-6.5.
2. The formulation of claim 1, comprising or consisting of: an antibody or antigen binding fragment thereof at a concentration of 10-260mg/mL in aqueous solution, 10-25mM acetate or histidine, 172.7-259.1mM glycine, 17.3-25.9mM trehalose, 0.2-0.6g/L polysorbate 20 (polyoxyethylene (20) -sorbitan-monolaurate), and a pH of 5.2-5.8.
3. The formulation according to any one of claims 1 or 2, comprising or consisting of: an antibody or antigen binding fragment thereof at a concentration of 10 to 150mg/mL in aqueous solution, 20mM acetate or histidine, 220mM glycine, 20mM trehalose, 0.4g/L polysorbate 20, ph 5.5.
4. A formulation according to any one of claims 1 to 3, comprising or consisting of: an antibody or antigen binding fragment thereof at a concentration of 50mg/mL in 20mM acetate, 220mM glycine, 20mM trehalose, 0.4g/L polysorbate 20 in aqueous solution, pH 5.5.
5. The formulation according to any one of claims 1 to 4, wherein two or more, preferably two antibodies or antigen binding fragments thereof are comprised in the formulation.
6. Use of a formulation according to any one of claims 1 to 5 for administering an antibody or antigen binding fragment thereof to a patient at a dose of 10 to 50mg/kg body weight, preferably 30 to 50mg/kg body weight.
7. Use according to claim 6 or use of a formulation according to any one of claims 1 to 5 for administering an antibody or antigen binding fragment thereof to a patient, wherein the formulation is administered by one or more of the following routes: injections, including intravenous, intradermal, and subcutaneous; inhalation, including oral inhalation, nasal inhalation, and mask inhalation; topical, including transdermal, transmucosal, and rectal, preferably the formulations are administered intravenously, inhaled, and/or subcutaneously, including oral inhalation, nasal inhalation, and mask inhalation.
8. The use of claim 7, wherein the administration is by at least two different routes selected from intravenous; inhalation, including oral inhalation, nasal inhalation, and mask inhalation; and subcutaneously.
9. The use of any one of claims 6 to 8, wherein the formulation is administered to a patient via at least two different routes, and the concentration of antibody or antigen binding fragment thereof within the formulation administered by a first of the at least two different routes contains at least twice the concentration of antibody or antigen binding fragment thereof as compared to the concentration of antibody or antigen binding fragment thereof within the formulation administered by a second of the at least two different routes.
10. The use according to any one of claims 6 to 9 or the use of a formulation according to any one of claims 1 to 5, wherein the formulation is administered to a patient by inhalation and the concentration of antibody or antigen binding fragment thereof in the formulation is from 1 to 150mg/mL, preferably 10 to 80mg/mL, more preferably 10 to 60mg/mL, most preferably 10 to 50mg/mL.
11. A method for treating a patient, wherein the formulation according to any one of claims 1 to 6 is administered to a patient at a dose of 1 to 50mg/kg of the patient's body weight, preferably 10 to 50mg/kg of an antibody or antigen binding fragment thereof.
12. The method for treating a patient according to claim 11 or the method for treating a patient with the formulation according to any one of claims 1 to 5, wherein the antibody or antigen binding fragment thereof within the formulation is administered to the patient by one or more of the following routes: injections, including intravenous, intradermal, and subcutaneous; inhalation, including oral inhalation, nasal inhalation, and mask inhalation; topical, including transdermal, transmucosal, and rectal, preferably the formulations are administered intravenously, inhaled, and/or subcutaneously, including oral inhalation, nasal inhalation, and mask inhalation.
13. The method for treating a patient according to claim 12, wherein the administration is performed by at least two different routes selected from intravenous; inhalation, including oral inhalation, nasal inhalation, and mask inhalation; and subcutaneously.
14. The method for treating a patient according to any one of claims 11 to 13, wherein the antibody or antigen binding fragment thereof within the formulation is administered to the patient by at least two different routes, and the concentration of the antibody or antigen binding fragment thereof within the formulation administered by a first of the at least two different routes contains at least twice the concentration of the antibody or antigen binding fragment thereof as the concentration of the antibody or antigen binding fragment thereof within the formulation administered by a second of the at least two different routes.
15. The method for treating a patient according to any one of claims 11 to 14 or the method for treating a patient with the formulation according to any one of claims 1 to 5, wherein the formulation is administered to the patient by inhalation and the concentration of the antibody or antigen binding fragment thereof in the formulation is from 10 to 150mg/mL, preferably 10 to 80mg/mL, more preferably 10 to 60mg/mL, most preferably 10 to 50mg/mL.
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| EPPCT/EP2021/082892 | 2021-11-24 | ||
| EP2021082892 | 2021-11-24 | ||
| PCT/EP2021/085139 WO2022122993A1 (en) | 2020-12-11 | 2021-12-10 | Formulation for multi-purpose application |
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