Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2839—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily
  • C07K16/2842—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily against integrin beta1-subunit-containing molecules, e.g. CD29, CD49
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
  • A61K39/39591—Stabilisation, fragmentation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
  • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
  • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Definitions

• the present invention relates to a stable liquid formulation of an anti-a4B7 antibody.
• proteins are larger and more complex than traditional organic and inorganic drugs (i.e., possessing multiple functional groups in addition to complex three- dimensional structures), the formulation of such proteins poses special problems.
• a formulation must preserve the conformational integrity of at least a core sequence of the protein's amino acids, while at the same time protecting the protein's multiple functional groups from degradation.
• Proteins may suffer from a lack of stability, and monoclonal and polyclonal antibodies in particular may be relatively unstable. Numerous characteristics may affect a protein's stability. In fact, even in the case of purified antibodies, the antibody structures may be heterogenous, which further complicates the formulation of such systems.
• the excipients included in antibody formulations preferably minimize any potential immune response.
• Degradation pathways for proteins can involve chemical instability (i.e., any process which involves modification of the protein by bond formation or cleavage resulting in a new chemical entity) or physical instability (i.e., changes in the higher order structure of the protein).
• Chemical instability is manifested in, for example, deamidation, isomerization, hydrolysis, oxidation, fragmentation, glycan beta elimination or disulfide exchange.
• Physical instability can result from denaturation, aggregation, precipitation or adsorption, for example.
• the four most common protein degradation pathways are protein fragmentation, aggregation, deamidation, and oxidation.
• Consequences of chemical or physical instability of therapeutic protein include a lowering of the effective administered dose, decreased safety of the therapy due to, for example irritation or immunological reactivity, and more frequent manufacturing due to short shelf life.
• Formulations for each route of administration and dosage forms may be unique and, therefore, have specific requirements.
• Solid dosage forms such as lyophilized powders
• lyophilized powders are generally more stable than liquid (aqueous) formulations.
• reconstitution of the lyophilized formulation requires a significant vial overfill, care in handling and involves high production cost relative to a liquid formulation.
• liquid formulations are advantageous in these and are usually preferred for injectable protein therapeutics (in terms of convenience for the end user and ease of preparation for the manufacturer), this form may not always be feasible given the susceptibility of proteins to denaturation, aggregation and oxidation under stresses such as temperature, pH changes, agitation etc.,. All of these stress factors could result in the loss of biological activity of a therapeutic protein / antibody.
• high concentration liquid formulations are susceptible to degradation and/or aggregation. Nevertheless, high concentration formulations may be desirable for subcutaneous or intravenous route of administration, as the frequency of administration and injection volume is reduced. On the other hand, specific treatment schedule and dosing might require a low concentration formulation and prefer intravenous route of administration for more predictable delivery and complete bioavailability of the therapeutic drug.
• WO2012151247 discloses stable liquid pharmaceutical formulation of Vedolizumab comprising Citrate or EDTA as chelating agent or antioxidant. It further discloses free amino acid which is selected from the group consisting of histidine, alanine, arginine, glycine, glutamic acid and combinations thereof. More particularly, it discloses stable liquid pharmaceutical formulation comprising a mixture of an anti-a4p7 antibody, citrate, histidine, arginine, and polysorbate 80.
• a formulation combination with increased concentration of protein and /or stabilizers may increase the viscosity of the formulation, in turn increasing the injection time and pain at the site of injection and also pose difficulties during processing of the drug substance.
• the main object of the present invention is to provide stable liquid pharmaceutical formulation comprising a mixture of an anti-a4B7 antibody, a buffer, stabilizer, antioxidant, viscosity reducer and surfactant.
• Another object of the present invention is to provide stable liquid pharmaceutical formulation comprising anti-a4B7 antibody, a buffer, stabilizer, L-methionine as an antioxidant, L-lysine HC1 as a viscosity reducer and surfactant.
• Another object of the present invention is provide stable liquid pharmaceutical formulation of an anti-a4B7 antibody comprising buffer, sugar, viscosity reducer, antioxidant and surfactant at pH about 5.8 to 6.8, wherein the molar ratio of sugar to anti-a4p7 antibody (mole:mole) is less than 150:1.
• Another object of the present invention is to provide stable liquid pharmaceutical formulation comprising at least about 50 mg/ml to about 220 mg/ml anti-a4B7 antibody, a buffering agent, stabilizer, L-methionine as an antioxidant, L-lysine HC1 as a viscosity reducer and surfactant.
• Another object of the present invention is to provide stable liquid pharmaceutical formulation of an anti-a4B7 antibody comprising a buffer, stabilizer, viscosity reducer, antioxidant and surfactant, wherein the formulation has pH about 5.8 to 6.8.
• Another object of the present invention is provide stable liquid pharmaceutical formulation of an anti-a4B7 antibody comprising sucrose as a stabilizer, L-lysine HC1 as a viscosity reducer and L- methionine as an antioxidant, wherein the formulation has pH about 5.8 to 6.8..
• Another object of the present invention is provide stable liquid pharmaceutical formulation of an anti-a4B7 antibody comprising L-histidine, L-histidine monohydrochloride, sucrose, L-lysine HC1, L-methionine and polysorbate 80, wherein the formulation has pH about 5.8 to 6.8.
• Another object of the present invention is to provide stable liquid pharmaceutical formulation of an anti-a4B7 antibody comprising buffer, stabilizer, viscosity reducer, antioxidant and surfactant; wherein the anti-a4B7 antibody is at a concentration of about 50-220 mg/mL, buffer is at a concentration range of 0-100 mM, stabilizer is at a concentration range of 0-100 mg/mL, viscosity reducer is at a concentration range of 0-10 mg/mL, antioxidant is at a concentration range of 0-2 mg/mL and surfactant is at a concentration range of 0-2 mg/mL, wherein the formulation has pH about 5.8 to 6.8.
• Another object of the present invention is to provide stable liquid pharmaceutical formulation of an anti-a4B7 antibody comprising sucrose as a stabilizer, L-lysine HC1 as a viscosity reducer and L-methionine as an antioxidant; wherein the anti-a4B7 antibody is at concentration of about 50- 220 mg/mL, sucrose is in the concentration range of 0-100 mg/mL, L-lysine HC1 is in the concentration range of 0-10 mg/mL and L-methionine is in the concentration range of 0-2 mg/mL, wherein the formulation has pH about 5.8 to 6.8.
• Another object of the present invention is to provide stable liquid pharmaceutical formulation of an anti-a4B7 antibody comprising 0-100 mM histidine/histidine monohydrochloride, 0-100 mg/mL sucrose, 0-10 mg/mL L-lysine HC1, 0-2 mg/mL L-methionine and 0-2 mg/mL polysorbate 80, wherein the formulation has pH about 5.8 to 6.8.
• Another object of the present invention is to provide stable liquid pharmaceutical formulation of an anti-a4B7 antibody comprising 50 mM histidine/histidine HC1, 45 mg/mL sucrose, 8 mg/mL L- lysine HC1, 1.49 mg/mL L-methionine and 2 mg/mL polysorbate 80, wherein the formulation has pH about 5.8 to 6.8.
• the main aspect of the present invention is to provide stable liquid pharmaceutical formulation comprising a mixture of an anti-a4B7 antibody, a buffer, stabilizer, antioxidant, viscosity reducer and surfactant.
• Another aspect of the present invention is to provide stable liquid pharmaceutical formulation comprising anti-a4B7 antibody, a buffer, stabilizer, L-methionine as an antioxidant, L-lysine HC1 as a viscosity reducer and surfactant.
• Another aspect of the present invention is provide stable liquid pharmaceutical formulation of an anti-a4B7 antibody comprising buffer, sugar, viscosity reducer, antioxidant and surfactant at pH about 5.8 to 6.8, wherein the molar ratio of sugar to anti-a4p7 antibody (mole:mole) is less than 150:1.
• Another aspect of the present invention is to provide stable liquid pharmaceutical formulation comprising at least about 50 mg/ml to about 220 mg/ml anti-a4B7 antibody, a buffering agent, stabilizer, L-methionine as an antioxidant, L-lysine HC1 as a viscosity reducer and surfactant.
• Another aspect of the present invention is to provide stable liquid pharmaceutical formulation of an anti-a4B7 antibody comprising a buffer, stabilizer, viscosity reducer, antioxidant and surfactant, wherein the formulation has pH about 5.8 to 6.8.
• Another aspect of the present invention is provide stable liquid pharmaceutical formulation of an anti-a4B7 antibody comprising sucrose as a stabilizer, L-lysine HC1 as a viscosity reducer and L- methionine as an antioxidant, wherein the formulation has pH about 5.8 to 6.8.
• Another aspect of the present invention is provide stable liquid pharmaceutical formulation of an anti-a4B7 antibody comprising L-histidine, L-histidine monohydrochloride, sucrose, L-lysine HC1, L-methionine and polysorbate 80, wherein the formulation has pH about 5.8 to 6.8.
• Another aspect of the present invention is to provide stable liquid pharmaceutical formulation of an anti-a4B7 antibody comprising buffer, stabilizer, viscosity reducer, antioxidant and surfactant; wherein the anti-a4B7 antibody is at a concentration of about 50-220 mg/mL, buffer is at a concentration range of 0-100 mM, stabilizer is at a concentration range of 0-100 mg/mL, viscosity reducer is at a concentration range of 0-10 mg/mL, antioxidant is at a concentration range of 0-2 mg/mL and surfactant is at a concentration range of 0-2 mg/mL, wherein the formulation has pH about 5.8 to 6.8.
• Another aspect of the present invention is to provide stable liquid pharmaceutical formulation of an anti-a4B7 antibody comprising sucrose as a stabilizer, L-lysine HC1 as a viscosity reducer and L-methionine as an antioxidant; wherein the anti-a4B7 antibody is at concentration of about 50- 220 mg/mL, sucrose is in the concentration range of 0-100 mg/mL, L-lysine HC1 is in the concentration range of 0-10 mg/mL and L-methionine is in the concentration range of 0-2 mg/mL, wherein the formulation has pH about 5.8 to 6.8.
• Another aspect of the present invention is to provide stable liquid pharmaceutical formulation of an anti-a4B7 antibody comprising 0-100 mM histidine/histidine monohydrochloride, 0-100 mg/mL sucrose, 0-10 mg/mL L-lysine HC1, 0-2 mg/mL L-methionine and 0-2 mg/mL polysorbate 80, wherein the formulation has pH about 5.8 to 6.8.
• Another aspect of the present invention is to provide stable liquid pharmaceutical formulation of an anti-a4B7 antibody comprising 50 mM histidine/histidine HC1, 45 mg/mL sucrose, 8 mg/mL L- lysine HC1, 1.49 mg/mL L-methionine and 2 mg/mL polysorbate 80, wherein the formulation has pH about 5.8 to 6.8.
• FIGURE 1 pH trend analysis of RMP & batch 1, 2 & 3 at 40° C.
• FIGURE 2 Percentage HMW (SEC) trend analysis of RMP & Batch 1, 2 & 3 at 40° C.
• FIGURE 3 Percentage purity (SEC) trend analysis of RMP & Batch 1, 2 & 3 at 40° C.
• FIGURE 4 Percentage LMW (SEC) trend analysis of RMP & Batch 1, 2 & 3 at 40° C.
• FIGURE 5 Percentage Acidic (CEX) trend analysis of RMP & Batch 1, 2 & 3 at 40° C.
• FIGURE 6 Percentage Purity (CEX) trend analysis of RMP & Batch 1, 2 & 3 at 40° C.
• FIGURE 7 Percentage Basic (CEX) trend analysis of RMP & Batch 1, 2 & 3 at 40° C.
• an element means one element or one or more elements.
• compositions are to be interpreted inclusively rather than exclusively.
• Consist are to be interpreted exclusively, rather than inclusively. While various embodiments in the specification are presented using “comprising” language, under other circumstances, a related embodiment is also intended to be interpreted and described using “consisting of or “consisting essentially of’ language.
• pharmaceutical formulation refers to a preparation that contains an anti- a4B7 antibody in such form as to permit the biological activity of the antibody to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.
• a “stable” formulation is one in which the antibody therein substantially retains its physical stability and/or chemical stability and/or its biological activity upon storage.
• the formulation substantially retains its physical and chemical stability, as well as its biological activity upon storage.
• the storage period is generally selected based on the intended shelf-life of the formulation.
• Various analytical techniques for measuring protein stability are available in the art.
• An antibody "retains its physical stability” in a pharmaceutical formulation if it shows substantially no signs of aggregation, precipitation and/or denaturation upon visual examination of color and/or clarity, or as measured by UV light scattering or by size exclusion chromatography.
• An antibody is said to “retain its chemical stability” in a pharmaceutical formulation when its shows no or minimal formation of product variants which may include variants as a result of chemical modification of antibody of interest such as deamination, oxidation etc.
• Analytical methods such as ion exchange chromatography and hydrophobic ion chromatography may be used to investigate the chemical product variants.
• buffering agent refers to a buffer that resists changes in pH by the action of its acid-base conjugate components.
• the buffering agent may be present in a liquid or solid formulation of the invention.
• the buffering agent of this invention adjusts the pH of the formulation to about 5.8 to 6.8.
• examples of buffering agents that alone or in combination, will control the pH in the 5.8 to 6.8 range include acetate, succinate, gluconate, histidine, citrate, phosphate, maleate, cacodylate, 2-[N- morpholinoj ethanesulfonic acid (MES), bis(2- hydroxyethyl)iminotris[hydroxymethyl]methane (Bis-Tris), N-[2-acetamido]-2- iminodiacetic acid (ADA), glycylglycine and other organic acid buffers.
• the buffering agent herein is histidine.
• a "histidine buffer” is a buffer comprising histidine ions.
• histidine buffers include histidine chloride, histidine acetate, histidine phosphate, histidine sulfate solutions.
• the histidine buffer or histidine-HCl buffer has a between about pH 5.8 to 6.8.
• a “surfactant” herein refers to an agent that lowers surface tension of a liquid.
• the surfactant can be a nonionic surfactant.
• examples of surfactants herein include polysorbate (polyoxyethylene sorbitan monolaurate, for example, polysorbate 20 and, polysorbate 80).
• antioxidant refers to an agent that inhibits the oxidation of other molecules.
• antioxidants herein include L-methionine, lipoic acid, uric acid, glutathione, tocopherol, carotene, lycopene, cysteine, phosphonate compounds, e.g., etidronic acid, desferoxamine and malate.
• an ‘anti-a4B7 antibody’ herein refers to Vedolizumab antibody.
• the main embodiment of the present invention is to provide stable liquid pharmaceutical formulation comprising a mixture of an anti-a4B7 antibody, a buffer, stabilizer, antioxidant, viscosity reducer and surfactant.
• Another embodiment of the present invention is to provide stable liquid pharmaceutical formulation comprising anti-a4B7 antibody, a buffer, stabilizer, L-methionine as an antioxidant, L-lysine HC1 as a viscosity reducer and surfactant.
• Another embodiment of the present invention is provide stable liquid pharmaceutical formulation of an anti-a4B7 antibody comprising buffer, sugar, viscosity reducer, antioxidant and surfactant at pH about 5.8 to 6.8, wherein the molar ratio of sugar to anti-a4p7 antibody (mole:mole) is less than 150: 1.
• sugar is sucrose.
• Another embodiment of the present invention is to provide stable liquid pharmaceutical formulation comprising at least about 50 mg/ml to about 220 mg/ml anti-a4B7 antibody, a buffering agent, stabilizer, L-methionine as an antioxidant, L-lysine HC1 as a viscosity reducer and surfactant.
• the stable liquid pharmaceutical formulation of anti-a4B7 antibody is high concentration formulation.
• the concentration of anti-a4B7 antibody in the formulation is about 160 mg/ml.
• Another embodiment of the present invention is to provide stable liquid pharmaceutical formulation of an anti-a4B7 antibody comprising a buffer, stabilizer, viscosity reducer, antioxidant and surfactant, wherein the formulation has pH about 5.8 to 6.8.
• Another embodiment of the present invention is provide stable liquid pharmaceutical formulation of an anti-a4B7 antibody comprising sucrose as a stabilizer, L-lysine HC1 as a viscosity reducer and L-methionine as an antioxidant, wherein the formulation has pH about 5.8 to 6.8.
• Another embodiment of the present invention is provide stable liquid pharmaceutical formulation of an anti-a4B7 antibody comprising L-histidine, L-histidine monohydrochloride, sucrose, L- lysine HC1, L-methionine and polysorbate 80, wherein the formulation has pH about 5.8 to 6.8.
• Another embodiment of the present invention is to provide stable liquid pharmaceutical formulation of an anti-a4B7 antibody comprising buffer, stabilizer, viscosity reducer, antioxidant and surfactant; wherein the anti-a4B7 antibody is at a concentration of about 50-220 mg/mL, buffer is at a concentration range of 0-100 mM, stabilizer is at a concentration range of 0-100 mg/mL, viscosity reducer is at a concentration range of 0-10 mg/mL, antioxidant is at a concentration range of 0-2 mg/mL and surfactant is at a concentration range of 0-2 mg/mL, wherein the formulation has pH about 5.8 to 6.8.
• Another embodiment of the present invention is to provide stable liquid pharmaceutical formulation of an anti-a4B7 antibody comprising sucrose as a stabilizer, L-lysine HC1 as a viscosity reducer and L-methionine as an antioxidant; wherein the anti-a4B7 antibody is at concentration of about 50-220 mg/mL, sucrose is in the concentration range of 0-100 mg/mL, L- lysine HC1 is in the concentration range of 0-10 mg/mL and methionine is in the concentration range of 0-2 mg/mL, wherein the formulation has pH about 5.8 to 6.8.
• Another embodiment of the present invention is to provide stable liquid pharmaceutical formulation of an anti-a4B7 antibody comprising 0-100 mM histidine/histidine monohydrochloride, 0-100 mg/mL sucrose, 0-10 mg/mL L-lysine HC1, 0-2 mg/mL L-methionine and 0-2 mg/mL polysorbate 80, wherein the formulation has pH about 5.8 to 6.8.
• Another embodiment of the present invention is to provide stable liquid pharmaceutical formulation of an anti-a4B7 antibody comprising 50 mM histidine/histidine HC1, 45 mg/mL sucrose, 8 mg/mL L-lysine HC1, 1.49 mg/mL L-methionine and 2 mg/mL polysorbate 80, wherein the formulation has pH about 5.8 to 6.8.
• the concentration of polysorbate 80 in the formulation of anti-a4B7 antibody is 0.2% w/v.
• the concentration of anti-a4B7 antibody in the formulation is about 160 mg/ml.
• formulation of anti-a4B7 antibody can be administered by subcutaneous route or intravenous route.
• Vedolizumab An anti -a4137 antibody, Vedolizumab, suitable for storage in the present pharmaceutical composition was produced by standard methods known in the art.
• Vedolizumab which was prepared by recombinant expression of immunoglobulin light and heavy chain genes in a mammalian host cell such as Chinese Hamster Ovary cells.
• the expressed Vedolizumab was harvested and the crude harvest was subjected to standard downstream process steps that include purification, filtration and optionally dilution or concentration steps.
• the crude harvest of Vedolizumab may be purified using standard chromatography techniques such as affinity chromatography, ion-exchange chromatography and combinations thereof.
• the purified Vedolizumab solution can additionally be subjected to one or more filtration steps, and the solution obtained was subjected to further formulation studies.
• Vedolizumab formulation was prepared in composition given in the table 1 by dissolving the excipients in water for injection.
• the protein concentration was set to 108 mg/0.68 mL (PFS)/ 158.8 mg/ mL and the pH of the formulation is set to 5.8 to 6.8.
• the Vedolizumab SC formulation drug product was formulated in above mention different buffers and putted on stress stability (40 °C ⁇ 2 °C and 50 °C) and evaluated for analytical techniques as below table 2 and table 3 : Table 2: Stability Study Plan at 40 °C ⁇ 2 °C
• BATCH 4 of formulation F-20 given in table 1 was prepared to assess the real time and accelerated time stability. Following is the result from the real time and accelerated time stability study.

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