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US20030113316A1 - Stable lyophilized pharmaceutical formulation of IgG antibodies - Google Patents

Stable lyophilized pharmaceutical formulation of IgG antibodies Download PDF

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Publication number
US20030113316A1
US20030113316A1 US10/206,469 US20646902A US2003113316A1 US 20030113316 A1 US20030113316 A1 US 20030113316A1 US 20646902 A US20646902 A US 20646902A US 2003113316 A1 US2003113316 A1 US 2003113316A1
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formulation
antibody
lyophilized
sucrose
protein
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Elizabet Kaisheva
Aleni Flores-Nate
Supriya Gupta
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PDL Biopharma Inc
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Individual
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Priority to US10/206,469 priority Critical patent/US20030113316A1/en
Assigned to PROTEIN DESIGN LABS, INC. reassignment PROTEIN DESIGN LABS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FLORES-NATE, ALENI, GUPTA, SUPRIYA, KAISHEVA, ELIZABET A.
Publication of US20030113316A1 publication Critical patent/US20030113316A1/en
Priority to US11/250,835 priority patent/US7592004B2/en
Priority to US12/540,320 priority patent/US8298530B2/en
Abandoned legal-status Critical Current

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    • 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
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • 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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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

Definitions

  • the present invention relates generally to the field of pharmaceutical formulation of antibodies. Specifically, the present invention relates to a stable, lyophilized, high concentration antibody formulation. This invention is exemplified by a stabilized lyophilized formulation of anti-IL 2 receptor antibody.
  • Immunoglobulins are recognized as possessing characteristics that tend to form aggregates and particulates in solution; thus requiring filtration of these formulations prior to using them for intravenous injection.
  • the formation of protein aggregates and particulates has long been a problem in the development of parenteral immunoglobulin products.
  • a stable pharmaceutical formulation comprising an antibody.
  • WO 89/11297 discloses a lyophilized composition
  • SynagisTM (MedImmune) is a humanized monoclonal IgG1 antibody produced by recombinant DNA technology, directed to an epitope in the A antigenic site of the T protein of respiratory syncytial virus (RSV).
  • SynagisTM is a composite of human (95%) and murine (5%) antibody sequences.
  • SynagisTM is supplied as a sterile lyophilized product for reconstruction with sterile water for injection. Reconstituted SynagisTM is required to stand at room temperature for a minimum of 20 minutes until the solution clarifies. Reconstituted SynagisTM is to be administered by intramuscular injection only.
  • SynagisTM contains the following excipients: 47 mM histidine, 3.0 mM glycine and 5.6% mannitol and the active ingredient, IgG1 antibody, at a concentration of 100 milligrams per vial. (See Physicians' Desk Reference®, Medical Economic Company, Inc., Montvale, N.J.)
  • U.S. Patent Application Publication No. U.S. 2001/0014326A1 discloses a prelyophilized antibody formulation containing 25 mg/ml anti-IgE antibody, 5 mM histidine, pH 6.0, 85 mM sucrose, and 0.01% polysorbate 20.
  • U.S. Pat. No. 6,171,586 discloses a stable aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody not subjected to prior lyophilization, and acetate buffer from about pH 4.8 to about 5.5, a surfactant, and a polyol, wherein the formulation lacks a tonicifying amount of sodium chloride.
  • WO 97/45140 discloses a monoclonal antibody preparation of a humanized antibody against the CDw52 antigen, having a concentration of 100 mg/ml or greater, wherein the preparation is substantially free from aggregates.
  • Cleland, et al. J. Pharm. Sci., 90:310-321 (2001) disclose that a 360:1 molar ratio of lyoprotectant to protein is required for storage stability of a lyophilized monoclonal antibody.
  • This invention is directed to a stable lyophilized pharmaceutical formulation prepared from an aqueous formulation comprising a high concentration, e.g., greater than 50 mg/ml of an IgG antibody in about 5-25 mM histidine buffer (pH from about 5.5 to about 6.5), about 0.005%-0.03% polysorbate, and sucrose, optionally in combination with serine, and/or mannitol.
  • This formulation retains the stability of the IgG antibody, and prevents the immunoglobulins intended for administration to human subjects from forming aggregates/particulates in the final product.
  • the lyophilized formulation is reconstituted with a liquid to a clarified solution containing greater than 50 mg/ml IgG antibody concentration within about 2 minutes or less.
  • This lyophilized formulation is stable at room temperature for at least 3 months, preferably 6 months, and more preferably 1 year.
  • the lyophilized formulation is also stable at 2-8° C. for 1 year, preferably 2 years.
  • This lyophilized formulation has a short reconstitution time of less than 2 minutes, and is suitable for parenteral administration such as intravenous, intramuscular, intraperitoneal, or subcutaneous injection.
  • FIG. 1 shows the effect of excipients on antibody stability by testing (A) the liquid after storage at 55° C. for 10 days and (B) the lyophile at 40° C. for 12 days.
  • FIGS. 2A and 2B show the comparison of model predictions and experimental observation for the test samples 1 - 15 .
  • FIG. 2A shows the % drop in monomer.
  • FIG. 2B shows the reconstruction time.
  • FIGS. 3A and 3B show the comparison of model predictions and experimental observation for the control samples 16 - 20 .
  • FIG. 3A shows the % drop in monomer.
  • FIG. 3B shows the reconstitution time.
  • FIG. 4 shows the model coefficients of (A) main effect, and (B) interaction effect.
  • FIG. 5A shows the % monomer drop.
  • FIG. 5B shows the reconstitution time.
  • FIG. 6A shows the % monomer drop.
  • FIG. 6B shows the reconstitution time.
  • FIG. 7A shows the % monomer drop.
  • FIG. 7B shows the reconstitution time.
  • FIG. 8A shows the % monomer drop.
  • FIG. 8B shows the reconstitution time.
  • FIGS. 9 A- 9 C show percent monomer in Formulations I, II and II as a function of time at (A) 5° C., (B) 25° C., and (C) 40° C.
  • FIGS. 10 A-C show percent aggregates in Formulations I, II and III as a function of time at (A) 5° C., (B) 25° C., and (C) 40° C.
  • FIGS. 11 A-C shows percent clips in Formulations I, II and III as a function of time at (A) 5° C., (B) 25° C., and (C) 40° C.
  • bulking agents comprise agents that provide the structure of the freeze-dried product.
  • Common examples used for bulking agents include mannitol, glycine, lactose and sucrose.
  • bulking agents may also impart useful qualities in regard to modifying the collapse temperature, providing freeze-thaw protection, and enhancing the protein stability over long-term storage. These agents can also serve as tonicity modifiers.
  • buffer encompasses those agents which maintain the solution pH in an acceptable range prior to lyophilization and may include succinate (sodium or potassium), histidine, phosphate (sodium or potassium), Tris(tris(hydroxymethyl)aminomethane), diethanolamine, citrate (sodium) and the like.
  • the buffer of this invention has a pH in the range from about 5.5 to about 6.5; and preferably has a pH of about 6.0. Examples of buffers that will control the pH in this range include succinate (such as sodium succinate), gluconate, histidine, citrate and other organic acid buffers.
  • cryoprotectants generally includes agents which provide stability to the protein against freezing-induced stresses, presumably by being preferentially excluded from the protein surface. They may also offer protection during primary and secondary drying, and long-term product storage. Examples are polymers such as dextran and polyethylene glycol; sugars such as sucrose, glucose, trehalose, and lactose; surfactants such as polysorbates; and amino acids such as glycine, arginine, and serine.
  • lyophilization refers to a process by which the material to be dried is first frozen and then the ice or frozen solvent is removed by sublimation in a vacuum environment.
  • An excipient may be included in pre-lyophilized formulations to enhance stability of the lyophilized product upon storage.
  • lyoprotectant includes agents that provide stability to the protein during the drying or ‘dehydration’ process (primary and secondary drying cycles), presumably by providing an amorphous glassy matrix and by binding with the protein through hydrogen bonding, replacing the water molecules that are removed during the drying process. This helps to maintain the protein conformation, minimize protein degradation during the lyophilization cycle and improve the long-term product stability.
  • examples include polyols or sugars such as sucrose and trehalose.
  • pharmaceutical formulation refers to preparations which are in such form as to permit the active ingredients to be effective, and which contains no additional components which are toxic to the subjects to which the formulation would be administered.
  • “Pharmaceutically acceptable” excipients are those which can reasonably be administered to a subject mammal to provide an effective dose of the active ingredient employed.
  • Reconstitution time is the time that is required to rehydrate a lyophilized formulation with a solution to a particle-free clarified solution.
  • a “stable” formulation is one in which the protein therein essentially retains its physical stability and/or chemical stability and/or biological activity upon storage.
  • Various analytical techniques for measuring protein stability are available in the art and are reviewed in Peptide and Protein Drug Delivery, 247-301, Vincent Lee Ed., Marcel Dekker, Inc., New York, N.Y., Pubs. (1991) and Jones, A. Adv. Drug Delivery Rev. 10:29-90 (1993). Stability can be measured at a selected temperature for a selected time period.
  • a “stable” lyophilized antibody formulation is a lyophilized antibody formulation with no significant changes observed at a refrigerated temperature (2-8° C.) for at least 12 months, preferably 2 years, and more preferably 3 years; or at room temperature (23-27° C.) for at least 3 months, preferably 6 months, and more preferably 1 year.
  • the criteria for stability are as follows. No more than 10%, preferably 5%, of antibody monomer is degraded as measured by SEC-HPLC. The rehydrated solution is colorless, or clear to slightly opalescent by visual analysis. The concentration, pH and osmolality of the formulation have no more than +/ ⁇ 10% change. Potency is within 70-130, preferably 80-120% of the control. No more than 10%, preferably 5% of clipping is observed. No more than 10%, preferably 5% of aggregation is formed.
  • An antibody “retains its physical stability” in a pharmaceutical formulation if it shows no significant increase of aggregation, precipitation and/or denaturation upon visual examination of color and/or clarity, or as measured by UV light scattering, size exclusion chromatography (SEC) and dynamic light scattering.
  • SEC size exclusion chromatography
  • the changes of protein conformation can be evaluated by fluorescence spectroscopy, which determines the protein tertiary structure, and by FTIR spectroscopy, which determines the protein secondary structure.
  • An antibody “retains its biological activity” in a pharmaceutical formulation, if the biological activity of the antibody at a given time is within a predetermined range of the biological activity exhibited at the time the pharmaceutical formulation was prepared.
  • the biological activity of an antibody can be determined, for example, by an antigen binding assay.
  • isotonic means that the formulation of interest has essentially the same osmotic pressure as human blood. Isotonic formulations will generally have an osmotic pressure from about 270-328 mOsm. Slightly hypotonic pressure is 250-269 and slightly hypertonic pressure is 328-350 mOsm. Osmotic pressure can be measured, for example, using a vapor pressure or ice-freezing type osmometer.
  • Tonicity Modifiers Salts (NaCl, KCl, MgCl 2 , CaCl 2 , etc) are used as tonicity modifiers to control osmotic pressure.
  • cryprotecants/lyoprotectants and/or bulking agents such as sucrose, mannitol, glycine etc. can serve as tonicity modifiers.
  • the analytical methods for evaluating the product stability include size exclusion chromatography (SEC), dynamic light scattering test (DLS), differential scanning calorimetery (DSC), iso-asp quantification, potency, UV at 340 nm, UV spectroscopy, and FTIR.
  • SEC size exclusion chromatography
  • DSC differential scanning calorimetery
  • iso-asp quantification potency, UV at 340 nm, UV spectroscopy, and FTIR.
  • SEC J. Pharm. Scien., 83:1645-1650, (1994); Pharm. Res., 11:485 (1994); J. Pharm. Bio. Anal., 15:1928 (1997); J. Pharm. Bio. Anal., 14:1133-1140 (1986)
  • DSC Pharm. Res., 15:200 (1998); Pharm.
  • the iso-asp content in the samples is measured using the Isoquant Isoaspartate Detection System (Promega).
  • the kit uses the enzyme Protein Isoaspartyl Methyltransferase (PIMT) to specifically detect the presence of isoaspartic acid residues in a target protein.
  • PIMT catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to isoaspartic acid at the ⁇ -carboxyl position, generating S-adenosyl-L-homocysteine (SAH) in the process.
  • SAH S-adenosyl-L-homocysteine
  • the potency or bioidentity of an antibody can be measured by its ability to bind to its antigen.
  • the specific binding of an antibody to its antigen can be quantitated by any method known to those skilled in the art, for example, an immunoassay, such as ELISA (enzyme-linked immunosorbant assay).
  • the invention herein relates to a stable formulation comprising an antibody.
  • the antibody is prepared using techniques available in the art for generating antibodies, exemplary methods of which are described in more detail in the following sections.
  • the antibody is directed against an antigen of interest.
  • the antigen is a biologically important polypeptide and administration of the antibody to a mammal may prevent or treat a disorder.
  • antibodies directed against nonpolypeptide antigens are also contemplated.
  • the antigen is a polypeptide, it may be a transmembrane molecule (e.g. receptor) or ligand such as a growth factor.
  • exemplary antigens include molecules such as renin; a growth hormone, including human growth hormone and bovine growth hormone; growth hormone releasing factor; parathyroid hormone; thyroid stimulating hormone; lipoproteins; alpha-1-antitrypsin; insulin A-chain; insulin B-chain; proinsulin; follicle stimulating hormone; calcitonin; luteinizing hormone; glucagon; clotting factors such as factor VIIIC, factor IX, tissue factor, and von Willebrands factor; anti-clotting factors such as Protein C; atrial natriuretic factor; lung surfactant; a plasminogen activator, such as urokinase or human urine or tissue-type plasminogen activator (t-PA); bombesin; thrombin; hemopoietic growth factor; tumor necrosis factor-alpha and
  • the antibody can be produced intracellularly, in the periplasmic space, or directly secreted into the medium. If the antibody is produced intracellularly, as a first step, the particulate debris, either host cells or lysed cells, is removed, for example, by centrifugation or ultrafiltration. Where the antibody is secreted into the medium, supernatants from such expression systems are generally first concentrated using a commercially available protein concentration filter, for example, an Amicon or Millipore Pellicon ultrafiltration unit. A protease inhibitor such as PMSF may be included in any of the foregoing steps to inhibit proteolysis and antibiotics may be included to prevent the growth of adventitious contaminants.
  • a protease inhibitor such as PMSF may be included in any of the foregoing steps to inhibit proteolysis and antibiotics may be included to prevent the growth of adventitious contaminants.
  • the antibody composition prepared from the cells can be purified using, for example, hydroxylapatite chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being the preferred purification technique.
  • affinity chromatography is the preferred purification technique.
  • the suitability of protein A as an affinity ligand depends on the species and isotype of any immunoglobulin Fc domain that is present in the antibody.
  • Protein A can be used to purify antibodies that are based on human ⁇ 1 , ⁇ 2 , or ⁇ 4 heavy chains (Lindmark et al., J. Immunol. Meth. 62:1-13 (1983)). Protein G is recommended for all mouse isotypes and for human ⁇ 3 (Guss et al., EMBO J.
  • the matrix to which the affinity ligand is attached is most often agarose, but other matrices are available. Mechanically stable matrices such as controlled pore glass or poly(styrenedivinyl)benzene allow for faster flow rates and shorter processing times than can be achieved with agarose.
  • the antibody comprises a C H3 domain
  • the Bakerbond ABXTM resin J. T. Baker, Phillipsburg, N.J. is useful for purification.
  • a preferred antibody encompassed by the present invention is an IgG antibody.
  • This invention is exemplified by an anti-IL-2 receptor antibody such as Daclizumab.
  • Daclizumab is a recombinant humanized monoclonal antibody, subclass IgG1. The molecule is composed of two identical heavy chain and two identical light chain subunits. Disulfide bridges link the four chains. Daclizumab monomer is approximately 150,000 daltons in molecular weight. Daclizumab binds to the p55 subunit of the IL-2 receptor expressed on activated T cells. The antigen target is designated CD25. Daclizumab is produced from a GS-NS0 cell line containing the heavy and light chain genes by fed- batch fermentation culture. Bioreactor harvests are processed to remove cells and debris and purified using a combination of ion-exchange and gel filtration chromatography and a series of ultrafiltration and filtration techniques to produce drug substance containing greater than 95% monomeric species.
  • the pharmaceutical formulation comprising the antibody is prepared.
  • the formulation development approach is as follows: selecting the optimum solution pH, selecting buffer type and concentration, evaluating the effect of various excipients of the liquid and lyophilized stability, and optimizing the concentration of the screened excipients using an I-optimal experimental design (Statistics for Experimental, Box, George E. P. John Wiley and Sons, Inc., 1978).
  • the following criteria are important in developing stable lyophilized protein products. Protein unfolding during lyophilization should be minimized. Various degradation pathways should be minimized. Glass transition temperature (Tg) should be greater than the product storage temperature. Residual moisture should be low ( ⁇ 1% by mass). A strong and elegant cake structure should be obtained. A preferred shelf life should be at least 3 months, preferably 6 months, more preferably 1 year at room temperature (22 to 28° C.). A reconstitution time should be short, for example, less than 5 minutes, preferably less than 2 minutes, and more preferably less than 1 minute. When the lyophilized product is reconstituted, the reconstituted sample should be stable for at least 48 hours at 2-8° C.
  • compositions of this invention minimize the formation of protein aggregates and particulates in reagents containing immunoglobulin antibodies and insure that the antibody in solution maintains its immunoreactivity over time.
  • the composition comprises a sterile, pharmaceutically acceptable lyophilized formulation prepared from an aqueous pre-lyophilized formulation comprising an antibody in a buffer having a neutral or acidic pH (pH 5.5-6.5), a surfactant, and a polyol.
  • the preferred composition additionally contains a bulking agent, and/or a tonicity modifier.
  • the antibody in the pre-lyophilized formulation has a high concentration of 50 mg/ml or greater.
  • a preferred antibody is an IgG antibody, preferably a monoclonal IgG antibody.
  • a buffer of pH 5.5-6.5 is used in the composition.
  • buffers that control the pH in this range include succinate (such as sodium succinate), gluconate, histidine, citrate and other organic acid buffers. Histidine is a preferred buffer for subcutaneous, intramuscular and peritoneal injection.
  • Sodium succinate buffer is less preferred because it does not have a good buffer capacity at low strength.
  • the amount of the excipients will have to be decreased in order to maintain the osmolarity in a desired range. If the lyophile is to be reconstituted with half of the fill volume, then the desired osmolarity of the pre-lyophilized (fill) liquid is about 140-160 mOsm.
  • histidine buffer is that 1 mmole of the histidine buffer only contributes 1 mOsm, whereas 1 mmole of the sodium succinate buffer contributes 3 mOsm. Because histidine buffer contributes less to the osmolarity, it allows more stabilizing excipients to be added to the formulation. Citrate buffer is also less preferred because it causes a painful reaction when injected subcutaneously. A preferred buffer contains about 5-25 mM histidine. A more preferred buffer contains about 10-20 mM histidine.
  • a surfactant is added to the antibody formulation.
  • exemplary surfactants include nonionic surfactants such as polysorbates (e.g. polysorbates 20, 80, such as Tween®20, Tween®80) or poloxamers (e.g. poloxamer 188).
  • the amount of surfactant added is such that it reduces aggregation of the formulated antibody and/or minimizes the formation of particulates in the formulation and/or reduces protein adsorption onto the container.
  • the surfactant also reduces the reconstitution time of the lyophilized formulation.
  • the surfactant is present in the formulation in an amount from about 0.001% to about 0.5%, preferably from about 0.005% to about 0.1% and most preferably from about 0.01% to about 0.05%.
  • a polyol which acts as a tonicifying agent and a cryoprotector/lyoprotector, is included in the formulation.
  • the polyol is a nonreducing sugar, such as sucrose or trehalose.
  • the polyol such as sucrose is the primary stabilizer against antibody aggregation, and it also plays an important role in reducing the reconstitution time of the lyophilized formulation to a particle-free solution.
  • the polyol is added to the formulation in an amount that may vary with respect to the desired tonicity of the formulation.
  • the lyophilized formulation after reconstitution is isotonic; however, hypertonic or hypotonic formulations may also be suitable.
  • Suitable concentrations of the polyol such as sucrose in the pre-lyophilized formulation are in the range from about 100-300 mM, preferably in the range from about 100-200 mM.
  • a bulking agent that provides good lyophilized cake properties such as serine, glycine, mannitol, can be optionally added to the present composition. These agents also contribute to the tonicity of the formulations and may provide protection to the freeze-thaw process and improve long-term stability.
  • a preferred bulking agent is serine at a concentration about 15-55 mM, and preferably about 20-30 mM.
  • Another preferred bulking agent is mannitol, at a concentration about 10-55 mM, and preferably about 20-45 mM.
  • the addition of serine or mannitol to the pre-lyophilized formulation reduces the concentration of polyol required for stabilizing the antibody, for example, to 30-180 mM and preferably 80-130 mM.
  • Tonicity modifiers such as salts (e.g., NaCl, KCl, MgCl 2 , CaCl 2 ) can be added to the formulation to control osmotic pressure.
  • salts e.g., NaCl, KCl, MgCl 2 , CaCl 2
  • Exemplary pre-lyophilized compositions are formulations comprising an IgG antibody at about 50 mg/ml or greater, about 10-20 mM histidine (pH 5.5-6.5), about 0.005-0.03 % polysorbate 20 or 80, and one of the following combinations of excipients: (a) 100-200 mM sucrose, (b) 110-130 mM sucrose and 20-45 mM mannitol, (c) 100-130 mM sucrose and 15-55 mM serine, and (d) 7-55 mM serine, 80-130 mM sucrose, and 10-55 mM mannitol.
  • the above pre-lyophilized formulation is lyophilized to form a dry, stable powder, which can be easily reconstituted to a particle-free solution suitable for administering to humans.
  • Lyophilization is a freeze drying process that is often used in the preparation of pharmaceutical products to preserve their biological activity.
  • the liquid composition is prepared, then lyophilized to form a dry cake-like product.
  • the process generally involves drying a previously frozen sample in a vacuum to remove the ice, leaving the non-water components intact, in the form of a powdery or cake-like substance.
  • the lyophilized product can be stored for prolonged periods of time, and at elevated temperatures, without loss of biological activity, and can be readily reconstituted into a particle-free solution by the addition of an appropriate diluent.
  • An appropriate diluent can be any liquid which is biologically acceptable and in which the lyophilized powder is completely soluble.
  • Water particularly sterile, pyrogen-free water, is a preferred diluent, since it does not include salts or other compounds which may affect the stability of the antibody.
  • the advantage of lyophilization is that the water content is reduced to a level that greatly reduce the various molecular events which lead to instability of the product upon long-term storage.
  • the lyophilized product is also more readily able to withstand the physical stresses of shipping.
  • the reconstituted product is particle free, thus it can be administered without prior filtration.
  • the liquid formulation can be lyophilized using appropriate drying parameters.
  • drying parameters are preferred: a primary drying phase temperature of about ⁇ 20° C. to ⁇ 50° C. and pressure between about 80 mTorr to about 120 mTorr; and a secondary drying phase at ambient temperature, and pressure between about 80 mTorr to 120 mTorr.
  • This lyophilized product retains the stability of immunological activity of the monoclonal antibody, and prevents the immunoglobulins intended for administration to human subjects from physical and chemical degradation in the final product.
  • the lyophilized product is rehydrated at the time of use in a diluent (e.g., sterile water or saline) to yield a particle-free solution.
  • a diluent e.g., sterile water or saline
  • the reconstituted antibody solution is particle-free even after prolonged storage of the lyophilized cake at ambient temperature.
  • the reconstituted solution is administered parenterally, preferably intravenously or subcutaneously, to the subject.
  • An important characteristic of the lyophilized product is the reconstitution time or the time taken to rehydrate the product. To enable very fast and complete rehydration, it is important to have a cake with a highly porous structure.
  • the cake structure is a function of a number of parameters including the protein concentration, excipient type and concentration, and the process parameters of the lyophilization cycle.
  • the reconstitution time increases as the protein concentration increases, and thus, a short reconstitution time is an important goal in the development of high concentration lyophilized antibody formulations.
  • a long reconstitution time can deteriorate the product quality due to the longer exposure of the protein to a more concentrated solution.
  • the product cannot be administered until the product is completely rehydrated. This is to ensure that the product is particulate-free, the correct dosage is administered, and its sterility is unaffected.
  • quick rehydration offers more convenience to the patients and the physicians.
  • the desired dosage can be obtained by lyophilizing the formulation at the target protein concentration and reconstituting the product with the same volume as that of the starting fill volume.
  • the desired dosage can also be obtained by lyophilizing a larger volume of a diluted formulation, and reconstituting it with a less volume.
  • a desired product dosage is 100 mg of protein in 1 mL of the formulation
  • the formulations can be lyophilized with the following liquid configurations: 1 mL of 100 mg/mL, 2 mL of 50 mg/ml, or 4 mL of 25 mg/mL protein formulation.
  • the final product can be reconstituted with 1 mL diluent to obtain the target protein concentration of 100 mg/mL.
  • the fill volume increases proportionately. This correspondingly increases the length of the lyophilization cycle (especially the primary drying time), and thus significantly adds to the cost of the product. For example, if 1 mL fill volume (1 mm height in vial) of frozen material takes approximately 1 hour to sublimate its free water, then 10 mL fill volume (10 mm height) of frozen product will take approximately 10 hours of primary drying time. Therefore, it is advantageous to have a concentrated pre-lyophilized formulation (with antibody greater than 50 mg/mL) such that the lyophilization process will be more efficient.
  • the present invention provides a highly concentrated pre-lyophilized antibody formulation (greater than 50 mg/mL), which is lyophilized efficiently and effectively to a dry formulation that retains the biological, physical and chemical stability of the antibody.
  • the dry formulation is stable for storage at least for 3 months, preferably 6 months, at room temperature.
  • the dry formulation can be reconstituted within a short time of less than 2 minutes to a particle-free solution containing greater than 50 mg/mL antibody.
  • Such highly concentrated antibody solution is ready for parenteral administration such as intravenous, intramuscular, intraperitoneal, or subcutaneous injection.
  • Rate 2° C./min
  • Rate 1° C./min
  • Rate 1° C./min
  • the formulation matrix contains 10 mg/ml anti-IL2 receptor antibody, 10 mM histidine, pH 6.0, and 0.015% Tween®80.
  • the excipients screened includes (a) cryoprotectors/lyoprotectors such as sucrose, trehalose, polyethylene glycol (PEG), and polyvinylpyrrolidone (PVP); (b) bulking agents and tonicity modifiers such as mannitol, glycine, and serine; and (c) Tg enhancers such as dextran.
  • sucrose, mannitol and serine were investigated using an I-Optimal (Hardin-Sloane) experimental design approach.
  • the formulation matrix contains 50 mg/ml anti-IL2 receptor antibody, 10 mM histidine, pH 6.0, and 0.015% Tween®80.
  • the excipients screened include serine (0-100 mM), sucrose (0-120 mM) and mannitol (0-170 mM).
  • the I-Optimal Design is shown as Table 1. Samples 1-15 are test formulations, and samples 16-20 are control formulations.
  • the lyophile product stability test was performed at 37° C. for 4 weeks. The formulations were distinguishable. The analytic methods of SEC and reconstitution time show statistically significant responses among the formulations.
  • FIG. 2 shows the comparison of model predictions and experimental observation for the test samples.
  • FIG. 3 shows the comparison of model predictions and experimental observation for the controls.
  • FIG. 4 shows the model coefficients of main effect and interaction effect.
  • sucrose and mannitol stabilize the protein against aggregation (sucrose>mannitol).
  • Sucrose has a favorable effect in reducing the reconstitution time. Using high concentrations of sucrose and mannitol, formulation stability is enhanced and cakes with short reconstitution time are obtained.
  • the results indicate that serine and mannitol stabilize the protein against aggregation (mannitol>serine).
  • serine increases the reconstitution time.
  • Formulation stability is enhanced using high concentrations of serine and mannitol, and their combination significantly reduces the reconstitution time.
  • Model simulations allow selection of conditions that provide isotonic formulations. Data supports maximizing the sucrose concentration. At 100 mM sucrose, the model provides conditions for optimizing serine and/or mannitol.
  • Sucrose had the strongest stabilizing effect on the lyophile stability, it also provides a cake with a short reconstitution time.
  • Formulations 1 and 2 were prepared and lyophilized according to procedures similar to those described in Example 1. The lyophilized formulation was incubated at 37° C. for 2.5 months. The lyophilized formulation at different time point was reconstituted with 1 mL water and tested by analytical methods.
  • T0 The formulation has been lyophilized and immediately after this reconstituted with 1 mL water for injection
  • T 2.5 months: The formulation was lyophilized; the cake was incubated at 37° C. for two and half months, then reconstituted with 1 mL water for injection (WFI).
  • Formulation I (FORM-I): 50 mg/mL anti-IL2 receptor antibody, 20 mM Histidine, 4% (117 mM) sucrose, 0.015% Tween® 80, pH 6.0.
  • Formulation II 80 mg/mL protein, 20 mM Histidine, 6.5% (190 mM) sucrose, 0.025% Tween 80, pH 6.0.
  • Formulation III 80 mg/mL protein, 20 mM Histidine, 4% sucrose, 0.015% Tween 80, pH 6.0.
  • FIG. 9 shows the % monomer measured by size exclusion chromatography for the three formulations as a function of time and temperature. At 5° C., over the 3 month duration, no significant change is observed in the monomer content of the three formulations. At 25 and 40° C., over the 3 month duration, less than 3% drop in the monomer content is observed for all three formulations compared with To.
  • FIG. 10 shows the % aggregates measured by size exclusion chromatography for the three formulations as a function of time and temperature. No significant increase in aggregation is observed at 5° C. At 25° C. for 3 months, the increase in aggregation for FORM-I and FORM-II is ⁇ 1% and ⁇ 2% for FORM-III. At 40° C. for 3 months, the increase in aggregation for FORM-I and FORM-II is about 2.5% and ⁇ 4% for FORM-III.
  • FIG. 11 shows the % clips measured by size exclusion chromatography for the three formulations as a function of time and temperature. Minimal changes in the % clips are observed for all three formulations over the three month duration at all temperatures. Thus, hydrolysis, which was a significant stability concern in the aqueous state, has been successfully curtailed in the lyophilized formulation.
  • FTIR Fourier Transform Infrared Spectroscopy

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