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Self-buffering protein formulations

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Title: Self-buffering protein formulations.
Abstract: The invention herein described, provides, among other things, self-buffering protein formulations. Particularly, the invention provides self-buffering pharmaceutical protein formulations that are suitable for veterinary and human medical use. The self-buffering protein formulations are substantially free of other buffering agents, stably maintain pH for the extended time periods involved in the distribution and storage of pharmaceutical proteins for veterinary and human medical use. The invention further provides methods for designing, making, and using the formulation. In addition to other advantages, the formulations avoid the disadvantages associated with the buffering agents conventionally used in current formulations of proteins for pharmaceutical use. The invention in these and other respects can be productively applied to a wide variety of proteins and is particularly useful for making and using self-buffering formulations of pharmaceutical proteins for veterinary and medical use, especially, in particular, for the treatment of diseases in human subjects. ...


Browse recent Amgen Inc. patents - Thousand Oaks, CA, US
Inventors: Yatin R. GOKARN, Eva Kras, Richard Louis Remmele, JR., David Brems, Susan Irene Hershenson
USPTO Applicaton #: #20120028877 - Class: 514 11 (USPTO) - 02/02/12 - Class 514 


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The Patent Description & Claims data below is from USPTO Patent Application 20120028877, Self-buffering protein formulations.

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REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of and claims full priority benefit of U.S. Provisional Application Ser. No. 60/690,582 filed 14 Jun. 2005, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The invention relates to the formulation of proteins, especially pharmaceutical proteins. In particular, it relates to self-buffering biopharmaceutical protein compositions, and to methods for designing, making, and using the compositions. It further relates to pharmaceutical protein compositions for veterinary and/or for human medical use, and to methods relating thereto.

BACKGROUND OF THE INVENTION

Many aspects of pharmaceutical production and formulation processes are pH sensitive. Maintaining the correct pH of a finished pharmaceutical product is critical to its stability, effectiveness, and shelf life, and pH is an important consideration in designing formulations for administration that will be acceptable, as well as safe and effective.

To maintain pH, pharmaceutical processes and formulations use one or more buffering agents. A variety of buffering agents are available for pharmaceutical use. The buffer or buffers for a given application must be effective at the desired pH. They must also provide sufficient buffer capacity to maintain the desired pH for as long as necessary. A good buffer for a pharmaceutical composition must satisfy numerous other requirements as well. It must be appropriately soluble. It must not form deleterious complexes with metal ions, be toxic, or unduly penetrate, solubilize, or absorb on membranes or other surfaces. It should not interact with other components of the composition in any manner which decreases their availability or effectiveness. It must be stable and effective at maintaining pH over the range of conditions to which it will be exposed during formulation and during storage of the product. It must not be deleteriously affected by oxidation or other reactions occurring in its environment, such as those that occur in the processing of the composition in which it is providing the buffering action. If carried over or incorporated into a final product, a buffering agent must be safe for administration, compatible with other components of the composition over the shelf-life of the product, and acceptable for administration to the end user.

Although there are many buffers in general use, only a limited number are suitable for biological applications and, of these, fewer still are acceptable for pharmaceutical processes and formulations. As a result, it often is challenging to find a buffer that not only will be effective at maintaining pH but also will meet all the other requirements for a given pharmaceutical process, formulation, or product.

The challenge of finding a suitable buffer for pharmaceutical use can be especially acute for pharmaceutical proteins. The conformation and activity of proteins are critically dependent upon pH. Proteins are susceptible to a variety of pH sensitive reactions that are deleterious to their efficacy, typically many more than affect small molecule drugs. For instance, to mention just a few salient examples, the side chain amides of asparagine and glutamine are deamidated at low pH (less than 4.0) and also at neutral or high pH (greater than 6.0). Aspartic acid residues promote the hydrolysis of adjacent peptide bonds at low pH. The stability and disposition of disulfide bonds is highly dependent on pH, particularly in the presence of thiols. Solubility, flocculation, aggregation, precipitation, and fibrillation of proteins are critically dependent on pH. The crystal habit important to some pharmaceutical formulations also is critically dependent on pH. And pH is also an important factor in surface adsorption of many pharmaceutical peptides and proteins.

Buffering agents that catalyze reactions that inactivate and/or degrade one or more other ingredients, moreover, cannot be used in pharmaceutical formulations. Buffers for pharmaceutical use must have not only the buffer capacity required to maintain correct pH, but also they must not buffer so strongly that their administration deleteriously perturbs a subject's physiological pH. Buffers for pharmaceutical formulations also must be compatible with typically complex formulation processes. For instance, buffers that sublime or evaporate, such as acetate and imidazole, generally cannot be relied upon to maintain pH during lyophilization and in the reconstituted lyophilization product. Other buffers that crystallize out of the protein amorphous phase, such as sodium phosphate, cannot be relied upon to maintain pH in processes that require freezing.

Buffers used to maintain pH in pharmaceutical end-products also must be not only effective at maintaining pH but also safe and acceptable for administration to the subject. For instance, several otherwise useful buffers, such as citrate at low or high concentration and acetate at high concentration, are undesirably painful when administered parenterally.

Some buffers have been found to be useful in the formulation of pharmaceutical proteins, such as acetate, succinate, citrate, histidine (imidazole), phosphate, and Tris. They all have undesirable limitations and disadvantages. And they all have the inherent disadvantage of being an additional ingredient in the formulation, which complicates the formulation process, poses a risk of deleteriously affecting other ingredients, stability, shelf-life, and acceptability to the end user.

There is a need, therefore, for additional and improved methods of maintaining pH in the production and formulation of pharmaceuticals and in pharmaceutical compositions, particularly in the production and formulation of biopharmaceutical proteins and in biopharmaceutical protein compositions.

SUMMARY

Therefore, it is among the various objects and aspects of the invention to provide, in certain of the preferred embodiments, protein formulations comprising a protein, particularly pharmaceutically acceptable formulations comprising a pharmaceutical protein, that are buffered by the protein itself, that do not require additional buffering agents to maintain a desired pH, and in which the protein is substantially the only buffering agent (i.e., other ingredients, if any, do not act substantially as buffering agents in the formulation).

In this regard and others, it is among the various objects and aspects of the invention to provide, in certain preferred embodiments, self-buffering formulations of a protein, particularly of a pharmaceutical protein, characterized in that the concentration of the formulated protein provides a desired buffer capacity.

It is further among the various objects and aspects of the invention to provide, in certain of the particularly preferred embodiments, self-buffering protein formulations, particularly pharmaceutical protein formulations, in which the total salt concentration is less than 150 mM.

It is further among the various objects and aspects of the invention to provide, in certain of the particularly preferred embodiments, self-buffering protein formulations, particularly pharmaceutical protein formulations, that further comprise one or more polyols and/or one or more surfactants.

It is also further among the various objects and aspects of the invention to provide, in certain of the particularly preferred embodiments, self-buffering formulations comprising a protein, particularly a pharmaceutical protein, in which the total salt concentration is less than 150 mM, that further comprise one or more excipients, including but not limited to, pharmaceutically acceptable salts; osmotic balancing agents (tonicity agents); surfactants, polyols, anti-oxidants; antibiotics; antimycotics; bulking agents; lyoprotectants; anti-foaming agents; chelating agents; preservatives; colorants; and analgesics.

It is additionally among the various objects and aspects of the invention to provide, in certain preferred embodiments, self-buffering protein formulations, particularly pharmaceutical protein formulations, that comprise, in addition to the protein, one or more other pharmaceutically active agents.

Various additional aspects and embodiments of the invention are illustratively described in the following numbered paragraphs. The invention is described by way of reference to each of the items set forth in the paragraphs, individually and/or taken together in any combination. Applicant specifically reserves the right to assert claims based on any such combination.

1. A composition according to any of the following, wherein the composition has been approved for pharmaceutical use by a national or international authority empowered by law to grant such approval preferably the European Agency for the Evaluation of Medical Products, Japan's Ministry of Health, Labor and Welfare, China's State Drug Administration, United States Food and Drug Administration, or their successor(s) in this authority, particularly preferably the United States Food and Drug Administration or its successor(s) in this authority.

2. A composition according to any of the foregoing or the following, wherein the composition is produced in accordance with good manufacturing practices applicable to the production of pharmaceuticals for use in humans.

3. A composition according to any of the foregoing or the following, comprising a protein, the protein having a buffer capacity per unit volume per pH unit of at least that of approximately: 2.0 or 3.0 or 4.0 or 5.0 or 6.50 or 8.00 or 10.0 or 15.0 or 20.0 or 30.0 or 40.0 or 50.0 or 75.0 or 100 or 125 or 150 or 200 or 250 or 300 or 350 or 400 or 500 mM sodium acetate buffer in pure water over the range of pH 5.0 to 4.0 or pH 5.0 to 5.5, preferably as determined in accordance with the methods described in Example 1 and 2, particularly preferably at least 2.0 mM, especially particularly preferably at least 3.0 mM, very especially particularly preferably at least 4.0 mM or at least 5.0 mM, especially particularly preferably at least 7.5 mM, particularly preferably at least 10 mM, preferably at least 20 mM.

4. A composition according to any of the foregoing or the following wherein, exclusive of the buffer capacity of the protein, the buffer capacity per unit volume per pH unit of the composition is equal to or less than that of 1.0 or 1.5 or 2.0 or 3.0 or 4.0 or 5.0 mM sodium acetate buffer in pure water over the range of pH 4.0 to 5.0 or pH 5.0 to 5.5, preferably as determined in accordance with the methods described in Example 1 and 2, particularly preferably less than that of 1.0 mM, very especially particularly preferably less than that of 2.0 mM, especially particularly preferably less than that of 2.5 mM, particularly preferably less than that of 3.0 mM, preferably less than that of 5.0 mM.

5. A composition according to any of the foregoing or the following comprising a protein wherein over the range of plus or minus 1 pH unit from the pH of the composition, the buffer capacity of the protein is at least approximately: 1.00 or 1.50 or 1.63 or 2.00 or 3.00 or 4.00 or 5.00 or 6.50 or 8.00 or 10.0 or 15.0 or 20.0 or 30.0 or 40.0 or 50.0 or 75.0 or 100 or 125 or 150 or 200 or 250 or 300 or 350 or 400 or 500 or 700 or 1,000 mEq per liter per pH unit, preferably at least approximately 1.00, particularly preferably 1.50, especially particularly preferably 1.63, very especially particularly preferably 2.00, very highly especially particularly preferably 3.00, very especially particularly preferably 5.0, especially particularly preferably 10.0, particularly preferably 20.0.

6. A composition according to any of the foregoing or the following comprising a protein wherein over the range of plus or minus 1 pH unit from the pH of the composition, exclusive of the protein, the buffer capacity per unit volume per pH unit of the composition is equal to or less than that of 0.50 or 1.00 or 1.50 or 2.00 or 3.00 or 4.00 or 5.00 or 6.50 or 8.00 or 10.0 or 20.0 or 25.0 mM sodium acetate buffer in pure water over the range pH 5.0 to 4.0 or pH 5.0 to 5.5, particularly preferably determined in accordance with Example 1 and/or Example 2.

7. A composition according to any of the foregoing or the following, wherein over a range of plus or minus 1 pH unit from a desired pH, the protein provides at least approximately 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 99.5% of the buffer capacity of the composition, preferably at least approximately 75%, particularly preferably at least approximately 85%, especially particularly preferably at least approximately 90%, very especially particularly preferably at least approximately 95%, very highly especially particularly preferably at least approximately 99% of the buffer capacity of the composition.

8. A composition according to any of the foregoing or the following, wherein the concentration of the protein is between approximately: 20 and 400, or 20 and 300, or 20 and 250, or 20 and 200, or 20 and 150 mg/ml, preferably between approximately 20 and 400 mg/ml, particularly preferably between approximately 20 and 250, especially particularly between approximately 20 and 150 mg/ml.

9. A composition according to any of the foregoing or the following, wherein the pH maintained by the buffering action of the protein is between approximately: 3.5 and 8.0, or 4.0 and 6.0, or 4.0 and 5.5, or 4.0 and 5.0, preferably between approximately 3.5 and 8.0, especially particularly preferably approximately 4.0 and 5.5.

10. A composition according to any of the foregoing or the following, wherein the salt concentration is less than: 150 mM or 125 mM or 100 mM or 75 mM or 50 mM or 25 mM, preferably 150 mM, particularly preferably 125 mM, especially preferably 100 mM, very particularly preferably 75 mM, particularly preferably 50 mM, preferably 25 mM.

11. A composition according to any of the foregoing or the following, further comprising one or more pharmaceutically acceptable salts; polyols; surfactants; osmotic balancing agents; tonicity agents; anti-oxidants; antibiotics; antimycotics; bulking agents; lyoprotectants; anti-foaming agents; chelating agents; preservatives; colorants; analgesics; or additional pharmaceutical agents.

12. A composition according to any of the foregoing or the following, comprising one or more pharmaceutically acceptable polyols in an amount that is hypotonic, isotonic, or hypertonic, preferably approximately isotonic, particularly preferably isotonic, especially preferably any one or more of sorbitol, mannitol, sucrose, trehalose, or glycerol, particularly especially preferably approximately 5% sorbitol, 5% mannitol, 9% sucrose, 9% trehalose, or 2.5% glycerol, very especially in this regard 5% sorbitol, 5% mannitol, 9% sucrose, 9% trehalose, or 2.5% glycerol.

13. A composition according to any of the foregoing or the following, further comprising a surfactant, preferably one or more of polysorbate 20, polysorbate 80, other fatty acid esters of sorbitan, polyethoxylates, and poloxamer 188, particularly preferably polysorbate 20 or polysorbate 80, preferably approximately 0.001 to 0.1% polysorbate 20 or polysorbate 80, very preferably approximately 0.002 to 0.02% polysorbate 20 or polysorbate 80, especially 0.002 to 0.02% polysorbate 20 or polysorbate 80.

14. A composition according to any of the foregoing or the following, wherein the protein is a pharmaceutical agent and the composition is a sterile formulation thereof suitable for treatment of a non-human or a human subject.

15. A composition according to any of the foregoing or the following, wherein the protein is a pharmaceutical agent effective to treat a disease and the composition is a sterile formulation thereof suitable for administration to a subject for treatment thereof.

16. A composition according to any of the foregoing or the following, wherein the protein does not induce a significantly deleterious antigenic response following administration to a subject.

17. A composition according to any of the foregoing or the following, wherein the protein does not induce a significantly deleterious immune response following administration to a subject.

18. A composition according to any of the foregoing or the following, wherein the protein is a human protein.

19. A composition according to any of the foregoing or the following, wherein the protein is a humanized protein.

20. A method according to any of the foregoing or the following, wherein the protein is an antibody, preferably an IgA, IgD, IgE, IgG, or IgM antibody, particularly preferably an IgG antibody, very particularly preferably an IgG1, IgG2, IgG3, or IgG4 antibody, especially an IgG2 antibody.

21. A composition according to any of the foregoing or the following, wherein the protein comprises a: Fab fragment, Fab2 fragment, Fab3 fragment, Fc fragment, scFv fragment, bis-scFv(s) fragment, minibody, diabody, triabody, tetrabody, VhH domain, V-NAR domain, VH domain, VL domain, camel Ig, Ig NAR, or peptibody, or a variant, derivative, or modification of any of the foregoing.

22. A composition according to any of the foregoing or the following, wherein the protein comprises an Fc fragment or a part thereof or a derivative or variant of an Fc fragment or part thereof.

23. A composition according to any of the foregoing or the following, wherein the protein comprises a first binding moiety of a pair of cognate binding moieties, wherein the first moiety binds the second moiety specifically.

24. A composition according to any of the foregoing or the following, wherein the protein comprises (a) an Fc fragment or a part thereof or a derivative or variant of an Fc fragment or part thereof, and (b) a first binding moiety of a pair of cognate binding moieties.

25. A composition according to any of claim 1, 5, 7, 9, 11, 13, or 14, wherein the protein is selected from the group consisting of proteins that bind specifically to one or more CD proteins, HER receptor family proteins, cell adhesion molecules, growth factors, nerve growth factors, fibroblast growth factors, transforming growth factors (TGF), insulin-like growth factors, osteoinductive factors, insulins and insulin-related proteins, coagulation and coagulation-related proteins, colony stimulating factors (CSFs), other blood and serum proteins blood group antigens; receptors, receptor-associated proteins, growth hormone receptors, T-cell receptors; neurotrophic factors, neurotrophins, relaxins, interferons, interleukins, viral antigens, lipoproteins, integrins, rheumatoid factors, immunotoxins, surface membrane proteins, transport proteins, homing receptors, addressins, regulatory proteins, and immunoadhesins,

26. A composition according to any of the foregoing or the following, wherein the protein is selected from the group consisting of OPGL specific binding proteins, myostatin specific binding proteins, IL-4 receptor specific binding proteins, IL1-R1 specific binding proteins, Ang2 specific binding proteins, NGF-specific binding proteins, CD22 specific binding proteins, IGF-1 receptor specific binding proteins, B7RP-1 specific binding proteins, IFN gamma specific binding proteins, TALL-1 specific binding proteins, stem cell factors, Flt-3 ligands, and IL-17 receptors.

27. A composition according to any of the foregoing or the following, wherein the protein is selected from the group consisting of proteins that bind specifically to one ormore of: CD3, CD4, CD8, CD19, CD20, CD34; HER2, HER3, HER4, the EGF receptor; LFA-1, Mol, p150,95, VLA-4, ICAM-1, VCAM, alpha v/beta 3 integrin; vascular endothelial growth factor (“VEGF”); growth hormone, thyroid stimulating hormone, follicle stimulating hormone, luteinizing hormone, growth hormone releasing factor, parathyroid hormone, mullerian-inhibiting substance, human macrophage inflammatory protein (MIP-1-alpha), erythropoietin (EPO), NGF-beta, platelet-derived growth factor (PDGF), aFGF, bFGF, epidermal growth factor (EGF), TGF-alpha, TGF-beta1, TGF-beta2, TGF-beta3, TGF-beta4, TGF-beta5, IGF-I, IGF-II, des(1-3)-IGF-I (brain IGF-I), insulin, insulin A-chain, insulin B-chain, proinsulin, insulin-like growth factor binding proteins; such as, among others, factor VIII, tissue factor, von Willebrands factor, protein C, alpha-1-antitrypsin, plasminogen activators, such as urokinase and tissue plasminogen activator (“t-PA”), bombazine, thrombin, and thrombopoietin; M-CSF, GM-CSF, G-CSF, albumin, IgE, flk2/flt3 receptor, obesity (OB) receptor, bone-derived neurotrophic factor (BDNF), NT-3, NT-4, NT-5, NT-6); relaxin A-chain, relaxin B-chain, prorelaxin; interferon-alpha, -beta, and -gamma; IL-1 to IL-10; AIDS envelope viral antigen; calcitonin, glucagon, atrial natriuretic factor, lung surfactant, tumor necrosis factor-alpha and -beta, enkephalinase, RANTES, mouse gonadotropin-associated peptide, Dnase, inhibin, and activin; protein A or D, bone morphogenetic protein (BMP), superoxide dismutase, decay accelerating factor (DAF).

28. A composition according to any of the foregoing or the following, wherein the protein is selected from the group consisting of: Actimmune (Interferon-gamma-1b), Activase (Alteplase), Aldurazme (Laronidase), Amevive (Alefacept), Avonex (Interferon beta-1a), BeneFIX (Nonacog alfa), Beromun (Tasonermin), Beatseron (Interferon-beta-1b), BEXXAR (Tositumomab), Tev-Tropin (Somatropin), Bioclate or RECOMBINATE (Recombinant), CEREZME (Imiglucerase), ENBREL (Etanercept), Eprex (epoetin alpha), EPOGEN/Procit (Epoetin alfa), FABRAZYME (Agalsidase beta), Fasturtec/Elitek ELITEK (Rasburicase), FORTEO (Teriparatide), GENOTROPIN (Somatropin), GlucaGen (Glucagon), Glucagon (Glucagon, rDNA origin), GONAL-F (follitropin alfa), KOGENATE FS (Octocog alfa), HERCEPTIN (Trastuzumab), HUMATROPE (SOMATROPIN), HUMIRA (Adalimumab), Insulin in Solution, INFERGEN® (Interferon alfacon-1), KINERET® (anakinra), Kogenate FS (Antihemophilic Factor), LEUKIN (SARGRAMOSTIM Recombinant human granulocyte-macrophage colony stimulating factor (rhuGM-CSF)), CAMPATH (Alemtuzumab), RITUXAN® (Rituximab), TNKase (Tenecteplase), MYLOTARG (gemtuzumab ozogamicin), NATRECOR (nesiritide), ARANESP (darbepoetin alfa), NEULASTA (pegfilgrastim), NEUMEGA (oprelvekin), NEUPOGEN (Filgrastim), NORDITROPIN CARTRIDGES (Somatropin), NOVOSEVEN (Eptacog alfa), NUTROPIN AQ (somatropin), Oncaspar (pegaspargase), ONTAK (denileukin diftitox), ORTHOCLONE OKT (muromonab-CD3), OVIDREL (choriogonadotropin alfa), PEGASYS (peginterferon alfa-2a), PROLEUKIN (Aldesleukin), PULMOZYME (dornase alfa), Retavase (Reteplase), REBETRON Combination Therapy containing REBETOL® (Ribavirin) and INTRONS A (Interferon alfa-2b), REBIF (interferon beta-1a), REFACTO (Antihemophilic Factor), REFLUDAN (lepirudin), REMICADE (infliximab), REOPRO (abciximab)ROFERON®-A (Interferon alfa-2a), SIMULECT (baasiliximab), SOMAVERT (Pegivisomant), SYNAGIS® (palivizumab), Stemben (Ancestim, Stem cell factor), THYROGEN, INTRON® A (Interferon alfa-2b), PEG-INTRON® (Peginterferon alfa-2b), XIGRIS® (Drotrecogin alfa activated), XOLAIR® (Omalizumab), ZENAPAX® (daclizumab), and ZEVALIN® (Ibritumomab Tiuxetan).

29. A composition according to any of the foregoing or the following, wherein the protein is Ab-hCD22 or a fragment thereof, or a variant, derivative, or modification of Ab-hCD22 or of a fragment thereof; Ab-hIL4R or a fragment thereof, or a variant, derivative, or modification of Ab-hIL4R or of a fragment thereof; Ab-hOPGL or a fragment thereof, or a variant, derivative, or modification of Ab-hOPGL or of a fragment thereof, or Ab-hB7RP1 or a fragment thereof, or a variant, derivative, or modification of Ab-hB7RP1 or of a fragment thereof.

30. A composition according to any of the foregoing or the following, wherein the protein is: Ab-hCD22 or Ab-hIL4R or Ab-hOPGL or Ab-hB7RP1.

31. A composition according to any of the foregoing or the following comprising a protein and a solvent, the protein having a buffer capacity per unit volume per pH unit of at least that of 4.0 mM sodium acetate in water over the range of pH 4.0 to 5.0 or pH 5.0 to 5.5, particularly as determined by the methods described in Examples 1 and 2, wherein the buffer capacity per unit volume of the composition exclusive of the protein is equal to or less than that of 2.0 mM sodium acetate in water over the same ranges preferably determined in the same way.

32. A composition according to any of the foregoing or the following comprising a protein and a solvent, wherein at the pH of the composition the buffer capacity of the protein is at least 1.63 mEq per liter for a pH change of the composition of plus or minus 1 pH unit wherein the buffer capacity of the composition exclusive of the protein is equal to or less than 0.81 mEq per liter at the pH of the composition for a pH change of plus or minus 1 pH unit.

33. A lyophilate which upon reconstitution provides a composition in accordance with any of the foregoing or the following.

34. A kit comprising in one or more containers a composition or a lyophilate in accordance with any of the foregoing or the following, and instructions regarding use thereof.

35. A process for preparing a composition or a lyophilate according to any of the foregoing or the following, comprising removing residual buffer using a counter ion.

36. A process for preparing a composition or a lyophilate according to any of the foregoing or the following, comprising removing residual buffer using any one or more of the following in the presence of a counter ion: chromatography, dialysis, and/or tangential flow filtration.

37. A process for preparing a composition or a lyophilate according to any of the foregoing or the following, comprising removing residual buffer using tangential flow filtration.

38. A process for preparing a composition or a lyophilate according to any of the foregoing or the following comprising a step of dialysis against a solution at a pH below that of the preparation, and, if necessary, adjusting the pH thereafter by addition of dilute acid or dilute base.

39. A method for treating a subject comprising administering to a subject in an amount and by a route effective for treatment a composition according to any of the foregoing or the following, including a reconstituted lyophilate.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts titration data and buffer capacity as a function of concentration for sodium acetate standard buffers over the range from pH 5.0 to 4.0. Panel A is a graph that depicts the pH change upon acid titration of several different concentrations of a standard sodium acetate buffer, as described in Example 1. pH is indicated on the vertical axis. The amount of acid added to each solution is indicated on the horizontal axis in microequivalents of HCl added per ml of solution (μEq/ml). The linear least squares trend lines are depicted for each dataset. Acetate concentrations are indicated in the inset. Panel B is a graph that depicts the buffer capacity of the acetate buffers over the acidic pH range as determined from the titration data depicted in Panel A, as described in Example 1. Buffer capacity is indicated on the vertical axis as microequivlents of acid per ml of buffer solution per unit change in pH (μEq/ml-pH). Acetate concentration is indicated on the horizontal axis in mM.

FIG. 2 depicts titration data and buffer capacity as a function of concentrations for sodium acetate standard buffers over the range from pH 5.0 to 5.5. Panel A is a graph that depicts the pH change upon base titration of several different concentration of a standard sodium acetate buffer, as described in Example 2. pH is indicated on the vertical axis. The amount of base added to each solution is indicated on the horizontal axis in microequivalents of NaOH added per ml of solution (μEq/ml). The linear least squares trend lines are depicted for each dataset. Acetate concentrations are indicated in the inset. Panel B is a graph that depicts the buffer capacity of the acetate buffers over the basic pH range as determined from the titration data depicted in Panel A and described in Example 2. Buffer capacity is indicated on the vertical axis as microequivlents of base per ml of buffer solution per unit change in pH (μEq/ml-pH). Acetate concentration is indicated on the horizontal axis in mM.

FIG. 3 depicts the determination of acetate concentration in acetate buffer standards, as described in Example 3. The graph shows a standard curve for the determinations, with peak area indicated on the vertical axis and the acetate concentration indicated on the horizontal axis. The nominal and the measured amounts of acetate in the solutions used for the empirical determination of buffer capacity are tabulated below the graph.

FIG. 4 is a graph that depicts the pH change upon acid titration of several different concentrations of Ab-hOPGL over the range of pH 5.0 to 4.0, as described in Example 4. pH is indicated on the vertical axis. The amount of acid added to the solutions is indicated on the horizontal axis in microequivalents of HCl added per ml of buffer solution (μEq/ml). The linear least squares trend lines are depicted for each dataset. Ab-hOPGL concentrations are indicated in the inset.

FIG. 5 is a graph that depicts the pH change upon base titration of several different concentrations of Ab-hOPGL over the range 5.0 to 6.0, as described in Example 5. pH is indicated on the vertical axis. The amount of base added to the solutions is indicated on the horizontal axis in microequivalents of NaOH added per ml of buffer solution (μEq/ml). The linear least squares trend lines are depicted for each dataset. Ab-hOPGL concentrations are indicated in the inset.

FIG. 6 shows the residual acetate levels in Ab-hOPGL solutions used for determining buffer capacity. The graph shows the standard curve used for the acetate determinations as described in Example 6. The nominal and the experimentally measured acetate concentrations in the solutions are tabulated below the graph.

FIG. 7 is a graph depicting the buffer capacity of Ab-hOPGL plus or minus residual acetate in the pH range 5.0 to 4.0. The data were obtained as described in Example 7. The upper line shows Ab-hOPGL buffer capacity with residual acetate. The lower line shows Ab-hOPGL buffer capacity adjusted for residual acetate. The vertical axis indicates buffer capacity in microequivalents of acid per ml of Ab-hOPGL solution per unit of pH (μEq/ml-pH). The horizontal axis indicates the concentration of Ab-hOPGL in mg/ml. The buffer capacities of different concentrations of standard acetate buffers as described in Example 1 are shown as horizontal lines. The concentrations of the buffers are indicated above the lines.

FIG. 8 is a graph depicting the buffer capacity of Ab-hOPGL plus or minus residual acetate in the basic pH range pH 5.0 to 6.0. The data were obtained as described in Example 8. The upper line depicts Ab-hOPGL buffer capacity with residual acetate. The lower line depicts Ab-hOPGL buffer capacity adjusted for residual acetate. The vertical axis indicates buffer capacity in microequivalents of base added per ml of buffer solution per unit of pH (μEq/ml-pH). The horizontal axis indicates the concentration of Ab-hOPGL in mg/ml. The buffer capacities of several concentrations of standard sodium acetate buffers as described in Example 2 are indicated by horizontal lines, The acetate concentrations are indicated above each line.

FIG. 9 depicts, in a pair of charts, pH and Ab-hOPGL stability in self-buffering and conventionally buffered formulations. Panel A depicts the stability of self-buffered Ab-hOPGL, Ab-hOPGL formulated in acetate buffer, and Ab-hOPGL formulated in glutamate as a function of storage time at 4° C. over a period of six months. The vertical axis indicates Ab-hOPGL stability in percent Ab-hOPGL monomer determined by SE-HPLC. Storage time is indicated on the horizontal axis. Panel B depicts the pH of the same three formulations measured over the same period of time. The determinations of protein stability and the measurements of pH are described in Example 9.

FIG. 10 depicts titration curves and buffer capacities for several concentrations of self-buffering Ab-hB7RP1 formulations over the range of pH 5.0 to 4.0. Panel A shows the titration data. pH is indicated on the vertical axis. The amount of acid added to the solutions is indicated on the horizontal axis in microequivalents of HCl added per ml of buffer solution (μEq/ml). The linear least squares trend lines are depicted for each dataset. The Ab-hB7RP1 concentrations are indicated in the inset. Panel B depicts the buffer capacities of Ab-hB7RP1 formulations. The upper line shows the buffer capacities for the formulations including the contribution of residual acetate. The lower line shows the buffer capacities for formulations after subtracting the contribution of residual acetate based on SE-HPLC determinations as described in Example 3. Linear least squares trend lines are shown for the two data sets. The vertical axis indicates buffer capacity in microequivalents of acid per ml of buffer solution per unit of pH (μEq/ml-pH). The concentration of Ab-hB7RP1 is indicated on the horizontal axis in mg/ml. The buffer capacities of several concentrations of standard sodium acetate buffers as described in Example 1 are shown by dashed horizontal lines. The acetate buffer concentration are shown below each line. The results were obtained as described in Example 10.

FIG. 11 depicts titration curves and buffer capacities for several concentrations of self-buffering Ab-hB7RP1 formulations over the range of pH 5.0 to 6.0. Panel A shows the titration data. pH is indicated on the vertical axis. The amount of base added to the solutions is indicated on the horizontal axis in microequivalents of NaOH added per ml of buffer solution (μEq/ml). The linear least squares trend lines are depicted for each dataset. The Ab-hB7RP1 concentrations are indicated in the inset. Panel B depicts the buffer capacities of Ab-hB7RP1 formulations. The upper line shows the buffer capacities for the formulations containing residual acetate. The lower line shows the buffer capacities for formulations adjusted to remove the contribution of residual acetate. Linear least squares trend lines are shown for the two data sets. The vertical axis indicates buffer capacity in microequivalents of base per ml of buffer solution per unit of pH (μEq/ml-pH). The concentration of Ab-hB7RP1 is indicated on the horizontal axis in mg/ml. The buffer capacities of several concentrations of standard sodium acetate buffers as described in Example 2 are shown by dashed horizontal lines. The acetate buffer concentrations are shown above each line. The results were obtained as described in Example 11.

FIG. 12 depicts Ab-hB7RP1 stability in self-buffering and conventionally buffered formulations at 4° C. and 29° C. Panel A depicts the stability of self-buffered Ab-hB7RP1, Ab-hB7RP1 formulated in acetate buffer, and Ab-hB7RP1 formulated in glutamate as a function of storage at 4° C. over a period of six months. The vertical axis depicts Ab-hB7RP1 monomer in the samples determined by SE-HPLC. Time is indicated on the horizontal axis. Panel B depicts the stability of the same three formulations as a function of storage at 29° C. over the same period of time. Axes in Panel B are the same as in Panel A. The determinations of protein stability by HPLC-SE are described in Example 12.

FIG. 13 depicts pH stability in self buffer formulations of Ab-hB7RP1 at 4° C. and 29° C. The vertical axis indicates pH. Time, in weeks, is indicated on the horizontal axis. Temperatures of the datasets are indicated in the inset. The data were obtained as described in Example 13.

FIG. 14 depicts the buffer capacity of self-buffering formulations of Ab-hCD22 as a function of Ab-hCD22 concentration over the range of pH 4.0 to 6.0. Panel A depicts the buffer capacities of self-buffering Ab-hCD22 formulations as a function of Ab-hCD22 concentration over the range of pH 4.0 to 5.0. Panel B depicts the buffer capacities of self-buffering Ab-hCD22 formulations as a function of concentration over the range of pH 5.0 to 6.0. In both panels the vertical axis indicates buffer capacity in microequivalents of base per ml of buffer solution per unit of pH (μEq/ml-pH), and the horizontal axis indicates Ab-hCD22 concentrations in mg/ml. For reference, the buffer capacity of 10 mM sodium acetate as described in Example 1 is shown in both panels by a dashed horizontal line. The results shown in the Figure were obtained as described in Example 14.

FIG. 15 depicts titration curves and buffer capacities for several concentrations of self-buffering Ab-hIL4R formulations over the range of pH 5.0 to 4.0. Panel A shows the titration data. pH is indicated on the vertical axis. The amount of acid added to the solutions is indicated on the horizontal axis in microequivalents of HCl added per ml of buffer solution (μEq/ml). The linear least squares trend lines are depicted for each dataset. The Ab-hIL4R concentrations are indicated in the inset. Panel B depicts the buffer capacities of Ab-hIL4R as a function of concentration. The linear least squares trend line is shown for the dataset. The vertical axis indicates buffer capacity in microequivalents of base per ml of buffer solution per unit of pH (μEq/ml-pH). The concentration of Ab-hIL4R is indicated on the horizontal axis in mg/ml. The buffer capacities of several concentrations of standard sodium acetate buffers as described in Example 1 are shown by dashed horizontal lines. The acetate buffer concentrations are shown above each line. The results were obtained as described in Example 15.

FIG. 16 depicts titration curves and buffer capacities for several concentrations of self-buffering Ab-hIL4R formulations over the range of pH 5.0 to 6.0. Panel A shows the titration data. pH is indicated on the vertical axis. The amount of base added to the solutions is indicated on the horizontal axis in microequivalents of NaOH added per ml of buffer solution (μEq/ml). The linear least squares trend lines are depicted for each dataset. The Ab-hIL4R concentrations are indicated in the inset. Panel B depicts the buffer capacities of Ab-hIL4R as a function of concentration. The linear least squares trend line is shown for the dataset. The vertical axis indicates buffer capacity in microequivalents of base per ml of buffer solution per unit of pH (μEq/ml-pH). The concentration of Ab-hIL4R is indicated on the horizontal axis in mg/ml. The buffer capacities of several concentrations of standard sodium acetate buffers as described in Example 2 are shown by dashed horizontal lines. The acetate buffer concentrations are shown above each line. The results were obtained as described in Example 16.

FIG. 17 depicts Ab-hIL4R and pH stability in acetate buffered and self-buffered formulations of Ab-hIL4R at 37° C. as a function of time. Panel A is a bar graph showing Ab-hIL4R stability over four weeks at 37° C. The vertical axis indicates stability in percent monomeric Ab-hIL4R as determined by SE-HPLC. The horizontal axis indicates storage time in weeks. The insert identifies the data for the acetate and for the self-buffered formulations. Panel B shows the pH stability of the same formulations for the same conditions and time periods. The pH is indicated on the vertical axis. Storage time in weeks is indicated on the horizontal axis. Data for the acetate and self-buffered formulations are indicated in the inset. The data were obtained as described in Example 17.

GLOSSARY

The meanings ascribed to various terms and phrases as used herein are illustratively explained below.

“A” or “an” herein means “at least one;” “one or more than one.”

“About,” unless otherwise stated explicitly herein, means V 20%. For instance about 100 herein means 80 to 120, about 5 means 4 to 6, about 0.3 means 0.24 to 0.36, and about 60% means 48% to 72% (not 40% to 80%).

“Agonist(s)” means herein a molecular entity that is different from a corresponding stimulatory ligand but has the same stimulatory effect. For instance (although agonists work through other mechanisms), for a hormone that stimulates an activity by binding to a corresponding hormone receptor, an agonist is a chemically different entity that binds the hormone receptor and stimulates its activity.

“Antagonist(s)” means herein a molecular entity that is different from a corresponding ligand and has an opposite effect. For instance (although antagonists work through other mechanisms), one type of antagonist of a hormone that stimulates an activity by binding to a corresponding hormone receptor is a chemical entity that is different from the hormone and binds the hormone receptor but does not stimulate the activity engendered by hormone binding, and by this action inhibits the effector activity of the hormone.

“Antibody(s)” is used herein in accordance with its ordinary meaning in the biochemical and biotechnological arts.

Among antibodies within the meaning of the term as it is used herein, are those isolated from biological sources, including monoclonal and polyclonal antibodies, antibodies made by recombinant DNA techniques (also referred to at times herein as recombinant antibodies), including those made by processes that involve activating an endogenous gene and those that involve expression of an exogenous expression construct, including antibodies made in cell culture and those made in transgenic plants and animals, and antibodies made by methods involving chemical synthesis, including peptide synthesis and semi-synthesis. Also within the scope of the term as it is used herein, except as otherwise explicitly set forth, are chimeric antibodies and hybrid antibodies, among others.

The prototypical antibody is a tetrameric glycoprotein comprised of two identical light chain-heavy chain dimers joined together by disulfide bonds. There are two types of vertebrate light chains, kappa and lambda. Each light chain is comprised of a constant region and a variable region. The two light chains are distinguished by constant region sequences. There are five types of vertebrate heavy chains: alpha, delta, epsilon, gamma, and mu. Each heavy chain is comprised of a variable region and three constant regions. The five heavy chain types define five classes of vertebrate antibodies (isotypes): IgA, IgD, IgE, IgG, and IgM. Each isotype is made up of, respectively, (a) two alpha, delta, epsilon, gamma, or mu heavy chains, and (b) two kappa or two lambda light chains. The heavy chains in each class associate with both types of light chains; but, the two light chains in a given molecule are both kappa or both lambda. IgD, IgE, and IgG generally occur as “free” heterotetrameric glycoproteins. IgA and IgM generally occur in complexes comprising several IgA or several IgM heterotetramers associated with a “J” chain polypeptide. Some vertebrate isotypes are classified into subclasses, distinguished from one another by differences in constant region sequences. There are four human IgG subclasses, IgG1, IgG2, IgG3, and IgG4, and two IgA subclasses, IgA1 and IgA2, for example. All of these and others not specifically described above are included in the meaning of the term “antibody(s)” as used herein.

The term “antibody(s)” further includes amino acid sequence variants of any of the foregoing as described further elsewhere herein.

“Antibody-derived” as used herein means any protein produced from an antibody, and any protein of a design based on an antibody. The term includes in its meaning proteins produced using all or part of an antibody, those comprising all or part of an antibody, and those designed in whole or in part on the basis of all or part of an antibody. “Antibody-derived” proteins include, but are not limited to, Fc, Fab, and Fab2 fragments and proteins comprising the same, VH domain and VL domain fragments and proteins comprising the same, other proteins that comprise a variable and/or a constant region of an antibody, in whole or in part, scFv(s) intrabodies, maxibodies, minibodies, diabodies, amino acid sequence variants of the foregoing, and a variety of other such molecules, including but not limited to others described elsewhere herein.

“Antibody-related” as used herein means any protein or mimetic resembling in its structure, function, or design an antibody or any part of an antibody. Among “antibody-related” proteins as the term is used herein are “antibody-derived” proteins as described above. It is to be noted that the terms “antibody-derived” and “antibody-related” substantially overlap; both terms apply to many such proteins. Examples of “antibody-related” proteins, without implying limitation in this respect, are peptibodies and receptibodies. Other examples of “antibody-related” proteins are described elsewhere herein.



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stats Patent Info
Application #
US 20120028877 A1
Publish Date
02/02/2012
Document #
13188329
File Date
07/21/2011
USPTO Class
514/11
Other USPTO Classes
International Class
61K38/02
Drawings
15


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