Patent Application
20170106090
This application is related to Indian Provisional Application 1248/MUM/2014 filed 2 Apr. 2014 and is incorporated herein in its entirety.
The present invention relates to a liquid pharmaceutical composition comprising an anti-TNFα antibody, buffer, sugar, and surfactant.
Tumor necrosis factor is a polypeptide cytokine involved in inflammation and the acute phase response. TNF-alpha is present in larger quantities in persons with rheumatoid arthritis or Crohn's disease. It is also involved in Juvenile Idiopathic Arthritis (JIA), Psoriatic Arthritis (PA), Ankylosing Spondylitis (AS), Ulcerative Colitis and Plaque Psoriasis. Direct inhibition of TNF-alpha by the biological agents has produced significant advances in rheumatoid arthritis and other auto-immune disease treatment and has validated the extra-cellular inhibition of this pro-inflammatory cytokine as an effective therapy. One such biological agent is Adalimumab.
Adalimumab (Anti-TNFα antibody), marketed as HUMIRA® by Abort Inc., is a recombinant human IgG1 monoclonal antibody specific for human tumor necrosis factor (TNF). Adalimumab was created using phage display technology resulting in an antibody with human derived heavy and light chain variable regions and human IgG1 constant regions. Adalimumab is produced by recombinant DNA technology in a mammalian cell expression system and is purified by a process that includes specific viral inactivation and removal steps. It consists of 1330 amino acids and has a molecular weight of approximately 148 kilodaltons.
Generally, proteins have a very short half-life, and undergo denaturation (such as aggregation, dissociation, and adsorption on the surface of vessels) upon exposure to various factors such as unfavorable temperatures, water-air interface, high-pressure, physical/mechanical stress, organic solvents and microbial contamination. Consequently, the denatured protein loses intrinsic physicochemical properties and physiological activity. Denaturation of proteins is often irreversible, and therefore proteins, once denatured, may not recover their native properties to the initial state.
In the biopharmaceutical industry, the long term storage of proteins, prepared using recombinant DNA technology in aqueous formulations, is generally a difficult task. To overcome the stability problem of proteins in aqueous formulations, therapeutic protein products are made more stable via lyophilization (freeze-drying). Lyophilized products are usually accompanied by sterile aqueous media for reconstitution. After reconstitution, the formulations typically have short useful storage lives, even when stored at low temperatures (e.g., 5° C.). Example of TNF alpha inhibitors which are available in the market in the lyophilized form are Enbrel® and Remicade® and both the compositions should be reconstituted before use.
Typical practices to improve polypeptide stability can be addressed by varying the concentration of elements with the formulation, or by adding excipients to modify the formulation.
U.S. Pat. No. 5,580,856 discloses the stabilization of dried proteins against loss of biological activity in the formulations by adding a reconstitution stabilizer upon rehydration of the dried protein. A kit for producing a formulation by dissolving the dried composition in a solvent containing the reconstitution stabilizer is also described.
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, a buffer maintaining the pH in the range from about 4.5 to about 6.0, a surfactant and a polyol, along with uses for such a formulation.
EP1314437 relates to an invention of stabilized preparations containing an antibody in a glycine buffer and/or a histidine butter and also provides processes for preparing a protein-containing stabilized preparation, comprising adjusting the pH with a basic amino acid or a basic amino acid derivative or a salt thereof.
EP1478394 discloses about the invention that relates to an aqueous pharmaceutical composition suitable for long-term storage of polypeptides containing an Fc domain of an immunoglobulin, methods of manufacture, methods of administration and kits containing same.
U.S. Pat. No. 8,216,583 disclose formulation of human antibodies for treating TNF-α associated disorder. The antibody claimed in the invention is adalimumab. It discloses a liquid aqueous pharmaceutical formulation is described which has a high protein concentration, a pH of between about 4 and about 8, and enhanced stability.
U.S. Pat. No. 8,420,081 discloses an aqueous formulation comprising water and a protein, and methods of making the same. The invention is directed towards the findings that proteins formulated in water maintain solubility, as well as stability, even at high concentrations, during long-term liquid storage or other processing steps, such as freeze/thawing and lyophilization.
Hence, there is a need for a stable aqueous pharmaceutical formulation with an extended shelf life, comprising an antibody which is suitable for therapeutic use to inhibit or counteract detrimental TNFα activity. There is also a need for a stable aqueous pharmaceutical formulation with an extended shelf life, comprising an antibody suitable for therapeutic use which is easily administered and contains a high protein concentration.
The main object of the present invention is to provide a novel and stable pharmaceutical composition of anti-TNFα antibody along with pharmaceutically acceptable carriers.
Another object of the present invention is to provide a novel and stable pharmaceutical composition comprising adalimumab (anti-TNFα antibody), buffer, stabilizer, surfactant and pH range of 4.5 to 6.5.
Yet another object of the present invention is to provide a novel and stable pharmaceutical composition of anti-TNFα antibody comprising a buffer system selected from the group consisting of glycine, acetate, arginine, succinate, histidine either alone or a combination thereof.
Yet another object of the present invention is to provide a novel and stable pharmaceutical composition of anti-TNFα antibody comprising sugar or polyol stabilizer selected from the group consisting of monosaccharide such as glucose and mannose, and the like either alone or in combination thereof, disaccharides such as sucrose, trehalose, and maltose, and the like either alone or in combination thereof, sugar alcohols; such as mannitol and xylitol, and the like either alone or in combination thereof.
Yet another object of the present invention is to provide a novel and stable pharmaceutical composition of anti-TNFα antibody comprising the ionic surfactant selected from the group consisting of a polysorbate-based non-ionic surfactant and a poloxamer-based non-ionic surfactant or a combination thereof.
Yet another object of the present invention is to provide a novel and stable pharmaceutical composition of anti-TNFα antibody wherein the formulation is maintained at a pH of about 4.5 to 6.5, more preferably at pH 5.0 to 6.0, in a buffer system selected from the group consisting of glycine, acetate, arginine, succinate, histidine either alone or a combination thereof.
Yet another object of the present invention is to provide a novel and stable pharmaceutical composition which encompasses adalimumab as anti-TNFα antibody comprising glycine, acetate and arginine as buffer either alone or in combination thereof, sucrose as stabilizer, polysorbate 80 as surfactant and formulation is maintained at pH of about 5.0 to 6.0.
Yet another object of the present invention is to provide a novel and stable pharmaceutical composition comprising adalimumab as anti-TNFα antibody, buffer, stabilizer and surfactant; wherein buffer is at concentration of 5 mM to 25 mM and wherein the pH of the composition is in a range of about 4.5 to 6.5; wherein stabilizer is at concentration of 0.1% to 20% w/v; wherein surfactant is at concentration of 0.004% to 0.4% w/v.
The main aspect of the present invention is to provide a novel and stable pharmaceutical composition of anti-TNFα antibody along with pharmaceutically acceptable carriers.
Another aspect of the present invention is to provide a novel and stable pharmaceutical composition comprising adalimumab (of anti-TNFα antibody), buffer, stabilizer, surfactant and pH range of 4.5 to 6.5.
Yet another aspect of the present invention is to provide a novel and stable pharmaceutical composition of anti-TNFα antibody comprising a buffer system selected from the group consisting of glycine, acetate, arginine, succinate, histidine either alone or a combination thereof.
Yet another aspect of the present invention is to provide a novel and stable pharmaceutical composition of anti-TNFα antibody comprising sugar or polyol stabilizer selected from the group consisting of monosaccharide such as glucose and mannose, and the like either alone or in combination thereof, disaccharides such as sucrose, trehalose, and maltose, and the like either alone or in combination thereof, sugar alcohols such as mannitol and xylitol, and the like either alone or in combination thereof.
Yet another aspect of the present invention is to provide a novel and stable pharmaceutical composition of anti-TNFα antibody comprising the ionic surfactant selected from the group consisting of a polysorbate-based non-ionic surfactant and a poloxamer-based non-ionic surfactant or a combination thereof.
Yet another aspect of the present invention is to provide a novel and stable pharmaceutical composition of anti-TNFα antibody wherein the formulation is maintained at a pH of about 4.5 to 6.5, more preferably at pH 5.0 to 6.0, in a buffer system selected from the group consisting of glycine, acetate, arginine, succinate, histidine, arginine either alone or a combination thereof.
Yet another aspect of the present invention is to provide a novel and stable pharmaceutical composition which encompasses adalimumab as anti-TNFα antibody comprising glycine, acetate and arginine as buffer either alone or in combination thereof, sucrose as stabilizer, polysorbate 80 as surfactant and formulation is maintained at pH of about 5.0 to 6.0.
Yet another aspect of the present invention is to provide a novel and stable pharmaceutical composition comprising adalimumab as anti-TNFα antibody, buffer, stabilizer and surfactant; wherein buffer is at concentration of 5 mM to 25 mM and wherein the pH of the composition is in a range of about 4.5 to 6.5; wherein stabilizer is at concentration of 0.1% to 20% w/v; wherein surfactant is at concentration of 0.004% to 0.4% w/v.
The following definitions are provided to facilitate understanding of certain terms used throughout the specification.
The present invention relates to a liquid pharmaceutical composition comprising an anti-TNFα antibody, buffer, sugar, and surfactant.
The term “human TNFα” (which may be abbreviated as hTNFα, or simply hTNF), as used herein, is intended to refer to a human cytokine that exists as a 17 kD secreted form and a 26 kD membrane associated form, the biologically active form of which is composed of a trimer of noncovalently bound 17 kD molecules. Treatment with anti-TNF monoclonal antibodies (infliximab, adalimumab and certolizumab pegol) has been shown to provide substantial benefit to patients through reductions in both localized and systemic expression of markers associated with inflammation.
The present invention relates to a novel and stable pharmaceutical composition comprising adalimumab (of anti-TNFα antibody), buffer, stabilizer and surfactant having pH range of 4.5 to 6.5.
Adalimumab is the first phage-display-derived human antibody brought into the clinic, and was generated by ‘guided selection’ using a mouse monoclonal antibody. (Jespers L. S., Biotechnology 12, 899-903, 1994). Adalimumab (Anti-TNFα antibody), marketed as HUMIRA® by Abott Inc., is a recombinant human IgG1 monoclonal antibody specific for human tumor necrosis factor (TNF). Adalimumab was created using phage display technology resulting in an antibody with human derived heavy and light chain variable regions and human IgG1 constant regions. Adalimumab is produced by recombinant DNA technology in a mammalian cell expression system and is purified by a process that includes specific viral inactivation and removal steps. It consists of 1330 amino acids and has a molecular weight of approximately 148 kilodaltons.
In the present invention, buffers are required for maintaining pH of the formulation. The buffer system of the present invention comprises glycine, acetate, arginine, succinate, histidine either alone or a combination thereof giving desired pH range from 4.5 to 6.5.
In one embodiment, stabilizers used in the present invention are selected from the group that consists of: sugar or polyol stabilizer selected from the group consisting of monosaccharide such as glucose and mannose, and the like either alone or in combination thereof, disaccharides such as sucrose, trehalose, and maltose, and the like either alone or in combination thereof, sugar alcohols such as mannitol and xylitol, and the like either alone or in combination thereof.
In the present invention, surfactant is used in order to prevent adsorption of antibody on the surface of the vial, ampoule, carpoule, cartridge or syringe. Surfactants lower surface tension of a protein solution, thereby, preventing its adsorption or aggregation on to a hydrophobic surface. Preferred surfactants of the present invention include a polysorbate based non-ionic surfactant and polyoxyethylene copolymer, polyvinylpyrrolidone, either alone or in combination.
The novel aqueous pharmaceutical composition of anti-TNFα antibody described in the present invention has the following advantages:
The specific embodiments described herein are offered by way of example only, and the invention is to be limited by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled.
Method of Preparation:
Adalimumab formulation was prepared in formulation composition given in the above table by dissolving the excipients in water for injection. The protein concentration was set to 50 mg/mL and the pH of the formulation is set to 5.2 similar to the reference formulation. 0.8 mL solution filled in 2 mL USP type 1 vial and sealed with coated bromobutylated rubber stopper and aluminum seal. Filled vial were charged at 40° C. for 15 days stress stability study. During stability study following test were done:
a) Physical Appearance:
b) pH:
c) CEX-HPLC:
d) SEC-HPLC:
e) Relative Potency:
f) Differential Scanning Calorimetry:
Rationale:
Based on the above data, all three buffer shows a good buffering capacity, and thermo stability profile. To confirm the results obtained during the initial screening, another set of stability study were carried out with the formulation 1, 2 and 3. Composition of all formulation buffer as given in below table.
Method of Preparation:
Adalimumab formulation was prepared in formulation composition given in the above table by dissolving the excipients in water for injection. The protein concentration was set to 50 mg/mL and the pH of the formulation is set to 5.2 similar to the reference formulation. 0.8 mL solution filled in 2 mL USP type 1 vial and sealed with coated bromobutylated rubber stopper and aluminum seal. Filled vial were charged at 40° C. for 15 days stress stability study, At 5° C. for 6 months and at 25° C. for 6 months as described in the above table. During stability study following test were done:
a) Physical Appearance:
b) pH
c) CEX Data
d) SEC-HPLC Data
Observation: All three formulations are showing good stability and comparable in SEC profile. Results are shown in
e) Potency
| Number | Date | Country | Kind |
|---|---|---|---|
| 1248/MUM/2014 | Apr 2014 | IN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IN2015/000092 | 2/18/2015 | WO | 00 |
