MX2007001951A - Il-1 antagonist formulations - Google Patents

Abstract

Formulations of an interleukin-1 (IL-1) antagonist are provided including a pre-lyophilized formulation, a reconstituted lyophilized formulation, and a stable liquid formulation. Preferably, the IL-1 antagonist is an IL-1 trap composed of a dimer of two fusion protein having an amino acid sequence selected from the group consisting of SEQ ID NO:2, 4, 6, 8, 10, 12,14, 16, 18, 20, 22, 24, and 26. Most preferably, the fusion protein has the sequence of SEQ ID NO:10.

Description

FORMULATIONS ANTAGONISTS OF IL-1 BACKGROUND OF THE INVENTION Field of the Invention The present invention is directed to pharmaceutical formulations comprising agents capable of inhibiting interleukin-1 (IL-1), and to methods for preparing and using said formulations. Discussion of the Related Art Interleukin-1 (IL-1) antagonists have been described, capable of blocking or inhibiting the biological action of IL-1. An exemplary IL-1 antagonist, an IL-1 trap, is described in U.S. Patent Publication No. 2003/0143697, published July 31, 2003. An IL-1 trap is a fusion protein, specific for IL-1, comprising two IL-1 receptor components and a multimerizing component. Lyophilization (freeze drying under controlled conditions) is commonly used for protein storage for a long time. The lyophilized protein is substantially resistant to degradation, aggregation, oxidation and other degenerative processes while in the freeze-dried state (see, for example, U.S. Patent No. 6,436,897). BRIEF DESCRIPTION OF THE INVENTION Stable formulations of interleukin-1 (IL-1) antagonist are provided herein. Acceptable formulations for pharmacological use, of the present invention, comprise an IL-1 trap, with a carrier acceptable for pharmaceutical use. In the specific modalities, liquid and freeze-dried or freeze-dried formulations are provided. In a first exemplary aspect, the invention incorporates a pre-lyophilization formulation of an interleukin-1 (IL-1) antagonist, comprising an IL-1 protein antagonist, capable of binding to and inhibiting the biological action of , IL-1; a regulator, an organic cosolvent or volume imparting agent, and one or more lyoprotectants. In a specific embodiment, the IL-1 antagonist is a fusion protein, capable of binding to IL-1, the regulator is histidine, the organic cosolvent or volume imparting agent is PEG and the / the lyoprotectants are / are less one of: glycine, arginine and sucrose. In one embodiment, the formulation of the pre-lyophilized invention does not contain preservative. In one embodiment of the pre-lyophilization formulation of the invention, the formulation comprises 5 to 100 mM histidine, 0.5 to 3.0 percent PEG, 0.25 to 3.0 percent glycine, 5 to 50 mM arginine , from 0.5 to 30.0 percent sucrose and from 5 to 50 mg / mL of an IL-1 antagonist, at a pH of around 6.5. In one embodiment, the pre-lyophilization formulation may additionally comprise up to 5 mM citrate and / or 0.003 to 0.005 percent polysorbate. The polysorbate present can be, for example, polysorbate 20 or 80.

In a more specific embodiment, the pre-lyophilization formulation of an IL-1 antagonist comprises approximately 20 mM histidine, approximately 1.5 percent PEG 3350, approximately 0.5 percent glycine, approximately 25 mM arginine, approximately 1.0 percent of sucrose and approximately 40 mg / mL of IL-1 trap, at a pH of approximately 6.5. In a specific embodiment, the IL-1 antagonist is an IL-1 trap fusion protein, such as that shown in SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20 , 22, 24, 26. It is more preferred that the IL-1 trap be the trap shown in SEQ ID NO. 10. In a preferred embodiment, the pre-lyophilization IL-1 antagonist formulation consists essentially of about 20 mM histidine, about 1.5 percent PEG 3350, about 0.5 percent glycine, about 25 mM of arginine, about 1.0 percent sucrose and about 40 mg / mL of IL-1 fusion protein having the sequence of SEQ ID NO: 10, at a pH of about 6.5. Citrate (less than or equal to about 0.15 mM) and polysorbate (less than or equal to about 0.005 percent) may be present. In a second aspect, the invention incorporates an IL-1, pre-lyophilization antagonist formulation, consisting essentially of approximately 20 mM histidine, approximately 1.5 percent PEG 3350, approximately 0.5 percent glycine, approximately 25 mM arginine, about 1.0 percent sucrose and about 40 mg / mL of the IL-1 fusion protein having the sequence of SEQ ID NO: 10, at a pH of about 6.5; wherein the pre-lyophilization formulation contains no preservative, phosphate buffer, more than oligomeric amounts of NaCl and / or more than 1.5 percent sucrose. Citrate may be present in amounts of less than about 0.15 mM and may also be present up to about 0.005-0.01 percent Polysorbate 20. In a d aspect the invention incorporates a method for producing a lyophilized formulation of an IL-1 antagonist. , which comprises subjecting the IL-1 antagonist formulation, of pre-lyophilization, of the invention, to lyophilization, to generate a lyophilized formulation of IL-1 antagonist. The lyophilized formulation can be lyophilized by any method known in the art to lyophilize a liquid. In a fourth related aspect, the invention incorporates a method for producing a lyophilized, reconstituted formulation of an IL-1 antagonist, which comprises reconstituting the lyophilized formulation of the invention to a reconstituted formulation. In one embodiment, the reconstituted formulation has twice the concentration as the pre-lyophilized formulation; for example, the method of the invention comprises: (a) producing a pre-lyophilization formulation of an IL-1 antagonist, which consists of about 20 mM histidine, about 1.5 percent PEG 3350, about 0.5 glycine percent, about 25 mM arginine, about 1.0 percent sucrose and about 40 mg / mL of an IL-1 protein antagonist, at pH around 6.5; (b) subjecting the pre-lyophilized formulation from step (a) to lyophilization; and (c) reconstituting the lyophilized formulation from step (b) to a composition consisting of about 40 mM histidine, about 3 percent PEG 3350, about 1 percent glycine, about 50 mM arginine, about 2.0 percent sucrose and about 80 mg / mL of the IL-1 protein antagonist, where the reconstituted formulation can additionally contain about 0.2 mM citrate and / or about 0.008 percent Polysorbate 20. In a modality specifically, the IL-1 antagonist is a fusion protein that is an IL-1 trap, as shown in SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26. It is more preferred that the IL-1 ramp be the trap shown in SEQ ID NO: 10. In separate embodiments, the reconstituted formulation has three times the concentration of the pre-lyophilized formulation, eg, a pre-lyophilization formulation is reconstituted with 20 mg of antagonist protein d and IL-1 / mL, to a final formulation of 60 mg of IL-1 / mL antagonist protein. In general, the lyophilized formulation is reconstituted with sterile water suitable for injection. In one embodiment, the reconstitution liquid may be bacteriostatic water. In specific embodiments of the method for producing a reconstituted lyophilized formulation, a pre-lyophilization solution is present in a bottle as a 40 mg solution of I L-1 antagonist protein per ml of a pre-lyophilization formulation; which is lyophilized and reconstituted to a solution of 80 mg / mL. Another method is freeze-dried a 20 mg / mL solution of pre-lyophilization solution, and reconstituted in a 40 mg / mL solution. In another embodiment, 25 mg / mL of pre-lyophilization solution is lyophilized and reconstituted. to a solution of 50 mg / mL. In another embodiment, 1 2.5 mg / mL of pre-lyophilization solution is lyophilized and reconstituted at 25 mg / mL of solution. In another embodiment, 1 2.5 mg / mL of pre-lyophilization solution is lyophilized and reconstituted at 50 mg / mL of solution. In another embodiment, 25 mg / mL of pre-lyophilization solution is lyophilized and reconstituted at 75 mg / mL of solution. In another embodiment, 40 mg / mL of pre-lyophilization solution is lyophilized and reconstituted to a solution of 1 20 mg / m L. In another embodiment, 40 mg / mL of pre-lyophilization solution is lyophilized and reconstituted to a solution of 20 mg / mL. Preferably the reconstituted lyophilized formulation does not contain preservative. In another embodiment, the reconstituted formulation includes up to 30 percent sucrose and one or more preservatives. In a fifth aspect, the invention incorporates a stable liquid formulation of an I L-1 antagonist which comprises an I L-1 antagonist protein, capable of binding to I L-1 and inhibiting its biological action; a regulator, an organic cosolvent and one or more thermal stabilizers. In a specific embodiment the I L-1 antagonist is a fusion protein that is a trap of I L-1, as shown in SEQ ID NO: 2, 4, 6, 8, 10, 14, 14 1 6, 1 8, 20, 22, 24, 26. More preferably, the IL-1 trap is the trap shown in SEQ ID NO: 10. In one embodiment the regulator is a phosphate regulator. In one embodiment, the organic cosolvent is PEG, preferably PEG 3350. In one embodiment, the thermal stabilizers are NaCl and / or sucrose. It is more preferred that the thermal stabilizers be NaCl and sucrose. In a specific embodiment the stable liquid formulation of an IL-1 antagonist comprises from 5 to 100 mM of phosphate buffer, from 0.5 to 3 percent of PEG, from 25 to 150 mM of NaCl, from 5 to 30 percent of sucrose , from 10 to 500 mg / mL of a trap protein for IL-1, at a pH of approximately 6-6.5. In a more specific embodiment, the stable liquid formulation of an IL-1 antagonist comprises 10 mM phosphate buffer, 3 percent PEG 3350, 50 mM NaCl, 5 to 20 percent sucrose, 12.5 to 50 mg / mL of an IL-1 trap protein, at a pH of about 6-6.5. In addition, low or oligomeric amounts of citrate or polysorbate buffer may be present. The stable liquid formulation of the IL-1 antagonist of the invention exhibits little or no precipitation, as determined by visual inspection after storing a 50 mg / mL IL-1 trap formulation for up to about 29 months at 5 °. C. Additionally, little or no aggregate formation is observed when determined by size exclusion chromatography, e.g., HPLC, after storing a 50 mg / mL IL-1 trap formulation for up to about 24 months at 5 °. C.

Other objectives and advantages will become apparent from a review of the detailed description that follows. DETAILED DESCRIPTION OF THE INVENTION The present invention is not limited to particular methods or to the experimental conditions described, since such methods and conditions may vary. It should also be understood that the terminology used herein is solely for the purpose of describing particular embodiments, and is not intended to be limiting, unless indicated, since the scope of the present invention will be limited solely for the claims to nexus. As used in this description and the appended claims, the singular forms "a", "a" and "the", "the", include references to the plural, unless the context clearly dictates otherwise. . Thus, for example, references to "a method" include one or more methods and / or steps of the type described herein and / or those which will be apparent to persons with experience in the art when reading this description. Unless stated otherwise, all technical and scientific terms and phrases used herein shall have the same meaning as those ordinarily understood by those having ordinary experience in the subject matter of the invention. While any method and any material similar or equivalent to those described herein can be used, in the practice or tests of the present invention, preferred methods and materials will now be described. General description Safe handling and safe administration of formulations comprising proteins represent major challenges for the pharmaceutical formulator. Proteins have unique chemical and physical properties that present stability problems: there is a variety of degradation pathways for proteins, which involve both chemical and physical instability. The chemical instability includes deamination, formation of aggregates, truncating of the peptide skeleton and oxidation of methionine residues. Physical instability comprises many phenomena including, for example, the formation of aggregates. Chemical and physical stability can be promoted by removing the water from the protein. Lyophilization (freeze drying under controlled conditions) is commonly used to store proteins for a long time. The lyophilized protein is substantially resistant to degradation, aggregate formation, oxidation and other degenerative processes while in the freeze-dried state. Normally the lyophilized protein is reconstituted with water optionally containing a bacteriostatic preservative (eg, benzyl alcohol) before administration. Definitions By the term "therapeutically effective dose" or "pharmaceutically effective" is meant a dose that produces the desired effect for which it is administered. The exact dose will depend on the purpose of the treatment and will be determinable by someone with experience in the field using known techniques (see, for example, Lloyd (1 999) The Art, Science and Technology of Pharmaceutical Compounding). By the term "blocker", "inhibitor" or "antagonist" is meant a substance that retards or prevents a reaction or physiological or physiological response. Blockers or inhibitors include, but are not limited to, antisense molecules, antibodies, antagonists and their derivatives. The term "pharmaceutically acceptable" or "acceptable for pharmaceutical use" includes approval by a regulatory agency of the federal or state government, or that is listed in the United States Pharmacopoeia or other generally recognized pharmacopoeia, for use in animals and , more in particular, in humans. The term "carrier" includes a diluent, an adjuvant, an excipient or a vehicle with which a composition is administered. Carriers may include sterile fluids, such as, for example, water and oil, including petroleum oils, of animal, vegetable or synthetic origin, such as, for example: peanut oil, soybean oil, mineral oil, sesame oil and the like. The term "excipient" includes a non-therapeutic agent added to a pharmaceutical composition to provide a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example: starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, gypsum, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dry skim milk, glycerol , propylene glycol, water, ethanol and the like. The term "freeze-dried" or "freeze-dried" includes the condition of a substance that has been subjected to a drying process, such as lyophilization, in which at least 50 percent of the moisture has been removed. The phrase "bulking agent" includes a compound that is acceptable for pharmaceutical use and that adds bulk to a lyophilization cake. In general, volume forming agents known in the art include, for example: carbohydrates, which include simple sugars, such as dextrose, ribose, fructose and the like; alcohol sugars, such as mannitol, inositol and sorbitol; the disaccharides, which include trehalose, sucrose and lactose; polymers that occur in nature, such as: starch, dextrans, chitosan, hyaluronate, proteins (for example, gelatin and serum albumin), glycogen and monomers and synthetic polymers. In the formulations of the invention, PEG 3350 is an organic cosolvent that is used to stabilize the IL-1 protein antagonist when agitated, mixed or processed, and as a bulking agent to help produce a volume or acceptable body. The term "lyoprotectant" includes a substance that can be added to a freeze-dried or freeze-dried formulation, to help maintain the protein structure when freeze-dried or lyophilized. A "preservative" includes a bacteriostatic, bactericidal, fungistatic or fungicidal compound, which is generally added to the formulations to retard or eliminate the growth of bacteria or other contaminating microorganisms in the formulations. The preservatives include, for example: benzyl alcohol, phenol, benzalkonium chloride, m-cresol, thimerosol, chlorobutanol, methylparaben, propylparaben and the l Other examples of preservatives acceptable for pharmaceutical use can be found in the United States Pharmacopoeia. IL-1 Antagonists An IL-1 antagonist is a compound capable of blocking or inhibiting the biological action of IL-1, which includes fusion proteins capable of trapping IL-1, such as an IL-1 trap. In a preferred embodiment, the IL-1 trap is a fusion protein specific for IL-1, comprising two IL-1 receptor components and a multimerizing component, for example, an IL-1 trap described in the publication of U.S. Patent No. 2003/0143697, published July 31, 2003. In a specific embodiment, the IL-1 trap is the fusion protein shown in SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26. A preferred IL-1 trap is shown in SEQ ID NO: 10. The invention includes the use of an IL-1 trap substantially identical to the SEQ ID protein. NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26; that is, a protein having at least 95 percent identity, preferably at least 97 percent identity and, more preferably, at least 98 percent identity, with the protein of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, and capable of binding to IL-1 and inhibiting it. Additionally, in specific embodiments, the IL-1 antagonist is a modified trap of IL-1 comprising one or more receptor components and one or more immunoglobulin-derived components, specific for IL-1 and / or an IL-1 receptor. . In another embodiment, the IL-1 antagonist is a modified trap of IL-1 comprising one or more immunoglobulin-derived components, specific for IL-1 and / or an IL-1 receptor. The IL-1 trap of the methods and formulations of the present invention can be prepared by any suitable method known in the art or coming to be known, which is useful for preparing an IL-1 trap. Preferably the IL-1 trap is substantially free of protein contaminants at the time it is used to prepare the formulation acceptable for pharmaceutical use. By the term "substantially free of protein contaminants" is meant, preferably, at least 90 percent by weight of the protein of an IL-1 trap preparation, used to form a formulation comprising a trap of IL-1, is an IL-1 trap protein; more preferable, at least 95 percent and, what is most preferred, at least 99 percent. The IL-1 trap is preferably substantially free of aggregates. "Substantially free of aggregates" means that at least 90% of the weight of the IL-1 trap protein is not present in an aggregate at the time the IL-1 trap is used to prepare the effective formulation for use. pharmacist. The IL-1 trap of the methods and the formulations of the present invention may contain low or oligomeric amounts of compounds, as a result of the purification process; for example, low or oligomeric amounts of citrate and / or polysorbate. In one embodiment of the pre-lyophilization formulation of the invention containing about 40 mg of IL-1 / mL trap, citrate may be present at a concentration of approximately 0.1 mM and / or the polysorbate may be present at a concentration Approximately 0.004 percent. If the pre-lyophilization formulation is reconstituted, after having lyophilized it to half the original volume (for example, 80 mg / mL of the IL-1 trap), the resulting concentrations can be: 0.2 mM citrate and / or 0.008 percent polysorbate. If the pre-lyophilization formulation is reconstituted, after lyophilization to one third of the original volume (for example, 120 mg / mL of the IL-1 trap), the resulting concentrations may be 0.6 mM citrate and / or 0.012 percent polysorbate. Lyophilization and lyophilized formulations In one aspect of the invention a pharmaceutically acceptable formulation comprising an IL-1 trap is provided; wherein the formulation is a freeze dried or lyophilized formulation. Preferably, the freeze-dried or lyophilized formulation comprises a pharmaceutically effective amount of an I L-1 trap. The lyophilized formulations can be reconstituted to solutions, suspensions, emulsions or any other form suitable for administration or use. The lyophilized formulations are first prepared, typically, as liquids; Then they are frozen and lyophilized. The total volume of liquid before lyophilization can be less than, equal to or greater than the final reconstituted volume of the lyophilized formulation. The lyophilization process is well known to those of ordinary skill in the art, and typically includes the sublimation of water from a frozen formulation, under controlled conditions. Freeze-dried formulations can be stored at a wide range of temperatures. Freeze-dried formulations can be stored at 30 ° C or less; for example, they can be refrigerated at 4 ° C or stored at room temperature (for example, at approximately 25 ° C). Preferably, the lyophilized formulations are stored at less than about 25 ° C, more preferably at about 4 to 20 ° C; at less than about 4 ° C, at less than about -20 ° C, at about -40 ° C or at about -70 ° C. Lyophilized formulations are typically reconstituted for use, by the addition of an aqueous solution to dissolve the lyophilized formulation. A wide variety of aqueous solutions can be used to reconstitute a lyophilized formulation. Preferably, the lyophilized formulations are reconstituted using ag ua. Preferably, lyophilized formulations are reconstituted with a solution consisting essentially of water (eg, WFI or water for USP injection) or bacteriostatic agent (eg, WF I USP with 0.9 percent benzyl alcohol). However, solutions can also be used which comprise regu lators and / or excipients and / or u or more acceptable carriers for pharmaceutical use. Freeze-dried or lyophilized formulations are typically prepared from liquids, ie, solutions, suspensions, emulsions and the like. Thus, the liquid which is to be subjected to freeze drying or lyophilization, preferably comprises all the desired components in a final reconstituted liquid formulation. As a result, when reconstituted, the freeze-dried or lyophilized formulation will produce a desired liquid formulation upon reconstitution. A preferred liquid formulation used to generate a freeze-dried or freeze-dried formulation comprises an I L-1 trap in a pharmaceutically effective amount, a regulator, a stabilizer and a bulking agent. Freeze dried or lyophilized formulations preferably comprise histidine, since hystidine, in comparison with phosphate, is more effective in stabilizing the IL-1 trap when freeze-drying the IL-1 trap. Organic cosolvents, such as PEG 3350, are used to stabilize the IL-1 trap when it is stirred, mixed or handled. Preferably, a lyoprotectant is used in the freeze-dried or lyophilized formulations. The lyoprotectants help maintain the secondary structure of the proteins when they are freeze-dried or freeze-dried. Three preferred examples of lyoprotectants are: glycine, arginine and sucrose, which are preferably used together. Stable liquid formulations In one aspect, the invention provides a stable formulation, acceptable for pharmaceutical use, comprising an IL-1 trap, wherein the formulation is a liquid formulation. Preferably the liquid formulation comprises a pharmaceutically effective amount of an IL-1 trap. The formulation may also comprise one or more acceptable carriers for pharmaceutical use, regulators, volume imparting agents, stabilizers, preservatives and / or excipients. An example of a pharmaceutically acceptable liquid formulation comprising an IL-1 trap comprises an IL-1 trap in a pharmaceutically effective amount, a regulator, a cosolvent and one or more stabilizers. A preferred liquid formulation comprises phosphate buffer, an organic cosolvent and one or more thermal stabilizers to minimize the formation of aggregates and low molecular weight products when stored, and about 12.5 mg / mL to about 50 mg / mL of a trap. IL-1; where the formulation has a pH of approximately 6.0 to 6.75. A more preferred liquid formulation comprises 10 mM of phosphate buffer, 3 percent of PEG, 50 mM of NaCl, 5 to 20 percent of sucrose and 10 to 100 mg / mL of trap of IL-1; where the formulation is at a pH of about 6.0 to 6.5. Although NaCl or sucrose can be used as a stabilizer, it has been determined that a combination of NaCl and sucrose more effectively stabilizes the IL-1 trap than any of those individual stabilizers. Preferably, PEG is PEG 3350, which has been determined to increase the stability of the IL-1 trap. Table 1 shows the natural IL-1 trap percentage or the IL-1 trap percentage added in samples containing 5 percent or 20 percent sucrose, when determined over a period of up to 24 months, when incubate at 5 ° C. In the presence of 20 percent sucrose, the natural (non-aggregated) form of the IL-1 trap fell from 92.6 percent on day zero, to 88.9 percent in 24 months; and the aggregate percentage increased from 2.3 percent to 3.4 percent during the same period of time. The 5% sucrose formulation had a natural (unadreated) form of IL-1 trap that decreased from 92.4 percent on day zero to 86.9 percent at 24 months, and the percentage of aggregate was increased by 2.6 percent to 3.6 percent during the same period of time.

Table 1 Table 2 shows the percent natural IL-1 trap in samples containing 0.5 or 20 percent sucrose, when determined over a period of up to 2.9 months, when incubated at 5 ° C (50 mg / mL trap) of IL-1, 10 mM phosphate, 0.2 percent polysorbate 20, 50 or 135 (with zero percent sucrose), mM NaCl, pH 6.5 In the presence of zero percent sucrose the natural form (no aggregates ) of the IL-1 trap fell from 96.4 percent on zero day to 0.5 percent at 2.9 months The formulation with 5 percent sucrose had a natural (no aggregate) form of the IL-1 trap that fell from 96.5 percent on zero day to 39.2 percent at 2.9 months The formulation with 20 percent sucrose had a natural form (without aggregates) of the IL-1 trap that fell from 96.4 percent on day zero to 95.3 percent at 2.9 months.

Table 2 The formulations, either liquid or freeze-dried and freeze-dried, can be stored in an environment devoid of oxygen. Oxygen-free environments can be generated by storing the formulations under an inert gas, such as, for example, argon, nitrogen or helium. The stability of the pre-lyophilized and lyophilized formulations was determined. A pre-lyophilized formulation containing 40 mg / mL trap of IL-1 (SEQ ID NO: 10), 20 mM histidine, 1.5 percent PEG-3350 was incubated at 5 ° C for 0 to 52 weeks. , 1 percent sucrose, 0.5 percent glycine, 25 mM arginine hydrochloride, pH 6.5. As shown in Table 3, the natural form (without aggregates) of IL-1 decreased from 94.9 (zero weeks) to 92.3 (52 weeks, and the percentage of aggregates increased from 1 percent to 1.8 percent in the same period Table 3 It was incubated at 25 ° C for zero to 56 weeks, a lyophilized formulation containing 40 mg / mL of trap of IL-1 (SEQ ID NO: 10), 20 mM of histidine, 1.5 percent of PEG-3350, 1% of sucrose, 0.5 percent glycine, 25 mM arginine hydrochloride, pH 6.5 (concentrations before lyophilization), to determine its stability. As shown in Table 4, the natural form (without aggregate) of IL-1 decreased from 97.0 (zero weeks) to 94.0 (56 weeks), and the percentage of aggregate increased from 0.8 percent to 3.6 percent in the same period. Table 4 Although the preceding invention has been described in some detail, by way of illustration and examples, it will be apparent to those of ordinary skill in the art that certain changes and modifications can be made to the teachings of the invention, without departing from it. of the spirit or scope of the claims that come to continuation.

Claims (11)

1. A formulation suitable for lyophilization comprising 5 to 100 mM histidine, 0.5 to 3.0 percent PEG, 0.25 to 3 percent glycine, 5 to 50 mM arginine, 0.5 to 30 percent sucrose and from 5 to 50 mg / mL of an IL-1 protein antagonist.

2. The formulation according to claim 1, wherein the IL-1 antagonist is a dimer of a fusion protein selected from SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 and 26; preferably SEQ ID NO: 10.

The formulation according to claim 1 or 2, comprising about 20 mM histidine, about 1.5 percent PEG 3350, about 0.5 percent glycine, about 25 mM arginine, approximately 1.0 percent sucrose and approximately 40 mg / mL IL-1 antagonist.

The formulation according to any of the preceding claims, which does not contain a phosphate buffer, more than about 1.5 percent sucrose, more than about 0.15 mM citrate and more than about 0.005 percent Polysorbate 20.

5. The formulation according to any of the preceding claims, wherein the pH can be from 6 to 6.75, preferably from 6 to 6.5, more preferably, 6.5.

6. A method for producing a lyophilized formulation of an IL-1 antagonist, comprising: reconstituting the claimed formulation of any of the preceding claims, to generate a lyophilized formulation of IL-1 antagonist.

The method according to claim 6, wherein the reconstituted formulation comprises approximately 20 to 120 mg / mL of the IL-1 antagonist.

8. A stable liquid formulation comprising an IL-1 protein antagonist capable of binding IL-1 and inhibiting its biological action; a regulator an organic cosolvent or a bulking agent, and one or more thermal stabilizers; wherein the IL-1 antagonist is a dimer comprising two fusion proteins shown in SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26.

9. The liquid formulation according to claim 8, wherein the fusion protein comprises SEQ ID NO:

10. The liquid formulation according to claim 8 or 9, comprising: from 5 to 100 mM of phosphate buffer, of 10 mM phosphate buffer preference; from 0.5 to 3 percent of PEG 3350, preferably 3 percent of PEG 3350; 25 to 150 mM NaCl, preferably 50 mM NaCl; from 5 to 30 percent sucrose, preferably from 5 to 20 percent sucrose; and from 10 to 100 mg / mL of the IL-1 antagonist.

11. The liquid formulation according to any of claims 8 to 10, wherein the IL-1 antagonist exhibits less than 4 percent aggregate formation, by visual inspection, after storing a 50 mg / mL formulation. of IL-1 trap for 29 months at 5 ° C.