WO2014130811A1

WO2014130811A1 - Interferon beta formulation

Info

Publication number: WO2014130811A1
Application number: PCT/US2014/017689
Authority: WO
Inventors: Mark Brader
Original assignee: Biogen Idec Ma Inc
Priority date: 2013-02-22
Filing date: 2014-02-21
Publication date: 2014-08-28

Abstract

Stable preserved compositions of interferon-beta and pegylated-interferon-beta are described. Stability data for these compositions demonstrate good stability for long term storage at 5 degrees C, and in-use stability (room temperature).

Description

INTERFERON BETA FORMULATION

TECHNICAL FIELD

[01] This description relates to stable preserved compositions of interferon-β and pegylated- interferon-β.

BACKGROUND

[02] Multiple sclerosis (MS) is one of the most common diseases of the cenal nervous system and affects over 2.5 million people worldwide. Treatment of multiple sclerosis include the administration of interferon-beta to a patient. For example, interferon-beta- 1 a is marketed in the United States under the trade names of AVONEX™ (Biogen Idee MA Inc.) and REBIF™ (EMD Serono) and interferon-beta- lb is marketed in the United States as BETASERON™ (Berlex) and EXTAVIA™ (Novartis).

[03] A pegylated form of interferon-beta- 1 a exists, in which the a-amino group of the N- terminal amino acid residue has been modified with a single, linear molecule of 20,000 Da methoxypoly(ethyleneglycol)-0-2-methylpropionaldehyde (20 kDa mPEG-O-2- methylpropionaldehyde) as illustrated in Figure 1 and described in Baker et al. Bioconjugate Chem. (2006) 17, 179-188. Pegylated interferon-beta- 1 a has been developed to provide improved pharmacokinetic properties relative to interferon-beta- 1 a therapy and offers potential to allow once monthly or biweekly dosing.

[04] The interferon-beta- 1 a sequence (Figure 2) has not been modified to enable the coupling reaction to 20 kDa mPEG-O-2-methylpropionaldehyde. Human interferon-beta is a 166 amino acid glycoprotein with a predicted molecular weight of approximately 22,500 Da. AVONEX^® is an interferon-beta- la therapeutic approved for the treatment of multiple sclerosis produced by recombinant DNA technology expressed in Chinese hamster ovary cells. The amino acid sequence of AVONEX^® is given in Figure 2 and is identical to that of natural human interferon beta.

[05] Single use drug formulations of interferon do not contain a preservative. Additionally, if the sterility of the single use drug product is compromised, the drug must be used within 24 hours or else there may be significant patient safety issues with contamination from microbial growth. Current multi-use drug formulations contain benzyl alcohol which can act as a preservative and allows a series of doses to be administered from a single container. When used over long periods of time, proteins are generally physically or chemically unstable in the presence of pharmaceutical preservatives. For mterferon-beta, the primary problems are degradation, aggregation and deamidation.

SUMMARY

[06] The composition described herein confers good stability to interferon-beta, for example, interferon-beta- 1 a, interferon-beta- 1 b, pegylated interferon-beta- 1 a or pegylated interferon-beta- lb.

[07] The inventors have surprisingly found that particular combinations of components in an interferon-beta formulation lead to enhanced stability and robustness. In one embodiment, an aqueous pharmaceutical composition that includes interferon beta at a concentration of about 0.10 mg/ml to about 0.25 mg/ml, 125-175 niM L-arginine-HCl, about 0.002-0.005%, Polysorbate 20, and a pH of 4.4-5.2 is described. The interferon beta can be interferon beta-la or pegylated interferon beta- l a or interferon beta- lb. The interferon beta can be at a concentration of 0.1 mg/ml or at a concentration of 0.2 mg/ml. The salt can be sodium acetate. The pH of the composition can be about 4.5 to about 6.0. The pH of the composition can be about 4.4, 4.8 or 5.2. The composition can be stable and robust as measured by high molecule weight impurity (HMWI), purity by reverse-phase high pressure liquid chromatography (RP-HPLC), oxidation, particle count, desialylation, dcPEGylation and biological activity. The composition can be stable and robust under thermal stress, freeze-thaw and agitation. The composition can be stable and robust in siliconized and unsiliconized fixed needle pre-filled syringe (PFS) or Luer-Lok syringe. In other embodiments, the composition can be stable for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 12 months or 24 months when stored at about 2 to 40° C, and specifically at 5° C, at 25° C, or at 40° C.

[08] The composition can be formulated as a multi-use pharmaceutical formulation.

[09] Other features will become apparent from the following detailed description, taken in conjunction with the accompanying drawings, which illustrate by way of example, the features of the various embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

[010] FIG. 1 is an illustration of the pegylated interferon-beta- 1 a structure.

[011] FIG. 2 is the interferon-beta- 1 a amino acid sequence. [012] FIG. 3 is a table showing stability results for pegylated interferon compositions after 2 weeks at 40°C.

[013] FIG. 4 is a table showing stability results for pegylated interferon compositions after 12 weeks at 25°C.

[014] FIG. 5 is a table showing stability results for pegylated interferon compositions after 4 weeks at 40°C.

[015] FIG. 6 is a table showing stability results for pegylated interferon compositions after 24 months at 5°C.

DETAILED DESCRIPTION

[016] Stable preserved compositions of interferon-beta that contain the combination of L- arginine HCl and polysorbate 20 that can be used in a single dose or multi-dose formulation are described. The term "robust" means that critical quality attributes (CQAs) remain within their accepted criteria until the end of the shelf-life and in-use period of the formulation.

[017] The term "interferon" or "IFN" as used herein means the family of highly homologous species-specific proteins that inhibit viral replication and cellular proliferation and modulate immune response. Human interferons are grouped into two classes; Type I, including alpha and beta-interferon, and Type II, which is represented by gamma-interferon only. Recombinant forms of each group have been developed and are commercially available. Subtypes in each group are based on antigenic/structural characteristics. An example of interferon used herein is a glycosylated, human, interferon-beta that is glycosylated at residue 80 (Asn 80) and that is derived via recombinant DNA technologies.

[018] This glycosylated interferon-beta is also known as "interferon-beta- 1 a" or "IFN-beta-la" or "interferon beta la," all used interchangeably. The term "interferon-beta- 1 a" is also meant to encompass mutants thereof, provided that such mutants are also glycosylated at residue 80 (Asn 80). Recombinant DNA methods for producing proteins, including interferons are known. See for example, U.S. Pat. Nos. 4,399,216, 5,149,636, and 5,179,017 (Axel et al) and U.S. Pat. No. 4,470,461 (Kaufman). These patents, as well as WO 98/28007 and U.S. Patent Application Publication No. 2012/0269770, are incorporated by reference herein in their entireties.

[019] Mutants of interferon-beta- 1 a may be used. Mutations are developed using conventional methods of directed mutagenesis, known to those of ordinary skill in the art and can include

. functionally equivalent interferon-beta- 1 a polynucleotides that encode for functionally equivalent interferon-beta- 1 a polypeptides.

[020] The construction of recombinant DNA plasmids containing sequences encoding at least part of human fibroblast interferon and the expression of a polypeptide having immunological or biological activity of human fibroblast interferon is also contemplated. The construction of hybrid beta-interferon genes containing combinations of different subtype sequences can be accomplished by techniques known to those of skill in the art.

[021] Typical suitable recombinant interferon-betas which may be used in the compositions described herein include but are not limited to interferon beta- la such as AVONEX™ (Biogen Idee MA Inc.) and REBIF™ (EMD Serono) and interferon-beta- 1 b, marketed in the United States as BETASERON™ (Berlex) and EXTAVIA™ (Novartis).

[022] The interferon-beta protein may be conjugated to polyalkylene glycol residues of CI -C4 alkyl polyalkylene glycols, preferably polyethylene glycol (PEG), or poly(oxy)alkylene glycol residues of such glycols. Thus, the polymer to which the protein is attached can be a

homopolymer of polyethylene glycol (PEG) or is a polyoxyethylated polyol, provided in all cases that the polymer is soluble in water at room temperature. Non-limiting examples of such polymers include polyalkylene oxide homopolymers such as PEG or polypropylene glycols, or polyoxyethylenated glycols, copolymers thereof or block copolymers thereof, provided that the water solubility of the block copolymer is maintained. Examples of polyoxyethylated polyols include, for example, polyoxyethylated glycerol, polyoxyethylated sorbitol, polyoxyethyl ated glucose, or the like. The glycerol backbone of polyoxyethylated glycerol is the same backbone occurring naturally in, for example, animals or humans in mono-, di-, or triglycerides. Therefore, this branching would not necessarily be seen as a foreign agent in the body.

[023] As an alternative to polyalkylene oxides, dextran, polyvinyl pyrrolidones,

polyacrylamides, polyvinyl alcohols, carbohydrate-based polymers or the like may be used. Those of ordinary skill in the art will recognize that the foregoing list is merely illustrative and that all polymer materials having the qualities described herein are contemplated. The polymer need not have any particular molecular weight, but it is preferred that the molecular weight be between about 300 and 100,000, more preferably between 10,000 and 40,000. In particular, sizes of 20,000 or more are best at preventing protein loss due to filtration in the kidneys.

[024] Polyalkylene glycol derivatization has a number of advantageous properties in the formulation of polymer-interferon-beta la conjugates, as associated with the following properties of polyalkylene glycol derivatives: improvement of aqueous solubility, while at the same time eliciting no antigenic or immunogenic response; high degrees of biocompatibility; absence of in vivo biodegradation of the polyalkylene glycol derivatives; and ease of excretion by living organisms. Conjugation of interferon-beta to PEG is further described in U.S. Pat. No. 7,446,173 and U.S. Application Publication No. 20050107277, both of which are herein incorporated by reference in their entireties.

[025] The compositions described herein can be formulated as aqueous pharmaceutical compositions. In the alternative, the interferon-beta described herein can be formulated in lypholized form and can include a diluent. A stable composition of interferon-beta exhibits little or no signs of any one or more of aggregation, fragmentation, deamidation, oxidation, or change in biological activity over an extended period of time, e.g., 12 months, 24 months, 36 months or longer. For example, in one embodiment, less than 10% of the composition is aggregated, fragmented, or oxidated. Aggregation, precipitation, and/or denaturation can be assessed by known methods, such as visual examination of color and/or clarity, or by UV light scattering or size exclusion chromatography. HPLC or reversed phase HPLC (RP-HPLC) or variants of HPLC may be used to measure the quantity of covalently intact and soluble protein in a composition. Loss of protein represents degradation due to instability. Other known methods that can be used are as described in Manning et al., Pharmaceutical Research, Vol. 27, No. 4, April 2010, herein incorporated by reference, may also be used to measure protein formulation stability.

[026] The ability of the protein to retain its biological activity can be assessed by detecting and quantifying chemically altered forms of the protein. Size modification (e.g., clipping), which can be evaluated using size exclusion chromatography, SDS-PAGE and/or matrix-assisted laser desorption ionization/time-of-flight mass spectrometry (MALDI/TOF MS), or peptide mapping of endoproteinase-treated protein, for example. Other types of chemical alteration include charge alteration (e.g., occurring as a result of deamidation), which can be evaluated by ion-exchange chromatography, for example. A protein retains its biological activity in a pharmaceutical formulation, if the biological activity of the protein at a given time is within about 10% of the biological activity exhibited at the time the pharmaceutical formulation was prepared as determined in an assay.

[027] Interferon-beta or interferon-beta- 1 a, for example, can be provided in a buffered solution at a concentration of about 0.1 mg/ml to about 0.9 mg/ml, of about 0.1 mg/ml to about 0.5 mg/ml, of about 0.1 mg ml to about 0.3 mg/ml or of about 0.1 mg/ml to about 0.2 mg/ml. Interferon- beta- la can be provided in a buffered solution at a concentration of 0.25 mg/ml. The composition can be stored at 2-25° C, at 5° C, at 10° C, at 15° C, at 20° C. or at 25° C. The composition can be stable at room temperature for 1, 2, 3, 4, or 5 days or more. Room temperature can be about 18° C, 19° C, 20° C, 21° C, 22° C, 23° C, 24° C. or 25° C). The composition can be stored at a first low temperature, for example, less than 18° C. or from about freezing but at or below 15° C, 10° C. or 4° C. and can be stored at second higher temperature, for example, without refrigeration or at room temperature, for about 1-5 days. In other embodiments, the interferon-beta which is formulated as described below can be stable for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months or 12 months or more when stored at 2-40° C, at 5° C, at 10° C, at 15° C, at 20° C. at 25° C. or when stressed at 40° C.

[028] In one embodiment, interferon-beta- 1 a can be formulated with L -arginine HCl, polysorbate, and a salt. Polysorbate is used when the composition is anticipated to be subject to agitation, and can be omitted if that is not the case. In addition, other polysorbates, such as Polysorbate 80, can be substituted for Polysorbate 20.

[029] In another embodiment, lyophilized interferon-beta- la can be formulated at a pH of about 4 to about 7, about 4.2-6.0, about 4.4-5.2, and about 5.1-5.2. In particular embodiments, the pH can be 4.4, 4.8 or 5.2.

[030] The composition can include arginine, including L-arginine and salts thereof, including L-arginine HCl. The arginine can be included at 100-200 mM. L-arginine HCl can be included at about 100 mM, about 125 mM, about 150 mM, about 175 mM and about 200 mM.

[031] The composition can include a pharmaceutically acceptable salt which refers to a salt that retains the desired biological activity of the antibody and does not impart any undesired toxicological effects (see e.g., Berge, S. M., et al. (1977) J. Pharm. Sci. 66:1-19). Examples of such salts include acid addition salts and base addition salts. Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, or the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids, free amino acids, or the like. Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium or the like, as well as from nontoxic organic amines, such as Ν,Ν'- dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine or the like. [032] The composition can include a salt, such as sodium acetate or sodium chloride at a concentration of about 10 mM to about 200 mM. The composition can contain sodium acetate at a concentration of 20 mM, 30 mM, 40 mM, 50 mM, 100 mM, 125 mM, 150 mM or 175 mM.

[033] In another embodiment, the composition can contain a pharmaceutically acceptable excipient, such as a surfactant, such as polysorbate 20, in an amount of about 0.0005% to about 2.0%, about 0.001% to about 0.4%, about 0.002 to about 0.005% (w/v) (e.g., about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005). Other excipients that can be used can include polyoxyethylene derivatives, Tween, Pluronic, glycerin monostearate, polyoxyl stearate, lauromacrogol, or sorbitan oleate. The pH of the composition can be about 5.0±0.5, or about 4.0±0.5. The pH of the composition can be about pH 4.4 to about 5.2. The pH of the composition can be 4.4. The pH of the composition can be 4.8. The pH of the composition can be 5.2.

[034] Pharmaceutical compositions are sterile and stable under the conditions of manufacture and storage. A pharmaceutical composition can also be tested to insure it meets regulatory and industry standards for administration.

[035] Interferon can be used in methods of immunomodulation . Exemplary conditions which can be treated with interferon include, but are not limited to, cell proliferation disorders, in particular multiple sclerosis, cancer (e.g., hairy cell leukaemia, Kaposi's sarcoma, chronic myelogenous leukaemia, multiple myeloma, basal cell carcinoma and malignant melanoma, ovarian cancer, cutaneous T cell lymphoma), or viral infections. Without limitation, treatment with interferon may be used to treat conditions which would benefit from inhibiting the replication of interferon-sensiti ve viruses. For example, interferon can be used alone or in combination with AZT in the treatment of human immunodeficiency virus (HIV)/AIDS or in combination with ribavirin in the treatment of HCV. Viral infections which may be treated in accordance with the invention include, but are not limited to, hepatitis A, hepatitis B, hepatitis C, other non-A/non-B hepatitis, herpes virus, Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex, human herpes virus type 6 (HHV-6), papilloma, poxvirus, picornavirus, adenovirus, rhinovirus, human T lymphotropic virus-type 1 and 2 (HTLV-1/-2), human rotavirus, rabies, retroviruses including HIV, encephalitis, or respiratory viral infections.

[036] The IFN-beta or pegylated IFN-beta is administered in a pharmacologically-effective amount to treat any of the conditions described above. The term "pharmacologically-effective amount" means the amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician. It is an amount that is sufficient to significantly affect a positive clinical response while maintaining diminished levels of side effects. The amount of IFN-beta which may be

administered to a subject in need thereof is in the range of 0.01-100 μg/kg, or more preferably 0.01-10 μg/kg, administered in single or divided doses. Administration of the described dosages may be every other day, but preferably occurs once a week or once every other week. Doses are administered over at least a 24 week period by injection. The dosage regimen utilizing the composition described herein is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; or the particular compound or salt thereof employed. The activity of the interferon-beta and sensitivity of the patient to side effects are also considered. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

[037] In yet another embodiment, the composition is suitable for subcutaneous or

intramuscular administration. In even another embodiment, the composition is suitable for IV administration. The compositions described herein can be administered by a parenteral mode (e.g., subcutaneous, intraperitoneal, or intramuscular injection). The phrases "parenteral administration" and "administered parenterally" as used herein mean modes of administration other than enteral and topical administration, usually by injection, and include, subcutaneous or intramuscular administration, as well as intravenous, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcuticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection or infusion. Administration of the dose can be intravenous, subcutaneous, intramuscular, or any other acceptable systemic method. Based on the judgment of the attending clinician, the amount of drug administered and the treatment regimen used will, of course, be dependent on the age, sex and medical history of the patient being treated, the neutrophil count (e.g., the severity of the neutropenia), the severity of the specific disease condition and the tolerance of the patient to the treatment as evidenced by local toxicity or by systemic side-effects.

[038] Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. For example, when a subcutaneous injection is used to deliver 0.01-100 μg/kg, or more preferably 0.01 -10 μg/kg of PEGylated IFN-beta over one week, two injections of 0.005-50 ^§, or more preferably 0.005-5 μg/kg, respectively, may be administered at 0 and 72 hours. Additionally, one approach for parenteral administration employs the implantation of a slow-release or sustained-released system, which assures that a constant level of dosage is maintained, according to U.S. Pat. No. 3,710,795, incorporated herein by reference in its entirety.

[039] Lyophilized compositions for injections can, for example, be prepared by dissolving, dispersing, etc. The active compound is dissolved in or mixed with a pharmaceutically-pure solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, or the like, to form the injectable solution or suspension. Additionally, solid/lyophilized forms suitable for dissolving in liquid prior to injection can be formulated. Injectable compositions are preferably aqueous isotonic solutions or suspensions. The compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutical ly- valuabl e substances.

[040] Pharmaceutical compositions can be administered with medical devices. For example, pharmaceutical compositions can be administered with a needleless hypodermic injection device, such as the devices disclosed in U.S. Pat. Nos. 5,399,163, 5,383,851, 5,312,335, 5,064,413, 4,941 ,880, 4,790,824, or 4,596,556. Examples of well-known implants and modules include: U.S. Pat. No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Pat. No. 4,486,194, which discloses a therapeutic device for administering medicants through the skin; U.S. Pat. No. 4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; U.S. Pat. No. 4,447,224, which discloses a variable flow implantable infusion apparatus for continuous drug delivery; U.S. Pat. No. 4,439,196, which discloses an osmotic drug delivery system having multi-chamber compartments; and U.S. Pat. No. 4,475,1 6, which discloses an osmotic drug delivery system. The therapeutic composition can also be in the form of a biodegradable or nonbiodegradable sustained release formulation for subcutaneous or intramuscular administration. See, e.g., U.S. Pat. Nos. 3,773,919 and 4,767,628 and PCT Application No. WO 94/15587. Continuous

administration can also be achieved using an implantable or external pump. The administration can also be conducted intermittently, e.g., single daily injection, or continuously at a low dose, e.g., sustained release formulation. The delivery device can be modified to be optimally suited for administration of interferon-beta. For example, a syringe can be siliconized to an extent that is optimal for storage and delivery of interferon-beta. Of course, many other such implants, delivery systems, and modules are also known.

EXAMPLES

[041] The objective of this study was to evaluate stability of interferon-beta- 1 a drug product formulations directly in a prefilled syringe container closure. In this study stability indicating analytical attributes of purity by reverse phase HPLC, aggregation by size exclusion HPLC, oxidation by peptide map and desialylation by carbohydrate analysis are evaluated.

[042] This design studies four formulation composition factors (pH, protein concentration, polysorbate 20 concentration and L-arginine.HCl concentration) each varied over three levels. The design comprises ten different formulation compositions with a center point triplicate to give a total of 12 samples all in fixed needle syringes. Results are provided in Figures 3-6, as well as in U.S. Provisional Application Serial No. 61/768,087, filed on February 22, 2013, which is incorporated herein by reference in its entirely.

Claims

What is claimed is:

1. An aqueous pharmaceutical composition comprising interferon beta at a concentration of about 0.1 mg/ml to about 0.2 mg/ml, L-arginine HCl at about 125-175 mM, a salt and pH from 4.4-5.2.

2. The composition of claim 1, wherein the interferon beta is interferon beta- la.

3. The composition of claim 1 , wherein the interferon beta is pegylated interferon beta-la.

4. The composition of claim 1 , wherein the interferon beta is interferon beta- lb.

5. The composition of claim 1 , wherein the interferon beta is pegylated interferon beta- lb.

6. The composition of claim 1, wherein the interferon beta is at a concentration of about 0.1 mg/ml.

7. The composition of claim 1 , wherein the interferon beta is at a concentration of about 0.2 mg/ml.

8. The composition of claim 1 , wherein the L-arginine HCl is at a concentration of about 125 mM.

9. The composition of claim 1, wherein the L-arginine HCl is at a concentration of about 150 mM.

10. The composition of claim 1 , wherein the L-arginine HCl is at a concentration of about 175 mM. . The composition of claim 1, wherein the salt is sodium acetate.

12. The composition of claim 1, further comprising polysorbate.

13. The composition of claim 12, wherein the polysorbate is Polysorbate 20 or Polysorbate 80.

14. The composition of claim 12, wherein the polysorbate 20 at about 0.002 to 0.005%.

15. The composition of claim 14, wherein the polysorbate 20 is at about 0.002%.

16. The composition of claim 14, wherein the polysorbate 20 is at about 0.005%.

17. The composition of claim 1, wherein the pH is about 4.4.

18. The composition of claim 1 , wherein the pH is about 4.8.

19. The composition of claim 1, wherein the pH is about 5.2.

20. The composition of claim 1, wherein the interferon beta is at a concentration of about 0.1 mg/ml, the L-arginine HCl is at a concentration of about 125 mM, the polysorbate 20 is at a concentration of about 0.002%, and the pH is about 4.4.

21. The composition of claim 1 , wherein the interferon beta is at a concentration of about 0.1 mg/ml, the L-arginine HCl is at a concentration of about 150 mM, the polysorbate 20 is at a concentration of about 0.005%, and the pH is about 5.2.

22. The composition of claim 1, wherein the interferon beta is at a concentration of about 0.2 mg/ml, the L-arginine HCl is at a concentration of about 175 mM, the polysorbate 20 is at a concentration of about 0.002%, and the pH is about 5.2.

23. The composition of claim 1 , wherein the interferon beta is at a concentration of about 0.1 mg/m, the L-arginine HCl is at a concentration of about 150 mM, the polysorbate 20 is at a concentration of about 0.005%, and the pH is about 4.8.

24. The composition of claim 1 , wherein the composition is stable after freeze-thaw cycling.

25. The composition of claim 1, wherein the composition is stable after agitation stress.

26. The composition of claim 1 , wherein the composition is stable at room temperature.

27. The composition of claim 1 , wherein the composition is contained in a pre-filled syringe.

28. The composition of claim 1, wherein the composition is contained in a Luer-Lok syringe.

29. The composition of claim 1, wherein the composition is formulated as a multi-use pharmaceutical formulation.