WO2024257040A1

WO2024257040A1 - Composition and stable liquid formulations comprising humanized anti-human interleukin 6 (il-6) receptor monoclonal antibodies

Info

Publication number: WO2024257040A1
Application number: PCT/IB2024/055846
Authority: WO
Inventors: Nildip CHAUHAN; Abijar BHORI; Kinnari DAVE; Himanshu Gadgil
Original assignee: Enzene Biosciences Ltd
Current assignee: Enzene Biosciences Ltd
Priority date: 2023-06-14
Filing date: 2024-06-14
Publication date: 2024-12-19
Anticipated expiration: 2025-12-14

Abstract

The present invention provides a composition comprising of unique combination of the anti- human interleukin 6 (IL-6) receptor monoclonal antibodies with buffer, viscosity reducing agent, stabilizer / isotonic agent and surfactants, which is stable, has isotonicity pH 6.0 and viscosity range suitable for subcutaneous administration to a subject without inflicting pain which is usually observed with high viscosity antibody formulation during administration.

Description

COMPOSITION AND STABLE LIQUID FORMULATIONS COMPRISING HUMANIZED ANTI- HUMAN INTERLEUKIN 6 (IL-6) RECEPTOR MONOCLONAL ANTIBODIES

FIELD OF INVENTION

[0001] The present disclosure relates to a pharmaceutical compositions comprising a humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody. In particular the present disclosure relates to a composition comprising a humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody, succinate buffer, and combination of amino acid and salt; and stable, isotonic formulations thereof.

BACKGROUND OF THE INVENTION

[0002] Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

[0003] Interleukin-6 (IL-6) is an essential cytokine in particular involved in the regulation of immune cell proliferation and differentiation. IL-6 is strongly overproduced during inflammatory processes, and this overproduction is observed in many diseases such as infections, acute or chronic inflammatory diseases, and cancer.

[0004] IL-6 thus appears to be the driving signal in several inflammatory diseases. Preclinical studies in animal models of human diseases have shown that blocking IL-6 activity alleviates symptoms or even completely prevents the onset of the disease.

[0005] In recent years, several classes of therapeutics targeting the components of the IL-6 signaling pathway have been developed. The efficacy of therapeutic interventions to neutralizing IL-6 or interfering with its signaling has demonstrated the major deleterious role of IL-6 in a number of diseases.

[0006] For example, IL-6R blocker tocilizumab, the first monoclonal antibody developed against the IL-6 pathway, is now approved for the treatment of moderate to severe active rheumatoid arthritis (RA) in adults.

[0007] High concentration monoclonal antibody formulations are manufactured using various technology such as ultrafiltration and diafiltration (UF/DF), lyophilization and then reconstituting monoclonal antibody powder to prepare high concentration liquid solution prior to subcutaneous injection. [0008] However, before administration, antibody formulations undergo storage and transportation during which physical and chemical degradation of the antibody occurs, and such instabilities may reduce the potency and/or increase the immunogenicity of the antibody. Thus a stable formulation to ensure that the antibody remains therapeutically active and safe until the administration is needed. While, attempts have been made in the past, none of the present approaches provide a desired solution. Such formulations suffer from severe limitations in terms of stability, high viscosity. For formulating antibodies, buffer systems comprising acetate and amino acid such as histidine is used. As antibodies are required to be formulated at relatively low pH values, at such pH for example, buffers such as acetate and histidine have certain limitations. Acetate buffer cannot be utilized for lyophilized products due to the risk of a flash-off, while histidine offers a poor buffering capacity. With respect to its physical appearance, in case of histidine buffer, change in color is observed under accelerated temperature condition and acidic pH extract iron from stainless steel vessels during manufacturing operation or storage condition. Also most of the biologies formulation contains anionic surfactant either polysorbate 20 or polysorbate 80 in the formulation to prevent aggregation during long term storage. It is known that polysorbate 20 or polysorbate 80 degradation in the presence of a histidine buffer system because of imidazole group present in to the histidine. Hence, ester hydrolysis leads to the degradation of polysorbate 20 or polysorbate 80 in a formulation containing histidine buffer. Also, Polysorbate 20 or polysorbate 80 degradation by hydrolysis results in the accumulation of free fatty acids, which can lead to particle formation and oxidation. Other challenges with the high concentration antibody injections include pain inflicted to a patient, swelling and induration risk due to the high break loose force and glide force; while administration with syringe having thin wall needle or prefdled delivery devices.

[0009] Hence, there remains an unmet and urgent need to address the above mentioned one or more shortcomings existing in the hitherto known antibody composition or formulation, especially the ones comprising humanized antihuman interleukin 6 (IL-6) receptor monoclonal antibodies.

OBJECTS OF THE INVENTION

[0010] The primary objective of the present invention is to provide a composition comprising a humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody for a stable, isotonic formulation.

[0011] Another objective of the present invention is to provide stable, isotonic, high concentration monoclonal antibody formulations which are suitable for subcutaneous injection.

[0012] Another objective of the present invention is to provide a monoclonal antibody formulation wherein the viscosity of the formulation is between 2-20 cps for betterment of injectability.

[0013] Another objective of the present invention is to provide a monoclonal antibody formulations that reduce pain during subcutaneous administration.

SUMMARY

[0014] The technical problem to be solved by the present invention is to provide a composition comprising a humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody for a stable, isotonic formulation that can be delivered with delivery device such as prefdled syringe having safety needle guard or two step auto injectors. The present invention is directed to provide a high concentration monoclonal antibody formulation that is stable, isotonic, and suitable for subcutaneous injection with a desirable low break loose force and glide force for easy flow during administration from the syringe that reduce pain, swelling and induration risk.

[0015] According to an aspect of the present disclosure, a composition comprising a humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody is provided. The composition comprises: a. a monoclonal antibody; b. a buffer system; c. a viscosity reducing agent; d. a stabilizer; and e. pharmaceutically acceptable excipients.

[0016] According to one aspect of the present disclosure, a composition comprising a. a humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody; b. a succinate buffer; c. a viscosity reducing agent comprising an amino acid; d. a solution of sodium chloride; and e. pharmaceutically acceptable excipients.

[0017] In another aspect, the present disclosure provides a stable, isotonic, high concentration monoclonal antibody formulations comprising a. a monoclonal antibody; b. a buffer system; c. a viscosity reducing agent; d. a stabilizer; and e. pharmaceutically acceptable excipients.

[0018] In one aspect, the present disclosure provides a stable, isotonic, high concentration monoclonal antibody formulations comprising a. a humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody; b. a succinate buffer; c. a viscosity reducing agent comprising an amino acid; d. a solution of sodium chloride; and e. pharmaceutically acceptable excipients.

[0019] Various objects, features, aspects and advantages of the present disclosure will become more apparent from the following detailed description of preferred embodiments, along with the accompanying drawing figures in which like numerals represent like features.

BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The accompanying drawings are included to provide a further understanding of the present disclosure and are incorporated in and constitute a part of this specification. The drawings illustrate exemplary embodiments of the present disclosure and, together with the description, serve to explain the principles of the present disclosure.

[0021] Figure 1 illustrates a representation flow chart of manufacturing process of the finished formulation.

[0022] Figure 2 is a graph elucidating the density of the formulation in accordance with one of the exemplary embodiment of the present disclosure and the comparative formulation of the marketed product.

[0023] Figure 3 is a graph elucidating the viscosity of the formulation in accordance with one of the exemplary embodiment of the present disclosure and the comparative formulation of the marketed product.

[0024] Figure 4 is a graph elucidating the glide force of different make syringes filled with a formulation in accordance with one of the exemplary embodiment of the present disclosure and the comparative formulation of the marketed product.

[0025] Figure 5 is a graph elucidating the Break loose force of different make syringes filled with a formulation in accordance with one of the exemplary embodiment of the present disclosure and the comparative formulation of the marketed product.

[0026] Figure 6 is a graph elucidating the functionality testing showing the Break loose force and glide force of syringe of make 2 filled with the formulation in accordance with one of the exemplary embodiment of the present disclosure.

[0027] Figure 7 is a graph elucidating the functionality testing showing the Break loose force and glide force of syringe of make 2 filled with the comparative formulation of the marketed product.

DETAILED DESCRIPTION OF THE INVENTION

[0028] The following is a detailed description of embodiments of the disclosure. The embodiments are in such detail as to clearly communicate the disclosure.

[0029] However, the amount of detail offered is not intended to limit the anticipated 30 variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.

[0030] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.

[0031] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0032] In some embodiments, numbers have been used for quantifying weights, percentages, ratios, and so forth, to describe and claim certain embodiments of the invention and are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.

[0033] The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0034] Various terms as used herein are shown below. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.

[0035] Unless the context requires otherwise, throughout the specification which follows, the word “comprise” and variations thereof, such as “comprises” and

[0036] ‘ ‘comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”

[0037] As used in the description herein and throughout the claims that follow,

[0038] 10 the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise.

[0039] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each value falling within the range.

[0040] Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.

[0041] All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0042] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. [0043] When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified.

[0044] The description that follows, and the embodiments described therein, is provided by way of illustration of an example, or examples, of particular embodiments of the principles and aspects of the present disclosure. These examples are provided for the purposes of explanation, and not of limitation, of those principles and of the disclosure.

[0045] It should also be appreciated that the present disclosure can be implemented in numerous ways, including as a system, a method, or a device. In this specification, these implementations, or any other form that the invention may take, may be referred to as processes. In general, the order of the steps of the disclosed processes may be altered within the scope of the invention.

[0046] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.

[0047] The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus, if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.

[0048] The term "or", as used herein, is generally employed in its sense including "and/or" unless the content clearly dictates otherwise.

[0049] Various terms are used herein to the extent a term used is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.

[0050] The term "formulation" refers to a composition that maintains the biological activity of the active component in an effective manner and does not contain other components that are unacceptably toxic to the subject. Such preparations are sterile.

[0051] The term "sterile" refers to the absence of live bacteria or the absence or substantial absence of all live microorganisms and their spores.

[0052] As used herein, a "stable" formulation refers to a formulation in which the active component retains substantially its physical stability and/or chemical stability, and/or biological activity after storage. Preferably, the formulation retains substantially its physical and chemical stability, as well as its biological activity after storage. [0053] The terms “patient” or “subject” are used interchangeably and refer to any mammal suffering from a condition or disease in accordance with the present invention. Preferably, human.

[0054] As used herein, “buffer” refers to a buffer solution that resists pH changes through the action of its conjugate acid-base pairs.

[0055] As used herein, “surfactant” refers to a surface active agent.

[0056] Protein "stability" can be assessed qualitatively and/or quantitatively after storage at selected temperatures for selected periods in some different ways, including assessment of aggregate formation (e.g. using size exclusion chromatography, measuring turbidity, and/or by visual inspection); assessment of charge heterogeneity using cation exchange chromatography, image capillary isoelectric focusing (icIEF) or capillary zone electrophoresis; analysis of aminoterminal or carboxy-terminal sequence; mass spectrometry; SDS-PAGE analysis to compare reduced and intact antibodies; peptide mapping (e.g., trypsin or LYS-C) analysis; assessment of biological activity or antigen-binding function of antibodies; etc.

[0057] The term "antibody" refers to an immunoglobulin molecule and refers to any form of antibody that exhibits the desired biological activity. These include, but are not limited to, monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies and multi-specific antibodies (e.g., bispecific antibodies), and even antibody fragments. Typically, the full-length antibody structure preferably contains four polypeptide chains, two heavy (H) chains, and two light (L) chains, typically interconnected by disulfide bonds. Each heavy chain contains a heavy chain variable region and a heavy chain constant region. Each light chain contains a light chain variable region and a light chain constant region. In addition to this typical full-length antibody structure, the structure also includes other derivative forms.

[0058] The term “chimeric” antibody refers to an antibody in which a portion of the heavy and/or light chain is derived from a specific source or species and the remainder is derived from a different source or species. “Humanized antibodies" are a subset of "chimeric antibodies".

[0059] The term "humanized antibody" or "humanized antigen-binding fragment" is defined herein as an antibody or antibody fragment that: (i) antibodies derived from a non-human source (e.g., a transgenic mouse carrying a heterologous immune system) and based on a human germline sequence; or (ii) chimeric antibodies in which the variable region is of non- human origin and the constant region is of human origin; or (iii) CDR grafts in which the CDR in the variable region is of non-human origin and one or more of the framework regions in the variable region is of human origin and the constant region, if any, is of human origin. The purpose of "humanization" is to eliminate the immunogenicity of nonhuman origin antibodies in humans while retaining the greatest possible affinity. It is advantageous to select the human framework region sequence that is most similar to the framework region sequence of the non-human source antibody as the template for humanization. In some cases, it may be necessary to replace one or more amino acids in the human framework region sequence with the corresponding residues in the nonhuman framework region to avoid loss of affinity.

[0060] The term "monoclonal antibody" refers to an antibody derived from a substantially homogeneous population of antibodies, i.e., every single antibody comprised in the population is identical except for possible mutations (e.g., natural mutations) that may be present in very small amounts. Thus, the term "monoclonal" indicates the nature of said antibodies, i.e., not a mixture of unrelated antibodies. In contrast to polyclonal antibody preparations, which usually include different antibodies against different antigenic determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a separate antigenic determinant. In addition to their specificity, monoclonal antibody preparations have the advantage that they are usually not contaminated with other antibodies. The term "monoclonal" should not be construed as requiring any particular method of producing said antibody. The term monoclonal antibody specifically includes chimeric antibodies, humanized antibodies, and human antibodies.

[0061] The present invention relates to a composition comprising a humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody for a stable, isotonic formulation.

[0062] In one embodiment, the present disclosure provides a composition comprising: a. a monoclonal antibody; b. a buffer system; c. a viscosity reducing agent; d. a stabilizer; and e. pharmaceutically acceptable excipients.

[0063] In one embodiment of the present disclosure provides a monoclonal antibody formulation comprising: a. a monoclonal antibody; b. a buffer system; c. a viscosity reducing agent; d. a stabilizer; and e. pharmaceutically acceptable excipients.

[0064] In some embodiments, the viscosity of the formulation is between 2-20 cps, preferably 5-12 for betterment of injectability.

[0065] In some embodiments, the monoclonal antibody is anti-IL-6 antibody.

[0066] In some embodiments, the monoclonal antibody is lyophilized antibody.

[0067] In one embodiment, the present disclosure provides a composition comprising: a. an anti-IL-6 antibody; b. a buffer system; c. a viscosity reducing agent; d. a stabilizer; and e. pharmaceutically acceptable excipients.

[0068] In one embodiment of the present disclosure provides an anti-IL-6 antibody formulation comprising: a. an anti-IL-6 antibody; b. a buffer system; c. a viscosity reducing agent; d. a stabilizer; and e. pharmaceutically acceptable excipients.

[0069] In some embodiments, the buffer is selected from one or more of succinate buffer, citric acid buffer, acetate buffer, and glycine buffer.

[0070] In some embodiments, the viscosity reducing agent is selected from one or more of amino acids or their salts thereof.

[0071] In one embodiment, the stabilizer is isotonic solution of a salt.

[0072] In one embodiment, the present disclosure provides a composition comprising: a. an anti-IL-6 antibody; b. a buffer system selected from one or more of succinate buffer, citric acid buffer, acetate buffer, and glycine buffer; c. a viscosity reducing agent selected from an amino acid or salt thereof; d. an isotonic solution of a salt; and e. pharmaceutically acceptable excipients.

[0073] In one embodiment of the present disclosure provides an anti-IL-6 antibody formulation comprising: a. an anti-IL-6 antibody; b. a buffer system selected from one or more of succinate buffer, citric acid buffer, acetate buffer, and glycine buffer; c. a viscosity reducing agent selected from an amino acid or salt thereof; d. an isotonic solution of a salt; and e. pharmaceutically acceptable excipients.

[0074] In one embodiment the salt for isotonic solution is selected from but not limiting to sodium chloride, sodium acetate or the like or the combination thereof.

[0075] In certain embodiment, the amino acid and salt is in a ratio ranging from 1 : 0.2 to 1: 12, preferably ranging from 1:0.4 to 1: 10.

[0076] In certain exemplary embodiments, the amino acid and salt can be in a ratio of 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1: 1, 1: 1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:95 or 1: 10.

[0077] In some embodiments, the stabilizer is NaCl. In some embodiments NaCl is used as the stabilizer as well as the viscosity reducing agent.

[0078] In some embodiments, the buffering system is succinate buffer.

[0079] In some embodiments, the viscosity reducing agent is selected from one or more of valine, methionine, histidine, lysine, proline or their salts thereof.

[0080] In some embodiments, the viscosity reducing agent is lysine HC1.

[0081] In some embodiments, the anti-IL-6 antibody is selected from sarilumab, olokizumab, elsilimomab, clazakizumab, sirukumab, levilimab, and gerilimzumab.

[0082] In some embodiments, the anti -IL-6 antibody is tocilizumab.

[0083] In one embodiment, the present disclosure provides a composition comprising: a. tocilizumab; b. succinate buffer; c. lysine; d. an isotonic solution of salt; and e. pharmaceutically acceptable excipients.

[0084] In one embodiment of the present disclosure provides a monoclonal antibody formulation comprising: a. tocilizumab; b. succinate buffer; c. lysine; d. an isotonic solution of salt; and e. pharmaceutically acceptable excipients.

[0085] In some embodiments, the pharmaceutically acceptable excipients include but not limited to antioxidants, surfactants, a carrier, a diluent, a preservative and combinations thereof.

[0086] In some embodiments, the surfactant is selected from but not limiting to polysorbate 80, polysorbate 20 and poloxamer 188.

[0087] In some embodiments, the antioxidant is selected from but not limiting to methionine, citric acid and ascorbic acid.

[0088] the pH In some embodiments, the formulation is in the range from pH 5.0 to 7.0.

[0089] In one embodiment of the present invention, the purity of the sample after storage of the selected time period is detected by molecular exclusion high performance liquid chromatography : separation and quantification according to the different molecular sizes, and thus information on the amount of the sample monomers, aggregates, and fragments is obtained; charge isomers are detected by cation exchange high performance liquid chromatography (CE-HPLC): separation and quantification according to the different protein charges, and thus information on the charge heterogeneity of the sample is obtained; or the charge isomers are detected by imaging capillary isoelectric focusing electrophoresis (IEF): separation and quantification based on the different isoelectric points of the proteins, thus obtaining information on the amount of acidic and basic proteins in the sample; determination of the "biological activity" of the sample by reporter gene assay.

[0090] The present invention provides a composition comprising a humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody for a stable, isotonic formulation that can be delivered with delivery device such as prefilled syringe having safety needle guard or two step auto injectors.

[0091] The present advantageously provides a high concentration monoclonal antibody formulation that is stable, isotonic, and suitable for subcutaneous injection with a desirable low break loose force and glide force for easy flow during administration from the syringe that reduce pain, swelling and induration risk.

Examples

[0092] The present invention is further explained in the form of following examples. However, it is to be understood that the following examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Abbreviations:

[0093] The abbreviations used in present application are defined below:

SE HPLC : Size Exclusion High performance liquid chromatography

CEX HPLC : Cation Exchange High performance liquid chromatography RP HPLC : Reverse phase High performance liquid chromatography HMW : High molecular weight

LMW : Low molecular weight

% : percentage

Tm : melting temperature mg/mL : milligram/milliliter

°C : degree Celsius mM : milli molar

OD : Optical Density

Example 1

Preparation of Formulations

[0094] Based on the developmental data provided in the provisional specification, following formulation comprising Tocilizumab antibody was further formulated for further characterization and long term stability studies using following formulation composition (As per Table 1). For the comparison, a comparative formulation composition of the marketed (innovator) product has also been included in Table 1. Three batches were manufactured as per the process flow described below (As per Figure 1).

[0095] Manufacturing process started with the thawing of drug substance Tocilizumab stored at lower temperature, followed by preparation of equilibration buffer/formulation buffer, concentration of the Tocilizumab NLT 200mg/mL by using 50 KDA cassette. The concentrated product was diluted to target concentration of 180mg/ml for formulated bulk solution preparation. Addition of Polysorbate 20, fdtration, fdling and stoppering, visual inspection and labelling was done. Table 1: Formulations

Fl : Formulation in accordance with the present invention CF: Comparative formulation

Example 2

Determination of Viscosity

[0096] Viscosity was checked using Brookfield cone and plate viscometer using small spindle size at different rpm and torque at room temperature condition. Viscosity of the formulation on average was found to be in the range of 10 to 12 cPs.

Table 1: Density and viscosity of formulations

Fl : Formulation in accordance with the present invention

CF: Comparative formulation (innovator product) available in the market

Example 3

Determination of Glide force and Break loose force

[0097] Formulation of the present invention as per Example 1 and comparative formulation (marketed innovator’s product) were pre-filled in syringes regular wall or thin walled of different make having needle size 29G and 27G and glide force and break loose force were measured. Below are the data of glide force and break loose force of the Fl (Enzene NIF) formulation of the present invention comparative formulation (innovator’s marketed product formulation). Two type of syringes were evaluated mainly, the regular wall and the thin walled, which are used routinely for the subcutaneous injection. Since the viscosity of the antibody formulation is higher as compared to other small molecule (chemical) drugs, thin wall syringe is more suitable for its intended application and administration. The data from these tests are provided in below Table 3. The graphical representation is provided in Figures 4-5 and Figures 6-7.

[0098] Prefdled syringe of 27 G regular wall and 27 G thin wall both can be used for administration, more preferably 27 G thin wall syringe can be used for administration of solution for injection. Table 2: Glide force and Break loose force data of the formulation of the present invention and comparative formulation

R-Regular wall, TW-Thin wall

Example 4: Stability study

[0099] Stability study of the formulation Fl (present invention formulation prepared in accordance with the present invention), performed to check product quality for a period of time at different condition, real time, accelerated and stress. Real time and accelerated condition stability was carried out up to 3M and stress stability was carried out up to 4 weeks. No changes in Physicochemical parameters are observed during stability. Monomer purity of the formulation was checked using size exclusion HPLC and Cation exchange chromatography. Potency of the formulation was checked by In vitro bioassay. Overall stability data shows protein stability in current formulations. The stability data mentioned in the below

Conclusion: Formulation comprising Tocilizumab (162mg/0.9mL) was found to be stable for

3 months at 5 ± 3 °C.

Conclusion- Formulation comprising Tocilizumab (162mg/0.9mL) was found to be stable for

3 months at 25 ± 2°C/60%RH.

4 weeks at 40 ± 2°C/75%RH.

ADVANTAGES OF THE INVENTION [0100] The present invention provides a stable, isotonic, high concentration monoclonal antibody formulations which are suitable for subcutaneous injection.

[0101] The present invention provides a monoclonal antibody formulations wherein the viscosity of the formulation is between 5-12 cps for betterment of injectability.

[0102] The present invention provides a monoclonal antibody formulations that reduce pain during subcutaneous administration.

[0103] Although the present invention has been described with reference to preferred embodiments, it is submitted that various modifications can be made to the exemplary embodiments without departing from the spirit and scope of the invention.

Claims

We Claim:

1. A composition comprising: a. an anti-IL-6 antibody; b. a buffer system selected from one or more of succinate buffer, citric acid buffer, acetate buffer, and glycine buffer; c. a viscosity reducing agent selected from an amino acid or salt thereof; d. an isotonic solution of a salt; and e. pharmaceutically acceptable excipients.

2. The composition as claimed in claim 1, wherein the anti -IL-6 antibody is selected from sarilumab, olokizumab, elsilimomab, clazakizumab, sirukumab, levilimab, and gerilimzumab.

3. The composition as claimed in any one of claims 1-2, wherein the anti -IL-6 antibody is tocilizumab.

4. The composition as claimed in any one of claims 1-4, wherein the viscosity reducing agent is selected from one or more of valine, methionine, histidine, lysine, proline or their salts.

5. The composition as claimed in any one of claims 1-5, wherein the viscosity reducing agent is lysine.

6. The composition as claimed in any one of claims 1-5, wherein the salt for isotonic solution is selected from sodium chloride and sodium acetate.

7. The composition as claimed in any one of claims 1-6, wherein the ratio of amino acid to salt is from 1 : 1.2 to 1: 1.12.

8. The composition as claimed in any one of claims 1-7, wherein the buffering system is succinate buffer.

9. An anti -IL-6 antibody formulation comprising: a. an anti-IL-6 antibody; b. a buffer system selected from one or more of succinate buffer, citric acid buffer, acetate buffer, and glycine buffer; c. a viscosity reducing agent selected from an amino acid or salt thereof; d. an isotonic solution of a salt; and e. pharmaceutically acceptable excipients.

10. The formulation as claimed in claim 9, wherein the anti-IL-6 antibody is selected from sarilumab, olokizumab, elsilimomab, clazakizumab, sirukumab, levilimab, and gerilimzumab.

11. The formulation as claimed in any one of claims 9-10, wherein the anti -IL-6 antibody is tocilizumab.

12. The formulation as claimed in any one of claims 9-11, wherein the buffering system is succinate buffer.

13. The formulation as claimed in any one of claims 9-12, wherein the viscosity reducing agent is selected from one or more of valine, methionine, histidine, lysine, proline or their salts.

14. The formulation as claimed in any one of claims 9-13, wherein the viscosity reducing agent is lysine.

15. The formulation as claimed in any one of claims 9-14, wherein the salt for isotonic solution is selected from sodium chloride and sodium acetate.

16. The formulation as claimed in any one of claims 9-15, wherein the ratio of amino acid to salt is from 1:0.2 to 1: 12.

17. The formulation as claimed in any one of claims 9-16, wherein the pharmaceutically acceptable excipients include antioxidants, surfactants, a carrier, a diluent, a preservative and combinations thereof.

18. The formulation as claimed in any one of claims 9- 17, wherein the surfactant is selected from polysorbate 80, polysorbate 20 and poloxamer 188.

19. The formulation as claimed in any one of claims 9- 18, wherein the antioxidant is selected from methionine, citric acid and ascorbic acid.

20. The formulation as claimed in any one of the claims 1-20, wherein the pH of formulation is in the range from pH 5.0 to 7.0.