Liquid pharmaceutical composition

专利摘要:
The invention relates to novel liquid pharmaceutical compositions of adalimumab which include adalimumab or a biosimilar agent thereof, a citrate buffer agent / system such as sodium citrate / citric acid, and a sugar stabilizer such as trehalose. Such a combination of constituents provides formulations with a stability (e.g., by storage or exposures to loads) that are comparable to or improved from those known in the art and with fewer constituents. Such advances will promote the availability of adalimumab treatments at a lower cost and extend the shelf life of pre-filled dispensing devices (eg pre-filled syringes), thus reducing unnecessary waste of the drug.
公开号:DK202000030U1
申请号:DK202000030U
申请日:2020-04-08
公开日:2020-04-28
发明作者:Rinaldi Gianluca；FRATARCANGELI Silvia；Del Rio Alessandra
申请人:Fresenius Kabi Deutschland Gmbh；
IPC主号:

专利说明:

Liquid pharmaceutical composition
Introduction
The production relates to a new protein formulation. In particular, the preparation relates to a liquid pharmaceutical composition of adalimumab, a process for preparing the composition, a kit containing the composition, a package containing the composition, a method of preparing the package and methods of treatment using the composition and / or package.
Background
Treatment of tumor necrosis factor-alpha (TNF-α) -related autoimmune disease such as arthritis rheumatoides, psoriasis and other autoimmune diseases has been achieved using FDA-approved drugs such as Adalimumab (HUMIRA®, Abbott Corporation). Adalimumab is a human monoclonal antibody that inhibits human TNF-α activity, preventing activation of TNF receptors, thereby downregulating inflammatory responses associated with autoimmune diseases. Approved medical indications for Adalimumab include arthritis rheumatoid, psoriatic arthritis, Bechterew's disease, Crohn's disease, ulcerative colitis, moderate to severe chronic psoriasis and arthritis.
Adalimumab is generally administered to a patient by subcutaneous injection, and is thus administered in liquid form, typically in packs such as vials, pre-filled syringes or pre-filled pen devices. Commercially available pen devices (HUMIRA® Pen) generally include a pre-filled 1 ml glass syringe pre-filled with 0.8 ml of a sterile formulation of 40 mg Adalimumab (see below) with a solid needle (either gray natural rubber or a latex-free version) and a needle protector. Commercial Formulations (HUMIRA®) by Adalimumab contain the following ingredients:
Component Quantity per container (mg);(fill volume = 0.8 ml) Amount (mg / ml) adalimumab 40 50 Citric 1.04 1.3 dibasicnatriumphosphatdihydrat 1.22 1.53 mannitol 9.6 12
DK 2020 00030 U1
Monobasic sodium phosphate dihydrate 0.69 0.86 Polysorbate 80 0.8 1 Sodium chloride 4.93 6.16 Sodium 0.24 0.3 WFI and sodium hydroxide q.b. to set the pH to 5.2 q.b to set the pH to 5.2
Adalimumab, and its mode of preparation, are described in WO997 / 29131 (BASF) as D2E7, and elsewhere in the professional literature.
Although the aforementioned commercial formulation of Adalimumab is stable (at least to some extent), the relevant antibody may be unstable over extended periods of time or under stressed conditions, precluding longer storage of the formulations. Such degradation of the formulation may be due to several factors including:
Physical effects, such as:
o Inadequate aggregation inhibition of the relevant protein molecules (a function to be performed by Tween-80);
o Inadequate precipitation inhibition;
o Inadequate adsorption inhibition of the relevant protein molecules in the water-air interface or at the contact surface of any packaging material (a function to be performed by Tween-80);
o Inadequate control of osmotic pressure (a function to be performed by mannitol);
Chemical effects, such as:
o Insufficient oxidation regulation (a function to be performed by mannitol and potentially undermined by Tween-80 which can promote the oxidation of double bonds);
o Insufficient photooxidation inhibition;
o Inadequate inhibition of the hydrolysis of ester bonds leading to the formation of acid, aldehyde and peroxide products, thereby affecting the stability of the antibody;
o Inadequate stabilization and maintenance of the pH;
o Inadequate inhibition of protein fragmentation;
o Inadequate inhibition of protein unfolding.
Any, any or all of the above factors may lead to an unsustainable drug product (which may be unsafe for use in medical treatments) or a drug product whose viability is variable and unpredictable, especially in light of various loads ( movement, heat, light) to which various portions of the drug product may be subjected during manufacture, transport and storage.
With regard to the physical and chemical stabilization of Adalimumab, the complex range of constituents in the aforementioned commercial formulations appears to be performing poorer than expected, especially in view of the large number of constituents. Although this particular combination of excipients undoubtedly represents a delicate balance (given the interplay of various technical factors) and was the result of extensive research and development work, it is doubtful, given the apparent risk of poor performance, whether such a high number of various excipients are warranted, especially given that this inevitably increases the manufacturing and cost burdens, toxicity risks and the risk of harmful interactions between constituents that can compromise the formulation. Even if the overall function of the commercial formulations could not be surpassed, an alternative formulation with comparable function but containing fewer constituents would represent a highly desirable substitute for the commercial formulations for at least the aforementioned reasons.
To guarantee reproducible clinical function of a protein-based pharmaceutical product, it must remain in a stable and consistent form over time. It is well known that molecular changes can occur at all stages of the manufacturing process, including during the final formulation production and during storage. Molecular changes can alter a quality property of a biopharmaceutical product, resulting in an undesirable change in the identity, strength or purity of the product. Some such issues are outlined above.
The primary goal of formulation development is to provide a pharmaceutical composition that will support the stability of a biopharmaceutical protein at all stages of its production, storage, transport and use. Formulation development of an innovative biopharmaceutical protein or biosimilar monoclonal antibody (mAb) is essential for its safety, clinical efficacy and commercial success.
Therefore, there is a need to provide alternative or improved liquid formulations of adalimumab. Desirably, new formulations should solve at least one of the aforementioned problems and / or at least one problem inherent in the prior art, and could suitably solve two or more of these problems. It was
DK 2020 00030 U1 desirable whether the problem or problems in the prior art could be solved while reducing the complexity of the formulation.
Summary of the production
According to a first aspect of the preparation, there is provided a liquid pharmaceutical composition comprising adalimumab (which suitably includes any biosimilar compound thereto); a citrate buffer agent (or citrate buffer system); and a sugar stabilizer; wherein the composition optionally comprises (or excludes) one or more additional ingredients defined herein in association with a liquid pharmaceutical composition (e.g., including tonic, without arginine, etc.), optionally in any amount, concentration or form set forth herein ; and wherein the composition optionally exhibits one or more parameters or properties mentioned herein in connection with a liquid pharmaceutical composition (e.g., pH, osmolality, aggregation, fragmentation, protein unfolding, turbidity, general stability, durability, etc.).
According to another aspect of the preparation, a liquid pharmaceutical composition comprising adalimumab is provided; a citrate buffer agent (or citrate buffer system); and a sugar stabilizer; wherein the isoform profile of adalimumab in the composition, as measured (or measured) with reference to the integral area of the main peak of adalimumab in an electropherogram formed by isoelectronic focusing (preferably capillary oesectronic focusing as described herein, or any other standard isoelectronic focusing protocols known in the art) subject area) does not change by more than 20% when exposed to light exposure (appropriate is 7 hours exposure to 765 W / m ² light, preferably in accordance with current ICH Q1 Guidelines from the European Medicines Agency (EMA) preferably document CPMP / ICH / 279 / 95).
According to a third aspect of the preparation, a liquid pharmaceutical composition comprising adalimumab is provided; a citrate buffer agent (or citrate buffer system); and a sugar stabilizer; wherein the composition is either (substantially or completely) free of phosphate buffer agents (e.g., sodium dihydrogen phosphate, disodium hydrogen phosphate) or comprises a phosphate buffer system (including one or more phosphate buffer agents and / or corresponding acid / base conjugate (s)) at a concentration of not more than 0.1 mM.
According to a fourth aspect of the preparation, a liquid pharmaceutical composition comprising adalimumab is provided; a citrate buffer agent (elDK 2020 00030 U1 or a citrate buffer system); and a sugar stabilizer; wherein the composition has a pH greater than or equal to 5.4.
According to a fifth aspect of the preparation, there is provided a package (e.g., a pre-filled syringe, pen, intravenous bag or package / container containing any of the aforementioned) comprising a liquid pharmaceutical composition as defined herein.
According to a sixth aspect of the invention, a drug dispensing device (e.g., a pre-filled syringe or pen or intravenous bag) is provided comprising a liquid pharmaceutical composition as defined herein.
According to a seventh aspect of the invention, there is provided a set of portions comprising a drug dispensing device, a liquid pharmaceutical composition as defined herein (optionally contained in a package or container), and optionally a guide with directions for administration (e.g., subcutaneously) of the liquid. pharmaceutical composition.
According to an eighth aspect of the invention, there is provided a process for preparing a liquid pharmaceutical composition which comprises admixing adalimumab; a citrate buffer agent (or citrate buffer system); a sugar stabilizer; and optionally one or more additional components defined herein in connection with a liquid pharmaceutical composition, optionally in any amount, concentration or form determined; and optionally setting one or more parameters given herein in connection with a liquid pharmaceutical composition (e.g., pH, osmolality).
According to a ninth aspect of the preparation, a liquid pharmaceutical composition is provided which is obtainable, obtained or obtained directly by a process for preparing a liquid pharmaceutical composition as defined herein.
According to a tenth aspect of the invention, there is provided a process for the preparation of a package or drug dispensing device, which method incorporates a liquid pharmaceutical composition as defined herein in a package or drug dispensing device.
According to an eleventh aspect of the manufacture, a gasket or a drug dispensing device is provided which is obtainable, obtained or obtained directly by a method of preparing a pack or drug dispensing device as defined herein.
DK 2020 00030 U1
According to a twelfth aspect of the invention, there is provided a method for treating a disease or medical disorder in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of a liquid pharmaceutical composition as defined herein.
According to a thirteenth aspect of the preparation, a liquid pharmaceutical composition as defined herein is provided for use in treatment.
According to a fourteenth aspect of the preparation, the use of a liquid pharmaceutical composition as defined herein is provided for the preparation of a medicament for the treatment of a disease or disorder.
According to a fifteenth aspect of the invention, there is provided a method for treating a tumor necrosis factor-alpha (TNF-α) -related autoimmune disease in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of a liquid pharmaceutical composition which as defined herein.
According to a sixteenth aspect of the preparation, a liquid pharmaceutical composition as defined herein is provided for use in the treatment of a tumor necrosis factor-alpha (TNF-α) -related autoimmune disease.
According to a seventeen aspect of the preparation, use of a liquid pharmaceutical composition as defined herein is provided for the preparation of a medicament for the treatment of a tumor necrosis factor-alpha (TNF-0) -related autoimmune disease.
According to an eighteenth aspect of the invention, there is provided a method for treating rheumatoid arthritis, psoriatic arthritis, Bechterew's disease, Crohn's disease, ulcerative colitis, moderate to severe chronic psoriasis, and / or child rheumatoid arthritis in a patient in need of such treatment, the method comprising administering a therapeutically effective amount of a liquid pharmaceutical composition as defined herein.
According to a nineteenth aspect of the invention, a liquid pharmaceutical composition as defined herein is provided for use in the treatment of rheumatoid arthritis, psoriatic arthritis, Bechterew's disease, Crohn's disease, ulcerative colitis, moderate to severe chronic psoriasis and / or rheumatoid arthritis.
According to a twentieth aspect of the invention, there is provided the use of a liquid pharmaceutical composition as defined herein for the manufacture of a medicament for the treatment of arthritis rheumatoides, psoriatic arthritis, Bechterew's disease, Crohn's disease, ulcerative colitis, moderate to severe chronic psoriasis.
DK 2020 00030 U1 and / or child rheumatoid arthritis.
In further aspects, the invention provides a liquid pharmaceutical composition, a package, a drug dispensing device, a set of parts, a process for preparing a liquid pharmaceutical composition, a process for preparing a package or a drug dispensing device, a process for treatment, a liquid pharmaceutical composition for use, and use of a liquid pharmaceutical composition for the manufacture of a drug, substantially as defined herein (including in any of the aforementioned aspects) except that the preparation, instead of being specific for adalimumab (and biosimilar agents thereto) may be applied to (and thereby defined as related to) any TNF-α inhibitory antibody (anti-TNF antibody) (or any biosimilar compound thereto), but preferably an antibody which inhibits human TNF α activity, and most preferably a human monoclonal antibody which inhibits human TNF-α activity. The anti-TNF-α antibody is suitably a therapeutically effective drug (at least when administered in appropriate amounts to a patient in need thereof) (or a biosimilar agent therefor - see below for definitions of biosimilar agents in association with adalimumab, which likewise, all anti-TNF-α antibodies), preferably one, which has received FDA approval. As such, any reference herein to adalimumab, except if incompatible therewith, may be construed as referring to any antiTNF-α antibody for the purpose of these additional aspects of its production (whether this relates to absolute or relative amounts, concentrations, parameters or properties or whether it concerns specific definitions, such as what constitutes a biosimilar agent).
One of these additional aspects of the preparation provides a liquid pharmaceutical composition comprising an anti-TNF-α antibody (which preferably includes any biosimilar compound thereto); a citrate buffer agent (or citrate buffer system); and a sugar stabilizer; wherein the composition optionally comprises (or excludes) one or more additional ingredients defined herein in association with a liquid pharmaceutical composition (e.g., including tonic, without arginine, etc.), optionally in any amount, concentration or form set forth herein ; and wherein the composition optionally exhibits one or more parameters or properties mentioned herein in connection with a liquid pharmaceutical composition (e.g., pH, osmolality, accumulation / aggregation, fragmentation, protein unfolding, turbidity)
DK 2020 00030 U1, etc.).
In a particular embodiment, the anti-TNF-α antibody is selected from the group comprising adalimumab, infliximab, certolizumab pegol, golimumab.
Any feature, including optional, suitable and preferred features described in connection with a given aspect of the production, may also be features including optional, suitable and preferred features of any other aspect of the production.
Brief description of the drawings
For a better understanding of the invention, and to show how embodiments thereof are implemented, reference is now made by way of example to the following diagrammatic drawings, in which:
Figure 1 is a bar graph showing the protein content (mg / ml), as determined by OD, of DoE1 formulations (from Example 1) along with standard references (representing HUMIRA® comparison formulations) at an arbitrary starting point (blue bars, time = 0 ) and after 4 weeks (red bars) for the formulation (s) heated to 40 ° C.
Figure 2 is a bar graph showing% accumulation, as determined by SEHPLC, of the DoE1 formulations (from Example 1) along with standard references (representing HUMIRA® comparison formulations) at an arbitrary starting point (blue bars, time = 0) and after both 2 weeks (green bars) and 4 weeks (orange bars) for the formulation (s) heated to 40 ° C.
Figure 3 is a bar graph showing% fragmentation, as determined with a Bioanalyzer, of the DoE1 formulations (from Example 1) along with standard references (representing HUMIRA® comparison formulations) at an arbitrary starting point (dark blue bars, time = 0) and after both 2 weeks (pink bars) and 4 weeks (light blue bars) for the formulation (s) heated to 40 ° C.
Figure 4 is a bar graph showing the unfolding temperature (° C), as determined by DSF, for the DoE1 formulations (from Example 1) along with standard references (representing HUMIRA® comparison formulations).
Figure 5 is a bar graph showing% aggregation, as determined by SEHPLC, of the DoE2 formulations (from Example 2) together with standard references (representing HUMIRA® comparison formulations) at an arbitrary starting point (red bars, time = 0) and after both 2 weeks (green bars) and 4 weeks (purple bars) for the formulation (s) heated to 40 ° C.
Figure 6 is a bar graph showing% fragmentation, as determined with a Bioanalyzer, of the DoE2 formulations (from Example 2) together with standard 2020 00030 U1 reference (representing HUMIRA® comparison formulations) at an arbitrary starting point (blue bars, time = 0) and after both 2 weeks (red bars) and 4 weeks (green bars) for the formulation (s) heated to 40 ° C.
Figure 7 is a bar chart showing the main top isoform profile, as determined by iCE280 analysis, of the DoE2 formulations (from Example 2) at an arbitrary starting point (blue bars, time = 0) and after both 2 weeks (red bars) and 4 weeks (green bars) for the formulation (s) heated to 40 ° C.
Figure 8 is a bar graph showing the cluster cluster topoform profile, as determined by iCE280 analysis, of the DoE2 formulations (from Example 2) at an arbitrary starting point (blue bars, time = 0) and after both 2 weeks (red bars) and 4 weeks (green bars) for the formulation (s) heated to 40 ° C.
Figure 9 is a bar graph showing the turbidity, as determined by nephelometry, of the DoE2 formulations (from Example 2) at an arbitrary starting point (blue bars, time = 0) and after both 2 weeks (red bars) and 4 weeks (green columns) for the formulation (s) heated to 40 ° C.
Figure 10 is a bar graph showing% aggregation, as determined by SE-HPLC, of the DoE2 formulations (from Example 2) at an arbitrary starting point (blue bars, time = 0) and after both 24 hours (red bars) and 48 hours (green bars) for the formulation (s) moving mechanically (shaking).
Figure 11 is a bar graph showing% fragmentation, as determined with a Bioanalyzer, of the DoE2 formulations (from Example 2) at an arbitrary starting point (blue bars, time = 0) and after both 24 hours (red bars) and 48 hours (green bars) for the mechanically moved (shake) formulation (shaking).
Figure 12 is a bar graph showing the turbidity, as determined by nephelometry, of the DoE2 formulations (from Example 2) at an arbitrary starting point (blue bars, time = 0) and after both 24 hours (red bars) and 48 hours (green columns) for the mechanically moved (shake) formulation (s).
Figure 13 is a bar graph showing% aggregation, as determined by SE-HPLC, of the DoE2 formulations (from Example 2) together with standard references (representing HUMIRA® comparison formulations) before exposure to light (blue bars, time = 0) and after 7 hours of light exposure at 765 W / m ² (red bars).
Figure 14 is a bar graph showing% fragmentation, as determined with a Bioanalyzer, of the DoE2 formulations (from Example 2) before exposure to light (blue bars, time = 0) and after 7 hours of light exposure at 765 W / m ² ( red bars).
Figure 15 is a bar graph showing the main top isoform profile, as beDK 2020 00030 U1 voted by iCE280 analysis, of the DoE2 formulations (from Example 2) along with standard references (representing HUMIRA® comparison formulations) before exposure to light (blue bars, time = 0) and after 7 hours of light exposure at 765 W / m ² (red bars).
Figure 16 is a bar graph showing the cluster cluster topoform profile, as determined by iCE280 analysis, of the DoE2 formulations (from Example 2) together with standard references (representing HUMIRA® comparison formulations) before exposure to light (blue bars, time = 0) and after 7 hours of light exposure at 765 W / m ² (red bars).
Figure 17 is a bar graph showing the turbidity, as determined by nephelometry, of the DoE2 formulations (from Example 2) before exposure to light (blue bars, time = 0) and after 7 hours of light exposure at 765 W / m ² (red bars) ).
Detailed description of the production
definitions
Unless otherwise stated, the following terms used in the specification and claims have the following meanings given below.
References herein to adalimumab include the original drug substance (as commercially available) adalimumab as defined in WO97 / 29131 (BASF) (in particular D2E7 therein) and elsewhere in the art, and also biosimilar agents thereof. D2E7k of WO97 / 29131 has a CDR3 light chain domain comprising the amino acid sequence of SEQ ID NO: 3 and a CDR3 heavy chain domain comprising the amino acid sequence of SEQ ID NO: 4. Preferably, the D2E7 antibody has a variable light chain region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a variable heavy chain region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2. WO97 / 29131 provides details for each of these sequence entries. References herein to adalimumab may include biosimilar agents which may have, for example, at least 75%, preferably at least 80%, preferably at least 85%, preferably at least 90%, preferably at least 95%, preferably at least 96%, preferably at least 97%, preferably at least 98% or most preferably at least 99% protein sequence similarity with any of the protein sequences described in either WO97 / 29131 (particularly with respect to D2E7) or elsewhere with respect to adalimumab. Alternatively or additionally, references herein to adalimumab may include biosimilar agents exhibiting at least 75%, preferably at least 80%, preferably at least 85%, preferably at least 90%, preferably at least 95%, preferably at least 96%, preferably at least
DK 2020 00030 U1%, preferably at least 98% or most preferably at least 99% protein sequence homology with any of the protein sequences described in either WO97 / 29131 (especially with respect to D2E7) or elsewhere with respect to adalimumab. Alternatively or additionally, a biosimilar agent may have a (slightly) different glycosylation profile, although the protein sequence is substantially the same or different to the extent indicated above.
The term biosimilar agent (also known as follow-on biologics) is well known in the art, and those of skill in the art will know immediately when a drug substance can be considered a biosimilar agent for adalimumab. In addition, such biosimilar agents would have to be officially approved as a biosimilar agent for marketing before the biosimilar agent is placed on the market. The term biosimilar agent is generally used to describe subsequent versions (usually from another source) of an original biopharmaceutical product (biotechnological product whose drug substance is formed from a living organism or is derived from a living organism or through recombinant DNA or guided gene expression methodologies). previously granted marketing authorization. Because biotechnology products have a high degree of molecular complexity and are generally vulnerable to changes in the manufacturing processes (for example, if different cell lines are used in their production) and since subsequent follow-up producers do not normally have access to the original product's molecular clone, cell bank , know-how with regard to fermentation and purification processes or to the active drug substance itself (only the original manufacturer's drug product in the trade), a given biosimilar agent is unlikely to be exactly the same as the original preparation.
For the purpose of various molar calculations (e.g. molar ratio of adalimumab to another component of the liquid pharmaceutical composition of the invention), the molecular weight of adalimumab can be estimated at 144190.3 g / mol (reference molecular weight) based on details given in the CAS database for CAS # 331731-18-1, Adalimumab, wherein the molecular formula is given as C6428H9912N1694O1987S46. As such, a liquid pharmaceutical composition containing 50 mg / ml adalimumab can be considered a 0.347 mM (or 347 μΜ) solution of adalimumab. This is not intended in any way limiting as to the nature of a given biosimilar agent, covered by the scope of protection of the present invention or as to the level of glycosylation, each of which may affect the molecular weight. However, where a biosimilar agent has a different molecular weight, the aforementioned reference model 2020 202030 U1 molecular weight should be used to assess whether such biosimilar agent falls within the scope of molar definitions set forth in this specification. So the molar number in a known weight amount of the biosimilar agent should be calculated for the purpose of this production using the above reference molecular weight.
The term buffer or buffer solution refers to a generally aqueous solution comprising a mixture of an acid (usually a weak acid, e.g. acetic acid, citric acid, imidazolium form of histidine) and its corresponding base (e.g., an acetate or citrate salt, e.g. for example, sodium acetate, sodium citrate or histidine) or, alternatively, a mixture of a base (usually a weak base, e.g., histidine) and its corresponding acid (e.g., protonated histidine salt). The pH of a buffer solution will change only slightly with the addition of a small amount of strong acid or base due to the buffering effect imparted by the buffering agent.
A buffer system herein comprises one or more buffering agents and / or a corresponding acid / base thereto, and suitably comprises only one buffering agent and a corresponding acid / base thereto. Unless otherwise stated, concentrations determined herein in connection with a buffer system (ie, a buffer concentration) refer to the total concentration of all the relevant buffer elements (ie the elements in dynamic equilibrium with each other, eg citrate / citric acid). As such, a given concentration of a citrate buffer system generally relates to the total concentration of citrate (or citrate salt (s), e.g., sodium citrate) and citric acid. The overall pH of the composition comprising the relevant buffer system is generally a reflection of the equilibrium concentration of each of the relevant buffer elements (i.e., the balance between buffer agents and corresponding acids and bases thereof).
The term buffer means herein refers to an acid or base component (usually a weak acid or weak base) in a buffer or buffer solution. A buffering agent helps maintain the pH of a given solution at or near a predetermined value and the buffering agents are generally selected to complement the predetermined value. Suitably, a buffering agent is a single compound which gives rise to a desired buffering effect, especially when the buffering agent is mixed with (and preferably capable of proton exchange with) an appropriate amount (depending on the desired predetermined pH) of its corresponding acid / base -conjugate, or if the required amount of its corresponding acid / base is formed in situ - this can be achieved by adding strong acid or base until the desired pH is reached. As an example:
DK 2020 00030 U1 • A citrate buffer may conveniently be a citrate salt, for example sodium citrate, preferably mixed with its acid / base conjugate, citric acid. Such a buffer system can be formed simply by mixing a given amount of sodium citrate with a given amount of citric acid. Alternatively, however, such a buffer may be formed by adding a given amount of base, preferably a strong base (e.g., sodium hydroxide) to the citric acid, until the desired pH (and thus the desired balance of sodium citrate and citric acid) is reached. In the present context, all concentrations given in connection with a citrate buffer or citrate buffer, unless otherwise indicated, preferably refer to the combined concentration of buffer agent (e.g. sodium citrate) and / or corresponding acids / bases thereof (e.g. citric acid) . Those skilled in the art can readily calculate such concentrations, and may do so by reference to the combined concentrations of buffer agent / agents and acid / base conjugate (s), wherein a buffer system is formed by simply mixing buffer agent / agents and acid / base conjugate (s). is). Alternatively, such concentrations may conveniently be calculated by reference to the starting amount (s) / concentration (s) of the buffer agent (s) or the corresponding acid (s) / base (s), respectively, where a buffer system is formed by mixing either the buffer agent (s) or corresponding acid (s) / base (s) with a pH adjusting agent (e.g. strong acid or strong base) to form a mixture of each. Where e.g. a buffer system is formed using a known amount / concentration of citric acid which is mixed with a pH adjusting agent (eg sodium hydroxide) until the desired pH is reached, the concentration of the buffer system can be calculated with reference to the original amount of citric acid.
Herein, an acid / base conjugate refers to the corresponding acid or base (whichever is relevant at a given pH value typically the corresponding acid in the context of the present invention) to a given buffer. The corresponding acid / base for a citrate buffer (e.g. sodium citrate) is suitably citric acid.
The term buffer element refers to the particular elements (excluding any associated counter anions or counter cations - i.e., disregarding sodium ions in sodium citrate / citric acid systems) in a given buffer system which is in dynamic balance with (and proton exchanges with) each other. For example, citrate anions and citric acid together form the citrate buffer elements in one
DK 2020 00030 U1 citrate buffer system.
Since it can often be somewhat difficult to define amounts (whether absolute or relative) of a buffer system by reference to the weight (since the total weight will depend on the desired pH which will affect the amount of counterions present), weight-based amounts can herein is instead determined by reference to a theoretical weight of the relevant buffer element. At least two elements are usually present in a given amount of buffer elements (relative amounts which can only be determined by reference to the pH), each with a different molecular weight (which usually differs by only 1). Therefore, for this purpose, the weight of a given set of buffer elements is given as a theoretical weight based on only one of the buffer elements, namely the most acidic of the buffer elements (i.e., the most protonated form at a given pH) to allow durable weight calculations - and referrals. So, the weight of a given amount of buffer elements is given as the weight of base element equivalents. As an example, the citrate buffer elements of a citrate buffer system may consist of citrate anions (ignore countercations) and citric acid. Therefore, the weight of the buffer element is calculated as if citric acid was the only element present in the buffer system (although citrate is obviously present with citric acid). Thus, any reference to a weight or weight ratio of a citrate buffer element preferably refers to the theoretical weight of citric acid equivalents in the buffer system. As such, the initial weight of citric acid in which a composition is formed by adding a pH adjusting agent (e.g., sodium hydroxide) to a fixed amount of citric acid can be considered as the weight of the buffer element regardless of the final pH. Alternatively, if the concentration (i.e., the molarity) of a buffer system is known, it can be converted to a weight of buffer elements by reference to the molecular weight of the most acidic form of the relevant buffer element (e.g., citric acid) and by ignoring the fact that citrate anions is also present.
Unless otherwise indicated, references herein refer to an amino acid or amino acids, either specific (e.g., arginine, histidine) or general (e.g., any amino acid), in the context of their presence or in compositions (in particular, pharmaceutical liquid compositions of generation) to the corresponding free amino acids (regardless of their protonation state and / or salt form, but for the sake of uniformity,
DK 2020 00030 U1 amounts preferably with reference to the free amino acid per se). This may suitably include natural and / or artificial amino acids. Unless otherwise indicated, such references are not intended to relate to amino acid residue (s) covalently incorporated as part of a larger compound (as opposed to a composition comprising multiple compounds), such as a peptide or protein (where such amino acid residues are linked via peptide bonds). While adalimumab as a protein contains amino acid residues, it is not considered as encompassing some free amino acid (s). For example, a composition defined as being free of arginine does not contain free arginine, but it may still contain one or more proteins (e.g. such as adalimumab), which itself contains arginine residues.
Unless otherwise stated, references herein refer to one or more amino acids, either specific or general, preferably to the L stereoisomers or a racemate thereof, preferably L-amino acids.
The term substantially free when used in conjunction with a given constituent of a composition (e.g., a liquid pharmaceutical composition substantially free of arginine) refers to a composition for which substantially none of said constituent has been added. As explained above, such references do not relate to the presence of amino acid residues in a protein structure. When a composition is substantially free of a given constituent, the composition preferably comprises no more than 0.001% by weight of the constituent, preferably no more than 0.0001% by weight of the constituent, preferably no more than 0.00001% by weight of the constituent. the component, preferably not more than 0.000001% by weight of the component, preferably not more than 0.000000001% by weight of the component, most preferably not more than 0.0001 ppb (by weight).
The term completely free when used in conjunction with a given component of a composition (e.g., a liquid pharmaceutical composition completely free of arginine) refers to a composition which does not contain said component. As explained above, such references do not relate to the presence of amino acid residues in a protein structure.
In the context of this specification, a strong acid is preferably one with a pKa value of -1.0 or less, while a weak acid is preferably
DK 2020 00030 U1 one with a pKa value of 2.0 or more. In the context of this specification, a strong base is preferably one whose corresponding acid has a pKa value of 12 or greater (preferably 14 or greater), while a weak base is preferably one whose corresponding acid has a pKa value of 10 or less.
A stabilizer refers to an ingredient which facilitates the maintenance of the structural integrity of the biopharmaceutical, especially during freezing and / or freeze-drying and / or storage (especially during exposure to loads). This stabilizing effect can occur for all sorts of reasons, however, such stabilizers can typically act as osmolytes that protect against protein denaturation. Typically, stabilizers include amino acids (i.e., free amino acids that are not part of a peptide or protein - for example, glycine, arginine, histidine, aspartic acid, lysine) and sugar stabilizers such as a sugar polyalcohol (e.g. mannitol, sorbitol) and / or a disaccharide (e.g., trehalose, sucrose, maltose, lactose), although the liquid pharmaceutical compositions of the invention include a stabilizer, at least one of which is a sugar stabilizer (i.e., either a sugar alcohol or a disaccharide). Preferably, the at least one sugar stabilizer is a non-reducing sugar (be it a sugar alcohol or a disaccharide).
Here, a non-reducing sugar is usually a sugar without aldehyde groups or without the ability to form an aldehyde group (for example, by isomerism).
A tonicity modifier or tonic agent refers to an agent whose inclusion in a composition appropriately contributes to (or enhances) the overall osmolality and osmolarity of the composition. Preferably, a tonizing agent as used herein includes an agent which makes a solution similar to physiological fluids for osmotic characteristics.
References to specific amounts of a given constituent of a composition, in particular a buffering agent, stabilizer, amino acid, surfactant or tonic, preferably refer to the amounts of the pure anhydrous form of the relevant ingredient (or compounds formed using these amounts of the pure anhydrous). form), although such an ingredient may be used in a non-anhydrous form when the composition is formed. Amounts of corresponding non-anhydrous forms (eg monohydra
DK 2020 00030 U1 ter, dihydrates, etc.) can be calculated easily by simply using the right multiplier. For example, unless otherwise stated, amounts determined for trehalose (as in the Examples where amounts relate to trehalose dihydrate) refer to the anhydrous form of trehalose (or compositions formed using the determined amounts / concentrations of anhydrous trehalose) which have a molecular weight of 342,296 g / mol, so to calculate the corresponding amount of trehalose dihydrate needed to form the same compound (less water needs to be added), it is necessary to multiply the amount determined by 378,33 / 342,296 since 378.33 is the molecular weight of trehalose dihydrate. The person skilled in the art will readily understand by adjusting the amount of diluent / water, depending on the shape of the ingredients used, to deduce the target concentrations.
The term pharmaceutical composition herein refers to a formulation of a pharmaceutical active ingredient which makes the biological activity of the active ingredient therapeutically effective but does not include other ingredients which are obviously toxic to a subject to which the formulation is intended to be administered.
The term stable herein refers generally to the physical stability and / or chemical stability and / or biological stability of a component, typically an active ingredient or composition thereof during preservation / storage.
It should be understood that referrals to treatment or treatment include prevention as well as relief of established symptoms of a condition. Therefore, treating or treating a condition, disorder or disorder includes: (1) preventing or delaying the appearance of clinical symptoms of the condition, disorder or disorder that develops in a person who may be afflicted or predisposed to the condition, the disorder; or the disorder, but not yet experiencing or exhibiting clinical or subclinical symptoms of the condition, disorder or disorder; (2) inhibiting the condition, disorder or disorder; stopping, reducing or delaying the progression of the disease or its recurrence (in the case of maintenance therapy) or at least one clinical or subclinical symptom thereof; or (3) alleviating or attenuating the disease; cause regression of the condition, disorder or disorder, or at least one of its clinical or subclinical symptoms.
For the purposes of this invention, a therapeutic means
An effective amount or effective amount of the antibody is an amount that is effective when administered to a mammal for the treatment of a disease or disorder in prophylactic and therapeutic terms, and the antibody is effective for the treatment of the diseases in question.
The therapeutically effective amount will vary depending on the compound, the disease and its severity as well as the age, weight, etc. of the mammal to be treated.
The term human TNF-α refers to the human cytokine which exists in a secreted 17 kD form and a membrane associated 26 kD form, and in a biologically active form, TNF-α is seen as a trimer of a covalently bound 17 kD molecule. Its specific structure can be found in Pennica, D. et al. (1984) Nature 312: 724-729; Davis, J.M. et al. (1987) Biochemistry 26, 1322-1326; and Jones, E.Y et al. (1989) Nature 338: 225-228.
The term recombinant human antibody shall include a human antibody produced, expressed, produced or isolated using a recombinant method.
Quantities provided herein for constituents and ingredients, whether expressed in parts, ppm (parts per million) percentages (%, eg% by weight) or ratios are by weight, unless otherwise stated.
When the amount or concentration of a given component of a given composition is given as a percentage by weight (% by weight or% v / v), the percentage by weight refers to the percentage of the component by weight relative to the total weight of the composition as a whole. Those skilled in the art will appreciate that the sum of percentages by weight of all components of a composition (specified or not) will amount to a total of 100% by weight. However, where not all ingredients are enumerated (e.g., where compositions are said to comprise one or more particular ingredients), the weight percent balance may optionally be supplemented to 100% by weight of unspecified ingredients (e.g., a diluent such as water or other non - essential but suitable additives).
Here, the term parts (e.g., parts by weight, pbw) when used in conjunction with multiple ingredients / constituents refers to relative proportions between the multiple ingredients / constituents. Expressing molar or weight ratios of two, three or more constituents gives rise to the same effect (for example, a molar ratio of x, y and z xi: yi: zi, respectively, or an interval xi-x2:
DK 2020 00030 U1 yi-y2: zi-z2). Although the amounts of individual ingredients in a composition in many embodiments can be given as a weight percent value, some or all such weight percent values in alternative embodiments may be converted to parts by weight (or relative ratio) to define a composition of multiple ingredients. It is thus because the relative proportions of the constituents are often more important than the absolute concentrations thereof in the liquid pharmaceutical compositions of the invention. Where a composition comprising several constituents is described solely by parts by weight (i.e., to indicate only relative ratios of constituents), it is not necessary to determine the absolute amounts or concentrations of the constituents (either in whole or individually), because the benefit of production may result. from the relative proportions of the respective constituents rather than from their absolute quantities or concentrations. However, in certain embodiments, such compositions consist essentially of or consist of the constituents and a diluent (e.g., water).
Where a composition is said to comprise multiple constituents (optionally in fixed amounts or concentrations), the composition may optionally include additional constituents in addition to the constituents. However, in certain embodiments, a composition which is said to comprise several constituent constituents may actually consist essentially or consist of all the constituent constituents.
Where a composition herein is said to consist essentially of a given component, the compound preferably comprises at least 70% by weight of the component, preferably at least 90% thereof, preferably at least 95% thereof, most preferably at least 99% thereof. Preferably, a composition said to consist essentially of a given component consists of that component except one or more trace impurities.
The term particle size or pore size herein refers, respectively, to the length of the longest dimension of a given particle or pore. Both sizes can be measured using a laser particle size analyzer and / or electron microscopes (tunnel electron microscope, TEM, or scanning electron microscope, SEM). The particle number (for any given size) can be obtained using the protocols and equipment described in the Examples which relate to counting of invisible particles.
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Liquid pharmaceutical composition
The present invention provides a liquid pharmaceutical composition, conveniently as defined herein. Suitably, the composition comprises a human monoclonal antibody, suitably one which inhibits human TNF-g activity, suitably so that activation of TNF receptors is prevented. Most suitably, the liquid pharmaceutical compositions comprise adalumimab which itself suitably includes any biosimilar agents therefor. Suitably, the composition comprises a citrate buffer agent (or citrate buffer system). Suitably, the composition comprises a sugar stabilizer. The isoform profile of adalimumab in the composition, as measured (or measured) with reference to the integral area of the main peak of adalimumab in an electropherogram formed during isoelectronic focusing (preferably capillary electrochemical focusing as described herein or any other standard isoelectronic focusing methods well known in the art) ), does not change by more than 20% when exposed to light exposure (appropriate 7 hour exposure to 765 W / m ² light, preferably in accordance with current European Medicines Agency (EMA) ICH QlB guidelines, appropriate document
CPMP / ICH / 279/95). Suitably, the composition is either (substantially or completely) free of phosphate buffer agents (e.g., sodium dihydrogen phosphate, disodium hydrogen phosphate) or comprises a phosphate buffer system (including one or more phosphate buffer agents and / or corresponding acid / base conjugates) at a concentration not exceeding 0, l mM. Suitably, the composition has a pH value above or equal to 5.4. Suitably, the composition is (substantially or completely) free of arginine or comprises arginine at a concentration not exceeding 0.1 µM. Alternatively or additionally, the composition may conveniently include any one or more additional ingredients defined herein in connection with a liquid pharmaceutical composition (i.e., including surfactant, exclusive arginine, etc.), optionally in any amount, concentration or form determined here; and wherein the composition optionally exhibits any one or more parameters or properties given herein in connection with a liquid pharmaceutical composition (e.g., pH, osmolality).
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The preparation advantageously provides alternative and improved liquid pharmaceutical compositions which generally exhibit better stability and viability than the prior art. As shown herein (see Examples), the liquid pharmaceutical formulations of the preparation have comparable or improved properties as compared to conventional formulations of adalimumab, for example the commercially available formulation Humira® when subjected to various stressful conditions (thermal, mechanical and light). Their performance is also generally comparable to or better than many other comparison formulations that underwent the same stress test. Since these stressful conditions are highly representative of the type of stresses to which such formulations are subjected during manufacture, transport and storage, they provide an excellent indication of the benefits of production. Such good stability can be achieved with less complex formulations with fewer excipients,
was considered surprising given the general teaching technique. in the known adalimumab Adalimumab, which is available in trade in HUMIRA®- formulations, and its method of preparation, are described in WO97 / 29131
(BASF) such as D2E7 and elsewhere in the prior art. It is described as having a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3 and a heavy chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4 (wO97 / 29131). In addition, the D2E7 antibody is described as having a variable light chain region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a variable heavy chain region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2 (WO97 / 29131).
Adalimumab's medical indications and function have been described above.
In the context of the invention, adalimumab includes biosimilar agents as defined above, and those skilled in the art will readily understand the scope of the term adalimumab in the context of production.
In one embodiment, the liquid pharmaceutical composition comprises adalimumab at a concentration of from about 5 to about 150 mg / ml, preferably from about 25 to about 75 mg / ml. For example, adaliDK 2020 00030 U1 mumab may be present in the formulation at a concentration of about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, or about 75 mg / ml. In one embodiment, adalimumab is present at a concentration of from about 45 to about 55 mg / ml. In one embodiment, adalimumab is present at a concentration of about 50 mg / ml.
Buffer, buffer and pH
Preferably, the liquid pharmaceutical composition is a buffered solution whose pH is stabilized by a buffer agent (or buffer system), suitably in combination with a corresponding acid / base of the buffer agent. As such, the liquid pharmaceutical composition comprises suitably a buffering agent as defined herein. Preferably, the liquid pharmaceutical composition further comprises a corresponding acid / base, wherein the corresponding acid / base corresponds to the corresponding acid or base of the buffer, depending on whether the buffer itself is a base or an acid, respectively. Taken together, the buffering agent and its corresponding acid / base may be considered a buffer system. Thus, the liquid pharmaceutical composition comprises a buffer system (preferably comprising one or more buffering agents and one or more corresponding acids / bases), and any concentration determined in connection with the buffer system generally relates to the combined concentrations of buffering agents and corresponding acids / bases. Suitably, any buffer system comprises a weak acid and a weak base (see definitions above).
Suitably, the buffering agent is a citrate buffering agent. Suitably, the citrate buffer is a citrate salt, suitably comprising anionic citrate and one or more pharmaceutically acceptable countercations. A suitable citrate salt may include a metal citrate salt (e.g., an alkali metal citrate or an alkaline earth metal citrate) or a non-metal citrate salt (e.g., ammonium citrate, triethylammonium citrate). In a particular embodiment, the buffering agent (and citrate salt) is sodium citrate.
Suitably, the liquid pharmaceutical composition comprises an acid / base conjugate of the buffer, most suitably citric acid as the corresponding acid to a citrate salt. The combination of the buffering agent and its corresponding acid / base forms a buffer system. Preferably, the liquid pharmaceutical composition comprises the buffering agent and its cores
DK 2020 00030 U1 sponding acid / base, suitably such that the buffering agent and its corresponding acid / base are present together at a level (i.e. absolute amount or concentration) and in a relative amount (or concentration) sufficient to give the desired pH value for the composition. The buffer system may be formed by simply mixing the buffer with its corresponding acid / base or alternatively may be formed by mixing an acid or base with either the buffer or its corresponding acid / base to form in situ the desired mixture of buffer and corresponding acid / base. For example, the buffer system can be formed by simply mixing the citrate buffer agent (e.g., sodium citrate) with its corresponding acid / base (i.e. citric acid), suitably in a ratio suitable to produce the desired pH value. Alternatively, the buffer system may be formed by adding a base (e.g., sodium hydroxide) to the acid / base conjugate (i.e., citric acid) of the citrate buffer, preferably in an amount appropriate to provide the desired pH and mixing of the buffer (e.g., sodium citation) and the corresponding acid / base (i.e., citric acid). Alternatively, any of the methods for forming the buffer system can be used and the pH value can be adjusted to the discretion of either adding additional acid (preferably strong acid such as HCl) or additional base (preferably strong base such as sodium hydroxide) until the required pH is reached. value is reached.
The buffer system is most suitably a citrate buffer system, suitably comprising a citrate salt and citric acid.
Suitably, the liquid pharmaceutical composition comprises at most one buffering agent.
Suitably, the liquid pharmaceutical composition comprises at most one buffering agent.
Suitably, the liquid pharmaceutical composition has a pH greater than or equal to 5.0, suitably greater than or equal to 5.4. Suitably, the liquid pharmaceutical composition has a pH less than or equal to 6.7, suitably less than 6.5.
In a particular embodiment, especially where the buffering agent is a citrate buffering agent, the liquid pharmaceutical composition has a pH between 5.2 and 6.2, more suitably between 5.4 and 6.0. In a particular embodiment, the liquid pharmaceutical composition has a pH between 5.7 and 5.9. In a particular embodiment, the liquid pharmaceutical composition 2020 00030 U1 spoon composition has a pH of about 5.8.
Suitably, the liquid pharmaceutical composition comprises a buffer system (suitably a citrate buffer system comprising a citrate buffer agent) at a concentration of from about 2 to about 50 mM. In one embodiment, the buffer system (s) are present at a concentration of between 5 and 14 mM, most suitably about 10 mM. In one embodiment, the liquid pharmaceutical composition comprises a sodium citrate / citric acid buffer system at a concentration of 10 mM. This suitably includes where the buffering agent (e.g., sodium citrate) is formed by the addition of a strong base (e.g., sodium hydroxide) to the corresponding acid to the buffering agent (e.g., citric acid).
The liquid pharmaceutical composition preferably comprises the buffer elements (preferably citrate buffer elements) at a concentration of from about 0.38 g / ml to about 9.6 mg / ml. In one embodiment, the buffer element is present at a concentration of between 0.96 mg / ml and 2.69 mg / ml, preferably about 1.9 mg / ml, most suitably about 1.9 mg / ml. This includes where the buffer (e.g., sodium citrate) is formed by the addition of a strong base (e.g., sodium hydroxide) to the corresponding acid to the buffer (e.g., citric acid).
The liquid pharmaceutical composition suitably comprises the buffer system (suitably the citrate buffer system) in a buffer to adalimumab molar ratio of from about 5: 1 to about 145: 1. In one embodiment, the buffer system is present in a buffer ratio of adalimumab buffer of from about 14: 1 to about 40: 1, most suitably about 29: 1. In one embodiment, the buffer system is present at a concentration of 29: 1. This includes where the buffering agents (e.g., sodium citrate) are formed by the addition of a strong base (e.g., sodium hydroxide) to the corresponding acid to the buffer (e.g., citric acid).
As illustrated in the example section, liquid pharmaceutical compositions according to the invention, including a citrate buffer system, perform particularly well in strain tests, particularly in terms of fragmentation and protein unfolding, which may be important indicators of stability and drug product durability. In addition, liquid pharmaceutical compositions whose citrate buffer system maintains a stable pH of 5.8 perform particularly well.
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sugar stabilizer
Suitably, the liquid pharmaceutical composition comprises a stabilizer, most suitably a sugar stabilizer. Such a component facilitates appropriate maintenance of the structural integrity of the biopharmaceutical, especially during freezing and / or freeze-drying and / or storage (in particular under stress exposure).
The liquid pharmaceutical composition may comprise one or more sugar stabilizers, although only a single sugar stabilizer is present in preferred embodiments.
Suitably, the sugar stabilizer is a sugar poly alcohol (including sugar alcohols) and / or a disaccharide.
The sugar stabilizer is suitably selected from the group including trehalose, mannitol, sucrose, sorbitol, maltose, lactose, xylitol, arabitol, erythritol, lactitol, maltitol, inositol.
In a particular embodiment, the sugar stabilizer is selected from the group including trehalose, mannitol, sucrose, maltose, lactose, xylitol, arabitol, erythritol, lactitol, maltitol, inositol.
In a particular embodiment, the sugar stabilizer is a non-reducing sugar, optionally a non-reducing sugar, listed anywhere herein.
In a particular embodiment, the sugar stabilizer is selected from the group including trehalose and mannitol.
In a particular embodiment, the sugar stabilizer is trehalose. Trehalose is a particularly advantageous sugar stabilizer for use with a citrate buffer agent / buffer system in liquid adalimumab formulations.
Suitably the liquid pharmaceutical formulation comprises at most one sugar stabilizer, suitably at most one sugar polyol and / or one disaccharide. Suitably, the liquid pharmaceutical composition comprises trehalose as the sole sugar stabilizer.
Suitably, the trehalose used to form the liquid pharmaceutical composition is trehalose dihydrate, although all amounts determined in connection with trehalose are appropriately (unless otherwise stated - as in the Examples) for pure, anhydrous trehalose. Such quantities
DK 2020 00030 U1 can be converted to an amount of trehalose dihydrate using an appropriate multiplier. In addition, an amount of trehalose dihydrate for assessing whether a given formulation falls within some of the trehalose amount definitions given herein can be readily converted to a corresponding amount of pure, anhydrous trehalose (with a corresponding mole number) by using the multiplier inversely. This principle can be used for any sugar stabilizer component. Concentrations, when given as a molar concentration, will, of course, be the same regardless of the hydration state of the sugar stabilizer.
Suitably, the liquid pharmaceutical composition comprises the sugar stabilizer (most suitably trehalose) at a concentration of from 50 to about 400 mM, more suitably from about 100 to about 300 mM, more suitably from about 150 to about 250 mM. In one embodiment, the sugar stabilizer is present at a concentration of between 190 and 210 mM, most suitably about 200 mM. In one embodiment, trehalose is present at a concentration of 200 mM.
Suitably, the liquid pharmaceutical composition comprises the sugar stabilizer (most suitably trehalose) at a concentration of from about 15 mg / ml to about 140 mg / ml, more suitably from about 5 mg / ml to about 100 mg / ml, more suitably from about 45 mg. / l to 80 mg / l. In one embodiment, the sugar stabilizer is present at a concentration of between 65 mg / l and 72 mg / l, most suitably about 68 mg / ml. In a particular embodiment, trehalose is present at a concentration of about 68 mg / ml (which is equivalent to about 75.7 mg / ml trehalose dihydrate).
The liquid pharmaceutical composition suitably comprises the sugar stabilizer (most suitably trehalose) in a sugar-to-adalimumab molar ratio of from about 145: 1 to about 1150: 1, more suitably from about 290: 1 to about 860: 1, more suitably from about 430: 1 to about 720: 1. In one embodiment, the sugar stabilizer is present in a molar ratio of sugar stabilizer to adalimumab of from about 550: 1 to about 605: 1, most suitably about 576: 1. In one embodiment, trehalose is present in a mole ratio of trehalose to adalimumab of approximately 576: 1.
As shown in the example section, liquid pharmaceutical compositions according to the invention, including a sugar stabilizer as defined herein, perform particularly well in stress tests, especially with regard to
DK 2020 00030 U1 aggregation, fragmentation and protein unfolding, which may be important indications of stability and drug product durability. In addition, liquid pharmaceutical compositions comprising trehalose as a sugar stabilizer perform particularly well.
diluent
The liquid pharmaceutical compositions of the invention may include any or more pharmaceutically acceptable diluents or a mixture thereof. Most suitably, the liquid pharmaceutical composition is an aqueous pharmaceutical composition. Most suitably, the diluent is water and preferably water alone. The water is appropriate water for injection (WFI).
Suitably, the diluent may comprise the rest of the constituents of a given liquid pharmaceutical composition, for example, so that the total weight percentages are 100%. Suitably, any concentration given herein in relation to any constituent of the liquid pharmaceutical composition represents the concentration of the constituent in (and preferably dissolved in) the diluent in admixture with any other constituent.
The liquid pharmaceutical composition according to the preparation is suitably a solution and is suitably (substantially or completely) free of particles or precipitates.
Absent or sparsely present constituents
Little / no arginine.
The liquid pharmaceutical composition is either (substantially or completely) free of arginine (preferably L-arginine) and comprises arginine at a concentration of at most 0.1 mM, more suitably at most 0.01 mM, most suitably at most 0.001 mM.
The liquid pharmaceutical composition is either (substantially or completely) free of arginine (preferably L-arginine) or comprises arginine in a mole ratio of arginine to buffer system of not more than 1: 150 (i.e., less than or equal to one mole of arginine for each 150 moles of buffering agent or buffer system), more appropriate not more than 1: 1500, most appropriate 1: 15,000.
The liquid pharmaceutical composition is either (substantially or completely) free of arginine or includes arginine in a weight ratio of arginine to adalimumab of not more than 1: 3000 (ie less than or equal to one part of arginine by weight for each 3000 parts adalimumab by weight), more appropriately not more than 1: 30,000, most appropriately not more than 1: 300,000.
The liquid pharmaceutical composition is either (substantially or completely) free of arginine or comprises arginine in a mole ratio of arginine to adalimumab of not more than 1: 3.75 (i.e., less than or equal to one mole of arginine for each 3.75 moles adalimumab), more appropriately at most 1: 37.5, most appropriately at most 1: 375.
As explained herein, such references to arginine in the context of their presence or not in liquid pharmaceutical compositions relate to the corresponding free amino acid (s) and not amino acid residue (s) covalently incorporated as part of a major compound such as a peptide or protein .
As shown in the example section, liquid pharmaceutical compositions according to the invention which (substantially or completely) exclude arginine, perform particularly well in stress tests, particularly with regard to accumulation, fragmentation and protein unfolding.
Few / no amino acids.
Suitably, the liquid pharmaceutical composition is either (substantially or completely) free of amino acids or comprises one or more amino acids at a (total) concentration of not more than 0.1 mM, more suitably not more than 0.01 mM, most suitably 0.001 mM.
Suitably, the liquid pharmaceutical composition is either (substantially or completely) free of amino acids or comprises one or more amino acids in a (total) amino acid to buffer system ratio of not more than 1: 150 (i.e., less than or equal to one mole of amino acids for every 150 moles of buffer system), more appropriately not more than 1: 1500, most appropriately 1: 15,000
Suitably, the liquid pharmaceutical composition is either (substantially or completely) free of amino acids or comprises one or more amino acids in a (total) weight ratio of amino acids to adalimumab of not more than 1: 3000 (i.e., less than or equal to some amino acids after weight for each 3000 parts of adalimumab by weight), more appropriately not exceeding 1: 30,000, most appropriately exceeding 1: 300,000.
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The liquid pharmaceutical composition is either suitably (substantially or completely) free of amino acids or comprises one or more amino acids in a (total) amino acid to adalimumab molar ratio of not more than 1: 3.75 (i.e., less than or equal to one mole amino acids for each 3.75 moles of adalimumab), more suitably at most 1: 37.5, most suitably at most 1: 375.
As explained herein, such references to amino acids in the context of their presence or not in liquid pharmaceutical compositions relate to the corresponding free amino acids and not amino acid residues covalently incorporated as part of a major compound such as a peptide or protein.
The amino acids referred to in this section (and considered to be either absent or present in small quantities) may conveniently be natural and / or artificial amino acids, although they are preferably natural amino acids. In particular, the liquid pharmaceutical compositions are either (substantially or completely) free of any amino acid selected from the group including: arginine, lysine, aspartic acid and histidine; or comprises one or more of the aforementioned amino acids in an amount, concentration, molar ratio or weight ratio as previously defined with respect to amino acids.
As shown in the example section, liquid pharmaceutical compositions according to the invention which (substantially or completely) exclude amino acids or certain amino acids, as defined above, perform particularly well in stress tests, particularly with respect to accumulation, fragmentation and protein unfolding.
Scarce / no surfactants.
Suitably, the liquid pharmaceutical composition is either (substantially or completely) free of surfactants (be it cationic, anionic, amphoteric or nonionic) with the possible exception of polysorbate 80 (polyoxyethylene (20) sorbitan monoeleate) or comprises one or more several of said surfactants (optionally except for polysorbate 80) in a (total) concentration of not more than 1 mM, more appropriately not more than 0.1 mM, more appropriately not more than 0.01 mM, more appropriately not more than 0.001 mM, most suitably no more than 0, 00001 mM. The liquid pharmaceutical
In such circumstances, the composition may optionally comprise polysorbate 80 as defined herein.
Suitably, the liquid pharmaceutical composition is either (substantially or completely) free of surfactants (be it cationic, anionic, amphoteric or nonionic) with the possible exception of polysorbate 80 (polyoxyethylene (20) sorbitan monoeleate) or comprises one or more several of said surfactants (optionally without polysorbate 80) in a (total) molar ratio of surfactant to buffer agent (or buffer system) of not more than 1:10, more conveniently at most 1: 100, more appropriately at most 1: 1000, more appropriately at most 1 : 10,000, most suitably no more than 1: 100,000. The liquid pharmaceutical composition may optionally comprise polysorbate 80 as defined herein.
The liquid pharmaceutical composition is preferably either (substantially or completely) free of surfactants (be it cationic, anionic, amphoteric or non-ionic) with the possible exception of polysorbate 80 (polyoxyethylene (20) sorbitan monoeleate) or comprises one or more several of said surfactants (optionally without polysorbate 80) in a (total) weight ratio of surfactant to adalimumab of not more than 1:50 (ie less than or equal to one part by weight of surfactant for every 50 parts by weight of adalimumab ), more appropriate maximum 1: 500, more appropriate maximum 1: 5000, more appropriate maximum 1: 50,000, most appropriate maximum 1: 500,000. The liquid pharmaceutical composition may optionally comprise polysorbate 80 as defined herein.
The liquid pharmaceutical composition is preferably either (substantially or completely) free of surfactants (be it cationic, anionic, amphoteric or non-ionic) with the possible exception of polysorbate 80 (polyoxyethylene (20) sorbitan monoeleate) or comprises one or more several of said surfactants (optionally without polysorbate 80) in a (total) molar ratio of surfactants to adalimumab of not more than 3: 1, more appropriately not more than 0.3: 1, more appropriately not more than 0.003: 1, more appropriately not more than 0.0003 : 1, most suitably not more than 0.00003: 1. The liquid pharmaceutical composition may optionally comprise polysorbate 80 as defined herein.
The surfactants referred to in this section (and assessed
Preferably, either being absent or present in small amounts) may preferably be cationic, anionic, amphoteric or nonionic surfactants. Preferably, the surfactants referred to in this section (which are considered either absent or present in small amounts) include cationic, anionic and amphoteric surfactants, but nonionic surfactants may be excluded (e.g., polysorbates). and spans) or may at least optionally be free of polysorbate 80. As such, the liquid pharmaceutical composition is either (substantially or completely) free of cationic, anionic or amphoteric surfactants or comprises one or more of the surfactants in an amount , concentration, molar ratio or weight ratio not exceeding that laid down in any preceding section of this subchapter with respect to surfactants more generally.
The liquid pharmaceutical composition is either (substantially or completely) free of nonionic surfactants with the exception of polysorbate 80, or comprises one or more of said surfactants in an amount, concentration, mole ratio, or weight ratio not exceeding that of is set out in any of the preceding sections of this subchapter with respect to surfactants more generally.
The liquid pharmaceutical composition is either (substantially or completely) free of polysorbate surfactants with the optional exception of polysorbate 80 or comprises one or more of said surfactants in an amount, concentration, mole ratio, or weight ratio of not more than , set out in any of the preceding sections of this subchapter with respect to surfactants more generally. In such circumstances, the liquid pharmaceutical composition may optionally comprise polysorbate 80 as defined herein.
The liquid pharmaceutical composition is either (substantially or completely) free of surface active substances in the form of polysorbate 20 (also known as Tween 20 polyoxyethylene (20) sorbitan monolaurate) or comprises one or more of said surfactants in an amount, concentration , molar ratio, or weight ratio not exceeding that set in any of the preceding paragraphs of this subchapter with respect to surfactants more generally.
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The liquid pharmaceutical composition is preferably either (substantially or completely) free of surfactants in the form of polysorbate 80 or comprises said surfactants in an amount, concentration, molar ratio, or weight ratio as defined above with respect to surfactants. The liquid pharmaceutical composition is either (substantially or completely) free of surfactants in the form of polysorbate 80 or comprises one or more of said surfactants in an amount, concentration, mole ratio, or weight ratio not exceeding that set in a any of the preceding sections of this subchapter with respect to surfactants more generally.
As shown in the example part, liquid pharmaceutical compositions according to the invention which (substantially or completely) exclude surfactants or certain surfactants as defined above, perform particularly well in stress tests, particularly with regard to accumulation, fragmentation and protein unfolding.
Scarce / no phosphate.
The liquid pharmaceutical composition is preferably either (substantially or completely) free of phosphate buffer agents (e.g., sodium dihydrogen phosphate, disodium hydrogen phosphate) or comprises a phosphate buffer system at a concentration of at most 0.1 mM, more suitably at most 0.01 mM, most suitably not more than 0.001 mM.
Suitably, the liquid pharmaceutical composition is either (substantially or completely) free of phosphate buffer agents (e.g., sodium dihydrogen phosphate, disodium hydrogen phosphate) or comprises a phosphate buffer system in a phosphate buffer system molar ratio to any non-phosphate buffer system present at a maximum of 1: 150 (i.e. than or equal to one mole of phosphate buffer system for each 150 mole of non-phosphate buffer system present), more suitably not more than 1: 1500, most suitably not more than 1: 15,000.
Suitably, the liquid pharmaceutical composition is either (substantially or completely) free of phosphate buffer agents or comprises a phosphate buffer system in a phosphate buffer system molar ratio of at most 1: 3.75 (i.e., less than or equal to one mole of phosphate buffer system for every 3). 75 moles of adalimumab), more appropriate at most
DK 2020 00030 U1
1: 37.5, most suitably not more than 1: 375.
References to phosphate buffer agents in the context of their presence or not in liquid pharmaceutical compositions relate to any phosphate salt in any protonation state, including phosphate, monohydrogen phosphate and dihydrogen phosphate. However, any phosphate group or residue covalently incorporated as part of a larger compound is conveniently not included herein, such as a phosphorylated or glycosylated peptide or protein.
As shown in the exemplary portion, liquid pharmaceutical compositions of the invention which (substantially or completely) exclude phosphate buffer agents are particularly well-versed in stress tests, particularly with respect to accumulation, fragmentation and protein unfolding.
Any additional ingredients
Toniseringsmiddel.
Preferably, the liquid pharmaceutical composition of the invention comprises a tonicity modifier (or tonic agent) or one or more tonic agents, as defined herein.
The inclusion of a tonic agent appropriately contributes to (or increases) the overall osmolality and osmolarity of the composition. A tonizer is suitably present in the composition in an amount or concentration sufficient for the composition to be (substantially) isotonic with body fluids. A tonizer is suitably present in the composition in an amount or concentration sufficient for the composition to have an osmolarity or osmolality at an interval defined herein.
Any suitable tonic may be used. However, the tonic is suitably selected from the group including water-soluble metal salts (e.g., sodium chloride, potassium chloride, magnesium chloride, calcium chloride), water-soluble tonic sugars / sugar alcohols (e.g., glucose, sucrose, mannitol) and / or other water-soluble polyalcohols. The tonizer is preferably non-buffering (i.e., gives little or no buffering effect). As such, all metal salt tonizers are suitably non-buffering agents.
Suitably, the liquid pharmaceutical composition may comprise one or more tonic agents, preferably only a single tonic agent is present (notwithstanding any tonic effects conferred on the composition of constituents intended for a different function as defined herein).
Most preferably, the tonizing agent is or comprises a metal salt (preferably a non-buffering water-soluble metal salt). The metal salt is or is suitably a metal halide, suitably an alkali or alkaline earth metal halide, suitably an alkali metal chloride.
In a particular embodiment, the tonizing agent is or is sodium chloride. In a particular embodiment, the tonic is sodium chloride. Sodium chloride is a particularly advantageous stabilizer for use with a citrate buffer agent / buffer system in liquid adalimumab formulations.
The liquid pharmaceutical composition comprises suitably the tonizer (s) (most suitably sodium chloride) at a concentration of from about 10 to about 200 mM, more preferably from about 20 to about 100 mM, more preferably from about 25 to about 75 mM. In one embodiment, the tonic agents are present at a concentration of between 40 and 60 mM, most preferably about 50 mM. In one embodiment, sodium chloride is present at a concentration of 50 mM.
The liquid pharmaceutical composition comprises suitably the tonizing agents (most suitably sodium chloride) at a concentration of from about 0.5 mg / l to about 12 mg / ml, more suitably from about 1.2 mg / ml to about 5 mg / ml, more suitably from about 1.5 mg / ml to about 4.4 mg / ml. In one embodiment, the tonic agent (s) is present at a concentration of between 2.7 mg / ml and 3.1 mg / ml, most suitably about 2.9 mg / ml. In a particular embodiment, sodium chloride is present at a concentration of about 2.9 mg / ml.
The liquid pharmaceutical composition suitably comprises the tonizing agents (most suitably sodium chloride) in a tonic to adalimumab molar ratio of from about 30: 1 to about 580: 1, more suitably from about 60: 1 to about 290: 1, more suitably from about 70: 1 to about 220: 1. In one embodiment, the tonic agents are present in a molar ratio of tonic agent to adalimumab of from about 115: 1 to about 175: 1, suitably about 145: 1. In one embodiment, sodium chloride is present in a molar ratio of sodium chloride to adalimumab of approximately 145: 1.
As shown in the example part, liquid pharmaceutical copes
Generally, compositions of this invention, including a tonic agent as defined herein, perform particularly well in stress tests, particularly with respect to aggregation, fragmentation and protein unfolding, which may be important indicators of stability and drug product durability. In addition, pharmaceutical compositions containing sodium chloride, especially in an amount range as indicated, perform particularly well.
Surfactant.
The liquid pharmaceutical composition of the invention may comprise a surfactant or surfactant (s), as defined herein.
The inclusion of a surfactant appropriately contributes to the stabilization of the adalimumab protein.
Any suitable surfactant can be used. However, the surfactant is suitably a polysorbate (polyoxyethylene glycol sorbitan alkyl esters) or span (sorbitan alkyl esters) surfactants.
Although one or more surfactants may be included in the liquid pharmaceutical composition of the invention, preferably only a single surfactant is present, most preferably a single nonionic surfactant (preferably as defined herein).
The surfactants are suitably selected from Polysorbate 20 (polyoxyethyl (polyoxyethyl (polyoxyethyl) (polyoxyethylene (20) sorbitan monolaurate), Polysorbate 40 len (20) sorbitan monopalmitate), Polysorbate 60 len (20) sorbitan monostearate), Polysorbate (20) , sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate and / or sorbitan monooleate.
In a particular embodiment, the surfactant (s) are selected from Polysorbate 20, Polysorbate 40, Polysorbate 60 and / or Polysorbate 80. In a particular embodiment, the liquid pharmaceutical composition comprises a single surfactant selected from Polysorbate 20, Polysorbate 40 , Polysorbate 60 and Polysorbate 80.
In a particular embodiment, the surfactant is polysorbate 80 or polysorbate 20. In a particular embodiment, the surfactant is polysorbate 80.
Suitably, the liquid pharmaceutical composition comprises
The surfactant (s) (most suitably polysorbate 80) at a concentration of from about 0.0001 to about 5 mM (i.e., 0.1 µM-5 mM), more preferably from about 0.001 to about 2 mM, more preferably from about 0.01 to about 1.0 mM. In one embodiment, the surfactant (s) are present at a concentration of between 0.72 and 0.80 mM, most preferably about 0.76 mM. In one embodiment, polysorbate 80 is present at a concentration of 0.76 mM.
Suitably, the liquid pharmaceutical composition comprises the surfactant (s) (most suitably polysorbate 80) at a concentration of from about 0.001 mg / ml to about 5 mg / ml, more suitably from about 0.01 mg / l to about 2 more preferably from about 0.05 mg / ml to about 1.5 mg / ml. In one embodiment, the surfactant is present at a concentration of between 0.9 mg / ml and 1.1 mg / ml, most suitably about 1.0 mg / ml. In a particular embodiment, polysorbate 80 is present at a concentration of about 1.0 mg / ml.
Preferably, the liquid pharmaceutical composition comprises the surfactant / agent (most preferably polysorbate 80) in a surfactant-adalimumab molar ratio of from about 1: 3500 to about 15: 1, more preferably from about 1: 350 to about 6. : 1, more preferably from about 1:35 to about 3: 1. In one embodiment, the surfactant is present in a molar ratio of surfactant to adalimumab of from about 2.1: 1 to about 2.3: 1, most preferably about 2.2: 1. In one embodiment, polysorbate 80 is present in molar ratio of polysorbate 80 to adalimumab of about 2.2: 1.
As illustrated in the Example section, liquid pharmaceutical compositions of the invention, including a surfactant as defined herein, perform particularly well in loading experiments, particularly with regard to accumulation, fragmentation and protein unfolding, which may be important indicators of stability and drug product durability. In addition, liquid pharmaceutical compositions comprising polysorbate, especially in an amount range as prescribed, perform particularly well.
Other parameters of production
Osmolality.
The osmolality of the liquid pharmaceutical composition is pass
DK 2020 00030 U1 transmit between 200 and 405 mOsm / kg, more preferably between 220 and 390 mOsm / kg, more preferably between 230 and 350 mOsm / kg, more preferably between 240 and 340 mOsm / kg, more preferably between 260 and 320 mOsm / kg, most preferably between 280 and 310 mOsm / kg. The relative amounts and concentrations of the various constituents of the composition can be adjusted by discretion to achieve the desired osmolality, and the particular new combinations of constituents allow to achieve this to a large extent without compromising other important parameters. However, the relative amounts and concentrations of the various constituents of the composition may be suitably selected to optimize other parameters of this disclosure, including the examples and protocols set forth therein, to allow the skilled person to fulfill this purpose and to achieve some, all or all of the beneficial effects of this invention.
Proteinudfoldningstemperatur.
The protein unfolding temperature (appropriately measured via the DSF protocols defined herein) for adalimumab in the liquid pharmaceutical composition of the preparation is greater than or equal to 65 ° C, suitably higher than or equal to 70 ° C. The new combination of constituents present in the composition according to the invention allows the person skilled in the art to obtain high unfolding temperatures, which may be considered desirable from a heat stability perspective.
Parameters during exposure to heat stress.
The amount (or concentration) of aggregates (appropriately derived from adalimumab and appropriately as determined by the SE-HPLC protocols defined herein) present in the liquid pharmaceutical composition suitably increases by no more than a factor of 4 (i.e., 4 times the amount). relative to an arbitrary initial time) when the composition is heat-loaded to 40 ° C (i.e., the composition is kept at a temperature of 40 ° C) over a period of 28 days, appropriate by no more than a factor of no more than 3, adequate by no more than a factor of 2.5, appropriate by no more than a factor of 2.2.
The amount (or concentration) of fragments (appropriately derived from adalimumab and appropriately measured by the bioassay protocols defined herein)
Suitably, the 2020 202030 U1 present in the liquid pharmaceutical composition increases by no more than a factor of 4 (i.e., 4 times the amount relative to an arbitrary initial time) when the composition is heat-loaded to 40 ° C (i.e., the composition is maintained at a temperature of 40 ° C) over a period of 28 days, appropriate by no more than a factor of 3, adequate by no more than a factor of 2.5, adequate by not more than a factor of 2.2
The turbidity (appropriately measured by nephelometry in accordance with the protocols set forth herein) of the liquid pharmaceutical composition conveniently increases by no more than a factor of 2 (i.e., 2 times the amount relative to an arbitrary initial time) when the composition is heat-loaded at 40 ° (i.e. the composition is maintained at a temperature of 40 ° C) over a period of 28 days, suitably by no more than a factor of 1.5, suitably by no more than a factor of 1.2, and preferably the turbidity does not increase at all.
The pH of the liquid pharmaceutical composition changes (either by rise or fall, but usually by a decrease in pH) suitably by a maximum of 0.5 pH units when the composition is heat-loaded at 40 ° C (i.e., the composition is maintained at a temperature of 40 ° C) over a period of 28 days, suitable with no more than 0.2 pH units, adequate with no more than 0.1 pH units, most suitably does not change the pH value at all (with a decimal accuracy ).
Parameters under mechanical load exposure.
The amount (or concentration) of aggregates (preferably derived from adalimumab and suitably as determined by the SE-HPLC protocols defined herein) suitably in the liquid pharmaceutical composition increases suitably by no more than a factor of 2 (i.e. 2 times the amount relative to an arbitrary onset time) when the composition is mechanically loaded (i.e., shaken according to the protocols herein) over a period of 48 hours, appropriate by no more than a factor of 1.5, adequate by no more than a factor of 1.2, adequate by not more than a factor of 1.1.
The amount (or concentration) of fragments (appropriately derived from adalimumab and appropriately measured by the bioassay protocols defined herein) present in the liquid pharmaceutical composition suitably increases by no more than a factor of 2 (i.e. twice the amount relative to an arbitDK 2020 00030 U1 when the composition is mechanically loaded (i.e. shaken according to the protocols herein) over a period of 48 hours, appropriate by no more than a factor of 1.5, adequate by no more than a factor of 1.2, adequate by no more than a factor of 1.1.
The turbidity (appropriately measured by nephelometry in accordance with the protocols set forth herein) of the liquid pharmaceutical composition suitably increases by no more than a factor of 2 (i.e. 2 times the amount relative to an arbitrary initial time) when the composition is mechanically loaded (i.e., shaken according to the protocols given herein) over a period of 48 hours, appropriate by no more than a factor of 1.5, adequate by no more than a factor of 1.2, adequate by no more than a factor of 1.1, and suitably the turbidity does not increase at all .
The pH of the liquid pharmaceutical composition changes (either by rise or fall, but usually by a decrease in pH) suitably by no more than 0.5 pH units when the composition is mechanically loaded (i.e., shaken according to the protocols given herein) over a period of 48 hours, appropriate with no more than 0.2 pH units, adequate with no more than 0.1 pH units, most suitably, the pH does not change at all (with a decimal accuracy).
Parameters under exposure to light exposure.
The amount (or concentration) of aggregates (appropriately derived from adalimumab and appropriately as determined by the SE-HPLC protocols defined herein) suitably in the liquid pharmaceutical composition increases suitably by a maximum of a factor of 50 (i.e., 50 times the amount relative to an arbitrary starting time) when the composition is exposed to light (i.e., the composition is exposed to light in accordance with the protocols described herein, i.e., 7 hours at 765 W / m ² ), appropriately by no more than one factor 45, appropriate by no more than one factor 35, appropriate by no more than a factor of 30.
The amount (or concentration) of fragments (appropriately derived from adalimumab and appropriately measured by the bioassay protocols defined herein) suitably in the liquid pharmaceutical composition increases suitably by no more than a factor of 4 (i.e., 4 times the amount relative to an arbitrary onset time), when the composition is exposed to light (i.e. samDK 2020 00030 U1 the composition is exposed to light in accordance with the protocols described herein, i.e. 7 hours at 765 W / m ² ), appropriate by no more than one factor 3, appropriate by no more than one factor 2 , 5, appropriate by no more than one factor 2.
Conveniently, the turbidity (preferably measured by nephelometry in accordance with the protocols set forth herein) of the liquid pharmaceutical composition increases by no more than a factor of 2 (i.e., 2 times the amount relative to an arbitrary initial time) when the composition is exposed to light (i.e., the composition is exposed to light in accordance with the protocols described herein, i.e., 7 hours at 765 W / m ² ), appropriately by no more than a factor of 1.5, conveniently by no more than a factor of 1.2, and suitably the turbidity does not increase at all.
The pH of the liquid pharmaceutical composition changes (either by rise or fall, but usually by a decrease in pH) suitably by a maximum of 0.5 pH units when the composition is exposed to light (i.e., the composition is exposed to light in accordance with the protocols described herein, i.e., 7 hours at 765 W / m ² ), suitably with no more than 0.2 pH units, conveniently with no more than 0.1 pH units, most suitably do not change the pH value at all ( with a decimal accuracy).
The isoform profile of adalimumab, in particular the integral area of the main peak, in the liquid pharmaceutical composition (appropriately measured via isoelectronic focusing, appropriate cIEF, appropriately using an iCE280, appropriately using a program as presented herein) is suitably reasonably stable when the composition is exposed to light (i.e., the composition is exposed to light in accordance with the programs described herein, i.e., 7 hours at 765 W / m ^2. Light exposure is preferably performed in accordance with current ICH QlB guidelines of the European Medicines Agency (regarding photostability testing of new active agents). constituents and medical products), preferably as illustrated by document CPMP / ICH / 279 / 95. Appropriately changes the isoform profile of adalimumab in the composition, as measured by reference to the integrated area of the main peak for adalimumab in an electropherogram formed by isoelectronic focusing (appropriate isoelectronic focusing which describe t, or any other standard isoelectronic focusing methods well known in the art), say no more than 20% upon exposure to
DK 2020 00030 U1 light load (appropriate 7 hour exposure to 765 W / m ² , appropriate in accordance with current ICH Q1B guidelines of the European Medicines Agency, appropriate document CPMP / ICH / 279/95). Conveniently, the isoform profile of adalimumab in the composition (appropriately measured by reference to the integrated area of the main peak for adalimumab) does not change more than 15% (be it by increasing or decreasing the peak area) by light exposure in this way, suitably not by more than 10 %, adequate by no more than 5%, adequate by no more than 4%. The adalimumab compositions of the prior art exhibit poor isoform profile stability due to a photo-oxidation phenomenon which is suitably inhibited by the use of a citrate buffer in the particular liquid pharmaceutical compositions of the invention. As such, adalimumab in the liquid pharmaceutical compositions of the invention exhibits superior photostability. In a particular embodiment, in the liquid pharmaceutical composition of the invention, adalimumab has a photostability greater than the commercially available HUMIRA® formulations as defined herein (appropriate as indicated by the relative isoform profiles, particularly in connection with the adalimumab head). It will be appreciated that the major peak corresponding to adalimumab refers to the main adalimuma peak in an electropherogram (i.e., the one with the largest integrated peak area) obtained by isoelectric focusing measurements, suitably designed as defined herein. The electropherogram is recorded appropriately at 280 nm, suitably over the pre-focusing and focusing periods of 1 and 6 minutes, respectively, suitably at a voltage of 1500 V (pre-focusing) and 3000 V (focusing). The peaks are suitably absorbent peaks, suitably at 280 nm. Suitably, the separation of the various isoforms is achieved using 100 mM sodium hydroxide (in 0.1% methylcellulose) as the cathode solution and preferably 80 mM ophosphoric acid (in 0.1% methylcellulose) as the anode solution. Samples for isoelectronic focusing measurements are appropriately prepared according to a specification defined herein or elsewhere in the prior art, but may in particular comprise one or more or all among: i) purification; ii) removal of salts (eg by centrifugation, appropriate with a cut-off at 10 kDa); iii) pre-dilution to obtain a protein content of about 5.0 mg / ml, suitably about 1.0 mg / ml, the diluent optionally including methyl cellulose, Pharmalyte 5-8 (GE Healthcare), Pharmalyte 8-10.5 (GE Healthcare) .
DK 2020 00030 U1 low pi marker 7.05 (Protein Simple), high pi marker 9.50 (Protein Simple) and purified water; iv) one or more additional centrifugation steps (e.g., 3 minutes at 10000 rpm, suitably followed by 2 minutes at 7000 rpm, suitably with a sample of 150 microliters. using an iCE280 system from Protein Simple.
Methods for stabilizing antibody.
In view of the aforementioned points in this subsection and the data reproduced in the Examples, the preparation also provides a method for stabilizing liquid adalimumab compositions (chemical and / or physical, optionally with respect to one or more of the aforementioned parameters / properties), comprising admixing adalumimab with any relevant constituent necessary to form a liquid pharmaceutical composition as defined herein. Suitably, various embodiments will require mixing of various combinations of constituents, potentially in different amounts, and those skilled in the art can readily deduce such combinations and amounts by referring to the foregoing description of the liquid pharmaceutical composition. Such various combinations of constituents can stabilize liquid adalimumab compositions in various respects. For example, mixing adalimumab with the aforementioned ingredients to form a liquid pharmaceutical composition as defined herein can stabilize adalimumab by:
i) increasing adalimumab's protein unfolding temperature;
ii) inhibiting the formation of aggregates;
iii) inhibiting the formation of fragments iv) inhibiting the formation of invisible particles (either <25 microns or <10 microns);
v) inhibiting turbidification;
vi) inhibiting pH changes;
vii) to inhibit photooxidation, and / or viii) to reduce instability after freeze / thaw cycles.
The generation, as such, provides a method for obtaining one, some, or all of the following beneficial advantages:
DK 2020 00030 U1
i) increased protein unfolding temperatures for adalimumab;
ii) inhibition of aggregate formation;
iii) inhibition of fragment formation;
iv) inhibition of formation of invisible particles (either <25 microns or <10 microns);
v) inhibition of turbidification;
vi) inhibition of pH changes;
(vii) photooxidation inhibition;
(viii) reduced instability following freeze / thaw cycles and / or ix) stabilization of the isoform profile (in particular with respect to the main peak as defined herein);
wherein the method comprises preparing a liquid pharmaceutical composition of adalimumab as defined herein.
Suitably, the liquid pharmaceutical compositions of the invention have a shelf life of at least 6 months, suitably at least 12 months, suitably at least 18 months, more suitably at least 24 months. Suitably, the liquid pharmaceutical compositions of the invention have a shelf life of at least 6 months, suitably at least 12 months, suitably at least 18 months, more suitably at least 24 months, at a temperature of 2-8 ° C.
To enable the skilled person to optimize essential stability properties.
The new combination of constituents presented for use in liquid pharmaceutical compositions of the invention enables those skilled in the art to form (and, by reasonable judgment, fine-tune) compositions which exhibit comparable or improved properties to those of the prior art. In particular, this specification now provides all necessary tools for optimizing the formulation stability for those skilled in the art, in particular for optimizing one or more among: aggregation inhibition, fragmentation, protein unfolding, precipitation, pH sliding and oxidation (especially photooxidation). In addition, those skilled in the art are guided to achieve such optimizations (by varying the compositions by discretion) and to minimize harmful side effects along the way. The present disclosure sets forth the person skilled in the art
DK 2020 00030 U1 is capable of exerting production over its entire scope of protection to form all kinds of specific compositions which exhibit comparable or improved properties to the prior art compositions, and this can be achieved using fewer ingredients.
Particular embodiments
In one embodiment, the liquid pharmaceutical composition comprises:
- adalimumab;
a citrate buffer agent (e.g., sodium citrate) (or a citrate buffer system);
- a sugar stabilizer (eg trehalose); and
a surfactant (eg polysorbate 80).
In one embodiment, the liquid pharmaceutical composition comprises:
- adalimumab;
a citrate buffer agent (e.g., sodium citrate) (or citrate buffer system);
- a sugar stabilizer (eg trehalose);
a tonic agent (eg sodium chloride); and
- optionally a surfactant (eg polysorbate 80).
In one embodiment, the liquid pharmaceutical composition comprises adalimumab, citrate buffer system and a sugar stabilizer in a molar ratio of 1: 14-40: 288-865, respectively. In one embodiment, the liquid pharmaceutical composition comprises adalimumab, citrate buffer system, sugar stabilizer and a tonizing agent in a molar ratio of 1: 1440: 288-865: 28-576, respectively. In one embodiment, the liquid pharmaceutical composition comprises adalimumab, citrate buffer system, sugar stabilizer, tonic and surfactant in a mole ratio of 1: 14-40: 288-865: 28-576: 0.1-3.2, respectively.
In one embodiment, the liquid pharmaceutical composition comprises adalimumab, citrate buffer system and a sugar stabilizer in a molar ratio of 1: 14-40: 548-605, respectively. In one embodiment, the liquid pharmaceutical composition comprises adalimumab, citrate buffer system, sugar stabilizer and a tonizing agent in a molar ratio of 1: 14DK 2020 00030 U1: 548-605: 115-173, respectively. In one embodiment, the liquid pharmaceutical composition comprises adalimumab, citrate buffer system, sugar stabilizer, tonic and surfactant in a molar ratio of 1: 14-40: 548-605: 115-173: 2-2.4, respectively.
In one embodiment, the liquid pharmaceutical composition comprises adalimumab, sodium citrate / citric acid buffer system and trehalose at a molar ratio of 1: 5.7-145: 288-865, respectively. In one embodiment, the liquid pharmaceutical composition comprises adalimumab, sodium citrate / citric acid buffer system, trehalose and sodium chloride in a molar ratio of 1: 5.7-145: 288-865: 28-576, respectively. In one embodiment, the liquid pharmaceutical composition comprises adalimumab, sodium citrate / citric acid buffer system, trehalose, sodium chloride and polysorbate 80 in a molar ratio of 1: 5.7-145: 288-865: 28-576: 0.002-11, respectively.
In one embodiment, the liquid pharmaceutical composition comprises adalimumab, sodium citrate / citric acid buffer system and trehalose in a molar ratio of 1: 14-40: 548-605, respectively. In one embodiment, the liquid pharmaceutical composition comprises adalimumab, sodium citrate / citric acid buffer system, trehalose and sodium chloride in a molar ratio of 1: 14-40: 548-605: 115-173, respectively. In one embodiment, the liquid pharmaceutical composition comprises adalimumab, sodium citrate / citric acid buffer system, trehalose, sodium chloride and polysorbate 80 in a molar ratio of 1: 14-40: 548-605: 115-173: 2-2.4, respectively.
In one embodiment, the liquid pharmaceutical composition comprises adalimumab, sodium citrate / citric acid buffer system and trehalose at a molar ratio of 1: 28.8: 576, respectively. In one embodiment, the liquid pharmaceutical composition comprises adalimumab, sodium citrate / citric acid buffer system, trehalose and sodium chloride in a mole ratio of 1: 28.8: 576: 144, respectively. In one embodiment, the liquid pharmaceutical composition comprises adalimumab, sodium citrate / citric acid buffer system, trehalose, sodium chloride and polysorbate 80 at a molar ratio of 1: 28.8: 576: 144: 2.2, respectively.
In one embodiment, the liquid pharmaceutical composition comprises adalimumab, citrate buffer elements and trehalose at a molar ratio of 25-75: 0.38-9.6: 15-140, respectively. In one embodiment, the liquid pharmaceutical composition comprises adalimumab, citrate buffer eleK 2020 00030 U1 ments, trehalose and sodium chloride in a molar ratio of 25-75: 0.38-9.6: 15140: 0.5-12, respectively. In one embodiment, the liquid pharmaceutical composition comprises adalimumab, citrate buffer elements, trehalose, sodium chloride and polysorbate 80 in a molar ratio of 25-75: 0.38-9.6: 15-140: 0.5-12: 0.01-2, respectively.
In one embodiment, the liquid pharmaceutical composition comprises adalimumab, citrate buffer elements and trehalose at a molar ratio of 45-55: 0.96-2.69: 65-72, respectively. In one embodiment, the liquid pharmaceutical composition comprises adalimumab, citrate buffer system, trehalose and sodium chloride in a molar ratio of 45-55: 0.96-2.69: 6572: 2.7-3.1, respectively. In one embodiment, the liquid pharmaceutical composition comprises adalimumab, citrate buffer elements, trehalose, sodium chloride and polysorbate 80 in a molar ratio of 45-55: 0.96-2.69: 65-72: 2.7-3.1: 0.9- 1.1, respectively.
In one embodiment, the liquid pharmaceutical composition comprises adalimumab, citrate buffer elements and trehalose at a molar ratio of 50: 1.9: 68, respectively. In one embodiment, the liquid pharmaceutical composition comprises adalimumab, citrate buffer elements, trehalose and sodium chloride in a molar ratio of 50: 1.9: 68: 2.9, respectively. In one embodiment, the liquid pharmaceutical composition comprises adalimumab, citrate buffer elements, trehalose, sodium chloride and polysorbate 80 at a mole ratio of 50: 1.9: 68: 2.9: 1, respectively.
Any of the aforementioned embodiments with respect to mole and / or weight ratios of the various constituents can be further defined by reference to the (substantial or complete) absence of small amounts of constituents such as arginine, amino acids, surfactants (optionally with the exception of polysorbate 80). and / or phosphate buffer agents / systems as defined anywhere herein.
Those skilled in the art will appreciate that the buffering agent (e.g., sodium citrate) or the buffer system (e.g., citrate / citric acid) of any of the aforementioned embodiments may be directly incorporated into the compositions or may be formed in situ, for example, by an acid -base reaction, preferably by reacting a corresponding acid to the buffer (eg citric acid) with a base (eg sodium hydroxide). Regardless of the method used to provide or produce the buffering agent or buffer systemDK 2020 00030 U1, the resulting composition ultimately has an appropriate balance between the buffering agent and any corresponding acid / base to obtain the desired pH value.
In one embodiment, the liquid pharmaceutical composition comprises the following:
- adalimumab;
a citrate buffer agent (e.g., sodium citrate) (or citrate buffer system);
- a sugar stabilizer (eg trehalose)
a tonic agent (eg sodium chloride);
- optionally a surfactant (eg polysorbate 80); and
- water (of injection purity);
wherein the composition:
o is (substantially or completely) free of arginine (preferably L-arginine) or comprises arginine at a concentration not exceeding 0.1 mM;
o is (substantially or completely) free of amino acids or comprises one or more amino acids at a (total) concentration not exceeding 0.1 mM;
o are (substantially or completely) free of surfactants, with the exception of polysorbate 80, or comprise one or more of said surfactants (optionally exclusive polysorbate 80) at a (total) concentration not exceeding 1 mM; and / or o are (substantially or completely) free of phosphate buffer agents (e.g., sodium dihydrogen phosphate, disodium hydrogen phosphate) or comprise a phosphate buffer system at a concentration not exceeding 0.1 mM.
In one embodiment, the liquid pharmaceutical composition comprises the following:
- Adalimumab (appropriate at a concentration as defined herein);
- 5 to 14 mM citrate buffer system (eg citrate / citric acid);
- 100 to about 300 mM sugar stabilizer (eg trehalose);
- 10 to about 200 mM tonizing agent (e.g., sodium chloride);
optionally 0.05 mg / ml to about 1.5 mg / ml surfactant
DK 2020 00030 U1 (eg polysorbate 80), and
- water (of injection purity);
wherein the composition:
o has a pH of between 5.4 and 6.2 (e.g. 5.8);
o is (substantially or completely) free of arginine (preferably L-arginine) or comprises arginine at a concentration not exceeding 0.1 mM;
o is (substantially or completely) free of amino acids or comprises one or more amino acids at a (total) concentration not exceeding 0.1 mM;
o are (substantially or completely) free of surfactants, with the exception of polysorbate 80, or comprise one or more of said surfactants (optionally exclusive polysorbate 80) at a (total) concentration not exceeding 1 mM; and / or o are (substantially or completely) free of phosphate buffer agents (e.g., sodium dihydrogen phosphate, disodium hydrogen phosphate) or comprise a phosphate buffer system at a concentration not exceeding 0.1 mM.
In one embodiment, the liquid pharmaceutical composition comprises the following:
25 to about 75 mg / ml adalimumab;
- 2 to about 50 mM sodium citate / citric acid buffer system;
- 100 to about 300 mM trehalose;
10 to about 200 mM sodium chloride;
optionally 0.001 mg / ml to about 5 mg / ml polysorbate 80; and
- water (of injection purity);
wherein the composition:
o has a pH of between 5.4 and 6.0;
o is (substantially or completely) free of arginine (preferably L-arginine) or comprises arginine at a concentration not exceeding 0.1 mM;
o is (substantially or completely) free of amino acids or comprises one or more amino acids at a (total) concentration not exceeding 0.1 mM;
DK 2020 00030 U1 o is (substantially or completely) free of surfactants with the possible exception of polysorbate 80 or comprises one or more of said surfactants at a (total) concentration not exceeding 1 mM; and / or o are (substantially or completely) free of phosphate buffer agents (e.g., sodium dihydrogen phosphate, disodium hydrogen phosphate) or comprise a phosphate buffer system at a concentration not exceeding 0.1 mM.
In one embodiment, the liquid pharmaceutical composition comprises the following:
45 to about 55 mg / ml adalimumab;
- 5 to 14 mM sodium citrate / citric acid buffer system;
- 190 to 210 mM trehalose;
- 40 to 60 mM sodium chloride;
optionally 0.9 mg / ml to 1.1 mg / ml polysorbate 80; and
- water (of injection purity);
wherein the composition:
o has a pH of between 5.7 and 5.9;
o is (substantially or completely) free of arginine (preferably L-arginine) or comprises arginine at a concentration not exceeding 0.001 mM;
o is (substantially or completely) free of amino acids or comprises one or more amino acids at a (total) concentration not exceeding 0.001 mM;
o are (substantially or completely) free of surfactants with the possible exception of polysorbate 80 or comprise one or more of said surfactants (optionally exclusive polysorbate 80) at a (total) concentration not exceeding 0.0001 mM; and / or are (substantially or completely) free of phosphate buffer agents (e.g., sodium dihydrogen phosphate, disodium hydrogen phosphate) or comprise a phosphate buffer system at a concentration not exceeding 0.001 mM.
In one embodiment, the liquid pharmaceutical composition comprises the following:
DK 2020 00030 U1
- 50 mg / ml adalimumab;
- 10 mM sodium citrate / citric acid buffer system;
- 200 mM trehalose;
- 50 mM sodium chloride;
optionally 1.0 mg / ml polysorbate 80; and
- water (of injection purity);
wherein the composition:
o has a pH of 5.8;
o is free of arginine;
o is free of amino acids;
o is free from surfactants; and o is free of phosphate buffer systems.
Preferably, the liquid pharmaceutical composition consists essentially of:
25 to about 75 mg / ml adalimumab;
- 2 to about 50 mM sodium citrate / citric acid buffer system;
- 100 to about 300 mM trehalose;
10 to about 200 mM sodium chloride; and
- water (of injection purity);
o where the composition has a pH of between 5.4 and 6.0.
Preferably, the liquid pharmaceutical composition consists essentially of:
40 to about 60 mg / ml adalimumab;
- 5 to about 15 mM sodium citrate / citric acid buffer system;
- 175 to about 225 mM trehalose;
25 to about 75 mM sodium chloride; and
- water (of injection purity);
o where the composition has a pH of between 5.7 and 5.9.
Preferably, the liquid pharmaceutical composition consists essentially of:
- 50 mg / ml adalimumab;
- 10 mM sodium citrate / citric acid buffer system;
- 200 mM trehalose;
- 50 mM sodium chloride; and
- water (of injection purity);
DK 2020 00030 U1 o where the composition has a pH of 5.8.
Suitably, the liquid pharmaceutical composition may be as presented in any of the foregoing embodiments except that the absence or low content of ingredients such as arginine, amino acids, surfactants (optionally with polysorbate 80) and phosphate buffer agents / systems rather than may be defined by reference to concentrations (i.e., molarity) may be defined instead by reference to corresponding molar ratios of the component to the buffer agent / buffer system; corresponding component weight ratio of adalimumab or corresponding component molar ratio of adalimumab. The person skilled in the art will readily deduce for each ingredient from the relevant section of this specification the specific ingredient, which mole and weight ratios correspond to which concentrations, since the relevant mole and weight ratios are listed to correspond to the respective given concentrations . For example, in the case of arginine, the possible concentrations of at most 0.1 mM, more suitably at most 0.01 mM, most suitably at most 0.001 mM, respectively, correspond to a molar ratio of arginine to at most 1: 150 ... more appropriate not more than 1: 1500, most suitably not more than 1: 15,000, for a weight ratio of arganine to adalimumab of not more than 1: 3000 .... more appropriately not more than 1: 30,000 .... most appropriately not more than 1: 300,000, and for a mole ratio of arginine and adalimumab at most 1: 3.75 ... more appropriate at most 1: 37.5, most appropriate at most 1: 375. The same correspondences apply to amino acids, surfactants and phosphate buffering agents / systems.
Process for the preparation of a liquid pharmaceutical composition
The preparation provides a process for producing a liquid pharmaceutical composition, conveniently as defined herein. The process suitably comprises admixing any relevant constituents required to form a liquid pharmaceutical composition as defined herein in any order considered appropriate. Those skilled in the art can rely on the Examples or techniques well known in the art for the manufacture of liquid pharmaceutical compositions (especially those for injection by syringe). Different embodiments will suitably require mixing of different combinations of constituents, potentially in different amounts. Those skilled in the art can readily deduce such combinations and amounts by referring to the foregoing description of the liquid pharmaceutical composition.
The process comprises suitably admixing the relevant ingredients in preferably a diluent (e.g., water), suitably so that all ingredients (substantially or completely) dissolve in the diluent.
The process may include first preparing a premix (or pre-solution) of some or all of the ingredients (optionally with some or all of the solvent) without adalimumab, and then adalimumab itself (optionally with or pre-dissolved in any of the diluent) may be mixed in the premix (or pre-solution) ) to obtain the liquid pharmaceutical composition or a composition to which final ingredients are subsequently added to give the final liquid pharmaceutical composition. Most suitably, the premix contains all the ingredients except adalimumab and optionally also some diluent (which can be used to pre-dissolve adalimumab), suitably so that adalimumab is added to a mixture which offers optimal stabilization of adalimumab. Preferably, said premix is prepared at the desired pH for the final liquid pharmaceutical formulation.
The method comprises suitably forming a buffer system, suitably a buffer system comprising a buffer agent as defined herein. The buffer system is suitably formed in a premix prior to the addition of adalimumab, although the buffer system may be formed in the presence of adalimumab. The buffer system can be formed by simply mixing the buffer agent (supplied ready-made) with its corresponding acid / base (preferably in appropriate relative amounts to obtain the desired pH value - this can be determined by one skilled in the art either theoretically or experimentally). In the case of a citrate buffer system, this causes a mixture of sodium citrate with citric acid. Alternatively, the buffer system may be formed by the addition of a strong acid (e.g., HCl) to the buffer (e.g., Na
DK 2020 00030 U1 triumph citrate) to form in situ the corresponding acid / base (e.g. citric acid) (again preferably in appropriate relative amounts to obtain the desired pH value). Alternatively, the buffer system may be formed by the addition of a strong base (e.g., sodium hydroxide) to the corresponding acid / base (e.g., citric acid) to the buffer (e.g., sodium citrate) to form the buffer (again preferably in appropriate form). relative amounts to obtain the desired pH). The pH of the premix of liquid pharmaceutical composition may be adjusted by reasonable assessment by adding the required amount of strong base or special acid or even a quantity of buffer or corresponding acid / base.
In certain embodiments, the buffer agent and / or buffer system is distilled as a separate mixture and the buffer system is transferred to a precursor of the liquid pharmaceutical composition (comprising some or all of the components except the buffer agent and / or buffer system, suitably comprising adalimumab and potentially only adalimumab) ( for example using diafiltration until the appropriate concentration or osmolality is reached). Additional excipients may then be added if necessary to form the final liquid pharmaceutical composition. The pH can be adjusted once or before all the ingredients are present.
Any, some or all of the constituents may be pre-dissolved or premixed with a diluent prior to mixing with other constituents.
The final liquid liquid composition can be filtered, suitably to remove particulate matter. Suitable filtration is done through filters in the size below or equal to 1 μm, suitably in the size 0.22 μm. Suitably, the filtration is done through either PES filters or PVDF filters, preferably 0.22 μm PES filters.
The preparation also provides a liquid pharmaceutical composition which is obtainable by, obtained by, or obtained directly by the process of preparation described herein.
drug delivery
The preparation provides a drug dispensing device comprising a liquid pharmaceutical composition as defined.
DK 2020 00030 U1 herein. Suitably, the drug dispensing device comprises a chamber in which the pharmaceutical composition is present. Suitably, the drug dispensing device is sterile.
The drug dispensing device may be a vial, ampoule, syringe, injection pen (eg, substantially comprising a syringe) or intravenous bag. Most suitably, the drug dispensing device is a syringe, preferably an injection pen. The syringe is preferably a glass syringe. The syringe preferably comprises a needle, preferably a 29G needle.
The invention provides a process for the preparation of a drug dispensing device, preferably as defined herein, wherein the method comprises incorporating a liquid pharmaceutical composition as defined herein into a drug dispensing device. Such preparation typically comprises loading the liquid pharmaceutical composition as defined herein onto a syringe, preferably via a needle attached thereto. The needle can then be removed, replaced or remain.
According to one aspect of the manufacture, there is provided a drug dispensing device obtainable by, obtained by or obtained directly by the method of preparation defined herein.
Packing
The preparation provides a package comprising a liquid pharmaceutical composition as defined herein. Suitably, the package comprises a drug dispensing device as defined herein, suitably several drug dispensing devices. The package may comprise any suitable container for accommodating one or more drug dispensing devices.
The process provides a process for preparing a package which comprises incorporating a liquid pharmaceutical composition as defined herein into a package. This is conveniently accomplished by incorporating the liquid pharmaceutical composition into one or more drug dispensing devices and then incorporating one or more pre-filled drug dispensing devices into a container contained in the package.
The generation provides a gasket which is obtainable by is obtained
DK 2020 00030 U1 or directly obtained by a method of preparation defined herein.
Set of parts
The invention provides a set of parts comprising a drug dispensing device (without the liquid pharmaceutical composition incorporated therein), a liquid pharmaceutical composition as defined herein (optionally contained in a separate package or container) and optionally a set of instructions for administration (e.g. subcutaneous) of the liquid pharmaceutical composition. Thus, the user may fill the drug dispensing device with the liquid pharmaceutical composition (which may be contained in a vial or ampoule or the like) prior to administration.
Applications of pharmaceutical liquid composition and methods of treatment
According to a twelfth aspect of the invention, a method of treating a disease or medical disorder is provided; a liquid pharmaceutical composition for use in treatment: use of a liquid pharmaceutical composition for the manufacture of a medicament for the treatment of a disease or disorder; a method of treating a tumor necrosis factor-alpha (TNF-α) -related autoimmune disease; a liquid pharmaceutical composition for use in the treatment of a tumor necrosis factor-alpha (TNF-o) -related autoimmune disease; use of a liquid pharmaceutical composition for the manufacture of a medicament for the treatment of a tumor necrosis factor-alpha (TNF-0) associated autoimmune disease; a method of treating rheumatoid arthritis, psoriatic arthritis, Bechterew's disease, Crohn's disease, ulcerative colitis, moderate to severe chronic psoriasis and arthritis; a liquid pharmaceutical composition for use in the treatment of rheumatoid arthritis, psoriatic arthritis, Bechterew's disease, Crohn's disease, ulcerative colitis, moderate to severe chronic psoriasis, and childhood arthritis; and use of a liquid pharmaceutical composition for the manufacture of a medicament for the treatment of rheumatoid arthritis, psoriatic arthritis, Bechterew's disease, Crohn's disease, ulcerative colitis, moderate to severe chronic psoriasis, and rheumatoid arthritis, as defined herein.
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The liquid pharmaceutical compositions defined herein can be used to treat any or more of the aforementioned diseases or medical disorders. In a particular embodiment, the liquid pharmaceutical compositions are used to treat rheumatoid arthritis, preferably Crohn's disease and psoriasis.
The liquid pharmaceutical compositions are conveniently administered parenterally, suitably via subcutaneous injection.
EXAMPLES
Materials and equipment
The following materials were used to prepare formulations described in the following examples:
Ingredient Adalimumab DS arginine monohydrochloride aspartic acid Citric Dibasic sodium phosphate dihydrate lysine hydrochloride mannitol Monobasic sodium phosphate dihydrate Poloxamer 188 Polysorbate 80 Sodium chloride Sodium Sodium hydroxide solution30% trehalose dihydrate WFI
The following disposable equipment and material were used in the examples and screening experiments as follows.
Equipment Code Supplier Eppendor tubes (0.5 mL, 1.5 REACH Eppendorf
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mL, 2.0 mL) Falcon 352096 (15 mL), 352070 (50 mL) polypropylene tube Becton Dickinson PES membrane (0.22 µm)filter unit MillexGP Express PES membrane REF SLGP033RS Millipore PETG bottles 3420-1000, 3420-0500, 2019-0250, 3420-0125,3420-0060, 2019-0030 Nalgene
The following packaging was used in the examples and screening experiments as follows.
Equipment Code Supplier DIN2R Type I glass vials 0212060.6112 11200000A Nuova Ompi 1 mL stops S2-F451 RSV; D 21-7S RB2-40 Daikyo Seiko, LTD 13mm flip-off cap 12000350 MS-A
The following equipment was used in the examples and screening experiments as follows.
Equipment Against. Producer Analytical weights AX205, PG2002-S Mettler Toledo Benchtop xenon instrument Suntest CPS + Atlas Calibrated pipettes P20, P100, P200, P1000 Gilson HPLC Alliance Waters iCE280 Fixed IEF Analyzer Convergent Bioscience osmometer Osmomat 030 / D Gonotec PCR 7500 Fast Real-Time AB Applied Biosystem pH meters Seven Multi Mettler Toledo refrigerators + 2-8 ° C Angelantoni Software Design Expert ver. 7.1.5 Stat-Ease, Inc. Thermostatic cabinets + 25 ° C, + 40 ° C Angelantoni turbiditor 2100AN IS Hach Lange UV Spectrophotometer Lambda 35 Perkin Elmer
Analytical techniques and protocols
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The following analytical protocol procedures were used in the Examples and Screening Experiments, as follows, for the reasons given in the table below:
Method No. Analytical method Purpose of testing 1 Bioanalyzer purity 2 DSF The unfolding 3 iCE280 Isoformprofiler 4 OD protein 5 SE-HPLC Aggregatbestemmelse 6 nephelometry turbidity 7 osmolality Osmolality of solution 8 PH pH determination 9 Invisible particles particle Counting
The protocols for each of the above analytical methods are described below, and reference in the examples and screening experiments to any of such analytical methods and screening experiments has been using these protocols.
1. Purity - Bioanalyzer
A 2100 Bioanalyzer was used. Minutes are provided in the current instruction manuals. However, the protocols are further adjusted as follows.
solutions:
Gel-Dye Mix (staining solution):
Add 25 µl 230plus color concentrate to a protein 230plus gel matrix tube. Thoroughly swirl and centrifuge the tube for 15 seconds. Transfer to a spin filter and spin at 2500rpm for at least 20min. The solution is ready to use. Store the solution at + 5 ± 3 ° C for a maximum of 4 weeks.
destaining:
Pipette 650pl gel matrix into a spin filter. Centrifuge at 2500rpm for at least 25 minutes. Store the solution at + 5 ± 3 ° C for a maximum of 4 weeks.
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Sample Buffer:
It is recommended to divide the 200 μΙ sample buffer into measured portions of 25 μΙ and re-freeze a measured portion for each chip. Store the sample buffer stock solution and measured portions at -20 ° C, but not longer than the expiration date specified by the supplier.
Maleimide stock:
Dissolve 23.4 mg of maleimide in 1 ml of MilliQ water (0.24M). Shake the solution thoroughly. Subsequently, the solution is diluted 1: 4 with MilliQ water. (eg 50 µl stock solution + 150 µl MilliQ). The final concentration of the diluted maleimide solution is 60mM. (As data on the stability of this solution are not yet available, it must be freshly prepared for each assay).
OTf solution:
For analysis of Adalimumab samples, the reducing solution must be prepared with 1M DTT, therefore dissolve 154.0 mg of DTT in 1 ml of MilliQ water.
Non-reducing solution:
Add 1 μl MilliQ water to a metered sample buffer portion (25 μθ and centrifuge for 5 seconds. Use the non-reducing solution on the same day as it was prepared.
Reducing resolution:
Add 1 μl DTf solution to a metered sample buffer portion (25 μθ and spin for 5 seconds. Use the reducing solution on the same day as it was prepared.
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Sample preparation:
• Samples with a concentration range between 2.4 and 3 mg / ml are analyzed.
• If necessary, the samples can be diluted to the desired concentration with Milli Q water.
Samples are prepared in accordance with the Reagent Kit Guide using reducing and non-reducing sample buffers according to the Reagent Kit Guide and also as described above. Contrary to the instructions, it is strongly recommended to use larger volumes to obtain reproducible and accurate results. An example of how the marker and samples are prepared are given below:
Sample preparation Resolution; reducing and non-reducing conditions
reagent Volume, pl Total volume, pl Sample diluted to 3 mg / ml 3pl 6 pl Sample Buffer (Reducing or Non-Reducing) 2 pl Maleimide solution 1 pl Samples should be well mixed (with vortex shaker) and centrifuged. All samples and the marker are heated at 70 ° C for 5 minutes. MilliQ water 84 pl 90 pl Shake well and spin; refill 6 µl, whole sample and marker
Note 1: For those IPCs whose concentration is between 2.4 mg / ml and 3.0 mg / ml, the sample preparation follows the table above, except for the volume of MilliQ water added after sample heating, which is calculated for a final protein concentration of 0.1 mg / ml.
An example of a sample having a concentration of between 2.4 and 3.0 mg / ml is given below:
Sample preparation Resolution; reducing and non-reducing conditions
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reagent Volume, pl Total volume, pl Sample diluted to (2.6 mg / ml) 3pl 6 pl Sample Buffer (Reducing or Non-Reducing) 2 pl Maleimide solution 1 pl Samples should be well mixed (with vortex shaker) and centrifuged. All samples and the marker are heated at 70 ° C for 5 minutes. MilliQ water 72 pl 78 pl Shake well and spin; refill 6 µl, whole sample and marker
Note 2: All wells must be filled. If the number of samples is lower than the number of wells, the empty wells can be used for extra duplicate or blank samples.
Preparing the system and chip:
To clean the system before and after an analysis, the Electrode Cleaner is filled with 600 µL MilliQ water and placed in the Agilent 2100 Bioanalyzer, the lid is closed and the system shuts down. Nothing further is required.
Adjust the base plate of the chip priming station to position A and the spray clip to its intermediate position.
Preparing the chip
System Preparation
Insert a new protein chip into the priming station
Pipette 12 µl of Gel-Dye mixture into the well labeled G (top right)
Set the plunger to 1 ml and close the chip priming station
Press the plunger down until it is held by the chip
Wait 60 seconds and then release the chip
Wait 5 seconds and slowly withdraw the plunger to the 1 ml mark
Open the chip priming station
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Remove the solution in this well
Pipette 12 μΙ Gel-Dye mixture into the well labeled G (top right) and into all other wells labeled G
Pipette 12 μl of decolorizing solution into the well labeled DS
Marker and sample application:
Transfer 6 µL of each sample to the sample well and likewise 6 µL of the marker into the 5 well indicated, which is clearly indicated by a marker symbol. Place the chip in the Agilent 2100 Bioanalyzer and start the analysis within 5 min.
Example of test set
Well Sample Quantity, µl 1 Blank 6 2 Blank 6 3 Unknown sample 1, rep 1 6 4 Unknown sample 1, rep 2 6 5 Unknown sample 2, rep 1 6 6 Unknown sample 2, rep 2 6 7 Unknown sample 3, rep 1 6 8 Unknown sample 3, rep 2 6 9 Current reference material, rep 1 6 10 Current reference material, rep 2 6 Marker Marker 6
Data analysis and evaluation of results:
To get results, the following steps must be performed at least:
• Place the chip in the designated location and close the lid.
DK 2020 00030 U1 • In instrument, select Assay - Electrophoresis-Protein-Protein
230 Plus.
• Press START to start the analysis, which is completed within 30 minutes.
• Raw data is displayed by pressing Data Analysis, which lists all experiments performed that day. Press the desired test and select it • The gel generated from the selected trial opens automatically.
• Data can be displayed as an electropherogram or gel-like image.
Detailed information on the integration of peaks in the electropherogram (for purity data) is provided in the manual of the software. The purity of the sample is given by the system by automatic integration, but if necessary manual integration can be used.
results:
Under non-reducing conditions, the results are given as% Purity (purity) and% LMW (sum of peaks before monomer).
Under reducing conditions, the results are given as% Purity as the sum of the heavy and light chain.
The indicative molecular weight is given in the table below:
Indicative molecular weight of Adalimumab
conditions Result KDa Non-reducing monomer 151 reducing LC 27 HC 58
2. Unfolding temperature - DSF
DSF (differential scanning fluorimetry) was performed as follows:
DK 2020 00030 U1 microliters of Sypro Orange (Orange protein gel color, cod. S6650, Life Technologies) pre-diluted 500-fold in water of injection was added 20 microliters of drug product solution. When adding Sypro Orange, DP solutions (samples in triplicate) are filled into 96-well plates (MicroAmp Fast 96W Reaction Plate 0.1 ml, cod. 4346907). The plates are then sealed with a protective transparent cover (MicroAmp Optical Adhesive Film, cod. 4311971) and then centrifuged to remove air bubbles. The plates are then inserted into the 7500 Fast Real-Time AB Applied Biosystem PCR system and scanned for emission profiles at temperatures from room temperature to 90-100 ° C. Fluorescence emission intensity dependence on temperature is a curve that typically shows a turning point / stop at denaturation temperature, and is a parameter used to compare the various compositions.
3. Profile of isoforms - iCE280 cIEF at iCE280 (profile of isoformers): After purification and removal of salts by centrifugation in an Amicon Ultra-4 centrifuge (cut off 10 kDa), the samples were pre-diluted to a concentration of 5.0 mg / ml with purified water. A next dilution was then made to 1.0 mg / ml with a solution consisting of: methyl cellulose, Pharmalyt 5-8 (GE Healthcare), Pharmalyt 8 - 10.5 (GE Healthcare), low pI marker 7.05 (Protein Simple ), high pI marker 9.50 (Protein Simple) and purified water. After dilution, the samples were centrifuged at 10000 rpm for 3 minutes. An additional centrifugation step (2 minutes at 7000 rpm) is then performed with 150 microliters of each sample transferred to glass inserts. cIEF (capillary isoelectric focusing) was performed with the iCE280 system with Protein Simple, using capillary cassettes Fc with 100 micron ID coating and a total length of 50 nm (Cat. No. 101700/101701 by Protein Simple). Separation of the various isoforms is done using 100 mM sodium hydroxide (in 0.1% methylcellulose) as cathodic solution and 80 mM o-phosphoric acid (in 0.1% methylcellulose) as anodic solution. The electropherogram appears at 280 nm at pre-focusing and focusing times of 1 and 6 minutes, respectively, at a voltage of 1500 V (pre-focusing) and 3000 V (focusing).
4th
Protein content - OD
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OD (protein content) measurements were performed on samples which were pre-diluted gravimetrically (three independent dilutions were prepared) with relevant buffer or placebo from initial concentrations to approximately 10 mg / ml. The diluted solutions were tested for absorbance at 280 and 320 nm in 0.1 cm long quartz incubators, at room temperature, with a double-beam spectrophotometer (Lambda35 from Perkin Elmer). The value of 1.35 was used as the molar extinction coefficient for Adalimumab.
5. Unit Determination - SE-HPLC
The samples were diluted with DPBS 1X to a concentration of 0.5 ml and injected (20 microliters of injection volume) into a TSK gel Super SW3000 4.6mm ID X 30.0 cm cod.18675 column from Tosoh while maintaining isocratic conditions (mobile phase: 50mM sodium phosphate + 0.4M sodium perchlorate, pH 6.3 ± 0.1). UV detection was performed at 214 nm at a flow rate of 0.35 ml. Each analytical cycle had a duration of 15 minutes. Prior to analysis, samples were stored at 2-8 ° C in the Waters Alliance HPLC system autosampler used for this analysis.
6. Turbidity - nephelometry
Turbidity was evaluated by nephelometric (the effect based on the light-diffusion effect caused by particles with dimensions typically <1 micron) measurements performed with a turbidimeter 2100AN IS Turbidimeter from Hach at room temperature. Minimum quantities of 3 ml solution were added to reduced volume glass cuvettes and tested for diffusive power after prior calibration of the instrument with a range of standard solutions (0.1 - 7500 NTU).
7. Determination of Osmolality - Osmolality
Osmolality was measured based on the cryoscopic characteristics of the solutions. The analyzes were performed with an Osmomat 030-D from Gonotech, where 50 microliters of the samples were frozen. The freezing temperature depends on the osmolality of the solution (i.e., the presence of agents dissolved such as salts, sugars, other ionic and non-ionic compounds, etc.).
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8, pH determination - pH pH was determined by potentiometric measurements at room temperature with Mettler Toledo Seven Multi pH meter.
9. Particle Count - Non-particulate particles
The samples were diluted 5-fold with purified water to a final volume of 25 ml. The number of particles is determined at room temperature with PAMAS SVSS from Amin10 struments by collecting four independent runs and taking an average of the results from each dimensional fraction of interest.
Example 1 - Formulations for first formulation screening
The following first set of formulations (often referred to as DoEl formulations herein) are shown below in Table 1.
Table 1: List of DoE1 formulations for subsequent screening experiment 1
Form# Salt (NaCl) wife (mM) Buffer type (10 mM) pH stabilizer 11 25 citrate 5.4 Trehalose dihydrate (200 mM) 12 25 citrate 5.4 Arginine monohydrochloride + aspartic acid (80 mM + 20 mM) 13 75 citrate 5.6 Mannitol (200 mM) 14 50 citrate 5.6 Lysine hydrochloride (100 mM) 15 100 citrate 5.6 Mannitol (200 mM) 16 100 citrate 5.8 Lysine hydrochloride (100 mM) 17 75 citrate 5.8 Arginine monohydrochloride + aspartic acid (80 mM + 20 mM)
The formulations in Table 1 were prepared starting with a preformulated surfactant-free DS material.
Measured portions of DS were diafiltered with a 10 mM sodium citrate / citric acid buffer at pH 5.2 until a three-fold volume yield with the buffer was obtained. Then, the indicated excipients were added to the buffer-exchanged DS materials
DK 2020 00030 U1 and pH adjusted to the target by adding a dilute solution of sodium hydroxide. Each formulation was filtered through 0.22 μm PES filters.
In Table 2, the results in terms of material recovery and osmolality of the three buffer-exchanged DS materials are given.
Table 2: Recovery and osmolality of DS materials after buffer depletion
buffer outputDSvolume Starting DS concentrate on (mg / ml) Processed Protein (mg) Final volume after replacement (ml) Final concentrate on after exchange (mg / ml) Recovered protein after replacement (mg) Yield (%) Osmolal density (mOsm / kg) citrate 200 63.3 12660 200 54.5 10900 86 39
There was a good recovery of the sodium citrate buffer (<90%). Values of osmolality indicate that a satisfactory degree of buffer exchange has been achieved with a minimal residue of substances derived from the original DS.
Example 2 - Formulations for second formulation screening
The following second set of formulations (often referred to as DoE2 formulations herein) are shown below in Table 3 (as derived from Table 4 below again).
Table 1: List of DoE2 Formulinos for Later Screeninous Experiment 2 (Formulations Derived from those shown in Table 4, with the additional surfactant as indicated)
formulations Polysorbate 80 concentration (mg / mL) 0 0.5 1 Form 4 (derived from Form B, Table 4) X - - Form 5 (derived from Form B, Table 4) - X - Form 6 (derived from Form B, Table 4) - - X
Table 4: _____ Formulation prototype derived from the DoEl screening
Form Salt (NaCl) mM Buffer type (10 mM) pH stabilizer B 100 citrate 5.8 Trehalose dihydrate (200 mM)
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The DoE2 formulations (Table 3) were prepared starting with a preformulated surfactant-free DS material.
Three measured portions of DS have been diafiltered until a three-fold volume yield is obtained. Subsequently, the required excipients have been added to the buffer-exchanged DS materials and the pH has been adjusted to the target value by the addition of a dilute sodium hydroxide solution. Each formulation was filtered through 0.22 µm PES filters.
Table 5 presents the osmolality and turbidity results for buffer-exchanged DS materials.
The osmolality values (<40 mOsm / kg) indicated the satisfactorily achieved degree of buffer exchange with a minimal residue of substances derived from the original DS.
Table 5: Osmolality and turbidity of the DS materials after buffer exchange
buffer turbidity(NTU) osmolality(MOsm / kg) citrate 52 42
Example 3 - Comparative formulations for both first and second screening
For comparison and control purposes, three reference formulations were prepared or obtained, including Ref-1 (Humira® composition manufactured by applicant); Ref-2 (RMP US - Humira®, US commercial drug product); and Ref-3 (RMP EU - Humira®, EU commercial pharmaceutical product). All of these reference formulations have the composition shown in Table 6.
Table 6: Composition of Humira DP
Ingredient Amount per container (mg) (fill volume = 0.8 ml) Amount (mg / ml) adalimumab 40 50 Citric 1.04 1.3 Dibasic sodium phosphate dehydrate 1.22 1.53 mannitol 9.6 12 Monobasic sodium phosphate dehydrate 0.69 0.86 Polysorbate 80 0.8 1
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Sodium chloride 4.93 6.16 Sodium 0.24 0.3 WFI and sodium hydroxide q.b. for adjusting the pH to 5.2 q.b. to adjust pH 5.2
SCREENING
An initial formulation screening (DoE1) led to the determination of various factors (e.g., pH, presence of NaCl, excipient type) responsible for protein stability, and ultimately selection of formulations to be pursued in a second screening. (DoE2), which sought to fine-tune the formulations and assess how surfactants such as Polysorbate 80 may affect the stability of the protein.
Each of the two screenings included various analytical tests, as defined above and referred to below, on a variety of formulations subjected to varying degrees of heat load, mechanical load, and light load over a longer period of time (e.g., 1 month ). These formulation screenings made it possible to gather a significant amount of data, which provided surprising and valuable insights that allow the development of new beneficial formulations.
The results of the two formulation screenings are presented below.
Screening Experiment 1 - Analysis and Screening of Formulations of Example 1 Compared to the Comparative Formulations of Example 3
The preliminary DoE screening (Step 1) evaluated the effect that ionic strength (given by NaCl), pH, and various stabilizers exert on the protein during short-term stability studies.
A statistical response surface-D-Optimal design was used. Three factors are taken into account:
loneliness (driven by the NaCl concentration, which varied in the range of 25 mM-100 mM and set as a numerical factor);
- pH (range 5.4-6.4) buffered by citrate was investigated;
- stabilizer / excipient (category factor comprising several levels: lysine hydrochloride, arginine + aspartic acid, mannitol, trehalose dihydrate).
These formulations were prepared as described in Example 1 above, starting from DS without Polysorbate 80 and were therefore free of surfactants.
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Table 7 below summarizes the formulations tested in this screening. In addition to the proposed 7 formulations, two controls have also been analyzed for comparison:
• Commercial Humira drug product DP (formulated as i
Example 3 above) • MS drug DS DS formulated as commercial Humira-DP (formulated as in Example 3 above).
Table 7: List of DoE1 formulations (Step 1) screened under heat stress conditions (stability at 40 ° C and high speed determination of protein10 unfolding temperature (DSF).
Form# Salt (NaCl) wife (mM) Buffer type (10 mM) pH stabilizer 11 25 citrate 5.4 Trehalose dihydrate (200 mM) 12 25 citrate 5.4 Arginine monohydrochloride + aspartic acid (80 mM + 20 mM) 13 75 citrate 5.6 Mannitol (200 mM) 14 50 citrate 5.6 Lysine hydrochloride (100 mM) 15 100 citrate 5.6 Mannitol (200 mM) 16 100 citrate 5.8 Lysine hydrochloride (100 mM) 17 75 citrate 5.8 Arginine monohydrochloride + aspartic acid (80 mM + 20 mM) Ref-1 (MS) Humira composition (formulation prepared with MS drug substance) - Example 3 Ref-2 (RMPUS) Commercial Humira-DP (USA) - Example 3 Ref-3 (RMPEU) Commercial Humira DP (EU) - Example 3
The formulations were investigated according to the plan presented in Table 8. Heat stress up to 1 month at 40 ° C is taken into account. High-speed assessment by DSF technique (which aims at rapid screening based on determination of protein inlet temperature) was performed at TO.
Table 8: Summary of Analytical Tests Performed on Preliminary DoE Formulations (Step 1): 1 month heat load at 40 ° C,
Accelerated (40 ° C) Stability time (weeks) methods test 0 2u 4u OD Contents X - X
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SE-HPLC Attachment X X X Bioanalyzer purity X X X pH pH X X X osmolality osmolality X - - DSF Unfolding T X - -
1.1 Osmolality Screening
The osmolality of the total DoEl fortunes starting with the buffer-exchanged DS materials (Section 5.1.1) is presented in Table 9.
Most formulations were found to be in the osmolality range of 250-400 mOsm / kg, while slightly higher values were seen at the highest sodium chloride concentrations.
Table 9: Osmolality (mOsm / kg) recorded at time 0 for DoEl Screening Formulations
Form tt Salt (NaCl) concentration (mM) Buffer type (10 mM) pH stabilizer Time 0 11 25 citrate 5.4 Trehalose dihydrate (200 mM) 0320 12 25 citrate 5.4 Arginine monohydrodoride + aspartic acid (80 mM + 20 mM) 0276 13 75 citrate 5.6 Mannitol (200 mM) 0422 14 50 citrate 5.6 Lysine hydrochloride (100 mM) 0331 15 100 citrate 5.6 Mannitol (200 mM) 0473 16 100 citrate 5.8 Lysine hydrochloride (100 mM) 0432 17 75 citrate 5.8 Arginine monohydrodoride + aspartic acid (80 mM + 20 mM) 0372 Reference In-House (Humira composition, Merck Serono DS) 0374 RMP (USA) Humira REACH RMP (EU) Humira 0310
1.2 Protein content (OD)
The protein content of DoE1 formulations was determined at time 0 and after 1 month at 40 ° C.
FIG. Figure 1 is a bar graph showing the protein content (mg / ml) of the DoE115 formulations (from Example 1), together with reference standards (representing HUMIRA® comparison formulations), at an arbitrary starting point
DK 2020 00030 U1 (blue bars, time = 0) and after 4 weeks (red bars) of the formulation (s) heated to 40 ° C.
The results shown in Figs. 1 showed no occurrence of significant changes over time. All concentrations were found to be in line with the target value of 50 mg / ml.
1.3 Aggregation (SE-HPLC)
FIG. 2 is a bar graph showing% aggregation as determined by SEHPLC of DoE1 fortunes (from Example 1) along with standard references (representing HUMIRA® comparison formulations for an arbitrary start time (blue bars, time = 0) and both 2 weeks (green bars) ) and 4 weeks (orange bars) after the formulations have been heated to 40 ° C. The total amount of aggregates observed by SE-HPLC against the stability at 40 ° C is graphically depicted in Fig. 2. Minimal increases in aggregation / however, all aggregation levels even after 1 month amounted to less than 1%.
1.4 Fragmentation (Bioanalyzer)
FIG. Figure 3 is a bar graph showing% fragmentation as determined by a Bioanalyzer, of the DoE1 formulations (from Example 1), along with standard references (representing HUMIRA® comparison formulations) for an arbitrary start time (dark blue bars, time = 0) and both 2 weeks (pink bars) and 4 weeks (light blue bars) after the formulations have been heated to 40 ° C.
In FIG. 3 shows the variation of fragments over time as determined by Bioanalyzer. Formulations at lower pHs tend to have higher fragmentation rates. Furthermore, the presence of amino acids in this pH range can significantly aggravate the stability profile. The destructive effect of amino acid forms is also confirmed at a pH of 5.4 (Formulation 12)
At pH> 5.0 and in the presence of sugar / polyalcohols, all the formulations, including the references, are comparable (fragmentation below 1% after 1 month at 40 ° C.
Data were analyzed using ANOVA which confirmed the statistical significance of the pH factor (p-value <0.001), which also indicates that pH values> 5.0 should be intended to minimize fragmentation.
DK 2020 00030 U1
Sodium chloride was not found to be a factor critical to stability in the range of 25-100 mM.
1.5 pH screenina
Table 10 shows the pH of the DoE1 formulations (from Example 1) together with standard references (representing HUMIRA Comparative Formulations) for an arbitrary start time (time = 0) and after both 2 weeks and 4 weeks for formulations heated to 40 ° C.
As shown in Table 10, no deviations from the intended pH value were seen.
Table 10: pH value of DoE1 screening formulations determined relative to stability at 40 ° C
Stability time Form Salt (NaCl) wife (mM) Buffer type (10 mM) pH stabilizer Time 0 2 weeks 40 ° C 4 weeks 40 ° C 11 25 citrate 5.4 Trehalose dihydrate (200 mM) 5.5 5.5 5.3 12 25 citrate 5.4 Arginine monohydrocloride + aspartic acid (80 mM + 20 mM) 5.4 5.5 5.3 13 75 citrate 5.6 Mannitol (200 mM) 5.6 5.6 5.5 14 50 citrate 5.6 Lysine hydrochloride (100 mM) 5.6 5.6 5.5 15 100 citrate 5.6 Mannitol (200 mM) 5.6 5.6 5.5 16 100 citrate 5.8 Lysine hydrochloride (100 mM) 5.8 5.8 5.7 17 75 citrate 5.8 Arginine monohydrocloride + aspartic acid (80 mM + 20 mM) 5.8 5.8 5.7 Reference In-House (Humira composition, Merck Serono DS) 5.2 5.2 5.2 RMP (USA) Humira 5.3 5.3 5.3 RMP (EU) Humira 5.3 5.3 5.3
1.6 Unfolding temperature (DSF)
DSF is a high-speed method aimed at determining the unfolding temperature of proteins by increasing interactions with fluorescent probes as the temperature of the samples increases. As the protein begins to unfold, it will increasingly expose hydrophobic portions to the solvent, attracting the fluorescent probes that will transition from the free state in the solution (non-fluorescent) to the bound state (via hy2 drophobic interactions) with the protein, thereby amplifying the fluorescence signal.
DK 2020 00030 U1
From the assessment of the fluorescence signal, it was possible to determine the midpoint of the sigmoidal curves indicating the transition point of each formulation. It is assumed that the higher the transition point, the higher the resistance of the formulation to heat load.
The results of the assessment made on the DoE1 screening formulations are presented in Figs. 4. FIG. 4 is a bar graph showing the unfolding temperature (° C) as determined by the DSF of the DoE1 formulations (from Example 1) together with standard references (representing HUMIRA® comparison formulations).
Conclusion on Screening Experiment 1
The results obtained from the Bioanalyzer and DSF tests are combined using the response surface ANOVA model to determine the best compositions that could possibly guarantee the highest thermal stability of the protein.
The list of recommended compositions is presented in Table 12, which also compares the results for the obtained prototype formulations with Humira-RMP in terms of unfolding temperature and fragmentation change over 1 month at 40 ° C.
Formulation B was extrapolated using the software and the values included in the table are therefore theoretical.
By comparing these formulations with RMP, it can be concluded that the performance of these prototype formulations in response to heat load is comparable to that seen for RMP.
Table 12: Results of DoEl experiments: recommended compositions for second screening
Form Salt (NaCl) mM Buffer type (10 mM) pH stabilizer B 100 citrate 5.8 Trehalose dihydrate (200 mM)
Somewhat unexpectedly, formulations containing trehalose dihydrate as the sole stabilizer performed very well, especially with regard to fragmentation inhibition, unfolding inhibition and pH maintenance. Such trehalose-based
DK 2020 00030 U1 formulations also performed well in terms of aggregation / accumulation and precipitation. Trehalose being such a strong stabilizer candidate, especially alone, was highly promising in view of its antioxidant properties, which will impart additional long-term chemical stability (especially to oxidation and / or photooxidation) to adalimumab formulations. Furthermore, it was considered particularly encouraging that trehalose can be used alone and yet still perform excellently, and it paves the way for less complex formulations that use fewer ingredients, which in turn will reduce the processing and costs associated with producing the relevant adalimum drug product. . As such, these trehalose-based formulations were passed on to another round of screening experiments to fine-tune the formulations.
Screening Experiment 2 - Analysis and Screening of Formulations of Example 2 versus Comparative Formulations of Example 3
A formulation prototype from the previous screening was determined (Table 12). Since the previous step was carried out without added surfactant, the second step aimed to screen a number of levels of surfactant in the form of Polysorbate 80 (range: 0-1 mg / ml) to assess whether surfactant addition is necessary for to promote protein stability.
Table 3 (Example 2) summarizes the design of this second step of the study and lists the formulations (DoE2 formulations) investigated in this second screening round.
Typically, surfactants have been observed to contrast with aggregation induced by mechanical loading, and shake-load studies have therefore been conducted to assess how Polysorbate 80 affects protein stability and the reaction to shaking.
As for step 1, the reference compositions described in Example 3 have also been evaluated to provide an assessment basis for the development of a new formulation.
The complete list of analyzes performed on this group of formulations is presented in Table 13. In this second screening, the respective formulations were subjected to three different types of load, namely heat load, mechanical load and light load.
DK 2020 00030 U1
Table 13: Overview of Analytical Tests Performed on DoE2 Formulas ftrin
2): 1 month heat load conditions at 40 ° C (AL rvst load at
200 oom (B) and Ise Exposure according to ICH O1B (C)
A. Heat load at 40 ° C
Forced (40 ° C) Stability time (weeks) methods test 0 2u 4u OD Contents X - X ICE280 isoforms X X X SE-HPLC Attachment X X X Bionalyzer purity X X X pH pH X X X osmolality osmolality X - - nephelometry turbidity X X X DSF UdfoldningsT X - -
B. Shaking load conditions
Shake load (200 rpm) Stability time (hours) methods test 0 241 481 OD Contents X - - SE-HPLC Attachment X X X Bioanalyzer purity X X X pH pH X X X nephelometry turbidity X X X
C. Light exposure, 7 hours exposure at 765W / m ² (ICH Q1B).
Light exposure Sample methods test Tido exposed OD Contents X - iCE280 isoforms X X SE-HPLC Attachment X X Bioanalyzer purity X X pH pH X X nephelometry turbidity X X
DK 2020 00030 U1
Heat stress studies were performed by simply heating a sample of the relevant formulations at the set temperature for the stipulated period (typically 2 weeks or 4 weeks / one month).
Mechanical load studies were performed by simply shaking a sample of the relevant room temperature formulations at 200 rpm for the stipulated period (typically 24 hours or 48 hours).
Light exposure studies were performed by simply exposing a sample of the relevant formulations to 765 W / m ² light (in accordance with the European Medicines Agency's ICH QlB Guidelines on Photostability Testing of New Active Substances and Medical Products) for 7 hours.
2.1 Osmolality
The osmolality of the DoE2 screening formulations is presented in Table 14. The values, in the range of 378-401 mOsm / kg, are probably overestimated due to the presence of trehalose dihydrate which may lead to some increase in viscosity, which affects the cryoscopic point of the solutions and thus the osmolality. This was confirmed by measurements for other test formulations, which were diluted 3 times with WFI prior to the osmolality test to lower the viscosity: the true osmolality for all these formulations is <350 mOsm / kg.
Table 14: Osmolality of DoE2 Screeninase Formulas (Undesired Undesirables)
Form# Salt (NaCl) concentration (mM) Buffer type (10 mM) pH stabilizer Surfactant (Polysorbate 80) concentration (mg / ml) Time 0 DoE2-4 50 citrate 5.8 Trehalose dihydrate (200 mM) 0 391 DoE2-5 50 citrate 5.8 Trehalose dihydrate (200 mM) 0.5 401 DoE2-6 50 citrate 5.8 Trehalose dihydrate (200 mM) 1 394
2.2 Protein content
The protein content of all DoE2 formulations at time 0 was in line with the protein concentration target of 50 mg / ml (Table 15).
Table 15: Protein content (OD) of DoE2 screeninase formulas (investigated undesired)
DK 2020 00030 U1
Form# Salt (NaCl) concentration (mM) Buffer type (10 mM) pH stabilizer Surfactant (Polysorbate 80) concentration (mg / ml) Time 0 DoE2-4 50 citrate 5.8 Trehalose dihydrate (200 mM) 0 49.9 DoE2-5 50 citrate 5.8 Trehalose dihydrate (200 mM) 0.5 50.2 DoE2-6 50 citrate 5.8 Trehalose dihydrate (200 mM) 1 50.4
2.3 Heat Load Units (SE-HPLC)
The variations in the total amount of aggregates by SE-HPLC are presented in Figs. 5. FIG. 5 is a bar graph showing% aggregation, as determined by SE-HPLC, of the DoE2 formulations (from Example 2) together with standard references (representing HUMIRA® comparison formulations) at an arbitrary starting point (red bars, time = 0) and after both 2 weeks (green bars) and 4 weeks (purple bars) for formulations heated to 40 ° C.
Minimal changes were seen in all formulations, with the total amount of aggregates after 1 month at 40 ° C being below 1%.
The DoEl screening formulations did just as well as the RMP materials or slightly better.
2.4 Fragmentation with Heat Load (Bioanalyzer)
The variations in fragments with Bioanalyzer are shown in Figs. 6. Figure 6 is a bar graph showing% fragmentation, as determined with a Bioanalyzer, of the DoE2 formulations (from Example 2) along with standard references (representing HUMIRA® comparison formulations) at an arbitrary starting point (blue bars, time = 0) and after both 2 weeks (red bars) and 4 weeks (green bars) for formulations heated to 40 ° C.
For sodium citrate, variations comparable to those observed with RMP were observed. Significant differences among the three formulations can be seen.
2.5 Isoform profile with heat load (iCE280)
The changes with respect to the main peak and acid cluster for the three formulations over 1 month at 40 ° C are shown in Figs. 7 and 8.
Figure 7 is a bar graph showing the main top isoform profile, as determined by iCE280 analysis, of the DoE2 formulations (from Example 2) at an arbitrary starting point (blue bars, time = 0) and after both 2 weeks (red bars) and 4 weeks (green bars) for formulations heated to 40 ° C.
Figure 8 is a bar graph showing the cluster cluster topoform profile, as determined by iCE280 analysis, of the DoE2 formulations (from Example 2) at an arDK 2020 00030 U1 bitter starting point (blue bars, time = 0) and after both 2 weeks (red bars) ) and 4 weeks (green bars) for formulations heated to 40 ° C.
The results for acid cluster are in line with the observations made for the main peak.
2.6 øH screenina with heat load
The variation in pH of the DoE2 formulations (from Example 2) over a period of time during which the formulations are heated to 40 ° C is shown in Table 16.
pH decrease was seen in DoE2-5, as shown in Table 16. This may be due to possible contamination / bacterial propagation in the samples.
Table 16: DoE2 screenina: pH (heat load at 40 ° C)
Form# Salt (NaCl) concentration (mM) Buffer type (10 mM) pH stabilizer Surfactant (Polysorbate 80) concentration (mg / ml) Time 0 2 weeks (40 ° C) 4weeks (40 ° C) DoE2-4 50 citrate 5.8 Trehalose dihydrate (200 mM) 0 5.8 5.8 5.8 DoE2-5 50 citrate 5.8 Trehalose dihydrate (200 mM) 0.5 5.8 5.8 5.2 DoE2-6 50 citrate 5.8 Trehalose dihydrate (200 mM) 1 5.8 5.8 5.9
2.7 Turbidity with heat load (nephelometry)
FIG. Figure 9 is a bar graph showing the turbidity, as determined by nephelometry, of the DoE2 formulations (from Example 2) at an arbitrary starting point (blue bars, time = 0) and after both 2 weeks (red bars) and 4 weeks (green bars) ) for formulations heated to 40 ° C.
The turbidity of the three solutions is currently 0 in the range of typical opalescent solutions (6-18 NTU). With regard to the original DS materials with typical turbidity of 19-52 NTU, the DP solutions after aseptic filtration are considerably clear.
2.8 Mechanical load units (SE-HPLC)
Figure 10 is a bar graph showing% aggregation, as determined by SE-HPLC, of the DoE2 formulations (from Example 2) at an arbitrary starting point (blue bars, time = 0) and after both 24 hours (red bars) and 48 hours (green bars) mechanically moved pre-shake (shaking).
The variations in the total amount of aggregates calculated by SE-HPLC are shown in Figs. 10th
Minimal changes (+ 0.1%) were observed for all citrate buffer formulations.
2.9 Fragmentation with mechanical loading (Bioanalyzer)
FIG. 11 is a bar graph showing% fragmentation as determined by
DK 2020 00030 U1 a Bioanalyzer, of the DoE2 formulations (from Example 2) at an arbitrary starting point (blue bars, time = 0) and after both 24 hours (red bars) and 48 hours (green bars) mechanically moved ( shaking).
The variations in fragments when calculated with Bioanalyzer are presented in Figs. 11. Minimal changes are seen as all recorded values are equal to or below 0.5%.
After 48 hours shaking at room temperature, all samples showed fragmentation between 0.2 and 0.4%. No tendency was observed for increasing fragmentation after mechanical shaking.
2 · 10 pH screening with mechanical loading
The variation in pH of the DoE2 formulations (from Example 2) over a period of time during which the formulations are mechanically moved (shaking) is shown in Table 17. No changes were seen.
Table 17: DoE2-screenino: pH value mechanical shaking)
Form ff Salt (NaCl) concentration (mM) Buffer type (10 mM) pH stabilizer Surfactant (Polysorbate 80) concentration (mg / mL) Time 0 24 hours 48 hours DoE2-4 50 citrate 5.8 Trehalose dihydrate (200 mM) 0 5.8 5.8 5.8 DoE2-5 50 citrate 5.8 Trehalose dihydrate (200 mM) 0.5 5.8 5.8 5.8 DoE2-6 50 citrate 5.8 Trehalose dihydrate (200 mM) 1 5.8 5.9 5.9
2.11 Turbidity with mechanical load (nephelometry)
Figure 12 is a bar graph showing% turbidity, as determined by nephelometry, of the DoE2 formulations (from Example 2) at an arbitrary starting point (blue bars, time = 0) and after both 24 hours (red bars) and 48 hours ( green bars) for mechanically moving formulations (shaking). No changes were observed.
2 · 12 Aggregates with Frost Load fSE-HPLC)
Figure 13 is a bar graph showing% accumulation / aggregation, as determined by SE-HPLC, of the DoE2 formulations (from Example 2) along with standard references (representing HUMIRA® comparison formulations) before exposure to light (blue bars, time = O) and after 7 hours of light exposure at 765 W / m ² (red bars).
Comparisons were also made with Humira samples (from the US and the EU) subject to the same conditions. In the RMP, the aggregation increases up to 9-15% after light exposure (at time 0 the aggregate amount is below 1%). All DoE2 formulations
DK 2020 00030 U1 shows less or comparable increases and thus better / comparable resistance to heat load. In greater detail:
• Citrate buffer formulations: 4.2 -> 6.1% total amount of aggregates after light exposure.
2.13 Fragmentation with Light Load (Bioanalyzer)
Figure 14 is a bar graph showing% fragmentation, as determined with a Bioanalyzer, of the DoE2 formulations (from Example 2) before exposure to light (blue bars, time = 0) and after 7 hours of light exposure at 765 W / m ² ( red bars).
Minimal increases were noted (maximum + 0.3% after exposure). All fragments are well below 1% after 7 hours of exposure (Fig. 14).
2.14 Light load isoform profile (iCE2280)
Figure 15 is a bar graph showing the main top isoform profile, as determined by iCE280 analysis, of the DoE2 formulations (from Example 2) together with standard references (representing HUMIRA® comparison formulations) before exposure to light (blue bars, time = 0) and after 7 hours of light exposure at 765 W / m ² (red bars).
Figure 16 is a bar graph showing the cluster cluster topoform profile, as determined by iCE280 analysis, of the DoE2 formulations (from Example 2) together with standard references (representing HUMIRA® comparison formulations) before exposure to light (blue bars, time = 0) and after 7 hours of light exposure at 765 W / m ² (red bars).
In Humira-RMP, light exposure produces significant effects: most notably, decreases in head peak frequency (approximately -9%) and concomitant increase in acidic cluster (up to +15%) associated with photo-oxidation phenomena.
Citrate buffer formulations can significantly improve the protein's resistance to degradation phenomena: reductions in the main peak occurrence are around -3.5% or lower, increases in acid cluster showed a maximum of +4%.
2.15 Turbidity with light load (nephelometry).
Figure 17 is a bar graph showing the turbidity, as determined by nephelometry, of the DoE2 formulations (from Example 2) before exposure to light (blue bars, time = 0) and after 7 hours of light exposure at 765 W / m ² (red bars) ). There were virtually no changes.
2.16 pH screening with light exposure
The variation in pH in the DoE2 formulations (from Example 2) over a period of time during which the formulations are exposed to light at 765 W / m ² viDK 2020 00030 U1 for 7 hours is not seen in Table 18. No changes were seen.
Table 18: DoE2 Screenina: pH (Iv Exposure)
Form ff Salt (NaCl) concentration (mM) Buffer type (10 mM) PH stabilizer Surfactant (Polysorbate 80) concentration (mg / ml) Time 0 After exposure DoE2-4 50 citrate 5.8 Trehalose dihydrate (200 mM) 0 5.8 5.8 DoE2-5 50 citrate 5.8 Trehalose dihydrate (200 mM) 0.5 5.8 5.8 DoE2-6 50 citrate 5.8 Trehalose dihydrate (200 mM) 1 5.8 5.9
Conclusion on Screeninos Experiment 2
On the basis of the data collected relevant to heat load, mechanical load and light load, the following conclusion can be drawn:
Formulations in 10 mM sodium citrate / citric acid buffer at pH 5.8 (DoE2 4, DoE2 - 8, DoE2 - 5, DoE2 - 6):
- At heat load, properties similar to Humira were found; Minimal increase of aggregation after mechanical shaking; Improved properties compared to Humira by exposure to continuous (7 hours) irradiation.
Based on the screening work performed on various formulations varying in buffer / pH, stabilizer, amount of isotonicity agent (NaCl) and surfactant content (Polysorbate 80), the best composition exhibits comparable or even improved properties in relation to to Humira under various load conditions (heat load, mechanical load, light) have been identified as:
[0001]
Ingredient Amount (mg / ml) adalimumab 50 Citric 2.10 * trehalose dihydrate 75.67 ** Polysorbate 80 1.00 Sodium chloride 2.92 *** WFI and sodium hydroxide q b to adjust the pH to 5Ό
* corresponding to 10 mM sodium citrate / citric acid buffer; ** equivalent to 200 mM; *** equivalent to 50 mM
Such formulations can easily be incorporated into pre-filled glass syringes with 29G '/' needles.
DK 2020 00030 U1
ABBREVIATIONS
Die Experimental Design DP Pharmaceutical Product DS drug Substance DSF Differentialscanningfluorimetri FT-IR Fourier transform infrared spectroscopy MS-A Merck Serono-Aubonne MS-V Merck Serono-Vevey OD Optical density PES polyethersulfone rPM RPM RT room temperature SE-HPLC High performance size exclusion liquid chromatography SMI Summary Manufacturing Instructions SOP Standard Operating Procedure WI Work Instructions
DK 2020 00030 U1

权利要求:
Claims (1)
[1]
A liquid pharmaceutical composition comprising:
- 50 mg / ml adalimumab;
a citrate buffer system;
- a sugar stabilizer;
a tonic agent;
a surfactant; and
- water (of injection purity);
wherein said adalimumab, citrate buffer system, sugar stabilizer, tonic agent and surfactant are present in a molar ratio of 1: 14-40: 288-865: 28-576: 0.1-3.2, respectively.

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MX2017016884A|2017-12-19|2019-06-20|Probiomed S A De C V|Stable pharmaceutical formulation of an anti-tnf? protein.|

法律状态:
2020-04-28| UAT| Utility model published|Effective date: 20200408 |

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2020-05-26| UME| Utility model registered|Effective date: 20200526 |

优先权:

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申请号 | 申请日 | 专利标题

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EP14169755.7A|EP2946767B1|2014-05-23|2014-05-23|Liquid pharmaceutical composition|

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