HK1095534B - Pharmaceutical preparation containing an antibody against the egf receptor - Google Patents

Description

Pharmaceutical formulation comprising an anti-EGF receptor antibody

The present invention relates to stable pharmaceutical formulations comprising antibodies against Epidermal Growth Factor Receptor (EGFR), their preparation and use.

Various in vitro and in vivo studies have demonstrated that: blocking EGFR with antibodies can be at various levels against tumors, e.g., inhibiting cancer cell proliferation, reducing tumor-mediated angiogenesis, inducing cancer cell apoptosis, and enhancing the toxic effects of radiation therapy and conventional therapies.

MAB c225 (INN: cetuximab) is an antibody that has been clinically demonstrated to bind to the EGF receptor. Cetuximab is a chimeric antibody whose variable regions are of murine origin and whose constant regions are of human origin. Cetuximab was prepared by Naramura et al in Cancer immunol. immunotherapy, 1993, 37: 343-.

MAB425 is a murine antibody against EGFR that is overexpressed in tumor cells, particularly in a431 cancer cells. Humanized and chimeric forms thereof have been disclosed, for example, in EP 0531472 a 1; kettleborough et al, Protein Engineering 1991, 4: 773-783; bier et al, Cancer chemither, pharmacol.2001, 47: 519-524; bier et al, cancer immunol. immunol.1998, 46: 167-. EMD72000 (h425) is a form of MAB425, which is in phase I/II clinical phase and whose constant region consists of the kappa chain and the human gamma-1 chain.

Human anti-EGFR antibodies can be provided by XenoMouse technology, as described in WO91/10741A1, WO94/02602A1, and WO96/3735A 1. One specific antibody produced by this technique and currently undergoing clinical trials is ABX-EGF (Abgenix, Crit. Rev. Oncol. Hematol.2001, 38: 17-23; Cancer Research 1999, 59: 1236-43).

Other anti-EGFR antibodies are described, for example, in EP 0586002B 1 and j. natl. cancer inst.1993, 85: 27-33 (MAB 528).

Similar to other antibodies, anti-EGFR antibodies can also be used parenterally as solutions for therapeutic use. One particular problem with solutions containing these antibodies is their tendency to polymerize and form protein multimers. With respect to recoverable multimers, this can be attributed to intermolecular disulfide bridges formed randomly by the interaction between two moieties in proximity. Hydrophobic interactions and the consequent formation of non-reverting multimers are also possible. In addition, deamidation reactions may occur which would subsequently lead to protein degradation reactions. The denaturation reactions can occur, in particular, during storage at high temperatures or during shear stress (e.g., during transport).

As a consequence of said aggregation tendency, precipitation of the product occurs during storage of the antibody solution, which means that it is doubtful whether or not a drug can be reproducibly taken from the container containing the solution. In addition, solutions containing microparticles may become embolized when administered parenterally. This makes it not always possible to ensure that the anti-EGFR antibody is administered to the patient in the necessary dosage using the antibody solution in a reproducible manner, and that it cannot be administered with the necessary reliability.

Although filtration prior to injection can remove aggregates, this method involves an additional step and is therefore complicated and not very suitable for clinical implementation. Furthermore, the problem of dose reproducibility remains open, since in each case an unknown fraction of the antibody is separated from the solution, and the particle formation after filtration still represents a safety risk.

A common method for stabilizing monoclonal antibodies is to lyophilize a solution containing the antibody and excipients. However, lyophilization is very time and energy consuming and therefore expensive. Furthermore, the lyophilized powder must first be reconstituted prior to administration.

EP 0073371 describes preparations containing immunoglobulins for intravenous administration which have a pH value of 3.5 to 5.0 for stability. However, such low pH values lead to undesirable incompatible reactions at the injection site.

US6,171,586B1 discloses the use of acetate buffers, surfactants and polyols at pH4.48 to 5.5 in aqueous antibody formulations, excluding NaCl for isotonicity adjustment. Incompatible reactions may also occur at the injection site due to the lack of isotonic regulation.

As further examples of antibodies containing a particular antibody, reference may be made in this regard to EP 0280358, EP 0170983 and US5,945,098.

Among them, EP 0280358 describes the addition of dextran to antibody solutions to stabilize against certain hormones for more than 9 months.

EP 0170983 describes the stabilization of thermolabile monoclonal antibodies by heating with hydrolysed ovalbumin, with the result that the antibodies remain stable after 7 days of storage at 45 ℃. However, the addition of other kinds of proteins to formulations for parenteral administration is undesirable due to the problems associated therewith, in particular their possible antigenicity.

US5,945,098 discloses the use of glycine, polysorbate 80 and polyethylene glycol to stabilize aqueous solutions of immunoglobulin G.

DE10133394a1 discloses the use of phosphate buffers at pH6 to pH8 and polyoxyethylene sorbitan fatty acid esters to stabilize aqueous solutions of cetuximab. Although this can significantly reduce the formation of macroscopic aggregates, its chemical stability, especially under stress conditions, is significantly impaired. Furthermore, the formulation does not show stability under (extreme) heat stress conditions (e.g. long term storage at 40 ℃).

It is an object of the present invention to find an aqueous dosage form, in particular for an anti-EGFR antibody, suitable for parenteral administration, which has good tolerability and is stable for at least more than 24 months when stored at room temperature. It should also remain stable in storage under shear stress during transport and under changing climatic conditions, in particular at elevated temperatures and atmospheric humidity. Furthermore, the preparation should have a simple structure and should not contain any auxiliary materials which are considered to be questionable from a toxicological point of view.

Surprisingly, it has been found that formulations in solution form which meet these requirements comprise, in addition to an antibody against epidermal growth factor (anti-EGFR antibody), a buffer, an amino acid and a surfactant. The invention therefore relates to an aqueous pharmaceutical formulation comprising, in addition to an anti-EGFR antibody, a buffer, an amino acid and a surfactant.

For the purposes of the present invention, aqueous preparations are preparations in which at least some of the solvent present consists of water. Other solvent compositions which may be present are all solvents suitable for parenteral use, in particular alcohols, such as ethanol, propanol, propylene glycol or glycerol. The aqueous formulation preferably comprises water or an ethanol/water mixture as solvent; the solvent particularly preferably consists of water.

The antibody present may be any anti-EGFR antibody, in particular the murine, human or chimeric antibodies mentioned at the outset and human anti-EGFR antibodies which have been and can be prepared by the XenoMouse technique described. Preferably the anti-EGFR antibody cetuximab or EMD72000 or one of its corresponding murine, human or chimeric antibody analogs. Particularly preferred are aqueous formulations comprising cetuximab or EMD72000 as antibody.

The anti-EGFR antibody may be present in the formulations of the present invention at a concentration of from 0.1mg/ml to 50mg/ml, preferably from 2mg/ml to 10mg/ml, particularly preferably about 5 mg/ml.

Buffers which can be employed are essentially all physiologically acceptable substances which are suitable for setting the desired pH, for example citrate, acetate, histidine, succinate, maleate, phosphate or lactate, and/or their respective free acids or bases, and also mixtures of different salts and/or their acids or bases. The buffer preferably consists of one or more of citrate, acetate, histidine, succinate, maleate, phosphate or lactate and/or their respective free acids or bases or a mixture of one or more different salts and/or their acids or bases. The term "mixture" herein encompasses mixtures of different salts of the same acid (e.g., mixtures of different citrates) and mixtures of salts of different acids (e.g., mixtures of citrates and acetates). The buffer preferably consists of one or more of citrate and/or its free acid (e.g. citric acid, citric acid monohydrate, trisodium citrate dihydrate, tripotassium citrate monohydrate), acetate and/or its free acid (e.g. acetic acid, sodium acetate trihydrate) or L-histidine and/or its acid addition salt (e.g. L-histidine monohydrochloride monohydrate). The formulations of the invention advantageously comprise a buffer in a concentration of from 10 to 100mmol/l, preferably from 2 to 20mmol/l, particularly preferably about 10 mmol/l.

The pH of the formulation is in the range of 5.0 to 6.0, preferably 5.2 to 5.8, particularly preferably about 5.5.

The formulations of the invention have good physiological tolerance, are easy to prepare, can be dosed accurately, and are stable with respect to analysis of breakdown products and aggregates during storage, repeated freeze-thaw processing, and mechanical stress. It remains stable for storage at refrigerator temperatures (2-8 ℃) for periods of at least 3 months to 4 years. Surprisingly, the formulations of the present invention are stable upon storage at elevated temperatures and higher atmospheric humidity levels (e.g., 25 ℃ and 60% relative atmospheric humidity) for more than 2 years, or for more than 3 months at 40 ℃ and 75% relative atmospheric humidity.

The amino acids present in the formulation may be basic (e.g. arginine, histidine, ornithine, lysine) or neutral (e.g. glycine, methionine, isoleucine, leucine and alanine) or aromatic (e.g. phenylalanine, tyrosine or tryptophan). Preference is given to using basic amino acids in the form of inorganic salts (the hydrochloride form, i.e.advantageously as amino acid hydrochloride). The amino acids used are in each case preferably in the L-form. The amino acids present in the formulations of the invention are particularly preferably L-arginine, glycine and L-methionine.

The preparation contains amino acids in a concentration of 2 to 200mmol/l, preferably 50 to 150mmol/l, particularly preferably about 100 mmol/l.

Surfactants which can be used are all surfactants customarily used in pharmaceutical preparations, preferably polyethylene sorbitan fatty acid esters and polyoxyethylene-polyoxypropylene copolymers. Polyethylene sorbitan fatty acid esters are also known under the trade name tween. Suitable polyethylene sorbitan fatty acid esters are polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate and polyoxyethylene (20) sorbitan monostearate. Polyoxyethylene (20) sorbitan monolaurate and polyoxyethylene (20) sorbitan monooleate are preferred, and polyoxyethylene (20) sorbitan monooleate is particularly preferred. Polyoxyethylene-polyoxypropylene copolymers are also known under the trade name poloxamers. A particularly preferred polyoxyethylene-polyoxypropylene copolymer is poloxamer 407(CAS 9003-11-6).

The surfactant may be present in the formulation at a concentration of 0.001% to 1.0% by weight. If polyethylene sorbitan fatty acid esters are present as surfactants, they are preferably present in an amount of from 0.005% to 0.1% by weight, particularly preferably in an amount of about 0.01% by weight. If present, the polyoxyethylene-polyoxypropylene copolymer is preferably present in an amount of 0.01-0.5% by weight, particularly preferably about 0.1% by weight.

To improve tolerability of parenteral administration, the osmolality is preferably in the isotonic range, i.e. an osmolality of about 250 to 350 mOsmol/kg. The preparation can thus be administered directly intravenously, intraarterially and also subcutaneously substantially without pain.

According to an advantageous embodiment, the formulations of the invention therefore additionally comprise an isotonicity adjusting agent, preferably a physiologically tolerable salt (e.g. sodium chloride or potassium chloride) or a physiologically tolerable polyol (e.g. glucose or glycerol), in the concentrations necessary for isotonicity adjustment. Thus, the invention also relates to aqueous formulations comprising an anti-EGFR antibody, a buffer, an amino acid, a surfactant and an isotonicity adjusting agent at a concentration necessary for isotonicity adjustment. Sodium chloride is particularly preferably present as an isotonicity adjusting agent.

Furthermore, the solutions of the invention may comprise other physiologically tolerable adjuvants, such as antioxidants (e.g. ascorbic acid or glutathione), preservatives (e.g. phenol, m-cresol, methyl or propyl paraben, chlorobutanol, thimerosal or benzalkonium chloride), polyethylene glycols (PEG) (e.g. PEG 400, PEG3000, 3350, 4000 or 6000), disaccharides (e.g. trehalose or sucrose) or cyclodextrins (e.g. hydroxypropyl- β -cyclodextrin, sulfobutyl ether- β -cyclodextrin, α -cyclodextrin or γ -cyclodextrin).

According to a particularly advantageous embodiment of the invention, the aqueous formulation comprises about 5mg/ml of cetuximab or EMD72000, about 10mmol/L of citrate or histidine buffer having a pH of about 5.5, about 100mmol/L of glycine, arginine or L-methionine, about 100mmol/L of sodium chloride and about 0.01% of polyoxyethylene (20) sorbitan monooleate.

The aqueous formulation may be prepared by adding the adjuvant to a solution containing an anti-EGFR antibody. For this purpose, a defined volume of stock solution containing the further excipients in defined concentrations is advantageously added to the solution containing the anti-EGFR antibody in defined concentrations (as obtained from its preparation) and the mixture is diluted with water or buffer as appropriate to a pre-calculated concentration. Alternatively, the adjuvant may be added as a solid to the starting solution containing the anti-EGFR antibody. If the anti-EGFR antibody is in solid form, for example in the form of a lyophilizate, the formulations of the present invention can be prepared as follows: each antibody is first dissolved in water or an aqueous solution containing one or more further adjuvants, followed by addition of the required amounts of each stock solution containing the further adjuvants, the further adjuvants in solid form and/or water. The anti-EGFR antibody can also advantageously be dissolved directly in a solution containing all the other adjuvants.

One or more adjuvants present in the formulations of the invention may advantageously have been added during or after the preparation of a particular EGFR antibody. This can preferably be done as follows: in the final step of purification, which is carried out after its preparation, the anti-EGFR antibody is directly dissolved in an aqueous solution containing one, more or all of the other adjuvants. In order to prepare the formulations, the various other ingredient(s) need in each case only be added in minor amounts and/or not at all. It is particularly preferred to dissolve the various ingredients directly in the aqueous solution containing all the other adjuvants in the last step of the purification carried out after their preparation.

If the solution containing the respective antibody and adjuvant does not yet have the desired pH, it can be set by adding an acid or a base, preferably an acid or a base already present in the buffer system. Followed by sterile filtration.

The aqueous formulations of the present invention may advantageously be used for the treatment of tumor diseases.

These examples illustrate the invention but are not limited thereto.

Example 1 (comparative example 1)

The aqueous solution comprises:

2mg/ml cetuximab

10mmol/l sodium phosphate buffer pH7.2

145mmol/l sodium chloride

Prepared by mixing a predetermined volume of an aqueous solution containing each excipient at a predetermined concentration. The following solutions were used:

solution A(active ingredient solution) comprising:

18mg/ml cetuximab

10mmol/l sodium phosphate buffer pH7.2

(consisting of 2.07h/l disodium hydrogen phosphate 7 hydrate and 0.31g/l sodium dihydrogen phosphate monohydrate)

145mmol/l sodium chloride

(the last step of purification, carried out after the preparation of the active ingredient, was obtained by rebuffering the solution B without active ingredient by means of tangential flow filtration.)

Solution B(buffer/salt solution)

Identical to solution a, but containing no active ingredient.

To prepare comparative solution 1, 1.11 parts by volume of solution A and 8.89 parts by volume of solution B were mixed with each other.

The prepared solution was filtered through a sterile filter before transfer and transferred into an injection vial. The injection vial was then sealed with a stopper and crimped.

Example 2 (comparative example 2)

The aqueous solution comprises:

2mg/ml cetuximab

10mmol/l sodium phosphate buffer pH7.2

145mmol/l sodium chloride

0.01% by weight of polyoxyethylene (20) sorbitan monooleate

Prepared by mixing a predetermined volume of an aqueous solution containing the components at a predetermined concentration. In addition to solution a, the following solutions were used:

solution C(buffer/salt solution, containing polyoxyethylene (20) sorbitan monooleate)

Consistent with solution B, but additionally containing 0.0125% by weight of polyoxyethylene (20) sorbitan monooleate.

To prepare comparative solution 2, 1.11 parts by volume of solution A and 8.89 parts by volume of solution C were mixed with each other.

The prepared solution was filtered through a sterile filter before transfer and transferred into an injection vial. The injection vial was then sealed with a stopper and crimped.

Example 3 (formulation of the invention)

5mg/ml cetuximab

10mmol/l citrate buffer pH5.5

100mmol/l glycine

100mmol/l sodium chloride

0.01% by weight of polyoxyethylene (20) sorbitan monooleate

Prepared by mixing a predetermined volume of an aqueous solution containing the components at a predetermined concentration.

Solution D(solution of active ingredient in citric acid buffer)

16mg/ml cetuximab

10mmol/l citrate buffer pH5.5

(consisting of 2.1014g/l citric acid monohydrate)

(the last step of purification, carried out after the preparation of the active ingredient, was obtained by rebuffering the solution E without active ingredient by means of tangential flow filtration.)

Solution E(buffer solution):

consistent with solution D, but containing no active ingredient.

Solution F(buffer/salt solution):

corresponds to solution E, but comprises

145.5mmol/l Glycine

145.5mmol/l sodium chloride and

0.015% by weight of polyoxyethylene (20) sorbitan monooleate

To prepare the formulation of the invention, 3.125 parts by volume of solution D and 6.875 parts by volume of solution F were mixed with each other.

The prepared solution was filtered through a sterile filter before transfer and transferred into an injection vial. The injection vial was then sealed with a stopper and crimped.

Example 4

The following solutions were prepared in analogy to the procedure of the above examples:

example 4.1, solution, comprising:

5mg/ml cetuximab

100mmol/l glycine

0.01% by weight of polyoxyethylene (20) sorbitan monooleate

10mmol/l citrate buffer pH5.5

(consisting of 2.9410g/l trisodium citrate dihydrate)

Example 4.2, solution, comprising:

5mg/ml cetuximab

100mmol/l glycine

100mmol/l sodium chloride

0.01% by weight of polyoxyethylene (20) sorbitan monooleate

10mmol/l citrate buffer pH5.5

(consisting of 2.1014g/l citric acid monohydrate)

Example 4.3, solution, comprising:

5mg/ml EMD 72000

100mmol/l glycine

100mmol/l sodium chloride

0.01% by weight of polyoxyethylene (20) sorbitan monooleate

10mmol/l citrate buffer pH5.5

(consisting of 2.1014g/l citric acid monohydrate)

Example 4.4, solution, comprising:

5mg/ml cetuximab

100mmol/l L-methionine

0.01% by weight of polyoxyethylene (20) sorbitan monooleate

10mmol/l citrate buffer pH5.5

(consisting of 2.1014g/l citric acid monohydrate)

Example 4.5, solution, comprising:

5mg/ml cetuximab

100mmol/l glycine

0.01% by weight of polyoxyethylene (20) sorbitan monooleate

10mmol/l acetate buffer pH5.5

(consisting of 1.3608g/l sodium acetate trihydrate)

Example 4.6, solution, comprising:

5mg/ml cetuximab

100mmol/l glycine

0.01% by weight of polyoxyethylene (20) sorbitan monooleate

10mmol/l histidine buffer pH5.5

(consisting of 2.069g/l L-histidine monohydrochloride monohydrate)

Example 4.7, solution, comprising:

5mg/ml cetuximab

100mmol/l glycine

0.01% by weight of polyoxyethylene (20) sorbitan monooleate

10mmol/l citrate buffer pH5.5

(consisting of 2.1014g/l citric acid monohydrate)

Example 4.8, solution, comprising:

5mg/ml cetuximab

100mmol/l glycine

0.01% by weight of a polyoxyethylene-polyoxypropylene copolymer 407 (Poloxamer 407)

10mmol/l citrate buffer pH5.5

(consisting of 2.1014g/l citric acid monohydrate)

Example 5

The stability of the formulations of the invention was tested by stress testing. For this purpose, vials containing the solution of example 3 and vials containing the solutions of examples 1 and 2 for comparison purposes were stored at 25 ℃ and 60% relative atmospheric humidity and at 40 ℃ and 75% relative atmospheric humidity. In addition, vials containing the solutions of examples 1, 2 and 3 were placed on a shaker for 150min^-1Is shaken at room temperature for five days and is frozen continuously at-20 ℃ and subsequently thawed three times at +5 ℃. Before storage and after defined storage times, the vials were visually inspected using direct illumination with a cold light source to determine the absorbance at 350nm of the solution, which represents a measure of turbidity. To illustrate the effect of storage or handling, the relative turbidity of each was calculated relative to the starting value. In addition, vials were analyzed for cetuximab, aggregates and decomposition product content using HPLC gel filtration.

The results of the stability studies are shown in Table 1.

Test solutions	Storage [ time/Condition]	Cetuximab [% ]]	Of aggregates [% ]]	Decomposition products [% ]]	Turbidity (λ 350nm)	Relative turbidity (λ 350nm)	Visual inspection of
								Example 1	0 week	99.67	0.12	0.22	0.005	1.00	Small particles, small amount, clarification
Example 1	8 weeks 25 ℃/60% relative humidity	98.99	0.28	0.73	0.0081	1.62	Large particle, large quantity, clarification
								Example 1	8 weeks 40 ℃/75% relative humidity	95.08	3.23	1.69	0.0235	4.70	Large particle, large quantity, clarification
Example 1	150rpm and shaking at room temperature for 5 days	99.60	0.17	0.24	0.829	165.80	Very large particles, very large particle count, turbidity
								Example 1	Three cycles of freezing/thawing at-20 ℃ and +5 ℃	99.68	0.14	0.18	0.0089	1.78	Large particles, high particle content, slight turbidity
								Example 2	0 week	99.62	0.18	0.21	0.0048	1.00	No particles, clarification

Example 2	8 weeks 25 ℃/60% relative humidity	99.02	0.28	0.70	0.0071	1.48	Small particles, small amount, clarification
								Example 2	8 weeks 40 ℃/75% relative humidity	93.95	4.34	1.72	0.0241	5.02	Small particles, small amount, clarification
Example 2	150rpm and shaking at room temperature for 5 days	99.51	0.26	0.23	0.0075	1.56	No particles, clarification
								Example 2	Three cycles of freezing/thawing at-20 ℃ and +5 ℃	99.61	0.21	0.18	0.0064	1.48	No particles, clarification
								Example 3	0 week	99.72	0.15	0.14	0.018	1.00	No particles, clarification

Example 3

8 weeks 25 ℃/60% relative humidity

99.38

0.18

0.44

0.020

1.08

Small particles, small amount, clarification

Example 3	8 weeks 40 ℃/75% relative humidity	98.15	0.46	1.40	0.030	1.63	Small particles, small amount, clarification
								Practice ofExample 3	150rpm and shaking at room temperature for 5 days	99.15	0.70	0.15	0.019	1.04	No particles, clarification
Example 3	Three cycles of freezing/thawing at-20 ℃ and +5 ℃	99.75	0.14	0.12	0.018	1.00	No particles, clarification

Table 1: summary of stability data for the formulation of the invention (example 3) and for the two comparative solutions (examples 1 and 2)

The results clearly show that the formulations of the invention have significantly improved stability compared to the comparative solutions of the prior art.

Claims (16)

1. An aqueous solution formulation consisting of: a solvent, wherein at least some of the solvent present consists of water; anti-epidermal growth factor receptor antibodies; a buffering agent; an amino acid; a surfactant; and sodium chloride as an isotonicity adjusting agent.

2. Formulation according to claim 1, characterized in that the antibody is cetuximab or EMD 72000.

3. Formulation according to claim 1, characterized in that the buffer consists of one or more citrates, acetates, histidines, succinates, malates, phosphates or lactates and/or the respective free acids or bases or a mixture of one or more different salts and/or acids or bases thereof.

4. Formulation according to claim 3, characterized in that the buffer consists of one or more citrates and/or the free acids thereof, acetates and/or the free acids thereof or L-histidine and/or the acid addition salts thereof.

5. Formulation according to claim 1, characterized in that the amino acid is L-arginine, glycine or L-methionine.

6. Formulation according to claim 1, characterized in that the surfactant is a polyoxyethylene sorbitan fatty acid ester or a polyoxyethylene-polyoxypropylene copolymer.

7. Formulation according to claim 6, characterized in that the polyoxyethylene sorbitan fatty acid ester surfactant is polyoxyethylene (20) sorbitan monooleate or polyoxyethylene (20) sorbitan monolaurate.

8. Preparation according to claim 6, characterized in that the surfactant is poloxamer 407.

9. Formulation according to claim 1, characterized in that the solvent is water or a mixture of water and alcohols.

10. Preparation according to claim 9, characterized in that the alcohols are ethanol, propanol, propylene glycol and/or glycerol.

11. Formulation according to any one of claims 1 to 10, characterized in that it has a pH value of 5 to 7.

12. Formulation according to claim 11, characterized in that it has a pH value of 5.2 to 6.0.

13. Formulation according to claim 11, characterized in that it has a pH value of 5.5.

14. Formulation according to any one of claims 1 to 10, characterized in that it comprises 5mg/ml cetuximab or EMD72000, 10mmol/L citrate or histidine buffer, 100mmol/L glycine, L-arginine or L-methionine, 100mmol/L sodium chloride and 0.01% polyoxyethylene (20) sorbitan monooleate and has a pH value of 5.5.

15. Method for the preparation of a formulation according to any one of claims 1 to 14, characterized in that an adjuvant according to any one of claims 1 to 11 is added to a solution comprising an anti-epidermal growth factor receptor antibody.

16. Use of a formulation according to any one of claims 1 to 14 in the manufacture of a medicament for the treatment of a neoplastic disease.