WO2018038687A1

WO2018038687A1 - Pharmaceutical formulations comprising a bortezomib-cyclodextrin complex

Info

Publication number: WO2018038687A1
Application number: PCT/TR2016/000122
Authority: WO
Inventors: Turgay AYDINLAR
Original assignee: Mustafa Nevzat Ilac Sanayii AS
Current assignee: Mustafa Nevzat Ilac Sanayii AS
Priority date: 2016-08-22
Filing date: 2016-08-22
Publication date: 2018-03-01
Anticipated expiration: 2019-02-22

Abstract

The present invention relates to the pharmaceutical formulations comprising a bortezomib- cyclodextrin complex; to the preparation processes of the pharmaceutical formulations comprising a bortezomib-cyclodextrin complex; and to the pharmaceutical formulations comprising a bortezomib-cyclodextrin complex for use in the treatment of certain types of cancer, such as multiple myeloma and mantle cell lymphoma.

Description

PHARMACEUTICAL FORMULATIONS COMPRISING

A BORTEZOMIB-CYCLODEXTRIN COMPLEX

DESCRIPTION

Field of the Invention

Background of the Invention

The present invention relates to the pharmaceutical formulations comprising a bortezomib- cyclodextrin complex.

Bortezomib is the first anti-neoplastic dipeptidyl boronic acid proteasome inhibitor. The chemical name for bortezomib is [(lR)-3-methyl-l-[[(2S)-l-oxo-3-phenyl-2- [(pyrazinylcarbonyl)amino] propyl]amino]butyl]boronic acid. Bortezomib has the following chemical structure:

Compound I

Bortezomib, a potent and selective inhibitor of the proteolytic activity of the proteasome, has shown anti-neoplastic activity against multiple myeloma and mantle cell lymphoma. Multiple myeloma is a cancer of the blood. It affects the part of bone called bone marrow. Myeloma cells multiply quickly and prevent bone marrow from making enough blood cells for the body to fight the diseases. Mantle cell lymphoma is a type of blood cancer that affects white blood cells called lymphocytes. It affects lymphocytes in the mantle zone of a lymph node. Mantle cell lymphoma is considered to be an aggressive cancer. Bortezomib is currently available on the market as a lyophilized powder containing bortezomib in the form of a mannitol boronic ester under the brand name of Velcade^®. Lyophilized formulation in a single-dose vial contains 3.5 mg bortezomib and 35 mg mannitol. When reconstituted with 3.5 ml 0.9% sodium chloride saline, each ml contains 1 mg bortezomib and 10 mg mannitol.

Bortezomib has been first disclosed in the PCT application WO 96/13266 Al . Said invention provides potent and highly selective proteasome inhibitors, a method for reducing the rate of muscle protein degradation in a cell comprising contacting said cell with a proteasome inhibitor, a method for reducing the activity of NF-κΒ in a cell comprising contacting the cell with a proteasome inhibitor, a method of reducing the rate of degradation of p53 protein in a cell comprising administering to the cell a proteasome inhibitor, a method for inhibiting cyclin degradation in a cell comprising contacting said cells with a proteasome inhibitor, a method for inhibiting the growth of a cancer cell comprising contacting said cell with a proteasome inhibitor, a method for inhibiting antigen presentation in a cell comprising administering to the cell a proteasome inhibitor, a method for inhibiting inducible NF-KB dependent cell adhesion in an animal comprising administering to said animal a proteasome inhibitor, a method for inhibiting HIV replication in an animal comprising administering to said animal a proteasome inhibitor, an approach for inhibiting cytolytic immune responses, pharmaceutical compositions that comprise proteasome inhibitors in an amount effective to inhibit proteasome function in a mammal, and a pharmaceutically acceptable carrier or diluent. However, any pharmaceutical composition comprising a proteasome inhibitor of the invention has not been illustrated.

Formulation of the Velcade^®, original product currently available on the market, has been disclosed in the PCT application WO 02/059130 Al . Said invention provides pharmaceutical compositions prepared by the lyophilization of an aqueous mixture comprising a boronic acid compound, which is bortezomib, and a compound having at least two hydroxyl groups, which is mannitol. Said composition readily releases the boronic acid compound from the mannitol boronic ester upon dissolution in aqueous media.

Boronic acids including bortezomib are difficult to be formulated due to their solubility and stability issues. As mentioned in WO 02/059130 Al, alkylboronic acids are relatively difficult to obtain in analytically pure form. Snyder et al., J. Am. Chem. Soc, Vol. 80, Issue 14, 1958, p. 361 1, teaches that alkylboronic acid compounds readily form boroxines (anhydrides) under dehydrating conditions. Also, alkylboronic acids and their boroxines are often air-sensitive. Korcek et al., J. Chem. Soc, Perkin Trans. 2, 1972, p. 242, teaches that butylboronic acid is readily oxidized by air to generate 1-butanol and boric acid.

These difficulties indicate that there is still a need for alternative formulations of bortezomib with enhanced solubility, stability and longer shelf life compared to the free boronic acid compound. Said formulations are expected to release the boronic acid compound upon dissolution in aqueous media when administered to a subject.

The PCT applications WO 2014/015016 Al, WO 2014/015027 Al, WO 2013/169282 Al, WO 2013/169897 Al, WO 2006/063154 Al relate to pharmaceutical compositions comprising a peptide epoxy ketone proteasome inhibitor and a cyclodextrin. However, the inventions are merely limited to the peptide epoxy ketone proteasome inhibitors that differ structurally and mechanistically from the boronate-based proteasome inhibitor bortezomib.

The PCT application WO 2010/039762 A2 relates to sugar-free pharmaceutical compositions of bortezomib. Many basic sugar-free pharmaceutical compositions have been disclosed in the patent specification such as pharmaceutical compositions comprising bortezomib, 'sodium chloride, a vitamin, a carboxylic acid, or an amino acid', and optionally a stabilizing agent (EDTA); pharmaceutical compositions comprising bortezomib and a solvent which comprises at least one alcohol; pharmaceutical compositions comprising bortezomib and 'a solubilizer or a cyclodextrin'. However, any technical data relating to the cyclodextrin compositions has not been given to demonstrate the stability. The only stability data being related to the pharmaceutical compositions comprising a solvent as the single excipient indicates that the subject-matter of the patent application is actually directed to the use of solely a solvent.

The EPC application EP2238973 Al relates to pharmaceutical compositions comprising a drug selected from a group of proteasome inhibitors and a cyclodextrin. Preferred compounds of the invention are novel proteasome inhibitors other than bortezomib and all of the examples have illustrated pharmaceutical compositions comprising these novel compounds. Any example relating to the compositions of bortezomib has not been given. In addition, it has been disclosed in the patent specification that merely the formulations including said novel compounds together with 'a cyclodextrin and a surfactant (preferably a polysorbate)' or 'a cyclodextrin and a bulking agent (preferably mannitol)' were reconstituted within two minutes to provide clear, colorless, particulate-free solutions. According to the invention, Formulation 4 (formulation with said novel compounds, cyclodextrin and mannitol) demonstrated excellent stability and referred as well-suited formulation for injection. However, the matter of which one of the ingredients used in Formulation 4 provided stability cannot be understood from the patent specification: cyclodextrin or mannitol. As it has been known from the PCT application WO 02/059130 Al, pharmaceutical compositions comprising bortezomib and mannitol had already demonstrated the enhanced stability. Furthermore, it is clear that even the addition of a small amount of mannitol results in bortezomib-mannitol esterification and provides stabilizer effect.

Therefore, above-mentioned prior art documents do not disclose alternative lyophilized pharmaceutical compositions comprising a bortezomib-cyclodextrin complex having enhanced solubility, stability and longer shelf life as well as less toxic side effects.

Summary of the Invention

The present invention relates to a lyophilized pharmaceutical composition comprising bortezomib, hydroxypropyl β-cyclodextrin and at least one disaccharide. The present invention relates to a process for preparing a lyophilized pharmaceutical composition of bortezomib, wherein the process comprises the steps of:

a) preparing a mixture comprising

i) bortezomib,

ii) hydroxypropyl β-cyclodextrin,

iii) at least one disaccharide,

iv) tert-butanol,

v) water, and

b) lyophilizing the mixture.

The present invention also relates to a lyophilized pharmaceutical composition comprising bortezomib, hydroxypropyl β-cyclodextrin and at least one disaccharide for use in the treatment of cancer.

Detailed Description of the Invention

It has been found that lyophilized pharmaceutical compositions of bortezomib comprising a cyclodextrin derivative and at least one bulking agent, wherein the cyclodextrin derivative is hydroxypropyl β-cyclodextrin and wherein the at least one bulking agent is selected from disaccharides, provide enhanced solubility, stability and longer shelf life. Said pharmaceutical compositions of the invention in the form of a powder for solution for injection readily release bortezomib upon dissolution in aqueous media. Process for preparing said lyophilized pharmaceutical compositions of the invention comprises the steps of:

a) preparing a mixture comprising

i) bortezomib,

ii) hydroxypropyl β-cyclodextrin,

iii) at least one disaccharide,

iv) tert-butanol,

v) water, and

b) lyophilizing the mixture.

Embodiments of the present invention are directed to the pharmaceutical compositions comprising a bortezomib-cyclodextrin complex and the preparation processes thereof.

Loftsson et al., Expert Opin. Drug Deliv., Vol. 2, Issue 2, 2005, pp. 335-351, teaches that injectable formulations of lipophilic water-insoluble drugs (such as bortezomib) frequently contains mixtures of water, organic cosolvents and surfactants. Organic solvents and surfactants can be replaced by isotonic aqueous cyclodextrin solutions. Numerous studies have shown that these aqueous cyclodextrin vehicles containing the active drug will in general not alter the intrinsic pharmacokinetics of a drug. On parenteral administration, especially after intravenous injection, the drug is both rapidly and quantitatively released from the cyclodextrin complex upon dilution, competitive replacement, and binding of drug molecules to plasma proteins and tissue. However, because cyclodextrins are rapidly eliminated in the urine, cyclodextrins can increase renal clearance of lipophilic water- insoluble drugs. Finally, the hydrophilic cyclodextrin derivatives, such as hydroxypropyl β- cyclodextrin (HPCD) and sulfobutylether β-cyclodextrin (SBECD), are relatively non-toxic compared with organic solvents and surfactant formulations. Furthermore, as they have a minimal effect on the intrinsic pharmacokinetics of drugs, cyclodextrin-containing formulations are increasingly being used during in vitro and in vivo screening of new pharmacologically active compounds. Pharmaceutical compositions of the invention comprise bortezomib and a cyclodextrin in molar ratios of a cyclodextrin to bortezomib ranging from about 0.5:1 to about 100:1. Pharmaceutical compositions of the invention comprise the cyclodextrin in an amount up to about 99% w/w, preferably in an amount more than about 40% w/w, more preferably in an amount from about 60% to about 95% w/w of the lyophilized composition.

Pharmaceutical compositions of the present invention include at least one further pharmaceutically acceptable excipient. Further pharmaceutically acceptable excipients of the invention may be selected from the group comprising, without limitation, bulking agents, solvents or cosolvents, surfactants, or a combination thereof. Baheti et al., Excipients used in lyophilization of small molecules. J. Excipients and Food Chem., Vol. 1, Issue 1, 2010, pp. 41-54, teaches that bulking agents are used in the lyophilized products in order to form the bulk of the lyophilized product, provide an adequate structure to the lyophilized cake and prevent the degradation of a molecule both during freeze-drying and during storage. The structure of the lyophilized cake is important, since proper cake formation leads to proper pore formation that provides the means for vapor to escape from the product during the drying cycle. Baheti et al. also teaches that mannitol and glycine, are the most commonly used bulking agents, followed by glucose, sucrose, lactose, trehalose and dextran.

Bulking agent(s) of the invention may include, but are not limited to, monosaccharides (i.e. fructose, galactose, glucose, etc.), disaccharides (i.e. lactose, maltose, sucrose, trehalose, etc.), oligosaccharides (i.e. maltodextrins, etc.), polysaccharides (i.e. cellulose, starches, etc.), sugar alcohols (i.e. mannitol, sorbitol, xylitol, etc.), amino acids (i.e. arginine, glycine, etc.) and/or mixtures thereof. Bulking agent(s) of the invention preferably include at least one disaccharide. Pharmaceutical compositions of the invention comprise the bulking agent in an amount up to about 99% w/w, preferably in an amount less than about 60% w/w, more preferably in an amount from about 5% to about 40% w/w of the lyophilized composition.

Baheti et al. also teaches that solvents or cosolvents are used in the lyophilized products. Water is the most commonly used solvent for lyophilization. However, organic solvents are sometimes used to increase the primary drying rate by increasing the sublimation rates, improve product stability, decrease reconstitution time by improving drug wettability or solubility, and also enhance the sterility assurance of the sample solution. Since lyophilization works on the principle of vapor pressure differential, it is necessary for excipients to have low vapor pressure, to minimize their loss during the lyophilization process. However, cosolvents are added due to their high vapor pressure to facilitate faster removal from the product during drying process and thus speeding up the lyophilization process. The rate of degradation of active constituent in the presence of water can be reduced by addition of non-aqueous solvents.

Organic solvents of the invention are miscible with water and removable by lyophilization. Organic solvent(s) of the invention may include, but are not limited to, alcohols such as ethanol, propanol and tert-butanol. Cosolvent system of the invention preferably include tert-butanol/water combination. Pre-lyophilized pharmaceutical compositions of the invention comprise the organic solvent in an amount up to about 90% v/v, preferably in an amount less than about 60% v/v, more preferably in an amount from about 5% to about 50% v/v of the pre-lyophilized composition.

Furthermore, surfactants may also be used in the lyophilized products. However, many of the commonly used surfactants have toxic side effects such as hemolysis, damage to membrane permeability, changes to protein conformation, alteration of bioactivity of other compounds, and the like. These side effects are enhanced by the non-degradable nature of some surfactants. Thus, limitations exist in developing safe lyophilized pharmaceutical formulations of poorly soluble and insoluble therapeutic agents such as bortezomib. The stability results demonstrated that the pharmaceutical compositions of the present invention provide enhanced solubility and stability without the addition of a surfactant. Hence, side effects that may result from the use of a surfactant is eliminated.

Development of the pharmaceutical compositions of the invention in the dosage form of a lyophilized powder for solution for injection comprising bortezomib and a cvclodextrin Based on the studies, it has been found that preferably surfactant-free lyophilized pharmaceutical compositions comprising bortezomib, hydroxypropyl β-cyclodextrin and at least one disaccharide, display enhanced solubility, stability and longer shelf life as well as less toxic side effects.

As used herein; "N.D." refers to "not detected" for related substances, and "D.L." refers to "disregard limit" which is 0.1 % for related substances. As used herein; "low-concentrate" refers to the cyclodextnn derivative amount up to about 70% w/w; "mid-concentrate" refers to the cyclodextrin derivative amount from about 70% to 90% w/w, and "high-concentrate" refers to the cyclodextrin derivative amount more than about 90% w/w. Furthermore, "low to mid-concentrate" refers to the cyclodextrin derivative amount near the lower limit of the indicated range of "mid-concentrate"; and "mid to high- concentrate" refers to the cyclodextrin derivative amount near the upper limit of the indicated range of "mid-concentrate".

As used herein; "low-concentrate" refers to the bulking agent amount up to about 10% w/w; "mid-concentrate" refers to the bulking agent amount from about 10% to 30% w/w, and "high-concentrate" refers to the bulking agent amount more than about 30% w/w. Furthermore, "low to mid-concentrate" refers to the bulking agent amount near the lower limit of the indicated range of "mid-concentrate"; and "mid to high-concentrate" refers to the bulking agent amount near the upper limit of the indicated range of "mid-concentrate".

According to the invention; alcohol/water combination (preferably, 40:60 or 50:50) is the preferred cosolvent system.

Following experiments have been performed during the pharmaceutical development process.

1. Pharmaceutical compositions with bulking agents; without a cyclodextrin

These compositions did not provide a suitable impurity profile.

• lactose (high-concentrate) + tert-butanol

Table 1

• trehalose (high-concentrate) + tert-butanol

Table 2

Pharmaceutical compositions with a cyclodextrin; without a bulking agent

These compositions did not provide a suitable impurity profile and/or desired solubility. However, the stability-enhancing effect in the presence of HPCD and tert- butanol was promising.

• HPCD (high-concentrate) + ethanol

6-month stability data at 25°C / 60% RH was comparable to the stability data obtained from the original formulation of Velcade^®. However, solubility of the active ingredient was low. The increase in dissolution time resulted in the increase of impurities.

• SBECD (high-concentrate) + ethanol

6-month stability results at 25°C / 60% RH were not satisfactory and solubility of the active ingredient was low. The increase in dissolution time resulted in the increase of impurities.

• SBECD (high-concentrate) + tert-butanol

6-month stability data at 25°C / 60% RH was comparable to the stability data obtained from the original formulation of Velcade^®. Table 3

Pharmaceutical compositions with a cyclodextrin and a bulking agent

Pharmaceutical compositions with SBECD did not provide a suitable impurity profile. However, the solubility and stability-enhancing effect in the presence of HPCD, disaccharides and tert-butanol was promising.

• glycine (low to mid-concentrate) + SBECD (mid-concentrate) + tert-butanol

1 -month stability results at 40°C / 75% RH were not satisfactory.

Table 4

• lactose (low to mid-concentrate) + SBECD (mid-concentrate) + tert-butanol

1 -month stability results at 40°C / 75% RH were not satisfactory.

Table 5

• trehalose (low to mid-concentrate) + SBECD (mid-concentrate) + tert-butanol

1 -month stability results at 40°C / 75% RH were not satisfactory. Table 6

• trehalose (mid to high-concentrate) + SBECD (mid-concentrate) + tert-butanol

1 -month stability results at 40°C / 75% RH were not satisfactory.

Table 7

• trehalose (mid-concentrate) + SBECD (mid-concentrate) + ethanol

15-day stability results at 40°C / 75% RH were not satisfactory.

Table 8

RRT 0.60 0.03 < D.L. 0.03 < D.L.

RRT 0.73 0.04 < D.L. 0.07 < D.L.

Total impurity 0.73% 1.62%

• trehalose (mid-concentrate) + HPCD (mid-concentrate) + ethanol

15-day stability results at 40°C / 75% RH were not satisfactory.

Table 9

• glycine (low to mid-concentrate) + HPCD (mid-concentrate) + tert-butanol

1 -month stability results at 40°C / 75% RH were not satisfactory.

Table 10

• trehalose (mid-concentrate) + HPCD (mid-concentrate) + tert-butanol

15-day stability results at 25°C / 60% RH + 40°C / 75% RH were promising.

Table 12

Optimum cyclodextrin (HPCD) and bulking agent (disaccharide) amounts

The most suitable amount of the cyclodextrin (HPCD) was determined to be preferably from about 60% to about 95% w/w of the lyophilized composition.

The most suitable amount of the bulking agent (at least one disaccharide) was determined to be preferably from about 5% to about 40% w/w of the lyophilized composition.

• lactose (low to mid-concentrate) + HPCD (mid-concentrate) + tert-butanol

2-month stability results at 25°C / 60% RH and 1 -month stability results at 40°C / 75% RH were suitable.

Table 13

• trehalose (mid-concentrate) + HPCD (mid-concentrate) + tert-butanol

2-month stability results at 25°C / 60% RH and 1 -month stability results at 40°C / 75% RH were suitable. Table 14

As demonstrated by the preceding experiments, preferably surfactant-free lyophilized pharmaceutical compositions comprising bortezomib, a cyclodextrin derivative and at least one bulking agent, wherein the cyclodextrin derivative is hydroxypropyl β-cyclodextrin and wherein the at least one bulking agent is selected from disaccharides, provided the desired solubility, stability and safety. Moreover, tert-butanol/water combination used in the pre- lyophilized composition as cosolvent system contributed to the enhanced solubility and stability.

Said pharmaceutical compositions of the invention provided clear, colorless and particulate- free solutions upon reconstitution.

Pharmaceutical compositions with a bulking agent and without a cyclodextrin derivative; pharmaceutical compositions with a cyclodextrin derivative and without a bulking agent; pharmaceutical compositions with SBECD and a bulking agent failed to provide the desired stability.

Furthermore, pharmaceutical compositions with ethanol/water system together with a cyclodextrin derivative and/or bulking agent also failed to provide the desired solubility and stability.

These unexpected results indicated that not all of the cyclodextrin derivatives and/or bulking agents and/or cosolvent systems could provide the desired solubility and stability of the lyophilized pharmaceutical compositions of bortezomib.

Further stability data for the lyophilized pharmaceutical compositions according to the invention comprising bortezomib, hydroxypropyl β-cyclodextrin and at least one disaccharide (Table 15 for lactose and Table 16 for trehalose, respectively) is shown below. Tert-butanol/water cosolvent system is used in the pre-lyophilized composition. Table 15

* inv.: inverted; upr.: upright

Table 16

* inv.: inverted; upr.: upright

Bulk Solution Preparation Procedure The extent of the invention should not be limited by the following examples of the pharmaceutical formulations and preparation processes of the invention. The examples below are only given to illustrate the invention. Table 17. Lyophilized pharmaceutical composition of bortezomib

Solvents are removed during lyophilization.

.: quantity sufficient

Preparation process of the lyophilized pharmaceutical composition of bortezomib

Two stock solutions are prepared seperately in order to obtain final solution.

Stock Solution 1

1) About 35% of WFI is transferred at 20°C - 25°C into a production container.

2) The disaccharide(s) and HPCD are added under moderate stirring and complete dissolution is achieved.

Stock Solution 2

4) Before preparing stock solution 2, tert-butanol should be liquified in a suitable water bath heated to 30°C in order to avoid tert-butanol crystallization.

5) About 10% of WFI is transferred at 30°C - 35°C into a production container.

6) Tert-butanol is transferred into a production container containing WFI.

7) Bortezomib is added under moderate stirring. The added ingredient is stirred and the temperature is kept between 30°C - 35°C until complete dissolution is achieved.

8) Upon complete dissolution of API, heating is stopped and the production container is cooled to 22°C - 26°C.

Final Solution

9) Stock solution 1 is transferred into the production container containing stock solution 2 and stirred.

10) The solution with WFI is diluted to final volume and stirred.

11) The bulk solution is filtered through 0.2 micron filter and filled in the vials prior to freeze-drying. Filling volume per vial is: 3.5 mL ± 2%. The pharmaceutical compositions of the invention can readily be reconstituted by adding an aqueous solvent. Examples of solvents suitable for reconstitution include, without limitation, water, saline, and phosphate buffered saline. The pharmaceutical compositions of the invention are preferably reconstituted with sterile saline (0.9% w/v). The pharmaceutical compositions of the invention comprising bortezomib, hydroxypropyl β-cyclodextrin and at least one disaccharide are for use in the treatment of certain types of cancer, such as multiple myeloma and mantle cell lymphoma.

Claims

1. A lyophilized pharmaceutical composition comprising bortezomib, hydroxypropyl β-cyclodextrin and at least one disaccharide.

2. A lyophilized pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises bortezomib and hydroxypropyl β-cyclodextrin in molar ratios of hydroxypropyl β-cyclodextrin to bortezomib ranging from 0.5:1 to 100:1.

3. A lyophilized pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises hydroxypropyl β-cyclodextrin in an amount up to 99% w/w of the lyophilized composition.

4. A lyophilized pharmaceutical composition according to claim 3, wherein the pharmaceutical composition comprises hydroxypropyl β-cyclodextrin preferably in an amount more than 40% w/w of the lyophilized composition.

5. A lyophilized pharmaceutical composition according to claim 4, wherein the pharmaceutical composition comprises hydroxypropyl β-cyclodextrin more preferably in an amount from 60% to 95% w/w of the lyophilized composition.

6. A lyophilized pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises at least one disaccharide selected from the group comprising lactose, maltose, sucrose and trehalose.

7. A lyophilized pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises at least one disaccharide in an amount up to 99% w/w of the lyophilized composition.

8. A lyophilized pharmaceutical composition according to claim 7, wherein the pharmaceutical composition comprises at least one disaccharide preferably in an amount less than 60% w/w of the lyophilized composition.

9. A lyophilized pharmaceutical composition according to claim 8, wherein the pharmaceutical composition comprises at least one disaccharide more preferably in an amount from 5% to 40% w/w of the lyophilized composition.

10. A lyophilized pharmaceutical composition according to claim 1, wherein the pharmaceutical composition preferably does not comprise a surfactant.

1 1. A lyophilized pharmaceutical composition according to claim 1 , wherein the pre-lyophilized composition comprises tert-butanol/water cosolvent system.

12. A lyophilized pharmaceutical composition according to claim 1 1 , wherein the pre-lyophilized composition comprises tert-butanol in an amount up to 90% v/v of the pre-lyophilized composition.

13. A lyophilized pharmaceutical composition according to claim 12, wherein the pre-lyophilized composition comprises tert-butanol preferably in an amount less than 60% v/v of the pre-lyophilized composition.

14. A lyophilized pharmaceutical composition according to claim 13, wherein the pre-lyophilized composition comprises tert-butanol more preferably in an amount from 5% to 50% v/v of the pre-lyophilized composition.

15. A process for preparing a lyophilized pharmaceutical composition of bortezomib, wherein the process comprises the steps of:

a) preparing a mixture comprising

i. bortezomib,

ii. hydroxypropyl β-cyclodextrin,

iii. at least one disaccharide,

iv. tert-butanol,

v. water; and

b) lyophilizing the mixture.

16. A process for preparing a lyophilized pharmaceutical composition according to claim 15, wherein the process further comprises reconstituting the lyophilized mixture by adding an aqueous solvent.

17. A lyophilized pharmaceutical composition prepared in accordance with the process of claim 15.

18. A lyophilized pharmaceutical composition comprising bortezomib, hydroxypropyl β-cyclodextrin and at least one disaccharide for use in the treatment of cancer.