EA038105B1 - Method of producing a pharmaceutical composition comprising bortezomib, product of the method - Google Patents

Abstract

Described herein is a method of producing a pharmaceutical composition comprising, as an active agent, bortezomib in the form of a lyophilized powder for preparing an injection solution. Preferably, a lyophilized powder for preparing an injection solution in vials is used. The proposed method provides producing a pharmaceutical composition with high stability and low impurity content.

Description

The technical field to which the invention relates

The present invention relates to the pharmaceutical industry, more specifically, to a method for preparing a pharmaceutical composition in the form of an injection solution containing bortezomib as an active ingredient, and to a pharmaceutical composition obtained by the claimed method.

Prior art

Compound [(1R) -3-methyl-1 - [[(2S) -1-oxo-3-phenyl-2 - [(pyrazinylcarbonyl) amino] npropyl] amino] butyl] boronic acid, also known as bortezomib (Formula I )

I

Formula I is an anticancer agent and is used therapeutically as a proteasome inhibitor.

US Pat. No. 5,780,454 describes bortezomib and its pharmaceutically acceptable salts containing bortezomib, a pharmaceutical composition and use for inhibiting proteasome function in mammals. Additionally, a method for producing bortezomib and its analogs is described.

Polymorphism is defined as the ability of a substance to exist in the form of two or more crystalline phases differing in the arrangement and / or conformation of molecules in the crystal lattice. Thus, strictly speaking, polymorphs are different crystalline forms of the same pure substance, which differ in the arrangement and / or configuration of the molecules. Polymorphic modifications can also differ in their physical properties, such as melting point, solubility, X-ray diffraction pattern, etc. Although these differences disappear after dissolution of the substance, they significantly affect the pharmaceutically significant properties of the solid form, such as, for example, dissolution rate and stability. These properties can have a significant impact on the processing, shelf life and commercial acceptance of a polymorphic compound. Therefore, it is important to investigate solid drug forms, including all polymorphic forms, and determine the stability, dissolution and fluidity of each of them. Polymorphic forms of a substance can be determined using analytical methods such as X-ray diffraction, differential scanning calorimetry, and spectrometry.

Of great importance for obtaining a crystalline form, and not other forms, are the solvent environment and the crystallization mode.

Bortezomib can exist in various polymorphic modifications that differ from each other in stability, physical properties, spectral data and methods of preparation.

US Pat. No. 6,713,446 describes a lyophilized bortezomib ester composition. According to this patent, bortezomib obtained by the method of US Pat. No. 5,780,454 is a white amorphous powder. The publications WO 2011107912 and WO 2011099018 describe methods for preparing polymorphic forms I, II and amorphous bortezomib.

The present invention solves the problem of creating new technological methods for the production of an improved finished pharmaceutical product bortezomib.

Summary of the invention

The present invention describes a method for preparing a pharmaceutical composition containing bortezomib as an active ingredient in the form of a lyophilized solution for injection. The proposed method provides a pharmaceutical composition with high stability and low content of associated impurities.

Lyophilized powder for solution for injection is dispensed into vials. The finished pharmaceutical product is administered intravenously.

A method of obtaining a pharmaceutical composition in the form of a lyophilized powder solution for injection includes obtaining a solution of an active substance with its subsequent lyophilization.

A method of obtaining a pharmaceutical composition of bortezomib in the form of a lyophilized powder for preparing a solution for injection containing bortezomib as an active ingredient provides for obtaining a solution of bortezomib with auxiliary substances, followed by sterilization filtration and lyophilization of the solution, including freezing and drying, characterized in that freezing is carried out at temperature mode of at least -20 ° C to -10 ° C, followed by cooling to a temperature range of -40 ° C to -47 ° C.

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Brief Description of Drawings

The present invention is illustrated by the following drawings:

fig. 1 - X-ray powder diffractogram of bortezomib.

fig. 2 - determination of the characteristics of bortezomib by ¹ H NMR and ¹³ C NMR spectroscopy.

Spectra were measured in DMSO solution, using a spectrophotometer Bruker Avance II 500 (spectra 1 H - 500.13 MHz, 11B - 160 MHz and ¹³ C - 125.76 MHz, respectively). Spectra from the spectrometer library were used to measure the spectra in the COZY, HSQC-ed, and HMBC experiments. Mass spectrum was measured in acetonitrile-water solution using a Bruker microTOF-Q II spectrometer after direct injection;

fig. 3 - chromatogram of bortezomib;

fig. 4 is a chromatogram of a pharmaceutical composition according to the invention containing bortezomib as active ingredient.

Detailed description of the invention

The present invention provides a method for preparing a pharmaceutical composition containing bortezomib as an active ingredient in the form of a lyophilized powder for preparing a solution for injection. The lyophilized powder for solution for injection is preferably dosed in vials. The proposed method allows you to obtain a pharmaceutical composition with high stability and low percentage of impurities.

A method of obtaining a pharmaceutical composition of bortezomib in the form of a lyophilized powder for preparing a solution for injection containing bortezomib as an active ingredient provides for obtaining a solution of bortezomib with auxiliary substances, followed by sterilization filtration and lyophilization of the solution, including freezing and drying, characterized in that freezing is carried out at temperature mode of at least -20 ° C to -10 ° C, followed by cooling to a temperature range of -40 ° C to -47 ° C.

The technical result, to which the proposed invention is directed, is the optimization of the process, which makes it possible to obtain a lyophilized preparation of bortezomib with a high degree of stability and a low percentage of impurities for the treatment of oncological diseases.

A method of obtaining a pharmaceutical composition in the form of a lyophilized powder for preparation of a solution for injection involves obtaining a solution of an active ingredient and subsequent sterilization filtration and lyophilization, including:

freezing at low temperatures;

freeze-drying the ice contained in the frozen product, usually at very low pressure.

Freezing the material

Any product should be frozen in such a way as to ensure that there is no change during the subsequent freeze-drying process. The important parameters of freezing are: the temperature at which the maximum hardening occurs;

optimal cooling rate;

minimum initial melting point.

The purpose of this process is to provide a solid structure for the already frozen product without voids in which the concentrated liquid is located, since with this structure the drying takes place entirely by sublimation. After freezing, various mixtures of structures can be obtained, including ice crystals, eutectic structures, mixtures of eutectic amorphous glassy zones. The formation of such zones is facilitated by the presence of sugars, alcohols, ketones, aldehydes and acids and also by high concentrations of solids in the initial product.

Freeze drying

The drying process does not have to be carried out at low pressure, but under such conditions the diffusion process is much more efficient. Converting ice to steam requires a large amount of energy supplied under high vacuum conditions, since the drying boundary moves towards the interior of the sample and heat must cross the frozen layers, creating a significant risk of melting the intermediate material or burning the surface of an already dry product.

In the process of lyophilization, with the beginning of an increase in the heat of sublimation between the dry layer and the frozen layer of the sample, a frontal boundary or boundary of the sublimation zone is formed, which gradually increases at the temperature of the contact interaction surface corresponding to a certain saturation pressure.

Mass transfer is carried out by vapor migration through the dry layer of the sample under the influence of a pressure difference and this transfer is high at a large pressure difference.

The following three phases are distinguished:

Phase 1 is based on thermal conductivity. Initially, when the sample is heated, the sublimation rate increases rapidly until it reaches its maximum value. This is a relatively short phase during which most of the water (75 to 90%) is removed from the product. During this phase,

- 2 038105 heat transfer mechanism due to thermal conductivity.

During the 2nd phase, which is the first diffusion phase, the sublimation rate is significantly reduced due to the formation of a porous layer of dry material, which provides an increasing resistance to heat and vapor flows.

In the third phase (the second diffusion phase), the sublimation rate continues to decrease and approaches zero due to the fact that the heat required to remove bound water exceeds the sublimation heat. Since at low humidity the diffusion capacity of the vapors is noticeably reduced, at this stage it is possible to increase the heating and product temperatures to values close to 50 ° C, depending on the material to be processed.

During heat transfer and mass transfer, the combined effect of temperature and pressure gradients acts as a driving force that must overcome resistance due to the thickness and physical characteristics of the sample. The thickness of the sample plays an important role. With a thinner sample, the resistance to heat and mass flux is less than in the case of a thicker sample. Heat transfer occurs as a result of heat conduction: convection of gases and radiation, or a combination of these two mechanisms. At very low pressures, radiation is the predominant mechanism.

Lyophilization involves adding water to a substance, followed by freezing the resulting suspension or solution and sublimating the water contained in the substance. In preferred embodiments of the invention, at least one organic solvent is added to the suspension / solution. In other preferred embodiments of the invention, the suspension / solution further comprises an excipient.

Solvents used in the present invention include water and organic solvents which form stable bortezomib solutions in which the compound does not undergo significant degradation and which can be evaporated / sublimated by lyophilization. Examples of suitable organic solvents include, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, or mixtures of these. The preferred organic solvent is tert-butanol.

The product obtained by the claimed method has high stability during storage and a low content of impurities.

A method of obtaining a pharmaceutical composition in the form of a lyophilized powder for preparing a solution for injection includes the stage of obtaining a solution of the active substance and the subsequent stage of lyophilization.

In the proposed method for preparing a pharmaceutical composition in the form of a lyophilized powder for the preparation of a solution for injection, including the steps of obtaining a solution of the active ingredient and the subsequent process of lyophilization, a solution of bortezomib for lyophilization is prepared in accordance with Example 1.

The lyophilization process begins with a cooling stage at a rate of 5 to 10 ° C / h to a temperature of at least -20 ° C, then the temperature is raised to at least -10 ° C, followed by rapid cooling at a rate of 8-12 ° C / h to temperatures from -40 ° C to -47 ° C.

The cooling stage is completed by keeping the lyophilized block at a temperature of -35 ° C to -38 ° C for 9-12 hours.

An increase and a sharp decrease in temperature provides a change in the crystal structure of the frozen mass, preventing the destruction of the lyophilized block.

The primary sublimation stage begins with a linear increase in temperature at a rate of 1.0 to 1.5 ° C / h to reach a temperature of at least -10 ° C and then proceed to create a vacuum.

The isocratic temperature regime is maintained for 5-7 hours, then the temperature continues to increase linearly at a rate from 0.5 to 2.5 ° C / h to a temperature of 25-35 ° C.

The drying stage is continued with an isocratic temperature increase from 35 ° C so that the residual moisture content does not exceed 2.0%.

Freeze drying is carried out for 55-80 hours.

The freezing regime, carried out until a temperature of at least -20 ° C is reached, then the temperature is raised to about -10 ° C, followed by cooling to a temperature range of -40 ° C to -47 ° C, provides crystalline rearrangement without boiling of the material undergoing lyophilization , as well as improved stability of the finished product, a low percentage of impurities in it, which is demonstrated by the comparative data presented in example 4 (table. 1).

The table shows comparative data of stability and content of impurities in the product obtained without using in the freezing step of raising the temperature before the subsequent lowering of the temperature (control), and the product obtained by the method according to the invention, after storage for 24 months at 25 ° C and 60% humidity. ...

The method according to the invention ensures uniformity of different batches of the finished product (high degree of consistency between different batches) during the shelf life. The product can be stored

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The present invention is illustrated by the following examples:

Example 1. Obtaining a solution of bortezomib for lyophilization.

To obtain a solution with a mannitol concentration of 0.5 to 1.5 mg / ml, mannitol is dissolved in water for injection, taken in an amount of 45-55% of the final mass of the prepared solution, at a temperature of 20 to 30 ° C.

Then, 100% mannitol is added over 5-10 minutes with stirring. After 5-10 minutes tert-butanol is added with stirring at 5-8 rpm.

Then slowly add bortezomib until the active substance is completely dissolved, slowly introducing bortezomib into the funnel of the cone formed with stirring.

Bring the pH of the solution to 4.0-6.0 using a 0.1 N hydrochloric acid solution or 0.1 N sodium hydroxide solution.

The solution is filtered under sterile conditions and poured into ampoules for subsequent lyophilization. Sterilization filtration is carried out at a pressure of 0.2-0.7 Pa.

Freeze-drying vials (ampoules) are pre-cooled at a temperature from 0 ° C to -10 ° C. The serving size is preferably 3.5-3.7 ml.

In a preferred embodiment of the method, the product contains the active ingredient in an amount of 3.5 and 35.0 mg of mannitol.

Example 2. Lyophilization.

Freeze dryer trays are pre-conditioned at -2 ° C to -7 ° C for rapid cooling.

The lyophilization process begins with a cooling step at a rate of 5 ° C / h to a temperature of about -20 ° C, then the temperature is raised to about -10 ° C, followed by rapid cooling at a rate of 8 ° C / h to a temperature of -40 ° C.

The cooling stage is completed at a temperature of -35 ° C for 12 hours until complete cooling.

The primary sublimation stage begins with a linear increase in temperature at a rate of about 1.0 ° C / h until a temperature of about -10 ° C is reached. Maintain the isocratic temperature regime for 5 hours, then continue to increase the temperature linearly at a rate of 0.5 ° C / h to a temperature of 35 ° C.

The drying step is continued with an isocratic temperature increase from 35 ° C until a residual moisture content of not more than 2.0% is reached.

Freeze drying is carried out for 55 hours.

Example 3. Lyophilization.

The lyophilization process begins with a cooling step at a rate of 10 ° C / h to a temperature of at least -20 ° C, then the temperature is raised to at least -10 ° C, followed by rapid cooling at a rate of 12 ° C / h to a temperature of -47 ° C.

The cooling stage is completed by keeping the lyophilized block at -38 ° C for 9 hours.

An increase and a sharp decrease in temperature provides a change in the crystal structure of the frozen mass, preventing the destruction of the lyophilized block.

The primary sublimation stage begins with a linear increase in temperature at a rate of about 1.5 ° C / h until a temperature of at least -10 ° C is reached. Maintain the isocratic temperature regime for 7 hours, then continue to increase the temperature linearly at a rate of 2.5 ° C / h to a temperature of 25 ° C.

The drying step is continued with an isocratic temperature increase from 35 ° C until a residual moisture content of not more than 2.0% is reached.

Freeze drying is carried out for 80 hours.

Example 4. Data on the stability of the product according to the invention and the loading of impurities therein.

A solution for lyophilization was prepared according to example 1.

Lyophilization was carried out in accordance with example 2 (batch 1) and example 3 (batch 2).

Comparative data of stability and content of impurities in the product obtained without using at the stage of freezing the temperature rise before its sharp decrease (control), and the product obtained according to the invention (batch 1 [form II] and batch 2 [amorphous bortezmib]), after storage in for 24 months at 25 ° C and 60% humidity are presented in the table. The content of impurities was determined using chromatographic analysis (see Fig. 4. Chromatogram of the pharmaceutical composition according to the invention, batch 2).

Bortezomib 3.5 mg 25 ° С / 60% humidity - 24 months Control PART 1 PART 2 Total impurity 1.39% 0.73% 0.51%

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The content of impurities in the product of batches 1 and 2 after 24 months of storage at 25 ° C and 60% humidity was 0.75 and 0.54%, respectively. The content of impurities in the control product after a month of storage at 25 ° C and 60% humidity was 1.39%. The data presented in the table indicate an improved stability of the product obtained according to the invention and a lower content of impurities in it compared to the control.

Claims (3)

CLAIM 1. A method of obtaining a pharmaceutical composition of bortezomib in the form of a lyophilized powder for preparation of a solution for injection containing bortezomib as an active ingredient, providing for a solution of bortezomib with auxiliary substances, subsequent sterilization filtration and lyophilization of the solution, including freezing and sublimation, characterized in that freezing is carried out until reaching a temperature of -20 ° C, after reaching a temperature of -20 ° C, the temperature is raised to about -10 ° C, followed by cooling (over-freezing) to a temperature range from -40 ° C to -47 ° C, moreover, freezing to a temperature of -20 ° C is carried out at a temperature of 5-10 ° C / h, and after increasing the temperature to about -10 ° C, freezing to a temperature of -40 ° C to -47 ° C is carried out at a temperature of 8-12 ° C / h and then sublimation. 2. A method of obtaining a pharmaceutical composition of bortezomib according to claim 1, characterized in that the sublimation includes a stage of primary sublimation, which begins at a temperature of 1.0-1.5 ° C / h until a temperature of -10 ° C is reached. 3. A method of obtaining a pharmaceutical composition of bortezomib according to claim 2, characterized in that the isocratic temperature regime is maintained at about -10 ° C for 5-7 hours, then the temperature continues to increase linearly at a rate of 0.5 to 2.5 ° C / h to a temperature of 25-35 ° C.