Manufacturing method of a pharmaceutical composition comprising empagliflozin with an organic solvent

Abstract

The present invention relates to a process for the preparation of an oral pharmaceutical composition comprising empagliflozin, characterized in that empagliflozin is dissolved in a solution prepared with an organic solvent and a pH adjusting agent, and wet granulation or spray granulation technique is used in the process.

Description

[0001] MANUFACTURING METHOD OF A PHARMACEUTICAL COMPOSITION COMPRISING EMPAGLIFLOZIN WITH AN ORGANIC SOLVENT

[0002] Technical Field

[0003] The present invention relates to a process for the preparation of an oral pharmaceutical composition comprising empagliflozin, characterized in that empagliflozin is dissolved in a solution prepared with an organic solvent and a pH adjusting agent, and wet granulation or spray granulation technique is used in the process.

[0004] State Of The Art

[0005] Orally administered selective SGLT 2 inhibitor of Empagliflozin is a new and potent compound. It is an antidiabetic drug used to improve glucose control in people with type 2 diabetes. Empagliflozin is used to improve glycemic control in adults with type 2 diabetes mellitus and to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and proven cardiovascular disease. It was approved in the EU on May 23, 2014 and in August 2014 in the US for the treatment of adults with type 2 diabetes who fail to achieve adequate blood glucose control with diet and exercise.

[0006] Inhibition of SGLT 2 reduces renal reabsorption of glucose, thus it supports glucose excretion in urine with a consequent reduction in blood glucose levels.

[0007] Empagliflozin is commercially available in free base form and it is sold as oral tablets in doses of 10 mg and 25 mg under the brand name of Jardiance®. It is also commercially available as a combination product with Metformin and as a combination product with Linagliptin.

[0008] The chemical name of empagliflozin (Formula 1 ) is "(1 S)-1 ,5-anhydro-1 -(4-chloro-3-{4-[(3S)- tetrahydrofuran- 3-oxyl ]benzyl}phenyl]-D-glucitol" and its molecular weight is 450.91 . It is very slightly soluble in water, quite soluble in methanol, slightly soluble in ethanol and acetonitrile, soluble in 50% acetonitrile / water mixture; and practically insoluble in toluene.

[0009] Formula 1 The bioavailability class of empagliflozin is 3. This class includes compounds with high solubility and low permeability. Since the permeability of empagliflozin is rate limiting, the absorption of Empagliflozin is variable.

[0010] EP 1730131 B1 (Boehringer Ingelheim) discloses the molecule Empagliflozin, its use and composition of a tablet comprising empagliflozin with lactose, corn starch, polyvinylpyrrolidone, magnesium stearate, etc.

[0011] EP 1888551 B1 (Boehringer Ingelheim) and EP 1888552 B1 (Boehringer Ingelheim) disclose specific crystal forms of Empagliflozin.

[0012] EP2395968 A1 / W0 2010 / 092126 A1 (Boehringer Ingelheim) discloses the particle size and particle size distribution of Empagliflozin, especially very small particles, have an adverse impact on reproducibility by adhering or forming a film during tableting, on the other hand, very large particles have a negative impact on dissolution properties and thus on bioavailability, and that the particle size distribution of Empagliflozin in the composition D(90) is between 1 micron and 200 microns to overcome these problems.

[0013] TR 2021 / 022062 (WORLD MEDICINE) D90 rate with less than 20 pm is mixed with lactose monohydrate in a way that Empagliflozin amount would be 25-55% and then brought to 10- 20% in the tablet mixture by geometric dilution.

[0014] WO 2022 / 180444 A1 (Mandge) relates to lactose-free formulation.

[0015] WO 2016 / 169534 A1 (Zentiva) with hydroxypropyl cellulose discloses amorphous solid forms of empagliflozin stabilized in solid solution form with polymers such as hydroxypropyl methylcellulose, hypromellose acetate succinate, povidone PVR K30, Soluplus™, PEG 6000 or copovidone VA64. For the preparation of amorphous solid forms of empagliflozin by solubilization, empagliflozin and polymer were dissolved in a mixture of methylene chloride and alcohol and amorphous empagliflozin was obtained by removing the solvent through vacuum evaporation or lyophilization.

[0016] WO 2017 / 203457 A1 (Dr. Reddy's) discloses solid dispersions comprising amorphous Empagliflozin.

[0017] CN 106692069 A (Foshan) discloses solid dispersion of Empagliflozin comprising povidone and lubricant. \N02016 / 051368 A1 (Mylan) discloses amorphous solid dispersions of Empagliflozin prepared with cyclodextrin.

[0018] In light of the prior art, there is a need for pharmaceutical compositions comprising Empagliflozin with an improved dissolution profile, sufficient physical and chemical stability and prepared by an economical process suitable for use on a commercial scale.

[0019] Purpose of the Invention

[0020] It is known that the dissolution rate of Empagliflozin with D90>100 microns is low. With the present invention, it is intended to increase the solubility and dissolution rate of Empagliflozin. Since the application EP2395968 A1 (Boehringer) is directed to the formulations comprising Empagliflozin whose D90 particle size is between 5 and 100 microns, there is a need for a process for the preparation of formulations comprising Empagliflozin with different particle sizes, as well as the need for pharmaceutical compositions comprising Empagliflozin with an improved dissolution profile, with sufficient physical and chemical stability and that is prepared by an economical process suitable for use on a commercial scale in the state of the art.

[0021] Explanation of Figures

[0022] Figure 1. Comparative Dissolution Rate Analysis Result Graph of Formula 1 with reference product (0.1 N HCI - Comparative Dissolution Rate Profile)

[0023] Figure 2. Comparative Dissolution Rate Analysis Result Graph of Formula 2 with reference product (0.1 N HCI - Comparative Dissolution Rate Profile)

[0024] Figure 3. Comparative Dissolution Rate Analysis Result Graph of Formula 3 with reference product (0.1 N HCI - Comparative Dissolution Rate Profile)

[0025] Figure 4. Comparative Dissolution Rate Analysis Result Graph of Formula 4 with reference product (0.1 N HCI - Comparative Dissolution Rate Profile)

[0026] Figure 5. Comparative Dissolution Rate Analysis Result Graph of Formula 5 with reference product (0.1 N HCI - Comparative Dissolution Rate Profile)

[0027] Description of the Invention

[0028] The present invention relates to a process for the preparation of an oral pharmaceutical composition comprising Empagliflozin.

[0029] The term "Empagliflozin" used in the application refers to the free base, any physiologically acceptable salt, hydrate or crystalline form of Empagliflozin. Since Empagliflozin is a poorly soluble drug with a slow dissolution rate, the dissolution rate of the drug affects the absorption of the drug directly. Low dissolution rate leads to low bioavailability and affects the efficacy of the drug.

[0030] In consideration of this problem in the prior art, various pharmaceutical compositions comprising Empagliflozin have been reported. In the disclosed compositions, empagliflozin is present in crystalline form or in amorphous form. It is understood that the particle size must be carefully controlled for the crystalline form. For this purpose, micronization of raw materials requires specialized airflow grinding equipment, which leads to large losses and low yields, resulting in waste and increased costs.

[0031] And the amorphous form involves the preparation of solid dispersions or solid solutions with the processes such as evaporation of the solvent via a rotary evaporator or lyophilization.

[0032] Solid dispersion procedures are not well suited for use on an industrial scale. Furthermore, there are several drawbacks when methylene chloride is used as solvent on an industrial scale. Amorphous solid dispersions prepared by prior art processes require time-consuming and economically disadvantageous processes such as grinding, sieving, mixing with other inactive substances, granulating before compression into tablets. To overcome all these difficulties, a simple and economical process has been developed for the manufacturing of tablets by wet granulation of empagliflozin active substance dissolved in organic solvent.

[0033] However, there are official rules regarding organic solvents used in pharmaceutical manufacturing. Pharmaceutical products should not comprise higher levels of residual solvents than can be supported by safety data. Commonly used solvents are grouped by toxicity according to the ICH Q3C guideline. Solvents in Class 1 , the most toxic solvents, should not be used in the manufacture of agents and excipients and the dosage forms unless their use is strongly justified in a risk-benefit assessment. Methylene chloride and methanol are restricted in pharmaceutical products due to their inherent toxicity as Class 2 solvents. Ideally, less toxic solvents (Class 3) should be used.

[0034] With the present invention, an easy and economical method of preparation of an empagliflozin tablet having a suitable dissolution profile has been suggested.

[0035] In the process of the invention related to the preparation of an oral pharmaceutical composition comprising Empagliflozin, the empagliflozin is dissolved in a solution prepared with an organic solvent and a pH adjusting agent, and the process uses a wet granulation or spray granulation technique.

[0036] Thus, formulations with a suitable dissolution profile independent of the particle size of Empagliflozin can be obtained. For example, Empagliflozin with D90 particle size less than 5 microns or greater than 100 microns can be used. In addition, it has been proven with the in- vivo / bioequivalence studies that the formulations obtained with the process of the subject of the invention is bioequivalent to the reference product.

[0037] According to the state of the art, the solubility of the active substance may vary according to the size of the particle. Therefore, the particle size of the active substance should be within a certain size range so as not to affect solubility, and the specification of maximum and minimum particle size should be determined. In the original product, it is thought that an active substance with a D90 value of less than 20 microns was used. Since empagliflozin with a D90 value between 5 and 100 microns is within the scope of the application EP2395968 A1 (Boehringer), an active substance smaller than 5 microns or larger than 100 microns can be used. However, the use of this size of active substance has difficulties in terms of manufacturing and it is risky in terms of bioequivalence.

[0038] With the process of the invention, the solubility of the active substance was increased without using micronized API.

[0039] The ratio of the organic solvent to empagliflozin used in the process of the invention can be at least 2:1 (w / w). The ratio of the organic solvent to empagliflozin is most preferably about 4:1 (w / w).

[0040] The pH value of the granulation solution obtained by dissolving empagliflozin in a solution prepared with an organic solvent and pH adjusting agent is preferably at least 12.

[0041] Organic solvents used in the process can be selected from Class 2 or Class 3 organic solvents. Water can be used in the process if necessary.

[0042] Class 2 organic solvents are listed in Table 1 below.

[0043] Table 1

[0044] Class 3 organic solvents are listed in Table 2 below.

[0045] Table 2

[0046] The organic solvent can be selected from class 2 and class 3 solvents, preferably from the group comprising Acetone, Dichloromethane, Dimethyl sulfoxide, Butyl Alcohol, Methanol, Ethanol, Ethyl acetate, 1 -Propanol and 2-Propanol. The selected organic solvents can be used solely and / or as a mixture. As a pH adjuster in the process, one of the basic agents in Table 3 below can be selected as a pH adjusting agent.

[0047] Table 3

[0048] Sodium Hydroxide is most preferably used as a pH adjusting agent.

[0049] In the most preferred embodiment of the invention, Acetone is used as organic solvent and Sodium Hydroxide / Sodium Hydroxide solution is used as pH adjusting agent.

[0050] A preferred embodiment of the invention is a process comprising the following steps: a. The internal phase powder mixture is prepared by mixing the Filler and / or Diluent agent with the Binder, b. Empagliflozin is added into the solution prepared by mixing organic solvent and pH adjusting agent and granulation solution is prepared, c. Wet granulation or spray granulation is performed using the granulation solution of the internal phase powder mixture, d. The obtained granules are dried, e. The dried granules are sieved, f. Disintegrant and Flow Regulator are added to the granulate obtained as a result of step e and mixed, g. Lubricant is added and mixed to obtain the final mixture.

[0051] In the above process, Acetone can preferably be used as organic solvent and Sodium Hydroxide as pH adjusting agent.

[0052] In case of wet granulation in the process, a high shear granulator can be used. In case of spray granulation, a fluidized bed granulator can be used.

[0053] The final mixture obtained can be turned into tablets by tablet compression method or capsule form by filling into capsules. In this context, the term oral pharmaceutical composition in the application refers to oral tablets / capsules or similar dosage forms that can be taken orally.

[0054] According to the present invention, since the active ingredient Empagliflozin is dissolved in an organic solvent during manufacturing, changes in the particle size of the active ingredient do not affect its solubility. Under normal conditions, differences in particle size between the production series of Empagliflozin, which is patented for use in the range of 5pm<D90<100pm in EP2395968 A1 / W0 2010 / 092126 A1 patent, may cause variations in the solubility rate. However, this problem is eliminated with the process of the present invention. Even when Empagliflozin with two different particle sizes is used (e.g., one with a D90 value of 130 microns and the other with a D90 value of 300 microns), the solubility rates of both products are the same in the production carried out with the process of the invention. This is because Empagliflozin is used in dissolved form in the process. In addition, with this method, Empagliflozin is homogeneously distributed throughout the product. Therefore, the need to use micronized api is eliminated.

[0055] According to the present invention, the active substance is distributed more homogeneously in the tablet than in the prior art since empagliflozin is dissolved in organic solvent and wet granulated.

[0056] The process of the invention is explained with the following examples. These examples are not limiting, but they are provided for a better understanding of the invention.

[0057] With regard to the invention, the particle size of Empagliflozin used is preferably d90>100 microns.

[0058] Examples

[0059] The trials carried out during the development stage of the process subject to the invention are given below. The examples given below are provided for a better understanding of the invention and do not limit the scope of the invention in any way.

[0060] Example 1

[0061] Formula 1 , which was studied during the development stage, is given below.

[0062] Table 4.

[0063]

[0064] * Empagliflozin with particle size of D90 > 100 microns was used.

[0065] Manufacturing Method:

[0066] 1 - Empagliflozin, Lactose Monohydrate, Microcrystalline Cellulose and Hydroxypropyl Cellulose are mixed.

[0067] 2- The mixture in step 1 is granulated with purified water.

[0068] 3- The granules are dried.

[0069] 4- The dried granules are sieved.

[0070] 5- Croscarmellose Sodium and Colloidal Silicon Dioxide are added to sieved granule in step 4 and mixed.

[0071] 6- Magnesium Stearate is added and mixed.

[0072] 7- The mixture in step 6 is compressed using a tablet press machine.

[0073] 8- The compressed tablets are coated.

[0074] The dissolution rate method for Formula 1 is given below.

[0075] Table 5.

[0076] Dissolution Rate Analysis Results for Formula 1 are stated below.

[0077] Table 6.

[0078] Dissolution Rate Analysis Result Graph of Formula 1 in comparison with the reference product is presented in Figure 1 below. As a result, the dissolution profile analysis results of the products manufactured with the process specified in Formula 1 are slower than the reference product.

[0079] Example 2

[0080] Formula 2 studied during the development stage is indicated below.

[0081] Table 7.

[0082] * Empagliflozin with a particle size of D90 > 100 microns was used.

[0083] Manufacturing Method:

[0084] 1 - Empagliflozin, Lactose Monohydrate, Microcrystalline Cellulose and Hydroxypropyl Cellulose are mixed.

[0085] 2- The mixture in step 1 is granulated with purified water.

[0086] 3- The granules are dried. 4- The dried granules are sieved.

[0087] 5- Croscarmellose Sodium and Colloidal Silicon Dioxide are added to sieved granule in step 4 and mixed.

[0088] 6- Magnesium Stearate is added and mixed.

[0089] 7- The mixture in step 6 is compressed using a tablet press machine.

[0090] 8- The compressed tablets are coated.

[0091] The dissolution rate method carried out for Formula 2 is indicated below.

[0092] Table 8.

[0093] Dissolution Rate Analysis Results for Formula 2 are indicated below.

[0094] Table 9.

[0095] Dissolution Rate Analysis Result Graph of Formula 2 compared to the reference product is presented in Figure 2.

[0096] As a result, increasing the amount of the disintegrant in the manufacturing of Formula 2 was observed not to affect the solubility of the active ingredient.

[0097] Example 3

[0098] Formula 3, which was studied during the development stage, is given below.

[0099] Table 10.

[0100] Empagliflozin with a particle size of D90 > 100 microns was used.

[0101] Manufacturing Method:

[0102] 1 - Lactose Monohydrate, Microcrystalline Cellulose and Hydroxypropyl Cellulose are mixed.

[0103] 2- Granulation Solution: acetone and sodium hydroxide solution is mixed. Empagliflozin is added therein and stirred until completely dissolved.

[0104] 3- The mixture in step 1 is granulated with the granulation solution.

[0105] 4- Granules are dried.

[0106] 5- The dried granules are sieved.

[0107] 6- Croscarmellose Sodium and Colloidal Silicon Dioxide are added to sieved granule in step 5 and mixed.

[0108] 7- Magnesium Stearate is added and mixed.

[0109] 8- The mixture in step 7 is compressed using a tablet press machine.

[0110] 9- The compressed tablets are coated.

[0111] The dissolution rate method for Formula 3 is given below. Table 11.

[0112] Dissolution Rate Analysis Results for Formula 3 are stated below.

[0113] Table 12.

[0114] Dissolution Rate Analysis Result Graph of Formula 3 compared to the reference product is given in Figure 3.

[0115] As a result, as seen in the dissolution profile analysis results, the use of the active substance by dissolving in organic solvent increased the solubility. When assessment is made based on the similarity factor f2 with the reference product for the dissolution analysis, high similarity was obtained in terms of dissolution rate.

[0116] Example 4

[0117] Formula 4, which was studied during the development stage, is given below.

[0118] Table 13.

[0119] Empagliflozin with a particle size of D90 > 100 microns was used.

[0120] Manufacturing Method:

[0121] 1 - Lactose Monohydrate, Microcrystalline Cellulose and Hydroxypropyl Cellulose are mixed.

[0122] 2- Granulation Solution: acetone and sodium hydroxide solution is mixed. Empagliflozin is added therein and stirred until completely dissolved.

[0123] 3- The mixture in step 1 is granulated with the granulation solution.

[0124] 4- Granules are dried.

[0125] 5- The dried granules are sieved.

[0126] 6- Croscarmellose Sodium and Colloidal Silicon Dioxide are added to sieved granule in step 5 and mixed.

[0127] 7- Magnesium Stearate is added and mixed.

[0128] 8- The mixture in step 7 is compressed using a tablet press machine.

[0129] 9- The compressed tablets are coated.

[0130] The dissolution rate method for Formula 4 is given below.

[0131] Table 14. Dissolution Rate Analysis Results for Formula 4 are given below.

[0132] Table 15.

[0133] Dissolution Rate Analysis Result Graph of Formula 4 in comparison with the reference product is presented as Figure 4.

[0134] Example 5

[0135] Formula 5, which was studied during the development stage, is given below. Table 16.

[0136] *Empagliflozin with a particle size of D90 > 100 microns was used.

[0137] Manufacturing Method:

[0138] 1 - Lactose Monohydrate, Microcrystalline Cellulose and Hydroxypropyl Cellulose are mixed.

[0139] 2- Granulation Solution: acetone and sodium hydroxide solution is mixed. Empagliflozin is added therein and stirred until completely dissolved.

[0140] 3- The mixture in step 1 is granulated with the granulation solution.

[0141] 4- Granules are dried.

[0142] 5- The dried granules are sieved.

[0143] 6- Croscarmellose Sodium and Colloidal Silicon Dioxide are added to sieved granule in step 5 and mixed.

[0144] 7- Magnesium Stearate is added and mixed.

[0145] 8- The mixture in step 7 is compressed using a tablet press machine.

[0146] 9- The compressed tablets are coated.

[0147] The dissolution rate method for Formula 5 is given below.

[0148] Table 17.

[0149] Dissolution Rate Analysis Results for Formula 5 are given below.

[0150] Table 18.

[0151] Dissolution Rate Analysis Result Graph of Formula 5 compared to the reference product is given in Figure 5.

[0152] The dissolution rate analysis results of products manufactured with varying amounts of acetone in the formulations given above show similar outcomes. Similarly, they exhibit high similarity with the reference product.

Claims

CLAIMS1. A process for the preparation of an oral pharmaceutical composition comprising empagliflozin, characterized in that it is prepared by wet granulation or spray granulation, dissolving empagliflozin in a solution prepared with an organic solvent and a pH adjusting agent.

2. A process according to claim 1 , characterized in that the ratio of organic solvent to empagliflozin is at least 2:1 (w / w)3. A process according to claim 2, characterized in that the ratio of organic solvent to empagliflozin is preferably about 4:1 (w / w) for wet granulation.

4. A process according to claim 2, characterized in that the ratio of organic solvent to empagliflozin is preferably about 20:1 (w / w) for spray granulation.

5. A process according to any one of the preceding claims, characterized in that the granulation solution which is obtained by dissolving empagliflozin in a solution prepared with an organic solvent and a pH adjusting agent has a pH of at least 12.

6. A process according to any one of the preceding claims, characterized in that the organic solvent is selected from Class 2 or Class 3 organic solvents.

7. A process according to any one of the preceding claims, characterized in that the organic solvent is selected from the group consisting of Acetone, Dichloromethane, Dimethyl Sulfoxide, Butyl Alcohol, Methanol, Ethanol, Ethyl Acetate, Ethyl Acetate, 1 -Propanol and 2-Propanol among class 2 and class 3 solvents. The selected organic solvents can be used solely and / or as a mixture. This mixture may comprise water if necessary.

8. A process according to any one of the preceding claims, characterized in that the pH adjusting agent is selected from the group consisting of Sodium Hydroxide, Sodium Carbonate, Sodium Bicarbonate, Meglumin, L-Arginine.

9. A process according to any one of the preceding claims, characterized in that it comprises Acetone as organic solvent and Sodium Hydroxide as pH adjusting agent.

10. A process according to any one of the preceding claims, characterized in that it comprises the following steps: a. Preparation of the internal phase powder mixture by mixing the filler and / or diluting agent with the binder, b. Preparation of granulation solution by adding Empagliflozin into the solution prepared by mixing organic solvent and pH adjusting agent, c. Performing wet granulation or spray granulation by the granulation solution of the internal phase powder mixture, d. Drying of the granules obtained, e. Sieving of dried granules,f. Adding and mixing the disintegrant and flow regulator to the granulate obtained as a result of step e, g. Addition of the lubricant and mixing to obtain the final mixture.

11. A process according to claim 9 and / or 10, characterized in that a high shear granulator is used during wet granulation.

12. A process according to claim 9 and / or 10, characterized in that a fluidized bed granulator is used during spray granulation.

13. A process according to any one of claims 10-12, characterized in that Acetone is used as organic solvent and Sodium Hydroxide is used as pH adjusting agent.

14. A process according to any one of the preceding claims, wherein the particle size of Empagliflozin is d90>100 microns.

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