Method for the production of a pharmaceutical composition comprising empagliflozin and a second active ingredient with organic solvent

Abstract

The present invention relates to a process for the preparation of an oral pharmaceutical composition comprising Empagliflozin and a second active ingredient, Metformin Hydrochloride or Linagliptin, characterised in that Empagliflozin is dissolved in a solution prepared with an organic solvent and a pH adjusting agent, and the process employs a wet granulation or spray granulation technique.

Description

[0001] DESCRIPTION

[0002] METHOD FOR THE PRODUCTION OF A PHARMACEUTICAL COMPOSITION COMPRISING EMPAGLIFLOZIN AND A SECOND ACTIVE INGREDIENT WITH ORGANIC SOLVENT

[0003] Technical Field

[0004] The present invention relates to a process for the preparation of an oral pharmaceutical composition comprising empagliflozin and a second active ingredient, characterized in that empagliflozin is dissolved in a solution prepared with an organic solvent and a pH adjusting agent, and the process employs a wet granulation or spray granulation technique.

[0005] State of The Art

[0006] Empagliflozin is a new and potent compound that is administered per os as a selective SGLT 2 inhibitor. It is an antidiabetic medicine used to improve glucose control in patients 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 established cardiovascular disease. It was approved in the EU on May 23, 2014 and in the U.S. in August 2014 for the treatment of adults with type 2 diabetes who cannot achieve adequate blood glucose control with diet and exercise.

[0007] Inhibition of SGLT-2 reduces renal reabsorption of glucose, thereby favoring urinary excretion of glucose, resulting in a reduction in blood glucose levels.

[0008] The chemical name of Empagliflozin (Compound 1 ) is “(1 S)-1 ,5-anhydro-1 -(4- chloro-3-{4-[(3S)-tetrahydrofuran-3- oxyl ]benzyl}phenyl]-D-glucitol” with a molecular weight of 450.91. Very slightly soluble in water, very soluble in methanol, slightly soluble in ethanol and acetonitrile, soluble in 50% aceton itrile / water mixture; practically insoluble in toluene.

[0009] Compound 1

[0010] Empagliflozin is in bioavailability class 3. This class includes compounds with high solubility and low permeability. Empagliflozin absorption is variable as the permeability of Empagliflozin is rate limiting. Metformin (Compound 2) is a biguanide antihyperglycemic agent with the chemical name “N,N-dimethylimidodicarbonimidic diamide”. It works by increasing GDF15 secretion by decreasing glucose production in the liver and increasing insulin sensitivity of body tissues. Metformin is a first-line medication used specifically for the treatment of type 2 diabetes.

[0011] Compound 2

[0012] Linagliptin (Compound 3) is an inhibitor of the enzyme dipeptidyl peptidase-4 (DPP- 4) with the chemical name “1 H-Purine-2, 6-dione, 8-[(3R)-3-amino-1 -piperidinyl]-7- (2- butyn-1 -yl)-3,7dihydro-3-methyl-1 -[(4-methyl-2-quinazolinyl)methyl]”. It is commonly used in combination with exercise and diet to treat type 2 diabetes.

[0013] Compound 3

[0014] Film-coated tablets containing Empagliflozin and Metformin Hydrochloride (5mg / 850mg, 5mg / 1000mg, 12.5mg / 850mg, 12.5mg / 1000mg) are available under the trade name Synjardy. Synjardy tablets contain Com starch, Copovidone, Colloidal anhydrous silica and Magnesium stearate as excipients.

[0015] Film-coated tablets containing Empagliflozin and Linagliptin (10mg / 5mg, 25mg / 5mg) are available under the trade name Glyxambi. Glyxambi tablets contain Mannitol, Pregelatinized starch, Corn starch, Copovidone, Crospovidone, Talc and Magnesium stearate as excipients.

[0016] EP 1730131 B1 (Boehringer Ingelheim) discloses the molecule Empagliflozin, its use and composition of a tablet containing empagliflozin with excipients such as lactose, corn starch, polyvinylpyrrolidone, magnesium stearate. EP 1888551 B1 (Boehringer Ingelheim) and EP 1888552 B1 (Boehringer Ingelheim) discloses specific crystal forms of Empagliflozin.

[0017] EP2395968 A1 / W0 2010 / 092126 A1 (Boehringer Ingelheim) discloses that the particle size and particle size distribution of Empagliflozin, particularly very small particles, adversely affect producibility by adhering or forming a film during tableting; on the other hand, very large particles adversely affect dissolution properties and hence bioavailability, and to overcome these problems, the particle size distribution of Empagliflozin in the composition is between D(90) 1 micron and 200 microns.

[0018] WO 2022 / 180444 A1 (Mandge) relates to a lactose-free composition.

[0019] WO 2016 / 169534 A1 (Zentiva) discloses amorphous solid forms of empagliflozin stabilized in solid solution form with polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hypromellose acetate succinate, povidone PVP K30, Soluplus™, PEG 6000 or copovidone VA64. For the preparation of amorphous solid forms of empagliflozin by dissolution, empagliflozin and polymer were dissolved in a mixture of methylene chloride and alcohol and the solvent was removed by vacuum evaporation or lyophilization to get amorphous empagliflozin.

[0020] WO 2017 / 203457 A1 (Dr. Reddy's) discloses solid dispersions containing amorphous Empagliflozin.

[0021] CN 106692069 A (Foshan) discloses Empagliflozin solid dispersion containing povidone and lubricant.

[0022] WO 2016 / 051368 A1 (Mylan) discloses Empagliflozin amorphous solid dispersions prepared with cyclodextrin.

[0023] Based on the prior art, there is a need for fixed dose combinations comprising Empagliflozin with an improved dissolution profile, sufficient physical and chemical stability and prepared by an economical process suitable for commercial use. Furthermore, a single composition has been developed that does not require Empagliflozin to be combined separately with both Metformin and Linagliptin.

[0024] Purpose of Invention

[0025] Empagliflozin with D90>100 microns is known to have a low dissolution rate. This invention aims to improve the solubility and dissolution rate of Empagliflozin. In the prior art, as well as the need for pharmaceutical compositions comprising Empagliflozin and Metformin HCI or Linagliptin as a second active ingredient with an improved dissolution profile, with sufficient physical and chemical stability and prepared by an economical process suitable for commercial use, since application EP2395968 A1 (Boehringer) is related to compositions containing Empagliflozin with particle size D90 between 5 and 100 microns, there is a need for a process for the preparation of compositions containing Empagliflozin with different particle sizes and Metformin HCI or Linagliptin as a second active ingredient.

[0026] Disclosure of invention

[0027] The present invention relates to a process for the preparation of an oral pharmaceutical composition comprising Empagliflozin and Metformin HCI or Linagliptin as a second active ingredient.

[0028] The term “Empagliflozin” as used in the application refers to the free base, any physiologically acceptable salt, hydrate or crystalline form of Empagliflozin.

[0029] Since Empagliflozin is a poorly soluble drug with a low dissolution rate, the dissolution rate of the drug directly affects the absorption of the drug. Low dissolution rate leads to low bioavailability and affects the efficacy of the drug.

[0030] Various pharmaceutical compositions comprising Empagliflozin have been reported in the prior art related to this problem. In the disclosed compositions empagliflozin is present in either crystalline form or amorphous form. It is understood that particle size must be carefully controlled for crystalline form. Micronization of raw materials for this purpose requires special air flow grinding equipment, which results in high losses and low yields, leading to waste and increased costs.

[0031] The amorphous form includes the preparation of solid dispersions or solid solutions by processes such as evaporation of the solvent through a rotary evaporator or lyophilization.

[0032] Solid dispersion procedures are not well suited for use on an industrial scale. The use of methylene chloride as a solvent on an industrial scale also has several disadvantages. Amorphous solid dispersions prepared by prior art methods require time consuming and economically disadvantageous processes such as grinding, sieving, mixing with other inactive substances, granulation prior to compression into tablets. To overcome these challenges, a simple and economical process was developed to dissolve the active ingredient empagliflozin in an organic solvent and produce tablets by wet granulation. However, there are regulatory requirements for organic solvents used in pharmaceutical production. Pharmaceutical products should not contain 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. Class 1 solvents, the most toxic solvents, should not be used in the production of active ingredients, excipients and dosage forms unless their use is strongly justified by a risk-benefit assessment. Methylene chloride and methanol are restricted as Class 2 solvents in pharmaceutical products due to their inherent toxicity.

[0033] Ideally, less toxic solvents (Class 3) should be used.

[0034] The present invention provides an easy and economical method of preparing a tablet comprising empagliflozin with a proper dissolution profile and Metformin HCI or Linagliptin as a second active ingredient.

[0035] The process according to the invention for the preparation of an oral pharmaceutical composition comprising empagliflozin and Metformin HCI or Linagliptin as a second active ingredient, characterized in that the empagliflozin is dissolved in a solution prepared with an organic solvent and a pH adjusting agent, and the process employs a wet granulation or spray granulation technique.

[0036] Thus, compositions with a proper dissolution profile, independent of the particle size of Empagliflozin, can be obtained. For example, Empagliflozin with a D90 particle size of less than 5 microns or more than 100 microns can be used. In addition, the compositions obtained by the process of the invention have been shown to be bioequivalent to the reference product through in vivo / bioequivalence studies.

[0037] According to the prior art, the solubility of the active ingredient may vary according to the particle size. Therefore, the particle size of the active ingredient should be within a certain size range so as not to affect solubility and a maximum and minimum particle size specification should be determined. It is thought that the original product used an active ingredient with a D90 value of less than 20 microns. Since empagliflozin with a D90 value between 5 and 100 microns is covered by application EP2395968 A1 (Boehringer), active ingredient less than 5 microns or more than 100 microns can be used. However, using an active ingredient of this size presents production challenges and bioequivalence risks. The method of the invention increases the solubility of the active ingredient without the use of micronized active ingredient.

[0038] The ratio of the organic solvent used in the process of the invention to empagliflozin may be at least 2:1 (w / w).

[0039] When the wet granulation technique is used in the process, the ratio of solvent to empagliflozin is preferably at least 4:1 (w / w).

[0040] When the spray granulation technique is used in the process, the ratio of solvent to empagliflozin is preferably at least 20:1 (w / w).

[0041] The pH 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.

[0042] The organic solvents used in the process can be selected from Class 2 or Class 3 organic solvents.

[0043] Water can be used in the process if necessary.

[0044] Class 2 organic solvents are listed in Table 1 below.

[0045] Table 1 Class 3 organic solvents are listed in Table 2 below.

[0046] Table 2 The organic solvent can be selected from class 2 or class 3 solvents, preferably from the group containing 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 in a mixture. This mixture may contain water if necessary.

[0047] As a pH adjuster in the process, one of the basic agents in Table 3 below can be selected as a pH adjusting agent.

[0048] Table 3

[0049] Sodium Hydroxide is most preferably used as a pH adjusting agent.

[0050] In the most preferred embodiment of the invention, Acetone is used as the organic solvent and Sodium Hydroxide / Sodium Hydroxide solution is used as the pH adjusting agent.

[0051] A preferred embodiment of the invention is a process for preparing a composition comprising Empagliflozin and Metformin Hydrochloride comprising the following steps: a. The inner layer powder mixture is prepared by mixing Metformin Hydrochloride, Filler and / or Diluent agent and Binder, b. The granulation solution is prepared by adding Empagliflozin into the solution prepared by mixing organic solvent and pH adjusting agent, c. Inner layer powder mixture is wet granulated or spray granulated with granulation solution, d. The resulting granules are dried, e. The dried granules are sieved, f. Disintegrant and Flow Regulator are added to the granule obtained as a result of step e and mixed, g. Lubricant is added and mixed to obtain the final mixture.

[0052] A preferred embodiment of the invention is a process for preparing the composition comprising Empagliflozin and Linagliptin comprising the following steps: a. The inner layer powder mixture is prepared by mixing Linagliptin, Filler and / or Diluent agent and Binder, b. The granulation solution is prepared by adding Empagliflozin into the solution prepared by mixing organic solvent and pH adjusting agent, c. Inner layer powder mixture is wet granulated or spray granulated with granulation solution, d. The resulting granules are dried, e. The dried granules are sieved, f. Disintegrant and Flow Regulator are added to the granule obtained as a result of step e and mixed, g. Lubricant is added and mixed to obtain the final mixture. In the above process, Acetone can preferably be used as organic solvent and Sodium Hydroxide as pH adjusting agent.

[0053] When wet granulation is used in the process, a high shear granulator can be used. In case of spray granulation, a fluidised bed granulator can be used.

[0054] The final mixture can be compressed into tablets using tablet compression or filled into capsules using capsule filling. In this context, the expression oral pharmaceutical composition in the application refers to oral tablets / capsules or similar dosage forms that can be taken orally.

[0055] According to the present invention, since the active ingredient empagliflozin is prepared by dissolution in an organic solvent, changes in the particle size of the active ingredient do not affect the solubility. Under normal conditions, differences in particle size between production batches of Empagliflozin, which is patented for use in the range of 5pm<D90<100pm in the patent EP2395968 A1 / W0 2010 / 092126 A1 , may cause variations in dissolution rate. However, the process of the present invention solves this problem. According to the process of the invention, even when Empagliflozin with two different particle sizes is used (e.g. one with a D90 of 130 microns and the other with a D90 of 300 microns), the dissolution rates of both are the same. This is because Empagliflozin is used in the process by dissolving it. In addition, this method ensures homogeneous distribution of Empagliflozin throughout the product. Therefore, the need to use micronised active ingredient has been eliminated.

[0056] According to the present invention, the active ingredient empagliflozin is dissolved in an organic solvent and wet granulated, resulting in a more homogeneous distribution of the active ingredient in the tablet than in the prior art.

[0057] The process of the invention is disclosed with the following examples. The examples given are not limiting and are provided for a better understanding of the invention.

[0058] According to the invention, the particle size of Empagliflozin used is preferably d90>100 microns.

[0059] Examples

[0060] According to the process of the invention, the trials carried out during the development phase are given below. The first five trial productions are related to the Empagliflozin + Metformin Hydrochloride compositions. The next five trials productions are related to the Empagliflozin + Linagliptin compositions. 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.

[0061] Examples 1 to 5 provide trial productions for Empagliflozin + Metformin Hydrochloride.

[0062] Example 1

[0063] Formula 1 used in the development phase is below.

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

[0065] Production Method:

[0066] 1 - Empagliflozin, Metformin Hydrochloride, Com Starch and Hydroxypropyl Cellulose are mixed.

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

[0068] 3- The granules are dried.

[0069] 4- The dried granules are sieved.

[0070] 5- Colloidal Silicon Dioxide is added to sieved granule prepared in step 4 and mixed.

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

[0072] 7- Mixture prepared in step 6 is compressed on the tablet compression machine.

[0073] 8- The compressed tablets are coated. Dissolution rate analytical method is below.

[0074] Empagliflozin Dissolution Rate Analytical Results for Formula 1 are below.

[0075] Below is the Empagliflozin dissolution rate analytical result graph of Formula 1 compared to the reference product.

[0076] Comparative Dissolution Rate Profile

[0077] Time (min) Below is the Metformin Hydrochloride Dissolution Rate Analytical Results for Formula 1 .

[0078] Below is the Metformin Hydrochloride dissolution rate analytical result graph of Formula 1 compared to the reference product.

[0079] Comparative Dissolution Rate Profile

[0080] Time (min)

[0081] Conclusion: The dissolution rate of Empagliflozin is slower than that of the reference product, as shown by the analytical results. The dissolution rate of Metformin Hydrochloride is similar to the reference product.

[0082] Example 2

[0083] Formula 2 used in the development phase is below.

[0084] *Empagliflozin was used with particle size D90 > 100 microns.

[0085] Production Method:

[0086] 1- Empagliflozin, Metformin Hydrochloride, Com Starch and Hydroxypropyl Cellulose are mixed.

[0087] 2- The mixture prepared in step 1 is granulated with purified water.

[0088] 3- The granules are dried.

[0089] 4- The dried granules are sieved.

[0090] 5- Hydroxypropyl Cellulose (Low Substituted) Colloidal Silicon Dioxide is added to sieved granule prepared in step 4 and mixed.

[0091] 6- Magnesium Stearate is added and mixed.

[0092] 7- Mixture prepared in step 6 is compressed on the tablet compression machine.

[0093] 8- The compressed tablets are coated. Empagliflozin Dissolution Rate Analytical Results for Formula 2 are below.

[0094] Below is the Empagliflozin dissolution rate analytical result graph of Formula 2 compared to the reference product.

[0095] Comparative Dissolution Rate Profile

[0096] Time (min)

[0097] Below is the Metformin Hydrochloride Dissolution Rate Analytical Results for Formula 2. Below is the Metformin Hydrochloride dissolution rate analytical result graph of Formula 2 compared to the reference product.

[0098] Comparative Dissolution Rate Profile

[0099] Time (min)

[0100] Conclusion: The dissolution rate of Empagliflozin is slower than that of the reference product, as shown by the analytical results. The dissolution rate of Metformin Hydrochloride is similar to the reference product.

[0101] To improve the solubility of the active ingredient Empagliflozin, granulation will be made by dissolving Empagliflozin in acetone and 0.2 M NaOH solution in the following trial production.

[0102] Example 3

[0103] Formula 3 used in the development phase is below.

[0104] *Empagliflozin was used with particle size D90 > 100 microns.

[0105] Production Method:

[0106] 1 - Metformin Hydrochloride, Com Starch and Hydroxypropyl Cellulose are mixed.

[0107] 2- Granulation Solution: Acetone and Sodium Hydroxide solution are mixed. Then, Empagliflozin is added therein and stirred until completely dissolved.

[0108] 3- The mixture prepared in step 1 is granulated with the granulation solution. The granulation is continued with water when necessary.

[0109] 4- The granules are dried.

[0110] 5- The dried granules are sieved.

[0111] 6- Hydroxypropyl Cellulose (Low Substituted) and Colloidal Silicon Dioxide is added to sieved granule prepared in step 5 and mixed.

[0112] 7- Magnesium Stearate is added and mixed.

[0113] 8- Mixture prepared in step 7 is compressed on the tablet compression machine.

[0114] 9- The compressed tablets are coated.

[0115] Empagliflozin Dissolution Rate Analytical Results for Formula 3 are below. Below is the Empagliflozin dissolution rate analytical result graph of Formula 3 compared to the reference product.

[0116] Comparative Dissolution Rate Profile

[0117] Time (min)

[0118] In conclusion, the Empagliflozin dissolution profile analytical results of the products produced by the process described in Formula 3 are similar to the reference product in terms of similarity factor f2.

[0119] Below is the Metformin Hydrochloride Dissolution Rate Analytical Results for Formula 3.

[0120] Below is the Metformin Hydrochloride dissolution rate analytical result graph of Formula 3 compared to the reference product. Comparative Dissolution Rate Profile

[0121] Time (min)

[0122] Conclusion: Dissolution profile analytical results showed that the use of Empagliflozin active ingredient by dissolving in organic solvent increased the solubility. For dissolution analysis, a high similarity in dissolution rate was obtained when evaluated by the similarity factor f2 with the reference product.

[0123] The formula and analytical results of the processes carried out with the ratio of acetone to active ingredient as 3:1 and 4:1 are given below.

[0124] Example 4

[0125] Formula 4 used in the development phase is below.

[0126] *Empagliflozin was used with particle size D90 > 100 microns.

[0127] Production Method:

[0128] 1 - Metformin Hydrochloride, Com Starch and Hydroxypropyl Cellulose are mixed.

[0129] 2- Granulation Solution: Acetone and Sodium Hydroxide solution are mixed. Then, Empagliflozin is added therein and stirred until completely dissolved.

[0130] 3- The mixture prepared in step 1 is granulated with the granulation solution. The granulation is continued with water when necessary.

[0131] 4- The granules are dried.

[0132] 5- The dried granules are sieved.

[0133] 6- Hydroxypropyl Cellulose (Low Substituted) and Colloidal Silicon Dioxide is added to sieved granule prepared in step 5 and mixed.

[0134] 7- Magnesium Stearate is added and mixed.

[0135] 8- Mixture prepared in step 7 is compressed on the tablet compression machine.

[0136] 9- The compressed tablets are coated.

[0137] Empagliflozin Dissolution Rate Analytical Results for Formula 4 are below. Below is the Empagliflozin dissolution rate analytical result graph of Formula 4 compared to the reference product.

[0138] Comparative Dissolution Rate Profile

[0139] Time (min)

[0140] In conclusion, the Empaqliflozin dissolution profile analytical results of the products produced by the process described in Formula 4 are similar to the reference product in terms of similarity factor f2.

[0141] Below is the Metformin Hydrochloride Dissolution Rate Analytical Results for Formula 4.

[0142] Below is the Metformin Hydrochloride dissolution rate analytical result graph of Formula 4 compared to the reference product. Comparative Dissolution Rate Profile

[0143] Time (min)

[0144] Example 5

[0145] Formula 5 used in the development phase is below.

[0146] *Empagliflozin was used with particle size D90 > 100 microns. Production Method:

[0147] 1 - Metformin Hydrochloride, Com Starch and Hydroxypropyl Cellulose are mixed.

[0148] 2- Granulation Solution: Acetone and Sodium Hydroxide solution are mixed. Then, Empagliflozin is added therein and stirred until completely dissolved.

[0149] 3- The mixture prepared in step 1 is granulated with the granulation solution. The granulation is continued with water when necessary.

[0150] 4- The granules are dried.

[0151] 5- The dried granules are sieved.

[0152] 6- Hydroxypropyl Cellulose (Low Substituted) and Colloidal Silicon Dioxide is added to sieved granule prepared in step 5 and mixed.

[0153] 7- Magnesium Stearate is added and mixed.

[0154] 8- Mixture prepared in step 7 is compressed on the tablet compression machine.

[0155] 9- The compressed tablets are coated.

[0156] Empagliflozin Dissolution Rate Analytical Results for Formula 5 are below.

[0157] Below is the Empagliflozin dissolution rate analytical result graph of Formula 5 compared to the reference product.

[0158] Comparative Dissolution Rate Profile

[0159] Time (min) In conclusion, the Empaqliflozin dissolution profile analytical results of the products produced by the process described in Formula 5 are similar to the reference product in terms of similarity factor f2.

[0160] Below is the Metformin Hydrochloride Dissolution Rate Analytical Results for Formula 5.

[0161] Below is the Metformin Hydrochloride dissolution rate analytical result graph of Formula 5 compared to the reference product.

[0162] Comparative Dissolution Rate Profile

[0163] Time (min)

[0164] Conclusion: The dissolution analytical results of the products with 3:1 and 4:1 ratio of acetone to the active ingredient Empagliflozin showed high similarity with the reference product in terms of f2 similarity factor. Examples 6 to 10 provide trial productions of the compositions for Empagliflozin and Linagliptin.

[0165] Example 6

[0166] Formula 6 used in the development phase is below.

[0167] *Empagliflozin was used with particle size D90 > 100 microns.

[0168] Production Method:

[0169] 1- Empagliflozin, Linagliptin, Mannitol, Com Starch and Copovidone are mixed.

[0170] 2- The mixture prepared in step 1 is granulated with purified water.

[0171] 3- The granules are dried.

[0172] 4- The dried granules are sieved.

[0173] 5- Talc, Pregelatinized Starch and Crospovidone are added to sieved granule prepared in step 4 and mixed.

[0174] 6- Magnesium Stearate is added and mixed.

[0175] 7- Mixture prepared in step 6 is compressed on the tablet compression machine.

[0176] 8- The compressed tablets are coated. Empagliflozin Dissolution Rate Analytical Results for Formula 6 are below.

[0177] Below is the Empagliflozin dissolution rate analytical result graph of Formula 6 compared to the reference product.

[0178] Comparative Dissolution Rate Profile

[0179] Time (min) Linagliptin Dissolution Rate Analytical Results for Formula 6 are below. 5 Below is the Linagliptin dissolution rate analytical result graph of Formula 6 compared to the reference product.

[0180] Comparative Dissolution Rate Profile

[0181] I C) Time (min)

[0182] Example 7

[0183] Formula 7 used in the development phase is below.

[0184] *Empagliflozin was used with particle size D90 > 100 microns.

[0185] 15 Production Method:

[0186] 1- Empagliflozin, Linagliptin, Mannitol, Com Starch and Copovidone are mixed.

[0187] 2- The mixture prepared in step 1 is granulated with purified water.

[0188] 3- The granules are dried.

[0189] 4- The dried granules are sieved.

[0190] 5- Talc, Pregelatinized Starch and Crospovidone are added to sieved granule prepared in step 4 and mixed.

[0191] 6- Magnesium Stearate is added and mixed.

[0192] 7- Mixture prepared in step 6 is compressed on the tablet compression machine.

[0193] 8- The compressed tablets are coated.

[0194] Empagliflozin Dissolution Rate Analytical Results for Formula 7 are below.

[0195] Below is the Empagliflozin dissolution rate analytical result graph of Formula 7 compared to the reference product.

[0196] Comparative Dissolution Rate Profile

[0197] Time (min) Linagliptin Dissolution Rate Analytical Results for Formula 7 are below.

[0198] Below is the Linagliptin dissolution rate analytical result graph of Formula 7 compared to the reference product.

[0199] Comparative Dissolution Rate Profile

[0200] Time (min)

[0201] Example 8

[0202] Formula 8 used in the development phase is below.

[0203]

[0204] *Empagliflozin was used with particle size D90 > 100 microns.

[0205] Production Method:

[0206] 1 - Linagliptin, Mannitol, Com Starch and Copovidone are mixed.

[0207] 2- Granulation Solution: Empagliflozin is added to the mixture of acetone and 0.2 M NaOH and dissolved while stirring. Then the mixture prepared in step 1 is granulated with the granulation solution.

[0208] 3- The granules are dried.

[0209] 4- The dried granules are sieved.

[0210] 5- Talc, Pregelatinized Starch and Crospovidone are added to sieved granule prepared in step 4 and mixed.

[0211] 6- Magnesium Stearate is added and mixed.

[0212] 7- Mixture prepared in step 6 is compressed on the tablet compression machine.

[0213] 8- The compressed tablets are coated.

[0214] Empagliflozin Dissolution Rate Analytical Results for Formula 8 are below. Below is the Empagliflozin dissolution rate analytical result graph of Formula 8 compared to the reference product.

[0215] Linagliptin Dissolution Rate Analytical Results for Formula 8 are below.

[0216] Below is the Linagliptin dissolution rate analytical result graph of Formula 8 compared to the reference product.

[0217] Comparative Dissolution Rate Profile Time (min)

[0218] Example 9

[0219] Formula 9 used in the development phase is below.

[0220] *Empagliflozin was used with particle size D90 > 100 microns.

[0221] Production Method:

[0222] 1 - Linagliptin, Mannitol, Com Starch and Copovidone are mixed.

[0223] 2- Granulation Solution: Empagliflozin is added to the mixture of acetone and 0.2 M NaOH and dissolved while stirring. Then the mixture prepared in step 1 is granulated with the granulation solution.

[0224] 3- The granules are dried.

[0225] 4- The dried granules are sieved.

[0226] 5- Talc, Pregelatinized Starch and Crospovidone are added to sieved granule prepared in step 4 and mixed.

[0227] 6- Magnesium Stearate is added and mixed.

[0228] 7- Mixture prepared in step 6 is compressed on the tablet compression machine.

[0229] 8- The compressed tablets are coated.

[0230] Empagliflozin Dissolution Rate Analytical Results for Formula 9 are below.

[0231] Below is the Empagliflozin dissolution rate analytical result graph of Formula 9 compared to the reference product.

[0232] Comparative Dissolution Rate Profile

[0233] Time (min)

[0234] Linagliptin Dissolution Rate Analytical Results for Formula 9 are below.

[0235] Below is the Linagliptin dissolution rate analytical result graph of Formula 9 compared to the reference product.

[0236] Comparative Dissolution Rate Profile

[0237] Time (min)

[0238] Example 10

[0239] Formula 10 used in the development phase is below.

[0240] *Empagliflozin was used with particle size D90 > 100 microns. Production Method:

[0241] 1 - Linagliptin, Mannitol, Com Starch and Copovidone are mixed.

[0242] 2- Granulation Solution: Empagliflozin is added to the mixture of acetone and 0.2 M NaOH and dissolved while stirring. Then the mixture prepared in step 1 is granulated with the granulation solution.

[0243] 3- The granules are dried.

[0244] 4- The dried granules are sieved.

[0245] 5- Talc, Pregelatinized Starch and Crospovidone are added to sieved granule prepared in step 4 and mixed.

[0246] 6- Magnesium Stearate is added and mixed.

[0247] 7- Mixture prepared in step 6 is compressed on the tablet compression machine.

[0248] 8- The compressed tablets are coated.

[0249] Empagliflozin Dissolution Rate Analytical Results for Formula 10 are below.

[0250] Below is the Empagliflozin dissolution rate analytical result graph of Formula 10 compared to the reference product.

[0251] Comparative Dissolution Rate Profile

[0252] Time (min) Linagliptin Dissolution Rate Analytical Results for Formula 10 are below.

[0253] Below is the Linagliptin dissolution rate analytical result graph of Formula 10 compared to the reference product.

[0254] Comparative Dissolution Rate Profile

[0255] Time (min) In the formulas of the trials for which analysis results are given above, the dissolution rate analysis results of the products produced at different Acetone ratios are similar. It also shows high similarity to the reference product.

Claims

CLAIMS1. A process for the preparation of an oral pharmaceutical composition comprising Empagliflozin and Metformin Hydrochloride or Linagliptin as a second active ingredient, characterised in that the empagliflozin is dissolved in a solution prepared with an organic solvent and a pH adjusting agent and prepared by wet granulation or spray granulation technique.

2. A process according to claim 1 , characterised in that the ratio of organic solvent to empagliflozin is at least 2:1 (w / w).

3. A process according to claim 2, characterised in that the ratio of organic solvent to empagliflozin is preferably about 4:1 (w / w) when prepared by wet granulation.

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

5. A process according to any one of the preceding claims, characterised in that the granulation solution 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, characterised 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, characterised 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 or class 3 solvents.

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

10. A process according to any one of the preceding claims, characterised in that the composition containing Metformin Hydrochloride as the second active ingredient comprising the following steps: a. Preparation of the inner layer powder mixture by mixing Metformin Hydrochloride, Filler and / or Diluent agent and Binder,b. Preparation of granulation solution by adding Empagliflozin into the solution prepared by mixing organic solvent and pH adjusting agent, c. Wet granulation or spray granulation of the inner layer powder mixture with granulation solution, d. Drying of the resulting granules, e. Sieving the dried granules, f. Adding the disintegrant and flow regulator to the granule obtained as a result of step e and mixing, g. Adding the lubricant and mixing to obtain the final mixture.

11. A process according to any one of claims 1 -9, characterised in that the composition comprising Linagliptin as the second active ingredient comprising the following steps: a. Preparation of the inner layer powder mixture by mixing Linagliptin, Filler and / or Diluent agents and Binder, b. Preparation of granulation solution by adding Empagliflozin into the solution prepared by mixing organic solvent and pH adjusting agent, c. Wet granulation or spray granulation of the inner layer powder mixture with granulation solution, d. Drying of the resulting granules, e. Sieving the dried granules, f. Adding the disintegrant agents and lubricant to the granule obtained as a result of step e and mixing, g. Adding the lubricant and mixing to obtain the final mixture.

12. A process according to claim 10 or 11 , characterised in that a high shear granulator is used during wet granulation.

13. A process according to claim 10 or 11 , characterised in that a fluidised bed granulator is used during spray granulation.

14. A process according to claim 10 or 11 , characterised in that Acetone is used as organic solvent and Sodium Hydroxide is used as pH adjusting agent.

15. A process according to any one of the preceding claims, characterised in that the particle size of Empagliflozin is d90>100 microns.

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