Empagliflozin composition with independent dissolution profile

Abstract

The present invention relates to immediate-release pharmaceutical compositions for oral administration, comprising and empagliflozin as active ingredient, and at least one pharmaceutically acceptable excipient, whose in-vitro profile is improved when empagliflozin particle size D90 value is between 2 µm to 60 µm.

Description

[0001] EMPAGLIFLOZIN COMPOSITION WITH INDEPENDENT DISSOLUTION PROFILE

[0002] Technical Field

[0003] The present invention relates to immediate -release pharmaceutical compositions for oral administration, comprising and empagliflozin as active ingredient, and at least one pharmaceutically acceptable excipient, whose in-vitro profile is improved when empagliflozin particle size D90 value is between 2 pm to 60 pm.

[0004] State Of The Art

[0005] Chronic kidney disease (CKD) is increasingly acknowledged as a global public health concern, affecting 10-15% of the population worldwide. It results from various causes, including diabetes, hypertension, vascular disease, or glomerulonephritis. However, diabetes continues to be the predominant cause of this condition. Approximately 40% of individuals diagnosed with type 2 diabetes meet criteria for CKD based on estimated glomerular filtration rate (eGFR) or albuminuria, with over 20% have clinically overt CKD.

[0006] Empagliflozin functions as a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), leading to urinary glucose excretion and a reduction in hyperglycemia, weight, plasma circulating volume, and blood pressure. This effect has been demonstrated that empagliflozin can safely translate into a decreased clinical risk of cardiovascular disease, particularly heart failure and cardiovascular death, in individuals with type 2 diabetes (T2D) and established cardiovascular disease.

[0007] Additionally, the inhibition of SGLT-2 with empagliflozin diminishes albuminuria and decelerates the annual decline in estimated glomerular filtration rate in individuals with T2D who maintain preserved kidney function.

[0008] Empagliflozin was developed by Boehringer Ingelheim International and was initially disclosed in the patent document numbered EP1730131. It is approved and marketed for the treatment of type 2 diabetes mellitus (T2DM), prevention of cardiovascular (CV) events in adults with T2DM and established CV disease, and for the treatment of adults with heart failure independent of left ventricular ejection fraction. The chemical name of empagliflozin is D-Glucitol,l,5-anhydro-l-C-[4-chloro-3-[[4-[[(3S)- tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-(lS). Its molecular formula is C23H27CIO7 and its molecular weight is 450.91.

[0009] The structural formula of empagliflozin is shown in Formula I.

[0010] Formula I

[0011] Empagliflozin is a white to yellowish, non-hygroscopic powder. It is very slightly soluble in water, sparingly soluble in methanol, slightly soluble in ethanol and acetonitrile, soluble in 50% acetonitrile / water, and practically insoluble in toluene.

[0012] Empagliflozin substance was first commercially authorized by the European Medicines Agency in May 2014. The medical product has been introduced as a film-coated tablet under the name of JARDIANCE®, containing either 10 or 25 mg of empagliflozin as active substance.

[0013] JARDIANCE® is indicated for the treatment of adults with insufficiently controlled T2DM as an adjunct to diet and exercise as monotherapy when metformin is considered inappropriate due to intolerance and in addition to other medicinal products for the treatment of diabetes. Moreover, JARDIANCE® is also used in adults for the treatment of symptomatic chronic heart failure and chronic kidney disease.

[0014] In the state of the art, there are many patents / patent applications, which are summarized below.

[0015] EP2395968 relates to pharmaceutical compositions comprising empagliflozin present in the range of 1.0% to 20% by the weight of the composition. Furthermore, the particle size distribution of the empagliflozin in crystalline form (1.9) ranges from 5 pm to 100 pm. Moreover, the disclosed pharmaceutical dosage forms are prepared using conventional manufacturing methods, including direct compression, dry granulation, and wet granulation.

[0016] EP3852730 relates to stable pharmaceutical compositions comprising empagliflozin or a cocrystal thereof with a particle size distribution D90 higher than 100 pm up to 500 pm, along with at least one diluent, at least one disintegrant, at least one lubricant, preferably manufactured by using dry granulation process. Moreover, in the composition microcrystalline cellulose is used as diluent, crospovidone is used as disintegrant, magnesium stearat is used as lubricant, and colloidal silicon dioxide is used as antiadherent, wherein the only excipient, antiadharent, is used in the extra granulation phase. Furthermore, the composition is free of hydroxypropyl cellulose.

[0017] EP4076402 relates to solid pharmaceutical dosage forms comprising an amorphous solid solution of empagliflozin with at least one polymer wherein at least one polymer is preferably polyvinylpyrrolidone. In the document, the pharmaceutical dosage forms are manufactured using wet granulation process.

[0018] WO2019244171 relates to a stable oral pharmaceutical composition comprising the amorphous form of empagliflozin manufactured using wet granulation process. The composition includes croscarmellose sodium as disintegrant within the range of 45% to 55% w / w, microcrystalline cellulose and maize starch as diluent within the range 14% to 30% w / w, hydroxypropyl methylcellulose as binding agent within the range 7% to 15%, and colloidal silicon dioxide and magnesium stearate as lubricants within the range 0.5% to 1.5%.

[0019] WO2016169534 relates to a composition comprising amorphous empagliflozin and povidone PVP 30 and / or copovidone VA64 as pharmaceutically acceptable polymer.

[0020] WO2022180444 relates to a composition comprising empagliflozin and at least one pharmaceutically acceptable excipient manufactured using a direct compression process, in which the composition is lactose-free.

[0021] WO2022124749 relates to a pharmaceutical composition comprising empagliflozin L-proline and having a water content of 3% or less in the composition.

[0022] EP3556355 relates to particles containing amorphous empagliflozin and a pharmaceutically acceptable polymer said particles having the size expressed as D(0.9) less than or equal to 100 pm, and to a process for preparation thereof by spray drying method.

[0023] WO202 1210929 relates to a pharmaceutical composition comprising an amorphous empagliflozin, polycarbophil, magnesium aluminometasilicat, and non-porous colloidal silica.

[0024] According to the pharmacokinetics properties, after oral administration, empagliflozin was rapidly absorbed, with peak plasma concentrations occurring at a median tmax of 1.5 hours postdose. Hence, plasma concentrations exhibited a biphasic decline, characterized by a rapid distribution phase followed by a relatively slow terminal phase. The estimated apparent terminal elimination half-life of empagliflozin was 12.4 hours.

[0025] Many pharmaceutical compositions are described in the aforementioned prior art documents, which include empagliflozin in amorphous or crystalline forms ranging from 5 to up to 500 pm. These compositions are formulated with at least one pharmaceutically acceptable excipient to obtain suitable dissolution profiles.

[0026] However, the inventors of the present invention has successfully developed a pharmaceutical composition comprising immediate-release empagliflozin and at least one pharmaceutically acceptable excipient manufactured by using wet granulation process, wherein the particle size D90 value of empagliflozin is between 2 pm to 60 pm, wherein the particle size distribution is by volume and determined by laser-diffraction method, and wherein,

[0027] - the composition comprises at least two diluents in amount ratio of 2:1,

[0028] - the composition comprises binder and disintegrant in amount ratio of 1:1 to 1:1.2.

[0029] Summary of the Invention

[0030] The object of this invention is to provide the immediate-release pharmaceutical compositions comprising a therapeutically effective amount of empagliflozin or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient.

[0031] The object of the present invention is to develop an immediate-release dosage form for the treatment of adults with insufficiently controlled T2DM, as an adjunct to diet and exercise, either as monotherapy when metformin is considered inappropriate due to intolerance or in combination with other medicinal products for the treatment of diabetes. Moreover, it is also intended for use in adults for the treatment of symptomatic chronic heart failure and chronic kidney disease.

[0032] Another object of the present invention is to provide immediate-release pharmaceutical compositions comprising empagliflozin in crystalline form. Preferably, the polymorph exists in crystalline form.

[0033] According to the state of the art, empagliflozin is generally used in crystalline form, having particle size ranging from 5 to 500 pm to address its insolubility and obtain suitable dissolution profile. However, in the present invention, the dissolution profile of the developed pharmaceutical composition is independent from the particle size of the empagliflozin.

[0034] Another object of the present invention is to provide immediate-release pharmaceutical compositions comprising empagliflozin in crystalline form and at least one pharmaceutically acceptable excipient manufactured by using wet granulation process.

[0035] Another object of the present invention is to provide immediate-release pharmaceutical compositions comprising the active ingredient, at least two diluents, disintegrant, binder, glidant, lubricant and granulation solvent selected as to be the most suitable ones with respect to the intended form of administration.

[0036] Another object of the present invention is to provide pharmaceutical compositions comprising empagliflozin and at least one pharmaceutically acceptable excipients, wherein

[0037] - the particle size D90 value of empagliflozin is between 2 pm to 60 pm, wherein the particle size distribution is by volume and determined by laser-diffraction method,

[0038] - the composition comprises at least two diluents in amount ratio of 2:1,

[0039] - the composition comprises binder and disintegrant in amount ratio of 1:1 to 1:1.2.

[0040] Detailed Description of the Invention

[0041] The present invention provides immediate release pharmaceutical compositions comprising empagliflozin or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient developed in the immediate release dosage form wherein the prepared composition is manufactured by using wet granulation process.

[0042] According to the state-of-the-art, the active substance empagliflozin is very slightly soluble in aqueous media within the pH range of 1.0 to 7.0 but demonstrates low intestinal permeability (BCS III).

[0043] In the preferred embodiment, the active substance empagliflozin is used in crystalline form.

[0044] In a preferred embodiment, the total amount of crystalline empagliflozin present in the pharmaceutical composition ranges from 8 to 15% w / w in respect of the total amount of the pharmaceutical composition. In another preferred embodiment of the present invention is to provide a pharmaceutical composition comprising crystalline empagliflozin manufactured using wet granulation process wherein provided for the manufacture of tablets containing the active ingredient, at least two diluents, disintegrant, binder, glidant, lubricant and granulation solvent selected as to be the most suitable ones with respect to the intended form of administration.

[0045] In a preferred embodiment, the pharmaceutical composition comprises at least two diluents selected from dibasic calcium phosphate dehydrate, polsaccharides, primarily microcrystalline cellulose, lactose, mannitol, primarily calcium salts and the like and mixtures thereof. Preferably, at least two diluents are microcrystalline cellulose and lactose or a mixture thereof.

[0046] In another preferred embodiment, the specified weight ratio of lactose to microcrystalline cellulose, used as diluents is 2:1.

[0047] In the preferred embodiment, the pharmaceutical composition comprises a disintegrant selected from starch, pregelatinized starch, sodium starch glycolate, povidone, croscarmellose sodium, crospovidone, sodium glycolate or mixture thereof. Preferably, the disintegrant is croscarmellose sodium.

[0048] In the preferred embodiment, the pharmaceutical composition comprises a binder selected from hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose or cellulose derivatives, pregelatinized starch, povidone, starch, sucrose, polyethylene glycol, or mixtures thereof. Preferably, the binder is hydroxypropyl cellulose.

[0049] In another preferred embodiment, the composition features a weight ratio of 1:1 to 1-1.2 between hydroxypropyl cellulose as a binder and croscarmellose sodium as a disintegrant.

[0050] In the preferred embodiment, the pharmaceutical composition comprises a lubricant selected from sodium stearyl fumarate, magnesium stearate, calcium stearate, talc, hydrogenated castor oil or mixtures thereof. Preferably, the lubricant is magnesium stearate.

[0051] In the preferred embodiment, the pharmaceutical composition comprises a glidant selected from colloidal silicon dioxide, powdered cellulose, talc, tribasic calcium phosphate and mixtures thereof. Preferably, the glidant is colloidal silicon dioxide.

[0052] The selection of the granulation solvent is a critical step in the granulation process. Typical granulation solvents usually include deionized water, ethanol, isopropanol, acetone, and methylene chloride, either individually or in combination. Preferably, the granulation solvents are ethanol and deionized water or mixture thereof.

[0053] The embodiment in accordance with the present invention were designed with adjusted quantitative composition composed of pharmaceutically acceptable ingredients mentioned above by using wet granulation process.

[0054] The proposed embodiment, based on the invention, provided a pharmaceutical composition with the amounts represented as w / w% by weight of the total composition, as specified in Table 1 below.

[0055] The composition was manufactured at the highest strength, containing 25 mg empagliflozin as the active substance.

[0056] Table 1: Unit formula of proposed embodiment

[0057] According to the state of the art, many studies have emphasized a manufacturing challenge associated with the low solubility of empagliflozin. Consequently, empagliflozin is preferably used in crystalline form, with a D90 particle sizes distribution, ranging from 2 pm to 60 pm in a pharmaceutical composition with improved processability and a suitable in-vitro release profile.

[0058] The particle size distribution is characterized by D90 values. The term “D90” is defined as 90% of the volume of particles having a diameter less than a specified diameter. In other preferred embodiments identified as Example 1, Example 2, Example 3 and Example 4, crystalline empagliflozin was employed in various particle sizes, ranging from 2 pm to 60 pm, as specified in the Table 2 below.

[0059] Except for the difference in the particle size of the empagliflozin, there was another distinction related to the proposed embodiments, specifically concerning the amount ratio of diluents, amounts of disintegrants and binder in w / w% unit. The remaining excipients were qualitatively and quantitatively the same. Additionally, the manufacturing processes were also the same.

[0060] Table 2: The workable range of particle sizes (D90) of empagliflozin

[0061] Furthermore, in a preferred embodiment, the process for the preparations of a pharmaceutical composition were manufactured using a wet granulation process, including the following steps: i. Empagliflozin, lactose, microcrystalline cellulose, croscarmellose sodium and hydroxypropyl cellulose were screened through a proper sieve and transferred into cubic mixer and stirred, ii. Sufficient quantity of ethyl alcohol 96% and deionize water were added to the preparation in Step (i) to perform granulation process, iii. The granules prepared in Step (ii) were dried in fluid-bed mixer and shifted through a proper sieve, iv. Magnesium stearate and colloidal silicon dioxide were screened through a proper sieve and added to the granules prepared in Step (iii) and stirred to obtain a uniform final blend. v. Tablet compressions were performed with the final blend in Step v.

[0062] According to the state-of-the-art information, one of the main documents, namely EP2395968, has disclosed that particle sizes smaller than 63 pm (D90 value) can negatively influence manufacturability by causing sticking or filming during tabletting. The declared preferred particle size with preferred formulations is between 60 pm < D90 < 150 pm on page 38, paragraph 2.

[0063] However, the inventors achieved to obtain pharmaceutical compositions presenting perfect in- vitro release profile even with a broader particle size range issued in Table 2, without facing any problem during production with the critical excipients used in specified ratios in the formulation.

[0064] According to the observations above, tablet compression was successfully achieved for all examples.

[0065] Then, the obtained tablets with the compositions of all examples were subjected to in vitro dissolution study set by US&FDA. According to the information provided, the main dissolution medium is 0.1N HC1. Other conditions are defined as; volume of the dissolution medium is 900 ml, temperature of the study is 37°C±0.5, rotation speed is 100 rpm, the apparatus is basket, and the duration of the dissolution study is 60 minutes.

[0066] Table 3: Comparison dissolution profiles of all examples with reference drug product in 0.1N

[0067] HC1

[0068] Table 4: Calculated f2 results between reference product and the examples individually

[0069] Based on the results presented in Table 3 and Table 4 above, it has been found that the comparative dissolution profiles of the reference product and all examples were quite similar', particularly with regard to the release particles, independent of the particle size of empagliflozin between the values of 2 pm to 60 pm (D90). According to all the results, in embodiments of the present invention, an immediate-release pharmaceutical composition comprising crystalline empagliflozin and at least one pharmaceutically acceptable excipient is manufactured by using the wet granulation process, wherein: - the particle size D90 value of empagliflozin is between 2 pm to 60 pm, the specified weight ratio of lactose to microcrystalline cellulose is 2: 1 the composition comprises binder and disintegrant in amount ratio of 1 : 1 to 1:1.2.

[0070] While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims

CLAIMS1. An immediate-release pharmaceutical composition comprising empagliflozin and at least one pharmaceutically acceptable excipient manufactured using wet granulation process, wherein the particle size D90 value of empagliflozin is between 2 pm to 60 pm, wherein the particle size distribution is by volume and determined by laser-diffraction method, and wherein,- the composition comprises at least two diluents in amount ratio of 2:1,- the composition comprises binder and disintegrant in amount ratio of 1:1 to 1:1.2.

2. An immediate-release pharmaceutical composition according to Claim 1, wherein one of at least two the diluents is microcrystalline cellulose.

3. An immediate-release pharmaceutical composition according to any one of the preceding claims, wherein one of at least two the diluents is lactose.

4. An immediate-release pharmaceutical composition according to any one of the preceding claims, wherein the binder is hydroxypropyl cellulose.

5. An immediate-release pharmaceutical composition according to any one of the preceding claims, wherein the disintegrant is croscarmellose sodium.

6. An immediate-release pharmaceutical composition according to any one of the preceding claims, wherein the composition further comprises at least one pharmaceutically acceptable excipient selected from lubricant, glidant and granulation solvent, and mixtures thereof.

7. An immediate-release pharmaceutical composition according to claim 6, wherein the composition comprises lubricant selected from sodium stearyl fumarate, magnesium stearate, calcium stearate, talc, hydrogenated castor oil and mixtures thereof.

8. An immediate-release pharmaceutical composition according to claim 7, wherein the lubricant is magnesium stearate.

9. An immediate-release pharmaceutical composition according to claim 6, wherein the composition comprises glidant selected from colloidal silicon dioxide, powdered cellulose, talc, tribasic calcium phosphate and mixtures thereof.

10. An immediate-release pharmaceutical composition according to claim 9, wherein the glidant is colloidal silicondioxide.

11. An immediate-release pharmaceutical composition according to claim 6, wherein the composition comprises granulation solvent selected from deionized water, ethanol, isopropanol, acetone, methylene chloride and mixtures thereof.

12. An immediate-release pharmaceutical composition according to claim 11, wherein the granulation solvent is ethanol.

13. An immediate-release pharmaceutical composition according to any one of the preceding claims, wherein the process comprising the steps of: i. Empagliflozin, lactose, microcrystalline cellulose, croscarmellose sodium and hydroxypropyl cellulose are screened through a proper sieve and transferred into cubic mixer and stirred, ii. Sufficient quantity of ethyl alcohol 96% and deionize water are added to the preparation in Step (i) to perform granulation process, iii. The granules prepared in Step (ii) are dried in fluid-bed mixer and shifted through a proper sieve, iv. Magnesium stearate and colloidal silicon dioxide are screened through a proper sieve and added to the granules prepared in Step (iii) and stirred to obtain a uniform final blend. v. Tablet compressions are performed with the final blend in Step v.

14. An immediate release pharmaceutical composition according to any one of the preceding claims, wherein the composition is in the form of tablet.

Images