EP4633610A1

EP4633610A1 - Monolayer tablet composition of empagliflozin and metformin hydrochloride

Info

Publication number: EP4633610A1
Application number: EP22968684.5A
Authority: EP
Inventors: Erol KIRESEPI; Ersin Yildirim
Original assignee: Santa Farma Ilac Sanayi AS
Current assignee: Santa Farma Ilac Sanayi AS
Priority date: 2022-12-16
Filing date: 2022-12-16
Publication date: 2025-10-22
Also published as: WO2024128996A1

Abstract

The present invention provides a monolayer tablet composition comprising empagliflozin or one of its pharmaceutically acceptable salt thereof and metformin hydrochloride manufactured by using a wet granulation method for the treatment of diabetes and/or to achieve glycemic control in type 1 or type 2 diabetes mellitus.

Description

MONOLAYER TABLET COMPOSITION OF EMPAGLIFLOZIN AND METFORMIN HYDROCHLORIDE

FIELD OF INVENTION

STATE OF ART

Diabetes mellitus is an increasingly prevalent lifelong metabolic disorder. Type 2 diabetes mellitus is the most common form that accounts for approximately 90% to 95% of all diagnosed diabetes and is a progressive disease resulting from an insulin secretory defect characterized by insulin resistance, impaired insulin secretion, and increased glucose production by the liver.

Chronic long-term hyperglycemia is associated with comorbidities that exacerbate cardiovascular risks, such as obesity and hypertension. The risk of cardiovascular disease is increased approximately 2 to 4 fold in adults with diabetes even after adjustment for conventional risk factors (age, sex, smoking status, body mass index, systolic blood pressure, and lipids). Thus, there is a proper treatment need to identify antihyperglycaemic agents that can reduce cardiovascular risk in patients with type 2 diabetes mellitus.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors (also known as glifozins) are one of a number of classes of antidiabetic agents that reduce hyperglycemia in patients with type 2 diabetes mellitus. However, glifozins can be distinguished from other antidiabetic agents due to their unique, insulin-independent mechanism of action (promoting glycosuria) which, in addition to lowering plasma glucose, ameliorates a number of other metabolic and haemodynamic abnormalities that are risk factors for cardiovascular disease.

Empagliflozin is a novel, orally administered, potent, and selective inhibitor of the human SGLT-2. 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]-, (IS). Its molecular formula is C23H27CIO7 and its molecular weight is 450.91. The structural formula of empagliflozin is shown in Formula I:

Formula I

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.

Empagliflozin and its pharmaceutically acceptable salts thereof first have been described in EP1730131 numbered patent document by Boehringer Ingelheim International for treatment of or prevention of metabolic disorders selected from among type 1 and type 2 diabetes mellitus and complications of diabetes.

For the treatment of chronic and progressive diseases such as diabetes, the treatment begins with diet and exercise, followed orally by antidiabetic monotherapy. However, these regimens do not sufficiently control glycaemia for many patients during long-term treatment.

Metformin, an oral anti-hyperglycemic agent, is considered the first-line therapy for type 2 diabetes mellitus without promoting weight gain or increasing the risk of hypoglycemia by being alone or combined form with other anti-hyperglycemic medications.

Moreover, it also provides benefits when it is used for the treatment of type 2 diabetes mellitus in patients with moderate renal impairment in terms of the reduction of cardiovascular risk and all-cause mortality. Furthermore, metformin treatment provides additional significant micro- and macrovascular benefits in this patient population.

The chemical name of metformin hydrochloride is 1,1-Dimethylbiguanide hydrochloride. The empirical formula of metformin hydrochloride is C4H12CIN5 and its relative molecular mass is 165.62 mg/mol. The structural formula of metformin hydrochloride is shown in Formula II.

Formula II It consists of white crystals, freely soluble in water, slightly soluble in alcohol, and practically insoluble in acetone, and in methylene chloride. Polymorphism is inexistent. The substance is non-hygroscopic.

Metformin and its acid addition salts, primarily the hydrochloride has been described in US3174901 numbered patent document by Jan Marcel Didier Aron Samuel for treating diabetes.

Thus, Boehringer Ingelheim International has developed a fixed-dose combination comprising empagliflozin and metformin hydrochloride in case a single medicine is not sufficient for patients to maintain blood glucose control in the long term.

Commercially, a pharmaceutical drug product comprising empagliflozin and metformin hydrochloride as active substances was first approved by the European Medicines Agency on May 2015 under the brand name SYNJARDY. The film-coated tablet dosage form of SYNJARDY contains 5 or 12.5 mg of empagliflozin (free base) with 850 or 1,000 mg of metformin hydrochloride used with diet and exercise to treat adults whose type 2 diabetes.

It can be used in patients whose diabetes is not sufficiently controlled by metformin alone; in combination with other diabetes medicines in patients whose diabetes is not sufficiently controlled on these medicines plus metformin; and in patients who are already taking metformin and empagliflozin as separate tablets.

In the state of the art, there are a few patents/patent applications, which are summarized below.

EP2482806 relates to solid pharmaceutical compositions comprising fixed dose combinations of the empagliflozin present in a dosage strength of 5 mg or 12.5 mg, and metformin hydrochloride present in a dosage strength of 5 mg or 12.5 mg. Moreover, it also discloses the solid pharmaceutical composition comprising copovidone as a binder.

EP3150200 relates to a method of manufacturing a mono-layer tablet comprising pharmaceutical compositions comprising fixed dose combinations of the empagliflozin present in a dosage strength of 1 mg or 25 mg, and metformin hydrochloride present in a dosage strength of 100 mg or 2000 mg, in which the manufacturing is provided by using wet granulation method.

EP2683366 relates to a pharmaceutical composition comprising fixed dose combinations of the metformin hydrochloride, linagliptin, and empagliflozin, wherein metformin hydrochloride is in the extended-release core and linagliptin and empagliflozin are in the immediate release coating.

Many pharmaceutical compositions comprising empagliflozin or its pharmaceutically acceptable salt thereof, in combination with metformin hydrochloride are explained in the prior art documents stated above.

However, there is a need for an immediate -release pharmaceutical formulation in the form of a monolayer tablet comprising empagliflozin or one of its pharmaceutically acceptable salt thereof and metformin hydrochloride manufactured by using a wet granulation method to provide enchanced dissolution profile.

SUMMARY OF THE INVENTION

The object of this invention is to provide an immediate-release pharmaceutical formulation comprising a therapeutically effective amount of empagliflozin or pharmaceutically acceptable salts thereof and metformin hydrochloride for improving glycemic control in a patient in need thereof, in particular in patients with type 2 diabetes mellitus.

According to the state-of-the-art, empagliflozin is very slightly soluble in aqueous media between pH 1-7.5. Thus, it is the objective of the present invention is to provide a pharmaceutical composition comprising a crystalline empagliflozin to improve its solubility and bioavailability.

Another object of the present invention is to provide a pharmaceutical formulation comprising crystalline empagliflozin, wherein the D(0.9) particle size of empagliflozin is less than or equal to 100 pm, preferably less than or equal to 50 pm, most preferably less than or equal to 20 pm.

Another object of the present invention is to provide an immediate-release pharmaceutical formulation comprising crystalline empagliflozin and metformin hydrochloride, which can be manufactured into a monolayer tablet dosage form.

Another subject of the present invention is to provide a monolayer tablet comprising 10 mg to 25 mg empagliflozin or one of its pharmaceutically acceptable salt thereof.

Another subject of the present invention is to provide a monolayer tablet comprising 500 to 1000 mg metformin hydrochloride. Another object of the present invention is to provide an immediate-release pharmaceutical formulation comprising empagliflozin and metformin hydrochloride manufactured by using a wet granulation method.

Another object of the present invention is to provide immediate-release pharmaceutical formulation comprising crystalline empagliflozin and metformin hydrochloride and one or more pharmaceutically acceptable excipients with optimized amounts that is manufactured by using a wet granulation method

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an immediate -release pharmaceutical composition comprising empagliflozin or pharmaceutically acceptable salts thereof and metformin hydrochloride manufactured by using a wet granulation method to get a suitable dissolution profile.

The term “pharmaceutical composition” as used herein refers to a finished dosage formulation, which contains the active substance empagliflozin and which is in the market for use.

The present invention relates to an immediate release solid oral composition comprising empagliflozin or pharmaceutically acceptable salts thereof and metformin hydrochloride and one or more acceptable excipients manufactured by using wet granulation process.

Another object of the present invention is to provide a preparation method of a pharmaceutical composition of empagliflozin or pharmaceutically acceptable salts thereof and metformin hydrochloride wherein the pharmaceutical compositions herein disclosed can be manufactured into solid dosage forms, such as tablet, film coated tablet, sachet, capsule having improved granule characteristics and the desired dissolution profiles.

The dissolution test for an immediate-release pharmaceutical composition comprising the active substances of empagliflozin and metformin hydrochloride as herein disclosed is performed in the following conditions: USP Apparatus: II (Paddle), Speed: 50 rpm, Medium: pH 6.8 phosphate buffer, Volume of media: 900 ml, and Temperature: 37°C±0.5°C.

According to the state-of-the-art, the active substance empagliflozin is very slightly soluble in aqeous media and has low intestinal permeability. Thus, in the preferred embodiment of the present invention, the active substance empagliflozin is used in crystalline form to improve its solubility and bioavailability. Another preferred embodiment of the present invention, crystalline empagliflozin has particle size as determined by electron microscopy image analysis expressed as D(0.9) less than or equal to 100 pm, preferably less than or equal to 50 pm, most preferably less than or equal to 20 pm to increase the solubility via increasing surface area.

In a preferred embodiment, the total amount of crystalline empagliflozin present in the pharmaceutical composition is less than 0.5% - 1.0% w/w in respect of the total amount of the pharmaceutical composition.

In a preferred embodiment, the total amount of metformin present in the pharmaceutical composition ranges from 65% to 68% w/w in respect of the total amount of the pharmaceutical composition.

Another object of the present invention is to provide pharmaceutical compositions containing empagliflozin or pharmaceutically acceptable salts thereof and metformin hydrochloride by using wet granulation method wherein provided for the manufacture of tablets containing the active ingredient, diluents, binders, disintegrants, lubricants and solvents etc.

In a preferred embodiment, the pharmaceutical composition comprises at least a disintegrant, preferably, it is selected from croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, starch, sodium starch glycolate, carmellose and mixtures thereof. More preferably, the disintegrant is croscarmellose sodium.

In a preferred embodiment, suitable diluents may include but are not limited to silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc, and thereof. Preferably, the diluent is colloidal silicon dioxide.

In a preferred embodiment, suitable binders may include but are not limited to hypromellose, cellulose or cellulose derivatives, povidone, starch, sucrose, polyethylene glycol, or mixtures thereof. The binder is dissolved in a solvent, for instance, water, an alcohol, or mixtures thereof. In particularly advantageous embodiments of the present invention, the binder solution is hydroxypropyl cellulose dissolved in a solvent mixture of water and ethanol.

In a preferred embodiment, suitable lubricants may include but are not limited to sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid and mixtures thereof. More preferably, the lubricant is magnesium stearate. In order to obtain a targetted product profile, quality attributes have been defined and discussed, the manufacturing process has been selected based on these aspects and a control strategy has been defined.

Multiple formulations were designed to overcome challenges that directly affect the dissolution profile and granule characteristics of pharmaceutical compositions comprising empagliflozin or pharmaceutically acceptable salts thereof and metformin hydrochloride.

An embodiment was performed with the formulation and manufacturing method below based on the information summarized above: i. Metformin hydrochloride, a specified amount of Starch and a specified amount of Croscarmellose sodium were stirred in wet granulator. ii. Hydroxypropyl cellulose and Empagliflozin were dissolved in a sufficient quantity of solvent. iii. Granulation process was performed by spraying the solution in step (ii) on the powder blend in step 1. iv. The granule in step (iii) was dried at a specified temperature till to obtain 1-2% moisture value. v. Dried granule with remaining part of Starch, remaining part of Croscarmellose sodium and Colloidal silicone dioxide were mixed. vi. The mixture in step (v) was lubricated with Magnesium stearate for 3 - 5 minutes. vii. Final blend in step (vi) was subjected to tablet compression process. viii. Optionally tablets obtained in step (vii) were coated.

Formulation I was investigated in comparison to reference drug product with the trade name Synjardy®. Obtained tablets were analyzed for disintegration time, the result is about 1 minute which is good for immediate-release solid dosage forms. Thus, in vitro dissolution profile analysis was performed with the tablets.

Dissolution conditions are performed in the following conditions: - Dissolution medium: phosphate buffer pH 6.8

Volume of dissolution medium: 900 ml

Apparatus: Paddle

Temperature: 37±0.5°C

Time: 60 minutes - Rotation speed: 50 rpm

Table 1: Results of in vitro dissolution study for Formulation I and Reference drug product_Metformin hydrochloride Table 2: Results of in vitro dissolution study for Formulation I and Reference drug product_Empagliflozin

Comparative results presented in Table 1 and Table 2 were evaluated.

In vitro dissolution results regarding both Metformin hydrochloride and Empagliflozin were not similar. Moreover, Formulation I was slow in releasing Empagliflozin and very fast in releasing Metformin hydrochloride. Therefore, a new formulation was planned to be able to make the facts of slowing the release of Metformin hydrochloride and getting faster the release of Empagliflozin. However, there is an unexpected problem that could be challenging in a monolayer tablet design.

The amounts of disintegrants and binders have significant missions in release profile. Therefore, the technical features of both active substances were examined regarding BCS classes; Metformin hydrochloride Class III and Empagliflozin Class III.

One of the aim of the next embodiment is to slow the release of Metformin hydrochloride.

Other aim of the next embodiment is to accelerate the release of Empagliflozin.

Based on all the information above the next embodiment was designed as below: i. Metformin hydrochloride, Starch and one-third of the amount of Croscarmellose sodium were stirred in wet granulator. ii. Hydroxypropyl cellulose and Empagliflozin were dissolved in a sufficient quantity of solvent. iii. Granulation process was performed by spraying the solution in step (ii) on the powder blend in step 1. iv. The granule in step (iii) was dried at a specified temperature till to obtain 1-2% moisture value. v. Dried granule with remaining part of two-thirds of the amount of Croscarmellose sodium, Colloidal silicone dioxide and Microcrystalline cellulose were mixed. vi. The mixture in step (v) was lubricated with Magnesium stearate for 3 - 5 minutes. vii. Final blend in step (vi) was subjected to tablet compression process. viii. Optionally tablets obtained in step (vii) were coated. An in vitro dissolution study was performed to evaluate and decide whether the approach to use specific excipients in specific amount in the specific part of the granulation was the solution for the problem. The in vitro dissolution conditions were kept same.

Table 3: Results of in vitro dissolution study for Formulation II and Reference drug product_Metformin hydrochloride

Table 4: Results of in vitro dissolution study for Formulation II and Reference drug product_Empagliflozin

Formulation II was provided by making the modifications below:

Microcrystalline cellulose was added as second disintegrant to Formulation I in an amount range between 12-14% w/w by total weight of the composition

The amount of Croscarmellose sodium was used in both extragranular phase and intragranular phase instead of using only in extragranular phase.

The amount ratio of Croscarmellose sodium used in intragranular phase to extragranular phase is 1:2.

These excipients were directly effective on the dissolution profile. Regarding the formulation of the invention comprising two active ingredients and in monolayer tablet dosage form, dedicated technical features should be designed in comparison with the reference drug product. Moreover, any change was without present in the amount or the type of binder.

The modifications were carried out to regulate the releases of both active substances as reversibly on the base of Formulation I. In Formulation II, surprisingly addition of microcrystalline cellulose as the second disintegrant and the amount of Croscarmellose sodium both used in the extragranular phase, which are effective on the release of empagliflozin to be accelerated until the desired levels were provided a formulation complied with the reference drug product.

In Formulation II, the amount of Croscarmellose sodium used in the intragranular phase surprisingly reduced the release of Metformin hydrochloride to the desired levels that are complied with the reference drug product.

Comparative results presented in Table 3 and Table 4 were evaluated.

In vitro dissolution results regarding both Metformin hydrochloride and Empagliflozin were far more similar than the results obtained with Formulation I. 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

1. A monolayer tablet composition manufactured by using wet granulation method comprising empagliflozin or one of its pharmaceutically acceptable salt thereof, metformin hydrochloride and pharmaceutically acceptable excipients wherein; the composition comprises

- Microcrystalline cellulose in extragranular phase, and

- Croscarmellose sodium in both extragranular phase and intragranular phase, and the amount ratio of Croscarmellose sodium in intragranular phase to extragranular phase is 1:2.

2. A monolayer tablet composition according to claim 1, wherein the composition comprises 12-14% w/w Microcrystalline cellulose by total weight of the composition.

3. A monolayer tablet composition according to any one of the preceding claims, wherein the composition comprises 10 mg to 25 mg empagliflozin or one of its pharmaceutically acceptable salt thereof.

4. A monolayer tablet composition according to any one of the preceding claims, wherein the composition comprises 500 to 1000 mg metformin hydrochloride.

7. A monolayer tablet composition according to any one of the preceding claims, wherein the composition comprises colloidal silicon dioxide as diluent.

8. A monolayer tablet composition according to any one of the preceding claims, wherein the composition comprises hydroxypropyl cellulose and starch as binders.

9. A monolayer tablet composition according to any one of the preceding claims, wherein the composition comprises deionized water and ethanol mixture as solvents.

10. A monolayer tablet composition according to any one of the preceding claims, wherein the composition comprises magnesium stearate as lubricant.

11. A monolayer tablet composition according to any one of the preceding claims, wherein the quantitative composition in w/w % is as stated below:

Metformin hydrochloride 65-68

Empagliflozin 0.5-1

Microcrystalline cellulose 12-14

Starch 4-9 Hydroxypropyl cellulose 1-3

Croscarmellose sodium 4-9

Colloidal silicone dioxide 0.1-0.5

Magnesium stearate 0.1-0.5

Solvent q.s. and the amount ratio of Croscarmellose sodium in intragranular phase to extragranular phase is 1:2.

12. A wet granulation process for preparing a pharmaceutical composition comprises empagliflozin or one of its pharmaceutically acceptable salt thereof, metformin hydrochloride and pharmaceutically acceptable excipients, wherein the process comprises the following steps: i. Metformin hydrochloride, Starch and one-third of the amount of Croscarmellose sodium are stirred in wet granulator. ii. Hydroxypropyl cellulose and Empagliflozin are dissolved in a sufficient quantity of solvent. iii. Granulation process is performed by spraying the solution in step (ii) on the powder blend in step 1. iv. The granule in step (iii) is dried at a specified temperature till to obtain 1-2% moisture value. v. Dried granule with the remaining part of two-thirds of the amount of Croscarmellose sodium, Colloidal silicon dioxide and Microcrystalline cellulose are mixed. vi. The mixture in step (v) is lubricated with Magnesium stearate for 3 - 5 minutes. vii. Final blend in step (vi) is subjected to the tablet compression process. viii. Optionally tablets obtained in step (vii) are coated.