ORAL FIXED-DOSE ONCE-DAILY PHARMACEUTICAL COMPOSITIONS OF EMPAGLILFOZIN AND SITAGLIPTIN OR PHARMCEUTICALLY ACCEPTABLE SALT THEREOF

Abstract

The present invention relates to a stable, fixed-dose, once-daily pharmaceutical composition comprising a fixed-dose combination of Empagliflozin and Sitagliptin, free from stabilizers, and utilizing mannitol to enhance dissolution. This innovative composition offers significant advantages for the management of diabetes by reducing blood glucose levels with high content uniformity, minimized degradation impurities, and optimized dissolution rates. The composition ensures immediate blood glucose control which lasts for 24 hours by improving therapeutic efficacy. Furthermore, the absence of stabilizers simplifies the composition, while the use of mannitol enhances the dissolution profile, contributing to better patient compliance and therapeutic outcomes. This invention provides a solution to the need for a simplified, yet effective, oral antidiabetic treatment with improved storage stability and bioavailability, offering a superior composition for diabetic patients.

Specification

Description:ORAL FIXED-DOSE ONCE-DAILY PHARMACEUTICAL COMPOSITIONS OF EMPAGLILFOZIN AND SITAGLIPTIN OR PHARMCEUTICALLY ACCEPTABLE SALT THEREOF

FIELD OF THE INVENTION:
The present invention relates to a stable, fixed-dose, once-daily pharmaceutical composition comprising a combination of a therapeutically effective amount of a Dipeptidyl Peptidase-4 (DPP-4) inhibitor and a Sodium-Glucose Co-Transporter-2 (SGLT2) inhibitor for the management of blood glucose levels in patients with diabetes. Specifically, the invention pertains to a composition that includes Sitagliptin or its pharmaceutically acceptable salts, solvates, or hydrates, and Empagliflozin or its pharmaceutically acceptable salts, solvates, or hydrates, in the absence of stabilizers. The composition also incorporates mannitol to enhance dissolution, optimized dissolution profiles and reduced degradation impurities. Additionally, this invention provides improved storage stability, superior bioavailability, and effective blood glucose control.

BACKGROUND OF THE INVENTION:
Type 2 diabetes is a chronic, progressive disease characterized by insulin resistance and impaired insulin secretion. Initial treatment typically involves lifestyle modifications such as diet and exercise, followed by oral antidiabetic monotherapy. However, over time, many patients require combination therapy as monotherapy often fails to maintain adequate glycemic control. While co-prescription of multiple oral antidiabetic drugs is common, it can complicate patients' treatment regimens, leading to decreased adherence.
Achieving the target hemoglobin A1c (HbA1c) levels in patients with type 2 diabetes mellitus (T2DM) can be particularly challenging, especially for those with a longer duration of the disease. To manage type 2 diabetes and related conditions like insulin resistance, various antidiabetic classes of compounds are employed, including but not limited to biguanides, glitazones, sulfonylureas, thiazolidinediones, alpha-glucosidase inhibitors, meglitinides, Sodium-Glucose Cotransporter-2 (SGLT2) inhibitors and dipeptidyl peptidase IV (DPP4) inhibitors. These drugs play a crucial role in controlling blood glucose levels and managing the progression of the disease.
For many patients, monotherapy often fails to adequately control blood glucose levels over the long term, necessitating the introduction of combination therapy within a few years of diagnosis. Although combining drugs with complementary mechanisms of action can enhance treatment effectiveness, it can also complicate the regimen, making it difficult for patients to adhere to. The increased number of pills, more frequent dosing, and potential side effects can reduce patient compliance, leading to suboptimal clinical outcomes. One effective strategy to address these challenges is the use of fixed-dose combinations, which simplify the treatment regimen.
A fixed-dose combination (FDC) tablet offers a simplified approach by combining two or more glucose-lowering agents into a dosage form, reducing the complexity of treatment. Effective and well-tolerated drug combinations are crucial in developing an FDC tablet. Two promising classes of antidiabetic agents, Dipeptidyl Peptidase-4 (DPP-4) inhibitors and Sodium-Glucose Cotransporter-2 (SGLT2) inhibitors, have complementary mechanisms of action. This makes them ideal candidates for a fixed-dose combination therapy, offering synergistic effects in controlling blood glucose levels while minimizing the burden on patients' daily routines.
Empagliflozin is a novel, orally administered, potent, and selective SGLT2 inhibitor, developed by Boehringer Ingelheim International GmbH. It is marketed under the brand name Jardiance® in various countries, including Europe and the United States. Empagliflozin is available in 10 mg and 25 mg immediate-release tablet forms. It is prescribed for the treatment of adults with insufficiently controlled type 2 diabetes mellitus, as an adjunct to diet and exercise.
Sitagliptin, a novel Dipeptidyl Peptidase-4 (DPP-IV) inhibitor developed by Merck & Co., is commercially available as Januvia® in various countries, including the United States and Europe. It is approved in tablet strengths of 25 mg, 50 mg, and 100 mg for adult patients with type 2 diabetes mellitus.
Indian Patent No. IN268846 which covers Empagliflozin, its stereoisomers, mixtures, and salts, as well as its method of preparation and its use in treating metabolic disorders like diabetes mellitus. Additionally, Indian Patent Application No. 7213/DELNP/2007 discloses the crystalline form of Empagliflozin, its preparation method, and pharmaceutical composition.
Indian Patent No. 209816 discloses Sitagliptin, its pharmaceutically acceptable salts, and methods for treating diabetes, while Indian Patent Application No. 5948/DELNP/2005 describes the dihydrogenphosphate salt of Sitagliptin, including its crystalline monohydrate form, its pharmaceutical compositions, preparation processes, and its use in treating type-2 diabetes.
WO2020/130502 (WO '502) discloses a pharmaceutical composition containing Empagliflozin and Sitagliptin as active ingredients, along with Lactose monohydrate, which facilitates immediate drug release, achieving up to 100% release within 15 minutes. However, this formulation may necessitate multiple dosing. Additionally, when the composition described in this prior art was tested, it encountered significant challenges during scale-up to industrial production. These issues included poor flowability and sticking during compression, primarily due hygroscopic nature of Lactose monohydrate in the formulation.
WO2023/062648 (WO '648) discloses a bilayer pharmaceutical composition containing nceEmpagliflozin and Sitagliptin as active pharmaceutical ingredients (APIs). To address the hygroscopic issues associated with Lactose monohydrate in WO '502, Patent No. '648 modifies the formulation by separating the two APIs into distinct layers, with Lactose monohydrate being excluded from one of the layers. However, the complex nature of both APIs led to stability issues, which were partially resolved by incorporating stabilizers into the formulation. Despite this, the addition of stabilizers resulted in allergic reactions such as rashes, itching, and swelling in some patients. Furthermore, the double compression method used for the bilayer tablet is less suitable for large-scale production, limiting the feasibility of scaling up the formulation.
From above prior-art publications, it is well understood that formulating a novel fixed-dose composition containing multiple drugs presents significant challenges. Achieving a balance between stability and release characteristics is crucial to ensure that the composition remains stable while also providing acceptable dissolution and pharmacokinetic properties.
During the development of pharmaceutical compositions involving selected DPP-4 inhibitors, it was observed that these inhibitors, particularly those containing a primary or secondary amino group, often encounter issues such as incompatibilities, degradation problems. Consequently, there is a need for pharmaceutical compositions that can effectively address these technical challenges associated with selected DPP-4 inhibitors.
Additionally, the European assessment report on Jardiance® highlights that Empagliflozin, a BCS class III molecule which has high solubility and but low permeability. In contrast, Sitagliptin phosphate monohydrate, which is a borderline BCS class I molecule. Such a huge physico-chemical difference between Sitagliptin phosphate monohydrate and Empagliflozin present significant challenges in developing a pharmaceutical composition that combines these two active pharmaceutical ingredients (APIs) into a fixed-dose formulation.
Therefore, there is a critical need to develop stable and effective pharmaceutical compositions that deliver a fixed-dose combination of Sitagliptin phosphate monohydrate and Empagliflozin. To overcome problems in above-mentioned prior-arts, the new developed formulation shall be free from stabilizers and also effectively addressing the problem of tablet sticking during the compression process. Furthermore, by eliminating Lactose monohydrate, the composition shall achieve an optimal dissolution profile, while also supporting a once-daily dosing regimen to enhance patient compliance.
Surprisingly, the inventors of the present invention have developed fixed-dose combinations of Empagliflozin and Sitagliptin, or pharmaceutically acceptable salts thereof, that address and resolve the issues inherent in prior art.
Unexpectedly, the inventors of the present invention have formulated a technically advanced stable fixed-dose combination of Empagliflozin and Sitagliptin, or pharmaceutically acceptable salts thereof, which is free from stabilizers and Lactose monohydrate, while still achieving an optimal dissolution profile without encountering the problem of tablet sticking during the compression process. Moreover, the inventors of the present invention have successfully developed a formulation that is administered once daily, thereby enhancing patient compliance.
Additionally, the present invention provides economic significance by embodying the composition in a monolayer tablet form, rather than a bilayer tablet, facilitating a more straightforward and highly scalable industrial manufacturing process. This streamlined process contributes to a reduction in production costs, rendering the formulation more affordable for public use.

OBJECTIVE OF THE INVENTION:
The principal objective of the present invention is to develop a stable, synergistic and therapeutic effective pharmaceutical composition that delivers a fixed-dose combination of Empagliflozin and Sitagliptin or pharmaceutically acceptable salt or solvate thereof.
In one objective of the present invention Sitagliptin or pharmaceutically acceptable salt or solvate thereof is Sitagliptin base or Sitagliptin phosphate anhydrous or Sitagliptin phosphate hydrate including monohydrate.
The prime objective of the present invention is to formulate a composition of Empagliflozin and Sitagliptin or pharmaceutically acceptable salt or solvate thereof that is free from stabilizers, including acidic agents, alkalizing agents, buffering agents, amino acids like L-Arginine, and antioxidants, which provide reduction in allergic reactions such as rashes, itching, and swelling in some patients.
Another important objective of the present invention is to eliminate Lactose monohydrate from the composition of Empagliflozin and Sitagliptin phosphate monohydrate, while effectively preventing tablet sticking during the compression process.
One more objective of the present invention is to provide once-daily dosing regimen of Empagliflozin and Sitagliptin phosphate monohydrate enhancing patient compliance.
One another objective of the present invention is to provide an economically viable pharmaceutical formulation in a monolayer tablet form, facilitating a simpler and scalable industrial manufacturing process, which reduces production costs and increases accessibility.
Yet another objective of the present invention is to provide the composition of Empagliflozin and Sitagliptin phosphate monohydrate containing an intra-granular portion and an extra-granular portion, both of which contain one or more glidants, with at least one glidant being colloidal silicon dioxide.
One another objective of the present invention is to provide the composition of Empagliflozin and Sitagliptin phosphate monohydrate containing an intra-granular portion and an extra-granular portion, both of which contain disintegrants, with at least one disintegrant being croscarmellose sodium.
One more objective of the present invention is to provide the composition of Empagliflozin and Sitagliptin phosphate monohydrate containing one or more sugar alcohols are selected from mannitol, sorbitol, or xylitol, with mannitol being the preferred sugar alcohol.
Yet another objective of the present invention is to provide the composition of Empagliflozin and Sitagliptin phosphate monohydrate in monolayer tablet form wherein tablet is uncoated tablets or film coated tablets prepared using granulation process.

SUMMARY OF THE INVENTION:
The present invention relates to an oral fixed-dose, once-daily pharmaceutical composition that comprises a stable and therapeutically effective combination of Empagliflozin and Sitagliptin or their pharmaceutically acceptable salts, solvates, or hydrates. This composition aims to provide enhanced control over blood glucose levels in patients with diabetes, without the use of stabilizers such as acidic agents, alkalizing agents, buffering agents, amino acids like L-Arginine, or antioxidants. The formulation also intentionally excludes Lactose monohydrate, thereby minimizing allergic reactions such as rashes, itching, and swelling that may arise in sensitive individuals.
The primary aspect of the present invention is to create a synergistic and stable pharmaceutical composition that effectively combines Empagliflozin and Sitagliptin for improved bioavailability, storage stability, and therapeutic efficacy. By formulating the combination in a stable monolayer tablet, the invention simplifies the manufacturing process, making it cost-effective and scalable for industrial production. This design also enhances patient compliance by providing a once-daily dosage form that minimizes the complexity of diabetes management.
One aspect of the present invention is to provide a pharmaceutical composition that incorporates mannitol as a sugar alcohol in place of lactose monohydrate. Mannitol plays a dual role in this formulation, serving as a filler and also enhancing the dissolution profile of the active ingredients. This selection not only optimizes the release of the drug in vivo but also supports the stability of the active ingredients, thus reducing degradation impurities over time.
One more aspect of the present invention is to address tablet production challenges, specifically avoiding tablet sticking and picking issues during the compression process. By including colloidal silicon dioxide in both the intra-granular and extra-granular portions, the composition achieves better flow properties, reduced sticking, and a smoother compression process. This innovation ensures the reproducibility and quality of the final product.
Yet another aspect of the present invention is to enhance patient compliance through a once-daily dosing regimen. The formulation achieves an optimal balance between efficacy and convenience, supporting sustained blood glucose control over a 24-hour period, which can improve long-term adherence to diabetes treatment protocols.
An additional aspect of the present invention is to provide the composition in an economically viable monolayer tablet form. This design streamlines the production process, minimizes costs, and allows for large-scale manufacturing without sacrificing quality or stability. As a result, the formulation is accessible to a larger population of patients requiring effective diabetes management.
Yet another aspect of the present invention emphasizes the composition's inclusion of both intra-granular and extra-granular disintegrants. Croscarmellose sodium is used as a disintegrant in these portions to facilitate rapid disintegration of the tablet upon administration, promoting a faster release and absorption of the active ingredients in the body. This carefully selected combination enhances the bioavailability and therapeutic efficacy of the composition.
One more aspect of the present invention involves the use of mannitol as the preferred sugar alcohol, though other sugar alcohols such as sorbitol or xylitol may also be employed. The formulation with mannitol offers a consistent dissolution rate, ensuring that the drug is efficiently absorbed in the body. This choice contributes to a stable release profile, improving the effectiveness of the medication in managing blood glucose levels.
One more aspect of the present invention that formulation as per the present invention demonstrates a rapid and complete release of active ingredients compared to comparative formulations, which indicates superior bioavailability. The exclusion of Lactose monohydrate and inclusion of mannitol contribute significantly to achieving these favorable release characteristics, establishing the technical advancement and therapeutic advantages of the composition.
Further aspects of the invention relate to the stability profile of the formulation. The composition as per the present invention shows superior stability over an extended period, with both potency and dissolution profile maintained under accelerated conditions. The formulation's stability is attributed to the deliberate exclusion of stabilizers and the inclusion of specific excipients, such as colloidal silicon dioxide and mannitol, which synergistically stabilize the active ingredients.
In one aspect, the present invention also encompasses findings from a Phase III clinical study, which substantiate the composition's therapeutic efficacy. In this clinical study, the fixed-dose combination of Empagliflozin and Sitagliptin shown to provide a significant reduction in HbA1c levels, with a higher proportion of patients achieving the target HbA1c level of <7% compared to a marketed alternative. This demonstrates the superior efficacy of the composition in managing blood glucose levels and underscores its potential as a leading treatment option for diabetes management.
Finally, the invention establishes that the absence of a stabilizer in this composition does not compromise its stability or efficacy, offering an advantage for patients who may experience adverse reactions to stabilizers. This reduction in stabilizer-related side effects represents a significant improvement in patient outcomes and compliance, contributing to the composition's overall therapeutic effectiveness.

BRIEF DESCRIPTION OF THE DRAWINGS:
Figure-1A shows mean change in HbA1c (%) from Baseline to the End of Week 16
Figure-1B shows mean Change in FPG from baseline at the end of Weeks 16
Figure-1C shows mean Change in PP2PG from baseline at the end of Weeks 16
Figure-2 shows comparative %CDR in 0.1 N HCl dissolution medium in 45 minutes of comparative example-1, comparative example-2 and example-1 of the present invention after 6-months of accelerated stability study

DETAILED DESCRIPTION OF THE INVENTION:
The following detailed description of the present subject matter the various embodiments. These embodiments are described in sufficient detail to enable those skilled in the art to practice the present subject matter. Other embodiments may be utilized and changes may be made without departing from the scope of the present subject matter.
References to "an", "one", or "various" embodiments in this disclosure are not necessarily to the same embodiment, and such references contemplate more than one embodiment. The following detailed description is, therefore, not to be taken in a limiting sense, and the scope is defined only by the appended claims, along with the full scope of legal equivalents to which such claims are entitled.
The present invention relates to a stable and effective pharmaceutical composition for delivering a fixed-dose combination of Sitagliptin phosphate monohydrate and Empagliflozin, specifically designed to achieve optimized therapeutic efficacy in treating type 2 diabetes mellitus.
The formulation as per the present invention excludes stabilizers and lactose hydrate, which not only enhances patient tolerability but also addresses known formulation challenges, such as tablet sticking during compression.
The primary embodiment of the present invention is to develop a pharmaceutical composition containing Sitagliptin phosphate monohydrate and Empagliflozin in a fixed-dose combination that does not require additional stabilizing agents. The removal of stabilizers minimizes formulation complexity, reduces excipient load, and enhances the tolerability of the formulation by excluding unnecessary additives.
One embodiment of the present invention is to provide a composition in a monolayer tablet form that integrates both active ingredients in a -layer matrix. This design is intended to enhance manufacturability by simplifying the tablet's structure and ensuring uniform distribution of each active pharmaceutical ingredient. The monolayer structure not only improves the compression properties of the tablet, thus avoiding sticking and related issues during the manufacturing process, but it also facilitates precise dosage control and a more consistent dissolution profile.
One more embodiment of the present invention is to optimize the dissolution profile of the monolayer tablet, ensuring that both Sitagliptin and Empagliflozin release in a controlled manner conducive to once-daily dosage administration.
The invention further embodies an industrially scalable process for the preparation of the monolayer tablet, incorporating optimized blending, dry mixing, and compression steps that enhance the efficiency of the manufacturing process. The method involves initial blending of Sitagliptin phosphate monohydrate and Empagliflozin with selected excipients to achieve a homogenous powder mix, followed by granulation and drying processes that ensure optimal particle size distribution.
A further embodiment of the present invention is the clinical efficacy of the composition, demonstrated through a Phase III clinical study which showed that the formulation achieves the desired therapeutic outcomes in patients with type 2 diabetes. The clinical study confirms that the fixed-dose combination is effective in managing blood glucose levels, with a favorable safety and tolerability profile. This evidence of clinical efficacy supports that the synergistic composition as per the present invention provides enhanced therapeutic efficacy.
In yet another embodiment, the invention provides a composition that simplifies the patient's medication regimen through a once-daily dosing strategy. By ensuring that both active ingredients are effectively delivered over a 24-hour period, the formulation supports adherence to treatment schedules, which is often a challenge in diabetes management due to the need for multiple medications. The once-daily dosing regimen enhances the practicality of the treatment and may lead to better overall health outcomes by promoting consistent medication adherence.
Another embodiment of the invention is to provide a pharmaceutical composition that is free from lactose, making it suitable for patients who are lactose intolerant. The absence of lactose hydrate in the composition aligns with the current trends in pharmaceutical development to create formulations that cater to diverse patient needs, especially those with lactose intolerance or other sensitivities.
In a further embodiment, the present invention provides synergistic effect which is achieved by optimizing the release profiles of the active ingredients so that blood sugar levels are regulated effectively over a 24-hour period. This formulation approach not only enhances the therapeutic efficacy of each dose but also provides consistent glycemic control, which is essential for effective diabetes management.
In a further embodiment, the invention also aims to provide a pharmaceutical composition that demonstrates a high degree of bioavailability, ensuring that both Sitagliptin and Empagliflozin are effectively absorbed and utilized by the body. Through a combination of optimized formulation and controlled-release characteristics, the invention maximizes the therapeutic potential of the active ingredients, allowing patients to achieve stable blood glucose levels with minimal side effects.
An oral fixed-dose pharmaceutical composition for once daily dosage administration comprising, 10 mg to 25 mg of Empagliflozin, Sitagliptin or pharmaceutically acceptable salt or solvate thereof equivalent to 100 mg of sitagliptin base, and at least one or more pharmaceutically acceptable excipients, wherein the composition comprises one or more sugar alcohol and the composition is devoid of stabilizers.
The pharmaceutical composition as per the present invention, wherein the one or more sugar alcohols are selected from mannitol, sorbitol, or xylitol, with mannitol being the preferred sugar alcohol.
The pharmaceutical composition as per the present invention, is free from stabilizers, including acidic agents, alkalizing agents, buffering agents, amino acids like L-Arginine, and antioxidants.
The pharmaceutical composition as per the present invention, is formulated as a monolayer tablet, wherein the composition is devoid of Lactose monohydrate.
The pharmaceutical composition as per the present invention, wherein the composition comprises an intra-granular portion and an extra-granular portion, both of which contain one or more glidants, with at least one glidant being colloidal silicon dioxide.
The pharmaceutical composition as per the present invention, wherein the composition comprises an intra-granular portion and an extra-granular portion, both of which contain one or more disintegrants, with at least one disintegrant being croscarmellose sodium.
The pharmaceutical composition as per the present invention, wherein the composition comprises one or more binder selected from polyvinylpyrrolidone (povidone), hydroxypropylcellulose (HPC), hydroxypropylmethyl cellulose (HMPC), and hydroxyethyl cellulose.
The pharmaceutical composition as per the present invention comprises, 1-10% w/w Empagliflozin, 31-40% w/w Sitagliptin Phosphate Monohydrate, 2-5% w/w glidant, 45-55% w/w diluent, 4-8% w/w disintegrant, 1-10% w/w binder, 0-3% w/w lubricant.
The pharmaceutical composition as per the present invention, wherein the composition of Empagliflozin 25 mg + Sitagliptin Phosphate Monohydrate eq. to 100 mg of Sitagliptin base comprising, 6.25% w/w Empagliflozin, 32.13% w/w Sitagliptin Phosphate Monohydrate, 2.50% w/w Colloidal Silicon Dioxide, 24.13% w/w Mannitol, 25.00% w/w Microcrystalline Cellulose, 5% w/w Croscarmellose sodium, 3% w/w Povidone K30, 2% w/w Magnesium Stearate.
The pharmaceutical composition as per the present invention, wherein the composition of Empagliflozin 10 mg + Sitagliptin Phosphate Monohydrate eq. to 100 mg of Sitagliptin base comprising, 2.50% w/w Empagliflozin, 32.13% w/w Sitagliptin Phosphate Monohydrate, 2.50% w/w Colloidal Silicon Dioxide, 27.88% w/w Mannitol, 25.00% w/w Microcrystalline Cellulose, 5% w/w Croscarmellose sodium, 3% w/w Povidone K30, 2% w/w Magnesium Stearate.
The pharmaceutical composition as per the present invention, wherein the process for preparing the pharmaceutical composition comprises the following steps, step-1) blending Sitagliptin phosphate monohydrate with a portion of colloidal silicon dioxide to form Blend-1, step-2) dry mixing Empagliflozin, Blend-1 from step 1, mannitol, croscarmellose sodium, and microcrystalline cellulose to obtain Blend-2, step-3) granulating Blend-2 obtained in step 2 using a povidone K30 solution in purified water to produce a wet granulated mass, step-4) drying the wet granulated mass obtained in step 3, step-5) blending the dried granulated mass obtained in step 4 with croscarmellose sodium and colloidal silicon dioxide to form pre-lubricated granules, step-6) lubricating the pre-lubricated granules obtained in step 5 with magnesium stearate to obtain lubricated granules, step-7) compressing the lubricated granules obtained in step 6 to provide a tablet formulation, step-8) optionally, coating the tablet formulation obtained in step 7.

EXAMPLES:
Having described the invention with reference to certain preferred embodiments, other aspects will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail by the preparation of the compounds of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
The following examples are provided for illustrative purpose only and these examples are in no way limitative on the present invention.

COMPARATIVE EXAMPLE-1: Composition of Empagliflozin and Sitagliptin as per WO '502
Empagliflozin 25 mg + Sitagliptin 100 mg
Ingredients Weight (mg / tablet) % w/w
Empagliflozin 25.00 7.46
Sitagliptin 100.00 29.85
Lactose monohydrate 150.00 44.78
Microcrystalline cellulose (MCC) 25.00 7.46
Low substituted hydroxypropylcellulose (L-HPC) 7.00 2.09
Croscarmellose sodium 18.00 5.37
Silicon dioxide 5.00 1.49
Sodium stearate 5.00 1.49
Weight of Uncoated Tablets 335.00 100.00
Opadry (HPMC based Coating) 11.00 3.28%

Process for preparation of above comparative example:
Empagliflozin, Sitagliptin, Lactose monohydrate, low-substituted hydroxypropylcellulose, microcrystalline cellulose, and croscarmellose sodium were mixed and subsequently subjected to wet granulation and drying of the granules. Silicon dioxide was initially mixed with the dried granules, followed by the addition of magnesium stearate and compression into tablets. Tablets were coated with HPMC (hydroxypropylmethyl cellulose) coating solution.

COMPARATIVE EXAMPLE-2:
Preparation of Tablet with Separate Granules of Sitagliptin and Empagliflozin and Stabilizer as per WO '648
Empagliflozin 25 mg + Sitagliptin Phosphate eq. to Sitagliptin base 100 mg
Ingredients Weight (mg / tablet) % w/w
Empagliflozin Granules
Empagliflozin 25.00 4.17
Lactose Monohydrate 113.00 18.83
MCC 40.00 6.67
Croscarmellose Sodium 4.00 0.67
Hydroxypropylcellulose (HPC) 6.00 1.00
Sitagliptin Granules
Sitagliptin Phosphate 124.06 20.68
MCC 66.14 11.02
Dibasic Calcium Phosphate 123.80 20.63
Croscarmellose Sodium 9.00 1.50
Povidone 12.00 2.00
L-Arginine 6.00 1.00
Extra-granular Part
MCC 35.00 5.83
Croscarmellose Sodium 10.00 1.67
Anhydorus colloidal silicon dioxide 2.00 0.33
Magnesium Stearate 6.00 1.00
Sodium Stearyl Fumarate 18.00 3.00
Weight of Unocoated Tablets 600.00 100.00
Opadry based Coating (PVA Based) 18.00 3.00 %

Process for preparation:
a) Empagliflozin, lactose monohydrate, microcrystalline cellulose, and croscarmellose sodium were blended and followed by addition of a binder solution which was prepared by adding hydroxypropyl cellulose to hot purified water to get wet granules. Wet granules were dried and sieved to obtain dried granules blend-1.
b) Sitagliptin phosphate monohydrate, microcrystalline cellulose, dibasic calcium phosphate, and croscarmellose sodium were blended and followed by addition of a binder solution which was prepared by adding Povidone to purified water to get wet granules. Wet granules were dried and sieved to obtain dried granules blend-2.
c) Croscarmellose sodium, anhydrous colloidal silicon dioxide, and microcrystalline cellulose were blended with the dried granules blend-1 and blend-2 to obtain pre-lubricated blend.
d) Magnesium stearate and sodium stearyl fumarate were mixed with pre-lubricated blend to obtain lubricated blend which was compressed to form tablet.
e) A coating dispersion was prepared by dispersing Opadry in purified water to coat the tablets.

EXAMPLE-1: An oral fixed-dose monolayer pharmaceutical composition of Empagliflozin and Sitagliptin Phosphate Monohydrate for once daily dosage administration (25/100 mg)
Empagliflozin 25 mg + Sitagliptin Phosphate Monohydrate eq. to 100 mg of Sitagliptin base
Ingredients Weight (mg / tablet) % w/w
Intra-granular portion
Empagliflozin 25.00 6.25
Sitagliptin Phosphate Monohydrate 128.50 32.13
Colloidal Silicon Dioxide 6.00 1.50
Mannitol 96.50 24.13
Microcrystalline Cellulose 100.00 25.00
Croscarmellose sodium 10.00 2.50
Povidone K30 12.00 3.00
Extra-granular portion
Croscarmellose sodium 10.00 2.50
Colloidal Silicon Dioxide 4.00 1.00
Magnesium Stearate 8.00 2.00
Weight of Uncoated Tablets 400.00 100.00
Anshcoat Aqua coating solution 8.00 2.00 %

Process for preparation:
Step-1) 128.50 mg Sitagliptin phosphate monohydrate was blended with a 6.00 mg colloidal silicon dioxide to form blend-1,
Step-2) 25.00 mg Empagliflozin, blend-1 from step 1, 96.50 mg mannitol, 10.00 mg croscarmellose sodium, and 100.00 mg microcrystalline cellulose were dry-mixed to obtain blend-2,
Step-3) blend-2 obtained in step-2 was granulated using a 12.00 mg povidone K30 solution in purified water to produce a wet granulated mass,
Step-4) the wet granulated mass obtained in step-3 was dried,
Step-5) the dried granulated mass obtained in step-4 was blended with 10.00 mg croscarmellose sodium and 4.00 mg colloidal silicon dioxide to form pre-lubricated granules,
Step-6) the pre-lubricated granules obtained in step-5 were lubricated with 8.00 mg magnesium stearate to obtain lubricated granules,
Step-7) the lubricated granules obtained in step-6 were compressed to provide an uncoated tablet formulation,
Step-8) the uncoated tablet formulation obtained in step-7 was coated with Anshcoat Aqua coating solution upto 2.00% w/w of uncoated tablets to obtain a film coated tablet formulation.

EXAMPLE-2: An oral fixed-dose monolayer pharmaceutical composition of Empagliflozin and Sitagliptin Phosphate Monohydrate for once daily dosage administration (10/100 mg)
Empagliflozin 10 mg + Sitagliptin Phosphate Monohydrate eq. to 100 mg of Sitagliptin base
Ingredients Weight (mg / tablet) % w/w
Intra-granular portion
Empagliflozin 10.00 2.50
Sitagliptin Phosphate Monohydrate 128.50 32.13
Colloidal Silicon Dioxide 6.00 1.50
Mannitol 111.50 27.88
Microcrystalline Cellulose 100.00 25.00
Croscarmellose sodium 10.00 2.50
Povidone K30 12.00 3.00
Extra-granular portion
Croscarmellose sodium 10.00 2.50
Colloidal Silicon Dioxide 4.00 1.00
Magnesium Stearate 8.00 2.00
Weight of Uncoated Tablets 400.00 100.00
Anshcoat Aqua coating solution 8.00 2.00 %

Example-2 was prepared in a similar way as mentioned process for preparation for Example-1.

EXAMPLE-3: Comparison of tablet sticking issue during compression in Comparative Example-1, Comparative Example-2 and Example-1 of the present invention
During the tablet compression process for the respective blends prepared in accordance with Comparative Example-1, Comparative Example-2, and Example-1 of the present invention, issues of sticking and picking were observed in the comparative examples, as detailed below.
Batch Comparative Example-1 Comparative Example-2 Example-1 without addition of colloidal silicon dioxide in intra-granular portion in step-1 Example-1 of the present invention
Sticking / Picking Problem Highly Observed Highly Observed Moderately Observed No Problem Observed

In comparative Example-1, it was observed that if the first step of the process, involving the addition of colloidal silicon dioxide to the intra-granular portion, was omitted, a moderate problem of sticking and picking occurred. Therefore, the exclusion of Lactose Monohydrate from the composition, combined with the addition of colloidal silicon dioxide in the first step of the process to the intra-granular portion, effectively resolved the sticking and picking issues during the compression of lubricated granules. Consequently, the results of this experiment demonstrated to the inventors that the removal of Lactose Monohydrate from the composition and the addition of colloidal silicon dioxide to the intra-granular portion were critical to achieving these desired outcomes.

EXAMPLE-4: Comparative In-Vitro Dissolution Profile Analysis of Comparative Example-1, Comparative Example-2 and Example-1 of the present invention
The tablets of respective examples were evaluated for in-vitro dissolution study using USP paddle type apparatus in 900 ml of 0.1 N HC1 at 50 RPM. Following are results for the same.
Time Points (Min) Cumulative % Drug Release
Comparative Example-1 Comparative Example-2 Example-1 of the present invention
Empagliflozin Sitagliptin Empagliflozin Sitagliptin Empagliflozin Sitagliptin
10 min 86.90 93.00 78.00 81.00 89.2 99.8
15 min 93.00 100.00 87.00 89.00 92.9 100.9
30 min 96.90 100.50 94.00 91.00 97.6 102.6
45 min 98.90 100.60 95.36 93.70 99.8 103.7
60 min 99.70 100.70 97.00 96.10 101.6 104.9

The results demonstrated a significant difference in the dissolution rates among the three formulations. Example-1 of the present invention, even after exclusion of lactose monohydrate and by addition of mannitol, exhibited more rapid and complete release of the active ingredients compared to the comparative examples, suggesting enhanced bioavailability and therapeutic efficacy. The above presented findings validate the technical advancement and synergistic effect of the composition.

EXAMPLE-5: Comparative Accelerated Stability Study Results of Comparative Example-1, Comparative Example-2 and Example-1 of the present invention
An accelerated stability study was conducted at 40±2℃ and 75±5% RH to assess stability of Example-1 of the present invention in comparison to Comparative Examples 1 and 2.

TIME POINTS Accelerated Stability Study Results at 40±2℃ and 75±5% RH
% Assay
(Limit: 90%-110%) %CDR in 0.1 N HCl dissolution medium in 45 minutes
(Limit: NLT 75%) Unknown Impurities
(%w/w)
(Limit: NMT 0.2%) Total Impurities
(% w/w)
(Limit: NMT 1.0%)
Empa Sita Empa Sita Empa Sita Empa Sita
Comparative Example-1
Initial 100.08 100.84 98.90 100.60 0.029 0.047 0.060 0.085
1M 99.26 100.06 95.87 97.12 0.091 0.113 0.148 0.492
3M 98.52 98.78 93.90 94.62 0.137 0.172 0.298 0.733
6M 96.79 95.21 90.73 90.89 0.168 0.237 0.459 1.289
Comparative Example-2
Initial 95.00 96.00 95.36 93.70 0.037 0.055 0.056 0.089
1M 93.78 94.53 93.85 93.13 0.117 0.121 0.178 0.511
3M 91.56 91.87 92.20 92.89 0.152 0.160 0.266 0.779
6M 90.12 90.46 90.78 90.51 0.181 0.203 0.423 1.251
Example-1 of the present invention
Initial 100.50 101.00 100.40 101.70 0.016 0.031 0.091 0.098
1M 99.95 100.38 99.90 100.29 0.023 0.032 0.134 0.105
3M 99.80 99.60 99.72 99.10 0.030 0.036 0.187 0.112
6M 99.38 99.20 98.20 98.60 0.030 0.037 0.193 0.137
Abbreviations: Initial = at 0 month, 1M = After 1 month, 2M = After 2 months, 3M = After 3 months, Empa = Empagliflozin, Sita = Sitagliptin, NMT = Not more than, %CDR = Cumulative % Drug release

Above-reported results demonstrated that Example-1 of the present invention exhibited superior stability, maintaining its potency and dissolution profile over an extended period, in contrast to the comparative examples, which showed a significant decline in both potency and dissolution profile. The inventors of the present invention observed that the inclusion of Mannitol was critical in minimizing the reduction in cumulative drug release (%CDR) in 0.1 N HCl dissolution medium within 45 minutes, even after six months under accelerated conditions. Thus, the inclusion of Mannitol was essential to achieve these favourable release profile results.
Moreover, the use of Lactose Monohydrate in the formulation of Comparative Examples 1 and 2 resulted in the failure of both formulations to meet the maximum International Council for Harmonisation (ICH) limits at 6 months of accelerated stability testing for unknown impurities required for commercialization. In contrast, the exclusion of Lactose Monohydrate in Example-1 of the present invention provided a distinct advantage, maintaining the levels of unknown impurities well within the acceptable ICH limits even at 6 months of accelerated stability testing. Therefore, the exclusion of Lactose Monohydrate was crucial to achieving these results.
Comparative Example 2 when compare to comparative example-1 demonstrated a slight reduction in a unknown and total impurity at 6 months of accelerated stability testing, likely attributable to the inclusion of the stabilizer. However, Example-1 of the present invention, through the synergistic interaction of its excipients, maintained levels of both impurities well within acceptable limits, even without the addition of a stabilizer. The exclusion of a stabilizer in Example-1 of the present invention offers a potential advantage for patients who may experience adverse reactions to stabilizers. This can contribute to increased patient compliance and overall therapeutic effectiveness.
The evidence clearly indicates that Example-1 of the present invention is less prone to degradation. Additionally, the data on total impurities and cumulative percentage of drug release in 0.1 N HCl dissolution medium within 45 minutes further corroborates these findings.

EXAMPLE-6: Human Clinical Study Phase-III report of Fixed Dose Combination (FDC) of Example-1 of the present invention
A Phase III, Randomized, Double Blind, Active- Controlled, Prospective, Comparative, Parallel Group, Multicentric Clinical Study to Evaluate the Efficacy, Safety and Tolerability of Fixed Dose Combination of Empagliflozin plus Sitagliptin Tablets Versus Fixed Dose Combination of Dapagliflozin plus Sitagliptin Tablets in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin Monotherapy was registered and performed with CTRI Number: CTRI/2023/12/060549.
Being a sponsor of this study, the applicant of the invention conducted this study comparing FDC of Empagliflozin 25 mg + Sitagliptin 100 mg Tablets as per the present invention (Test Product) against the marketed FDC of Dapagliflozin 10 mg + Sitagliptin 100 mg Tablets (Reference Product).
Primary objective of the study was to evaluate therapeutic efficacy of Test Product against Reference Product. Secondary objective of the study was to evaluate safety and tolerability of Test Product against Reference Product.
This study was performed on male and female patients aged between 18 to 65 years. A total of 312 patients were enrolled for the study program for 16 weeks (112±3 days) with the patient's written informed consent. Following is the summary for the results.

Significant Reduction in HbA1c level in Test Product:
The therapeutic glycemic response refers to the ability of a treatment to achieve a target HbA1c level, which is a key indicator of long-term blood glucose control in diabetic patients. In this context, HbA1c < 7% is a common target in diabetes management, representing well-controlled blood sugar levels over a few months.
In a Phase III human clinical study, the proportion of patients achieving a therapeutic glycemic response, as defined by an HbA1c level of <7% at the end of the study visit (week 16), was analysed. The data revealed that the Test Product exhibited a statistically significant 32% reduction in proportion of patients achieving a therapeutic glycemic response, defined as HbA1c < 7% levels compared to the Reference Product. This reduction underscores the superior therapeutic efficacy of the Test Product in achieving target glycemic control. As demonstrated in figure-1A, these results substantiate the claim that the Test Product provides a more effective therapeutic glycemic response, thereby enhancing patient outcomes in the management of diabetes.

Table: Mean Change in HbA1c (%) from Baseline to the End of Week 16
Visit Statistics Test Product
(N=102) Reference Product
(N=102)
Visit 1 / Baseline Mean (SD) 9.27 (0.68) 9.28 (0.61)
Median 9.00 9.10
(Min, Max) (8.50, 11.00) (8.50, 11.00)
Visit 5 / Week 12 (Day 84±3) Mean (SD) 7.87 (0.85) 8.05 (0.85)
Median 7.80 8.00
(Min, Max) (6.60, 10.30) (6.40, 9.90)
Visit 6 / Week 16 (Day 112±3) Mean (SD) 7.58 (0.91) 7.82 (0.88)
Median 7.50 7.80
(Min, Max) (6.20, 9.80) (6.40, 10.10)
Mean change from baseline to
Visit 5 / Week 12 (Day 84±3) LSM (SE) -1.4377 (0.0639) -1.2440 (0.0652)
LS mean difference -0.1937
95% CI of LS mean difference (-0.37, -0.01)
P-value 0.0344
Mean change from baseline to
Visit 6 / Week 16 (Day 112±3) LSM (SE) -1.7299 (0.0639) -1.4685 (0.0652)
LS mean difference -0.2614
95% CI of LS mean difference (-0.44, -0.08)
P-value 0.0044

Significant Fasting Plasma Glucose (FPG) Reduction in Test Product
Fasting plasma glucose (FPG) refers to blood sugar levels after an overnight fast and is an important measure in diagnosing and managing diabetes. Lower FPG levels indicate better control of blood glucose, which is crucial in preventing complications associated with diabetes.
The mean change in fasting plasma glucose (FPG) levels from baseline to the study's conclusion (week 16) was also examined during the Phase III clinical trial. The Test Product demonstrated a significant reduction in FPG levels, with around 10% more decrease compared to the Reference Product. As illustrated in figure-1B, this reduction indicates that the Test Product is more effective in controlling fasting blood glucose levels, an essential aspect of managing hyperglycemia and reducing the risk of diabetes-related complications.

Table: Mean Change in FBG from baseline at the end of Weeks 16
Visit Statistics Test Product
(N=102) Reference Product
(N=102)
Visit 1 / Baseline Mean (SD) 179.62 (25.29) 185.97 (25.65)
Median 177.00 183.00
(Min, Max) (104.00, 261.00) (124.00, 270.00)
Visit 5 / Week 12 (Day 84±3) Mean (SD) 147.23 (25.26) 155.45 (21.88)
Median 148.00 154.80
(Min, Max) (82.00, 245.00) (108.40, 220.00)
Visit 6 / Week 16 (Day 112±3) Mean (SD) 146.43 (19.68) 152.02 (18.32)
Median 144.50 150.50
(Min, Max) (117.00, 191.00) (110.00, 194.00)
Mean change from baseline to
Visit 5 / Week 12 (Day 84±3) LSM (SE) -32.3856 (2.4062) -30.5279 (2.4062)
LS mean difference -1.8577
95% CI of LS mean difference (-8.54, 4.82)
P-value 0.5852
Mean change from baseline to
Visit 6 / Week 16 (Day 112±3) LSM (SE) -33.1875 (2.4062) -33.9548 (2.4062)
LS mean difference 0.7673
95% CI of LS mean difference (-5.91, 7.44)
P-value 0.8216

Significant Postprandial Plasma Glucose (PP2PG) Reduction in Test Product
Postprandial plasma glucose (PP2PG) refers to blood sugar levels measured two hours after eating. Managing PP2PG is vital in controlling overall blood glucose levels and avoiding spikes that can lead to complications in diabetic patients.
Further analysis of the Phase III human clinical study focused on the mean change in 2-hour postprandial plasma glucose (PP2PG) levels from baseline to the end of the study (week 16). The Test Product achieved around 10% more reduction in PP2PG levels compared to the Reference Product. As depicted in figure-1C, these findings confirm the superior ability of the Test Product to manage postprandial glucose levels, which are critical in preventing glycemic excursions and optimizing overall glycemic control.
Table: Mean Change in PP2PG from baseline at the end of Weeks 16
Visit Statistics Test Product (N=102) Reference Product
(N=102)
Visit 1 / Baseline Mean (SD) 264.54 (40.51) 270.50 (36.42)
Median 268.00 276.50
(Min, Max) (160.00, 371.00) (182.00, 372.00)
Visit 5 / Week 12 (Day 84±3) Mean (SD) 216.91 (43.87) 226.59 (39.12)
Median 221.00 229.50
(Min, Max) (120.00, 368.00) (145.00, 370.00)
Visit 6 / Week 16 (Day 112±3) Mean (SD) 213.28 (33.53) 218.01 (32.12)
Median 214.00 217.50
(Min, Max) (136.00, 343.00) (148.00, 306.00)
Mean change from baseline to
Visit 5 / Week 12 (Day 84±3) LSM (SE) -47.6288 (3.2660) -43.9106 (3.2660)
LS mean difference -3.7183
95% CI of LS mean difference (-12.78, 5.35)
P-value 0.4210
Mean change from baseline to
Visit 6 / Week 16 (Day 112±3) LSM (SE) -51.2548 (3.2660) -52.4962 (3.2660)
LS mean difference 1.2413
95% CI of LS mean difference (-7.82, 10.30)
P-value 0.7882

Conclusion of study:
The results of the Phase III human clinical study clearly demonstrate the superior therapeutic efficacy of the Test Product over the Reference Product in achieving key glycemic control outcomes. The Test Product showed a more pronounced reduction in HbA1c, FPG, and PP2PG levels, establishing its superiority in managing diabetes.
The invention described herein comprises in various objects and their description as mentioned above, with respect to characteristics and processes adopted. While these aspects are emphasised in the invention, any variations of the invention described above are not to be regarded as departure from the spirit and scope of the invention as described.

 
, Claims:We Claim:
1. An oral fixed-dose pharmaceutical composition for once daily dosage administration comprising:
a. 10 mg to 25 mg of Empagliflozin,
b. Sitagliptin or pharmaceutically acceptable salt or solvate thereof equivalent to 100 mg of sitagliptin base, and
c. at least one or more pharmaceutically acceptable excipients;
wherein the composition comprises one or more sugar alcohol and the composition is devoid of stabilizers.

2. The pharmaceutical composition as claimed in claim 1, wherein the one or more sugar alcohols are selected from mannitol, sorbitol, or xylitol, with mannitol being the preferred sugar alcohol.

3. The pharmaceutical composition as claimed in claim 1, is free from stabilizers, including acidic agents, alkalizing agents, buffering agents, amino acids like L-Arginine, and antioxidants.

4. The pharmaceutical composition as claimed in claim 1, is formulated as a monolayer tablet, wherein the composition is devoid of Lactose monohydrate.

5. The pharmaceutical composition as claimed in claim 1, wherein the composition comprises an intra-granular portion and an extra-granular portion, both of which contain one or more glidants, with at least one glidant being colloidal silicon dioxide.

6. The pharmaceutical composition as claimed in claim 1, wherein the composition comprises an intra-granular portion and an extra-granular portion, both of which contain one or more disintegrants, with at least one disintegrant being croscarmellose sodium.

7. The pharmaceutical composition as claimed in claim 1, wherein the composition comprises one or more binder selected from polyvinylpyrrolidone (povidone), hydroxypropylcellulose (HPC), hydroxypropylmethyl cellulose (HMPC), and hydroxyethyl cellulose.

8. The pharmaceutical composition as claimed in claim 1 comprises:
1-10% w/w Empagliflozin,
31-40% w/w Sitagliptin Phosphate Monohydrate,
2-5% w/w glidant,
45-55% w/w diluent,
4-8% w/w disintegrant,
1-10% w/w binder,
0-3% w/w lubricant.

9. The pharmaceutical composition as claimed in claim 1, wherein the composition comprising following formula:
Ingredients Empagliflozin 25 mg + Sitagliptin Phosphate Monohydrate eq. to 100 mg of Sitagliptin base Empagliflozin 10 mg + Sitagliptin Phosphate Monohydrate eq. to 100 mg of Sitagliptin base
Weight
(mg / tablet) % w/w Weight
(mg / tablet) % w/w
Intra-granular portion
Empagliflozin 25.00 6.25 10.00 2.50
Sitagliptin Phosphate Monohydrate 128.50 32.13 128.50 32.13
Colloidal Silicon Dioxide 6.00 1.50 6.00 1.50
Mannitol 96.50 24.13 111.50 27.88
Microcrystalline Cellulose 100.00 25.00 100.00 25.00
Croscarmellose sodium 10.00 2.50 10.00 2.50
Povidone K30 12.00 3.00 12.00 3.00
Extra-granular portion
Croscarmellose sodium 10.00 2.50 10.00 2.50
Colloidal Silicon Dioxide 4.00 1.00 4.00 1.00
Magnesium Stearate 8.00 2.00 8.00 2.00
Weight of Uncoated Tablets 400.00 100.00 400.00 100.00
Anshcoat Aqua coating solution 8.00 - 8.00 -

10. The pharmaceutical composition as claimed in claim 9, wherein the process for preparing the pharmaceutical composition comprises the following steps:
Step-1) blending Sitagliptin phosphate monohydrate with a portion of colloidal silicon dioxide to form Blend-1,
Step-2) dry mixing Empagliflozin, Blend-1 from step 1, mannitol, croscarmellose sodium, and microcrystalline cellulose to obtain Blend-2,
Step-3) granulating Blend-2 obtained in step 2 using a povidone K30 solution in purified water to produce a wet granulated mass,
Step-4) drying the wet granulated mass obtained in step 3,
Step-5) blending the dried granulated mass obtained in step 4 with croscarmellose sodium and colloidal silicon dioxide to form pre-lubricated granules,
Step-6) lubricating the pre-lubricated granules obtained in step 5 with magnesium stearate to obtain lubricated granules,
Step-7) compressing the lubricated granules obtained in step 6 to provide a tablet formulation,
Step-8) optionally, coating the tablet formulation obtained in step 7.

Documents