Pharmaceutical compositions comprising ertugliflozin and metformin

Abstract

The present invention relates to a pharmaceutical composition comprising ertugliflozin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof, method of preparation thereof and its use in the treatment of type 2 diabetes mellitus. The pharmaceutical composition has an intra-granular phase having a granulate moisture content with a specific percentage, which are both present in an intra-granular and an extra-granular phase.

Description

[0001] DESCRIPTION

[0002] PHARMACEUTICAL COMPOSITIONS COMPRISING ERTUGLIFLOZIN AND METFORMIN

[0003] Field of invention

[0004] The present invention relates to a pharmaceutical composition comprising ertugliflozin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof, method of preparation thereof and its use in the treatment of type 2 diabetes mellitus. The pharmaceutical composition has an intra-granular phase having a granulate moisture content with a specific percentage, which are both present in an intra-granular and an extra-granular phase.

[0005] Background of the invention

[0006] Ertugliflozin, represented by structural Formula I and chemically named as (1S,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-l-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1] octane-2, 3, 4-triol, has a molecular weight of 436.9 g / mol.

[0007]

[0008] Formula 1

[0009] Perampanel has white to off-white powder, it does not exhibit stereoisomerism. Ertugliflozin exhibits stereoisomerism due to the presence of five asymmetric centres (1S,2S,3S,4R,5S). Ertugliflozin is very slightly soluble in water and aqueous media over the physiological pH range.

[0010] Metformin, represented by structural Formula 2 and chemically named as 3-(diaminomethylidene)- 1,1 -dimethylguanidine, has a molecular weight of 129.16 g / mol.

[0011]

[0012] Formula 2Metformin is a white, hygroscopiccrystalline powder that is odourless and has a bitter taste. The compound is freely soluble in water, slightly soluble in ethanol and practically insoluble in chloroform, acetone, ether and in ethylene chloride. It has a specific crystalline form and has not demonstrated polymorphism or solvates.

[0013] The brand name of the marketed ertugliflozin & metformin reference product is Segluromet. Segluromet is a trademark of MSD. Segluromet is used for the treatment of type 2 diabetes mellitus in adults.

[0014] Summary of the invention

[0015] The present invention relates to a pharmaceutical composition prepared by wet granulation in the form of tablet having extra-granular phase and intra-granular phase comprising:

[0016] a) ertugliflozin particles having a particle size distribution dw value of less than 150 pm, and larger than 50 pm,

[0017] b) intra-granular phase having a granulate moisture content between 1,5 and 2,5%. To overcome formulation development problems such as tablet hardness or impurity problems, adjustments must be made regarding particle size of active ingredient and granule moisture.

[0018] Detailed description of the invention

[0019] There are formulation development problems related to granule moisture for formulations containing ertugliflozin and metformin compositions. In particular, problems with impurity and stability, as well as failure to take pressure at the targeted hardness, are prominent.

[0020] To overcome above development problems, adjustments must be made regarding particle size of active ingredient and granule moisture.

[0021] Aspects of the present invention relate to particle size distribution of pharmaceutical formulation comprising ertugliflozin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof.

[0022] The present invention relates to the pharmaceutical compositions comprising ertugliflozin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, are prepared by a wet granulation process.

[0023] The present invention relates to the preparation of pharmaceutical compositions comprising ertugliflozin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceuticallyacceptable salt thereof particles having a specific particle size distribution range, wherein process including wet granulation method.

[0024] The present invention relates to the preparation of pharmaceutical compositions comprising ertugliflozin L-pyroglutamic acid and metformin hydrochloride particles having a specific particle size distribution range with relevant excipients, wherein process including wet granulation method.

[0025] The present invention relates to the preparation of pharmaceutical compositions comprising ertugliflozin or a pharmaceutically acceptable salt thereof particles having a particle size distribution with dw value of less than 150 pm, and larger than 50 pm.

[0026] The present invention relates to the preparation of pharmaceutical compositions comprising ertugliflozin or a pharmaceutically acceptable salt thereof particles having a particle size distribution with dw value of less than 150 pm, and larger than 50 pm wherein process including wet granulation method.

[0027] The present invention relates to a pharmaceutical composition prepared by wet granulation in the form of tablet comprising ertugliflozin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof particles, wherein the composition comprises an intra-granular phase and an extra-granular phase.

[0028] The present invention relates to a pharmaceutical composition prepared by wet granulation in the form of tablet comprising ertugliflozin L-pyroglutamic acid and metformin hydrochloride particles, wherein the composition comprises an intra-granular phase and an extra-granular phase.

[0029] The present invention relates to a pharmaceutical composition prepared by wet granulation in the form of tablet having extra-granular phase and intra granular phase comprising:

[0030] metformin, a filler, a binder, a surfactant and a solvent in an intra-granular phase, ertugliflozin, a disintegrant and a lubricant in an extra-granular phase.

[0031] The present invention relates to a pharmaceutical composition prepared by wet granulation in the form of tablet having extra-granular phase and intra granular phase comprising:

[0032] Metformin HCI, microcrystalline cellulose, povidon, sodium lauryl sulphate and purified water in intra-granular phase,Ertugliflozin L-Pyroglutamic acid, crospovidone and magnesium stearate in extra-granular phase.

[0033] The present invention relates to a pharmaceutical composition prepared by wet granulation in the form of tablet having extra-granular phase and intra granular phase comprising:

[0034] a) ertugliflozin or a pharmaceutically acceptable salt thereof particles having a specific particle size distribution with d90 value, and

[0035] b) intra-granular phase having a specific granulate moisture content.

[0036] The present invention relates to a pharmaceutical composition prepared by wet granulation in the form of tablet having extra-granular phase and intra granular phase comprising:

[0037] a) ertugliflozin or a pharmaceutically acceptable salt thereof particles having a particle size distribution with d90 value of less than 150 pm, and larger than 50 pm, and b) intra-granular phase having a granulate moisture content between 1,5 and 2,5%. The term "particle size" as used herein refers to the volume diameter of valsartan particles, as determined by laser light scattering using a Malvern-Mastersizer Apparatus MS 2000.

[0038] Methods of determining the size of particles are well known in the art. For example, Laser Diffraction, Dynamic Light Scattering, Image Particle Analysis, Acoustic Spectroscopy etc. The dxvalue indicates that a certain percentage X of the particles has a size below a certain limit, dw means that 90% of particles (V / V) have a higher volume diameter than the indicated value.

[0039] The particle size distribution (PSD) for active ingredients and related excipients may have high-level effect on final drug product and also manufacturing properties such as stability, dissolution, content uniformity, bioavailability, flowability, blend uniformity, compactibility. It also effective on bioequivalence results. Particle size distribution can effect its product properties such as safety, efficacy, and quality.

[0040] A dw value of less than 10 pm means that 90 % by volume of the particles have a diameter below 10 pm.

[0041] In the present invention the pharmaceutical compositions of ertugliflozin or a pharmaceutically acceptable salt thereof have a particle size such that dgo is 140 pm.

[0042] In the present invention the pharmaceutical compositions of ertugliflozin or a pharmaceutically acceptable salt thereof have a particle size such that dgo is 130 pm.In the present invention the pharmaceutical compositions of ertugliflozin or a pharmaceutically acceptable salt thereof have a particle size such that cbo is 120 pm.

[0043] In the present invention the pharmaceutical compositions of ertugliflozin or a pharmaceutically acceptable salt thereof have a particle size such that cbo is 110 pm.

[0044] In the present invention the pharmaceutical compositions of ertugliflozin or a pharmaceutically acceptable salt thereof have a particle size such that cbo is 100 pm.

[0045] In the present invention the pharmaceutical compositions of ertugliflozin or a pharmaceutically acceptable salt thereof have a particle size such that cbo is 90 pm.

[0046] In the present invention the pharmaceutical compositions of ertugliflozin or a pharmaceutically acceptable salt thereof have a particle size such that cbo is 80 pm.

[0047] In the present invention the pharmaceutical compositions of ertugliflozin or a pharmaceutically acceptable salt thereof have a particle size such that cbo is 70 pm.

[0048] In the present invention the pharmaceutical compositions of ertugliflozin or a pharmaceutically acceptable salt thereof have a particle size such that cbo is 75 pm.

[0049] In the present invention the pharmaceutical compositions of ertugliflozin or a pharmaceutically acceptable salt thereof have a particle size such that cbo is 60 pm.

[0050] In pharmaceutical manufacturing, "granulate moisture" (granule moisture) is a critical parameter, especially in the production of solid dosage forms (tablets, capsules). The moisture content in granules significantly impacts product quality, compressibility, and active ingredient distribution.

[0051] "Granulate moisture" may effect powder flowability, tablet compressibility, tablet hardness and also dissolution rate.

[0052] In process of wet granulation, binders are used to form granule form and moisture content must be carefully regulated.

[0053] "Granulate moisture” can be tested while preparing intra-granular phase in wet granulation process. It is given in Example 1 and Example 2.

[0054] "Granulate moisture" may also effect product stability and shelf life. High moisture levels can lead to hydrolysis of active ingredients or microbial contamination. Maintaining controlled moisture levels extends shelf life and preserves chemical stability. Proper moisture control optimizes the production process and enhances the final product’s performance.The present invention relates to a pharmaceutical composition comprising ertugliflozin, metformin as active ingredient with extra-granular phase and intra granular phase, wherein intra granular phase comprises a specific granulate moisture content.

[0055] The present invention relates to a pharmaceutical composition comprising ertugliflozin, metformin as active ingredient with extra-granular phase and intra granular phase, wherein intra granular phase comprises a granulate moisture content between 1,5 and 2,5%.

[0056] The present invention relates to a pharmaceutical composition comprising ertugliflozin, metformin as active ingredient with extra-granular phase and intra granular phase, wherein intra granular phase comprises a granulate moisture content is 1,6%.

[0057] The present invention relates to a pharmaceutical composition comprising ertugliflozin, metformin as active ingredient with extra-granular phase and intra granular phase, wherein intra granular phase comprises a granulate moisture content is 1,7%.

[0058] The present invention relates to a pharmaceutical composition comprising ertugliflozin, metformin as active ingredient with extra-granular phase and intra granular phase, wherein intra granular phase comprises a granulate moisture content is 1,8%.

[0059] The present invention relates to a pharmaceutical composition comprising ertugliflozin, metformin as active ingredient with extra-granular phase and intra granular phase, wherein intra granular phase comprises a granulate moisture content is 1,9%.

[0060] The present invention relates to a pharmaceutical composition comprising ertugliflozin, metformin as active ingredient with extra-granular phase and intra granular phase, wherein intra granular phase comprises a granulate moisture content is 2,0%.

[0061] The present invention relates to a pharmaceutical composition comprising ertugliflozin, metformin as active ingredient with extra-granular phase and intra granular phase, wherein intra granular phase comprises a granulate moisture content is 2,1%.

[0062] The present invention relates to a pharmaceutical composition comprising ertugliflozin, metformin as active ingredient with extra-granular phase and intra granular phase, wherein intra granular phase comprises a granulate moisture content is 2,2%.

[0063] The present invention relates to a pharmaceutical composition comprising ertugliflozin, metformin as active ingredient with extra-granular phase and intra granular phase, wherein intra granular phase comprises a granulate moisture content is 2,3%.The present invention relates to a pharmaceutical composition comprising ertugliflozin, metformin as active ingredient with extra-granular phase and intra granular phase, wherein intra granular phase comprises a granulate moisture content is 2,4%.

[0064] LOD (Loss on Drying) testing is performed using a Halogen Moisture Analyzer to determine the moisture content in granules. Granulate moisture content is determined as a percentage based on the initial and final weight of the sample by Halogen Moisture Analyzer-Mettler Toledo. This method is crucial in pharmaceutical manufacturing to ensure that the granules have an optimal moisture level for compression and stability.

[0065] LOD (Loss on Drying) testing provides fast, accurate, and reliable moisture analysis, ensuring consistency in tablet production and product stability.

[0066] It is surprisingly found that manufacturability problems are solved at both developing stage and also commercial scale using suitable granulate moisture content. Internal phase of granulate moisture content is critic on this invention. Critic values for granulate moisture content is between 1.5% to 2,5%.

[0067] Granulate moisture content effects tablet hardness, impurity rates and stability values.

[0068] If the internal phase moisture falls below 1.5%, the granules can not have adequate binding properties, leading to insufficient tablet hardness during compression. This can result in fragile or brittle tablets that may break easily.

[0069] Conversely, if the moisture content exceeds 2.5%, there is a higher risk of impurity formation, which can negatively impact the product's quality.

[0070] Additionally, excessive moisture may compromise the stability of the tablets over time, potentially leading to undesirable changes in their physical and chemical properties.

[0071] In one embodiment, the present invention relates to a pharmaceutical composition comprising perampanel and one or more pharmaceutically acceptable excipients.

[0072] In one embodiment, the present invention relates to a pharmaceutical composition comprising ertugliflozin, metformin, filler, binder, surfactant, disintegrant, lubricant and other pharmaceutically acceptable excipients.

[0073] In one embodiment, the present invention relates to a pharmaceutical composition comprising ertugliflozin having a specific particle size distribution range and one or more pharmaceutically acceptable excipients.Particle Size Distribution

[0074] In the pharmaceutical industry, particle size distribution is one of the critical parameter in the manufacturing of pharmaceutical products and directly effects physical properties of the final product such as powder flowability, compressibility, homogeneity etc.

[0075] In this invention, pharmaceutical composition have the particle size distribution as determined on a Malvern Mastersizer 3000.

[0076] Advantages

[0077] In this invention, a pharmaceutical formulation containing perampanel having specific particle size distribution range, it helps to provide a product that has properties such as stability, desired dissolution.

[0078] It is surprisingly found that manufacturability problems are solved at both developing stage and also commercial scale with determined particle size distribution and using a specific granule moisture.

[0079] The pharmaceutical composition according to the present invention has suitable physical and chemical properties with perampanel and also other related raw materials present in the composition. These properties result into the composition being stable and reproducible, without any unwanted interaction with the active ingredient, and it has the desired functionality and its preparation is cost effective.

[0080] The term "treatment" or "treating" means any treatment of a disease or condition in a subject, such as a mammal, including: 1) preventing or protecting against the disease or condition, that is, causing the clinical symptoms not to develop; 2) inhibiting the disease or condition, that is, arresting or suppressing the development of clinical symptoms; and / or 3) relieving the disease or condition that is, causing the regression of clinical symptoms.

[0081] Pharmaceutical composition of the present inventions may comprise one or more pharmaceutically acceptable excipient(s). Pharmaceutically acceptable excipients comprise, but are not limited to, stabilizers, antioxidants, fillers, disintegrants, diluents, binders, lubricants, glidants, masking agents, surfactants, sweeteners, solubilizers, aromatic agents, preservatives, buffering agent, adsorbents, coloring agents, and the like.

[0082] Suitable disintegrants according to the present invention include, but are not limited to, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, polyvinylpyrrolidone, crospovidone, alginic acid, microcrystalline cellulose, hydroxypropylcellulose, low substituted hydroxypropyl cellulose, polacrillin potassium, sodium alginate, sodium starch glycolate, , sodium carboxymethyl starch, and starch. The preferred disintegrants is crospovidone.

[0083] Suitable fillers according to the present invention include, but are not limited to, dibasic calcium phosphate, kaolin, microcrystalline cellulose, lactose, lactose monohydrate, sugars such as dextrose, maltose, saccharose, glucose, fructose or maltodextrine, mannitol, maltitol, sorbitol, xylitol, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate and starch. Fillers which are slightly hygroscopic or non-hygroscopic are preferred, with non-hygroscopic fillers being particularly preferred, in particular when the dosage form is to be used for tropical countries. The preferred filler is microcrystalline cellulose.

[0084] Suitable binders according to the present invention are selected from the group including, but are not limited to, microcrystalline cellulose, starches, lactose, sugar alcohols like mannitol, polyvinylpyrrolidone (Povidone), polyethylene glycol, isomalt, hypromellose (hydroxypropyl methylcellulose) and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred binder is Povidone.

[0085] Suitable surfactants according to the present invention are selected from a group including, but are not limited to, lecithins, sorbitol monooleate, polyoxyethylene stearate, benzalkonium chloride, polysorbates, sorbitan monopalmitate, sodium salts of fatty alcoholsulfates such as sodium lauryl sulfate, sodium dodecyl sulfate, ethoxylated triglycerides and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred surfactant is sodium lauryl sulfate.

[0086] Lubricants can be selected from the group, but are not limited to, magnesium stearate, calcium stearate, aluminium stearate, sodium starch fumarate, sodium lauryl sulphate, sodium stearyl fumarate, hydrogenated vegetable oils, stearic acid, macrogols. A preferred lubricant is magnesium stearate.

[0087] Composition examples

[0088] Example 1

[0089] The unit formula of the Ertugliflozin and Metformin tablet composition (Table 1).

[0090] Table 1 : Ertugliflozin & Metformin Tablet Unit Formula

[0091]

[0092] The process for the preparation of ertugliflozin & metformin pharmaceutical composition according to the comparative example 1 is carried out as specified below:

[0093] 1. Sieving: Metformin HCI and filler are sieved and then mixing.

[0094] 2. Granulation Solution Preparation: Surfactant and binder are mixed in a container. 3. Wet granulation: Using Stage 1 and Stage 2

[0095] 4. Drying. (LOD testing)

[0096] 5. Sieving: Ertugliflozin and disintegrant are sieved.

[0097] 6. Adding lubricant and mixing.

[0098] 7. Final mixing and compressing final powder into tablet with specified punches.

[0099] Example 2

[0100] The unit formula of the Ertugliflozin and Metformin tablet composition (Table 2).

[0101] Table 2: Ertugliflozin & Metformin Tablet Unit Formula

[0102]

[0103] The process for the preparation of ertugliflozin & metformin pharmaceutical composition according to the comparative example 1 is carried out as specified below:

[0104] 1. Sieving: Metformin HCI and microcrystalline cellulose are sieved and then mixing.

[0105] 2. Granulation Solution Preparation: Sodium Lauryl Sulphate and povidone are mixed in a container.

[0106] 3. Wet granulation: Using Stage 1 and Stage 2

[0107] 4. Drying. (LOD testing)

[0108] 5. Sieving: Ertugliflozin and Crospovidone are sieved.

[0109] 6. Adding magnesium sterate and mixing.

[0110] 7. Final mixing and compressing final powder into tablet with specified punches.

[0111] In one embodiment, when we use ertugliflozin D90 value of 30 micron, and granule moisture content is below 1,5% in the pharmaceutical composition comprising ertugliflozin and metformin, the desired hardness and appropriate formulation results such as impurity, stability could not be obtained.

[0112] In one embodiment, when we use ertugliflozin D90 value of 200 micron, and granule moisture content is below 1,5% in the pharmaceutical composition comprising ertugliflozin andmetformin, the desired hardness and appropriate formulation results such as impurity, stability could not be obtained.

[0113] In one embodiment, when we use ertugliflozin D90 value of 100 micron, and granule moisture content is below 1,5% in the pharmaceutical composition comprising ertugliflozin and metformin, the desired hardness and appropriate formulation results such as impurity, stability could not be obtained.

[0114] In one embodiment, when we use ertugliflozin D90 value of 100 micron, and granule moisture content is above 2,5% in the pharmaceutical composition comprising ertugliflozin and metformin, the desired hardness and appropriate formulation results such as impurity, stability could not be obtained.

[0115] In this invention, when we use ertugliflozin D90 value of 75 micron, and granule moisture content is between 1,5-2, 5% in the pharmaceutical composition comprising ertugliflozin and metformin, the desired hardness and appropriate formulation results such as impurity, stability could be obtained.

[0116] In this invention, when we use ertugliflozin D90 value of 100 micron, and granule moisture content is between 1,5-2, 5% in the pharmaceutical composition comprising ertugliflozin and metformin, the desired hardness and appropriate formulation results such as impurity, stability could be obtained.

[0117] Stability data

[0118] Pharmaceutical products comprising ertugliflozin and metformin prepared according to the invention were tested for stability in below storage conditions:

[0119] 25°C ± 2°C / %60 RH ± %5 RH

[0120] 30°C ± 2°C / %65 RH ± %5 RH

[0121] 40°C ± 2°C / %75 RH ± %5 RH

[0122] Result of the stability study indicates that present ertugliflozin and metformin composition in accordance with the present invention exhibits excellent storage stability.

[0123] During the stability period, the product was found to comply with specifications.

Claims

CLAIMS1. A pharmaceutical composition prepared by wet granulation in the form of tablet having extra-granular phase and intra granular phase comprising:a) ertugliflozin particles having a particle size distribution dw value of less than 150 pm, and larger than 50 pm,b) intra-granular phase having a granulate moisture content between 1,5 and 2,5%.

2. A pharmaceutical composition according to claim 1, wherein ertugliflozin particles having a particle size distribution dw value of 75 pm.

3. A pharmaceutical composition according to claim 1, wherein ertugliflozin particles having a particle size distribution dgo value of 100 pm.

4. A pharmaceutical composition according to claim 1, wherein intra-granular phase having a granulate moisture content of 1,8%.

5. A pharmaceutical composition according to claim 1, wherein intra-granular phase having a granulate moisture content of 2,0%.

6. A pharmaceutical composition according to any one of the preceding claims, wherein the composition further comprises a filler, a binder, a surfactant, a disintegrant, a lubricant, and any mixtures thereof.

7. A wet granulation process for preparing a pharmaceutical composition comprising ertugliflozin L-Pyroglutamic acid and metformin HCI, having intra-granular phase and extra-granular phase.

8. A wet granulation process according to Claim 7 comprising the steps of;a. Sieving: Metformin HCI and filler are sieved and then mixing.b. Granulation Solution Preparation: Surfactant and binder are mixed in a container. c. Wet granulation: Using Stage 1 and Stage 2,d. Drying.e. Sieving: Ertugliflozin and disintegrant are sieved.f. Adding lubricant and mixing.g. Final mixing and compressing final powder into tablet with specified punches.

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