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WO2025106049A1 - Composition pharmaceutique comprenant de l'empagliflozine et de la metformine - Google Patents

Composition pharmaceutique comprenant de l'empagliflozine et de la metformine Download PDF

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Publication number
WO2025106049A1
WO2025106049A1 PCT/TR2024/051331 TR2024051331W WO2025106049A1 WO 2025106049 A1 WO2025106049 A1 WO 2025106049A1 TR 2024051331 W TR2024051331 W TR 2024051331W WO 2025106049 A1 WO2025106049 A1 WO 2025106049A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
immediate release
empagliflozin
present
metformin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
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PCT/TR2024/051331
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English (en)
Inventor
Udaya Kumar DUDE
Manas Ranjan Mund
Emre Erol ALDENİZ
Mesut GÜNDAR
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abdi Ibrahim Ilac Sanayi Ve Ticaret AS
Original Assignee
Abdi Ibrahim Ilac Sanayi Ve Ticaret AS
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Priority claimed from TR2023/015093 external-priority patent/TR2023015093A1/tr
Application filed by Abdi Ibrahim Ilac Sanayi Ve Ticaret AS filed Critical Abdi Ibrahim Ilac Sanayi Ve Ticaret AS
Publication of WO2025106049A1 publication Critical patent/WO2025106049A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Definitions

  • the present invention relates to an immediate release monolithic tablet comprising a) granules comprising Metformin or its pharmaceutically acceptable salt, hydroxypropyl cellulose and at least one more pharmaceutically acceptable excipient, and b) powder mixture consisting essentially of Empagliflozin or its pharmaceutically acceptable salts, low substituted hydroxypropyl cellulose and at least one diluent, wherein said immediate release monolithic tablet doesn’t comprise copovidone.
  • the said tablet has a desirable pharmacokinetic characteristic, favorable storage stability and comparative dissolution properties.
  • the invention further relates to a process for the preparation of said pharmaceutical composition and use thereof as medicament in the treatment of diabetes.
  • SGLT2 sodium/glucose co-transporter-2
  • T2DM type 2 diabetes
  • the sodium glucose cotransporter 2 (SGLT-2) is a low-affinity, high-capacity, active sodium glucose symporter expressed at the apical membrane of epithelial cells lining the proximal renal tubule.
  • SLGT-2 is responsible for reabsorbing the majority of the glucose filtered at the glomerulus. In other words, SGLT-2 accounts for about 90 percent of glucose reabsorption into the blood.
  • Empagliflozin is available on the market in the form of a free base and is sold under trade name Jardiance®, as an oral tablet in 10 mg and 25 mg strengths. Further it is available on the market as a combination product with Metformin and a combination product with Linagliptin.
  • Metformin is chemically known as 1 ,1-dimetylbiguanidine hydrochloride, having the following formula (II),
  • Metformin is a biguanide antihyperglycemic agent and first-line pharmacotherapy used in the management of type II diabetes. Metformin improves hyperglycaemia primarily through its suppresion of hepatic glucose production and decreases absorption of glucose from the gastrointestinal tract. Metformin, belonging to the biguanide class, is the first-line drug of choice for the treatment of type 2 diabetes, in particular in overweight and obese people and those with normal kidney function. It is used singly or in combination with sulfonylureas, alpha glucosidase inhibitors, or insulin. Oral doses of metformin are generally recommended in the range of 500 mg to 2500 mg a day and a single dose may vary from 500 mg to 850 mg.
  • the biguanide antihyperglycemic agent metformin is disclosed in US Patent No. 3, 174, 901. Metformin was approved in Canada in 1972 and received subsequent FDA approval in the US in 1995.
  • Synjardy® is indicated for the treatment of adults with type 2 diabetes mellitus as an adjunct to diet and exercise:
  • Synjardy® contains maize starch, copovidone (K-value nominally 28), colloidal anhydrous silica, magnesium stearate, hypromellose, macrogol 400, titanium dioxide (E171), talc, iron oxide yellow (E 172) & iron oxide red (E 172) as excipient.
  • WO 2006/117359 A1 discloses stable a crystalline form of Empagliflozin and a pharmaceutical composition comprising the crystalline form. Additional crystalline forms of Empagliflozin are disclosed in WO 2006/117360 A1 and WO 2011/039107A1.
  • WO 2016169534 A1 discloses novel forms of amorphous Empagliflozin, processes for preparing the same and the use thereof in dosage forms. These solid forms of amorphous Empagliflozin can be advantageously used to increase the chemical and polymorphic stability of amorphous Empagliflozin.
  • EP 2482806 B1 discloses the preparation of a fixed dose combination of Empagliflozin and Metformin with desired QTPP.
  • EP ‘806 several water-soluble polymers including polyvinyl alcohol (PVA), hypromellose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose (MC), povidone (PVP) and copovidone were tested to improve compactability (compression force-crushing strength profile).
  • PVA polyvinyl alcohol
  • HPMC hypromellose
  • HPPC hydroxypropyl cellulose
  • MC methyl cellulose
  • PVP povidone
  • copovidone copovidone
  • the composition comprising the binder povidone and copovidone, in particular copovidone, showed the best powder behavior due to high bulk density and tapped density.
  • the use of hypromellose, hydroxypropyl cellulose or polyvinyl alcohol resulted in granulates, which were not able for tableting due to low bulk density.
  • polyvinyl alcohol was critical with respect to manufacturability, as the risk of blocking during fluid bed granulation process has been strongly increased.
  • the viscosity of HPC & HPMC granulation liquid was rather high compared to copovidone and povidone, which deemed not preferable from the manufacturing process point of view.
  • the viscosity of the copovidone and povidone granulation liquid was comparably low, and the fluid bed granulation process run without any blocking problem.
  • CN 106924237 B discloses a pharmaceutical composition containing Metformin hydrochloride, Empagliflozin, filler, adhesive, glidant & lubricant, wherein the filler is microcrystalline cellulose, and adhesive is copovidone va64, and glidant is silica, lubricant for magnesium stearate; wherein the copovidone va64 is added in the preparation with the concentration of 22-24.8% g/ml.
  • CN 114404436 A discloses a tablet comprising Metformin & Empagliflozin and a preparation method thereof.
  • the said tablet is prepared from the raw materials in parts by mass: 500 parts of Metformin hydrochloride, 5 parts of Empagliflozin, 30.13 parts of com starch, 47.2 parts of povidone, 2.95 parts of colloidal silicon dioxide, 4.72 parts of magnesium stearate and 29.5 parts of film coating premix.
  • CN 114848604 A discloses a composition comprising Empagliflozin granules and Metformin hydrochloride granules; the Empagliflozin granules comprise Empagliflozin, polacrilin potassium, maltose-cyclodextrin, a disintegrating agent and a binding agent; the Metformin hydrochloride granules comprise Metformin hydrochloride, a diluent, a disintegrant and a binder; wherein the particle size d0.9 of the Empagliflozin is not more than 30 micron.
  • CN 115154456 A discloses a preparation method of a pharmaceutical composition of Metformin and Empagliflozin, which comprises the following steps: S1 ) mixing part of the adhesive with water to obtain an adhesive aqueous solution; mixing the adhesive aqueous solution with the Empagliflozin to obtain a suspension; mixing Metformin and/or Metformin salt, a filler and the rest of the binder to obtain a dry mixture; and S2) mixing the dry mixture and the suspension, granulating, and drying to obtain the pharmaceutical composition of the Metformin and the Empagliflozin.
  • a pharmaceutical composition comprising immediate release of Empagliflozin or its pharmaceutically acceptable salt and Metformin or its pharmaceutically acceptable salt, which is physically and chemically stable, showing favorable dissolution profile, having easy to scale up, suitable on a commercial scale and allows an effective production with regard to time and costs of pharmaceutical dosage forms.
  • the inventors of the present invention have surprisingly developed a stable pharmaceutical composition comprising Empagliflozin or its pharmaceutically acceptable salt and Metformin or its pharmaceutically acceptable salt without using copovidone and without facing any manufacturing and tableting problems of prior art. Also, inventors have found simple manufacturing process to save time and cost to produce monolithic tablet of Metformin and Empagliflozin.
  • the composition of the present invention is not only stable but also exhibits a similar dissolution profile when compared to the reference product Synjardy® tablet.
  • An object of the present invention is to provide an immediate release monolithic tablet comprising Empagliflozin or its pharmaceutically acceptable salt and Metformin or its pharmaceutically acceptable salt having similar in-vitro and in-vivo profile to the reference product i.e., Synjardy® tablet.
  • Another object of the present invention is to provide an immediate release monolithic tablet comprising Empagliflozin or its pharmaceutically acceptable salt and Metformin or its pharmaceutically acceptable salt, which has desired content uniformity for both the active ingredients.
  • Another object of the present invention is to provide an immediate release monolithic tablet comprising Empagliflozin or its pharmaceutically acceptable salt and Metformin or its pharmaceutically acceptable salt, which allows an effective commercial scale manufacturing with regard to time and costs of pharmaceutical dosage forms.
  • Another object of the present invention is to provide an immediate release monolithic tablet comprising Empagliflozin or its pharmaceutically acceptable salt and Metformin or its pharmaceutically acceptable salt, which reduces sticking and capping during the production process of the composition.
  • Yet another object of the present invention is to provide an immediate release monolithic tablet comprising Empagliflozin or its pharmaceutically acceptable salt and Metformin or its pharmaceutically acceptable salt with simple and robust process.
  • Yet another object of the present invention is to provide an immediate release monolithic tablet comprising Empagliflozin or its pharmaceutically acceptable salt and Metformin or its pharmaceutically acceptable salt, which remains stable during manufacturing and stability.
  • Yet another object of the present invention is to provide an immediate release monolithic tablet comprising Empagliflozin or its pharmaceutically acceptable salt and Metformin or its pharmaceutically acceptable salt, which overcomes the problems of the prior art.
  • Yet another object of the present invention is to provide a pharmaceutical composition as mentioned herein above in combination with one or more additional therapeutic agent.
  • Yet another object of the present invention is to provide a pharmaceutical composition as mentioned herein above in combination with Linagliptin.
  • the present invention provides an immediate release monolithic tablet comprising: a) granules comprising Metformin or its pharmaceutically acceptable salt, hydroxypropyl cellulose and at least one more pharmaceutically acceptable excipient, and b) powder mixture consisting essentially of Empagliflozin or its pharmaceutically acceptable salts, low substituted hydroxypropyl cellulose and at least one diluent, wherein said immediate release monolithic tablet doesn’t comprise copovidone.
  • the present invention provides an immediate release monolithic tablet comprising: a) granules comprising Metformin or its pharmaceutically acceptable salt, hydroxypropyl cellulose and at least one more pharmaceutically acceptable excipient, and b) powder mixture consisting essentially of Empagliflozin or its pharmaceutically acceptable salts, low substituted hydroxypropyl cellulose and at least one diluent, wherein said immediate release monolithic tablet doesn’t comprise copovidone and wherein Empagliflozin or its pharmaceutically acceptable salt is present in amount of about from 0.1 % to 8 % by weight based on the total weight of the tablet.
  • the present invention provides an immediate release monolithic tablet comprising: a) granules comprising Metformin or its pharmaceutically acceptable salt, hydroxypropyl cellulose and at least one more pharmaceutically acceptable excipient, and b) powder mixture consisting essentially of Empagliflozin or its pharmaceutically acceptable salts, low substituted hydroxypropyl cellulose and at least one diluent, wherein said immediate release monolithic tablet doesn’t comprise copovidone and wherein Metformin or its pharmaceutically acceptable salt is present in amount of about from 40 % to 90 % by weight based on the total weight of the tablet.
  • the present invention provides an immediate release monolithic tablet comprising: a) granules comprising Metformin or its pharmaceutically acceptable salt, hydroxypropyl cellulose and at least one more pharmaceutically acceptable excipient, and b) powder mixture consisting essentially of Empagliflozin or its pharmaceutically acceptable salts, low substituted hydroxypropyl cellulose and at least one diluent, wherein said immediate release monolithic tablet doesn’t comprise copovidone and wherein hydroxypropyl cellulose is present in amount of about from 2 % to 10 % by weight based on the total weight of the tablet.
  • the present invention provides an immediate release monolithic tablet comprising: a) granules comprising Metformin or its pharmaceutically acceptable salt, hydroxypropyl cellulose and at least one more pharmaceutically acceptable excipient, and b) powder mixture consisting essentially of Empagliflozin or its pharmaceutically acceptable salts, low substituted hydroxypropyl cellulose and at least one diluent, wherein said immediate release monolithic tablet doesn’t comprise copovidone and wherein low substituted hydroxypropyl cellulose is present in amount of about from 0.05 % to 5 % by weight based on the total weight of the tablet.
  • the present invention provides an immediate release monolithic tablet comprising: a) granules comprising Metformin or its pharmaceutically acceptable salt, hydroxypropyl cellulose and at least one more pharmaceutically acceptable excipient, and b) powder mixture consisting essentially of Empagliflozin or its pharmaceutically acceptable salts, low substituted hydroxypropyl cellulose and at least one diluent, wherein said immediate release monolithic tablet doesn’t comprise copovidone and wherein Metformin or its pharmaceutically acceptable salt is present in amount of about from 40 % to 90 % and hydroxypropyl cellulose is present in amount of about from 2 % to 10 % by weight based on the total weight of the tablet.
  • the present invention provides an immediate release monolithic tablet comprising: a) granules comprising Metformin or its pharmaceutically acceptable salt, hydroxypropyl cellulose and at least one more pharmaceutically acceptable excipient, and b) powder mixture consisting essentially of Empagliflozin or its pharmaceutically acceptable salts, low substituted hydroxypropyl cellulose and at least one diluent, wherein said immediate release monolithic tablet doesn’t comprise copovidone and wherein Empagliflozin or its pharmaceutically acceptable salt is present in amount of about from 0.1 % to 8 % and low substituted hydroxypropyl cellulose is present in amount of about from 0.05 % to 5 % by weight based on the total weight of the tablet.
  • the present invention provides an immediate release monolithic tablet comprising: a) granules comprising Metformin or its pharmaceutically acceptable salt, hydroxypropyl cellulose and at least one more pharmaceutically acceptable excipient, and b) powder mixture consisting essentially of Empagliflozin or its pharmaceutically acceptable salts, low substituted hydroxypropyl cellulose and at least one diluent, wherein said immediate release monolithic tablet doesn’t comprise copovidone, and wherein Metformin or its pharmaceutically acceptable salt is present in amount of about from 40 % to 90 %; hydroxypropyl cellulose is present in amount of about from 2 % to 10 %; Empagliflozin or its pharmaceutically acceptable salt is present in amount of about from 0.1 % to 8 % and low substituted hydroxypropyl cellulose is present in amount of about from 0.05 % to 5 % by weight based on the total weight of the tablet.
  • the present invention provides an immediate release monolithic tablet comprising: a) granules comprising i) about 40 wt% to 90 wt% of Metformin or its pharmaceutically acceptable salt, ii) about 2 wt% to 10 wt% of hydroxypropyl cellulose, iii) about 1 wt% to 8 wt% of at least one more pharmaceutically acceptable excipient, b) powder mixture consisting essentially of i) about 0.1 wt% to 8 wt% of Empagliflozin or its pharmaceutically acceptable salt, ii) about 0.05 wt% to 5 wt% of low substituted hydroxypropyl cellulose, iii) about 5 wt% to 15 wt% of at least one diluent, c) about 0 wt% to 5 wt% of one or more of disintegrants, d) about 0 wt% to 3 wt% of one or more glidant,
  • Empagliflozin is present in crystalline or amorphous form.
  • a manufacturing process of the present invention comprises simple mixing of Metformin granules and powder mixture of Empagliflozin. In another aspect, the manufacturing process of the present invention comprises simple mixing of wet granulated granules of Metformin and powder mixture of Empagliflozin.
  • the present invention provides a pharmaceutical composition of any of the above aspects, wherein the said composition remains stable after storage for at least 3 months at 40°C and 75% relative humidity (RH).
  • the present invention provides a pharmaceutical composition as mentioned herein above in combination with one or more additional therapeutic agent.
  • the present invention provides a pharmaceutical composition as mentioned herein above in combination with Linagliptin.
  • the present invention discloses a use of such pharmaceutical composition as medicament in the treatment of diabetes.
  • Figure-1 Graph showing the in vivo results of Empagliflozin of example-1 vis-a-vis reference drug in fasting condition (Synjardy®)
  • Figure-2 Graph showing the in vivo results of Metformin of example-1 vis-a-vis reference drug in fasting condition (Synjardy®)
  • %, wt% used in this specification means the percentage by weight unless otherwise stipulated.
  • Empagliflozin ' as used in the present invention includes, but is not limited to, Empagliflozin per se, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, and pharmaceutically acceptable prodrugs thereof, and also its various crystalline and amorphous forms.
  • Metformin ' as used in the present invention includes, but is not limited to, Metformin per se, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, and pharmaceutically acceptable prodrugs thereof, and also its various crystalline and amorphous forms.
  • similarity factor refers to one way of comparing dissolution profiles of two different products (Multisource Pharmaceutical Products: Guidelines on Registration Requirements to establish Interchangeability, Quality Assurance and Safety: Medicines, Essential Drugs and Medicines Policy, World Health Organization, 1211 Geneva 27, Switzerland).
  • This model independent mathematical approach compares the dissolution profile of the two products: test and reference (or two strengths, or pre- and post-approved products from the same manufacturer). Tests are recommended to be performed under the same test conditions.
  • the dissolution time points for both the profiles should be the same, for example for immediate release products e.g., 10, 15, 30, 45, 60 minutes and for extended release products, e.g., 1 , 2, 3, 5 and 8 hours.
  • powder mixture refers to two or more powders, in other words, the mass of two or more solid species including active ingredient and one or more pharmaceutically acceptable excipient.
  • the powder mixture of the present invention is obtained by simply mixing process i.e. without using any dry or wet granulation process.
  • two or more different powders or solid species may be homogeneously dispersed or may be present in an in homogeneous state.
  • a present invention provides an immediate release monolithic tablet comprising: a) granules comprising Metformin or its pharmaceutically acceptable salt, hydroxypropyl cellulose and at least one more pharmaceutically acceptable excipient, and b) powder mixture consisting essentially of Empagliflozin or its pharmaceutically acceptable salts, low substituted hydroxypropyl cellulose and at least one diluent, wherein said immediate release monolithic tablet doesn’t comprise copovidone.
  • a composition of the present invention comprises active ingredient Metformin or its pharmaceutically acceptable salt in the amount about from 40 wt% to 90 wt% based on the total weight of the tablet. In one embodiment, a composition of the present invention comprises active ingredient Empagliflozin or its pharmaceutically acceptable salt in the amount about from 0.1 wt% to 8 wt% based on the total weight of the tablet.
  • a composition of the present invention comprises hydroxypropyl cellulose in amount about from 2 wt% to 10 wt% based on the total weight of the tablet.
  • a composition of the present invention comprises low substituted hydroxypropyl cellulose in amount about from 0.05 wt% to 5 wt% based on the total weight of the tablet.
  • a manufacturing process of the present invention comprises simple mixing of Metformin granules and powder mixture of Empagliflozin.
  • the manufacturing process of the present invention comprises simple mixing of wet granulated granules of Metformin and powder mixture of Empagliflozin.
  • an immediate release monolithic tablet of the present invention further comprises one or more pharmaceutically acceptable excipients.
  • the excipients to be used in accordance with the present invention are well known and are those excipients which are conventionally used by the person skilled in the art. Depending on the dosage form chosen for the pharmaceutical composition, the person skilled in the art will be able to select suitable pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipient can be selected from diluent, disintegrant, lubricant and glidant.
  • Diluent includes, but are not limited to, lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, pregelatinized starch, dextrates, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, and mixtures thereof.
  • the total amount of diluent is preferably from about 1 wt% to 30 wt%, more preferably from about 2 wt% to 20 wt% based on the total weight of the tablet.
  • the amount of diluent used in granules of Metformin or its pharmaceutically acceptable salt is preferably from about 0.1 wt% to 10 wt%, more preferably from about 1 wt% to 8 wt% based on the total weight of the tablet.
  • the amount of diluent used in powder mixture of Empagliflozin or its pharmaceutically acceptable salt is preferably from about 1 wt% to 20 wt%, more preferably from about 5 wt% to 15 wt% based on the total weight of the tablet.
  • Preferable diluent is microcrystalline cellulose, pregelatinized starch or mixture thereof.
  • Disintegrant includes, but are not limited to, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, starch, sodium alginate and mixtures thereof.
  • the amount of the disintegrant used in the present invention is preferably from about 0 wt% to 5 wt%, more preferably from about 0.5 wt% to 3 wt% based on the total weight of the tablet.
  • Lubricant/glidants includes, but are not limited to, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, com starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, waxes, DL-leucine, sodium lauryl sulfate, magnesium lauryl sulfate, colloidal silicon dioxide and mixtures thereof.
  • the amount of the glidant used in the present invention is preferably from about 0 wt% to about 3 wt%, more preferably from about 0.2 wt% to 1 wt% based on the total weight of the tablet.
  • the amount of the lubricant used in the present invention is preferably from about 0.1 wt% to about 5 wt%, more preferably from about 0.2 wt% to about 3 wt% based on the total weight of the tablet.
  • the metformin granules of the present invention can be obtained by using known conventional methods i.e. wet granulation or dry granulation.
  • the process to obtain the said granules includes, but is not limited to, wet granulation, fluid bed granulation, spray drying, or dry granulation, slugging & roller compaction.
  • solvent optionally contains binder, wherein solvent includes, but is not limited to, purified water, ethanol, methanol, isopropanol, acetone, N, N-dimethylformamide etc.
  • the powder mixture of Empagliflozin of the present invention can be obtained by simple mixing of Empagliflozin or its pharmaceutically acceptable salt, low-substituted hydroxypropyl cellulose and at least one diluent in suitable equipment until homogeneous blend obtained.
  • the immediate release monolithic tablet of the present invention can be obtained mixing a) granules comprising Metformin or its pharmaceutically acceptable salt, hydroxypropyl cellulose and at least one more pharmaceutically acceptable excipient, and b) powder mixture consisting essentially of Empagliflozin or its pharmaceutically acceptable salt, low substituted hydroxypropyl cellulose and at least one diluent.
  • the obtained final blend of both the active ingredients is further mixed with disintegrant, lubricant and glidant and then compressed into tablet.
  • the pharmaceutical composition of the present invention may further be coated with a film- forming polymer and one or more pharmaceutically acceptable excipients, using techniques well known in the art e.g., spray coating in a conventional coating pan, or a fluidized bed processor, or dip coating. Alternatively, coating can also be performed using a hot melt technique.
  • the film coating may contain one or more film-forming polymers, and optionally one or more pharmaceutically acceptable excipients.
  • a suitable film-forming polymer is selected from the group comprising hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose phthalate, cellulose acetate trimellitate, methacrylic acid copolymers e.g., Eudragit®, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, or mixtures thereof.
  • a preferred film forming polymer is hydroxypropyl methyl cellulose.
  • Other suitable film forming polymers which are known in art may also be used.
  • the film coating may also contain opacifiers like titanium dioxide, flow aids like talc and pigment like iron oxide yellow.
  • the pharmaceutical composition in accordance with the present invention may be used as a medicament for the treatment of diabetes.
  • the pharmaceutical composition of the present invention may be used in combination with one or more other types of antidiabetic agents and/or one or more other types of therapeutic agents which may be administered orally in the same dosage form, in a separate oral dosage form or by injection.
  • the other type of antidiabetic agent which may be optionally employed in combination with the pharmaceutical composition of the present invention may be one or more antidiabetic agents or antihyperglycemic agents including insulin secretagogues or insulin sensitizers, biguanides, sulfonylureas, glucosidase inhibitors, PPAR y agonists such as thiazolidinediones, aP2 inhibitors, PPAR a/y dual agonists, dipeptidyl peptidase IV (DPP4) inhibitors such as sitagliptin or linagliptin, and/or meglitinides, as well as insulin, glucagon-like peptide-1 (GLP-1), PTP1 B inhibitors, glycogen
  • composition of the present invention is very suitable for production on commercial scale making use of equipment and techniques commonly used in industry.
  • Metformin hydrochloride and pregelatinized starch were sieved through a suitable mesh size.
  • Hydroxypropyl cellulose was dissolved in the required amount of purified water.
  • step 4 Obtained granules of step 4 were dried and sieved through a suitable mesh size.
  • step 8 Magnesium stearate was sieved through a suitable mesh and added into the blend of step 7 and mixed. 9. The obtained blend of step 8 was compressed into tablets.
  • step 9 The obtained tablets of step 9 were loaded into coating pan and the coating solution of step 10 was sprayed on to core tablets until the target film tablet weight is reached.
  • Example 2 Preparation of monolithic tablet containing granules of Empagliflozin & granules of Metformin hydrochloride
  • step 2 The blend of step 1 was granulated with purified water and obtained granules were dried by using fluid bed granulator and sieved through a suitable mesh size.
  • Metformin hydrochloride and pregelatinized starch were sieved through a suitable mesh size.
  • Hydroxypropyl cellulose was dissolved in the required amount of purified water.
  • step 3 was loaded into fluid bed granulator and was granulated with binder solution of step 4.
  • step 5 The granules of step 5 were dried and sieved through a suitable mesh size.
  • step 9 The obtained blend of step 9 was compressed into tablets.
  • step 10 The obtained tablets of step 10 were loaded into coating pan and the coating solution of step 11 was sprayed on to core tablets until the target film tablet weight is reached.
  • Metformin hydrochloride and pregelatinized starch were sieved through a suitable mesh size.
  • Hydroxypropyl cellulose was dissolved in the required amount of purified water.
  • step 4 Obtained granules of step 4 were dried and sieved through a suitable mesh size.
  • step 8 Magnesium stearate was sieved through a suitable mesh and added into the blend of step 7 and mixed. 9. The obtained blend of step 8 was compressed into tablets.
  • step 9 The obtained tablets of step 9 were loaded into coating pan and the coating solution of step 10 was sprayed on to core tablets until the target film tablet weight is reached.
  • Example 4 Empagliflozin’s Dissolution Data of Example-1, Example-2 & Example- 3
  • Example 5 Metformin’s Dissolution Data of Example 1, Example 2 & Example 3 Table-5
  • the drug release was determined by using an HPLC method. From the above dissolution data given in table-5, it is evident that f2 is more than 50 or more than 85% of drug released within 15 minutes establishes sameness or equivalence of both products i.e. test products (of Example-1 , 2 & 3) and reference product in terms of its dissolution and performance.
  • Example 6 In vivo analysis of Example-1 and Reference Product (Synjardy®) in fasting condition Empagliflozin and Metformin film coated tablets of Example-1 were compared with the reference product Synjardy® film coated tablet under fasting conditions. In vivo analysis of Empagliflozin of Example-1 (Ex.-1) tablets and reference product Synjardy® tablets were given in Table-6. In vivo analysis of Metformin of Example-1 (Ex.-1) tablets and reference product Synjardy® tablets were given in Table-7.
  • Example 7 Stability Result of Empagliflozin & Metformin composition prepared according to Example 1
  • Example-1 The tablets prepared in Example-1 , were placed in PVC/ aluminum blisters, and stored for 3 months under conditions of 40°C/75% RH. 3 month stability result is presented herein below Table-8.

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Abstract

La présente invention concerne un comprimé monolithique à libération immédiate comprenant a) des granules comprenant de la metformine ou son sel pharmaceutiquement acceptable, de l'hydroxypropylcellulose et au moins un excipient plus pharmaceutiquement acceptable, et b) un mélange de poudres constitué essentiellement d'empagliflozine ou de ses sels pharmaceutiquement acceptables, d'hydroxypropylcellulose faiblement substituée et d'au moins un diluant, ledit comprimé monolithique à libération immédiate ne comprenant pas de copovidone. Ledit comprimé présente une caractéristique pharmacocinétique souhaitable, une stabilité au stockage favorable et des propriétés de dissolution comparatives. L'invention concerne en outre un processus de préparation de ladite composition pharmaceutique et son utilisation en tant que médicament dans le traitement des diabètes.
PCT/TR2024/051331 2023-11-15 2024-11-13 Composition pharmaceutique comprenant de l'empagliflozine et de la metformine Pending WO2025106049A1 (fr)

Applications Claiming Priority (2)

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TR2023/015093 TR2023015093A1 (tr) 2023-11-15 Empagliflozin ve metformin içeren farmasötik bir bileşim.
TR2023015093 2023-11-15

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WO2025106049A1 true WO2025106049A1 (fr) 2025-05-22

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180344647A1 (en) * 2015-12-04 2018-12-06 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
CN113616624A (zh) * 2021-09-16 2021-11-09 南京康川济医药科技有限公司 一种恩格列净二甲双胍缓释制剂及其制备方法
KR20230001000A (ko) * 2021-06-25 2023-01-03 (주)휴온스 약물방출 특성이 개선된 엠파글리플로진 및 메트포르민 복합제제

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180344647A1 (en) * 2015-12-04 2018-12-06 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
KR20230001000A (ko) * 2021-06-25 2023-01-03 (주)휴온스 약물방출 특성이 개선된 엠파글리플로진 및 메트포르민 복합제제
CN113616624A (zh) * 2021-09-16 2021-11-09 南京康川济医药科技有限公司 一种恩格列净二甲双胍缓释制剂及其制备方法

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