EP4103157A1 - Composition pharmaceutique contenant de la linagliptine et de la metformine - Google Patents

Composition pharmaceutique contenant de la linagliptine et de la metformine

Info

Publication number
EP4103157A1
EP4103157A1 EP21705444.4A EP21705444A EP4103157A1 EP 4103157 A1 EP4103157 A1 EP 4103157A1 EP 21705444 A EP21705444 A EP 21705444A EP 4103157 A1 EP4103157 A1 EP 4103157A1
Authority
EP
European Patent Office
Prior art keywords
metformin
linagliptin
dosage form
pharmaceutically acceptable
granule
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
Application number
EP21705444.4A
Other languages
German (de)
English (en)
Inventor
Tomasz KRUSI SKI
Szymon Przerada
Julia Hrakovsky
Przemys aw SKOCZE
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.)
Zaklady Farmaceutyczne Polpharma SA
Original Assignee
Zaklady Farmaceutyczne Polpharma SA
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Zaklady Farmaceutyczne Polpharma SA filed Critical Zaklady Farmaceutyczne Polpharma SA
Publication of EP4103157A1 publication Critical patent/EP4103157A1/fr
Pending legal-status Critical Current

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Classifications

    • 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
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K31/133—Amines having hydroxy groups, e.g. sphingosine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the combination of linagliptin and metformin as active ingredients.
  • linagliptin and metformin are well-established therapeutic strategy, which is effective and well-tolerated (Haak T, Initial combination with linagliptin and metformin in newly diagnosed type 2 diabetes and severe hyperglycemia, Adv. Ther., 2012, 29 (12), 1005-15).
  • Linagliptin is a selective, orally administered, xanthine-based inhibitor of dipeptidylpeptidase-4 (DPP-4) which is used for the treatment of type 2 diabetes.
  • DPP- 4 inhibitors are antidiabetic agents that lower blood glucose by extending the short half- life of the incretin hormones GLP-1 and GIP (glucagon-like peptide-1 , glucose- dependent insulinotropic polypeptide).
  • Metformin belongs to the class of drugs called biguanides and is also used to treat type 2 diabetes.
  • a convenient way for the combined administration of linagliptin and metformin is by using a fixed-dose combination of both drugs (Koliaki et al., Linagliptin/metformin fixed-dosed combination treatment: a dual attack to type 2 diabetes pathophysiology, Adv. Ther., 2012, 29 (12), 993-1004/
  • Jentadueto ® provides a fixed-dose combination of linagliptin and metformin hydrochloride and is available in the 2.5 mg/500 mg, 2.5 mg/850 mg and 2.5 mg/1000 mg strengths.
  • Jentadueto ® is in the form of film-coated tablets, which comprise arginine, copovidone, magnesium stearate, maize starch and silica colloidal anhydrous as excipients in the tablet core.
  • the film coating contains hypromellose, titanium dioxide, talc, red iron oxide and propylene glycol.
  • the international patent application WO2009/121945-A2 discloses fixed dose combinations of a DPP-4 inhibitor and a partner drug, for example metformin. It is disclosed that the preparation of pharmaceutical compositions comprising such combination may entail difficulties due to interactions between the DPP-4 inhibitor and the partner drug and/or excipients, and that such problems can be overcome by including a stabilizing agent to the composition, which can be a nucleophilic and/or basic agent.
  • a preferred stabilizing agent is L-arginine.
  • the preparation of 2.5/500 mg, 2.5/850 mg and 2.5/1000 mg strength mono-layer tablets comprising linagliptin, metformin hydrochloride, L-arginine, a filler (corn starch), a binder (copovidone), a glidant (colloidal anhydrous silica) and a lubricant (magnesium stearate) in the core, and a film coat comprising hypromellose, propylene glycol, talc, titanium dioxide, iron oxide yellow and iron oxide red.
  • the tablets are produced by conventional fluid-bed granulation of all core ingredients, except the glidant and the lubricant, which are added extra-granularly, and subsequent conventional compressing and film-coating.
  • the bi-layer and tablet-in tablet formulations involve the preparation of separate linagliptin granules (comprising arginine as stabilizing agent) and metformin granules.
  • the international patent application W02014/080383-A1 also discloses fixed- dose combination formulations comprising a DPP-4 inhibitor and an additional antidiabetic agent, preferably the combination of linagliptin and metformin.
  • the formulations are in the form of monolayer, bilayer or trilayer tablets and comprise an alkalinizing agent as stabilizer, which is not a basic amino acid.
  • alkalinizing agents are cited, and meglumine is said to be preferred.
  • Examples 1 and 4 disclose mono-layer tablets made of single granules comprising metformin, linagliptin together with the alkalinizing agent, which are subsequently mixed with extragranular ingredients (glidant, optionally disintegrant, and lubricant) and compressed.
  • Another option for preparing mono-layer tablets is disclosed in Example 6, wherein two different granules, one with linagliptin and one with metformin, are prepared, and the alkalinizing agent (meglumine) is added extragranularly.
  • Bilayer- tablets are disclosed in Example 2, wherein each layer is made of different kind of granules; the linagliptin layer comprises granules containing linagliptin and the alkalinizing agent, while the metformin layer comprises metformin granules which do not contain alkalinizing agent.
  • Tri-layer tablets are similarly disclosed in Example 3, comprising an additional intermediate layer made of a mixture of a diluents, a disintegrant and a lubricant.
  • the Chinese patent application CN104840960-A discloses pharmaceutical compositions comprising linagliptin and metformin hydrochloride, further comprising meglumine as stabilizer.
  • compositions disclosed are prepared by combining a first granule comprising linagliptin, meglumine as stabilizer, and a pharmaceutically acceptable excipient, and a second granule comprising metformin hydrochloride and a pharmaceutically acceptable excipient. Both granules are mixed, optionally with extragranular glidant and/or lubricant, compressed to form a tablet, and optionally film- coated.
  • the object of the present invention is an oral pharmaceutical dosage form comprising linagliptin and metformin.
  • Another aspect of the invention is a process for the preparation of such pharmaceutical dosage form.
  • Another aspect of the invention is the combined pharmaceutical dosage form for use in the treatment of type 2 diabetes mellitus.
  • the object of the present invention is an oral pharmaceutical dosage form comprising linagliptin and metformin, characterized in that it comprises: a) a first type of granule comprising linagliptin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient; and b) a second type of granule comprising metformin or a pharmaceutically acceptable salt thereof and meglumine.
  • the authors of the present invention have developed a pharmaceutical composition comprising linagliptin and metformin and comprising meglumine as stabilizing agent, made of separate granules for each active ingredient and wherein meglumine is included within the metformin granules. Surprisingly, it was found that the formulation was outstandingly stable despite the fact that meglumine was combined with metformin, rather than with linagliptin.
  • the amount (as weight, typically in mg) of linagliptin or a pharmaceutically acceptable salt thereof in the dosage form is always expressed as the equivalent weight of linagliptin free base, regardless of the form used, i.e., the linagliptin free base or a pharmaceutically acceptable salt.
  • the “equivalent amount”, as is well-known in the art, means the weight of linagliptin free base which is the equimolar amount of the actual linagliptin form used.
  • the amount (as weight, typically in mg) of metformin or a pharmaceutically acceptable salt thereof in the dosage form is always expressed as the equivalent weight of metformin hydrochloride regardless of the form used, i.e., the metformin free base, the hydrochloride salt or another pharmaceutically acceptable salt.
  • the “equivalent amount”, as is well-known in the art, means the weight of metformin hydrochloride which is the equimolar amount of the actual metformin form used.
  • the pharmaceutical dosage form of the present invention comprises a first type of granule (the linagliptin granule) comprising linagliptin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
  • Linagliptin is the International Nonproprietary Name (INN) to designate the substance 8-[(3f?)-3-aminopiperidin-1 -yl]-7-(but-2-yn-1 -yl)-3-methyl1 -[(4-methyl quinazolin-2-yl)methyl]-3,7-dihydro-1 /-/-purine-2, 6-dione (CAS 668270-12-0).
  • Linagliptin is a potent, selective, orally active, competitive, reversible and long- acting inhibitor of dipeptidyl-peptidase-4 (DPP-4) which is used to improve glycaemic control in adults with type 2 diabetes mellitus.
  • DPP-4 dipeptidyl-peptidase-4
  • Linagliptin can be used as such, i.e., as the free base, or may be in the form of a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salts of linagliptin include nontoxic acid addition salts, for example, with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, salicylic acid, tartaric acid, glutamic acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, among others.
  • linagliptin is used as such, i.e., as the free base, rather than as a pharmaceutically acceptable salt thereof.
  • linagliptin and the pharmaceutically acceptable salts thereof are meant to include also hydrates and solvates thereof.
  • linagliptin or a pharmaceutically acceptable salt thereof is used as a non-hydrated, non-solvated form.
  • the non-hydrated, non-solvated, free base form of linagliptin is used.
  • Linagliptin and the pharmaceutically acceptable salts thereof include any crystalline or amorphous form thereof.
  • linagliptin or a pharmaceutically acceptable salt thereof is in crystalline form.
  • linagliptin or a pharmaceutically acceptable salt thereof is in micronized form.
  • it may typically have a particle size volume distribution wherein D 90 is not more than 250 pm, preferably wherein D 90 is not more than 150 pm, and more preferably wherein D 90 is not more than 85 pm.
  • Said particle size distribution may be determined, for example, by laser diffraction (Malvern, Mastersizer 2000 and Malvern, Mastersizer 3000 and sample prepared by wet dispersion).
  • the content of linagliptin or a pharmaceutically acceptable salt thereof in the linagliptin granule is generally in the range 1-10 wt%, preferably in the range 2-8 wt%, and more preferably in the range 3-6 wt%, referred to the total weight of the linagliptin granule.
  • Granules as is well known in pharmaceutical technology, comprise powder particles that have been aggregated to form larger particles.
  • granulation is the process in which dry primary powder particles are processed to adhere to form larger multiparticle entities called granules.
  • the size of the linagliptin granule is not critical; for example, the size of the granule may be comprised between 0.05 mm and 2.0 mm, or preferably comprised between 0.05 mm and 1 .0 mm.
  • the granules may be prepared by conventional processes, typically by dry granulation or by wet granulation.
  • the linagliptin granules typically contain linagliptin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient can be selected, for example, from a filler, a binder, a disintegrant, and mixtures thereof.
  • the linagliptin granule comprises linagliptin or a pharmaceutically acceptable salt thereof and a filler.
  • a filler or diluent is a pharmaceutical excipient generally used to increase the bulk volume of the formulation.
  • the filler can be selected, for example, from calcium carbonate, calcium lactate, calcium phosphate dibasic, calcium phosphate tribasic, calcium silicate, calcium sulfate, microcrystalline cellulose, powdered cellulose, cellulose acetate, corn starch, pregelatinized starch, dextrin, dextrose, fructose, lactitol, lactose, maltodextrin, maltose, mannitol, sorbitol, sucrose, trehalose and xylitol, among others, and mixtures thereof.
  • the filler is selected from dextrose, mannitol, sorbitol, xylitol and mixtures thereof.
  • the filler is mannitol.
  • the content of filler in the linagliptin granule is generally in the range 75-98 wt%, preferably in the range 80-95 wt%, more preferably in the range 85-93 wt%, and more preferably is about 90 wt%, referred to the total weight of the linagliptin granule.
  • the linagliptin granule comprises linagliptin or a pharmaceutically acceptable salt thereof and a binder.
  • a binder is a pharmaceutical excipient generally used to adhere the powders forming the granule, to facilitate the granule formation.
  • the binder can be selected, for example, from acacia, agar, alginic acid, carbomers, carrageenan, chitosan, copovidone, starch, pregelatinized starch, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glyceryl behenate, guar gum, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hypromellose, lactose, maltodextrin, maltose, methylcellulose, pectin, polyethylene oxide, povidone, sodium alginate, sucrose, among others, and mixtures thereof.
  • the binder is selected from copovidone, hydroxypropyl cellulose, hypromellose, povidone and mixtures thereof, preferably selected from copovidone, povidone and mixtures thereof.
  • the binder is copovidone. In another embodiment, the binder is povidone.
  • the content of binder in the linagliptin granule is generally in the range 1-15 wt%, preferably in the range 2-10 wt%, more preferably in the range 3-7 wt% and still more preferably is about 5 wt%, referred to the total weight of the linagliptin granule.
  • the linagliptin granule comprises linagliptin or a pharmaceutically acceptable salt thereof and a disintegrant.
  • Disintegrants are generally used to promote the disintegration of the dosage form in the gastrointestinal tract.
  • the disintegrant can be selected, for example, from alginic acid, calcium alginate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, starch, pregelatinized starch, croscarmellose sodium, crospovidone, docusate sodium, hydroxypropyl cellulose low-substituted, polacrilin potassium, sodium alginate, and sodium starch glycolate, among others, and mixtures thereof.
  • the disintegrant is selected from croscarmellose sodium, crospovidone, sodium starch glycolate and mixtures thereof.
  • the disintegrant is sodium starch glycolate. In one embodiment, the disintegrant is crospovidone.
  • the linagliptin granule contains a disintegrant, it is in an amount generally comprised in the range 0.5-6 wt%, preferably comprised in the range 1 -3 wt%, referred to the total weight of the linagliptin granule.
  • the linagliptin granule comprises linagliptin or pharmaceutically acceptable salt thereof, a filler and a binder.
  • the linagliptin granule essentially consists of linagliptin or a pharmaceutically acceptable salt thereof, a filler and a binder.
  • the linagliptin granule comprises linagliptin or a pharmaceutically acceptable salt thereof, a filler, a binder and a disintegrant. In one embodiment, the linagliptin granule essentially consists of linagliptin or a pharmaceutically acceptable salt thereof, a filler, a binder and a disintegrant.
  • the pharmaceutical dosage form of the present invention comprises a second type of granule (the metformin granule) comprising metformin or a pharmaceutically acceptable salt thereof and meglumine.
  • Metformin is the International Nonproprietary Name (INN) to designate the substance 1 ,1 -dimethylbiguanide (CAS 657-24-9). Metformin is a biguanide with antihyperglycaemic effects. Metformin, and its pharmaceutically acceptable salts, can be prepared by known methods, or may be obtained from commercial sources. For example, the synthesis of metformin is disclosed in the French patent application FR2322860-A1 .
  • Metformin can be used as such, i.e, as the free base, or may be in the form of a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salts of metformin include nontoxic acid addition salts, for example, with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, salicylic acid, tartaric acid, glutamic acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, among others.
  • metformin is used as a salt, preferably, the hydrochloride salt (metformin hydrochloride) is used.
  • metformin or the pharmaceutically acceptable salts thereof, hydrates and solvates are also meant to be included.
  • non-hydrated, non-solvated metformin hydrochloride is used.
  • Metformin and the pharmaceutically acceptable salts thereof include any crystalline or amorphous forms thereof.
  • metformin or a pharmaceutically acceptable salt thereof in crystalline form is used.
  • Metformin or a pharmaceutically acceptable salt thereof, such as metformin hydrochloride may be used in any particle size for preparing the metformin granules.
  • it may typically have a particle size distribution by volume wherein D 90 is not more than 500 pm, preferably wherein D 90 is not more than 300 pm.
  • Said particle size distribution may be determined, for example, by laser diffraction (Malvern, Mastersizer 2000 and Malvern, Mastersizer 3000 and sample prepared by wet dispersion).
  • the content of metformin or a pharmaceutically acceptable salt thereof in the metformin granule is generally in the range 70-99 wt%, preferably in the range 75-95 wt%, more preferably in the range 80-92 wt%, and still more preferably in the range 85- 90 wt%, referred to the total weight of the metformin granule.
  • the size of the metformin granule is not critical.
  • the granule may have a size comprised between 0.05 mm and 2.0 mm, preferably comprised between 0.05 mm and 1.0 mm.
  • the metformin granules may be prepared by conventional processes, typically by dry granulation or by wet granulation.
  • the metformin granule comprises the active ingredient and meglumine.
  • Meglumine is also known as N-Methylglucamine or N-methyl-D-glucamine or as (2F?,3F?,4/ : ?,5S)-6-(Methylamino)hexane-1 ,2,3,4, 5-pentol (CAS 6284-40-8).
  • meglumine also includes any stereoisomer form thereof.
  • the weight ratio metformin or a pharmaceutically acceptable salt thereof: meglumine is generally comprised between 99:1 and 2:1 , preferably comprised between 85:1 and 15:1 , more preferably comprised between 70:1 and 20:1 , still more preferably comprised between 60:1 and 25:1 , still more preferably comprised between 50:1 and 30:1 , still more preferably comprised between 45:1 and 35:1 , and still more preferably is about 40:1 , wherein the weight of metformin or a pharmaceutically acceptable salt thereof is expressed as the equivalent weight of metformin hydrochloride.
  • the metformin granules comprise metformin or a pharmaceutically acceptable salt thereof, meglumine and an additional pharmaceutically acceptable excipient.
  • the additional pharmaceutically acceptable excipient may be, for example, a binder, a filler, a glidant, an antioxidant, a wetting agent, a disintegrant, or a mixture thereof.
  • the additional pharmaceutically acceptable excipient is selected from a binder, a glidant, a wetting agent, a disintegrant, and mixtures thereof.
  • the metformin granule comprises metformin or a pharmaceutically acceptable salt thereof, meglumine and a binder.
  • the binder can be selected, for example, from acacia, agar, alginic acid, carbomers, carrageenan, chitosan, copovidone, starch, pregelatinized starch, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glyceryl behenate, guar gum, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hypromellose, lactose, maltodextrin, maltose, methylcellulose, pectin, polyethylene oxide, povidone, sodium alginate, sucrose, among others, and mixtures thereof.
  • the binder is selected from copovidone, hydroxypropyl cellulose, hypromellose, povidone and mixtures thereof, preferably selected from copovidone, povidone and mixtures thereof.
  • the binder is copovidone. In one embodiment, the binder is povidone.
  • the content of binder in the metformin granule is generally in the range 2-20 wt%, preferably in the range 5-15 wt%, more preferably in the range 7- 12 wt% and still more preferably in the range 9-11 wt%, referred to the total weight of the metformin granule.
  • the metformin granule comprises metformin or a pharmaceutically acceptable salt thereof, meglumine, a binder and at least one additional excipient which is selected from a wetting agent, a disintegrant, a glidant, and mixtures thereof.
  • the metformin granule comprises a wetting agent.
  • Wetting agents typically are used in solid pharmaceutical compositions as an aid to the disintegration of the composition and to the dissolution of the drugs.
  • the wetting agent can be selected, for example, from sodium lauryl sulfate, a polysorbate and mixtures thereof.
  • Polysorbates are polyoxyethylene sorbitan fatty acid esters, which are nonionic surfactants. Examples of polysorbates are polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80.
  • the wetting agent is sodium lauryl sulfate.
  • the wetting agent is a polysorbate.
  • the content of wetting agent in the metformin granule is generally in the range 0.1-4 wt%, preferably in the range 0.1-3 wt%, more preferably in the range 0.1-2 wt% and still more preferably in the range 0.1-1 wt%, referred to the total weight of the metformin granule.
  • the metformin granule comprises a disintegrant.
  • the disintegrant can be selected, for example, from alginic acid, calcium alginate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, starch, pregelatinized starch, croscarmellose sodium, crospovidone, hydroxypropyl cellulose low-substituted, polacrilin potassium, sodium alginate, and sodium starch glycolate, among others, and mixtures thereof.
  • the disintegrant is selected from starch, croscarmellose sodium, crospovidone, sodium starch glycolate and mixtures thereof, more preferably is selected from starch, sodium starch glycolate and crospovidone and still more preferably is selected form starch and sodium starch glycolate.
  • the disintegrant is starch.
  • the disintegrant is sodium starch glycolate.
  • the content of disintegrant in the metformin granule is generally in the range 1-15 wt%, preferably in the range 2-12 wt%, and more preferably in the range 3-10 wt%, referred to the total weight of the metformin granule.
  • the metformin granule comprises a glidant, for example selected from colloidal silicon dioxide (also known as silica colloidal anhydrous), silicon dioxide, magnesium silicate, talc and combinations thereof.
  • the glidant is colloidal silicon dioxide.
  • metformin granule comprises a glidant
  • it is in an amount generally comprised in the range 0.05-4 wt%, preferably comprised in the range 0.1-1 wt%.
  • the metformin granule essentially consists of metformin or a pharmaceutically acceptable salt thereof, meglumine and a binder.
  • the metformin granule comprises metformin or a pharmaceutically acceptable salt thereof, meglumine, a binder and a glidant. In one embodiment, the metformin granule essentially consists of metformin or a pharmaceutically acceptable salt thereof, meglumine, a binder and a glidant. In one embodiment, the metformin granule comprises metformin or a pharmaceutically acceptable salt thereof, meglumine, a binder, a disintegrant and a wetting agent.
  • the metformin granule consists essentially of metformin or a pharmaceutically acceptable salt thereof, meglumine, a binder, a disintegrant and a wetting agent.
  • the pharmaceutical dosage form may be a granulate/powder mixture, typically available in mono-dose sachets, a capsule or a tablet, which can be coated or uncoated.
  • the pharmaceutical dosage form according to the present invention may contain, besides the linagliptin granules and the metformin granules, additional extragranular pharmaceutically acceptable excipients, i.e., that are not included neither in the linagliptin granules nor in the metformin granules.
  • additional extragranular pharmaceutically acceptable excipients i.e., that are not included neither in the linagliptin granules nor in the metformin granules.
  • the extragranular excipients are thoroughly mixed with the linagliptin granules and the metformin granules.
  • the extragranular excipients are selected from fillers, colorants disintegrants, glidants, lubricants, and mixtures thereof.
  • Colorants for example, may be added to distinguish between different strengths, when the dosage form is a non-coated tablet.
  • an extragranular disintegrant when there is an extragranular disintegrant, it can be selected, for example, from alginic acid, calcium alginate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, starch, pregelatinized starch, croscarmellose sodium, crospovidone, docusate sodium, hydroxypropyl cellulose low-substituted, polacrilin potassium, sodium alginate, and sodium starch glycolate, among others, and mixtures thereof.
  • alginic acid calcium alginate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, starch, pregelatinized starch, croscarmellose sodium, crospovidone, docusate sodium, hydroxypropyl cellulose low-substituted, polacrilin potassium, sodium alginate, and sodium starch glycolate, among others, and mixtures thereof.
  • an extragranular disintegrant When there is an extragranular disintegrant, it is typically in an amount in the range 0.05-5 wt%, preferably in the range 0.1-2 wt%, referred to the total weight of the dosage form.
  • the total weight of the dosage form as used herein means the weight of the capsule filling, when the dosage form is a capsule, or weight of the non-coated tablet core, when the dosage form is a tablet, or the weight of the mono-dose sachet filling, when the dosage form is in granulate/powder form.
  • the role of glidants is to improve the flowability of dry mixtures, i.e. powders and/or granules. When there is an extragranular glidant, it is typically selected from colloidal silicon dioxide, silicon dioxide, magnesium silicate and talc, among others, and mixtures thereof.
  • the glidant is colloidal silicon dioxide.
  • an extragranular glidant When there is an extragranular glidant, it is typically in an amount in the range 0.05-4 wt%, preferably in the range 0.1-1 wt%, referred to the total weight of the dosage form.
  • Lubricants are typically used when the dosage form is a tablet, to ensure that tablet formation and ejection can occur with low friction between the solid and the die wall.
  • a lubricant it can be selected from calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, magnesium stearate, medium-chain triglycerides, myristic acid, palmitic acid, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, and zinc stearate, among others, and mixtures thereof.
  • the lubricant is selected from calcium stearate, glyceryl behenate, hydrogenated castor oil, magnesium stearate, sodium stearyl fumarate, stearic acid and mixtures thereof.
  • a preferred lubricant is magnesium stearate.
  • a lubricant When there is a lubricant, it is typically in an amount in the range 0.2-5 wt%, preferably in the range 1 -3 wt%, referred to the total weight of the dosage form.
  • the composition comprises a glidant and a lubricant as extragranular excipients.
  • the extragranular pharmaceutically acceptable excipients essentially consist of a glidant and a lubricant.
  • the weight ratio metformi linagliptin in the dosage form is comprised between 500:1 and 100:1 , preferably comprised between 450:1 and 150:1 , and more preferably is comprised between 400:1 and 200:1 , wherein the weight of metformin is expressed as equivalent weight of metformin hydrochloride.
  • the weight ratio metformi linagliptin is about 400:1 , wherein the weight of metformin is expressed as equivalent weight of metformin.
  • the weight ratio metformi linagliptin is about 340:1 , wherein the weight of metformin is expressed as equivalent weight of metformin.
  • the weight ratio metformi linagliptin is about 200:1 , wherein the weight of metformin is expressed as equivalent weight of metformin.
  • the weight ratio metformin-granule:linagliptin-granrate in the dosage form is comprised between 5:1 and 20:1 , preferably comprised between 6:1 and 17:1 and more preferably comprised between 7:1 and 16:1.
  • the amount of metformin or a pharmaceutically acceptable salt thereof in the dosage form is comprised between 400 and 1100 mg, preferably comprised between 500 and 1000 mg, expressed as equivalent weight of metformin hydrochloride, and the amount of linagliptin or a pharmaceutically acceptable salt thereof is comprised between 1 and 5 mg, preferably comprised between 2 and 3 mg and more preferably is about 2.5 mg, expressed as equivalent weight of linagliptin free base.
  • the amount of meglumine in the dosage form is preferably comprised between 5 and 35 mg, more preferably comprised between 10 and 30 mg.
  • the amount of metformin or a pharmaceutically acceptable salt thereof in the dosage form is comprised between 900 and 1100 mg, preferably is about 1000 mg, expressed as equivalent weight of metformin hydrochloride, and the amount of linagliptin or a pharmaceutically acceptable salt thereof is comprised between 1 and 5 mg, preferably comprised between 2 and 3 mg and more preferably is about 2.5 mg, expressed as equivalent weight of linagliptin free base.
  • the amount of meglumine in the dosage form according this embodiment is preferably comprised between 20 and 30 mg, more preferably comprised between 22 and 28 mg.
  • the amount of metformin or a pharmaceutically acceptable salt thereof in the dosage form is comprised between 800 and 900 mg, preferably is about 850 mg, expressed as equivalent weight of metformin hydrochloride, and the amount of linagliptin or a pharmaceutically acceptable salt thereof is comprised between 1 and 5 mg, preferably comprised between 2 and 3 mg and more preferably is about 2.5 mg, expressed as equivalent weight of linagliptin free base.
  • the amount of meglumine in the dosage form according this embodiment is preferably comprised between 15 and 25 mg, more preferably comprised between 20 and 23 mg.
  • the amount of metformin or a pharmaceutically acceptable salt thereof in the dosage form is comprised between 400 and 600 mg, preferably is about 500 mg, expressed as equivalent weight of metformin hydrochloride, and the amount of linagliptin or a pharmaceutically acceptable salt thereof is comprised between 1 and 5 mg, preferably comprised between 2 and 3 mg and more preferably is about 2.5 mg, expressed as equivalent weight of linagliptin free base.
  • the amount of meglumine in the dosage form according this embodiment is preferably comprised between 8 and 20 mg, more preferably comprised between 11 and 14 mg.
  • the pharmaceutical dosage form may comprise an additional active ingredient, as a further partner drug to linagliptin and metformin, in order to provide a fixed-dose combination of three or more active ingredients useful in therapy.
  • the additional partner drug may be, for example, a further anti-diabetic agent.
  • Suitable anti-diabetic agents to be used in combination with linagliptin and metformin are, for example, sodium-glucose transport protein 2 (SGLT2) inhibitors, sulfonylureas, thiazolidinediones (TZD), glinides, alpha-glucosidase inhibitors, or glucagon-like peptide-1 (GLP-1) receptor agonists, among others.
  • Suitable SGLT2 inhibitors are for example, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin etabonate, sergliflozin etabonate, sotagliflozin or tofogliflozin, among others;
  • suitable sulfonylureas are, for example, tolbutamide, tolazamide, acetohexamide, carbutamide, chlorpropamide, glycyclamide, metahexamide, glyburide (glibenclamide), gliclazide, glipizide, glibornuride, gliquidone, glisoxepide, glyclopyramide, glymidine or glimepiride among others;
  • suitable thiazolidinediones are, for example, pioglitazone,
  • the additional active ingredient may be, typically, in the form of a further granule, which can be combined with the linagliptin granule, the metformin granule and, optionally, with the extragranular excipient, to prepare the combined dosage form.
  • the granule comprising the additional active ingredient may be prepared according to standard procedures.
  • the pharmaceutical oral dosage according to the present invention is in the form of granulate/powder mixture, typically available in mono-dose sachets.
  • the pharmaceutical dosage form is in the form of a capsule, i.e., linagliptin granules, metformin granules and, optionally, extragranular excipients are enclosed within either a hard or soft soluble shell.
  • a capsule i.e., linagliptin granules, metformin granules and, optionally, extragranular excipients are enclosed within either a hard or soft soluble shell.
  • the major component of capsules is gelatin, and typically they also comprise water, colorants, plasticizers, such as glycerine or sorbitol, and opacifying agents.
  • plasticizers such as glycerine or sorbitol
  • opacifying agents such as glycerine or sorbitol
  • hypromellose capsules may also be used.
  • the pharmaceutical dosage form is in the form of a tablet.
  • the tablets may have a film-coating layer (or overcoat, or finishing layer) applied onto the tablet core.
  • This film-coating layer comprises conventional immediate-release polymers, as are well-known in the art, for example, hydroxypropyl methylcellulose (or hypromellose, HPMC), methyl cellulose (MC), hydroxypropyl cellulose (HPC), polyvinyl pyrrolidone (PVP), copovidone, polyvinyl alcohol (PVA) or, mixtures thereof.
  • the film-coating layer may also contain other ingredients, as is well known by the skilled person in pharmaceutical formulation, such as an anti-tacking agent, a colourant, or a plasticizer, for example.
  • the anti-tacking agent can be selected, for example, from calcium silicate, magnesium silicate, colloidal silicon dioxide magnesium stearate, calcium stearate, magnesium oxide, talc and mixtures thereof.
  • Suitable plasticizers are, for example, polyethylene glycol, propylene glycol, diethyl phthalate, triethyl citrate, among others.
  • Suitable colourants include, among others, iron oxide pigments and titanium dioxide.
  • the weight of this layer amounts from about 2% to about 8% of the weight of the formulation (before applying said finishing layer).
  • total weight of the dosage form are calculated without including the weight of the film-coating layer, i.e., they refer to the weight of the core tablet, before applying the finishing layer.
  • Another aspect of the present invention is a process for the preparation of the combined oral pharmaceutical dosage form, as defined above, comprising the following steps: i) preparing granules comprising linagliptin, or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient; ii) preparing granules comprising metformin or a pharmaceutically acceptable salt thereof meglumine and, optionally, an additional pharmaceutically acceptable excipient; iii) mixing the granules obtained in steps i) and ii) and, optionally, an additional pharmaceutically acceptable excipient.
  • granules may be prepared, typically, by dry granulation or by wet granulation.
  • powders are aggregated at high pressure while in wet granulation, a granulation fluid is sprayed onto the particles as they are agitated, usually in a high-shear mixer or fluidized bed, which are common in the art.
  • the procedures used in the present invention for preparing the dosage form are standard processes well-known in pharmaceutical technology, as disclosed in reference books in the field, for example, in the book Aulton’s Pharmaceutics.
  • the design and manufacture of medicines M.E. Aulton and K.M.G. Taylor, editors, Churchill Livingstone Elsevier, Fourth Edition, 2013; or in the book Remington Essentials of Pharmaceutics, L. Felton, editor, Pharmaceutical Press, 2013; or in the book Pharmaceutics.
  • Basic principles and application to pharmacy practice A.K. Dash, S. Singh, and J. Tolman, editors, Academic Press, Elsevier, 2014.
  • the preparation of granules of steps i) and ii) are made by wet granulation, typically using a binder.
  • the granulation fluid is typically prepared by dissolving/dispersing the binder and optionally other pharmaceutically acceptable excipients in a suitable solvent.
  • the granulation solvent can be selected from water and a mixture of water and an alcohol, such as isopropanol or ethanol, for example.
  • the granulation solvent used in steps i) and ii) is water or a mixture of water and ethanol.
  • step i) comprises the following steps: i1) mixing linagliptin, a filler and, optionally, an additional pharmaceutically acceptable excipient; i2) preparing the granulation fluid by dissolving/dispersing a binder and, optionally, an additional pharmaceutically acceptable excipient, in the solvent;
  • step i2) granulating by spraying the granulation fluid of step i2) onto the mixture of step i1);
  • step i3) drying the granules obtained in step i3).
  • a disintegrant in the linagliptin granule it is preferably added in step i1), i.e., mixed with linagliptin.
  • no additional pharmaceutically acceptable excipient is added in step i2).
  • the binder may be divided in two parts and one part of binder is added to the granulation fluid (in step i2) and another part of the binder is mixed with linagliptin (in step i1).
  • step ii) comprises the following steps:
  • N2) preparing the granulation fluid by dissolving/dispersing a binder and, optionally, an additional pharmaceutically acceptable excipient, in the solvent; N3) granulating by spraying the granulation fluid of step N2) onto the mixture of step ii1); and
  • step N4 drying the granules obtained in step N3); wherein meglumine is either mixed with metformin (in step ii1), or is added to the granulation fluid (in step N2), or meglumine is divided in two parts and one part is mixed with metformin (in step ii1) and another part is added to the granulation fluid (in step N2).
  • step ii1) when there is a disintegrant in the metformin granule, it is preferably added in step ii1), i.e., it is mixed with metformin.
  • step N2 when there is a glidant in the metformin granule, it is preferably added in step N2), i.e., it is added to the granulation fluid.
  • step N2 when there is a wetting agent in the metformin granule, it is preferably added in step N2), i.e., it is added to the granulation fluid.
  • the binder may be divided in two parts and one part of binder is added to the granulation fluid (in step N2) and another part of the binder is mixed with metformin (in step ii1).
  • the percentage of meglumine which is added in step ii1) can range from about 20 to about 70 wt%, preferably from about 40 to about 60 wt% of the total meglumine.
  • the ingredients may be previously sieved through a sieve, for example, of 0.5 mm-2.00 mm.
  • the granules may be also screened through a wire mesh to break agglomerates of granules and for removing fine material which can be recycled.
  • Step iii) comprises mixing the granules obtained in steps i) and ii) and, optionally, an additional pharmaceutically acceptable extragranular excipient.
  • the preparation of the final dosage form is also performed following standard methods.
  • the mixture obtained in step iii) is typically filled into mono-dose sachets, or when the final dosage form is a capsule, the mixture is filled, for example, into hard gelatine capsules, or when the final dosage form is a tablet, the mixture obtained in step iii) is compressed using a tabletting machine.
  • the final dosage form is a tablet.
  • the process comprises the additional steps: iv) compressing the mixture obtained in step iii) to form a tablet; and v) optionally, coating the tablet obtained in step iv)
  • the coating of tablets of step v) is performed according to standard process, typically, by spraying a coating solution or suspension onto the surface of the tablets.
  • the preferred excipients used in each step, and the preferred amounts thereof are as disclosed above under the “Nnagliptin granule”, “metformin granule” and “dosage form” sections.
  • the dosage form according to the present invention is outstandingly stable and is therefore particularly suitable for treating diabetes type 2.
  • Example 4 shows that the present invention provides a dosage form (tablets 1A, 1 B) with better purity than the commercial product Jentadueto ® (C2).
  • the dosage form of the invention has particularly low levels of metformin-related impurities, including nitrosamines.
  • another aspect of the invention is the oral pharmaceutical dosage form comprising linagliptin or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof, according to the present invention, for use in medicine, in particular, for the treatment diabetes type 2.
  • Another aspect of the present invention is a method for treating diabetes type
  • the present invention relates to the following embodiments: 1.- An oral pharmaceutical dosage form comprising linagliptin and metformin, characterized in that it comprises: a) a first type of granule comprising linagliptin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient; and b) a second type of granule comprising metformin or a pharmaceutically acceptable salt thereof and meglumine. 2.- The oral pharmaceutical dosage form according to embodiment 1 , characterized in that linagliptin is in the form of free base.
  • linagliptin granule comprises linagliptin or a pharmaceutically acceptable salt thereof, a filler, a binder and, optionally, a disintegrant.
  • compositions 7 or 6 characterized in that content of filler in the linagliptin granule is comprised in the range 75-98 wt%, preferably in the range 80-95 wt%, more preferably in the range 85-93 wt%, and more preferably is about 90 wt%, referred to the total weight of the linagliptin granule.
  • the filler in the linagliptin granule is selected from the group consisting of calcium carbonate, calcium lactate, calcium phosphate dibasic, calcium phosphate tribasic, calcium silicate, calcium sulfate, microcrystalline cellulose, powdered cellulose, cellulose acetate, corn starch, pregelatinized starch, dextrin, dextrose, fructose, lactitol, lactose, maltodextrin, maltose, mannitol, sorbitol, sucrose, trehalose, xylitol and mixtures thereof; preferably is selected from the group consisting of dextrose, mannitol, sorbitol, xylitol and mixtures thereof; and more preferably the filler is mannitol.
  • the binder in the linagliptin granule is selected from the group consisting of acacia, agar, alginic acid, carbomers, carrageenan, chitosan, copovidone, starch, pregelatinized starch, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glyceryl behenate, guar gum, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hypromellose, lactose, maltodextrin, maltose, methylcellulose, pectin, polyethylene oxide, povidone, sodium alginate, sucrose, and mixtures thereof, preferably is selected from the group consisting of copovidone, hydroxypropyl cellulose, hypromellose and povidone; more preferably is selected from povidone, copovidone
  • the disintegrant is selected from the group consisting of alginic acid, calcium alginate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, starch, pregelatinized starch, croscarmellose sodium, crospovidone, docusate sodium, hydroxypropyl cellulose low-substituted, polacril
  • the weight ratio metformin or a pharmaceutically acceptable salt thereof:meglumine in the metformin granule is comprised between 99:1 and 2:1 , preferably comprised between 85:1 and 15:1 , more preferably comprised between 70:1 and 20:1 , still more preferably comprised between 60:1 and 25:1 , still more preferably comprised between 50:1 and 30:1 , still more preferably comprised between 45:1 and 35:1 , and still more preferably is about 40:1 , wherein the weight of metformin or a pharmaceutically acceptable salt thereof is expressed as the equivalent weight of metformin hydrochloride.
  • metformin granule comprises an additional pharmaceutically acceptable excipient selected from a binder, a filler, a glidant, an antioxidant, a wetting agent, a disintegrant and mixtures thereof, preferably selected from a binder, a glidant, a wetting agent, a disintegrant and mixtures thereof.
  • metformin granule comprises metformin or a pharmaceutically acceptable salt thereof, meglumine, a binder and at least one additional excipient which is selected from a wetting agent, a disintegrant, a glidant and mixtures thereof.
  • metformin granule comprises metformin or a pharmaceutically acceptable salt thereof, meglumine, a binder and a glidant, preferably the metformin granule essentially consists of metformin or a pharmaceutically acceptable salt thereof, meglumine, a binder and a glidant.
  • the metformin granule comprises metformin or a pharmaceutically acceptable salt thereof, meglumine, a binder, a disintegrant and a wetting agent, preferably the metformin granule essentially consists of metformin or a pharmaceutically acceptable salt thereof, meglumine, a binder, a disintegrant and a wetting agent.
  • the metformin granule essentially consists of metformin or a pharmaceutically acceptable salt thereof, meglumine, a binder, a disintegrant and a wetting agent.
  • the content of binder in the metformin granule is in the range 2-20 wt%, preferably in the range 5-15 wt%, more preferably in the range 7-12 wt% and still more preferably in the range 9-11 wt%, referred to the total weight of the metformin granule.
  • the binder in the metformin granule is selected from the group consisting of acacia, agar, alginic acid, carbomers, carrageenan, chitosan, copovidone, starch, pregelatinized starch, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glyceryl behenate, guar gum, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hypromellose, lactose, maltodextrin, maltose, methylcellulose, pectin, polyethylene oxide, povidone, sodium alginate, sucrose, and mixtures thereof; preferably is selected from the group consisting of copovidone, hydroxypropyl cellulose, hypromellose, povidone and mixtures thereof; more preferably is selected from povidone, copovidone and mixtures thereof, and still more preferably the binder is cop
  • glidant is selected from colloidal silicon dioxide, silicon dioxide, magnesium silicate, talc, and combinations thereof, preferably the glidant is colloidal silicon dioxide.
  • the oral pharmaceutical dosage form according to any one of embodiments 16 to 22, characterized in that the wetting agent is selected from sodium lauryl sulfate and a polysorbate. In one particular embodiment the wetting agent is sodium lauryl sulfate. In another particular embodiment the wetting agent is a polysorbate.
  • the oral pharmaceutical dosage form according to any one of embodiments 16 to 25, characterized in that the disintegrant is selected from starch, croscarmellose sodium, crospovidone, sodium starch glycolate and mixtures thereof, preferably is selected from starch, sodium starch glycolate and crospovidone and more preferably is selected from starch and sodium starch glycolate.
  • the disintegrant is starch.
  • the disintegrant is sodium starch glycolate.
  • the content of disintegrant in the metformin granule is comprised in the range 1-15 wt%, preferably in the range 2-12 wt%, and more preferably in the range 3-10 wt%, referred to the total weight of the metformin granule.
  • the extragranular excipient which is preferably selected from a filler, a colorant, a disintegrant, a glidant, a lubricant and mixtures thereof, more preferably is selected from a glidant, a lubricant and mixtures thereof, and more preferably the extragranular excipient essentially consists of a glidant and a lubricant.
  • the glidant is selected from the group consisting of colloidal silicon dioxide, silicon dioxide, magnesium silicate, talc and mixtures thereof; preferably, the glidant is colloidal silicon dioxide; and the lubricant is selected from the group consisting of calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, magnesium stearate, medium-chain triglycerides, myristic acid, palmitic acid, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, zinc stearate, and mixtures thereof, preferably, the lubricant is selected from calcium stearate, glyceryl behenate, hydrogenated castor oil, magnesium stearate, sodium stearyl fumarate, stearic acid and mixtures thereof, and more preferably the lubricant is magnesium stearate.
  • the weight ratio metformin :linagliptin in the dosage form is comprised between 500:1 and 100:1 , preferably comprised between 450:1 and 150:1 , and more preferably is comprised between 400:1 and 200:1 , wherein the weight of metformin is expressed as equivalent weight of metformin hydrochloride.
  • the amount of metformin or a pharmaceutically acceptable salt thereof in the dosage form is comprised between 400 and 1100 mg, preferably comprised between 500 and 1000 mg, expressed as equivalent weight of metformin hydrochloride, and the amount of linagliptin or a pharmaceutically acceptable salt thereof is comprised between 1 and 5 mg, preferably comprised between 2 and 3 mg and more preferably is about 2.5 mg, expressed as equivalent weight of linagliptin free base.
  • the amount of meglumine in the dosage form is comprised between 5 and 35 mg, preferably comprised between 10 and 30 mg.
  • the dosage form is a tablet.
  • 35. A process for the preparation of the pharmaceutical dosage form according to any one of embodiments 1 to 34, characterized in that it comprises the following steps: i) preparing granules comprising linagliptin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient; ii) preparing granules comprising metformin or a pharmaceutically acceptable salt thereof, meglumine and, optionally, an additional pharmaceutically acceptable excipient; iii) mixing the granules obtained in steps i) and ii) and, optionally, an additional pharmaceutically acceptable excipient.
  • 36. The process according to embodiment 35, characterized in that the granules of steps i) and ii) are prepared by wet granulation.
  • 37.- The oral pharmaceutical dosage form according to any one of embodiments 1 to
  • Example 1 Preparation of tablets comprising metformin HCI and linaaliptin (850/2.5) Tablets 1A and 1 B comprising 850 mg of metformin and 2.5 mg of linagliptin HCI were prepared using the ingredients disclosed in Table 1. Tablets 1 B comprised less amount of meglumine.
  • Linagliptin granules were prepared by wet granulation in a high-shear granulation apparatus. Linagliptin, mannitol, sodium starch glycolate and half of the copovidone were weighed and sieved through a sieve of 800-1000 microns, and added to the high-shear granulation bowl, where they were mixed. The granulation fluid was prepared by suspending the remaining half of copovidone in water, and it was sprayed onto the powder pre-mixture, maintaining the agitation. The formed granules were dried in a fluidized-bed dryer.
  • the metformin granules were prepared by wet granulation in a fluidized bed granulation apparatus. Metformin HCI and half of meglumine were uniformly mixed in the fluid bed granulator.
  • the granulation fluid was prepared by mixing copovidone, silica colloidal anhydrous and the remaining half of meglumine in water, and this granulation fluid was sprayed onto the powder mixture. After the granulation fluid was completely sprayed, the formed granules were maintained in the fluidized bed under airstream for drying the granules.
  • Linagliptin granules and metformin granules thus obtained were mixed in a vessel, silica colloidal anhydrous and magnesium stearate were successively added and mixed. The final mixture was compressed to form the tablets, using a rotary tableting machine with an oval, biconvex punch to produce a tablet weighting 1060 mg.
  • the Opadry ® coating blend was dispersed in water to prepare a film coating fluid.
  • the coating fluid was sprayed onto the tablet in a film coating machine, to produce a 1091.80 mg film-coated tablet containing 850 mg of metformin hydrochloride and 2.5 mg of linagliptin.
  • film-coated tablets 1C and 1 D of the same strength were prepared using the ingredients disclosed in Table 2:
  • metformin HCI and sodium starch glycolate were uniformly mixed in the fluid bed granulator.
  • the granulation fluid was prepared by mixing copovidone, meglumine, and sodium lauryl sulfate in a mixture of water and ethanol (30:70, by weight), and this granulation fluid was sprayed onto the powder mixture.
  • Example 2 Preparation of tablets comprising metformin HCI and linaaliptin (1000/2.5)
  • Film-coated tablets 2A comprising 1000 mg of metformin HCI and 2.5 mg of linagliptin were prepared analogously as disclosed in Example 1 , using the ingredients of Table 4:
  • film-coated tablets 2D, 2E and 2F of the same strength were prepared using the ingredients disclosed in Table 6:
  • metformin HCI and sodium starch glycolate were uniformly mixed in the fluid bed granulator.
  • the granulation fluid was prepared by mixing copovidone, meglumine, and sodium lauryl sulfate in a mixture of water and ethanol (30:70, by weight), and this granulation fluid was sprayed onto the powder mixture.
  • film-coated tablets 2G, 2H and 21 of the same strength were prepared using the ingredients disclosed in Table 7:
  • the preparation method was analogous as disclosed for Examples 2D, 2E and 2F, but replacing sodium lauryl sulfate with polysorbate 80 and/or sodium starch glycolate with maize starch, when appropriate.
  • Example 3 Preparation of tablets comprising metformin HCI and linaqliptin (500/2.5) Analogously, film-coated tablets 3A comprising 500 mg of metformin HCI and 2.5 mg of linagliptin were prepared using the ingredients disclosed in Table 8:
  • Comparative Example A comparative formulation example in the form of film-coated tablet comprising 850 mg of metformin and 2.5 mg of linagliptin HCI was prepared following the procedure disclosed in Example 1 , using the components disclosed for Example 1 B, but without using any amount of meglumine in the metformin granules.
  • Example 1A and 1 B The stability of the dosage forms according to the invention was tested using two film-coated tablets containing 850 mg of metformin HCI and 2.5 mg of linagliptin disclosed in Example 1 (Examples 1A and 1 B), and was compared with the tablet disclosed in Comparative Example containing the same amount of actives but containing no meglumine (C2) and with a commercial Jentadueto ® film-coated tablet of the same strength (C1 ), as shown in Table 9 below.
  • BRT means bellow reporting threshold.
  • the reporting threshold is 0.01%. It can be observed that the film-coated tablets of the invention (1 A and 1 B) are stable, whereas the amount of linagliptin-related impurities was clearly increased in the comparative tablets C2, which contained no meglumine.
  • the film-coated tablets according to the invention (1A and 1 B) showed better purity profile than the commercial product Jentadueto ® (C1).

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Abstract

La présente invention concerne une composition pharmaceutique contenant les principes actifs linagliptine et metformine en association.
EP21705444.4A 2020-02-13 2021-02-09 Composition pharmaceutique contenant de la linagliptine et de la metformine Pending EP4103157A1 (fr)

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WO2014080383A1 (fr) 2012-11-26 2014-05-30 Ranbaxy Laboratories Limited Composition pharmaceutique d'inhibiteurs de la dipeptidyl-peptidase-iv (dpp-iv) en association avec d'autres antidiabétiques
WO2015110962A1 (fr) * 2014-01-21 2015-07-30 Wockhardt Limited Compositions pharmaceutiques orales solides comprenant une combinaison de doses fixes de metformine et de linagliptine ou de leurs sels
CN104840960A (zh) 2014-02-14 2015-08-19 广东东阳光药业有限公司 抗糖尿病的药物组合物及其制备方法

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