EP4196107A1 - A tablet formulation comprising sitagliptin and metformín - Google Patents

A tablet formulation comprising sitagliptin and metformín

Info

Publication number
EP4196107A1
EP4196107A1 EP21856361.7A EP21856361A EP4196107A1 EP 4196107 A1 EP4196107 A1 EP 4196107A1 EP 21856361 A EP21856361 A EP 21856361A EP 4196107 A1 EP4196107 A1 EP 4196107A1
Authority
EP
European Patent Office
Prior art keywords
tablet formulation
sodium
formulation according
sitagliptin
pharmaceutically acceptable
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
EP21856361.7A
Other languages
German (de)
French (fr)
Other versions
EP4196107A4 (en
Inventor
Seval Ataman
Muge ULUSOY BOZYEL
Fatih Sunel
Onur Mutlu
Ezel URAZ
Seda AVERBEK
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.)
Sanovel Ilac Sanayi ve Ticaret AS
Original Assignee
Sanovel Ilac Sanayi ve Ticaret AS
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 Sanovel Ilac Sanayi ve Ticaret AS filed Critical Sanovel Ilac Sanayi ve Ticaret AS
Publication of EP4196107A1 publication Critical patent/EP4196107A1/en
Publication of EP4196107A4 publication Critical patent/EP4196107A4/en
Pending legal-status Critical Current

Links

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
    • A61K31/33—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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • 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
    • A61K9/2022—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
    • 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 a tablet formulation comprising sitagliptin or a pharmaceutically acceptable salts thereof and metformin hydrochloride.
  • the present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient process.
  • Diabetes mellitus is a group of disorders of carbohydrate metabolism in which the action of insulin is diminished or absent through altered secretion, decreased insulin activity or a combination of both factors.
  • Type 1 and Type 2 There are two main types of diabetes; Type 1 and Type 2:
  • Type 1 diabetes occurs because the insulin-producing cells of the pancreas (beta cells) are damaged. In Type 1 diabetes, the pancreas makes little or no insulin, so sugar cannot get into the body's cells for use as energy. People with Type 1 diabetes must use insulin injections to control their blood glucose.
  • Type 2 diabetes the pancreas makes insulin, but it either doesn't produce enough, or the insulin does not work properly. This diabetes occurs most often in people who are over 40 years old and overweight. Type 2 diabetes may sometimes be controlled with a combination of diet, weight management, and exercise. However, treatment also may include oral glucose-lowering medications or insulin injections.
  • Metformin is antidiabetics having an orally-administrated biguanide structure.
  • Metformin hydrochloride is a white to off-white crystalline compound and it is freely soluble in water and practically insoluble in acetone, ether and chloroform.
  • Oral doses of metformin are generally recommended in the range of 500 to 2500 mg a day and a single dose may vary from 250 to 1000mg. It is used singly or in combination with sulfonylureas, alpha-glucosidase inhibitors, or insulin.
  • metformin hydrochloride is 1 ,1 -dimethylbiguanide hydrochloride, has the following chemical structure of Formula I.
  • metformin Although metformin is effective at lowering blood glucose levels, its use is associated with gastrointestinal (Gl) adverse effects, particularly diarrhea and nausea. These adverse effects may limit the tolerated dose of metformin and cause patients to discontinue the therapy.
  • Gl gastrointestinal
  • Sitagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It is an oral antihyperglycemic of the dipeptidyl peptidase-4 (DPP-4) inhibitor class.
  • DPP-4 inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin.
  • DPP-4 dipeptidyl peptidase-4
  • GLP-1 glucagon-like peptide-1
  • GIP glucose-dependent insulinotropic peptide
  • Sitagliptin works by binding to DPP-4 and preventing it from breaking down the GLP-1 and GIP. This increases the levels of these hormones in the body and so increases their effect on controlling blood sugar.
  • sitagliptin is (3R)-3-amino-1-[3-(trifluoromethyl)-6,8-dihydro-5H- [1 ,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl) butan-1-one or (2R)-4-oxo-4- [3- (trifluoromethyl)-5,6-dihydro[1 ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1 -(2,4,5trifluorophenyl) butan-2-amine) and its chemical structure is shown in the Formula II.
  • Sitagliptin is disclosed in the patent US6699871.
  • a crystal phosphate monohydrate form of sitagliptin is disclosed in the patent W02005003135.
  • Sitagliptin increases plasma GLP-1 concentration and elevates cellular cAMP levels in pancreatic beta-cells leading to potentiate insulin secretion, whereas metformin improves glucose tolerance in patients with Type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action is different from other classes of oral antihyperglycemic agents in that metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Therefore, they both help to reduce blood glucose levels in different pathways in type 2 diabetes patients.
  • DPP-4 inhibitors especially sitagliptin have a novel mechanism of action and many studies are available which shows their efficacy and safety in monotherapy or combination therapy.
  • the single sitagliptin alone does not provide adequate glycemic control.
  • a tablet formulation for metformin and sitagliptin combination is commercially available under the trade name Janumet®. It contains either 500 or 850 or 1000 mg metformin, and 50 mg sitagliptin.
  • Pharmaceutical compositions comprising fixed-dose combinations of immediate- release sitagliptin and metformin are disclosed in WO 2007/078726 patent application which published on July 12, 2007.
  • metformin HCI and sitagliptin have some structural problems. Stability-related problems do occur in many active agents, including sitagliptin, under the influence of ambient and physical conditions. Sitagliptin is an active agent that is highly-susceptible to air and humidity. When sitagliptin is exposed to air and humidity, it degrades structurally and develops chemical behavioral changes. The stability of sitagliptin products developed is not at a desired level and the shelf life thereof is shortened. In addition, sitagliptin is reactive against the excipients employed in developing formulations containing the same. This fact causes impurities to occur in the formulation and leads to the inclusion of undesired components into the formulation. Also, as known, metformin is a very poorly compressible active.
  • US8758815 B2 discloses a pharmaceutical composition comprising at least two separate compartments, wherein one compartment contains a composition comprising metformin or a pharmaceutically acceptable salt thereof and wherein another compartment contains a composition comprising sitagliptin.
  • US2015374688(A1) discloses a solid oral pharmaceutical composition comprising combination of metformin and sitagliptin or salts thereof.
  • the patent application relates to a multilayered coated pharmaceutical composition comprising at least two compartments of metformin or salts thereof exhibiting immediate and extended release and at least one compartment of sitagliptin and metformin or salts thereof exhibiting immediate release.
  • WO2014174469(A1 ) discloses pharmaceutical compositions consisting essentially of sitagliptin, metformin, and a lubricant selected from the group consisting of glyceryl behenate, glyceryl palmitostearate, stearyl alcohol, cetostearyl alcohol, or mixtures thereof, wherein the pharmaceutical composition does not comprise a surfactant.
  • the main object of the present invention is to provide a tablet formulation comprising sitagliptin or a pharmaceutically acceptable salts thereof and metformin hydrochloride having the desired stability, dissolution profile, hardness and compressibility.
  • Another object of the present invention is to eliminate problems caused by active substances and bringing additional advantages to the relevant prior art.
  • the main object of the present invention is to provide a process for a stable combination.
  • the process is a simple, rapid, cost effective, time-saving and industrially convenient method.
  • a tablet formulation comprises sitagliptin or a pharmaceutically acceptable salts thereof and metformin hydrochloride wherein sitagliptin or a pharmaceutically acceptable salts thereof and at least one binder dissolved in a solvent.
  • sitagliptin or a pharmaceutically acceptable salts thereof and at least one binder is dissolved in a solvent
  • a solution containing a higher proportion of sitagliptin or a pharmaceutically acceptable salts thereof is obtained, this minimizes active substance losses during granulation and provides more homogeneous (content uniformity) and efficient tablet formulation.
  • solvents are then removed from the environment (preferably by fluid bed dryer), these steps of the method help to provide the desired uniformity and granule structure, so the desired stability of tablet is ensured.
  • the amount of sitagliptin or a pharmaceutically acceptable salts thereof is between 1 .0% and 20.0% by weight in the total formulation. Preferably, it is between 2.0% and 15.0% or 3.0% and 10.0% by weight in the total formulation.
  • the amount of metformin hydrochloride is between 60.0% and 90.0% by weight in the total formulation. Preferably, it is between 65.0% and 80.0% by weight in the total formulation.
  • metformin is a very poorly compressible active substance and in the present invention, metformin presents in high amounts in the tablet. It was surprisingly found that when prepared the tablet formulation with a solution sitagliptin or a pharmaceutically acceptable salts thereof and at least one binder, it was observed that the desired tablet hardness and compressibility of metformin HCI is provided. So, an easy method was created to eliminate the disadvantages of both active ingredients.
  • Suitable binders are selected from the group comprising polyvinylpyrrolidone, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate, pregelatinized starch, natural gums, sucrose, sodium alginate, carboxy methyl cellulose, methyl cellulose, gelatin, carrageenan, guar gum, carbomer, polymethacrylates, methacrylate polymers, gelatin, agar, alginate, xanthan gum, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, aluminum hydroxide, laponit, bentonit, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof.
  • the amount of binders is between 1 .0% and 15.0% by weight in the total formulation. Preferably, it is between 2.0% and 11 .0% or 3.0% and 8.0% by weight in the total formulation.
  • the binder is polyvinylpyrrolidone.
  • solvent is pure water.
  • sitagliptin or a pharmaceutically acceptable salts thereof and at least one binder is dissolved in a solvent and a solution is obtained. Also, after at least one binder is dissolved in a solvent and another solution is obtained.
  • introduction of the binder in two steps in this way is more advantageous than using a binder in one step (one granulation). It provides that granule bulk density is improved and also, the desired tablet hardness and compressibility has improved considerably.
  • the binder is added to the formulation in two steps.
  • the granulation final moisture (after solvents are removed from the environment) is between 2% and 3.5%.
  • the desired compressibility and hardness does not occur.
  • the desired hardness and compressibility of tablet is important. Because it helps to provide the desired dissolution profile of tablet.
  • excipients provided in a formulation may positively or negatively influence the physicochemical and pharmacokinetic properties, e.g. the solubility, absorption, bioavailability of an active agent. For this reason, the excipients which accompany an active agent have to be selected in a careful and conscious manner while a formulation is developed.
  • the formulations should have no physicochemical incompatibility between the active agents and the excipients.
  • a tablet further comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising fillers, disintegrants, lubricants, glidants, surfactants, coating agents or mixtures.
  • Suitable fillers are selected from the group comprising microcrystalline cellulose, talc, dibasic calcium phosphate, mannitol, spray-dried mannitol, lactose, lactose monohydrate, starch, dextrose, sucrose, fructose, sodium carbonate, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium bicarbonate, calcium carbonate or mixtures thereof.
  • the amount of fillers is between 1 .0% and 15.0% by weight in the total formulation. Preferably, it is between 2.0% and 11.0% or 3.0% and 8.0% by weight in the total formulation.
  • the filler is microcrystalline cellulose or talc or mixtures thereof.
  • Suitable disintegrants are selected from the group comprising croscarmellose sodium, sodium starch glycolate, pregelatinized starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, polyacryline potassium, sodium alginate, corn starch, alginates, ion-exchange resins, magnesium aluminum silica, sodium dodecyl sulphate, poloxamer, sodium glycine carbonate or mixtures thereof.
  • the amount of disintegrants is between 1.0% and 15.0% by weight in the total formulation. Preferably, it is between 2.0% and 11 .0% or 3.0% and 8.0% by weight in the total formulation.
  • the disintegrant is croscarmellose sodium.
  • Suitable lubricants are selected from the group comprising from sodium stearyl fumarate, magnesium stearate, calcium stearate, zinc stearate, waxes, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, glyceryl palmito sulphate or mixtures thereof.
  • the amount of lubricants is between 0.5% and 5.0% by weight in the total formulation.
  • the lubricant is sodium stearyl fumarate.
  • Suitable glidants are selected from the group comprising colloidal silicon dioxide, corn starch or mixtures thereof.
  • the amount of glidants is between 0.05% and 3.0% by weight in the total formulation.
  • the glidant is colloidal silicon dioxide.
  • Suitable surfactants are selected from the group comprising sodium lauryl sulphate, sodium docusate, glyceryl monooleate, polyethylene alkyl ether, polyoxyethylene stearates, polyethylene glycol, sodium benzoate, docusate sodium, alpha tocopherol, ascorbyl palmitate, polyoxyethylene hydrogenated castor oil or mixtures thereof.
  • the amount of surfactants is between 0.05% and 3.0% by weight in the total formulation.
  • the surfactant is sodium lauryl sulphate.
  • Suitable coating agents are selected from the group comprising copovidone, polymethacrylates, polydextrose, polyalkylacrylates copolymers, triacetin, hydroxyl propyl methyl cellulose, colloidal silicon dioxide, lactose monohydrate, medium chain triglycerides, hydroxypropyl cellulose, white wax, polyvinyl alcohol, polyethylene glycol, talc, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), all kinds of Opadry®, pigments, dyes, titanium dioxide, red iron oxide, black iron oxide or mixtures thereof.
  • the amount of coating comprising coating agents is between 0.5% and 5.0% by weight in the total formulation.
  • the coating agents are polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, red iron oxide, black iron oxide or mixture thereof.
  • particle size distribution means the cumulative volume size distribution as tested by any conventionally accepted method such as the laser diffraction method (i.e. malvern analysis) .
  • d(0.5) means, the size at which 50% by volume of the particles are finer
  • d(0.9) means, the size at which 90% by volume of the particles are finer.
  • sitagliptin or a pharmaceutically acceptable salts thereof has a particle size of d(0.5) less than 50 pm or less than 40 pm or less than 30 pm. This property provides improved flow properties, also it helps to provide the desired dissolution profile.
  • sitagliptin or a pharmaceutically acceptable salts thereof has a particle size of d(0.5) between 30 pm and 15 pm. According to one embodiment of the invention, sitagliptin or a pharmaceutically acceptable salts thereof has a particle size of d(0.9) less than 70 pm or less than 60 pm or less than 50 pm. This property provides improved flow properties, also it helps to provide the desired dissolution profile.
  • sitagliptin or a pharmaceutically acceptable salts thereof has a particle size of d(0.9) between 50 pm and 20 pm.
  • the tablet of the present invention may be prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression, wet granulation or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion/spheronization, slugging, spray drying and solvent evaporation.
  • Example 1 The tablet formulation comprising metformin HCI and sitagliptin HCI
  • Example 2 The tablet formulation comprising metformin HCI and sitagliptin HCI

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Abstract

The present invention relates to a tablet formulation comprising sitagliptin or a pharmaceutically acceptable salts thereof and metformin hydrochloride. The present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient process.

Description

A TABLET FORMULATION COMPRISING SITAGLIPTIN AND METFORMIN
Field of the Invention
The present invention relates to a tablet formulation comprising sitagliptin or a pharmaceutically acceptable salts thereof and metformin hydrochloride. The present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient process.
Background of the Invention
Diabetes mellitus is a group of disorders of carbohydrate metabolism in which the action of insulin is diminished or absent through altered secretion, decreased insulin activity or a combination of both factors. There are two main types of diabetes; Type 1 and Type 2:
Type 1 diabetes occurs because the insulin-producing cells of the pancreas (beta cells) are damaged. In Type 1 diabetes, the pancreas makes little or no insulin, so sugar cannot get into the body's cells for use as energy. People with Type 1 diabetes must use insulin injections to control their blood glucose.
In Type 2 diabetes, the pancreas makes insulin, but it either doesn't produce enough, or the insulin does not work properly. This diabetes occurs most often in people who are over 40 years old and overweight. Type 2 diabetes may sometimes be controlled with a combination of diet, weight management, and exercise. However, treatment also may include oral glucose-lowering medications or insulin injections.
Metformin is antidiabetics having an orally-administrated biguanide structure. Metformin hydrochloride is a white to off-white crystalline compound and it is freely soluble in water and practically insoluble in acetone, ether and chloroform. Oral doses of metformin are generally recommended in the range of 500 to 2500 mg a day and a single dose may vary from 250 to 1000mg. It is used singly or in combination with sulfonylureas, alpha-glucosidase inhibitors, or insulin.
The chemical name of metformin hydrochloride is 1 ,1 -dimethylbiguanide hydrochloride, has the following chemical structure of Formula I.
Formula I
Although metformin is effective at lowering blood glucose levels, its use is associated with gastrointestinal (Gl) adverse effects, particularly diarrhea and nausea. These adverse effects may limit the tolerated dose of metformin and cause patients to discontinue the therapy.
Sitagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It is an oral antihyperglycemic of the dipeptidyl peptidase-4 (DPP-4) inhibitor class. DPP-4 inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin. There are two types of incretin hormones found in the body, called glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). These hormones are naturally produced by the body in response to food intake. Their function is to help the body produce more insulin only when it is needed and reduce the amount of glucose being produced by the liver when it is not needed. Sitagliptin works by binding to DPP-4 and preventing it from breaking down the GLP-1 and GIP. This increases the levels of these hormones in the body and so increases their effect on controlling blood sugar.
The chemical name of sitagliptin is (3R)-3-amino-1-[3-(trifluoromethyl)-6,8-dihydro-5H- [1 ,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl) butan-1-one or (2R)-4-oxo-4- [3- (trifluoromethyl)-5,6-dihydro[1 ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1 -(2,4,5trifluorophenyl) butan-2-amine) and its chemical structure is shown in the Formula II.
Formula II Sitagliptin is disclosed in the patent US6699871. A crystal phosphate monohydrate form of sitagliptin is disclosed in the patent W02005003135.
Sitagliptin increases plasma GLP-1 concentration and elevates cellular cAMP levels in pancreatic beta-cells leading to potentiate insulin secretion, whereas metformin improves glucose tolerance in patients with Type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action is different from other classes of oral antihyperglycemic agents in that metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Therefore, they both help to reduce blood glucose levels in different pathways in type 2 diabetes patients.
DPP-4 inhibitors, especially sitagliptin have a novel mechanism of action and many studies are available which shows their efficacy and safety in monotherapy or combination therapy. The single sitagliptin alone does not provide adequate glycemic control.
A tablet formulation for metformin and sitagliptin combination is commercially available under the trade name Janumet®. It contains either 500 or 850 or 1000 mg metformin, and 50 mg sitagliptin. Pharmaceutical compositions comprising fixed-dose combinations of immediate- release sitagliptin and metformin are disclosed in WO 2007/078726 patent application which published on July 12, 2007.
Both metformin HCI and sitagliptin have some structural problems. Stability-related problems do occur in many active agents, including sitagliptin, under the influence of ambient and physical conditions. Sitagliptin is an active agent that is highly-susceptible to air and humidity. When sitagliptin is exposed to air and humidity, it degrades structurally and develops chemical behavioral changes. The stability of sitagliptin products developed is not at a desired level and the shelf life thereof is shortened. In addition, sitagliptin is reactive against the excipients employed in developing formulations containing the same. This fact causes impurities to occur in the formulation and leads to the inclusion of undesired components into the formulation. Also, as known, metformin is a very poorly compressible active.
US8758815 B2 discloses a pharmaceutical composition comprising at least two separate compartments, wherein one compartment contains a composition comprising metformin or a pharmaceutically acceptable salt thereof and wherein another compartment contains a composition comprising sitagliptin. US2015374688(A1) discloses a solid oral pharmaceutical composition comprising combination of metformin and sitagliptin or salts thereof. In particular, the patent application relates to a multilayered coated pharmaceutical composition comprising at least two compartments of metformin or salts thereof exhibiting immediate and extended release and at least one compartment of sitagliptin and metformin or salts thereof exhibiting immediate release.
WO2014174469(A1 ) discloses pharmaceutical compositions consisting essentially of sitagliptin, metformin, and a lubricant selected from the group consisting of glyceryl behenate, glyceryl palmitostearate, stearyl alcohol, cetostearyl alcohol, or mixtures thereof, wherein the pharmaceutical composition does not comprise a surfactant.
As seen in the above patent applications, there was not a solution for the disadvantages of sitagliptin and metformin in the prior art, or the solutions presented are long and costly processes.
There is thus still a need for a formulation comprising sitagliptin or a pharmaceutically acceptable salts thereof and metformin hydrochloride that provides a tablet having the desired stability, dissolution profile, hardness and compressibility, in another words the disadvantages seen in the active substances will able to overcome. The formulation has been developed by using standard techniques which is simple and cost-effective method.
Detailed Description of the Invention
The main object of the present invention is to provide a tablet formulation comprising sitagliptin or a pharmaceutically acceptable salts thereof and metformin hydrochloride having the desired stability, dissolution profile, hardness and compressibility.
Another object of the present invention is to eliminate problems caused by active substances and bringing additional advantages to the relevant prior art.
The main object of the present invention is to provide a process for a stable combination. The process is a simple, rapid, cost effective, time-saving and industrially convenient method.
Sitagliptin or a pharmaceutically acceptable salts thereof has stability problems and also it is used at a low rate in formulation, this leads to some stability and content uniformity problems. According to one embodiment of the invention, a tablet formulation comprises sitagliptin or a pharmaceutically acceptable salts thereof and metformin hydrochloride wherein sitagliptin or a pharmaceutically acceptable salts thereof and at least one binder dissolved in a solvent.
In the invention, when sitagliptin or a pharmaceutically acceptable salts thereof and at least one binder is dissolved in a solvent, a solution containing a higher proportion of sitagliptin or a pharmaceutically acceptable salts thereof is obtained, this minimizes active substance losses during granulation and provides more homogeneous (content uniformity) and efficient tablet formulation. Also, solvents are then removed from the environment (preferably by fluid bed dryer), these steps of the method help to provide the desired uniformity and granule structure, so the desired stability of tablet is ensured.
According to one embodiment of the present invention, the amount of sitagliptin or a pharmaceutically acceptable salts thereof is between 1 .0% and 20.0% by weight in the total formulation. Preferably, it is between 2.0% and 15.0% or 3.0% and 10.0% by weight in the total formulation.
According to one embodiment of the present invention, the amount of metformin hydrochloride is between 60.0% and 90.0% by weight in the total formulation. Preferably, it is between 65.0% and 80.0% by weight in the total formulation.
Also, as known, metformin is a very poorly compressible active substance and in the present invention, metformin presents in high amounts in the tablet. It was surprisingly found that when prepared the tablet formulation with a solution sitagliptin or a pharmaceutically acceptable salts thereof and at least one binder, it was observed that the desired tablet hardness and compressibility of metformin HCI is provided. So, an easy method was created to eliminate the disadvantages of both active ingredients.
Suitable binders are selected from the group comprising polyvinylpyrrolidone, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate, pregelatinized starch, natural gums, sucrose, sodium alginate, carboxy methyl cellulose, methyl cellulose, gelatin, carrageenan, guar gum, carbomer, polymethacrylates, methacrylate polymers, gelatin, agar, alginate, xanthan gum, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, aluminum hydroxide, laponit, bentonit, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof.
According to one embodiment of the present invention, the amount of binders is between 1 .0% and 15.0% by weight in the total formulation. Preferably, it is between 2.0% and 11 .0% or 3.0% and 8.0% by weight in the total formulation. According to one embodiment of the present invention, the binder is polyvinylpyrrolidone.
According to one embodiment of the invention, solvent is pure water.
According to one embodiment of the invention, sitagliptin or a pharmaceutically acceptable salts thereof and at least one binder is dissolved in a solvent and a solution is obtained. Also, after at least one binder is dissolved in a solvent and another solution is obtained. Surprisingly, it has been found that the introduction of the binder in two steps in this way is more advantageous than using a binder in one step (one granulation). It provides that granule bulk density is improved and also, the desired tablet hardness and compressibility has improved considerably.
According to one embodiment of the present invention, the binder is added to the formulation in two steps.
According to one embodiment of the present invention, the granulation final moisture (after solvents are removed from the environment) is between 2% and 3.5%. When the humidity is out of this range, the desired compressibility and hardness does not occur. The desired hardness and compressibility of tablet is important. Because it helps to provide the desired dissolution profile of tablet.
In general terms, excipients provided in a formulation may positively or negatively influence the physicochemical and pharmacokinetic properties, e.g. the solubility, absorption, bioavailability of an active agent. For this reason, the excipients which accompany an active agent have to be selected in a careful and conscious manner while a formulation is developed. The formulations should have no physicochemical incompatibility between the active agents and the excipients.
According to one embodiment of the invention, a tablet further comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising fillers, disintegrants, lubricants, glidants, surfactants, coating agents or mixtures.
Suitable fillers are selected from the group comprising microcrystalline cellulose, talc, dibasic calcium phosphate, mannitol, spray-dried mannitol, lactose, lactose monohydrate, starch, dextrose, sucrose, fructose, sodium carbonate, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium bicarbonate, calcium carbonate or mixtures thereof. According to one embodiment of the present invention, the amount of fillers is between 1 .0% and 15.0% by weight in the total formulation. Preferably, it is between 2.0% and 11.0% or 3.0% and 8.0% by weight in the total formulation.
According to one embodiment of the present invention, the filler is microcrystalline cellulose or talc or mixtures thereof.
Suitable disintegrants are selected from the group comprising croscarmellose sodium, sodium starch glycolate, pregelatinized starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, polyacryline potassium, sodium alginate, corn starch, alginates, ion-exchange resins, magnesium aluminum silica, sodium dodecyl sulphate, poloxamer, sodium glycine carbonate or mixtures thereof.
According to one embodiment of the present invention, the amount of disintegrants is between 1.0% and 15.0% by weight in the total formulation. Preferably, it is between 2.0% and 11 .0% or 3.0% and 8.0% by weight in the total formulation.
According to one embodiment of the present invention, the disintegrant is croscarmellose sodium.
Suitable lubricants are selected from the group comprising from sodium stearyl fumarate, magnesium stearate, calcium stearate, zinc stearate, waxes, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, glyceryl palmito sulphate or mixtures thereof.
According to one embodiment of the present invention, the amount of lubricants is between 0.5% and 5.0% by weight in the total formulation.
According to one embodiment of the present invention, the lubricant is sodium stearyl fumarate.
Suitable glidants are selected from the group comprising colloidal silicon dioxide, corn starch or mixtures thereof.
According to one embodiment of the present invention, the amount of glidants is between 0.05% and 3.0% by weight in the total formulation.
According to one embodiment of the present invention, the glidant is colloidal silicon dioxide. Suitable surfactants are selected from the group comprising sodium lauryl sulphate, sodium docusate, glyceryl monooleate, polyethylene alkyl ether, polyoxyethylene stearates, polyethylene glycol, sodium benzoate, docusate sodium, alpha tocopherol, ascorbyl palmitate, polyoxyethylene hydrogenated castor oil or mixtures thereof.
According to one embodiment of the present invention, the amount of surfactants is between 0.05% and 3.0% by weight in the total formulation.
According to one embodiment of the present invention, the surfactant is sodium lauryl sulphate.
Suitable coating agents are selected from the group comprising copovidone, polymethacrylates, polydextrose, polyalkylacrylates copolymers, triacetin, hydroxyl propyl methyl cellulose, colloidal silicon dioxide, lactose monohydrate, medium chain triglycerides, hydroxypropyl cellulose, white wax, polyvinyl alcohol, polyethylene glycol, talc, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), all kinds of Opadry®, pigments, dyes, titanium dioxide, red iron oxide, black iron oxide or mixtures thereof.
According to one embodiment of the present invention, the amount of coating comprising coating agents is between 0.5% and 5.0% by weight in the total formulation.
According to one embodiment of the present invention, the coating agents are polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, red iron oxide, black iron oxide or mixture thereof.
As used here in, ‘particle size distribution’ means the cumulative volume size distribution as tested by any conventionally accepted method such as the laser diffraction method (i.e. malvern analysis) .The term d(0.5) means, the size at which 50% by volume of the particles are finer, the term d(0.9) means, the size at which 90% by volume of the particles are finer.
According to one embodiment of the invention, sitagliptin or a pharmaceutically acceptable salts thereof has a particle size of d(0.5) less than 50 pm or less than 40 pm or less than 30 pm. This property provides improved flow properties, also it helps to provide the desired dissolution profile.
According to one embodiment of the invention, sitagliptin or a pharmaceutically acceptable salts thereof has a particle size of d(0.5) between 30 pm and 15 pm. According to one embodiment of the invention, sitagliptin or a pharmaceutically acceptable salts thereof has a particle size of d(0.9) less than 70 pm or less than 60 pm or less than 50 pm. This property provides improved flow properties, also it helps to provide the desired dissolution profile.
According to one embodiment of the invention, sitagliptin or a pharmaceutically acceptable salts thereof has a particle size of d(0.9) between 50 pm and 20 pm.
The tablet of the present invention may be prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression, wet granulation or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion/spheronization, slugging, spray drying and solvent evaporation.
Example 1 : The tablet formulation comprising metformin HCI and sitagliptin HCI
Process for example 1 ;
Internal phase
Sieving metformin,
Adding microcrystalline cellulose and croscarmellose sodium and then mixing and obtaining a powder mixture,
Preparing the solution 1 , o Dissolving sitagliptin and polyvinylpyrrolidone in a solvent, preferably pure water,
Preparing the solution 2, o Dissolving polyvinylpyrrolidone in a solvent, preferably pure water, Then, granulating the powder mixture and the solution 1 in the fluid bed dryer and drying,
- Sieving the mixture and obtained granules,
- Granulating the granules with the solution 2 in the fluid bed dryer and drying,
- Sieving the mixture and obtained granules.
External phase
- Mixing the granules, colloidal silicone dioxide and sodium lauryl sulphate,
- Adding sodium stearyl fumarate and mixing,
- Compressing the mixture to form of tablet,
- Coating tablets with a coating comprising coating agents.
Example 2: The tablet formulation comprising metformin HCI and sitagliptin HCI
Process for example 2;
Internal phase
Sieving metformin,
- Adding talc and croscarmellose sodium and then mixing and obtaining a powder mixture,
Preparing the solution 1 , o Dissolving sitagliptin and polyvinylpyrrolidone in a solvent, preferably pure water,
Preparing the solution 2, o Dissolving polyvinylpyrrolidone in a solvent, preferably pure water,
Then, granulating the powder mixture and the solution 1 in the fluid bed dryer and drying,
- Sieving the mixture and obtained granules,
- Granulating the granules with the solution 2 in the fluid bed dryer and drying,
- Sieving the mixture and obtained granules.
External phase
- Mixing the granules, colloidal silicone dioxide, croscarmellose sodium and sodium lauryl sulphate,
- Adding sodium stearyl fumarate and mixing,
- Compressing the mixture to form of tablet,
- Coating tablets with a coating comprising coating agents.

Claims

CLAIMS A tablet formulation comprises sitagliptin or a pharmaceutically acceptable salts thereof and metformin hydrochloride wherein sitagliptin or a pharmaceutically acceptable salts thereof and at least one binder dissolves in in a solvent. The tablet formulation according to claim 1 , wherein the amount of sitagliptin or a pharmaceutically acceptable salts thereof is between 1.0% and 20.0% by weight in the total formulation. The tablet formulation according to claim 1 , wherein the amount of metformin hydrochloride is between 60.0% and 90.0% by weight in the total formulation. The tablet formulation according to claim 1 , wherein binders are selected from the group comprising polyvinylpyrrolidone, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate, pregelatinized starch, natural gums, sucrose, sodium alginate, carboxy methyl cellulose, methyl cellulose, gelatin, carrageenan, guar gum, carbomer, polymethacrylates, methacrylate polymers, gelatin, agar, alginate, xanthan gum, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, aluminum hydroxide, laponit, bentonit, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof. The tablet formulation according to claim 4, wherein the amount of binders is between 1 .0% and 15.0% by weight in the total formulation. The tablet formulation according to claim 5, wherein the binder is polyvinylpyrrolidone. The tablet formulation according to claim 6, wherein the binder is added to the formulation in two steps. The tablet formulation according to claim 1 , wherein further comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising fillers, disintegrants, lubricants, glidants, surfactants, coating agents or mixtures. The tablet formulation according to claim 8, wherein fillers are selected from the group comprising microcrystalline cellulose, talc, dibasic calcium phosphate, mannitol, spray-dried mannitol, lactose, lactose monohydrate, starch, dextrose, sucrose, fructose, sodium carbonate, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium bicarbonate, calcium carbonate or mixtures thereof. The tablet formulation according to claim 9, wherein the amount of fillers is between 1 .0% and 15.0% by weight in the total formulation. The tablet formulation according to claim 9, wherein the filler is microcrystalline cellulose or talc or mixtures thereof. The tablet formulation according to claim 8, wherein disintegrants are selected from the group comprising croscarmellose sodium, sodium starch glycolate, pregelatinized starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, polyacryline potassium, sodium alginate, corn starch, alginates, ion-exchange resins, magnesium aluminum silica, sodium dodesyl sulphate, poloxamer, sodium glycine carbonate or mixtures thereof. The tablet formulation according to claim 12, wherein the amount of disintegrants is between 1 .0% and 15.0% by weight in the total formulation. The tablet formulation according to claim 1 , wherein sitagliptin or a pharmaceutically acceptable salts thereof has a particle size of d(0.5) less than 50 pm or less than 40 pm or less than 30 pm. The tablet formulation according to claim 1 , wherein sitagliptin or a pharmaceutically acceptable salts thereof has a particle size of d(0.9) less than 70 pm or less than 60 pm or less than 50 pm.
EP21856361.7A 2020-08-11 2021-08-02 A tablet formulation comprising sitagliptin and metformín Pending EP4196107A4 (en)

Applications Claiming Priority (2)

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TR2020/12601A TR202012601A2 (en) 2020-08-11 2020-08-11 TABLET FORMULATION CONTAINING CYTAGLIPTIN AND METFORMIN
PCT/TR2021/050760 WO2022035400A1 (en) 2020-08-11 2021-08-02 A tablet formulation comprising sitagliptin and metformi̇n

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US20080064701A1 (en) * 2007-04-24 2008-03-13 Ramesh Sesha Anti-diabetic combinations
US20150366863A1 (en) * 2013-03-28 2015-12-24 Wockhardt Limited Solid oral pharmaceutical compositions comprising fixed dose combination of metformin and sitagliptin or salts thereof
WO2014174469A1 (en) * 2013-04-25 2014-10-30 Ranbaxy Laboratories Limited Pharmaceutical compositions comprising a combination of sitagliptin and metformin
CN106074553B (en) * 2016-06-13 2019-02-22 杭州华东医药集团新药研究院有限公司 Pharmaceutical composition containing Xi Gelieting and melbine
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