EP4171532A1 - A stable combination of vildagliptin and metformin hci - Google Patents

A stable combination of vildagliptin and metformin hci

Info

Publication number
EP4171532A1
EP4171532A1 EP21828954.4A EP21828954A EP4171532A1 EP 4171532 A1 EP4171532 A1 EP 4171532A1 EP 21828954 A EP21828954 A EP 21828954A EP 4171532 A1 EP4171532 A1 EP 4171532A1
Authority
EP
European Patent Office
Prior art keywords
sodium
vildagliptin
tablet formulation
formulation according
mixtures
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
EP21828954.4A
Other languages
German (de)
French (fr)
Other versions
EP4171532A4 (en
Inventor
Vildan TOMBAYOGLU
Yildiz Gulkok
Arzu PALANTOKEN
Fatih Sunel
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 EP4171532A1 publication Critical patent/EP4171532A1/en
Publication of EP4171532A4 publication Critical patent/EP4171532A4/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
    • 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
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K9/2004—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

Definitions

  • the present invention relates to a tablet formulation comprising vildagliptin and metformin hydrochloride wherein vildagliptin and at least one acidifying agent is dissolved in a solvent.
  • 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.
  • Vildagliptin is a dipeptidyl dipeptidase-IV (DPP-IV) inhibitor developed for use in the treatment of type 2 diabetes (non-insulin dependent diabetes).
  • DPP-IV dipeptidyl dipeptidase-IV
  • vildagliptin inhibits the degradation of the dipeptidyl dipeptidase-IV enzyme, thereby inhibiting the effects of incretin hormones, glucagon-like peptide-1 (GLP-1), and of glucose-dependent insulinotropic peptide (GIP).
  • GLP-1 glucagon-like peptide-1
  • GIP glucose-dependent insulinotropic peptide
  • the chemical designation of vildagliptin is (S)- ⁇ [(3-hydroxyadamantan-1- yl)amino]acetyl ⁇ pyrrolidine-2-carbonitrile, with the chemical structure illustrated below in Formula 1 .
  • Formula 1 Vildagliptin is soluble in water and in organic polar solvents.
  • Vildagliptin is marketed under the trademark Galvus ® in 50 mg dosage forms. It is used against diabetes mellitus, but particularly in treating type 2 diabetes.
  • 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 500 to 850 mg. 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 II.
  • Combination product of vildagliptin and metformin hydrochloride is marketed under the trademark Eucreas® (50mg/850mg and 50mg/1000mg dosage forms of vildagliptin and metformin hydrochloride).
  • Eucreas® 50mg/850mg and 50mg/1000mg dosage forms of vildagliptin and metformin hydrochloride.
  • a tablet disclosed can contain, in addition to the active substances, usual excipients, for example fillers, binders, disintegrants, lubricants and colorants.
  • lubricants that are mentioned are colloidal silica, magnesium trisilicate, starch, talc, calcium phosphate, magnesium stearate, aluminium stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, cellulose and microcrystalline cellulose.
  • EP2477660 (A1) discloses a pharmaceutical composition
  • a pharmaceutical composition comprising an active agent metformin or its salt in combination with an active agent sitagliptin or vildagliptin or their salt, and a lubricant (more than 10 wt.%, based on the total weight of the composition).
  • the lubricant is polyethylene glycol or a mixture of polyethylene glycol with at least one of the other lubricant.
  • vildagliptin Both metformin HCI and vildagliptin have some structural problems. Stability-related problems do occur in many active agents, including vildagliptin, under the influence of ambient and physical conditions.
  • Vildagliptin is an active agent that is highly-susceptible to air and humidity. When vildagliptin is exposed to air and humidity, it degrades structurally and develops chemical behavioral changes. The stability of vildagliptin products developed is not at a desired level and the shelf life thereof is shortened.
  • vildagliptin 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.
  • vildagliptin salt was obtained and that it was tested while preparing the formulation and it was seen that is advantageous in that they show no measurable water absorption or loss. So, in this way was prevented degrade of vildagliptin and provided stabilizing of formulation.
  • vildagliptin and at least one acidifying agent is dissolved in a solvent and then vildagliptin salt is obtained. So, this formulation overcomes the above problems. In this way, starting with improved constancy of the physical parameters, an even higher quality of the formulations can be guaranteed.
  • the main object of the present invention is to provides a tablet comprising vildagliptin and metformin HCI capable of being compressed into a tablet having desired stability, rapid disintegration time and an acceptable dissolution profile.
  • Another object of the present invention is to eliminate problems and bringing additional advantages to the relevant prior art.
  • the main object of the present invention is to provides a process for a stable combination. The process is a simple, rapid, cost effective, time-saving and industrially convenient method.
  • solution means a form comprising vildagliptin, at least one acidifying agent and at least one binder are dissolved in a solvent, preferably 65% ethyl alcohol- water.
  • a tablet formulation comprises vildagliptin in a solution and metformin hydrochloride wherein the solution comprising dissolving vildagliptin and dissolving at least one acidifying agent and dissolving at least one binder in a solvent.
  • vildagliptin and at least one acidifying agent is dissolved in a solvent and then vildagliptin salt is obtained.
  • stability of the tablet formulation is provided, because vildagliptin salt is advantageous in that they show no measurable water absorption or loss and the active agent, vildagliptin, does not undergo degrade. This property is crucial in manufacture.
  • the solution comprising vildagliptin salts was used directly in the process without the need for crystallization. This allowed us to save time without using solvent. Thus, a stable combination was achieved a fast, practical and cheap.
  • vildagliptin salt helps to improve stability and dissolution profile when contained in a formulation comprising a further active ingredient, metformin HCI. Surprisingly, in the present invention, it was seen that the vildagliptin salt is also have the advantage to avoid or reduce the degradation of the further active ingredient.
  • Suitable acidifying agent is selected from the group comprising hydrochloric acid, citric acid, citric acid anhydrate, tartaric acid, ascorbic acid, malic acid, oxalic acid, succinate, acetic acid, butyric acid, malonic acid, formic acid, fumaric acid or mixtures thereof.
  • the amount of acidifying agent is between 0.1% and 5.0% by weight in the total formulation.
  • the amount of the acidifying agent in is from 1 mole to 1.5 moles per mole of the vildagliptin, preferably from 1.0 to 1.3 moles per mole of the vildagliptin. This proportions are very important for the preparation of vildagliptin salt, therefore for a stable combination.
  • the acidifying agent is hydrochloric acid.
  • 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, laponite, bentonite, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof.
  • the use of binders provides easy distribution of the solution in the formulation. So, it helps to provide the desired dissolution profile in the formulation.
  • the amount of binders is between 1 .0% and 20.0% by weight in the total formulation. Preferably, it is between 2.0% and 10.0% or 3.0% and 7.0% by weight in the total formulation.
  • the binder is polyvinylpyrrolidone or hydroxypropyl methyl cellulose or mixtures thereof.
  • preparing the solution comprises the following steps;
  • the amount of metformin hydrochloride is between 50.0% and 90.0% by weight in the total formulation. Preferably, it is between 60.0% and 80.0% by weight in the total formulation.
  • the amount of vildagliptin is between 2.0% and 20.0% by weight in the total formulation. Preferably, it is between 2.0% and 10.0% or 2.0% and 7.0% by weight in the total formulation.
  • a tablet comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising fillers, disintegrants, lubricants, glidants, surfactants, anti-caking agent, coating agents or mixtures.
  • 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.
  • Suitable fillers are selected from the group comprising microcrystalline cellulose, 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 2.0% and 20.0% by weight in the total formulation. Preferably, it is between 2.0% and 10.0% or 3.0% and 7.0% by weight in the total formulation.
  • the filler is microcrystalline cellulose.
  • 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 silicate, sodium dodecyl sulphate, poloxamer, sodium glycine carbonate or mixtures thereof.
  • the amount of disintegrants is between 2.0% and 10.0% by weight in the total formulation.
  • the disintegrant is croscarmellose sodium or sodium starch glycolate or mixtures thereof.
  • 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, glycerol 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 or magnesium stearate or mixtures thereof.
  • Suitable glidants are selected from the group comprising colloidal silicon dioxide, corn starch or mixtures thereof.
  • the amount of glidants is between 0.1% and 2.0% 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 0.1% and 2.0% by weight in the total formulation.
  • the surfactant is sodium lauryl sulphate.
  • Suitable anti-caking agent is selected from the group comprising talc, calcium phosphate, tribasic, calcium silicate, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate or mixtures thereof.
  • the anti-caking agent is talc.
  • the amount of anti-caking agent is between 0.01% and 3.0% by weight in the total formulation.
  • 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 2.0% 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.
  • the tablet of the present invention may be prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression, granulation wet 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 vildagliptin and metformin HCI
  • Example 2 The tablet formulation comprising vildagliptin and metformin HCI
  • Adding microcrystalline cellulose and croscarmellose sodium and then mixing and obtained a powder mixture Preparing the solution o Adding vildagliptin in a solvent, preferably 65% ethyl alcohol- water, o Then, adding hydrochloric acid (37.0% hydrochloric acid-water) and mixing, o Then, adding polyvinylpyrrolidone and mixing.
  • a solvent preferably 65% ethyl alcohol- water
  • hydrochloric acid 37.0% hydrochloric acid-water
  • Example 3 The tablet formulation comprising vildagliptin and metformin HCI
  • Example 4 The tablet formulation comprising vildagliptin and metformin HCI

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Abstract

The present invention relates to a tablet formulation comprising vildagliptin and metformin hydrochloride wherein vildagliptin and at least one acidifying agent is dissolved in a solvent. The present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient process.

Description

A STABLE COMBINATION OF VILDAGLIPTIN AND METFORMIN HCI Field of the Invention
The present invention relates to a tablet formulation comprising vildagliptin and metformin hydrochloride wherein vildagliptin and at least one acidifying agent is dissolved in a solvent. 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.
Vildagliptin is a dipeptidyl dipeptidase-IV (DPP-IV) inhibitor developed for use in the treatment of type 2 diabetes (non-insulin dependent diabetes). Vildagliptin inhibits the degradation of the dipeptidyl dipeptidase-IV enzyme, thereby inhibiting the effects of incretin hormones, glucagon-like peptide-1 (GLP-1), and of glucose-dependent insulinotropic peptide (GIP). The chemical designation of vildagliptin is (S)-{[(3-hydroxyadamantan-1- yl)amino]acetyl}pyrrolidine-2-carbonitrile, with the chemical structure illustrated below in Formula 1 .
Formula 1 Vildagliptin is soluble in water and in organic polar solvents.
Vildagliptin is marketed under the trademark Galvus® in 50 mg dosage forms. It is used against diabetes mellitus, but particularly in treating type 2 diabetes.
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 500 to 850 mg. 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 II.
Formula II
Combination product of vildagliptin and metformin hydrochloride is marketed under the trademark Eucreas® (50mg/850mg and 50mg/1000mg dosage forms of vildagliptin and metformin hydrochloride). Pharmaceutical formulations of combined respective active ingredients and the process for their preparation are disclosed in EP 1948149.
Combination preparations of metformin and vildagliptin are described in WO 2007/041053. A tablet disclosed can contain, in addition to the active substances, usual excipients, for example fillers, binders, disintegrants, lubricants and colorants. Examples of lubricants that are mentioned are colloidal silica, magnesium trisilicate, starch, talc, calcium phosphate, magnesium stearate, aluminium stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, cellulose and microcrystalline cellulose.
EP2477660 (A1) discloses a pharmaceutical composition comprising an active agent metformin or its salt in combination with an active agent sitagliptin or vildagliptin or their salt, and a lubricant (more than 10 wt.%, based on the total weight of the composition). The lubricant is polyethylene glycol or a mixture of polyethylene glycol with at least one of the other lubricant.
Both metformin HCI and vildagliptin have some structural problems. Stability-related problems do occur in many active agents, including vildagliptin, under the influence of ambient and physical conditions. Vildagliptin is an active agent that is highly-susceptible to air and humidity. When vildagliptin is exposed to air and humidity, it degrades structurally and develops chemical behavioral changes. The stability of vildagliptin products developed is not at a desired level and the shelf life thereof is shortened. In addition, vildagliptin 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.
In terms of the stability of this combination, alternative approaches were needed to overcome the above disadvantages of vildagliptin.
Improved physicochemical properties of certain salts or certain salt hydrates are of great importance both when produced as a pharmaceutically active substance and when producing and storing.
In the present invention, vildagliptin salt was obtained and that it was tested while preparing the formulation and it was seen that is advantageous in that they show no measurable water absorption or loss. So, in this way was prevented degrade of vildagliptin and provided stabilizing of formulation.
In the present invention, vildagliptin and at least one acidifying agent is dissolved in a solvent and then vildagliptin salt is obtained. So, this formulation overcomes the above problems. In this way, starting with improved constancy of the physical parameters, an even higher quality of the formulations can be guaranteed.
Detailed Description of the Invention
The main object of the present invention is to provides a tablet comprising vildagliptin and metformin HCI capable of being compressed into a tablet having desired stability, rapid disintegration time and an acceptable dissolution profile.
Another object of the present invention is to eliminate problems and bringing additional advantages to the relevant prior art. The main object of the present invention is to provides a process for a stable combination. The process is a simple, rapid, cost effective, time-saving and industrially convenient method.
As used here in, ‘solution’ means a form comprising vildagliptin, at least one acidifying agent and at least one binder are dissolved in a solvent, preferably 65% ethyl alcohol- water.
According to one embodiment of the invention, a tablet formulation comprises vildagliptin in a solution and metformin hydrochloride wherein the solution comprising dissolving vildagliptin and dissolving at least one acidifying agent and dissolving at least one binder in a solvent.
In the present invention, vildagliptin and at least one acidifying agent is dissolved in a solvent and then vildagliptin salt is obtained. So, stability of the tablet formulation is provided, because vildagliptin salt is advantageous in that they show no measurable water absorption or loss and the active agent, vildagliptin, does not undergo degrade. This property is crucial in manufacture. Also, the solution comprising vildagliptin salts was used directly in the process without the need for crystallization. This allowed us to save time without using solvent. Thus, a stable combination was achieved a fast, practical and cheap.
Furthermore, vildagliptin salt helps to improve stability and dissolution profile when contained in a formulation comprising a further active ingredient, metformin HCI. Surprisingly, in the present invention, it was seen that the vildagliptin salt is also have the advantage to avoid or reduce the degradation of the further active ingredient.
Suitable acidifying agent is selected from the group comprising hydrochloric acid, citric acid, citric acid anhydrate, tartaric acid, ascorbic acid, malic acid, oxalic acid, succinate, acetic acid, butyric acid, malonic acid, formic acid, fumaric acid or mixtures thereof.
According to one embodiment of the present invention, the amount of acidifying agent is between 0.1% and 5.0% by weight in the total formulation.
According to one embodiment of the present invention, the amount of the acidifying agent in is from 1 mole to 1.5 moles per mole of the vildagliptin, preferably from 1.0 to 1.3 moles per mole of the vildagliptin. This proportions are very important for the preparation of vildagliptin salt, therefore for a stable combination.
According to one embodiment of the present invention, the acidifying agent is hydrochloric acid. 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, laponite, bentonite, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof.
According to one embodiment of the present invention, the use of binders provides easy distribution of the solution in the formulation. So, it helps to provide the desired dissolution profile in the formulation.
According to one embodiment of the present invention, the amount of binders is between 1 .0% and 20.0% by weight in the total formulation. Preferably, it is between 2.0% and 10.0% or 3.0% and 7.0% by weight in the total formulation.
According to one embodiment of the present invention, the binder is polyvinylpyrrolidone or hydroxypropyl methyl cellulose or mixtures thereof.
According to one embodiment of the present invention, preparing the solution comprises the following steps;
- At room condition, adding vildagliptin in a solvent, preferably 65% ethyl alcohol- water,
- Then, adding at least one acidifying agent and mixing,
- Then, adding at least one binder and mixing.
According to one embodiment of the present invention, the amount of metformin hydrochloride is between 50.0% and 90.0% by weight in the total formulation. Preferably, it is between 60.0% and 80.0% by weight in the total formulation.
According to one embodiment of the present invention, the amount of vildagliptin is between 2.0% and 20.0% by weight in the total formulation. Preferably, it is between 2.0% and 10.0% or 2.0% and 7.0% by weight in the total formulation.
According to one embodiment of the invention, a tablet comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising fillers, disintegrants, lubricants, glidants, surfactants, anti-caking agent, coating agents or mixtures. 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.
Suitable fillers are selected from the group comprising microcrystalline cellulose, 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 2.0% and 20.0% by weight in the total formulation. Preferably, it is between 2.0% and 10.0% or 3.0% and 7.0% by weight in the total formulation.
According to one embodiment of the present invention, the filler is microcrystalline cellulose.
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 silicate, sodium dodecyl sulphate, poloxamer, sodium glycine carbonate or mixtures thereof.
According to one embodiment of the present invention, the amount of disintegrants is between 2.0% and 10.0% by weight in the total formulation.
According to one embodiment of the present invention, the disintegrant is croscarmellose sodium or sodium starch glycolate or mixtures thereof.
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, glycerol 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 or magnesium stearate or mixtures thereof.
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 0.1% and 2.0% 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 0.1% and 2.0% by weight in the total formulation.
According to one embodiment of the present invention, the surfactant is sodium lauryl sulphate.
Suitable anti-caking agent is selected from the group comprising talc, calcium phosphate, tribasic, calcium silicate, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate or mixtures thereof.
According to one embodiment of the present invention, the anti-caking agent is talc.
According to one embodiment of the present invention, the amount of anti-caking agent is between 0.01% and 3.0% by weight in the total formulation.
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 2.0% 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.
The tablet of the present invention may be prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression, granulation wet 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 vildagliptin and metformin HCI Example 2: The tablet formulation comprising vildagliptin and metformin HCI
Process for example 1 or 2;
Internal phase
Sieving metformin,
Adding microcrystalline cellulose and croscarmellose sodium and then mixing and obtained a powder mixture Preparing the solution o Adding vildagliptin in a solvent, preferably 65% ethyl alcohol- water, o Then, adding hydrochloric acid (37.0% hydrochloric acid-water) and mixing, o Then, adding polyvinylpyrrolidone and mixing.
- Then, granulating the powder mixture and the solution in the fluid bed dryer and drying,
Sieving the mixture,
Adding the remaining polyvinylpyrrolidone in the mixture and granulating in the fluid bed dryer and drying
- Sieving the mixture and obtained granule. External phase
- Mixing the granules and colloidal silicone dioxide and sodium lauryl sulfate,
- Adding sodium stearyl fumarate and mixing,
- Compressing the mixture to form of tablet,
- Coating tablets with coating agents.
Example 3: The tablet formulation comprising vildagliptin and metformin HCI Example 4: The tablet formulation comprising vildagliptin and metformin HCI
Process for example 3 or 4;
Internal phase
Sieving metformin,
- Adding microcrystalline cellulose and sodium starch glycolate and then mixing and obtained a powder mixture
Preparing the solution o Adding vildagliptin in a solvent, preferably 65% ethyl alcohol- water, o Then, adding hydrochloric acid (37.0% hydrochloric acid-water) and mixing, o Then, adding hydroxypropyl methyl and talc and mixing.
- Then, granulating the powder mixture and the solution in the fluid bed dryer and drying,
- Sieving the mixture and obtained granules.
External phase
- Mixing the granules and colloidal silicone dioxide,
- Adding magnesium stearate and mixing,
- Compressing the mixture to form of tablet,
- Coating tablets with coating agents.

Claims

1 . A tablet formulation comprising vildagliptin in a solution and metformin hydrochloride wherein the solution comprising dissolving vildagliptin and dissolving at least one acidifying agent and dissolving at least one binder in a solvent.
2. The tablet formulation according to claim 1 , wherein acidifying agent is selected from the group comprising hydrochloric acid, citric acid, citric acid anhydrate, tartaric acid, ascorbic acid, malic acid, oxalic acid, succinate, acetic acid, butyric acid, malonic acid, formic acid, fumaric acid or mixtures thereof.
3. The tablet formulation according to claim 2, wherein the amount of the acidifying agent in is from 1 mole to 1.5 moles per mole of the vildagliptin, preferably from 1.0 to 1.3 moles per mole of the vildagliptin.
4. The tablet formulation according to claim 3, wherein the acidifying agent is hydrochloric acid.
5. 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.
6. The tablet formulation according to claim 5, wherein the amount of binders is between 1 .0% and 20.0% by weight in the total formulation. Preferably, it is between 2.0% and 10.0% or 3.0% and 7.0% by weight in the total formulation.
7. The tablet formulation according to claim 6, wherein the binder is polyvinylpyrrolidone or hydroxypropyl methyl cellulose or mixtures thereof.
8. The tablet formulation according to claim 1 , further comprising at least one pharmaceutically acceptable excipient which is selected from the group comprising fillers, disintegrants, lubricants, glidants, surfactants, anti-caking agents, coating agents or mixtures.
9. The tablet formulation according to claim 8, wherein fillers are selected from the group comprising microcrystalline cellulose, 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.
10. 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 dodecyl sulphate, poloxamer, sodium glycine carbonate or mixtures thereof.
11. The tablet formulation according to claim 8, wherein 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, glycerol palmito sulphate or mixtures thereof.
12. The tablet formulation according to claim 8, wherein glidants are selected from the group comprising colloidal silicon dioxide, corn starch or mixtures thereof.
13. The tablet formulation according to claim 8, wherein 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.
EP21828954.4A 2020-06-25 2021-05-07 A stable combination of vildagliptin and metformin hci Pending EP4171532A4 (en)

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TR2020/09946A TR202009946A2 (en) 2020-06-25 2020-06-25 A STABLE COMBINATION WITH VILDAGLIPTIN AND METFORMIN HCI
PCT/TR2021/050442 WO2021262115A1 (en) 2020-06-25 2021-05-07 A stable combination of vildagliptin and metformin hci

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CN101181264A (en) * 2007-11-27 2008-05-21 北京润德康医药技术有限公司 Pharmaceutical composition taking metformin hydrochloride and vigelegting as active component as well as preparing method and uses thereof
CN101234105A (en) * 2008-01-09 2008-08-06 北京润德康医药技术有限公司 Pharmaceutical composition containing diabetosan and vildagliptin and preparation thereof
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EA032126B1 (en) * 2013-12-23 2019-04-30 Крка, Д.Д. Ново Место Solid pharmaceutical composition comprising metformin and vildagliptin and process for manufacturing same
MA40869A (en) * 2014-10-30 2017-09-05 Sanovel Ilac Sanayi Ve Ticaret As PHARMACEUTICAL COMBINATIONS OF VILDAGLIPTIN AND PPAR AGONISTS
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