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WO2021262114A1 - An orally disintegrating tablet formulation comprising sitagliptin - Google Patents

An orally disintegrating tablet formulation comprising sitagliptin Download PDF

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Publication number
WO2021262114A1
WO2021262114A1 PCT/TR2021/050440 TR2021050440W WO2021262114A1 WO 2021262114 A1 WO2021262114 A1 WO 2021262114A1 TR 2021050440 W TR2021050440 W TR 2021050440W WO 2021262114 A1 WO2021262114 A1 WO 2021262114A1
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Prior art keywords
orally disintegrating
disintegrating tablet
weight
sitagliptin
tablet formulation
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.)
Ceased
Application number
PCT/TR2021/050440
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French (fr)
Inventor
Seval Ataman
Muge ULUSOY BOZYEL
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
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Sanovel Ilac Sanayi ve Ticaret AS
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Priority to EP21830086.1A priority Critical patent/EP4167969A4/en
Publication of WO2021262114A1 publication Critical patent/WO2021262114A1/en
Anticipated expiration legal-status Critical
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    • 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
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to an orally disintegrating tablet formulation comprising sitagliptin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. Further, the present invention provides a method for the preparation of said orally disintegrating tablet.
  • 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.
  • 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.
  • the chemical name of sitagliptin is (R) -4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1 ,2,4] triazolo [4,3-a] pyrazin-7 (8H)-yl]-1- (2,4,5-trifluorophenyl) butan-2-amine), and the chemical structure of sitagliptin is shown in Formula 1.
  • the film-coated tablets of Sitagliptin named as Januvia ® are being marketed by Merck in the USA.
  • the Januvia ® tablet contains 32.13, 64.25, or 128.5 mg of sitagliptin phosphate monohydrate, which is equivalent to 25, 50, or 100 mg, respectively, of free base.
  • Conventional tablet dosage forms constitute a preferred route of administration but certain groups of patients including geriatric, bed-ridden, uncooperative, nauseated, on reduced water intake, and patients having dysphagia, difficulty in swallowing, encounter problems while taking these dosage forms. Moreover, patients while travelling may have little or no access to water, limiting the use of conventional tablet dosage forms. As antidiabetic drugs are prescribed chronically, such a problem could lead to a high level of patient non- compliance.
  • orally disintegrating tablet formulations provide the best alternative over conventional tablet dosage forms.
  • Orally disintegrating tablet compositions which rapidly disintegrate on contact with saliva or in a small amount of water, offer increased convenience and ease of administration with the potential to achieve better patient compliance. Especially, it provides extra advantage for geriatric, and neurodegenerative disease patients who have difficulty in swallowing conventional tablets or capsules. It will be easy and fast to use when the patient needs it.
  • the main objective of the invention is to realize a tablet comprising sitagliptin or a pharmaceutically acceptable salt thereof which can be taken by oral route without needing water, so it provides easy use for the patient.
  • an orally disintegrating tablet form is used. In this way, a form with both the easy use for the patient and the desired dissolution profile is provided.
  • Another object of the present invention is to provide the desired stability and a good taste for the patient's easy use.
  • an orally disintegrating tablet formulation comprises sitagliptin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
  • the formulation of the invention was designed without having to compromise on stability to achieve the rapidly absorbed and desired dissolution rate which was linked to the surprisingly coordinated effect of using sitagliptin or a pharmaceutically acceptable salt thereof as a source of sitagliptin and using the orally disintegrating tablet.
  • the present invention provides orally disintegrating tablet of sitagliptin or a pharmaceutically acceptable salt thereof that will rapidly disintegrate within three minutes. These compositions have an acceptable taste, offer a pleasant mouth feel, and leave minimal residue in the mouth after administration.
  • the present invention further provides processes for preparing said orally disintegrating tablet. It also provides a method of treating diabetes by administering said orally disintegrating tablet.
  • the amount of sitagliptin or a pharmaceutically acceptable salt thereof is 20.0% to 50.0% by weight in the formulation.
  • the amount of sitagliptin or a pharmaceutically acceptable salt thereof is 25.0% to 45.0% or 27.0% to 40.0% or 28.0% to 37.0% by weight in the formulation.
  • a pharmaceutically acceptable salt of sitagliptin is sitagliptin phosphate or sitagliptin hydrochloride or sitagliptin malate.
  • a pharmaceutically acceptable salt of sitagliptin is sitagliptin malate.
  • the orally disintegrating tablet formulation of sitagliptin or a pharmaceutically acceptable salt thereof needs to be adapted in particular by a careful excipient selection give a suitable porous structure with suitable disintegrating time and high stability.
  • the formulation comprises at least one the pharmaceutically acceptable excipients which are selected from diluents, disintegrants, glidants, lubricants, sweeteners or mixtures thereof.
  • Suitable diluents are selected from the group comprising mannitol, microcrystalline cellulose, sorbitol, sucrose, inorganic salts, calcium salts, polysaccharides, dextrose, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixtures, xylitol, trehalose, heavy magnesium carbonate, starch, sodium carbonate, sodium bicarbonate or mixtures thereof.
  • the amount of diluents is 45.0% to 70.0% by weight in the formulation.
  • the diluent is mannitol or microcrystalline cellulose or mixtures thereof.
  • Mannitol is one of the most suitable diluents for moisture-sensitive formulations, coupled with a pleasant taste and mouthfeel. It is inert, non-hygroscopic diluent used in formulations that are moisture sensitive.
  • Suitable disintegrants are selected from the group comprising crospovidone, alginic acid, ion exchange resins, magnesium aluminum silica, sodium dodecyl sulphate, croscarmellose sodium, sodium carboxymethyl starch, carboxy methyl cellulose calcium, docusate sodium, sodium starch glycolate, sodium glycine carbonate, sodium lauryl sulphate, low substituted HPC (hydroxy propyl cellulose), polyacrylin potasium, poloxamer, xanthan gum, calcium silicate, ion exchange resins and mixtures thereof.
  • the amount of disintegrants is 5.0% to 20.0% by weight, preferably 5.0% to 12.0% by weight in the formulation.
  • the disintegrant is crospovidone.
  • crospovidone is used as disintegrant in the formulation of this present invention to provide porous ODT structure. Further, used crospovidone in the formulation enhances the disintegration time of sitagliptin or a pharmaceutically acceptable salt thereof, so the desired dissolution profile is provided.
  • the orally disintegrating tablet formulation of sitagliptin or a pharmaceutically acceptable salt thereof is disintegrated in less than 1 min, preferably less than 30 sec thanks to the use of disintegrant, especially crospovidone.
  • Suitable glidants are selected from the group comprising talc, colloidal silicon dioxide, colloidal anhydrous silica, aluminium silicate or mixtures thereof.
  • the amount of glidants is 0.01% to 3.0% by weight in the formulation.
  • the glidant is talc.
  • Suitable lubricants are selected from the group comprising magnesium stearate, sodium stearyl fumarate, calcium stearate, sodium lauryl sulphate, magnesium lauryl sulphate, stearic acid, polyethylene glycol, paraffin, fumaric acid, glyceril palmitostearate, hydrogenated vegetable oil, zinc stearate or mixtures thereof.
  • the amount of lubricants is 0.01% to 3.0% by weight in the formulation.
  • the lubricant is magnesium stearate.
  • the ratio of disintegants to lubricants is used in a specific ratio.
  • the ratio is in the range of 1.0 to 12.0 by weight of the formulation, preferably it is in the range of 7.0 to 10.0 by weight of the formulation. It has been surprisingly found that with this ratio, desired flowability has been achieved to compress the formulation into ODTs.
  • the used sweeteners have been improved by using sweeteners that do not interact with the active ingredient, so the patient’s compliance is provided.
  • Suitable sweeteners are selected from the group comprising aspartame, sucralose, saccharin, sodium cyclamate, glucose, lactose, fructose, sorbitol, xylitol, erythritol or mixtures thereof.
  • the amount of sweeteners is 0.05% to 4.0% by weight in the formulation.
  • the sweetener is aspartame.
  • the orally disintegrating tablet formulation comprises;
  • microcrystalline cellulose - 20.0-30.0% by weight of microcrystalline cellulose
  • magnesium stearate - 0.01 -3.0% by weight of magnesium stearate
  • the orally disintegrating tablet formulation of the present invention can be prepared by conventional techniques such as direct compression, dry granulation, or wet granulation.
  • the orally disintegrating tablet formulation is prepared direct compression.
  • Example 1 The ODT formulation comprising sitagliptin or a pharmaceutically acceptable salt thereof
  • Example 2 The ODT formulation comprising sitagliptin malate Process for example 2;

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Abstract

The present invention relates to an orally disintegrating tablet formulation comprising sitagliptin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. Further, the present invention provides a method for the preparation of said orally disintegrating tablet.

Description

AN ORALLY DISINTEGRATING TABLET FORMULATION COMPRISING SITAGLIPTIN Field of the Invention
The present invention relates to an orally disintegrating tablet formulation comprising sitagliptin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. Further, the present invention provides a method for the preparation of said orally disintegrating tablet.
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.
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 (R) -4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1 ,2,4] triazolo [4,3-a] pyrazin-7 (8H)-yl]-1- (2,4,5-trifluorophenyl) butan-2-amine), and the chemical structure of sitagliptin is shown in Formula 1.
Figure imgf000003_0001
Formula 1. Sitagliptin
The film-coated tablets of Sitagliptin named as Januvia® are being marketed by Merck in the USA. The Januvia® tablet contains 32.13, 64.25, or 128.5 mg of sitagliptin phosphate monohydrate, which is equivalent to 25, 50, or 100 mg, respectively, of free base.
In the prior art, there are conventional forms such as tablet or capsule comprising sitagliptin or a pharmaceutically acceptable salt thereof.
Conventional tablet dosage forms constitute a preferred route of administration but certain groups of patients including geriatric, bed-ridden, uncooperative, nauseated, on reduced water intake, and patients having dysphagia, difficulty in swallowing, encounter problems while taking these dosage forms. Moreover, patients while travelling may have little or no access to water, limiting the use of conventional tablet dosage forms. As antidiabetic drugs are prescribed chronically, such a problem could lead to a high level of patient non- compliance.
In view of this, orally disintegrating tablet formulations provide the best alternative over conventional tablet dosage forms. Orally disintegrating tablet compositions which rapidly disintegrate on contact with saliva or in a small amount of water, offer increased convenience and ease of administration with the potential to achieve better patient compliance. Especially, it provides extra advantage for geriatric, and neurodegenerative disease patients who have difficulty in swallowing conventional tablets or capsules. It will be easy and fast to use when the patient needs it. Detailed Description of the Invention
The main objective of the invention is to realize a tablet comprising sitagliptin or a pharmaceutically acceptable salt thereof which can be taken by oral route without needing water, so it provides easy use for the patient. In the present invention, an orally disintegrating tablet form is used. In this way, a form with both the easy use for the patient and the desired dissolution profile is provided.
Another object of the present invention is to provide the desired stability and a good taste for the patient's easy use.
According to one embodiment of the invention, an orally disintegrating tablet formulation comprises sitagliptin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. The formulation of the invention was designed without having to compromise on stability to achieve the rapidly absorbed and desired dissolution rate which was linked to the surprisingly coordinated effect of using sitagliptin or a pharmaceutically acceptable salt thereof as a source of sitagliptin and using the orally disintegrating tablet.
The present invention provides orally disintegrating tablet of sitagliptin or a pharmaceutically acceptable salt thereof that will rapidly disintegrate within three minutes. These compositions have an acceptable taste, offer a pleasant mouth feel, and leave minimal residue in the mouth after administration. The present invention further provides processes for preparing said orally disintegrating tablet. It also provides a method of treating diabetes by administering said orally disintegrating tablet.
According to one embodiment of the invention, the amount of sitagliptin or a pharmaceutically acceptable salt thereof is 20.0% to 50.0% by weight in the formulation.
According to one embodiment of the invention, the amount of sitagliptin or a pharmaceutically acceptable salt thereof is 25.0% to 45.0% or 27.0% to 40.0% or 28.0% to 37.0% by weight in the formulation.
According to one embodiment of the invention, a pharmaceutically acceptable salt of sitagliptin is sitagliptin phosphate or sitagliptin hydrochloride or sitagliptin malate. Preferably, a pharmaceutically acceptable salt of sitagliptin is sitagliptin malate.
However, it is not easy to develop orally disintegrating formulations for all active agents because of several different reasons and requirements such as disintegration, stability, compressibility and taste masking. Dosage form must disintegrate in the oral cavity with the existence of saliva in a short period of time. So, those compositions should have a porous structure. Orally disintegrating tablets are usually pressed with lower compression forces than conventional tablets to obtain a higher porosity. However, these porous characteristics tend to be very sensitive to humidity and fragility and may be leads to stability problems.
To fulfill all these requirements, the orally disintegrating tablet formulation of sitagliptin or a pharmaceutically acceptable salt thereof needs to be adapted in particular by a careful excipient selection give a suitable porous structure with suitable disintegrating time and high stability.
According to one embodiment of the present invention, the formulation comprises at least one the pharmaceutically acceptable excipients which are selected from diluents, disintegrants, glidants, lubricants, sweeteners or mixtures thereof.
Suitable diluents are selected from the group comprising mannitol, microcrystalline cellulose, sorbitol, sucrose, inorganic salts, calcium salts, polysaccharides, dextrose, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixtures, xylitol, trehalose, heavy magnesium carbonate, starch, sodium carbonate, sodium bicarbonate or mixtures thereof.
According to one embodiment of the present invention, the amount of diluents is 45.0% to 70.0% by weight in the formulation.
According to one embodiment of the present invention, the diluent is mannitol or microcrystalline cellulose or mixtures thereof.
Mannitol is one of the most suitable diluents for moisture-sensitive formulations, coupled with a pleasant taste and mouthfeel. It is inert, non-hygroscopic diluent used in formulations that are moisture sensitive.
Suitable disintegrants are selected from the group comprising crospovidone, alginic acid, ion exchange resins, magnesium aluminum silica, sodium dodecyl sulphate, croscarmellose sodium, sodium carboxymethyl starch, carboxy methyl cellulose calcium, docusate sodium, sodium starch glycolate, sodium glycine carbonate, sodium lauryl sulphate, low substituted HPC (hydroxy propyl cellulose), polyacrylin potasium, poloxamer, xanthan gum, calcium silicate, ion exchange resins and mixtures thereof.
According to one embodiment of the present invention, the amount of disintegrants is 5.0% to 20.0% by weight, preferably 5.0% to 12.0% by weight in the formulation. According to one embodiment of the present invention, the disintegrant is crospovidone.
According to one embodiment of the present invention, crospovidone is used as disintegrant in the formulation of this present invention to provide porous ODT structure. Further, used crospovidone in the formulation enhances the disintegration time of sitagliptin or a pharmaceutically acceptable salt thereof, so the desired dissolution profile is provided.
In this invention, the orally disintegrating tablet formulation of sitagliptin or a pharmaceutically acceptable salt thereof is disintegrated in less than 1 min, preferably less than 30 sec thanks to the use of disintegrant, especially crospovidone.
Suitable glidants are selected from the group comprising talc, colloidal silicon dioxide, colloidal anhydrous silica, aluminium silicate or mixtures thereof.
According to one embodiment of the present invention, the amount of glidants is 0.01% to 3.0% by weight in the formulation.
According to one embodiment of the present invention, the glidant is talc.
Suitable lubricants are selected from the group comprising magnesium stearate, sodium stearyl fumarate, calcium stearate, sodium lauryl sulphate, magnesium lauryl sulphate, stearic acid, polyethylene glycol, paraffin, fumaric acid, glyceril palmitostearate, hydrogenated vegetable oil, zinc stearate or mixtures thereof.
According to one embodiment of the present invention, the amount of lubricants is 0.01% to 3.0% by weight in the formulation.
According to one embodiment of the present invention, the lubricant is magnesium stearate.
According to one embodiment of the present invention, the ratio of disintegants to lubricants is used in a specific ratio. The ratio is in the range of 1.0 to 12.0 by weight of the formulation, preferably it is in the range of 7.0 to 10.0 by weight of the formulation. It has been surprisingly found that with this ratio, desired flowability has been achieved to compress the formulation into ODTs.
As orally disintegrating tablet are designed to rapidly disintegrate as the drug comes in direct contact with the tongue, it remains a challenge to the formulators to effectively mask the taste of an active agent to increase the acceptability for these compositions. According to an embodiment of the invention, the used sweeteners have been improved by using sweeteners that do not interact with the active ingredient, so the patient’s compliance is provided.
Suitable sweeteners are selected from the group comprising aspartame, sucralose, saccharin, sodium cyclamate, glucose, lactose, fructose, sorbitol, xylitol, erythritol or mixtures thereof.
According to one embodiment of the present invention, the amount of sweeteners is 0.05% to 4.0% by weight in the formulation.
According to one embodiment of the present invention, the sweetener is aspartame.
The orally disintegrating tablet formulation formed thereby rapidly disintegrate on contact with saliva in the buccal cavity and have a pleasant taste (good creamy mouth feel) and provide rapid, substantially-complete release of the dose in the stomach.
According to one embodiment of the present invention, the orally disintegrating tablet formulation comprises;
- 20.0-50.0% by weight of sitagliptin malate 25.0-40.0% by weight of mannitol
- 5.0-20.0% by weight of crospovidone
- 20.0-30.0% by weight of microcrystalline cellulose
- 0.01 -3.0% by weight of magnesium stearate
- 0.01-3.0% by weight of talc
- 0.05-4.0% by weight of aspartame in the formulation.
According to one embodiment of the present invention, the orally disintegrating tablet formulation of the present invention can be prepared by conventional techniques such as direct compression, dry granulation, or wet granulation.
According to one embodiment of the present invention, the orally disintegrating tablet formulation is prepared direct compression. Example 1 : The ODT formulation comprising sitagliptin or a pharmaceutically acceptable salt thereof
Figure imgf000008_0001
Example 2: The ODT formulation comprising sitagliptin malate
Figure imgf000008_0002
Process for example 2;
- Adding sitagliptin malate, mannitol, crospovidone, microcrystalline cellulose, talc, aspartame and then mixing the mixture until obtained homogenous mixture,
- Adding magnesium stearate and the mixing,
Pressing the mixture to form of an orally disintegrating tablet.

Claims

1 . An orally disintegrating tablet formulation comprising sitagliptin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
2. The orally disintegrating tablet formulation according to claim 1 , wherein the amount of sitagliptin or a pharmaceutically acceptable salt thereof is 20.0% to 50.0% by weight in the formulation.
3. The orally disintegrating tablet formulation according to claim 2, wherein a pharmaceutically acceptable salt of sitagliptin is sitagliptin phosphate or sitagliptin hydrochloride or sitagliptin malate.
4. The orally disintegrating tablet formulation according to claim 3, wherein a pharmaceutically acceptable salt of sitagliptin is sitagliptin malate.
5. The orally disintegrating tablet formulation according to claim 1 , wherein at least one the pharmaceutically acceptable excipients are selected from diluents, disintegrants, glidants, lubricants, sweeteners or mixtures thereof.
6. The orally disintegrating tablet formulation according to claim 5, wherein diluents are selected from the group comprising mannitol, microcrystalline cellulose, sorbitol, sucrose, inorganic salts, calcium salts, polysaccharides, dextrose, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixtures, xylitol, trehalose, heavy magnesium carbonate, starch, sodium carbonate, sodium bicarbonate or mixtures thereof.
7. The orally disintegrating tablet formulation according to claim 6, wherein the amount of diluents is 45.0% to 70.0% by weight in the formulation.
8. The orally disintegrating tablet formulation according to claim 5, wherein disintegrants are selected from the group comprising crospovidone, alginic acid, ion exchange resins, magnesium aluminum silica, sodium dodecyl sulphate, croscarmellose sodium, sodium carboxymethyl starch, carboxy methyl cellulose calcium, docusate sodium, sodium starch glycolate, sodium glycine carbonate, sodium lauryl sulphate, low substituted HPC(hydroxy propyl cellulose), polyacrylin potasium, poloxamer, xanthan gum, calcium silicate, ion exchange resins and mixtures thereof.
9. The orally disintegrating tablet formulation according to claim 8, wherein the amount of disintegrants is 5.0% to 20.0% by weight, preferably 5.0% to 12.0% by weight in the formulation.
10. The orally disintegrating tablet formulation according to claim 5, wherein glidants are selected from the group comprising talc, colloidal silicon dioxide, colloidal anhydrous silica, aluminum silicate or mixtures thereof.
11. The orally disintegrating tablet formulation according to claim 5, wherein lubricants are selected from the group comprising magnesium stearate, sodium stearyl fumarate, calcium stearate, sodium lauryl sulphate, magnesium lauryl sulphate, stearic acid, polyethylene glycol, paraffin, fumaric acid, glyceril palmitostearate, hydrogenated vegetable oil, zinc stearate or mixtures thereof.
12. The orally disintegrating tablet formulation according to claim 11 , wherein the amount of lubricants is 0.01% to 3.0% by weight in the formulation.
13. The orally disintegrating tablet formulation according to claim 8 or 11 , wherein the ratio of disintegants to lubricants is in the range of 1.0 to 12.0 by weight of the formulation, preferably it is in the range of 7.0 to 10.0 by weight of the formulation.
14. The orally disintegrating tablet formulation according to claim 5, wherein sweeteners are selected from the group comprising aspartame, sucralose, saccharin, sodium cyclamate, glucose, lactose, fructose, sorbitol, xylitol, erythritol or mixtures thereof.
15. The orally disintegrating tablet formulation according to any preceding claim, wherein the formulation comprising;
- 20.0-50.0% by weight of sitagliptin malate
- 25.0-40.0% by weight of mannitol
- 5.0-20.0% by weight of crospovidone
- 20.0-30.0% by weight of microcrystalline cellulose
- 0.01 -3.0% by weight of magnesium stearate
- 0.01 -3.0% by weight of talc
- 0.05-4.0% by weight of aspartame in the formulation.
16. A process for preparing the orally disintegrating tablet formulation according to claim 15, comprising the following steps: - Adding sitagliptin malate, mannitol, crospovidone, microcrystalline cellulose, talc, aspartame and then mixing the mixture until obtained homogenous mixture,
Adding magnesium stearate and the mixing,
Pressing the mixture to form of an orally disintegrating tablet.
PCT/TR2021/050440 2020-06-23 2021-05-07 An orally disintegrating tablet formulation comprising sitagliptin Ceased WO2021262114A1 (en)

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TR2020/09724 2020-06-23
TR2020/09724A TR202009724A2 (en) 2020-06-23 2020-06-23 FORMULATION OF CYTAGLIPTIN IN ORAL DISTRIBUTION TABLET

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WO2010012781A2 (en) 2008-07-29 2010-02-04 Medichem, S.A. New crystalline salt forms of a 5,6,7,8-tetrahydro-1,2,4- triazolo[4,3-a]pyrazine derivative
WO2011123641A1 (en) 2010-03-31 2011-10-06 Teva Pharmaceutical Industries Ltd. Solid state forms of sitagliptin salts
WO2019151964A2 (en) * 2017-12-26 2019-08-08 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Orally disintegrating formulations of saxagliptin

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Publication number Priority date Publication date Assignee Title
WO2010012781A2 (en) 2008-07-29 2010-02-04 Medichem, S.A. New crystalline salt forms of a 5,6,7,8-tetrahydro-1,2,4- triazolo[4,3-a]pyrazine derivative
WO2011123641A1 (en) 2010-03-31 2011-10-06 Teva Pharmaceutical Industries Ltd. Solid state forms of sitagliptin salts
WO2019151964A2 (en) * 2017-12-26 2019-08-08 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Orally disintegrating formulations of saxagliptin

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Title
NAGA SUBRAHMANYAM S., G. V. PAVAN KUMAR AND G. V. NAGA RAJU: "Formulation And Evaluation Of Sitagliptin Oral Disintegration Tablets Using Synthetic Superdisintegrants", WORLD JOURNAL OF PHARMACEUTICAL RESEARCH, vol. 8, no. 1, 2018, India, pages 863 - 882, XP009533943, ISSN: 2277-7105, DOI: 10.20959/wjpr20191-13856 *
See also references of EP4167969A4
SHAKYA SUNITA: "Formulation and Optimization of Immediate Release Tablet of Sitagliptin Phosphate using Response Surface Methodology", INTERNATIONAL JOURNAL OF PHARMACY BIOLOGY AND MEDICAL SCIENCES, vol. 4, no. 1&2, 31 December 2015 (2015-12-31), XP055896346, ISSN: 2319-3026 *
SHOBANA M.: "FORMULATION AND EVALUATION OF FAST DISSOLVING ORAL FILM OF SITAGLIPTIN PHOSPHATE BY SOLVENT CASTING METHOD ", MASTERS THESIS, CHERRAAN'S COLLEGE OF PHARMACY, COIMBATORE, 31 October 2018 (2018-10-31), XP055896344, Retrieved from the Internet <URL:http://repository-tnmgrmu.ac.in/10618/1/260111618shobana.pdf> *

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TR202009724A2 (en) 2022-01-21
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