WO2019203771A2 - Solid oral pharmaceutical compositions comprising sitagliptin - Google Patents

Solid oral pharmaceutical compositions comprising sitagliptin Download PDF

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Publication number
WO2019203771A2
WO2019203771A2 PCT/TR2019/050139 TR2019050139W WO2019203771A2 WO 2019203771 A2 WO2019203771 A2 WO 2019203771A2 TR 2019050139 W TR2019050139 W TR 2019050139W WO 2019203771 A2 WO2019203771 A2 WO 2019203771A2
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Prior art keywords
weight
tablets
solid oral
oral pharmaceutical
pharmaceutical composition
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PCT/TR2019/050139
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French (fr)
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WO2019203771A3 (en
Inventor
Ali Turkyilmaz
Seval Ataman
Cagil ERKAY
Original Assignee
Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
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Priority to EP19788122.0A priority Critical patent/EP3781135A4/en
Publication of WO2019203771A2 publication Critical patent/WO2019203771A2/en
Publication of WO2019203771A3 publication Critical patent/WO2019203771A3/en

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    • 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
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to solid oral pharmaceutical compositions comprising sitagliptin and a pharmaceutically acceptable excipient thereof, providing high stability and improved dissolution profile.
  • Type 2 Diabetes Mellitus is an epidemic disease that is widespread worldwide and has important consequences for patients and even for the society.
  • depot insulin first phase insulin release
  • insulin produced in b cells (2nd phase insulin release) is used.
  • Increased insulin response to hyperglycemia after oral glucose uptake is called incretin effect.
  • the incretin hormones, glucagon-like peptide 1 (GLP-1) and gastric inhibitor polypeptide (GIP) play an important role in glucose homeostasis in healthy individuals by stimulating postprandial pancreatic insulin secretion and inhibiting glucagon release.
  • DPP-4 inhibitors inhibit the DPP-4 enzyme that cleaves and inactivate the incretin hormones released by the small intestine, causing elevated GLP-1 and GIP levels and lower glucose and ultimately glycosylated hemoglobin (HbA1c) levels in patients
  • DPP-4 inhibitors have been developed, mainly sitagliptin, vildagliptin, saxagliptin, alogliptin, denagliptin, ASP8497.
  • Different dosage forms comprising DPP-4 inhibitors are also disclosed in patent documents in the present art.
  • a document addresssing the problem of mechanical strength of immediate-release tablet forms containing DPP-4 inhibitors it was aimed to develop a formulation that would not reduce release rate or tablet strength by increasing porosity excessively.
  • 20-60% of diabetic patients also had hypertension and that should be taken into account when designing tablet formulations. Accordingly, tablet formulations with sodium content of less than 10 mg and potassium content of less than 15 mg have been proposed.
  • sitagliptin an antihyperglycemic agent that belongs to DDP-4 inhibitors class
  • DDP-4 inhibitors class DDP-4 inhibitors
  • sitagliptin (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 main object of the present invention is to obtain solid oral pharmaceutical compositions of sitagliptin which overcomes all the above-mentioned problems and brings additional advantages to the relevant prior art.
  • a further object of the present invention is to develop solid oral pharmaceutical compositions of sitagliptin with high flowability.
  • a further object of the present invention is to develop solid oral pharmaceutical compositions of sitagliptin with low moisture retention.
  • Yet another object of the present invention is to develop a preparation process for sitagliptin tablet dosage form, comprising slug compression and granulation technique.
  • Magnesium stearate serves both as glidant and lubricant in solid oral pharmaceutical formulations. Although providing high flowability in formulations, magnesium stearate has high moisture retention and increases destabilization rate by increasing degradation, making it less desirable especially for moisture-sensitive formulations.
  • sitagliptin or a pharmaceutically acceptable salt thereof is sitagliptin maleate.
  • the amount of sitagliptin maleate in the total composition is 5-60%, preferably 10-50%, most preferably 15-30% by weight.
  • the amount of sitagliptin in the composition is between 1 mg and 300 mg, preferably between 10 mg and 240 mg and more preferably between 20 mg and 120 mg. Most preferably, the composition of the invention comprises 25 mg or 50 mg or 100 mg sitagliptin. It has been observed that the use of sitagliptin maleate salt as the active ingredient increases both stability and solubility. Sitagliptin phosphate monohydrate has very low solubility and sitagliptin hydrochloride has very high moisture retention, making them non-desirable salts for the said invention.
  • the formulation of the invention was designed without having to compromise on stability to achieve high solubility and bioavailability, which was linked to the surprisingly coordinated effect of using sitagliptin maleate as a source of sitagliptin and the absence of magnesium stearate in the formulation.
  • Formulations prepared with sitagliptin phosphate monohydrate and sitagliptin hydrochloride did not have the same effect.
  • the composition does not comprise potassium.
  • the amount of sodium is kept below 15%, more preferably below 10% by weight of the composition. In this regard it is possible to develop solid oral pharmaceutical compositions of sitagliptin having safe components for hypertensive and cardiac patients.
  • the composition is in the form of coated tablets, trilayer tablets, bilayer tablets, multilayer tablets, orally disintegrating tablets, mini tablets, pellets, sugar pellets, buccal tablets, sublingual tablets, effervescent tablets, immediate release tablets, modified release tablets, film coated tablets, gastric disintegrating tablets, pills, capsules, oral granules, powders, coated bead systems, microspheres, tablet in tablets, inlay tablets, dragees, sachets or orally administrable films.
  • composition is preferably in the form of a tablet, most preferably in the form of a film- coated tablet.
  • the composition further comprises at least one excipient selected from fillers, disintegrants, lubricants, glidants or mixtures thereof.
  • the composition comprises at least one filler selected from microcrystalline cellulose, lactose, mannitol, spray dried mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dibasic calcium phosphate anhydrate, sodium chloride, dextrates, lactitol, maltodextrin , sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate polyols, dextrose, maltitol, or mixtures thereof.
  • a filler selected from microcrystalline cellulose, lactose, mannitol, spray dried mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin,
  • the composition comprises two fillers which are microcrystalline cellulose and dibasic calcium phosphate anhydrate.
  • the amount of microcrystalline cellulose is in the range of 5-60%, preferably 10-50%, most preferably 20-40% by weight of the total composition.
  • the amount of dibasic calcium phosphate anhydrate is 10-70%, preferably 20-60%, most preferably 30-45% by weight of the total composition.
  • the composition comprises at least one disintegrant selected from the group consisting of croscarmellose sodium, sodium carbonate, hydroxypropyl cellulose (HPC), cross-linked polyvinylpyrrolidone (crospovidone), copovidone, polycarbophil, low substituted poloxamer, sodium starch glycollate, starch, pregelatinized starch, alginic acid and alginates, ion exchange resins, magnesium aluminum silicate, sodium dodecyl sulfate, sodium carboxy methyl cellulose, carboxy methyl cellulose calcium, sodium docusate, guar gum, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, or mixtures thereof.
  • HPC hydroxypropyl cellulose
  • crospovidone cross-linked polyvinylpyrrolidone
  • copovidone polycarbophil
  • low substituted poloxamer sodium starch glycollate, starch, pregelatinized starch
  • the amount of disintegrant is kept below 10%, more preferably below 7% by weight of the composition, in order to ensure continued stability.
  • the composition comprises a single disintegrant which is croscarmellose sodium.
  • the composition comprises at least one lubricant and at least one glidant selected from the group consisting of calcium stearate, colloidal silicon dioxide, sodium stearyl fumarate, sodium lauryl sulfate, zinc stearate, calcium stearate, mineral oil, talc, polyethylene glycol, glyceryl monostearate, glyceryl palmitostearate, magnesium lauryl sulfate, fumaric acid, zinc stearate, stearic acid, hydrogenated natural oils, silica, paraffin or mixtures thereof.
  • the composition comprises sodium stearyl fumarate as lubricant.
  • the amount of sodium stearyl fumarate is between 0.5% and 5%, preferably between 1% and 3% by weight of the total composition.
  • the composition comprises colloidal silicon dioxide as glidant.
  • the amount of colloidal silicon dioxide is between 0.5% and 5%, preferably between 1% and 3% by weight of the total composition.
  • the ratio of lubricant to glidant is in the range of 0.1 :1 to 5:1 , preferably 0.5:1 to 2:1 in order to ensure the desired flowability. Most preferably, this ratio is 1 :1.
  • the ratios of the disintegrant, lubricant and glidant in the composition are also of great importance in order to obtain tablets providing high solubility and high stability.
  • the ratio of the total amount of disintegrant to the total amount of lubricant and glidant is in the range of from 3:1 to 0.5:1 , preferably 1.5:1 to 1 :1.
  • the composition comprises a film coating.
  • Suitable components used in the coating can be selected from the group consisting of polyvinyl alcohol, polyethylene glycol, polymethylmethacrylate derivatives, ethylcellulose dispersions (Surelease), Kerry-HPC, polyvinylpyrrolidone, vinyl acetate, pigments, dyes, titanium dioxide, iron oxide, talc and all Opadry types.
  • the composition comprises a polyvinyl alcohol based film coating that forms a barrier against moisture.
  • the said film coating is 1-5% by weight of the total composition.
  • the coating is preferably Opadry White.
  • the total composition comprises the following:
  • microcrystalline cellulose - 5-60% by weight of microcrystalline cellulose
  • the composition is prepared as biphasic using slug compression technique.
  • the method is comprised of the following steps:
  • sitagliptin maleate dibasic calcium phosphate anhydrate, 2/3 by weight of microcrystalline cellulose and 3/5 by weight of croscarmellose sodium
  • the following exemplary formulations can be used in tablet compositions of the invention.
  • Example 2 Film-coated tablet
  • Suitable binders are selected from the group consisting of copovidone, copolvidone, polyvinylpyrrolidone (PVP), povidone, carnauba wax, hydroxypropyl methyl cellulose (HPMC), pullulan, polymethacrylate, glyceryl behenate, hydroxypropyl cellulose (HPC), carboxy methyl cellulose (CMC), methyl cellulose (MC), hydroxyethyl cellulose, sodium carboxymethyl cellulose (Na CMC), carboxymethyl cellulose calcium, ethyl cellulose, microcrystalline cellulose, polymethacrylates, polyethylene oxide, polyvinyl alcohol, polycarbophyl, polyvinyl acetate and its copolymers, gelatin, starch, pregelatinized starch, xanthan gum, guar gum, alginate, carrageenan, collagen, agar, pectin, hyaluronic acid, carbomer, cellulose acetate phthalate, hydroxypropyl
  • povidone eliminates the necessity of tablet being biphasic and provides a formulation suitable for direct compression.
  • the total composition comprises the following:
  • microcrystalline cellulose - 5-60% by weight of microcrystalline cellulose
  • the composition is prepared as monophasic using direct compression.
  • the method is comprised of the following steps:

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Abstract

The present invention relates to solid oral pharmaceutical compositions comprising sitagliptin and a pharmaceutically acceptable excipient thereof, providing high stability and improved dissolution profile.

Description

SOLID ORAL PHARMACEUTICAL COMPOSITIONS COMPRISING SITAGLIPTIN
Field of the Invention
The present invention relates to solid oral pharmaceutical compositions comprising sitagliptin and a pharmaceutically acceptable excipient thereof, providing high stability and improved dissolution profile.
Background of the Invention
Type 2 Diabetes Mellitus (T2DM) is an epidemic disease that is widespread worldwide and has important consequences for patients and even for the society. In healthy individuals, immediately after oral glucose administration, depot insulin (first phase insulin release), previously produced by pancreatic beta cells, is secreted. Subsequently, insulin produced in b cells (2nd phase insulin release) is used. Increased insulin response to hyperglycemia after oral glucose uptake is called incretin effect. The incretin hormones, glucagon-like peptide 1 (GLP-1) and gastric inhibitor polypeptide (GIP), play an important role in glucose homeostasis in healthy individuals by stimulating postprandial pancreatic insulin secretion and inhibiting glucagon release.
However, in patients with T2DM, the insulin response that is supposed to increase after carbohydrate intake is reduced or delayed, glucagon release is increased, resulting in postprandial hyperglycaemia. In other words, GLP-1 -activated pancreatic insulin release is insufficient, insulinotropic effects of the incretin hormones in the peptide structure are diminished in patients with T2DM. Because both incretins are cleaved by dipeptidyl peptidase-4 (DPP-4) enzyme in minutes. In diabetic patients, DPP-4 cleaves and inactivates GLP-1 , the synthesis of which is increased due to elevated postprandial plasma glucose levels, resulting in disrupted balance in blood-glucose levels. In order to stabilize glucose levels, DPP-4 inhibitors inhibit the DPP-4 enzyme that cleaves and inactivate the incretin hormones released by the small intestine, causing elevated GLP-1 and GIP levels and lower glucose and ultimately glycosylated hemoglobin (HbA1c) levels in patients
In the art, many DPP-4 inhibitors have been developed, mainly sitagliptin, vildagliptin, saxagliptin, alogliptin, denagliptin, ASP8497. Different dosage forms comprising DPP-4 inhibitors are also disclosed in patent documents in the present art. For example, in a document adressing the problem of mechanical strength of immediate-release tablet forms containing DPP-4 inhibitors, it was aimed to develop a formulation that would not reduce release rate or tablet strength by increasing porosity excessively. In addition, it was stated that 20-60% of diabetic patients also had hypertension and that should be taken into account when designing tablet formulations. Accordingly, tablet formulations with sodium content of less than 10 mg and potassium content of less than 15 mg have been proposed.
In another document, the problem of flowability at the production stage of tablet formulations containing DPP-4 inhibitors has been addressed and the use of copolymers in different proportions has been proposed as a solution.
Studies conducted in the present art have shown that sitagliptin, an antihyperglycemic agent that belongs to DDP-4 inhibitors class, is indicated in patients with type 2 diabetes as an aid to their diet and exercise and provides patients with reliable treatment by preventing weight gain and reducing the risk for hypoglycemia. However, in vitro studies have also shown that sitagliptin increases pancreatic beta cell mass and maintains beta cell function.
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
In current T2DM treatments, sitagliptin is used alone or in combination with other oral antidiabetics. In order to provide high solubility in compositions available in the present art, sitagliptin is usually in the form of salts. A formulation in which sitagliptin phosphate monohydrate salt is used is registered under the trade name of JAN U VI A®. Patent documents in the present art also disclose formulations in which the hydrochloride salt of sitagliptin is used. In one of these examples, a tablet formulation comprising sitagliptin hydrochloride monohydrate salt has been developed. The goal in the development of said formulation is to increase the stability of the final dosage form by lowering the impurity ratio to below 5%. However, it is known that the moisture retention capacity of sitagliptin HCI salt is 3-10 times higher than other salts of sitagliptin. It is clear that this will adversely affect the tablet stability.
In sitagliptin formulations that are available in the present art, magnesium stearate having both glidant and lubricant properties is widely used to enable flowability. However, magnesium stearate is also disadvantageous for sitagliptin formulations for having alkaline property that accelerates chemical degradation and a high moisture retention capacity.
Given that the greatest problem encountered with solid oral dosage forms of sitagliptin is the lower stability of the product due to its hygroscopic feature, there is still a need in the art for a solid oral dosage form that provides high stability and thus a long shelf life, without compromising its dissolution, disintegration and flowability features while having a safe composition for use in hypertensive and cardiac patients.
Objectives and Brief Description of the Invention
The main object of the present invention is to obtain solid oral pharmaceutical compositions of sitagliptin which overcomes all the above-mentioned problems and brings additional advantages to the relevant prior art.
A further object of the present invention is to develop solid oral pharmaceutical compositions of sitagliptin having improved stability and prolonged shelf life.
A further object of the present invention is to develop solid oral pharmaceutical compositions of sitagliptin with high flowability.
A further object of the present invention is to develop solid oral pharmaceutical compositions of sitagliptin with low moisture retention.
A further object of the present invention is to develop tablet compositions of sitagliptin having a high dissolution rate, high solubility and thus high bioavailability. Another object of the present invention is to develop sitagliptin tablet compositions for use in the treatment of type 2 diabetic patients, that also have safe components for use in hypertensive and cardiac patients.
Another object of the present invention is to provide a sitagliptin tablet dosage form comprising at least one film coating which protects the composition against moisture, in order to maintain stability.
Yet another object of the present invention is to develop a preparation process for sitagliptin tablet dosage form, comprising slug compression and granulation technique.
Detailed Description of the Invention
For the purposes outlined above, detailed features of the present invention are provided herein.
The present invention relates to a solid oral pharmaceutical composition comprising sitagliptin or a pharmaceutically acceptable salt thereof, wherein the composition is free of magnesium stearate.
Magnesium stearate serves both as glidant and lubricant in solid oral pharmaceutical formulations. Although providing high flowability in formulations, magnesium stearate has high moisture retention and increases destabilization rate by increasing degradation, making it less desirable especially for moisture-sensitive formulations.
According to a preferred embodiment of the invention, sitagliptin or a pharmaceutically acceptable salt thereof is sitagliptin maleate.
According to this preferred embodiment, the amount of sitagliptin maleate in the total composition is 5-60%, preferably 10-50%, most preferably 15-30% by weight.
Yet according to this embodiment, the amount of sitagliptin in the composition is between 1 mg and 300 mg, preferably between 10 mg and 240 mg and more preferably between 20 mg and 120 mg. Most preferably, the composition of the invention comprises 25 mg or 50 mg or 100 mg sitagliptin. It has been observed that the use of sitagliptin maleate salt as the active ingredient increases both stability and solubility. Sitagliptin phosphate monohydrate has very low solubility and sitagliptin hydrochloride has very high moisture retention, making them non-desirable salts for the said invention.
The formulation of the invention was designed without having to compromise on stability to achieve high solubility and bioavailability, which was linked to the surprisingly coordinated effect of using sitagliptin maleate as a source of sitagliptin and the absence of magnesium stearate in the formulation. Formulations prepared with sitagliptin phosphate monohydrate and sitagliptin hydrochloride did not have the same effect.
Another point to be noted when creating the formulation of the invention is that the final product obtained has safe components for use in hypertensive and cardiac patients. Because it is known that the vast majority of type 2 diabetic patients also have these diseases. It is known that excessive use of potassium causes heartbeat irregularities, excessive use of sodium triggers hypertension by increasing intravascular volume.
In the preferred embodiment of the invention, the composition does not comprise potassium. The amount of sodium is kept below 15%, more preferably below 10% by weight of the composition. In this regard it is possible to develop solid oral pharmaceutical compositions of sitagliptin having safe components for hypertensive and cardiac patients.
According to one embodiment, the composition is in the form of coated tablets, trilayer tablets, bilayer tablets, multilayer tablets, orally disintegrating tablets, mini tablets, pellets, sugar pellets, buccal tablets, sublingual tablets, effervescent tablets, immediate release tablets, modified release tablets, film coated tablets, gastric disintegrating tablets, pills, capsules, oral granules, powders, coated bead systems, microspheres, tablet in tablets, inlay tablets, dragees, sachets or orally administrable films.
The composition is preferably in the form of a tablet, most preferably in the form of a film- coated tablet.
In one embodiment of the invention, the composition further comprises at least one excipient selected from fillers, disintegrants, lubricants, glidants or mixtures thereof.
According to one embodiment of the invention, the composition comprises at least one filler selected from microcrystalline cellulose, lactose, mannitol, spray dried mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dibasic calcium phosphate anhydrate, sodium chloride, dextrates, lactitol, maltodextrin , sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate polyols, dextrose, maltitol, or mixtures thereof.
In a preferred embodiment of the invention, the composition comprises two fillers which are microcrystalline cellulose and dibasic calcium phosphate anhydrate.
The amount of microcrystalline cellulose is in the range of 5-60%, preferably 10-50%, most preferably 20-40% by weight of the total composition.
The amount of dibasic calcium phosphate anhydrate is 10-70%, preferably 20-60%, most preferably 30-45% by weight of the total composition.
According to one embodiment of the invention, the composition comprises at least one disintegrant selected from the group consisting of croscarmellose sodium, sodium carbonate, hydroxypropyl cellulose (HPC), cross-linked polyvinylpyrrolidone (crospovidone), copovidone, polycarbophil, low substituted poloxamer, sodium starch glycollate, starch, pregelatinized starch, alginic acid and alginates, ion exchange resins, magnesium aluminum silicate, sodium dodecyl sulfate, sodium carboxy methyl cellulose, carboxy methyl cellulose calcium, sodium docusate, guar gum, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, or mixtures thereof.
Taking into account the moisture retention properties of the disintegrants; the amount of disintegrant is kept below 10%, more preferably below 7% by weight of the composition, in order to ensure continued stability. In a preferred embodiment of the invention, the composition comprises a single disintegrant which is croscarmellose sodium.
According to one embodiment of the invention, the composition comprises at least one lubricant and at least one glidant selected from the group consisting of calcium stearate, colloidal silicon dioxide, sodium stearyl fumarate, sodium lauryl sulfate, zinc stearate, calcium stearate, mineral oil, talc, polyethylene glycol, glyceryl monostearate, glyceryl palmitostearate, magnesium lauryl sulfate, fumaric acid, zinc stearate, stearic acid, hydrogenated natural oils, silica, paraffin or mixtures thereof. In a preferred embodiment of the invention, the composition comprises sodium stearyl fumarate as lubricant. The amount of sodium stearyl fumarate is between 0.5% and 5%, preferably between 1% and 3% by weight of the total composition.
In a preferred embodiment of the invention, the composition comprises colloidal silicon dioxide as glidant. The amount of colloidal silicon dioxide is between 0.5% and 5%, preferably between 1% and 3% by weight of the total composition.
In a preferred embodiment of the invention, the ratio of lubricant to glidant is in the range of 0.1 :1 to 5:1 , preferably 0.5:1 to 2:1 in order to ensure the desired flowability. Most preferably, this ratio is 1 :1.
It has also been found that the ratios of the disintegrant, lubricant and glidant in the composition are also of great importance in order to obtain tablets providing high solubility and high stability. In a preferred embodiment of the invention, the ratio of the total amount of disintegrant to the total amount of lubricant and glidant is in the range of from 3:1 to 0.5:1 , preferably 1.5:1 to 1 :1.
In one embodiment of the invention, the composition comprises a film coating. Suitable components used in the coating can be selected from the group consisting of polyvinyl alcohol, polyethylene glycol, polymethylmethacrylate derivatives, ethylcellulose dispersions (Surelease), Kerry-HPC, polyvinylpyrrolidone, vinyl acetate, pigments, dyes, titanium dioxide, iron oxide, talc and all Opadry types.
According to a preferred embodiment of the invention, the composition comprises a polyvinyl alcohol based film coating that forms a barrier against moisture. The said film coating is 1-5% by weight of the total composition. The coating is preferably Opadry White.
According to a preferred embodiment, the total composition comprises the following:
- 5-60% by weight of sitagliptin maleate
- 5-60% by weight of microcrystalline cellulose
- 10-70% by weight of dibasic calcium phosphate anhydrate
- 1-10% by weight of croscarmellose sodium
- 0.5-5% by weight of sodium stearyl fumarate
- 0.5-5% by weight of colloidal silicon dioxide
- 1 to 5% by weight film coating These selected ratios provide the effective dosages required for the treatment and improve the stability and dissolution profile of film-coated tablet of the invention.
In this embodiment of the invention, the composition is prepared as biphasic using slug compression technique. The method is comprised of the following steps:
-Mixing sitagliptin maleate, dibasic calcium phosphate anhydrate, 2/3 by weight of microcrystalline cellulose and 3/5 by weight of croscarmellose sodium
- Addition of 3/4 by weight of colloidal silicon dioxide and 1/2 by weight of sodium stearyl fumarate and mixing to form inner phase
-Compression of inner phase to tablets using slug compression
-Grinding of tablets so that the particle size thereof is below 1 pm
-Forming an outer phase onto the inner phase by adding 1/3 by weight of microcrystalline cellulose, 2/5 by weight of croscarmellose sodium, 1/4 by weight of colloidal silicon dioxide and 1/2 of sodium stearyl fumarate while the particules forming the inner phase are mixed
- Compression of the obtained mixture into tablets
- Coating the tablets with film coating
It has been observed that the use of the slug compression technique surprisingly enhances stability even for formulations of the invention which is free of any binder.
According to this embodiment, the following exemplary formulations can be used in tablet compositions of the invention.
Example 1 : Film-coated tablet
Figure imgf000009_0001
Example 2: Film-coated tablet
Figure imgf000010_0001
In another embodiment of the invention, the composition further comprises at least one binder.
Suitable binders are selected from the group consisting of copovidone, copolvidone, polyvinylpyrrolidone (PVP), povidone, carnauba wax, hydroxypropyl methyl cellulose (HPMC), pullulan, polymethacrylate, glyceryl behenate, hydroxypropyl cellulose (HPC), carboxy methyl cellulose (CMC), methyl cellulose (MC), hydroxyethyl cellulose, sodium carboxymethyl cellulose (Na CMC), carboxymethyl cellulose calcium, ethyl cellulose, microcrystalline cellulose, polymethacrylates, polyethylene oxide, polyvinyl alcohol, polycarbophyl, polyvinyl acetate and its copolymers, gelatin, starch, pregelatinized starch, xanthan gum, guar gum, alginate, carrageenan, collagen, agar, pectin, hyaluronic acid, carbomer, cellulose acetate phthalate, hydroxypropyl starch, hydroxyethyl methyl cellulose, poloxamer, polyethylene glycol (PEG), sugars, glucose syrups, natural gums, tragacanthan gum, polyacrylamide, aluminum hydroxide, bentonite, laponite, cetostearyl alcohol, polyethylene-alkyl ethers, arabic gum, polydextrose or mixtures thereof. In a preferred embodiment of the invention, the composition comprises povidone as binder. The amount of povidone is 1-10%, preferably 3-7% by weight of the total composition.
The use of povidone eliminates the necessity of tablet being biphasic and provides a formulation suitable for direct compression.
According to this preferred embodiment, the total composition comprises the following:
- 5-60% by weight of sitagliptin maleate
- 5-60% by weight of microcrystalline cellulose
- 10-70% by weight of dibasic calcium phosphate anhydrate
- 1-10% by weight of croscarmellose sodium
- 1-10% by weight of povidone
- 0.5-5% by weight of sodium stearyl fumarate
- 0.5-5% by weight of colloidal silicon dioxide
- 1 to 5% by weight film coating
In this embodiment of the invention, the composition is prepared as monophasic using direct compression.
The method is comprised of the following steps:
-Mixing of sitagliptin maleate, dibasic calcium phosphate anhydrate, microcrystalline cellulose, croscarmellose sodium and povidone
- Adding colloidal silicon dioxide and sodium stearyl fumarate to this mixture and mixing
- Compression of the obtained mixture into tablets
- Coating the tablets with film coating
According to this embodiment, the following exemplary formulations can be used in tablet compositions of the invention.
Example 3: Film-coated tablet
Figure imgf000011_0001
Figure imgf000012_0001
Example 4: Film-coated tablet
Figure imgf000012_0002

Claims

1. A solid oral pharmaceutical composition comprising sitagliptin or a pharmaceutically acceptable salt thereof, wherein the composition is free of magnesium stearate.
2. The solid oral pharmaceutical composition according to claim 1 , wherein sitagliptin or a pharmaceutically acceptable salt thereof is sitagliptin maleate.
3. The solid oral pharmaceutical composition according to claim 2, wherein the amount of sitagliptin maleate is in the range of 5-60%, preferably 10-50%, most preferably 15- 30% by weight of the total composition.
4. The solid oral pharmaceutical composition according to any one of the preceding claims, wherein the composition is in the form of coated tablets, trilayer tablets, bilayer tablets, multilayer tablets, orally disintegrating tablets, mini tablets, pellets, sugar pellets, buccal tablets, sublingual tablets, effervescent tablets, immediate release tablets, modified release tablets, film coated tablets, gastric disintegrating tablets, pills, capsules, oral granules, powders, coated bead systems, microspheres, tablet in tablets, inlay tablets, dragees, sachets or orally administrable films.
5. The solid oral pharmaceutical composition according to claim 4, wherein the composition is in the form of a film-coated tablet.
6. The solid oral pharmaceutical composition according to any one of the preceding claims, wherein the composition comprises at least one excipient selected from fillers, disintegrants, lubricants, glidants or mixtures thereof.
7. The solid oral pharmaceutical composition according to claim 6, wherein the amount of the disintegrant is less than 10%, more preferably less than 7% by weight of the composition.
8. The solid oral pharmaceutical composition according to claim 6 or 7, wherein the composition comprises at least one lubricant and at least one glidant selected from the group consisting of calcium stearate, colloidal silicon dioxide, sodium stearyl fumarate, sodium lauryl sulfate, zinc stearate, calcium stearate, mineral oil, talc, polyethylene glycol, glyceryl monostearate, glyceryl palmitostearate, magnesium lauryl sulfate, fumaric acid, zinc stearate, stearic acid, hydrogenated natural oils, silica, paraffin or mixtures thereof.
9. The solid oral pharmaceutical composition according to claim 8, wherein the composition comprises 0.5-5%, preferably 1-3% by weight of sodium stearyl fumarate as a lubricant.
10. The solid oral pharmaceutical composition according to claim 8, wherein the composition comprises 0.5-5%, preferably from 1-3% by weight of colloidal silicon dioxide as a glidant.
11. The solid oral pharmaceutical composition according to any one of the claims 6 to 10, wherein the ratio of lubricant to glidant is in the range of 0.1 :1 to 5:1 , preferably 0.5:1 to 2:1.
12. The solid oral pharmaceutical composition according to claim 11 , wherein the ratio of lubricant to glidant is 1 :1.
13. The solid oral pharmaceutical composition according to any one of the claims 6 to 12 wherein the ratio of the total amount of disintegrants to the total amount of lubricant and glidant is in the range of from 3: 1 to 0.5:1 , preferably 1.5: 1 to 1 :1.
14. The solid oral pharmaceutical composition according to any one of the claims 6 to 13, wherein the composition comprises 1-5% by weight of polyvinyl alcohol-based film coating.
15. The solid oral pharmaceutical composition according to any one of the preceding claims, wherein the composition comprises
- 5-60% by weight of sitagliptin maleate
- 5-60% by weight of microcrystalline cellulose
- 10-70% by weight of dibasic calcium phosphate anhydrate
- 1-10% by weight of croscarmellose sodium
- 0.5-5% by weight of sodium stearyl fumarate
- 0.5-5% by weight of colloidal silicon dioxide
- 1-5% film coating.
16. A process for preparing a solid oral pharmaceutical composition as biphasic using slug compression technique according to claim 15, wherein the said process comprises the following steps:
-Mixing sitagliptin maleate, dibasic calcium phosphate anhydrate, 2/3 by weight of microcrystalline cellulose and 3/5 by weight of croscarmellose sodium
- Addition of 3/4 by weight of colloidal silicon dioxide and 1/2 by weight of sodium stearyl fumarate and mixing to form inner phase
-Compression of inner phase to tablets using slug compression
-Grinding of tablets so that the particle size thereof is below 1 pm
-Forming an outer phase onto the inner phase by adding 1/3 by weight of microcrystalline cellulose, 2/5 by weight of croscarmellose sodium, 1/4 by weight of colloidal silicon dioxide and 1/2 of sodium stearyl fumarate while the particles forming the inner phase are mixed
- Compression of the obtained mixture into tablets
- Coating the tablets with film coating
17. The solid oral pharmaceutical composition according to any one of the preceding claims, wherein the composition further comprises at least one binder.
18. The solid oral pharmaceutical composition according to claim 17, wherein the binder is povidone.
19. The solid oral pharmaceutical composition according to claims 17 or 18, wherein the composition comprises
- 5-60% by weight of sitagliptin maleate
- 5-60% by weight of microcrystalline cellulose
- 10-70% by weight of dibasic calcium phosphate anhydrate
- 1-10% by weight of croscarmellose sodium
- 1-10% by weight of povidone
- 0.5-5% by weight of sodium stearyl fumarate
- 0.5-5% by weight of colloidal silicon dioxide
- 1-5% by weight of film coating.
20. A process for preparing a solid oral pharmaceutical composition as monophasic using direct compression technique according to claim 19, wherein the said process comprises the following steps: -Mixing of sitagliptin maleate, dibasic calcium phosphate anhydrate, microcrystalline cellulose, croscarmellose sodium and povidone
- Adding colloidal silicon dioxide and sodium stearyl fumarate to this mixture and mixing
- Compression of the obtained mixture into tablets
- Coating the tablets with film coating
PCT/TR2019/050139 2018-04-17 2019-03-06 Solid oral pharmaceutical compositions comprising sitagliptin WO2019203771A2 (en)

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TR2018/05447 2018-04-17

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