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EP3781135A2 - Compositoins pharmaceutiques solides d'administration par voie orale comprenant de la sitagliptine - Google Patents

Compositoins pharmaceutiques solides d'administration par voie orale comprenant de la sitagliptine

Info

Publication number
EP3781135A2
EP3781135A2 EP19788122.0A EP19788122A EP3781135A2 EP 3781135 A2 EP3781135 A2 EP 3781135A2 EP 19788122 A EP19788122 A EP 19788122A EP 3781135 A2 EP3781135 A2 EP 3781135A2
Authority
EP
European Patent Office
Prior art keywords
weight
tablets
solid oral
oral pharmaceutical
pharmaceutical composition
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
EP19788122.0A
Other languages
German (de)
English (en)
Other versions
EP3781135A4 (fr
Inventor
Ali Turkyilmaz
Seval Ataman
Cagil ERKAY
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 EP3781135A2 publication Critical patent/EP3781135A2/fr
Publication of EP3781135A4 publication Critical patent/EP3781135A4/fr
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
    • 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.
  • sitagliptin is used alone or in combination with other oral antidiabetics.
  • 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.
  • 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%.
  • 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.
  • magnesium stearate having both glidant and lubricant properties is widely used to enable flowability.
  • magnesium stearate is also disadvantageous for sitagliptin formulations for having alkaline property that accelerates chemical degradation and a high moisture retention capacity.
  • 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.
  • 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.
  • the present invention relates to a solid oral pharmaceutical composition
  • 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.
  • 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 1 Film-coated tablet
  • Example 2 Film-coated tablet
  • 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
  • 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:
  • the following exemplary formulations can be used in tablet compositions of the invention.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques solides d'administration par voie orale comprenant de la sitagliptine et un excipient pharmaceutiquement acceptable de ce dernier, offrant une grande stabilité et un profil de dissolution amélioré.
EP19788122.0A 2018-04-17 2019-03-06 Compositoins pharmaceutiques solides d'administration par voie orale comprenant de la sitagliptine Pending EP3781135A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR201805447 2018-04-17
PCT/TR2019/050139 WO2019203771A2 (fr) 2018-04-17 2019-03-06 Compositoins pharmaceutiques solides d'administration par voie orale comprenant de la sitagliptine

Publications (2)

Publication Number Publication Date
EP3781135A2 true EP3781135A2 (fr) 2021-02-24
EP3781135A4 EP3781135A4 (fr) 2021-12-29

Family

ID=68240633

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19788122.0A Pending EP3781135A4 (fr) 2018-04-17 2019-03-06 Compositoins pharmaceutiques solides d'administration par voie orale comprenant de la sitagliptine

Country Status (2)

Country Link
EP (1) EP3781135A4 (fr)
WO (1) WO2019203771A2 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3781261B1 (fr) * 2018-04-17 2025-11-26 Sanovel Ilac Sanayi ve Ticaret A.S. Compositions pharmaceutiques orales comprenant un inhibiteur de dpp-4
JP7423264B2 (ja) * 2019-10-17 2024-01-29 日本ジェネリック株式会社 シタグリプチン含有錠剤
BR112022012436A2 (pt) * 2019-12-24 2022-09-06 Hanmi Pharm Ind Co Ltd Formulação compósita e método para preparar a formulação compósita
CN111481520A (zh) * 2020-06-15 2020-08-04 千辉药业（安徽）有限责任公司 一种磷酸西他列汀片剂
CN112843010A (zh) * 2020-12-29 2021-05-28 浙江华海药业股份有限公司 一种西格列汀药物组合物及其制备工艺
CN114159401A (zh) * 2021-11-18 2022-03-11 苏州天马医药集团天吉生物制药有限公司 一种磷酸西格列汀片剂及其制备方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120258170A1 (en) * 2009-05-20 2012-10-11 Nutracryst Therapeutics Private Limited Pharmaceutical co-crystals of quercetin
EP2295083A1 (fr) 2009-09-15 2011-03-16 Ratiopharm GmbH Composition pharmaceutique renfermant les agents actifs metformine et sitagliptine ou vildagliptine
EP2906203B1 (fr) * 2012-10-11 2018-01-03 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Formulation effervescente de cefdinir
WO2014174469A1 (fr) * 2013-04-25 2014-10-30 Ranbaxy Laboratories Limited Compositions pharmaceutiques comprenant une combinaison de sitagliptine et de metformine
TR201310724A2 (tr) * 2013-09-12 2015-03-23 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Linagliptinin farmasotik formulasyonları.

Also Published As

Publication number Publication date
WO2019203771A2 (fr) 2019-10-24
WO2019203771A3 (fr) 2020-01-16
EP3781135A4 (fr) 2021-12-29

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