EP4213937A1 - Forme posologique solide comprenant de la sitagliptine et son procédé de préparation - Google Patents

Forme posologique solide comprenant de la sitagliptine et son procédé de préparation

Info

Publication number
EP4213937A1
EP4213937A1 EP21782434.1A EP21782434A EP4213937A1 EP 4213937 A1 EP4213937 A1 EP 4213937A1 EP 21782434 A EP21782434 A EP 21782434A EP 4213937 A1 EP4213937 A1 EP 4213937A1
Authority
EP
European Patent Office
Prior art keywords
sitagliptin
weight
pharmaceutical composition
composition according
dosage form
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
EP21782434.1A
Other languages
German (de)
English (en)
Inventor
Evangelos Karavas
Efthymios Koutris
Vasiliki SAMARA
Ioanna Koutri
Anastasia Kalaskani
Andreas KAKOURIS
Manolis FOUSTERIS
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.)
Pharmathen SA
Original Assignee
Pharmathen SA
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 Pharmathen SA filed Critical Pharmathen SA
Publication of EP4213937A1 publication Critical patent/EP4213937A1/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
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • 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 a stable pharmaceutical formulation for oral administration containing a therapeutically effective quantity of a dipepidyl peptidase-4 inhibitor (DPP -4 inhibitor) such as Sitagliptin or pharmaceutical acceptable salt, derivative or polymorph thereof and a method for the preparation thereof.
  • DPP -4 inhibitor dipepidyl peptidase-4 inhibitor
  • Diabetes mellitus is a condition defined by persistently high levels of sugar (glucose) in the blood.
  • Glucose is a small, simple sugar that serves as a primary fuel for energy production, especially for the brain, muscles and several other body organs and tissues.
  • Glucose also serves as a building block for larger structural molecules of the body, such as glycoproteins and glycolipids.
  • the human body tightly regulates glucose levels. Abnormally high or low levels result in serious, potentially life-threatening complications such as cardiovascular disease, stroke, chronic kidney disease, foot ulcers, damage to the nerves, damage to the eyes, cognitive impairment.
  • Type 2 diabetes is the most common form of diabetes. It was once called adult-onset diabetes because it typically begins in middle or older age. But more and more teens and young adults are also developing it now a day due to increased obesity.
  • Dipepidyl peptidase-4 (DPP-4) inhibitors represent a class of agents that are being developed for the treatment or improvement in glycemic control in type 2 diabetes.
  • DPP-4 inhibitors include sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin.
  • Sitagliptin works to competitively inhibit the enzyme DPP -4 resulting in driving blood glucose levels towards normal and tending to prevent an "overshoot" and subsequent low blood sugar (hypoglycemia), which is seen with some other oral hypoglycemic agents.
  • Sitagliptin Hydrochloride Monohydrate 7-[(3R)-3-Amino- 1 -oxo-4-(2, 4, 5-trifluorophenyl) butyl] -5, 6, 7, 8- tetrahydro -3- (trifluoromethyl)- 1,2,4-triazo lo[ 4,3- a. ]pyrazine hydrochloride monohydrate.
  • the molecular formula is Ci6Hi6ClF6NsO-H2O corresponding to a molecular weight of 461.79.
  • Sitagliptin Hydrochloride exhibits polymorphism.
  • the polymorph used in the present invention matches with API HCL Form HI (as per USV Ltd WO 2012/025944 A3 patent) and HCL crystalline form stated to WO 2012/147092 A2 (as per Cadila Healthcare Ltd).
  • the characteristic peaks of Sitagliptin Hydrochloride Monohydrate are the following: 6.6°, 8.0°, 13.7°, 16.0°, 18.0° and 27.0° 20 ⁇ 0.2° 20.
  • W02012/131005 relates to a pharmaceutical composition
  • a pharmaceutical composition comprising amorphous sitagliptin or a salt thereof, preferably amorphous sitagliptin hydrochloride.
  • WO2015/114152 relates to a pharmaceutical composition in the form of immediate release tablets comprising crystalline sitagliptin hydrochloride, preferably the monohydrate, wherein the pharmaceutical composition is prepared by dry granulation.
  • US10357525 discloses a method for the prophylaxis and/or treatment of type II diabetes in a subject comprising administering to the subject a dipeptidyl peptidase-4 (DPP -4) inhibitor and a polysaccharide mixture.
  • DPP -4 dipeptidyl peptidase-4
  • Further object of the present invention is to provide a solid dosage form for oral administration containing Sitagliptin or pharmaceutical acceptable salt, derivative or polymorph thereof, which can be formulated into dosage forms of different strengths by proportionally adjusting the amounts of the pharmaceutically acceptable excipients, as well as the active compound Sitagliptin.
  • a major object of the present invention is the selection of the optimal combination of pharmaceutical acceptable excipients and method of preparation in order to achieve the appropriate dissolution profile and stability for the finished dosage form.
  • Said dosage form affords predictable and reproducible drug release rates in order to achieve better treatment to a patient.
  • Another aspect of the present invention is to provide immediate release film-coated tablets comprising Sitagliptin or a pharmaceutically acceptable salt thereof comprising an appropriate amount of a disintegrant in the internal phase of the tablet core.
  • a further approach of the present invention is to provide a tablet composition for oral administration comprising Sitagliptin which is manufactured through a fast, simple and cost- effective process.
  • a process for the preparation of a stable, solid dosage form for oral administration containing a DPP -4 inhibitor and in particular Sitagliptin or pharmaceutical acceptable salt, derivative or polymorph thereof as an active ingredient and an effective amount of a disintegrating agent is provided, which comprises the following steps:
  • a pharmaceutical composition comprising an active ingredient (e.g. Sitagliptin) is considered to be “stable” if said ingredient degrades less or more slowly than it does on its own and/or in known pharmaceutical compositions.
  • an active ingredient e.g. Sitagliptin
  • the primary goal of the present invention is to develop an immediate release film-coated tablet formulation comprising Sitagliptin or a pharmaceutical acceptable salt thereof as the single drug substance that is simple to manufacture, bioavailable, cost effective, stable and possess good pharmacotechnical properties.
  • the Sitagliptin salt selected for the present development is Sitagliptin hydrochloride. This substance exhibits polymorphism.
  • Teva reported three crystalline forms (Form-Ill, Form-IV and Form-V) and process for their preparation in PCT patent application WO201 1/123641, while USV limited reported three crystalline forms (Form-Ill, Form-IV and Form-V) and their process were described in PCT patent application WO2012/025944.
  • Cadila also reported a crystalline form and its process in PCT patent application WO2012/147092.
  • Sitagliptin hydrochloride monohydrate is freely soluble in water and thus polymorph and particle size are not expected to be important aspects in the present formulation development.
  • the tablet composition also contains one or more inert materials known as excipients.
  • the primary composition includes diluents, disintegrants and lubricants.
  • Other excipients which give physical characteristics to the finished tablet are coloring agents, and flavors in the case of chewable tablets.
  • excipients are selected to impart good flow and compression characteristics to the material being compressed. Excipients are also selected with the perspective to enhance dissolution, physicochemical characteristics, and stability of the drug substance in the final dosage form.
  • Formulation trials were performed using both direct compression (dry mixing) and wet granulation methods to study the physicochemical properties as well as dissolution properties of the tablets.
  • Direct compression is regarded as a relatively quick process where the powdered materials are compressed directly without changing the physical and chemical properties of the drug.
  • the wet granulation method comprises an additional step of adding the granulating solution to the mixed powders to obtain a granulation.
  • direct compression is usually limited to those situations where the drug or active ingredient has physical characteristics required to form pharmaceutically acceptable tablets.
  • dry granulation process presents very to extremely poor flowability and the compression was not feasible in the tableting machine. Comparably, the flowability of wet granulation process could be considered as acceptable. Therefore, wet granulation process is chosen for the current development.
  • Lubricant is an essential component of the tablet formulation. Some pharmaceutical scientists believe that the manner of which a lubricant is added to a formulation must be carefully controlled. Accordingly, lubricants are usually added to a granulation by gentle mixing. It is also believed that prolonged blending of a lubricant with a granulate can materially affect hardness and disintegration time for the resulting tablets. For these reasons, composition of the tablet core is divided into two phases, an internal and an external phase. Lubricants are to be used in the external phase of the tablet core to avoid prolonged blending with the excipients used in the internal phase.
  • the preferred formulation of this invention comprises Sitagliptin as the active ingredient, a combination of diluents and a disintegrant in the internal phase of the tablet core and lubricants in the external phase of the tablet core.
  • Diluents are added to solid pharmaceutical dosage forms to make the product large enough for swallowing and handling, and more stable.
  • a combination of microcrystalline cellulose and dibasic calcium phosphate anhydrous are used in the present invention as diluents.
  • Microcrystalline cellulose is available from several suppliers. Suitable microcrystalline cellulose includes Avicel PH 101, Avicel PH 102, Avicel PH 103, Avicel PH 105 and Avicel PH 200, manufactured by FMC Corporation. Particularly preferred in the practice of this invention is Avicel PH 102, which has the smallest surface area and pore structure.
  • Anhydrous form of calcium phosphates is often used to overcome the problems related to dihydrate form.
  • Microcrystalline cellulose and dibasic calcium phosphate anhydrous are used in equal amounts. The sum of microcrystalline cellulose and dibasic calcium phosphate anhydrous may be present in an amount preferably from about 40% to about 80% by weight, more preferably from about 50% to about 75% by weight, and most preferably from about 60% to
  • Disintegrants are included to ensure that the tablet has an acceptable rate of disintegration.
  • examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone, cross-linked calcium carboxymethylcellulose and cross-linked sodium carboxymethylcellulose (croscarmellose sodium); soy polysaccharides; and guar gum, sodium starch glycolate.
  • Croscarmellose sodium is the preferred disintegrant used in the present invention. It may be present in an amount from about 1% to about 20%, more preferably from about 3% to about 14% by weight of the composition, and most preferably from about 5% to about 8% by weight of the composition.
  • Lubricants are typically added to prevent the tableting materials from sticking to punches, minimize friction during tablet compression and allow for removal of the compressed tablet from the die.
  • pharmaceutically acceptable lubricants include, but are not limited to, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystalline cellulose.
  • the lubricant component may be hydrophobic or hydrophilic.
  • Sodium stearyl fumarate is a water-soluble lubricant. It is usually preferred for better taste.
  • Magnesium stearate is also selected for the present invention. It aids in the flow of the powder in the hopper and into the die. It is stable and does not polymerize within the tableting mix.
  • Formulation development was mainly carried out on Sitagliptin lOOmg film-coated tablet and final formula was extrapolated linearly to produce the other strengths (25mg and 50mg). All 100 mg film-coated tablets were prepared by using a round (10 mm) slightly biconvex tablet punch.
  • composition of example 1 was prepared with both dry mixing and wet granulation. More specifically, Composition 1 and Composition 2 are identical and differ only to the method of their manufacturing.
  • Composition 1 was prepared by Dry mixing according to the following steps:
  • API microcrystalline cellulose, dibasic calcium phosphate anhydrous and croscarmellose sodium are sieved through a 16 mesh size sieve and they are mixed for 10 min.
  • Magnesium Stearate is sieved through a 30 mesh size sieve and it is mixed with above blend for 3 min.
  • Composition 2 was prepared by wet granulation according to the following steps:
  • API microcrystalline cellulose, dibasic calcium phosphate anhydrous and croscarmellose sodium are sieved through a 16 mesh size sieve and they are mixed for 10 min.
  • Magnesium Stearate is sieved through a 30 mesh size sieve and it is mixed with above blend for 3 min.
  • Table 3 Characteristics of the tablets obtained from Composition 2.
  • the wet granulation process led to increased disintegration times as well as hardness of the uncoated tablets in comparison with dry mixing process.
  • the dry mixing tablets exhibit acceptable values; however, the values are close to the lower limits of target characteristics.
  • the wet granulation process tablets are characterized by slightly higher disintegration time, which does not comply with target characteristics, but could be further optimized.
  • the main difference between the two processes appears in blend properties. More particularly, the Carr’s Index is high enough for both Trials, but the dry mixing blend presents a very poor - extremely poor flowability and the compression was not feasible in the tableting machine. Such powders with extremely poor flowability cannot be adequately compressed.
  • the flowability of wet granulation process could be considered as acceptable and that conclusion was reinforced by the smooth tablet machine operation during compression step. Therefore, wet granulation process was used for further development.
  • the disintegration time for Composition 2 does not comply with target characteristics. An even higher time is expected for coated tablets.
  • the disintegrant percentages tested were 2.0%wt in Comp 2, 3.5%wt in Comp 2.1, 5.0%wt in Comp 2.2, 6.5%wt in Comp 2.3 and 8.0%wt in Comp2.4.
  • the quantities of the diluents (microcrystalline cellulose & dibasic calcium phosphate anhydrous) were modified equally so that the weight of the final tablets remain the same among all formulation trials. Table 4 below displays the characteristics of the resulting tablets.
  • the dissolution rates indicate that the proportional increase of croscarmellose sodium quantity does affect the dissolution profiles. According to the above, the specification of >85% release at 15 min is fulfilled for disintegrant percentages > 5.0% and a range of 5.0 - 8.0% for disintegrant used is preferably selected.
  • the third group of trials focus on the granulation solvent.
  • the 5.0% disintegrant percentage was selected (Comp2.2) from second group of trials.
  • compositions and manufacturing processes of the two additional formulations are described below in Table 6.
  • Example 3 The composition of Example 3 was prepared with wet granulation. Compositions 2.2.1 & 2.2.2 are identical and differ only in the different type of granulation liquid used during wet granulation. More specifically, Composition 2.2.1 was prepared with EtOH as granulation liquid and Composition 2.2.2 was prepared with mixture 50/50% v/v Water/EtOH as granulation liquid.
  • compositions 2.2.1 & 2.2.2 are prepared according to the following steps:
  • Magnesium Stearate is sieved through a 30-mesh size sieve and mixed with above blend for 3 minutes;
  • All tablets of the present invention may be coated with a PVA based coating layer through a spray coating process.
  • composition 2.2 uses water as granulation liquid.
  • Sitagliptin film- coated tablets with qualitative/quantitative formula of Composition 2.2 were loaded into stability chambers and monitored with a fit-for-purpose HPLC analytical method.
  • Stability data (related substances) upon storage at zero-time & 6 months under long term (25°C ⁇ 2°C/60% ⁇ 5%RH) and accelerated storage conditions (40°C ⁇ 2°C/75% ⁇ 5%RH) are summarized in Table 9.
  • the in-vitro dissolution results under stability conditions are summarized in Table 10.
  • the nature of container closure system is aluminum blister.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Organic Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

La présente invention concerne une forme posologique solide utile pour le traitement du diabète de type 2. L'objectif principal de la présente invention est de fournir une formulation de comprimés comprenant de la sitagliptine ou un sel pharmaceutiquement acceptable de celle-ci qui est robuste et stable. L'invention concerne également un procédé de fabrication efficace pour la préparation desdits comprimés.
EP21782434.1A 2020-09-15 2021-09-14 Forme posologique solide comprenant de la sitagliptine et son procédé de préparation Pending EP4213937A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GR20200100560A GR1010089B (el) 2020-09-15 2020-09-15 Στερεη φαρμακοτεχνικη μορφη περιεχουσα σιταγλιπτινη και μεθοδος παρασκευης αυτης
PCT/EP2021/025344 WO2022058044A1 (fr) 2020-09-15 2021-09-14 Forme posologique solide comprenant de la sitagliptine et son procédé de préparation

Publications (1)

Publication Number Publication Date
EP4213937A1 true EP4213937A1 (fr) 2023-07-26

Family

ID=78464132

Family Applications (1)

Application Number Title Priority Date Filing Date
EP21782434.1A Pending EP4213937A1 (fr) 2020-09-15 2021-09-14 Forme posologique solide comprenant de la sitagliptine et son procédé de préparation

Country Status (3)

Country Link
EP (1) EP4213937A1 (fr)
GR (1) GR1010089B (fr)
WO (1) WO2022058044A1 (fr)

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2800507A1 (fr) 2010-03-31 2011-10-06 Teva Pharmaceuticals Industries Ltd. Formes a l'etat solide de sels de sitagliptine
US20130158265A1 (en) 2010-08-27 2013-06-20 Dhananjay Govind Sathe Sitagliptin, salts and polymorphs thereof
CN103476778A (zh) 2011-03-03 2013-12-25 卡迪拉保健有限公司 Dpp-iv抑制剂的新的盐
WO2012131005A1 (fr) 2011-03-29 2012-10-04 Krka, Tovarna Zdravil, D.D., Novo Mesto Composition pharmaceutique de sitagliptine
HUE049298T2 (hu) 2014-02-03 2020-09-28 Galenicum Health Sl Szitagliptin tartalmú stabil gyógyszerészeti készítmények azonnali hatóanyag leadású tabletta formájában
IN2014MU00651A (fr) * 2014-02-25 2015-10-23 Cadila Healthcare Ltd
US10357525B2 (en) 2017-05-31 2019-07-23 Trineo Biotechnology Co. Ltd Use of a polysaccharide mixture for treating hyperglycemia

Also Published As

Publication number Publication date
WO2022058044A1 (fr) 2022-03-24
GR1010089B (el) 2021-09-27

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