EP3731825A2 - Extended release compositions of fesoterodine - Google Patents

Extended release compositions of fesoterodine

Info

Publication number
EP3731825A2
EP3731825A2 EP18911327.7A EP18911327A EP3731825A2 EP 3731825 A2 EP3731825 A2 EP 3731825A2 EP 18911327 A EP18911327 A EP 18911327A EP 3731825 A2 EP3731825 A2 EP 3731825A2
Authority
EP
European Patent Office
Prior art keywords
weight
extended release
tablet
composition according
release 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
EP18911327.7A
Other languages
German (de)
French (fr)
Inventor
Nur PEHLIVAN AKALIN
Kerim AKKAYA
Ezgi USLU
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 EP3731825A2 publication Critical patent/EP3731825A2/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • 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
    • A61K9/2013—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates

Definitions

  • the present invention relates to extended release compositions comprising fesoterodine fumarate and at least one release retarding agent.
  • the present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient method of preparing the extended release compositions of fesoteradine fumarate.
  • Fesoterodine fumarate is the fumarate salt form of fesoterodine, a competitive muscarinic receptor antagonist with muscle relaxant and urinary antispasmodic properties. Fesoterodine is rapidly hydrolyzed in vivo into its active metabolite 5-hydroxy methyl tolterodine, which binds and inhibits muscarinic receptors on the bladder detrusor muscle, thereby preventing bladder contractions or spasms caused by acetylcholine. This results in the relaxation of bladder smooth muscle and greater bladder capacity, in addition to a reduction in involuntary muscle contractions and involuntary loss of urine. The active metabolite does not interact with alpha-adrenergic, serotonergic, histaminergic and excitatory amino acid receptors and is eliminated via renal excretion.
  • fesoterodine fumarate (E)-but-2-enedioic acid;[2-[(1 R)-3- [di(propan-2-yl)amino]-1 -phenylpropyl]-4-(hydroxymethyl)phenyl] 2-methylpropanoate. Its empirical formula is C 30 Fl 1 NO and has the following structural formula:
  • the drug fesoterodine fumarate is the active ingredient in a product being sold as TOVIAZ® tablets to treat urinary incontinence and frequency problems.
  • Inactive ingredients are glyceryl behenate, hypromellose, lactose monohydrate, soya lecithin, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and xylitol.
  • Fesoterodine fumarate is known in the art for its potency in treating urinary incontinence. However, fesoterodine may exhibit substantial degradation under stress conditions. It is believed that hydrolyzation and oxidation are among the major mechanisms resulting in degradation.
  • the main object of the present invention is to provide an extended release composition of fesoterodin fumarate which improves gastrointestinal (Gl) intolerance and allows once- daily dosing.
  • Another object of the present invention is to provide an extended release composition of fesoterodin fumarate which has the potential to improve patient adherence with a simple dosing regimen and increased tolerability.
  • Another object of the present invention is to provide pharmaceutical compositions of fesoteradin fumarate which are more stable against degradation over storage period and also provide desired extended release of the drug.
  • Another object of the present invention is to provide an extended release composition of fesoterodin fumarate which is characterized by desired dissolution profile and excellent pharmacotechnical properties, such as flowability, compressibility and homogeneity.
  • extended release may be defined as reaching desired plasma levels of an active agent of interest throughout a determined period of time and providing the drug release at a uniform and constant rate.
  • Fesoterodine fumarate is highly soluble in water. High solubility affects the dissolution profile and it may cause dose dumping which is a result of too rapid release of the active agent.
  • release retarding agents have been used.
  • the extended release composition comprises fesoterodine fumarate and at least one release retarding agent, optionally granulated and optionally compressed.
  • the amount of fesoterodine fumarate is between 0.5% and 25.0% w/w of the composition, preferably it is between 0.5% and 15.0% w/w of the composition.
  • the amount of release retarding agent is between 1.0 % and 60.0 % w/w, preferably 1.0 % and 55.0 % w/w, more preferably 5.0 % and 50.0 w/w of the composition.
  • the ratio of fesoteradine fumarate to the release retarding agent is in the range of between 0.5:60 and 25:1 by weight, preferably between 0.5:60 and 15:1 by weight, more preferably 0.5:10 and 10:1 by weight of the composition.
  • the composition comprises fesoterodin fumarate as an active ingredient and at least one polymer as a release retarding agent.
  • the polymer as release retarding agent is selected from the group comprising hydroxyl propyl methylcellulose (HPMC) such as HPMC E4M and HPMC K100, hydroxyethyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose, ethylcellulose, methacrylic acid - ethyl acrylate copolymer, polymethylmetacrylate or copolymers, polyvinyl acetate, polyvinyl alcohol, polyvinylpyrrolidine, glyceryl behenate, glyceryl dibehenate, polyethylene oxide, polyethylene glycol, cellulose acetate, vinyl acetate/croton ic acid copolymers, maleic anhydride/methyl vinyl ether copolymers, copolymer of acrylic or methacrylic acid esters
  • HPMC hydroxyl propyl
  • the polymer release retarding agents are selected from the group comprising hydroxyl propyl methylcellulose, glyceryl dibehenate, polyvinyl acetate, polyvinylpyrrolidone, sodium lauryl sulfate (SLS) or silica or mixtures thereof.
  • Polyvinyl acetate, polyvinylpyrrolidone, sodium lauryl sulfate (SLS) and silica mixture is known as Kollidon SR.
  • Polyvinyl acetate is a hydrophobic polymer and is also referred to as PVAc. It is insoluble and does not strongly swell as other extended release polymers.
  • PVAc which is available as dispersion comprising povidone as a pore former and sodium lauryl sulfate (SLS) as a stabilizer/wetting agent.
  • SLS sodium lauryl sulfate
  • the amount of polyvinyl acetate is between 50% and 95 % by weight, preferably it is between 60 % and 95 % by weight, more preferably it is between 70 % and 90 % by weight of the Kollidon SR (a mixture of polyvinyl acetate, polyvinylpyrrolidone, sodium lauryl sulfate (SLS) and silica).
  • the Kollidon SR a mixture of polyvinyl acetate, polyvinylpyrrolidone, sodium lauryl sulfate (SLS) and silica
  • the amount of polyvinylpyrrolidone is between 5% and 45 %, preferably it is between 5 % and 40 % by weight, more preferably it is between 10 % and 30 % by weight of the Kollidon SR. In one embodiment of this present invention, the rate of polyvinyl acetate to polyvinylpyrrolidone is 4:1 by weight of the Kollidon SR.
  • the extended release composition further comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising stabilizers, diluents, lubricants, coating agents or the mixtures thereof.
  • the extended release composition comprises fructose-sucrose mixture as stabilizer.
  • the fructose-sucrose mixture is a stabilizer which have binder properties.
  • it further enhances excellent pharmacotechnical properties (flowability, compressibility and homogeneity).
  • the amount of the fructose-sucrose mixture is between 1.0% and 40.0% by weight of the composition, preferably it is between 5.0% and 35.0% by weight, more preferably it is between 10.0% and 30.0% by weight.
  • Suitable diluents are selected from the group comprising lactose monohydrate, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose anhydrous, lactose dihydrate or mixtures thereof.
  • the extended release composition comprises lactose monohydrate- microcrystalline cellulose mixture as a diluent.
  • the amounts of diluents are between 5.0% and 50.0% w/w of the composition, preferably the amounts of diluents are between 7.0% and 40.0% w/w of the composition.
  • Suitable lubricants are selected from the group comprising from talc, calcium silicate, powdered cellulose, starch, colloidal silicon dioxide or mixtures thereof.
  • the extended release composition comprises talc as a lubricant.
  • lubricants are between 0.1 % and 5.0% w/w of the composition.
  • the extended release composition of fesoteradine fumarate is in the dosage form of tablet, bilayer tablet, multilayer tablet, mini tablet, intraoral tablet, sublingual tablet, effervescent tablet, rapid release tablets, intra-tablet tablet, inlay tablet, tablet in tablet, modified release tablet, modified release providing coated tablet, coated tablet, film-coated tablet, pellet, sugar pellet, capsule, oral granule, powder coated bead system, microsphere, , capsule in capsule, dragee, sachet or oral administered film.
  • the extended release composition of fesoteradin fumarate is preferably in the form of a tablet, most preferably a film-coated tablet.
  • the amount of film coating agents is between 0.1 % and 5.0% w/w of the composition.
  • Suitable film coating agents are selected from the group comprising, polyvinyl alcohol, polyethylene glycol, polymethylmethacrylate derivatives, ethylcellulose dispersions (Surelease), hydroxypropyl cellulose, polyvinylpyrrolidone, vinyl acetate, glyceryl monocaprylocaprate, sodium lauryl sulphate, titanium dioxide, iron oxide, talc, dyes (i.e. Fd&c blue, indigo carmine aluminum lake), pigments or their mixtures.
  • the film coating agents comprises opadry varieties, such as Opadry Amb II.
  • each type of particle comprises at least one active agent.
  • the extended release composition comprises;
  • the extended release composition comprises;
  • sucrose 0.10 % - 5.00 % by weight of sucrose
  • microcrystalline cellulose 2.50 % - 25.0 % by weight of microcrystalline cellulose
  • Kollidon SR comprises
  • the extended release composition comprises;
  • Kollidon SR comprises
  • SLS sodium lauryl sulfate
  • the extended release composition of the present invention may be prepared by direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion/spheronization, slugging, spray drying or solvent evaporation.
  • the extended release composition is prepared by wet granulation which is simple and cost-effective method. Also, this process helps to provide stability and dissolution profile of the tablet.
  • Process for preparing the extended release composition comprises the following steps; a) mixing fesoterodine fumarate, fructose and sucrose,
  • compositions possess improved stability.
  • the given below examples describes the extended release composition comprising fesoterodine.
  • Example 1 Extended release composition comprising fesoterodine fumarate
  • the process for preparation of the modified release composition comprises the following steps:
  • Example 2 Extended release composition comprising fesoteradine
  • Coating Agent is preferably Opadry Amb II a) Polyvinyl alcohol 15-50 % b) Talc 15-50% c) Titanium dioxide 10-40% d) Glyceryl monocaprylocaprate 1.0-10.0% e) Fd&c blue #2/indigo carmine aluminum lake 1.0 -5.0% f) Sodium lauryl sulphate 1.0 - 5.0 % Process for example 2:
  • the process for preparation of the modified release composition comprises the following steps:
  • Example 3 Extended release composition comprising fesoterodine
  • Coating Agent is preferably Opadry Amb II a) Polyvinyl alcohol 15 - 50 %
  • the process for preparation of the modified release composition comprises the following steps:

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Inorganic Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention relates to extended release compositions comprising fesoterodine fumarate and at least one release retarding agent. The present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient method of preparing the extended release tablet compositions of fesoteradine fumarate.

Description

EXTENDED RELEASE COMPOSITIONS OF FESOTERODINE
Field of the Invention
The present invention relates to extended release compositions comprising fesoterodine fumarate and at least one release retarding agent. The present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient method of preparing the extended release compositions of fesoteradine fumarate.
Background of the Invention
Fesoterodine fumarate is the fumarate salt form of fesoterodine, a competitive muscarinic receptor antagonist with muscle relaxant and urinary antispasmodic properties. Fesoterodine is rapidly hydrolyzed in vivo into its active metabolite 5-hydroxy methyl tolterodine, which binds and inhibits muscarinic receptors on the bladder detrusor muscle, thereby preventing bladder contractions or spasms caused by acetylcholine. This results in the relaxation of bladder smooth muscle and greater bladder capacity, in addition to a reduction in involuntary muscle contractions and involuntary loss of urine. The active metabolite does not interact with alpha-adrenergic, serotonergic, histaminergic and excitatory amino acid receptors and is eliminated via renal excretion.
The chemical name of fesoterodine fumarate is (E)-but-2-enedioic acid;[2-[(1 R)-3- [di(propan-2-yl)amino]-1 -phenylpropyl]-4-(hydroxymethyl)phenyl] 2-methylpropanoate. Its empirical formula is C30Fl 1NO and has the following structural formula:
Formula I
The drug fesoterodine fumarate is the active ingredient in a product being sold as TOVIAZ® tablets to treat urinary incontinence and frequency problems. Inactive ingredients are glyceryl behenate, hypromellose, lactose monohydrate, soya lecithin, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and xylitol.
Fesoterodine fumarate is known in the art for its potency in treating urinary incontinence. However, fesoterodine may exhibit substantial degradation under stress conditions. It is believed that hydrolyzation and oxidation are among the major mechanisms resulting in degradation.
Synthesis pathways for fesoterodine is described in EP 1 077 912 B1 . Salts of fesoterodine is described in EP 1 230 209 B1 . U.S. Patent No. 7,807,715 discloses fesoterodine tablet formulations containing a stabilizer against hydrolysis, wherein the stabilizer is preferably a sugar alcohol, such as sorbitol and xylitol. Furthermore, the drug needs to be involved in artificial polymer, so that an extended release could be achieved in a matrix. However, it was found that the amount of decomposition products can only be controlled if the proposed formulations were prepared by classical wet granulation. A direct compression or dry granulation also resulted in an identical composition to higher amounts of undesirable decomposition products (compared to the wet granulation).
There is thus still a need for a physically and chemically stable composition comprising fesoterodine that are stable against fesoterodine degradation over an extended period of time. In the present invention, stabilizers with binding properties was used, so while the stable formulation is provided without using extra load of excipients, also the formulation provide desired dissolution profile and excellent pharmacotechnical properties such as flowability, compressibility and homogeneity. Also, the formulation has been developed by using standard techniques which is simple and cost-effective method.
Detailed Description of the Invention
The main object of the present invention is to provide an extended release composition of fesoterodin fumarate which improves gastrointestinal (Gl) intolerance and allows once- daily dosing.
Another object of the present invention is to provide an extended release composition of fesoterodin fumarate which has the potential to improve patient adherence with a simple dosing regimen and increased tolerability. Another object of the present invention is to provide pharmaceutical compositions of fesoteradin fumarate which are more stable against degradation over storage period and also provide desired extended release of the drug.
Another object of the present invention is to provide an extended release composition of fesoterodin fumarate which is characterized by desired dissolution profile and excellent pharmacotechnical properties, such as flowability, compressibility and homogeneity.
The term“extended release” may be defined as reaching desired plasma levels of an active agent of interest throughout a determined period of time and providing the drug release at a uniform and constant rate. Fesoterodine fumarate is highly soluble in water. High solubility affects the dissolution profile and it may cause dose dumping which is a result of too rapid release of the active agent. In this present invention, to provide an extended release and to control the release rate, release retarding agents have been used.
In this invention, the extended release composition comprises fesoterodine fumarate and at least one release retarding agent, optionally granulated and optionally compressed.
In one embodiment of this present invention, the amount of fesoterodine fumarate is between 0.5% and 25.0% w/w of the composition, preferably it is between 0.5% and 15.0% w/w of the composition.
In one embodiment of this present invention, the amount of release retarding agent is between 1.0 % and 60.0 % w/w, preferably 1.0 % and 55.0 % w/w, more preferably 5.0 % and 50.0 w/w of the composition.
According to this embodiment, the ratio of fesoteradine fumarate to the release retarding agent is in the range of between 0.5:60 and 25:1 by weight, preferably between 0.5:60 and 15:1 by weight, more preferably 0.5:10 and 10:1 by weight of the composition.
In one embodiment of this present invention, the composition comprises fesoterodin fumarate as an active ingredient and at least one polymer as a release retarding agent. According to this embodiment, the polymer as release retarding agent is selected from the group comprising hydroxyl propyl methylcellulose (HPMC) such as HPMC E4M and HPMC K100, hydroxyethyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose, ethylcellulose, methacrylic acid - ethyl acrylate copolymer, polymethylmetacrylate or copolymers, polyvinyl acetate, polyvinyl alcohol, polyvinylpyrrolidine, glyceryl behenate, glyceryl dibehenate, polyethylene oxide, polyethylene glycol, cellulose acetate, vinyl acetate/croton ic acid copolymers, maleic anhydride/methyl vinyl ether copolymers, copolymer of acrylic or methacrylic acid esters, polyoxyethylene -alkyl ethers, sodium lauryl sulfate (SLS), silica or mixtures thereof.
Preferably the polymer release retarding agents are selected from the group comprising hydroxyl propyl methylcellulose, glyceryl dibehenate, polyvinyl acetate, polyvinylpyrrolidone, sodium lauryl sulfate (SLS) or silica or mixtures thereof.
Polyvinyl acetate, polyvinylpyrrolidone, sodium lauryl sulfate (SLS) and silica mixture is known as Kollidon SR.
Surprisingly, it has been found that, using the polyvinyl acetate as a release retarding agent, prevent instant release and avoid any dose dumping due to self-sealing property of polyvinyl acetate. Polyvinyl acetate is a hydrophobic polymer and is also referred to as PVAc. It is insoluble and does not strongly swell as other extended release polymers. PVAc, which is available as dispersion comprising povidone as a pore former and sodium lauryl sulfate (SLS) as a stabilizer/wetting agent. The povidone plays an important role in releasing the drug molecules from insoluble PVAc films and SLS provides an advantage for spreading the polymer during coating, hence leading to homogeneous films.
In one embodiment of this present invention, the amount of polyvinyl acetate is between 50% and 95 % by weight, preferably it is between 60 % and 95 % by weight, more preferably it is between 70 % and 90 % by weight of the Kollidon SR (a mixture of polyvinyl acetate, polyvinylpyrrolidone, sodium lauryl sulfate (SLS) and silica).
In one embodiment of this present invention, the amount of polyvinylpyrrolidone is between 5% and 45 %, preferably it is between 5 % and 40 % by weight, more preferably it is between 10 % and 30 % by weight of the Kollidon SR. In one embodiment of this present invention, the rate of polyvinyl acetate to polyvinylpyrrolidone is 4:1 by weight of the Kollidon SR.
According to another embodiment of this invention, the extended release composition further comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising stabilizers, diluents, lubricants, coating agents or the mixtures thereof.
In one embodiment of this present invention, the extended release composition comprises fructose-sucrose mixture as stabilizer.
According to one embodiment in the present invention, the fructose-sucrose mixture is a stabilizer which have binder properties. In addition, it further enhances excellent pharmacotechnical properties (flowability, compressibility and homogeneity).
In one embodiment of this present invention, the amount of the fructose-sucrose mixture is between 1.0% and 40.0% by weight of the composition, preferably it is between 5.0% and 35.0% by weight, more preferably it is between 10.0% and 30.0% by weight.
Suitable diluents are selected from the group comprising lactose monohydrate, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose anhydrous, lactose dihydrate or mixtures thereof.
In one embodiment of this present invention, the extended release composition comprises lactose monohydrate- microcrystalline cellulose mixture as a diluent.
According to another embodiment of this invention, the amounts of diluents are between 5.0% and 50.0% w/w of the composition, preferably the amounts of diluents are between 7.0% and 40.0% w/w of the composition.
Suitable lubricants are selected from the group comprising from talc, calcium silicate, powdered cellulose, starch, colloidal silicon dioxide or mixtures thereof. In one embodiment of this present invention, the extended release composition comprises talc as a lubricant.
According to another embodiment of this invention, lubricants are between 0.1 % and 5.0% w/w of the composition.
According to another embodiments of the invention, the extended release composition of fesoteradine fumarate is in the dosage form of tablet, bilayer tablet, multilayer tablet, mini tablet, intraoral tablet, sublingual tablet, effervescent tablet, rapid release tablets, intra-tablet tablet, inlay tablet, tablet in tablet, modified release tablet, modified release providing coated tablet, coated tablet, film-coated tablet, pellet, sugar pellet, capsule, oral granule, powder coated bead system, microsphere, , capsule in capsule, dragee, sachet or oral administered film.
According to this embodiment the extended release composition of fesoteradin fumarate is preferably in the form of a tablet, most preferably a film-coated tablet.
According to this embodiment, the amount of film coating agents is between 0.1 % and 5.0% w/w of the composition.
Suitable film coating agents are selected from the group comprising, polyvinyl alcohol, polyethylene glycol, polymethylmethacrylate derivatives, ethylcellulose dispersions (Surelease), hydroxypropyl cellulose, polyvinylpyrrolidone, vinyl acetate, glyceryl monocaprylocaprate, sodium lauryl sulphate, titanium dioxide, iron oxide, talc, dyes (i.e. Fd&c blue, indigo carmine aluminum lake), pigments or their mixtures.
According to this embodiment, preferably the film coating agents comprises opadry varieties, such as Opadry Amb II.
An embodiment of this present invention, each type of particle comprises at least one active agent. In one embodiment of the invention, the extended release composition comprises;
0.5 % - 25.0 % by weight of fesoteradine fumarate
1.0 % - 40.0 % by weight of stabilizer
5.0 % - 50.0 % by weight of diluent
1.0 % - 60.0 % by weight of release retarding agent
1.0 % - 5.0 % by weight of lubricant
1.0 % - 10.0 % by weight of coating agent
In one embodiment of the invention, the extended release composition comprises;
0.50 % - 25.0 % by weight of fesoterodine fumarate
0.90 % - 35.0 % by weight of fructose
0.10 % - 5.00 % by weight of sucrose
2.50 % - 25.0 % by weight of lactose monohydrate
2.50 % - 25.0 % by weight of microcrystalline cellulose
0.20 % - 5.00 % by weight of glyceryl dibehenate
0.40 % - 23.0 % by weight of hydroxypropyl methylcellulose
0.40 % - 32.0% by weight of polyvinyl acetate, polyvinylpyrrolidone, sodium lauryl sulfate and silica (Kollidon SR)
0.10 % - 10.00 % by weight of talc
1 .00 % - 10.0 % by weight of coating agent
According to the above embodiment of the invention, Kollidon SR comprises;
50.0 % - 95.0 % by weight of polyvinyl acetate
5.00 % - 45.0 % by weight of polyvinylpyrrolidone
0.10 % - 3.00 % by weight of sodium lauryl sulfate
0.05 % - 2.00 % by weight of silica
In one embodiment of the invention, the extended release composition comprises;
0.5 % - 15.0 % by weight of fesoterodine fumarate
4.9 % - 29.0% by weight of fructose
0.1 % - 1.0% by weight of sucrose
3.0 % - 23.0% by weight of lactose monohydrate
4.0 % - 17.0% by weight of microcrystalline cellulose
1.0 % - 4.0% by weight of glyceryl dibehenate
2.0 % - 20.0% by weight of hydroxypropyl methylcellulose 2.0 % - 26.0% by weight of polyvinyl acetate, polyvinylpyrrolidone, sodium lauryl sulfate and silica (Kollidon SR)
0.1 % - 10.0% by weight of talc
1.0% - 10.0% by weight of coating agent
According to the above embodiment of the invention, Kollidon SR comprises;
70.0 % - 90.0 % by weight of polyvinyl acetate
10.0 % - 30.0 % by weight of polyvinylpyrrolidone
0.1 % - 3.0 % by weight of sodium lauryl sulfate (SLS)
0.05 % - 2.0 % by weight of silica
The extended release composition of the present invention may be prepared by direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion/spheronization, slugging, spray drying or solvent evaporation.
Preferably, the extended release composition is prepared by wet granulation which is simple and cost-effective method. Also, this process helps to provide stability and dissolution profile of the tablet.
Process for preparing the extended release composition comprises the following steps; a) mixing fesoterodine fumarate, fructose and sucrose,
b) granulating the mixture with water then, sieving,
c) drying the mixture at 40°C until the humidity is less than 0.5%, then sieving the mixture,
d) adding lactose monohydrate, microcrystalline cellulose, glyceryl dibehenate, hydroxypropyl methylcellulose, kollidon SR and then mixing,
e) then, adding talc and mixing,
f) then, pressing to form tablet,
g) coating tablets with coating agent.
It has been found that using wet granulation process, wherein granulating fesoterodine fumarate and polyvinyl acetate as release retarding agent with the addition of excipients for wet granulation showed an improved stability of fesoterodine fumarate in the granulate and in the final pharmaceutical composition.
Also, it has been found that when the composition is prepared with using water-based granulation, resulting compositions possess improved stability. The given below examples describes the extended release composition comprising fesoterodine.
Example 1 : Extended release composition comprising fesoterodine fumarate
Process for example 1 :
The process for preparation of the modified release composition comprises the following steps:
a) mixing fesoterodine fumarate with at least two stabilizers
b) granulating the mixture with water then, sieving
c) drying the mixture at 40°c until the humidity is less than 0.5%, then sieving the mixture
d) adding diluents, release retarding agents and then mixing
e) then, adding lubricants and mixing
f) then, pressing to form tablet
g) optionally, coating tablets with coating agent
Example 2: Extended release composition comprising fesoteradine
* Kollidon SR comprising:
**Coating Agent is preferably Opadry Amb II a) Polyvinyl alcohol 15-50 % b) Talc 15-50% c) Titanium dioxide 10-40% d) Glyceryl monocaprylocaprate 1.0-10.0% e) Fd&c blue #2/indigo carmine aluminum lake 1.0 -5.0% f) Sodium lauryl sulphate 1.0 - 5.0 % Process for example 2:
The process for preparation of the modified release composition comprises the following steps:
g) mixing fesoterodine fumarate with fructose and sucrose
h) granulating the mixture with water then, sieving
i) drying the mixture at 40°C until the humidity is less than 0.5%, then sieving the mixture
j) adding lactose monohydrate, microcrystalline cellulose, glyceryl dibehenate, hydroxypropyl methylcellulose, Kollidon SR and then mixing
k) then, adding talc and mixing
L) then, pressing to form tablet
m) optionally, coating tablets with Opadry Amb II
Example 3: Extended release composition comprising fesoterodine
Kollidon SR*comprising
**Coating Agent is preferably Opadry Amb II a) Polyvinyl alcohol 15 - 50 %
b) Talc 15 - 50 %
c) Titanium dioxide 10 - 40 %
d) Glyceryl monocaprylocaprate 1.0 - 10.0%
e) Fd&c blue #2/indigo carmine aluminum lake 1.0 - 5.0 %
f) Sodium lauryl sulphate 1.0 - 5.0 %
Process for example 3:
The process for preparation of the modified release composition comprises the following steps:
a) mixing fesoterodine fumarate with fructose and sucrose
b) granulating the mixture with water then, sieving
c) drying the mixture at 40°c until the humidity is less than 0.5%, then sieving the mixture
d) adding lactose monohydrate, microcrystalline cellulose, glyceryl dibehenate, hydroxypropyl methylcellulose, Kollidon SR and then mixing
e) then, adding talc and mixing
f) then, pressing to form tablet
g) optionally, coating tablets with Opadry Amb II

Claims

CLAIMS:
1. An extended release composition comprising fesoterodine fumarate and at least one release retarding agent .
2. The extended release composition according to claim 1 , wherein the amount of fesoterodine fumarate is between 0.5% and 25.0% w/w of the composition, preferably it is between 0.5% and 15.0% w/w of the composition.
3. The extended release composition according to claim 1 , wherein the amount of release retarding agent is between 1.0 % and 60.0 %, preferably 1 .0 % and 55.0 %, more preferably 5.0 % and 50.0 w/w of the composition.
4. The extended release composition according to claim 2 or 3, wherein the ratio of fesoteradine fumarate to the release retarding agent is in the range of between 0.5: 60 and 25:1 , preferably between 0.5:60 and 15:1 and more preferably 0.5:10 and 10:1 by weight of the composition.
5. The extended release composition according to claim 1 , wherein the composition comprising fesoterodin fumarate as an active ingredient and at least one polymer as a release retarding agent.
6. The extended release composition according to claim 5, wherein at least one polymer as the release retarding agent is selected from the group comprising hydroxyl propyl methylcellulose,hydroxyethyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose, ethylcellulose, methacrylic acid - ethyl acrylate copolymer , polymethylmetacrylate or copolymers, polyvinyl acetate, polyvinyl alcohol, polyvinylpyrrolidine, glyceryl behenate, glyceryl dibehenate, polyethylene oxide, polyethylene glycol, cellulose acetate, vinyl acetate/croton ic acid copolymers, maleic anhydride/methyl vinyl ether copolymers, copolymer of acrylic or methacrylic acid esters, polyoxyethylene-alkyl ethers, sodium lauryl sulfate, silica or mixtures thereof.
7. The extended release composition according to claim 6, wherein the polymer release retarding agent is selected from the group comprising hydroxyl propyl methylcellulose, glyceryl dibehenate, polyvinyl acetate, polyvinylpyrrolidone, sodium lauryl sulfate or silica or mixtures thereof, preferably it is selected from a mixture comprising polyvinyl acetate, polyvinylpyrrolidone, sodium lauryl sulfate and silica.
8. The extended release composition according to claim 7, wherein the amount of polyvinyl acetate is between 50% and 95 % by weight of the polyvinyl acetate, polyvinylpyrrolidone, sodium lauryl sulfate (SLS) and silica mixture, preferably it is between 60 % and 95 % by weight, more preferably it is between 70 % and 90 % by weight of the said release retarding agent mixture.
9. The extended release composition according to claim 7, wherein the amount of polyvinylpyrrolidone is between 5% and 45 % by weight of the polyvinyl acetate, polyvinylpyrrolidone, sodium lauryl sulfate and silica mixture, preferably it is between 5 % and 40 % by weight, more preferably it is between 10 % and 30 % by weight of the said release retarding agent mixture.
10. The extended release composition according to claim 8 or 9, wherein the rate of polyvinyl acetate to polyvinylpyrrolidone is 4:1 by weight in the polyvinyl acetate, polyvinylpyrrolidone, sodium lauryl sulfate and silica mixture.
1 1. The extended release composition according to claim 1 , further comprising at least one pharmaceutically acceptable excipient which is selected from the group comprising stabilizers, diluents, lubricants, coating agents or the mixtures thereof.
12. The extended release composition according to claim 1 1 , wherein the extended release composition comprising the fructose-sucrose mixture as stabilizer.
13. The extended release composition according to claim 12, wherein the amount of the fructose-sucrose mixture is between 1.0% and 40.0% by weight of the composition, preferably it is between 5.0% and 35.0% by weight, more preferably it is between 10.0% and 30.0% by weight.
14. The extended release composition according to claim 1 1 , wherein the diluents are selected from the group comprising lactose monohydrate, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol. lactose anhydrous, lactose dihydrate or mixtures thereof.
15. The extended release composition according to claim 14, wherein the extended release composition comprising lactose monohydrate- microcrystalline cellulose mixture as a diluent.
16. The extended release composition according to claim 15, wherein the amounts of diluents are between 5.0% and 50.0% w/w of the composition, preferably the amounts of diluents are between 7.0% and 40.0% w/w of the composition.
17. The extended release composition according to any preceding claims, the composition comprising;
a. 0.50 % - 25.0 % by weight of fesoterodine fumarate
b. 0.90 % - 35.0 % by weight of fructose
c. 0.10 % - 5.00 % by weight of sucrose
d. 2.50 % - 25.0 % by weight of lactose monohydrate
e. 2.50 % - 25.0 % by weight of microcrystalline cellulose
f. 0.20 % - 5.00 % by weight of glyceryl dibehenate
g. 0.40 % - 23.0 % by weight of hydroxypropyl methylcellulose
h. 0.40 % - 32.0% by weight of polyvinyl acetate, polyvinylpyrrolidone, sodium lauryl sulfate (SLS) and silica
i. 0.10 % - 10.00 % by weight of talc
j. 1.00 % - 10.0 % by weight of coating agent
18. The extended release composition according to claim 17, wherein the mixture of polyvinyl acetate, polyvinylpyrrolidone, sodium lauryl sulfate (SLS) and silica comprising;
a. 50.0 % - 95.0 % by weight of polyvinyl acetate
b. 5.00 % - 45.0 % by weight of polyvinylpyrrolidone
c. 0.10 % - 3.00 % by weight of sodium lauryl sulfate (SLS)
d. 0.05 % - 2.00 % by weight of silica
19. A process for preparing the modified release composition according to claim 17, the composition comprising the following steps;
a. mixing fesoterodine fumarate and at least two stabilizers,
b. granulating the mixture with water then, sieving, c. drying the mixture at 40°C until the humidity is less than 0.5%, then sieving the mixture,
d. adding diluents, release retarding agents and then mixing,
e. then, adding lubricants and mixing,
f. then, pressing to form tablet,
g. optionally, coating tablets with coating agent.
20. The extended release composition according to any preceding claims, wherein the composition is in the dosage form of tablet, bilayer tablet, multilayer tablet, mini tablet, intraoral tablet, sublingual tablet, effervescent tablet, rapid release tablets, intra-tablet tablet, inlay tablet, tablet in tablet, modified release tablet, modified release providing coated tablet, coated tablet, film-coated tablet, pellet, sugar pellet, capsule, oral granule, powder coated bead system, microsphere, capsule in capsule, dragee, sachet or oral administered film.
21 . The extended release composition according to claim 20, wherein the composition is in the tablet form, most preferably in the film-coated tablet form.
22. The extended release composition according to claim 21 , wherein the amount of film coating agents is between 0.1% and 10.0% by weight of the composition.
23. The extended release composition according to claim 22, wherein the film coating agents are selected from the group comprising, polyvinyl alcohol, polyethylene glycol, polymethylmethacrylate derivatives, ethylcellulose dispersions, hydroxypropyl cellulose, polyvinylpyrrolidone, vinyl acetate, glyceryl monocaprylocaprate, sodium lauryl sulphate, titanium dioxide, iron oxide, talc, dyes (i.e Fd&c blue, indigo carmine aluminum lake), pigments or their mixtures.
EP18911327.7A 2017-12-25 2018-12-21 Extended release compositions of fesoterodine Pending EP3731825A2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
TR2017/21437A TR201721437A2 (en) 2017-12-25 2017-12-25 FORMULATIONS OF FESOTHERODY PROVIDING MODIFIED EMISSION
TR2018/19274A TR201819274A2 (en) 2017-12-25 2018-12-13 Extended release compositions of fesoterodine
PCT/TR2018/050858 WO2019209220A2 (en) 2017-12-25 2018-12-21 Extended release compositions of fesoterodine

Publications (1)

Publication Number Publication Date
EP3731825A2 true EP3731825A2 (en) 2020-11-04

Family

ID=67900979

Family Applications (4)

Application Number Title Priority Date Filing Date
EP18911327.7A Pending EP3731825A2 (en) 2017-12-25 2018-12-21 Extended release compositions of fesoterodine
EP18915776.1A Pending EP3731826A2 (en) 2017-12-25 2018-12-21 The bilayer tablet formulation of fesoterodine
EP18913635.1A Pending EP3731931A4 (en) 2017-12-25 2018-12-21 Modified release formulations of fesoterodine
EP18849451.2A Pending EP3731829A1 (en) 2017-12-25 2018-12-21 Tablet compositions of fesoterodine fumarate

Family Applications After (3)

Application Number Title Priority Date Filing Date
EP18915776.1A Pending EP3731826A2 (en) 2017-12-25 2018-12-21 The bilayer tablet formulation of fesoterodine
EP18913635.1A Pending EP3731931A4 (en) 2017-12-25 2018-12-21 Modified release formulations of fesoterodine
EP18849451.2A Pending EP3731829A1 (en) 2017-12-25 2018-12-21 Tablet compositions of fesoterodine fumarate

Country Status (3)

Country Link
EP (4) EP3731825A2 (en)
TR (4) TR201721437A2 (en)
WO (3) WO2019209220A2 (en)

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0957073A1 (en) 1998-05-12 1999-11-17 Schwarz Pharma Ag Novel derivatives of 3,3-diphenylpropylamines
DE29923134U1 (en) 1999-11-16 2000-06-29 Sanol Arznei Schwarz Gmbh Stable salts of novel derivatives of 3,3-diphenylpropylamines
CN101466371B (en) * 2006-06-09 2011-10-05 施瓦茨制药有限公司 Stabilized pharmaceutical compositions comprising fesoterodine
US7807715B2 (en) 2006-06-09 2010-10-05 Ucb Pharma Gmbh Pharmaceutical compositions comprising fesoterodine
WO2010043408A2 (en) 2008-10-17 2010-04-22 Ratiopharm Gmbh Microencapsulated fesoterodine
EP2508173A1 (en) * 2011-04-08 2012-10-10 LEK Pharmaceuticals d.d. Stabilized pharmaceutical composition comprising fesoterodine
US20130236544A1 (en) * 2012-03-08 2013-09-12 Dr. Reddy's Laboratories Ltd. Stable pharmaceutical compositions of fesoterodine
US20150182629A1 (en) * 2012-07-02 2015-07-02 Hetero Research Foundation Stable compositions of fesoterodine
IN2013MU02631A (en) * 2013-08-12 2015-06-19 Genepharm India Pvt Ltd

Also Published As

Publication number Publication date
WO2019194772A3 (en) 2020-01-02
WO2019209220A3 (en) 2019-12-26
TR201721437A2 (en) 2019-07-22
EP3731829A1 (en) 2020-11-04
EP3731931A4 (en) 2021-11-03
TR201819274A2 (en) 2019-07-22
WO2019194772A2 (en) 2019-10-10
WO2019221684A3 (en) 2020-01-30
EP3731826A2 (en) 2020-11-04
WO2019221684A2 (en) 2019-11-21
TR201819312A2 (en) 2019-07-22
WO2019194772A9 (en) 2020-03-19
WO2019209220A2 (en) 2019-10-31
EP3731931A2 (en) 2020-11-04
TR201819578A2 (en) 2019-07-22

Similar Documents

Publication Publication Date Title
CA2652712C (en) Stabilized pharmaceutical compositions comprising fesoterodine
US6558699B2 (en) High drug load immediate and modified release oral dosage formulations and processes for their manufacture
WO2006070781A1 (en) Matrix-type controlled release preparation comprising basic substance or salt thereof, and process for production of the same
US20090208575A1 (en) Pharmaceutical Composition Of Acid Labile Substances
US8617601B2 (en) Methods and formulations for making pharmaceutical compositions containing bupropion
HU204192B (en) Process for producing desintegrable gemfibrosil compositions of instant and prolonged delivery of the active component
KR20010086062A (en) Sustained release matrix systems for highly soluble drugs
US20100151018A1 (en) Sustained-release levetiracetam composition and preparation process
CA2644179C (en) Novel pharmaceutical composition comprising a disintegration matrix
EP2323632A1 (en) Retard tablets containing quetiapine
US20040019096A1 (en) Novel formulations of carvedilol
US20050169991A1 (en) Sustained release torsemide dosage forms
WO2009084041A4 (en) Pharmaceutical compositions of dexibuprofen
WO2013061338A1 (en) Pharmaceutical compositions of silodosin
US20100003319A1 (en) Raloxifene immediate release tablets
RU2435584C2 (en) Prolonged pharmaceutical composition drug form and method of its production (versions)
EP3731825A2 (en) Extended release compositions of fesoterodine
US20070160667A1 (en) Controlled release formulation of divalproex sodium
US20110223245A1 (en) Controlled-release formulations of pramipexole
US20120178810A1 (en) Extended release formulation of an antiepileptic agent
WO2019132832A1 (en) Tablet compositions of fesoterodine fumarate
US20070196482A1 (en) Sustained release torsemide dosage forms
RU2354358C1 (en) Solid medicinal form of matrix type, which has anti-inflammatory, analgesic, febrifugal activity, with prolonged release and method of its obtaining
JP6233911B2 (en) Irbesartan-containing tablets with improved chemical stability
AU2006335344A1 (en) Controlled release formulation of divalproic acid and its derivatives

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20200720

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

17Q First examination report despatched

Effective date: 20220317

P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20230708