WO2019011393A1 - Composition pharmaceutique à libération prolongée contenant de la fésotérodine et procédé de préparation de cette dernière - Google Patents

Composition pharmaceutique à libération prolongée contenant de la fésotérodine et procédé de préparation de cette dernière Download PDF

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Publication number
WO2019011393A1
WO2019011393A1 PCT/EP2017/000829 EP2017000829W WO2019011393A1 WO 2019011393 A1 WO2019011393 A1 WO 2019011393A1 EP 2017000829 W EP2017000829 W EP 2017000829W WO 2019011393 A1 WO2019011393 A1 WO 2019011393A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
agents
fesoterodine
active ingredient
ion exchange
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2017/000829
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English (en)
Inventor
Agni GRYPIOTI
Panagiotis BARMPALEXIS
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.)
Pharos Ltd
Rontis Hellas SA
Original Assignee
Pharos Ltd
Rontis Hellas 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 Pharos Ltd, Rontis Hellas SA filed Critical Pharos Ltd
Priority to PCT/EP2017/000829 priority Critical patent/WO2019011393A1/fr
Publication of WO2019011393A1 publication Critical patent/WO2019011393A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/2022—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
    • 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
    • A61K9/2095—Tabletting processes

Definitions

  • the present invention relates to an improved extended release dosage form, and in particular to a pharmaceutical composition for oral administration comprising a therapeutically effective quantity of fesoterodine or a pharmaceutically acceptable salt, metabolite, or derivative thereof, as an active ingredient, and an effective quantity of ion exchange resin in order to prevent the degradation of said active ingredient, and a process for the preparation thereof.
  • Fesoterodine is a muscarinic receptor antagonist used for the treatment of overactive bladder syndrome including urinary incontinence.
  • Fesoterodine' s chemical name is [2-[(lR)-3- (Di(propan-2-yl)amino)-l -phenylpropyl]-4-(hydroxymethyl)phenyl]2-methylpropanoate) and its chemical structure is presented by the following Formula I.
  • 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 dissolution profile of extended release pharmaceutical compositions containing fesoterodine or a pharmaceutical acceptable salt, derivative and metabolite thereof can also be influenced by the selection of the excipients, as the drug release rate is dependent from the gastrointestinal pH-value and/or ionic strength. It is favorable for an extended release formulation to possess drug release rates, independent or less dependent from the ionic strength and/or pH of the environment through out the whole gastrointestinal tract in order to achieve better treatment to a patient.
  • EP-B-2029134 discloses a pharmaceutical granulate comprising fesoterodine or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable stabilizer against hydrolysis, such as sorbitol, xylitol, polydextrose, isomalt, dextrose or combinations thereof. Further, said fesoterodine and stabilizer granulate is embedded in a gel matrix formed by a water swellable sustained release agent such as hydroxypropyl methylcellulose. According to said document, fesoterodine is more stable in a composition comprising sugar alcohols and in the presence of water e.g. by wet granulation. Dry granulation or direct compression resulted in higher amounts of undesirable degradation products.
  • EP-A-2508175 discloses a microencapsulated fesoterodine composition which is composed of a particle containing fesoterodine and a shell surrounding the fesoterodine-containing particle, wherein the shell comprises a hydrophobic polymer as rate-controlling agent, such as acrylate- based polymers, acrylates or methylacrylates and a pore-forming agent, such as water soluble polymer or water soluble salt.
  • the proposed composition requires a complex-structured pharmaceutical composition.
  • an object of the present invention to provide an improved sustained release solid dosage composition for oral administration containing fesoterodine or pharmaceutical acceptable salt, derivative and metabolite thereof as an active ingredient, which overcomes the deficiencies of the prior art.
  • an extended release pharmaceutical composition for oral administration comprising a therapeutically effective quantity of fesoterodine or a pharmaceutically acceptable salt, metabolite or derivative thereof, as an active ingredient and an effective quantity of ion exchange resin as a stabilizer in order to prevent the degradation and improve the physicochemical stability of the active ingredient in the finished dosage form.
  • a process for the preparation of an extended release pharmaceutical composition for oral administration comprising a therapeutically effective quantity of fesoterodine or a pharmaceutically acceptable salt, metabolite or derivative thereof as an active ingredient, and an effective quantity of ion exchange resin as a stabilizer in order to prevent the degradation of said active ingredient is provided, wherein said process comprises following steps:
  • a) Complexation Dissolving the total quantity of fesoterodine or a pharmaceutically acceptable salt, metabolite or derivative thereof into an appropriate solvent and forming a homogenous mixture by adding the total quantity of an ion exchange resin and mixing for appropriate time until the complexation reaction is completed, and subsequently separating the solid fraction (resinate) from prepared slurry by discarding the filtrate;
  • step d) Adding to the sieved resinate from step c) the total quantity of a rate controlling agent and at least one optional additional excipient such as binder, diluent, lubricant and/or glidant and mixing for appropriate time.
  • a rate controlling agent such as binder, diluent, lubricant and/or glidant and mixing for appropriate time.
  • step e) Compressing the final blend from step d) into a desired tablet form in a rotary compression machine using appropriate punches.
  • Fig. 1 shows dissolution profiles of fesoterodine containing pharmaceutical composition according to the present invention (composition 1) DETAILED DESCRIPTION OF THE INVENTION
  • a pharmaceutical composition comprising fesoterodine or salts, metabolites or derivatives thereof is considered to be “stable” if said ingredient degradates less or more slowly than it does on its own and/or in known pharmaceutical compositions during storage.
  • excipient is considered to be "incompatible” with fesoterodine or salts, metabolites or derivatives thereof if it promotes the degradation of said active ingredient, that is to say, if said active ingredient degrades more or faster in the presence of said excipient when compared with the degradation of said active ingredient on its own.
  • incompatibility is defined accordingly.
  • the active ingredient contained in a dosage form is "bioavailable", if when administered in a dosage form is released from the dosage form, absorbed and reaches, at least the same, concentration levels in plasma as any of the marketed products containing the same quantity of the same active ingredient and intended for the same use.
  • the pharmaceutical composition may be in various forms, the preferred solid forms are tablets, capsules and caplets.
  • the object of the present invention is achieved by employing an ion exchange resin such as Sodium Polysterene Sulfonate, in order to prevent the degradation and improve the physicochemical stability of the active ingredient in the finished dosage form.
  • an ion exchange resin such as Sodium Polysterene Sulfonate
  • Ion exchange resins are insoluble polymers that contain acidic or basic functional groups and have the ability to exchange counter-ions within aqueous solutions surrounding them.
  • the efficacy of ion exchange resins mainly depends upon their physical properties such as degree of cross-linking, porosity, acid base strength, stability, purity and particle size.
  • the most common resins used in pharmaceutical formulations are cross-linked polystyrene and polymethacrylate polymers.
  • the use of ion exchange resins into drug delivery systems have been encouraged because of the their physico-chemical stability, inert nature, uniform size, spherical shape assisting coating and equilibrium driven reproducible drug release in ionic environment.
  • the physical and chemical properties of the ion exchange resins will release the drug more uniformly than that of simple matrix formulations.
  • Complexes between ion exchange resins and drugs are known as resinates, which have been used in pharmaceutical formulations for several decades.
  • Resinates are usually prepared by mixing the resin with a drug solution and allowing sufficient time for loading. The resin/fluid slurry is then filtered and the filtrate washed. The resinate is then dried. The dried resinate will be free of flowing powder with physical properties similar to the original resin, which can be formulated into tablets, capsules, lozenges etc.
  • the weight ratio of fesoterodine to ion exchange resin in the solid composition according to the present invention may be selected from 1 : 05 to 1 : 80, preferably from 1 : 1.5 to 1 : 6, more preferably from 1 : 1.5 to 1 :5, and most preferably from 1 :2 to 1 :4.
  • the hydrophilic polymer with carboxylic acid groups to be used in accordance with the present invention has carboxylic acid groups in the Na+ form.
  • Ion exchange resin polymers according to the present invention may be selected from polyacrylate a copolymer of methacrylic acid and an acrylic or methacrylic ester, a copolymer of methacrylic acid and divinylbenzene or a sulfonated copolymer of styrene and divinylbenzene.
  • the preferred copolymer to be used in accordance with the present invention is also known as Sodium Polystyrene Sulfonate, which is a strong acid cation exchange resin.
  • Said resin is the sodium salt of a sulfonated copolymerization between styrene and divinylbenzene.
  • Said resins are commercially available under the trademark AmberliteTM IRP69.
  • compositions of the present invention may also contain one or more additional formulation ingredients selected from a wide variety of excipients. According to the desired properties of the composition, any number of ingredients may be selected, alone or in combination, based upon their known uses in preparation of solid dosage form compositions (tablet/capsule compositions).
  • Such ingredients include, but are not limited to, diluents, binders, rate controlling agents, compression aids, glidants, lubricants, water scavengers, colorants, coating agents and preservatives.
  • the optional excipients must be compatible with fesoterodine or salt, metabolite or derivative thereof so that it does not interfere with it in the composition.
  • any excipient may optionally be added to the above composition, provided that they are compatible with the active ingredient of the composition, in order to overcome problems associated with unfavorable pharmacotechnical characteristics of these substances, and in order to increase the stability of the drug and the self-life of the pharmaceutical product, and provide a product exhibiting excellent bioavailability.
  • composition of the present invention may include further additives (alone or in a combination) such as absorbents, acids, adjuvants, anticaking agents, glidants, antitacking agents, antifoamers, anticoagulants, antimicrobials, antiseptics, diluents, binders, chelating agents, sequestrants, coating agents, colorants, dyes, pigments, complexing agents, softeners, crystal growth regulators, denaturants, desiccants, dehydrating agents, dispersants, solubilizers, emollients, emulsifiers, fillers, flavor masking agents, gelling agents, humectants, lubricants, moisturizers, bufferants, pH control agents, plasticizers, retarding agents, stabilizers, suspending agents, thickening agents, surfactants, opacifiers, coloring agents, preservatives, antigellants, rheology control agents, tonicifiers etc.
  • further additives such as absorbents
  • Diluents may be selected from calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose anhydrous, lactose monohydrate, lactose dihydrate, lactose trihydrate, mannitol, sorbitol, starch, pregelatinized starch, sucrose, talc, xylitol, maltose, isomalt, maltodextrin, maltitol and the like. Diluents may be in the range of 10-90 weight % of the total weight of the composition.
  • Binders may be selected from acacia, alginic acid, carbomer, carboxymethylcellulose calcium, carbomethylcellulose sodium, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gelatin liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, sodium alginate, starch paste, pregelatinized starch, sucrose, tragacanth, low-substituted hydroxypropyl cellulose, glucose, sorbitol. Binders may be in the range of 1-40 weight % of the total weight of the composition.
  • Rate controlling agents may be selected from one or more polymers/copolymers of cellulose or its derivatives such as hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, methylcellulose, carboxymethylcellulose and its salts; polyacrylates, methylacrylates, polyethylene oxides, polyethylene glycols, gums, chitosan, starch derivatives, polyurethanes, galactomannans, polysaccharides, polyalcohols, acrylic acid or its derivatives, ethyl cellulose, glycerol palmitostearate, beeswax, glycowax, carnaubawax, hydrogenated vegetable oil, glycerol monostearate, stearylalcohol, glyceryl behenate, polyanhydrides, methylacrylates, polyamides, polycarbonates, polyalkylene, polyalkylene glycols, polyalkylene oxides, polyalkylene
  • Glidants may be selected from calcium silicate, powdered cellulose, starch, talc, colloidal silicon dioxide and the like. Glidants may be in the range of 0.01-2 weight % of the total weight of the composition.
  • Lubricants may be selected from magnesium stearate, stearic acid, sodium stearyl fumarate, magnesium lauryl sulphate, talc, polyethylene glycol, glyceryl behenate and the like. Lubricants may be in the range of 0.01-2 weight % of the total weight of the composition.
  • Another embodiment of the present invention is the use of a complexation process for the preparation of solid dosage forms for oral administration containing fesoterodine or salt, metabolite or derivative thereof.
  • the steps in complexation technique may be as follows:
  • step f) Adding to the sieved resinate from step e) the total quantity of a rate controlling agent and at least one optional additional excipient such as binder, diluent and/or glidant and mixing for appropriate time.
  • a rate controlling agent such as binder, diluent and/or glidant
  • step f) Lubricating the blend from step f) with suitable lubricants for appropriate time.
  • step h) Compressing the final blend of step g) into a desired tablet form in a rotary compression machine using appropriate punches.
  • the complexation process of the present invention may optionally be prepared by mixing the ion exchange resin with the total quantity of Fesoterodine fumarate, and then adding them in the suitable solvent.
  • the extended release pharmaceutical composition of the present invention comprising Fesoterodine fumarate as an active ingredient has been compared to extended release reference product ToviazTM consisting of fesoterodine fumarate with the following excipients xylitol, Lactose monohydrate, Microcrystalline cellulose, Hypromellose, Glycerol dibehenate, Talc, and as film-coating comprising Poly(vinyl alcohol), Titanium dioxide, Macrogol, Talc, Soya lecithin and indigo carmine aluminium lake.
  • ToviazTM consisting of fesoterodine fumarate with the following excipients xylitol, Lactose monohydrate, Microcrystalline cellulose, Hypromellose, Glycerol dibehenate, Talc, and as film-coating comprising Poly(vinyl alcohol), Titanium dioxide, Macrogol, Talc, Soya lecithin and indigo carmine aluminium lake.
  • compositions according to the present invention are characterized by excellent pharmacotechnical properties, such as homogeneity, flowability and compressibility. Thanks to these properties, the solid dosage forms prepared by the process according to the present invention exhibit excellent technical characteristics including dissolution rate, hardness, and stability.
  • Dissolution test One of the most critical pharmacotechnical tests is the Dissolution test as it is strongly correlated with the bioavailability of the product.
  • a Paddle Apparatus was used at rotation speed 75rpm, in aqueous dissolution medium with pH 6.8.
  • composition 1 according to the present invention shows an extended release of Fesoterodine as depicted in Fig. 1.
  • One of the main objects of the present invention was to prepare a product with acceptable stability. For this reason 3 batches of composition 1 were exposed to normal and accelerated stability studies according to the current ICH guidelines.
  • the tablets may be film coated with functional or non-functional coating.
  • Example 1 Composition 1 of Fesoterodine fumarate and AmberliteTM IRP69 (weight ratio: Fesoterodine fumarate : AmberliteTM, 1 :2)
  • the final blend was then compressed into the desired tablets in a rotary compression machine using appropriate punches.
  • the prepared tablets were coated using OpadryTM 200F in a suitable pan coater.
  • Another object of the present invention was to prepare a pharmaceutical composition that is stable for a long period of storage time. Therefore, tablets of Composition 1 in open vials were exposed to normal (25°C ⁇ 2°C/60% ⁇ 5% RH) and accelerated (40°C ⁇ 2°C/75% ⁇ 5% RH) stability studies according to the current ICH guidelines.
  • composition 1 The stability results of Composition 1 at accelerated conditions, 40°C/75%RH in comparison to the reference product, Toviaz® are shown in TABLE 3 below.
  • composition 1 of the present invention was improved compared to Toviaz®.
  • diol and total impurities of Composition 1 were 1.88% and 3.29%, respectively compared to reference product wherein diol impurity was 3.57% and total impurities was 6.50%.
  • Fesoterodine Composition 1 showed extended release of the active ingredient for a time period more than 20h.
  • a novel improved extended release composition of fesoterodine fumarate comprising a complex formed with an ion exchange resin, namely Sodium Polystyrene Sulfonate (AmberliteTM IRP69).
  • an ion exchange resin namely Sodium Polystyrene Sulfonate (AmberliteTM IRP69).
  • AmberliteTM IRP69 Sodium Polystyrene Sulfonate
  • the stability of the product as well as the simple and economic manufacturing process indicates the advantages of the present invention relative to the commonly used method and excipients for the formulation of fesoterodine.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
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Abstract

La présente invention concerne une composition pharmaceutique à libération prolongée pour administration orale comprenant comme principe actif une quantité thérapeutiquement efficace de fésotérodine ou d'un sel, métabolite ou dérivé de qualité pharmaceutique de cette dernière, une quantité efficace de résine échangeuse d'ions à rôle de stabilisant qui permet d'empêcher la dégradation et d'améliorer la stabilité physico-chimique du principe actif dans la forme posologique finie, et au moins un excipient de qualité pharmaceutique à rôle d'agent de régulation de la vitesse de libération permettant de modifier/réguler la libération du principe actif dans la forme posologique finie.
PCT/EP2017/000829 2017-07-12 2017-07-12 Composition pharmaceutique à libération prolongée contenant de la fésotérodine et procédé de préparation de cette dernière Ceased WO2019011393A1 (fr)

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Application Number Priority Date Filing Date Title
PCT/EP2017/000829 WO2019011393A1 (fr) 2017-07-12 2017-07-12 Composition pharmaceutique à libération prolongée contenant de la fésotérodine et procédé de préparation de cette dernière

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PCT/EP2017/000829 WO2019011393A1 (fr) 2017-07-12 2017-07-12 Composition pharmaceutique à libération prolongée contenant de la fésotérodine et procédé de préparation de cette dernière

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110151720A (zh) * 2019-05-09 2019-08-23 合肥信风科技开发有限公司 含非索罗定的药用组合物及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2029134B1 (fr) 2006-06-09 2011-07-27 UCB Pharma GmbH Compositions pharmaceutiques stabilisées contenant de la fésotérodine
EP2508175A1 (fr) 2011-04-08 2012-10-10 LEK Pharmaceuticals d.d. Composition pharmaceutique contenant de la fésotérodine ou un sel ou un solvate de celle-ci
WO2016001937A2 (fr) * 2014-06-30 2016-01-07 Rubicon Research Private Limited Formulations pharmaceutiques à libération modifiée

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2029134B1 (fr) 2006-06-09 2011-07-27 UCB Pharma GmbH Compositions pharmaceutiques stabilisées contenant de la fésotérodine
EP2508175A1 (fr) 2011-04-08 2012-10-10 LEK Pharmaceuticals d.d. Composition pharmaceutique contenant de la fésotérodine ou un sel ou un solvate de celle-ci
WO2016001937A2 (fr) * 2014-06-30 2016-01-07 Rubicon Research Private Limited Formulations pharmaceutiques à libération modifiée

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "FDA Approves Topiaz. Pfizer's Toviaz (fesoterodine fumarate) Receives FDA Approval for the Treatment of Overactive Bladder", October 2008 (2008-10-01), pages 1 - 2, XP002777878, Retrieved from the Internet <URL:https://www.drugs.com/newdrugs/pfizer-s-toviaz-fesoterodine-fumarate-receives-fda-approval-overactive-bladder-1167.html> [retrieved on 20180205] *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110151720A (zh) * 2019-05-09 2019-08-23 合肥信风科技开发有限公司 含非索罗定的药用组合物及其制备方法

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