WO2019170795A1 - Forme posologique orale solide pharmaceutique de solifénacine - Google Patents

Forme posologique orale solide pharmaceutique de solifénacine Download PDF

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Publication number
WO2019170795A1
WO2019170795A1 PCT/EP2019/055666 EP2019055666W WO2019170795A1 WO 2019170795 A1 WO2019170795 A1 WO 2019170795A1 EP 2019055666 W EP2019055666 W EP 2019055666W WO 2019170795 A1 WO2019170795 A1 WO 2019170795A1
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WIPO (PCT)
Prior art keywords
dosage form
solifenacin
minutes
pharmaceutically acceptable
less
Prior art date
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PCT/EP2019/055666
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English (en)
Inventor
Ana PURÓN VILLARREAL
Ainara LECUMBERRI MUNÁRRIZ
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Intas Third Party Sales 2005, S.L.
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Application filed by Intas Third Party Sales 2005, S.L. filed Critical Intas Third Party Sales 2005, S.L.
Priority to MX2020009204A priority Critical patent/MX2020009204A/es
Priority to JP2020546137A priority patent/JP2021526504A/ja
Publication of WO2019170795A1 publication Critical patent/WO2019170795A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration

Definitions

  • a pharmaceutical solid oral dosage form of solifenacin A pharmaceutical solid oral dosage form of solifenacin
  • the present invention relates to a pharmaceutical solid oral dosage form of solifenacin. More particularly, the present invention relates to a pharmaceutical solid oral dosage form of solifenacin that disintegrates in the buccal cavity before being swallowed by a human subject.
  • Solifenacin is represented by the structural formula (I) and its chemical name is
  • Solifenacin has an excellent selective antagonistic action against muscarinic M3 receptors and therefore, it is an effective therapeutic agent for the prevention and treatment of urinary tract conditions such as nervous pollakiuria, neurogenic bladder, overactive bladder, nocturnal enuresis, unstable bladder, bladder contracture, chronic cystitis and lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH).
  • solifenacin can be also used in the treatment of certain respiratory diseases such as chronic obstructive pulmonary disease, chronic bronchitis, asthma, rhinitis, etc.
  • Orodispersible tablets serve as an alternative dosage form for patients suffering from difficulty in swallowing. Such condition is particularly important amongst elderly, stroke victims or patients affected by psychiatric disorders who refuse to swallow. Furthermore, orodispersible tablets do not require water, and hence can be consumed in situations where patients do not have easy access to it, such as travels, thereby contributing to improve adherence to the treatment. However, not all drugs are appropriate for designing orodispersible tablets, especially drugs with unpleasant organoleptic properties or drugs for which absorption from the buccal cavity should be limited. In this respect, it is known that solifenacin and its salts have a very strong bitterness, are highly astringent, and can cause local numbness if they are absorbed from the buccal cavity. Therefore, the design of an orodispersible dosage form of solifenacin should be able to overcome all these hurdles.
  • Document EP 1787640 A1 discloses a fast disintegrating tablet (another name for orodispersible tablet) which comprises particles containing solifenacin or diphenhydramine at the core, a middle layer that contains an insolubilizer and an insolubilizing substance, and an outer layer for controlling water penetration speed.
  • orodispersible tablets as disclosed in EP 1787640 A1 require a precise control of the time for which drug release is suppressed (lag time), while at the same time, once lag time has elapsed, the drug should be quickly released (EP 1787640 A1 , para. [0006]).
  • lag time the time for which drug release is suppressed
  • EP 1728791 A1 reports that it is difficult to obtain formulations of solifenacin with sufficient stability under general pharmaceutical manufacturing processes.
  • the document reveals that the main cause of the degradation of solifenacin over time is the amorphous solifenacin generated during the manufacturing process of the drug products and hence, in order to avoid formation of degradation products, EP 1728791 A1 proposes to limit the formation of amorphous solifenacin by adjusting the moisture during wet granulation of the drug product (EP 17287791 , para. [0009] to [0012]).
  • solifenacin N-oxide EP 1728791 para. [0008] and Rami Reddy B. V., Development and Validation of a Specific Stability Indicating High Performance Liquid Chromatographic Methods for Related Compounds and Assay of Solifenacin Succinate, Journal of Chemistry, Vol.2013, Art. ID 412353, p.7).
  • the structural formula of solifenacin N-oxide is shown in formula (II) and its chemical name is 1-oxido-1-azabicyclo[2.2.2]octan-3-yl
  • Solifenacin N-oxide has been identified as the main non-pharmacologically active metabolite of solifenacin.
  • Krauwinkel et al. Kerat W.J.J., Effect of age on the pharmacokinetics of solifenacin in men and women, Int J Clin Pharmacol Then, 2005; vol. 43, pp. 227-238) almost 50% of solifenacin was recovered in the urine either as parent compound (8%-13%) or metabolites
  • solifenacin N-oxide 19-29%, other metabolites: 9.5%-16.9%. Consequently, degradation into solifenacin N-oxide could significantly reduce the efficacy of solifenacin products in the treatment of urinary tract conditions.
  • the inventors have been capable of designing a new solid oral dosage form of solifenacin wherein a therapeutically effective amount of solifenacin and an ion exchange resin polymer form a matrix so that the dosage form exhibits a dissolution profile at buccal pH which substantially prevents dissolution of solifenacin, thereby avoiding issues such as bad taste or local numbness.
  • the inventors have also surprisingly found that the total drug exposure exhibited after a unique dose administration of the composition of the present invention is bioequivalent to the total drug exposure obtained after a unique dose administration of the originator’s product (Vesicare ® , film coated tablet).
  • the inventors have surprisingly found that even that the composition of the present invention exhibits a dissolution profile at gastric pH faster than the originator’s product (Vesicare®), the composition of the invention is bioequivalent to the reference’s product (Vesicare®). It means that the composition of the present invention has comparable bioavailability, because the rate and extent to which the solifenacin is absorbed from the composition of the invention and becomes available at the site of drug action is the same as the reference sample.
  • the dosage form of the invention has the ability to disintegrate under the buccal cavity conditions of a human subject within a time of three minutes or less, particularly within two minutes and a half or less, more particularly within two minutes or less, and more particularly within one minute or less, before being swallowed, thereby they should be considered as orodispersible dosage forms, in accordance with the definition given by the European Pharmacopeia (Ph. Eur. 6.0, page 750). Furthermore, during the time in which the dosage forms of the invention disintegrate, no solifenacin is dissolved due to the dissolution profile that they exhibit at buccal pH, and hence, unpleasant feelings such as bitterness, dry mouth or local numbness caused by local absorption of solifenacin are avoided. Thus, dosage forms of the invention constitute a valuable therapeutic alternative for patients affected by urinary tract conditions that suffer from difficulty in swallowing (dysphagia) and could help those patients to improve their adherence to the treatment.
  • EP 1 728 791 A1 discloses that amorphous solifenacin is the main cause of formation of solifenacin degradation products; for those embodiments of the dosage form, wherein the polymer and solifenacin form a matrix, and comprise an amorphous content of solifenacin or other pharmaceutically acceptable salts thereof higher than 77%, the formation of degradation products, such as solifenacin N-oxide, is avoided.
  • the present invention also offers a new way of stabilizing drug products with high contents of amorphous solifenacin and prevent formation of degradation products over time.
  • a first aspect of the present invention relates to a pharmaceutical solid oral dosage form comprising solifenacin or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin and a polymer form a matrix and the dosage form exhibits a dissolution profile such that (i) after 5 minutes at pH from 6.5 to 7.5, less than 10% w/w of the solifenacin content is dissolved, and (ii) after 30 minutes at pH from 1.0 to 1.6, more than 80% w/w of the solifenacin content is dissolved, wherein the dissolution profile is determined using a European Pharmacopeia Apparatus II (paddles), placing the dosage form in 900 ml.
  • solifenacin and a polymer form a matrix and the dosage form exhibits a dissolution profile such that (i) after 5 minutes at pH from 6.5 to 7.5, less than 10% w/w of the solifenacin content is dissolved, and (ii) after 30 minutes at pH
  • a second aspect of the invention relates to a process for the preparation of the dosage form as defined in the first aspect of the invention which comprises: (a) preparing a mixture of solifenacin or a pharmaceutically acceptable salt thereof and a polymer in water; (b) mixing one or more diluents and optionally one or more binders, disintegrants, sweeteners, flavours, or other excipients or carriers; (c) granulating the mixture of step (b) by the addition of the liquid mixture of step (a) to obtain wet granules; (d) drying the wet granules obtained in step (c) to obtain dry granules; (e) mixing the dry granules obtained in step (d) with one or more lubricants and optionally with one or more diluents, binders, disintegrants, sweeteners and flavours, or other excipients or carriers; (f) compressing the mixture
  • a third aspect of the invention relates to a pharmaceutical solid oral dosage form obtainable by the process as defined in the second aspect of the invention, wherein the dosage form exhibits a dissolution profile such that (i) after 5 minutes at pH from 6.5 to 7.5, less than 10% of the solifenacin content is dissolved, and (ii) after 30 minutes at pH from 1.0 to 1.6, more than 80% of the solifenacin content is dissolved, wherein the dissolution profile is determined using a European Pharmacopeia Apparatus II (paddles), placing the dosage form in 900 ml. under the suitable pH conditions, at 37°C and stirring at 50 revolutions per minute.
  • a dissolution profile such that (i) after 5 minutes at pH from 6.5 to 7.5, less than 10% of the solifenacin content is dissolved, and (ii) after 30 minutes at pH from 1.0 to 1.6, more than 80% of the solifenacin content is dissolved, wherein the dissolution profile is determined using a European Pharmacopeia Apparatus
  • a fourth aspect of the invention relates to the dosage form as defined in the first or the third aspect of the invention for use in the treatment of lower urinary tract symptoms associated to overactive bladder syndrome such as urge incontinence, increased urinary frequency and urgency.
  • an aspect of the invention relates to an orodispersible pharmaceutical solid dosage form comprising a therapeutically effective amount of solifenacin or a
  • solifenacin or the pharmaceutically acceptable salt thereof and the ion exchange resin form a matrix and the dosage form exhibits a dissolution profile according to which: (i) after 5 minutes at pH from 6.5 to 7.5, less than 10% w/w of the solifenacin content is dissolved, and (ii) after 30 minutes at pH from 1.0 to 1.6, more than 80% w/w of the solifenacin content is dissolved, wherein the dissolution profile is determined using a European Pharmacopeia Apparatus II (paddles), placing the dosage form in 900 ml. under the suitable pH conditions, at 37°C and stirring at 50 revolutions per minute.
  • solifenacin or the pharmaceutically acceptable salt thereof and the ion exchange resin form a matrix and the dosage form exhibits a dissolution profile according to which: (i) after 5 minutes at pH from 6.5 to 7.5, less than 10% w/w of the solifenacin content is dissolved, and (ii) after 30 minutes at pH from 1.0 to 1.6, more than
  • Figure 1 shows the PXRD Diffractogram of the dried API-resin mixture. Intensity (I) is expressed in arbitrary units (a.u.); 2 Theta angle (20) is expressed in degrees (°).
  • Figure 2 shows the dissolution profiles of a Film Coated Tablet (FCT) of Vesicare ® versus Formulation 3 (Form 3) as defined in Example 1 at buccal pH. Percentage of dissolution (%D) is expressed in % w/w; time (t) is expressed in minutes (min).
  • Figure 3 shows the dissolution profiles of a Film Coated Tablet (FCT) of Vesicare ® versus Formulation 4 (Form 4) as defined in Example 1 at gastric pH. Percentage of dissolution (%D) is expressed in % w/w; time (t) is expressed in minutes (min).
  • FCT Film Coated Tablet
  • Figure 4 shows the Mean Plasma Concentration (MPC) versus time (t) curve of solifenacin as calculated in Example 8 for Reference product Vesicare ® 10 mg (Ref-R, circles) and Test product (Test-T, squares). Mean Plasma Concentration (MPC) is expressed in ng/ml_ and time (t) is expressed in hours (h).
  • solifenacin as used herein is defined as the molecule represented by the structural formula (I) but also as their pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts of solifenacin comprise any of a broad range of inorganic and organic acids. Examples of such salts include acid addition salts with a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, or phosphoric acid; and those with an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid,
  • polymer as used herein is defined as any pharmaceutically acceptable polymer suitable for forming a matrix with solifenacin or pharmaceutically acceptable salts thereof that modify the dissolution profile of solifenacin or pharmaceutically acceptable salts thereof.
  • polymer as used herein comprise any of a broad range of matrix-former polymers including hydrophilic polymers such as hydroxypropyl methylcellulose (HPMC), methylcellulose, sodium carboxymethyl cellulose, hydrophobic polymers such as ethylcellulose, and water insoluble polyelectrolytes such as ion exchange resins including sulfonated styrene-divinylbenzene copolymers, methacrylic acid-divinylbenzene copolymers, amongst others.
  • hydrophilic polymers such as hydroxypropyl methylcellulose (HPMC), methylcellulose, sodium carboxymethyl cellulose, hydrophobic polymers such as ethylcellulose, and water insoluble polyelectrolytes
  • ion exchange resins including s
  • ion exchange resin as used herein is defined as any pharmaceutically acceptable water insoluble polymer that can exchange their mobile ions with the ions in the surrounding medium.
  • the term as used herein comprise sodium or potassium salts or partial salts of sulfonated styrene-divinylbenzene copolymers or methacrylic acid- divinylbenzene copolymers, amongst others.
  • the term“cation exchange resin” as used herein is defined as any pharmaceutically acceptable water insoluble polymer that can exchange their mobile cations with the cations in the surrounding medium.
  • the term as used herein comprise sodium or potassium salts or partial sodium or potassium salts of sulfonated styrene-divinylbenzene copolymers or methacrylic acid-divinylbenzene copolymers, amongst others.
  • water insoluble polymer that can exchange their mobile cations with the cations in the surrounding medium and have acidic functional groups such as sulfonic or carboxylic groups.
  • acidic functional groups such as sulfonic or carboxylic groups.
  • the term as used herein comprise sodium or potassium salts or partial sodium or potassium salts of sulfonated styrene-divinylbenzene copolymers or methacrylic acid-divinylbenzene copolymers, amongst others.
  • weakly acidic cation exchange resin as used herein, is defined as any pharmaceutically acceptable water insoluble polymer that can exchange their mobile cations with the cations in the surrounding medium and have weakly acidic functional groups such as carboxylic groups.
  • the term as used herein comprise sodium or potassium salts or partial sodium or potassium salts of methacrylic acid-divinylbenzene copolymers, amongst others.
  • polycrilin potassium as used herein is defined as a partial potassium salt of a methacrylic acid-divinylbenzene copolymer wherein a weakly acidic salt is formed from the carboxylic acid functional groups of the methacryclic acid.
  • partialpolacrilin potassium is commercialized under several commercial names such as Purolite ® C1 15KMR, Amberlite ® IRP88, amongst others.
  • matrix as used herein is defined as the combination of a polymer and solifenacin or pharmaceutically acceptable salts thereof, wherein the solifenacin or the pharmaceutically acceptable salts thereof are bound to the polymer by intermolecular forces such as electrostatic interactions, hydrogen bonding and van der Waal forces, amongst others.
  • the polymer is an ion exchange resin
  • the solifenacin or the pharmaceutically acceptable salts thereof are primarily bound by electrostatic interactions.
  • solifenacin is primarily bound by electrostatic interactions to the negatively charged functional groups of the cation exchange resin.
  • solifenacin is primarily bound by electrostatic interactions to the negatively charged acidic functional groups of the acidic cation exchange resin.
  • solifenacin is primarily bound by electrostatic interactions to the negatively charged carboxylic acid groups of the methacrylic acid-divinylbenzene copolymer.
  • the term“orodispersible tablet” as used herein is defined in accordance with the
  • European Pharmacopeia (Ph. Eur. 6.0, page 750) as an uncoated tablet intended to be placed in the mouth where it disperses rapidly before being swallowed, more precisely orodispersible tablets disintegrate within three minutes in the disintegration test.
  • orodispersible tablet comprise solid oral dosage forms of different names such as orodispersible tablet, orally disintegrating tablet, fast disintegrating tablet, fast dissolving tablet and chewable tablet, amongst others.
  • biotetrach pH as used herein is defined as the pH found in saliva of a healthy human subject. Such pH normally varies from about 6.5 to about 7.5.
  • stomach pH as used herein is defined as the pH found in the stomach of a healthy human subject in the fasted-state. Such pH typically varies from about 1 to about 1 .6.
  • disintegrate as used herein is defined as the action whereby a solid dosage form is brought from a solid state to a state of complete disintegration.
  • complete disintegration is defined in accordance with the European Pharmacopeia (Ph. Eur. 6.0, page 263), where it is defined as that state in which any residue of the dosage form, except insoluble fragments, remaining on the screen of the test apparatus or adhering to the lower surface of the discs, if used, is a soft mass having no palpably firm core. Disintegration, as defined herein, does not imply complete dissolution of the dosage form or even of its active pharmaceutical ingredient.
  • dissolution profile refers to dissolution over time of solifenacin from the dosage form of the invention.
  • the dissolution profile is measured in weight of dissolved solifenacin per initial weight of solifenacin in the dosage form, and it is expressed in weight percentage (% w/w).
  • the dissolution profiles are determined using a European Pharmacopeia Apparatus II (paddles), placing the dosage form in 900 ml. under the suitable pH conditions, at 37°C and stirring at 50 revolutions per minute.
  • polycrilin potassium as used herein is defined as a partial potassium salt of a copolymer of methacrylic acid with divinyl benzene wherein a weakly acidic salt is formed from the carboxylic acid functional groups of the methacryclic acid.
  • Polacrilin potassium is commercialized under several commercial names such as Purolite ® C115KMR,
  • amorphous content as used herein is defined as the ratio of the amorphous solifenacin or pharmaceutically acceptable salts thereof to the total of amorphous and crystalline solifenacin or salts thereof.
  • amorphous content is given in weight percentage (% w/w).
  • normal storage conditions as used herein is defined as conditions of temperature from 20 to 30°C and relative humidity from 55 to 65%.
  • extractive as used herein is referred to the components added in the process steps after granulating.
  • degradation products or“degradation impurities” as used herein are defined as those impurities resulting from a chemical change in the drug substance brought about during manufacture and/or storage of the new drug product by the effect of, for example, light, temperature, atmospheric oxygen, water vapor, or by reaction with an excipient and/or the container closure system.
  • ICH Pharmaceuticals for Human use (ICH) establishes in its Guidelines for Impurities in New Drug Products Q3B(R2) thresholds for degradation products.
  • the qualification threshold is 0.5 % by weight of solifenacin N-oxide per weight of solifenacin in the dosage form
  • the identification threshold is 0.2 %
  • the reporting threshold is 0.1 %.
  • solifenacin N-oxide present in the dosage form of the invention is expressed in weight of solifenacin N-oxide per initial weight of solifenacin in the dosage form, and this amount is given in weight percentage (% w/w).
  • cross-linked disintegrant as used herein is defined as a cross-linked polymer that is used as disintegrant in pharmaceutical compositions. Such cross-linked
  • disintegrants are selected from the group of croscarmellose, crospovidone, and starch glycolate, amongst others.
  • friability refers to the tendency for a tablet to chip, crumble or break during handling.
  • the test of friability is carried out following the guidelines of the European Pharmacopeia (Ph. Eur. 6.0, pp. 278-279). A maximum loss of mass not greater than 1.0 % is considered acceptable for most products.
  • an aspect of the invention relates to a pharmaceutical solid oral dosage form comprising a therapeutically effective amount of solifenacin or a
  • the polymer is an ion exchange resin.
  • the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, a polymer, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the polymer form a matrix and the dosage form exhibits a dissolution profile according to which (i) after 5 minutes at pH from 6.5 to 7.5, less than 10% of the solifenacin content is dissolved, and (ii) after 30 minutes at pH from 1.0 to 1.6, more than 80% of the solifenacin content is dissolved.
  • the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, a polymer, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the polymer form a matrix and the dosage form exhibits a dissolution profile according to which (i) after 5 minutes at pH from 6.5 to 7.5, less than 5% of the solifenacin content is dissolved, and (ii) after 30 minutes at pH from 1.0 to 1.6, more than 80% of the solifenacin content is dissolved.
  • the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, a polymer, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the polymer form a matrix and the dosage form exhibits a dissolution profile according to which (i) after 5 minutes at pH from 6.5 to 7.5, less than 3% of the solifenacin content is dissolved, and (ii) after 30 minutes at pH from 1.0 to 1.6, more than 80% of the solifenacin content is dissolved.
  • the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, a polymer, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the polymer form a matrix and the dosage form exhibits a dissolution profile according to which (i) after 5 minutes at pH from 6.5 to 7.5, less than 2% of the solifenacin content is dissolved, and (ii) after 30 minutes at pH from 1.0 to 1.6, more than 80% of the solifenacin content is dissolved.
  • the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, a polymer, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the polymer form a matrix and the dosage form exhibits a dissolution profile according to which
  • the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, a polymer, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the polymer form a matrix and the dosage form exhibits a dissolution profile according to which
  • the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, a polymer, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the polymer form a matrix and the dosage form exhibits a dissolution profile according to which
  • the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, a polymer, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the polymer form a matrix and the dosage form exhibits a dissolution profile according to which
  • the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, a polymer, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the polymer form a matrix and the dosage form exhibits a dissolution profile according to which (i) after 5 minutes at pH from 6.5 to 7.5, less than 10% of the solifenacin content is dissolved, and
  • the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, a polymer, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the polymer form a matrix and the dosage form exhibits a dissolution profile according to which (i) after 5 minutes at pH from 6.5 to 7.5, less than 5% of the solifenacin content is dissolved, and (ii) after 30 minutes at pH from 1.0 to 1.6, more than 85% of the solifenacin content is dissolved.
  • the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, a polymer, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the polymer form a matrix and the dosage form exhibits a dissolution profile according to which (i) after 5 minutes at pH from 6.5 to 7.5, less than 3% of the solifenacin content is dissolved, and (ii) after 30 minutes at pH from 1.0 to 1.6, more than 85% of the solifenacin content is dissolved.
  • the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, a polymer, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the polymer form a matrix and the dosage form exhibits a dissolution profile according to which (i) after 5 minutes at pH from 6.5 to 7.5, less than 2% of the solifenacin content is dissolved, and (ii) after 30 minutes at pH from 1.0 to 1.6, more than 85% of the solifenacin content is dissolved.
  • the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, a polymer, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the polymer form a matrix and the dosage form exhibits a dissolution profile according to which
  • the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, a polymer, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the polymer form a matrix and the dosage form exhibits a dissolution profile according to which
  • the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, a polymer, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the polymer form a matrix and the dosage form exhibits a dissolution profile according to which
  • the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, a polymer, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the polymer form a matrix and the dosage form exhibits a dissolution profile according to which
  • the polymer of the invention is an ion exchange resin, preferably a cation exchange resin, more preferably an acidic or weakly acidic cation exchange resin.
  • the polymer of the invention is selected from sulfonated styrene- divinylbenzene copolymers and methacrylic acid-divinylbenzene copolymers.
  • the polymer of the invention is a partial potassium salt of a methacrylic acid- divinylbenzene copolymer wherein a weakly acidic salt is formed from the carboxylic acid functional groups of the methacryclic acid.
  • the polymer is polacrilin potassium.
  • the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, an ion exchange resin, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the ion exchange resin form a matrix and the dosage form exhibits a dissolution profile according to which (i) after 5 minutes at pH from 6.5 to 7.5, less than 10% of the solifenacin content is dissolved, and (ii) after 30 minutes at pH from 1.0 to 1.6, more than 80% of the solifenacin content is dissolved.
  • the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, an ion exchange resin, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the ion exchange resin form a matrix and the dosage form exhibits a dissolution profile according to which (i) after 5 minutes at pH from 6.5 to 7.5, less than 10% of the solifenacin content is dissolved, and (ii) after 30 minutes at pH from 1.0 to 1.6, more than 80% of the solifenacin content is dissolved.
  • the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, an ion exchange resin, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the ion exchange resin form a matrix and the dosage form exhibits a dissolution profile according to which (i) after 5 minutes at pH from 6.5 to 7.5, less than 10% of the solifenacin content is dissolved, and (ii) after 30 minutes at pH from 1.0 to 1.6, more than 80% of the solifenacin content is dissolved.
  • the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, an ion exchange resin, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the ion exchange resin form a matrix and the dosage form exhibits a dissolution profile according to which (i) after 5 minutes at pH from 6.5 to 7.5, less than 10% of the solifenacin content is dissolved, and (ii) after 30 minutes at pH from 1.0 to 1.6, more than 80% of the solifenacin content is dissolved.
  • the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, an ion exchange resin, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the ion exchange resin form a matrix and the dosage form exhibits a dissolution profile according to which (i) after 5 minutes at pH from 6.5 to 7.5, less than 5% of the solifenacin content is dissolved, and (ii) after 30 minutes at pH from 1.0 to 1.6, more than 80% of the solifenacin content is dissolved.
  • the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, an ion exchange resin, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the ion exchange resin form a matrix and the dosage form exhibits a dissolution profile according to which (i) after 5 minutes at pH from 6.5 to 7.5, less than 5% of the solifenacin content is dissolved, and (ii) after 30 minutes at pH from 1.0 to 1.6, more than 80% of the solifenacin content is dissolved.
  • the solid oral dosage form of the invention disintegrates at buccal pH within three minutes or less, preferably within two minutes and a half or less (about 150s), preferably within two minutes or less, more preferably within one minute or less.
  • the solid oral dosage form of the invention is a tablet.
  • the solid oral dosage form of the invention is an orodispersible tablet.
  • the solid oral dosage form of the invention is a chewable tablet.
  • the solid oral dosage form of the invention is an orodispersible solid dosage form such as orodispersible tablets, orodispersible granules, or oral thin films, amongst others.
  • the pharmaceutical solid oral dosage form of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, an ion exchange resin, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the ion exchange resin form a matrix, wherein the solid oral dosage form disintegrates at buccal pH within three minutes or less, particularly within two minutes and a half or less, more particularly within two minutes or less and more particularly within one minute or less; and the dosage form exhibits a dissolution profile according to which (i) after 5 minutes at pH from 6.5 to 7.5, less than 10% of the solifenacin content is dissolved, and (ii) after 30 minutes at pH from 1.0 to 1.6, more than 80% of the solifenacin content is dissolved.
  • the tablet of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, an ion exchange resin, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the ion exchange resin form a matrix, wherein the tablet disintegrates at buccal pH within three minutes or less, particularly within two minutes and a half or less, more particularly within two minutes or less and more particularly within one minute or less, and the tablet exhibits a dissolution profile according to which (i) after 5 minutes at pH from 6.5 to 7.5, less than 10% of the solifenacin content is dissolved, and (ii) after 30 minutes at pH from 1.0 to 1.6, more than 80% of the solifenacin content is dissolved.
  • the tablet of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, a cation exchange resin, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the cation exchange resin form a matrix, wherein the tablet disintegrates at buccal pH within three minutes or less, particularly within two minutes and a half or less, more particularly within two minutes or less, and more particularly within one minute or less, and the tablet exhibits a dissolution profile according to which (i) after 5 minutes at pH from 6.5 to 7.5, less than 10% of the solifenacin content is dissolved, and (ii) after 30 minutes at pH from 1.0 to 1.6, more than 80% of the solifenacin content is dissolved.
  • the tablet of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, an acidic or weakly acidic cation exchange resin, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the acidic or weakly acidiccation exchange resin form a matrix, wherein the tablet disintegrates at buccal pH within three minutes or less, particularly within two minutes and a half or less, more particularly within two minutes or less, and more particularly within one minute or less, and the tablet exhibits a dissolution profile according to which (i) after 5 minutes at pH from 6.5 to 7.5, less than 10% of the solifenacin content is dissolved, and (ii) after 30 minutes at pH from 1.0 to 1.6, more than 80% of the solifenacin content is dissolved.
  • the tablet of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, a partial potassium salt of a methacrylic acid-divinylbenzene copolymer, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the partial potassium salt of a methacrylic acid-divinylbenzene copolymer form a matrix, wherein the tablet disintegrates at buccal pH within three minutes or less, particularly within two minutes and a half or less, more particularly within two minutes or less, and more particularly within one minute or less, and the tablet exhibits a dissolution profile according to which (i) after 5 minutes at pH from 6.5 to 7.5, less than 10% of the solifenacin content is dissolved, and (ii) after 30 minutes at pH from 1.0 to 1.6, more than 80% of the solifenacin content is dissolved.
  • the tablet of the invention comprises a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, a polacrilin potassium, and one or more pharmaceutically acceptable excipients or carriers, wherein solifenacin or the pharmaceutically acceptable salt thereof and the polacrilin potassium form a matrix, wherein the tablet disintegrates at buccal pH within three minutes or less, particularly within two minutes and a half or less, more particularly within two minutes or less, and more particularly within one minute or less, and the tablet exhibits a dissolution profile according to which (i) after 5 minutes at pH from 6.5 to 7.5, less than 10% of the solifenacin content is dissolved, and (ii) after 30 minutes at pH from 1.0 to 1.6, more than 80% of the solifenacin content is dissolved.
  • the dosage form comprises an amorphous content of solifenacin or other pharmaceutically acceptable salts thereof higher than 77%.
  • EP 1 728 791 A1 discloses that amorphous solifenacin is the main cause of formation of solifenacin degradation products; the inventors have found that for those embodiments of the dosage form, wherein the polymer and solifenacin form a matrix, and comprise an amorphous content of solifenacin or other pharmaceutically acceptable salts thereof higher than 77%, the formation of degradation products, such as solifenacin N-oxide, is avoided.
  • the present invention also offers a new way of stabilizing drug products with high contents of amorphous solifenacin and prevent formation of degradation products over time.
  • the method for assessing the amorphous content of solifenacin or a pharmaceutically acceptable salts thereof in accordance with the invention is generally any method for identifying the crystalline structure of solifenacin or a salt thereof in the composition but includes for example powder X-ray diffraction (PXRD) method, Differential Scanning Calorimetry (DSC) method, solid Nuclear Magnetic Resonance (NMR) and Near Infrared (NIR) spectrometry.
  • PXRD powder X-ray diffraction
  • DSC Differential Scanning Calorimetry
  • NMR solid Nuclear Magnetic Resonance
  • NIR Near Infrared
  • a method for measuring the amorphous content of solifenacin succinate by NIR is described in EP 1 728 791 A1 par. [0029].
  • a method for measuring the amorphous content of solifenacin succinate by solid NMR is described in EP 1 728 791 A1 par. [0030].
  • the described methods can be easily adapted by a person skilled in the art for measuring the amorphous content of other pharmaceutically acceptable salts of solifenacin.
  • the dosage form of the invention comprises an amorphous content of solifenacin or other pharmaceutically acceptable salts thereof higher than 77%, preferably higher than 80%, more preferably higher than 90%, even more preferably higher than 95%.
  • the dosage form of the invention comprises an amorphous content of solifenacin or other pharmaceutically acceptable salts thereof higher than 99%.
  • solifenacin and polymers of the invention form a matrix, the content of amorphous solifenacin remains stable in time, and the conversion of amorphous solifenacin into crystalline solifenacin is avoided.
  • the dosage form of the invention after three months of storage under normal storage conditions comprises an amorphous content of solifenacin or other pharmaceutically acceptable salts thereof higher than 77%, preferably higher than 80%, more preferably higher than 90%, even more preferably higher than 95%.
  • the dosage form of the invention after three months of storage under normal storage conditions comprises an amorphous content of solifenacin or other pharmaceutically acceptable salts thereof higher than 77%, preferably higher than 80%, more preferably higher than 90%, even more preferably higher than 95%.
  • the dosage form of the invention after three months of storage under normal storage conditions comprises an amorphous content of solifenacin or other
  • a solid oral dosage form of the invention comprising an amorphous content of solifenacin or other pharmaceutically acceptable salts thereof higher than 77%, after three months of storage at a temperature between 20 and 30°C and at a relative humidity between 55 and 65%, contains less than 0.5 % of solifenacin N-oxide, preferably less than 0.2 % and, more preferably less than 0.1%.
  • a solid oral dosage form of the invention comprising an amorphous content of solifenacin or other pharmaceutically acceptable salts thereof higher than 77%, after six months of storage at a temperature between 20 and 30°C and at a relative humidity between 55 and 65%, contains less than 0.5% of solifenacin N- oxide, preferably less than 0.2% and, more preferably less than 0.1%.
  • a solid oral dosage form of the invention comprising an amorphous content of solifenacin or other pharmaceutically acceptable salts thereof higher than 77%, after three months of storage at a temperature between 30 and 40°C and at a relative humidity between 55 and 65%, contains less than 0.5% of solifenacin N- oxide, preferably less than 0.2% and, more preferably less than 0.1%.
  • a solid oral dosage form of the invention comprising an amorphous content of solifenacin or other pharmaceutically acceptable salts thereof higher than 77%, after six months of storage at a temperature between 30 and 40°C and at a relative humidity between 55 and 65%, contains less than 0.5% of solifenacin N- oxide, preferably less than 0.2% and, more preferably less than 0.1%.
  • a solid oral dosage form of the invention comprising an amorphous content of solifenacin or other pharmaceutically acceptable salts thereof higher than 77%, after three months of storage at a temperature between 30 and 40°C and at a relative humidity between 65 and 75%, contains less than 0.5% of solifenacin N- oxide, preferably less than 0.2% and, more preferably less than 0.1%.
  • a solid oral dosage form of the invention comprising an amorphous content of solifenacin or other pharmaceutically acceptable salts thereof higher than 77%, after six months of storage at a temperature between 30 and 40°C and at a relative humidity between 65 and 75%, contains less than 0.5% of solifenacin N- oxide, preferably less than 0.2% and, even preferably less than 0.1%.
  • solifenacin of the present invention is not particularly limited as long as it is a therapeutically effective amount. Such amount is preferably from 1 to 20 mg, more preferably from 1 to 5 mg or from 5 to 10 mg, and even more preferably is 2.5, 5 or 10 mg of solifenacin succinate or an equivalent amount of other pharmaceutically acceptable salt thereof.
  • the solid oral dosage form of the present invention comprises solifenacin in an amount from 0.5 to 50 % by weight of solifenacin in the dosage form, preferably from 1 to 25%, more preferably from 1.5 to 10%, even more preferably from 2 to 5%.
  • the amount of polymer of the present invention is not particularly limited as long as the solifenacin and the polymer form a matrix that has the dissolution profiles detailed above.
  • the weight-to-weight ratio of solifenacin to polymer is from 0.5:1 to 1 :10, preferably from 1 :1 to 1 :4, and more preferably from 1 :1.5 to 1 :3. In the most preferred embodiment the ratio is 1 :2.
  • the weight-to-weight ratio of solifenacin to ion or cation exchange resin is from 0.5:1 to 1 :10, preferably from 1 :1 to 1 :4, and more preferably from 1 :1.5 to 1 :3. In the most preferred embodiment the ratio is 1 :2.
  • the weight-to-weight ratio of solifenacin to an acidic or weakly acidic cation exchange resin is from 0.5:1 to 1 :10, preferably from 1 :1 to 1 :4, and more preferably from 1 :1.5 to 1 :3. In the most preferred embodiment the ratio is 1 :2.
  • the weight-to-weight ratio of solifenacin to a partial potassium salt of a methacrylic acid-divinylbenzene copolymer is from 0.5:1 to 1 :10, preferably from 1 :1 to 1 :4, and more preferably from 1 : 1.5 to 1 :3. In the most preferred embodiment the ratio is 1 :2.
  • the weight-to-weight ratio of solifenacin to a polacrilin potassium is from 0.5:1 to 1 :10, preferably from 1 :1 to 1 :4, and more preferably from 1 :1.5 to 1 :3. In the most preferred embodiment the ratio is 1 :2.
  • the solid oral dosage form of the invention comprises polymer in an amount from 1.5 % to 40 % by weight of the polymer in the dosage form, preferably from 3% to 15%, more preferably from 5% to 10% and even more preferably from 6% to 7%.
  • the solid oral dosage form of the invention comprises an ion or cation exchange resin in an amount from 1.5 % to 40 % by weight of the ion or cation exchange resin in the dosage form, preferably from 3% to 15%, more preferably from 5% to 10% and even more preferably from 6% to 7%.
  • the solid oral dosage form of the invention comprises an acidic or weakly acidic cation exchange resin in an amount froml .5 % to 40 % by weight of the acidic or weakly acidic cation exchange resin in the dosage form, preferably from 3% to 15%, more preferably from 5% to 10% and even more preferably from 6% to 7%.
  • the solid oral dosage form of the invention comprises a partial potassium salt of a methacrylic acid-divinylbenzene copolymer in an amount froml .5 % to 40 % by weight of the a partial potassium salt of a methacrylic acid-divinylbenzene copolymer in the dosage form, preferably from 3% to 15%, more preferably from 5% to 10% and even more preferably from 6% to 7%.
  • the solid oral dosage form of the invention comprises polacrilin potassium in an amount from 1.5 % to 40 % by weight of polacrilin potassium in the dosage form, preferably from 3% to 15%, more preferably from 5% to 10% and even more preferably from 6% to 7%.
  • the solid oral dosage form of the present invention may further comprise suitable pharmaceutically acceptable excipients and adjuvants, such as diluents, disintegrants, binders, glidants, lubricants, as well as colouring agents, flavours and sweetening agents.
  • suitable pharmaceutically acceptable excipients and adjuvants such as diluents, disintegrants, binders, glidants, lubricants, as well as colouring agents, flavours and sweetening agents.
  • the solid oral dosage form of the present invention may comprise one or more suitable diluents.
  • suitable diluents for the oral dosage form are for example, sugars like mannitol, lactose, preferably lactose monohydrate, starch and its derivatives, and cellulose and its derivatives, in particular microcrystalline cellulose, amongst others.
  • the oral dosage form of the present invention contains from 1 to 80% by weight of a diluent in the dosage form, preferably from 20 to 75% of a diluent, more preferably from 40 to 70 %, and even more preferably from 50 to 68%.
  • the oral dosage form of the present invention contains from 1 to 80% by weight of mannitol or lactose or mixtures thereof in the dosage form, preferably from 20 to 75%, more preferably from 40 to 70 %, and even more preferably from 50 to 68%.
  • the solid oral dosage form of the present invention may further comprise one or more suitable binders.
  • suitable binders for the oral dosage form are for example, sugars as sucrose, glucose, dextrose, molasses and lactose, natural and synthetic polymers, such as sodium alginate, gum arabic, polyvinylpyrrolidone (povidone), carboxymethylcellulose (carmellose), methylcellulose or hydroxypropyl methylcellulose (hypromellose), amongst others.
  • the oral dosage form of the present invention contains from 0.05 to 30% by weight of binder in the dosage form, preferably from 1 to 30%, more preferably from 2 to 30%. In another preferred embodiment, the oral dosage form of the present invention contains from 0.05 to 30% by weight of hypromellose or lactose or mixtures thereof in the dosage form, preferably from 1 to 30%, more preferably from 2 to 30%.
  • the solid oral dosage form of the present invention may further comprise one or more lubricants.
  • Suitable lubricants are for example stearic acid and derivatives thereof, such as calcium stearate, sodium stearyl fumarate or magnesium stearate, amongst others.
  • the lubricant is present in the solid oral dosage form in an amount from 0.01 to 2% by weight of lubricant in the dosage form, preferably from 0.1 to 1.8%, more preferably from 0.2 to 1.6%.
  • magnesium stearate is present in the solid oral dosage form in an amount from 0.01 to 2% by weight of magnesium stearate in the dosage form, preferably from 0.1 to 1.8%, more preferably from 0.2 to 1.6%.
  • the solid oral dosage form of the present invention may further comprise one or more disintegrants.
  • the amount and the identity of the disintegrant are not particularly limited as long as the solid oral dosage form of the invention is disintegrated at buccal pH within three minutes or less, particularly within two minutes and a half or less, more particularly within two minutes or less, and more particularly within one minute or less, before being swallowed.
  • the disintegrant may be selected from starches, clays, celluloses, algins, gums and cross-linked disintegrants.
  • the disintegrant is selected from cross-linked disintegrants such as cross-linked carboxymethylcellulose (croscarmellose), cross-linked polyvinylpolypyrrolidone (crospovidone) or starch glycolate, amongst others.
  • the solid oral dosage form of the invention comprises one or more disintegrants in an amount from 1 to 35 % by weight of disintegrant in the dosage form, preferably from 10 to 30%, more preferably from 20 to 28%.
  • the solid oral dosage form of the invention comprises one or more cross-linked disintegrants in an amount from 1 to 35 % by weight of cross-linked disintegrant in the dosage form, preferably from 10 to 30%, more preferably from 20 to 28%.
  • the solid oral dosage form of the invention comprises
  • the solid oral dosage form of the invention comprises
  • croscarmellose in an amount from 1 to 35% by weight of croscarmellose in the dosage form, preferably from 10 to 30% and, more preferably from 20 to 28%.
  • the solid oral dosage form of the invention comprises from 1 to 10 mg of solifenacin, an ion or cation exchange resin in a weight-to-weight ratio of solifenacin to the resin from 1 :1 to 1 :4, a diluent from 40 to 70% by weight, a binder from 1 to 30% by weight, a lubricant from 0.1 to 2% by weight, and a cross-linked disintegrant from 10 to 30% by weight.
  • the solid oral dosage form of the invention comprises from 1 to 10 mg of solifenacin, polacrilin potassium in a weight-to-weight ratio of solifenacin to polacrilin potassium from 1 :1 to 1 :4, a diluent from 40 to 70% by weight, a binder from 1 to 30% by weight, a lubricant from 0.1 to 2% by weight, and a cross-linked disintegrant from 10 to 30% by weight.
  • the solid oral dosage form of the invention comprises from 1 to 10 mg of solifenacin, polacrilin potassium in a weight-to-weight ratio of solifenacin to polacrilin potassium from 1 :1 to 1 :4, a diluent from 40 to 70% by weight, a binder from 1 to 30% by weight, a lubricant from 0.1 to 2% by weight, and crospovidone or croscarmellose or mixtures thereof from 10 to 30% by weight.
  • the solid oral dosage form of the invention comprises less than 100 mg of lactose, preferably less than 80 mg, and more preferably less than 70 mg.
  • the reference product of the invention Vesicare ®
  • the inventors have been able to additionally produce a solid oral dosage form of solifenacin that contains a low content of lactose as compared to Vesicare ® reference product while at the same time keeping acceptable values of friability.
  • lactose is one of the most commonly used excipients in solid oral dosage forms, and it is usually used as diluent with binding properties. Although some degree of lactose intolerance is reported to occur in approximately 25% of Europeans, the small amounts of lactose included in pharmaceutical products are usually considered safe. However, some individuals may develop gastrointestinal symptoms with lactose doses as low as 100 to 200 mg (Pawar S., Issues in the formulation of drugs for oral use in children: Role of excipients, Paediatr. Drugs, 2002; vol. 4(6), pp. 371-379). In another study (Eadala P., Quantifying the“hidden” lactose in drugs used for the treatment of gastrointestinal conditions, Aliment Pharmacol. Ther., 2009, vol. 29, pp. 677-687), the authors emphasize that patients often take more than one medication and so cumulative exposure to lactose may occur.
  • the solid oral dosage form of the invention comprises lactose in a weight-to-weight ratio of solifenacin to lactose from 1 :1 to 1 :10, preferably from 1 :1 to 1 :8, more preferably from 1 :1 to 1 :7, even more preferably from 1 :2 to 1 :7.
  • the inventors have been able to produce a dosage form that contains a low content of lactose as compared to Vesicare ® (the reference product) whereas at the same time keeping acceptable values of friability, i.e. less than 1%, preferably less than 0.5%, more preferably less than 0.2% (measured using the friability test as disclosed in the European Pharmacopeia 6.0, pp. 278-279).
  • the solid oral dosage form of the invention comprises lactose in a weight-to-weight ratio of solifenacin to lactose from 1 :1 to 1 :10 and the solid oral dosage form shows a friability below 1%, preferably from 1 :1 to 1 :8 and a friability below 1%, more preferably from 1 :1 to 1 :7 and a friability below 1%, even more preferably from 1 :2 to 1 :7 and a friability below 1%.
  • the solid oral dosage form of the invention shows hardness equal to or below 70N, preferably equal to or below 60N, even more preferably equal to or below 50N.
  • the solid oral dosage form of the invention disintegrates at buccal pH within three minutes or less, preferably within two minutes and a half or less (about 150s), preferably within two minutes or less, more preferably within one minute or less and shows a hardness equal to or below 70N, preferably equal to or below 60N, even more preferably equal to or below 50N.
  • the solid oral dosage form of the invention comprises one or more disintegrants as defined above in an amount from 1 to 35 % by weight of disintegrant in the dosage form, preferably from 10 to 30%, more preferably from 20 to 28%; and shows a hardness equal to or below 70N, preferably equal to or below 60N, even more preferably equal to or below 50N.
  • the solid oral dosage form of the invention disintegrates at buccal pH within three minutes or less, preferably within two minutes and a half or less (about 150s), preferably within two minutes or less, more preferably within one minute or less; shows a hardness equal to or below 70N, preferably equal to or below 60N, even more preferably equal to or below 50N.; and comprises one or more disintegrants as defined above in an amount from 1 to 35 % by weight of disintegrant in the dosage form, preferably from 10 to 30%, more preferably from 20 to 28%.
  • the composition of the present invention after an oral single-dose administration, exhibits a maximum plasma concentration (C max ) from 10 to 20ng/ml_, preferably from 12 to 19ng/ml_, more preferably from 14 to 16ng/ml_.
  • C max refers to the maximum concentration of solifenacin in the blood following an oral single- dose administration of the composition of the present invention.
  • the composition of the present invention after an oral single-dose administration, exhibits a time to maximum plasma concentration (T max ) from 2 to 24h, preferably from 3 to 1 1 h, more preferably from 6 to 8h, even more preferably T max is 7h.
  • T max refers to the time in hours when C max is achieved following an oral single- dose administration of the composition of the present invention.
  • the composition of the present invention exhibits an area under the time/plasma concentration curve from time 0 to time t hours (AUCo- t ) from 700 to 1800 ng-h/mL, preferably from 900 to 1500 ng-h/mL, more preferably from 1 100 to 1350 ng-h/mL, even more preferably from 1 150 to 1290 ng-h/mL.
  • time t hours AUCo- t
  • the composition of the present invention exhibits an area under the time/plasma concentration curve from time 0 to infinity (AUC 0 - ⁇ ) from 700 to 1900 ng-h/mL, preferably from 1000 to 1600 ng-h/mL, more preferably from 1 140 to 1450 ng-h/mL, even more preferably from 1200 to 1360 ng-h/mL.
  • AUC 0 - ⁇ time 0 to infinity
  • AUC refers to the area under the time/plasma concentration curve after an oral single-dose administration of the composition of the present invention.
  • AUC 0 - ⁇ denotes the area under the plasma concentration versus time curve from time 0 to infinity and AUCo- t denotes the area under the plasma concentration versus time curve from time 0 to time t.
  • the composition of the present invention after an oral single-dose administration, exhibits a half-life (T 1/2 ) from 44 to 91 h, preferably from 55 to 80h, more preferably from 60 to 73h, even more preferably from 63 to 69.
  • T 1/2 half-life
  • the solid oral dosage forms of the invention show equivalent pharmacokinetic parameters on bioavailability (e.g. C max , T max , AUCo-t, AUC 0 - ⁇ and T 1/2 ) of solifenacin, to that of solifenacin of the reference’s product, as set out in the European medicines Agency (EMA)“Guideline on the investigation of bioequivalence” (EMA CPMP/EWP/QWP/1401/98 Rev. 1/Corr ** ).
  • EMA European medicines Agency
  • EMA CPMP/EWP/QWP/1401/98 Rev. 1/Corr ** the solid oral dosage forms of the present invention can be considered bioequivalent to the single dose administration of Vesicare® according to the guidelines on the European medicines Agency (EMA).
  • the process for the preparation of the solid oral dosage form of the invention comprises: (a) preparing a mixture of solifenacin or a pharmaceutically acceptable salt thereof and a polymer in water;
  • step (c) granulating the mixture of step (b) by the addition of the liquid mixture of step (a) to obtain wet granules;
  • step (d) drying the wet granules obtained in step (c) to obtain dry granules
  • step (e) mixing the dry granules obtained in step (d) with one or more lubricants and optionally with one or more diluents, binders, disintegrants, sweeteners and flavours, or other excipients or carriers;
  • step (f) compressing the mixture obtained in step (e) to form a solid oral dosage form.
  • the polymer of step (a) is an ion exchange resin, preferably a cation exchange resin, more preferably an acidic or weakly acidic cation exchange resin.
  • the polymer of step (a) is a methacrylic acid-divinylbenzene copolymers, preferably a partial potassium salt of a methacrylic acid-divinylbenzene copolymers, more preferably a polacrilin potassium.
  • the one or more disintegrants of step (b) and (e) are cross- linked disintegrants selected from crospovidone, croscarmellose, starch glycolate or mixtures thereof.
  • Drying step (d) of the process of the invention may be performed by any method known in the state of the art for drying granules in a wet granulation process.
  • drying step (d) of the process of the invention is performed under vacuum conditions, preferably from 50 to 70°C, more preferably from 55 to 65°C.
  • vacuum conditions refers to a pressure from 0.5 mbar to 3 mbar; preferably comprised from 1 to 2 mbar.
  • the pharmaceutical solid oral dosage form as defined above is a wet granulation pharmaceutical solid oral dosage form.
  • the powder particles are aggregated through the use of a liquid phase called binder.
  • the aggregation step is performed by the use of the mixture of solifenacin or a pharmaceutically acceptable salt thereof and a polymer in water obtained in step (a) as granulating mixture (binder). It means that the process of the invention does not comprise drying the mixture of solifenacin or a pharmaceutically acceptable salt thereof and a polymer obtained in step (a).
  • Example 1 Manufacturing process of tablets
  • Solifenacin succinate is dissolved in water under stirring. Once the entire Active
  • API Pharmaceutical Ingredient
  • the result is a clear solution
  • the resin is added and the resulting mixture API-resin is stirred during 2 hours.
  • the granulation process was carried out in a TRI-CHOP MGR-5 (Lleal S.A., Spain) using the API-resin as granulating solvent.
  • the obtained granulate was then sieved through 1 mm.
  • the resulting powder is weighed and the yield is obtained in order to recalculate the necessary amount of extragranular excipients. All the extragranular excipients except for the lubricant are added previously sieved through 0.630 mm and mixed during 10 minutes at 20 rpms.
  • the sodium stearyl fumarate is added in a final step previously sieved through 0.630 mm and mixed during 5 minutes at 20 rpms. The final mixture is then compressed using 10 mm punches. Dosage forms of Table 1 were obtained following the manufacturing process described in the paragraph before.
  • Table 1 Composition of dosage forms obtained according to the process described in Example 1.
  • Example 2 PXRD characterization of the complex solifenacin-resin.
  • Solifenacin succinate was dissolved in water. Once the entire solifenacin succinate is dissolved, the resin is added and the resulting mixture API-resin is stirred during at least 2 hours. The mixture API-resin was either dried by spray drying or in a laboratory stove. Finally, the dried mixture API-resin was analyzed by Powder X-Ray Diffraction (PXRD).
  • PXRD Powder X-Ray Diffraction
  • the halo PXRD pattern of Figure 1 shows that solifenacin of the dosage forms of the invention is present in an amorphous form.
  • the powdered samples were deposited in the depression of a PMMA sample holders and smoothed flat with a glass slide. Special care was taken to avoid too much pressure.
  • Formulations as obtained in Example 1 were analyzed to quantify the amount of solifenacin N-oxide present after being stored for a certain amount of time under controlled conditions of temperature and Relative Humidity (RH). The results are shown in Table 3.
  • Table 3 Weight percentage of solifenacin N-oxide present in the dosage forms of the invention over time and the amount of total impurities.
  • Example 4 Dissolution profiles of the formulations of the invention at buccal pH.
  • Dissolution profiles of Formulation 3 as obtained in Example 1 and a commercial Film Coated Tablet (FCT) of Vesica re ® were measured at buccal pH. The results are shown in Table 4 and Figure 2.
  • Table 4 Dissolution profiles of Vesicare ® and Formulation 3 at buccal pH.
  • the dissolution profiles show that the dosage forms of the invention have a very low release of solifenacin at buccal pH, much lower than Vesicare ® under the same conditions.
  • Example 5 Dissolution profiles of the formulations of the invention at gastric pH.
  • Dissolution profiles of Formulation 4 as obtained in Example 1 and a commercial Film Coated Tablet (FCT) of Vesicare ® were measured at gastric pH. Table 6 and Figure 3 show the results.
  • Table 6 Dissolution profiles of Vesicare ® and a formulation of the invention at gastric pH.
  • Formulations of the invention were evaluated by a panel of 10 tasters in order to assess different parameters influencing palatability such as bitterness, dry mouth and numbness.
  • Table 8 Summary of panelists’ evaluation of the formulations of the invention.
  • Example 7 Friability test and disintegration test of tablets comprising low content of lactose.
  • Formulations 5 and 6 as described in Table 9 and formulations 7 and 8 as described in Table 1 having a content of lactose inferior to 100 mg per tablet, were obtained following the process described in Example 1.
  • Formulations of Table 9 were submitted for friability test in accordance with the guidelines of the European Pharmacopeia (Ph. Eur. 6.0, pp. 278-279). The results are shown in Table 10.
  • Table 9 Composition of Formulation 5 and 6 obtained according to the process described in Example 1.
  • Table 10 Friability results of tablets of Formulations 5 and 6 of Table 9 and Formulations 7 and 8 of Table 1. All tablets were compressed using a punch of 10 mm.
  • the study was an open label, balanced, randomized, two treatment, two sequence, two period, crossover, bioavailability of solifenacin succinate 10 mg orodispersible tablet of the present invention with Vesicare ® 10 mg, film coated tablet of Astellas Pharma, S.A. in healthy, adult human subjects under fasting condition, with a screening period of 28 days prior to IMP administration in Period-I.
  • 30 blood samples, including one pre-dose blood sample, were collected from each subject except for the
  • the pharmacokinetic parameters were calculated from the plasma concentration vs. time profile by non-compartmental model using Phoenix ® WinNonlin ® Version 6.4 (Certara L.P.) for solifenacin.
  • Statistical comparison of the pharmacokinetic parameters of the two formulations was carried out using PROC GLM of SAS ® Version 9.4 (SAS Institute Inc., USA) to assess the bioavailability between test and reference formulations.
  • Table 1 1 Number of subjects (planned and analysed)
  • BMI Body Mass Index
  • the samples used in the bioavailability test are the following:
  • Test sample The formulation 8 of Table 1 of example 1.
  • a single oral dose (10 mg) of the test product was administered with 20 ⁇ 02 ml. of drinking water in order to wet their mouth just before dosing at ambient temperature to the subjects in sitting posture.
  • the IMP administration was as per the randomisation schedule and under open label conditions. The subjects were asked to suck the tablet and not to swallow as whole and not to chew, bite or break the tablet until it completely disintegrated.
  • a single oral dose (10 mg) of the reference product was administered with 240 ⁇ 02 ml. of drinking water at ambient temperature to the subjects in sitting posture.
  • the IMP administration was as per the randomisation schedule and under open label conditions.
  • the tablet was swallowed whole without chewing or crushing.
  • blood was collected.
  • Blood samples were collected through an indwelling intravenous cannula (Venflon) placed in a forearm vein of the subjects.
  • Cannula was removed after collection of blood sample at 24 hours post-dose.
  • Blood samples after 24 hours post-dose were collected through a fresh vein puncture.
  • the blood sample for ambulatory samples in each period were collected using a fresh vein puncture.
  • the collection tube vacutainer was inverted gently several times to ensure the mixing of tube contents (i.e. anticoagulant).
  • vacutainers were placed upright in a rack kept in an ice cold water bath until centrifugation.
  • the blood samples were centrifuged at 3000 ref for 5 minutes below 10°C to separate plasma.
  • the blood samples were kept in an ice cold water bath before centrifugation and during separation.
  • the separated plasma was transferred to pre- labelled polypropylene tube in two aliquots (around 0.4 mL in first aliquot and remaining volume in second aliquot).
  • # T max is represented in median (min-max) value.
  • results of Table 13 show that solid oral dosage forms of the present invention (Test Product-T) when compared with Vesicare ® 10mg (Reference Product-R) meets the bioavailability criteria with respect to C max and AUCo-t for solifenacin under fasting condition as per criteria set in the protocol. Then, solid oral dosage forms of the present invention are bioequivalent to the reference product (Vesicare ® ).
  • Figure 4 shows the mean plasma concentration-time curve of the solid oral dosage forms of the invention vs. the reference product Vesicare ® .
  • Figure 4 highlights that the dosage forms of the invention display an extremely similar bioavailability profile compared to the reference product and in spite of the fact that the dissolution profiles at buccal and gastric pH of the compositions of the invention compared to the reference product ( Figures 2 and 3) are significantly different.
  • a pharmaceutical solid oral dosage form comprising a therapeutically effective amount of solifenacin or a pharmaceutically acceptable salt thereof, a polymer, and one or more pharmaceutically acceptable excipients or carriers, characterized in that solifenacin or the pharmaceutically acceptable salt thereof and the polymer form a matrix and the dosage form exhibits a dissolution profile according to which
  • dissolution profile is determined using a European Pharmacopeia Apparatus II (paddles), placing the dosage form in 900 mL under the suitable pH conditions, at 37°C and stirring at 50 revolutions per minute.
  • Clause 2 The dosage form according to clause 1 , characterized in that the pharmaceutical solid oral dosage form is a tablet, preferably an orodispersible tablet.
  • Clause 3 The dosage form according to clauses 1 to 2, characterized in that the polymer is an ion exchange resin.
  • Clause 4 The dosage form according to clauses 1 to 3, characterized in that the polymer is a cation exchange resin.
  • Clause 5 The dosage form according to clauses 1 to 4, characterized in that the polymer is an acidic or weakly acidic cation exchange resin.
  • Clause 6 The dosage form according to clauses 1 to 5, characterized in that the polymer is a methacrylic acid-divinylbenzene copolymer.
  • Clause 7. The dosage form according to clauses 1 to 6, characterized in that the polymer is a partial potassium salt of a methacrylic acid-divinylbenzene copolymer.
  • Clause 8 The dosage form according to clauses 1 to 7, characterized in that the polymer is a polacrilin potassium.
  • Clause 9 The dosage form according to clause 8, characterized in that the polacrilin potassium is Purolite ® C115KMR.
  • Clause 10 The dosage form according to clauses 1 to 9, characterized in that the dosage form exhibits a dissolution profile according to which
  • Clause 1 The dosage form according to clauses 1 to 10, characterized in that the dosage form exhibits a dissolution profile according to which
  • Clause 12 The dosage form according to clauses 1 to 11 , characterized in that the dosage form exhibits a dissolution profile according to which
  • Clause 13 The dosage form according to clauses 1 to 12, characterized in that the dosage form is disintegrated at pH from 6.5 to 7.5 within three minutes or less, wherein the disintegration time is determined by Test A of the European Pharmacopeia, placing the dosage form under the suitable pH conditions, at 37°C and 30 cycles per minute.
  • Clause 14 The dosage form according to clause 13, characterized in that the dosage form is disintegrated at pH from 6.5 to 7.5 within two minutes or less.
  • Clause 15 The dosage form according to clauses 13 to 14, characterized in that the dosage form is disintegrated at pH from 6.5 to 7.5 within one minute or less.
  • Clause 16 The dosage form according to clauses 1 to 15, characterized in that the dosage form comprises an amorphous content of solifenacin or other pharmaceutically acceptable salts thereof higher than 77% w/w.
  • Clause 17 The dosage form according to clauses 1 to 15, characterized in that the dosage form comprises an amorphous content of solifenacin or other pharmaceutically acceptable salts thereof higher than 80% w/w.
  • Clause 18 The dosage form according to clauses 1 to 15, characterized in that the dosage form comprises an amorphous content of solifenacin or other pharmaceutically acceptable salts thereof higher than 90% w/w.
  • Clause 19 The dosage form according to clause 16, characterized in that after three months of storage under conditions of temperature from 20 to 30°C and relative humidity from 55 to 65%, the dosage form comprises an amorphous content of solifenacin or other pharmaceutically acceptable salts thereof higher than 77% w/w.
  • Clause 20 The dosage form according to clause 17, characterized in that after three months of storage under conditions of temperature from 20 to 30°C and relative humidity from 55 to 65%, the dosage form comprises an amorphous content of solifenacin or other pharmaceutically acceptable salts thereof higher than 80% w/w.
  • Clause 21 The dosage form according to clause 18, characterized in that after three months of storage under conditions of temperature from 20 to 30°C and relative humidity from 55 to 65%, the dosage form comprises an amorphous content of solifenacin or other pharmaceutically acceptable salts thereof higher than 90% w/w.
  • Clause 22 The dosage form according to clauses 16 to 21 , characterized in that after three months of storage at a temperature between 20 and 30°C and at a relative humidity between 55 and 65%, the dosage form contains less than 0.5% w/w of solifenacin N- oxide.
  • Clause 23 The dosage form according to clauses 16 to 21 , characterized in that after three months of storage at a temperature between 20 and 30°C and at a relative humidity between 55 and 65%, the dosage form contains less than 0.2% w/w of solifenacin N- oxide.
  • Clause 24 The dosage form according to clauses 16 to 21 , characterized in that after three months of storage at a temperature between 20 and 30°C and at a relative humidity between 55 and 65%, the dosage form contains less than 0.1% w/w of solifenacin N- oxide.
  • Clause 25 The dosage form according to clauses 16 to 18, characterized in that after three months of storage at a temperature between 30 and 40°C and at a relative humidity between 65 and 75%, contains less than 0.5% of solifenacin N-oxide.
  • Clause 26 The dosage form according to clauses 16 to 18, characterized in that after three months of storage at a temperature between 30 and 40°C and at a relative humidity between 65 and 75%, contains less than 0.2% of solifenacin N-oxide.
  • Clause 27 The dosage form according to clauses 16 to 18, characterized in that after three months of storage at a temperature between 30 and 40°C and at a relative humidity between 65 and 75%, contains less than 0.1% of solifenacin N-oxide.
  • Clause 28 The dosage form according to clauses 16 to 21 , characterized in that after six months of storage at a temperature between 20 and 30°C and at a relative humidity between 55 and 65%, the dosage form contains less than 0.5% w/w of solifenacin N- oxide.
  • Clause 29 The dosage form according to clauses 16 to 21 , characterized in that after six months of storage at a temperature between 20 and 30°C and at a relative humidity between 55 and 65%, the dosage form contains less than 0.2% w/w of solifenacin N- oxide.
  • Clause 30 The dosage form according to clauses 16 to 21 , characterized in that after six months of storage at a temperature between 20 and 30°C and at a relative humidity between 55 and 65%, the dosage form contains less than 0.1% w/w of solifenacin N- oxide.
  • Clause 31 The dosage form according to clauses 16 to 18, characterized in that after six months of storage at a temperature between 30 and 40°C and at a relative humidity between 65 and 75%, contains less than 0.5% of solifenacin N-oxide.
  • Clause 32 The dosage form according to clauses 16 to 18, characterized in that after six months of storage at a temperature between 30 and 40°C and at a relative humidity between 65 and 75%, contains less than 0.2% of solifenacin N-oxide.
  • Clause 33 The dosage form according to clauses 16 to 18, characterized in that after six months of storage at a temperature between 30 and 40°C and at a relative humidity between 65 and 75%, contains less than 0.1% of solifenacin N-oxide.
  • Clause 34 The dosage form according to clauses 1 to 33, characterized in that the polymer is in a weight-to-weight ratio of solifenacin or pharmaceutically acceptable salts thereof to the polymer from 0.5:1 to 1 :10.
  • Clause 35 The dosage form according to clauses 1 to 33, characterized in that the polymer is in a weight-to-weight ratio of solifenacin or pharmaceutically acceptable salts thereof to the polymer from 1 :1 to 1 :4.
  • Clause 36 The dosage form according to clauses 1 to 33, characterized in that the polymer is in a weight-to-weight ratio of solifenacin or pharmaceutically acceptable salts thereof to the polymer from 1 : 1.5 to 1 :3.
  • Clause 37 The dosage form according to clauses 1 to 33, characterized in that the polymer is in a weight-to-weight ratio of solifenacin or pharmaceutically acceptable salts thereof to the polymer from 1 :2.
  • Clause 38 The dosage form according to clauses 34 to 37, characterized in that the polymer is an ion exchange resin.
  • Clause 39 The dosage form according to clauses 34 to 38, characterized in that the polymer is a cation exchange resin.
  • Clause 40 The dosage form according to clauses 34 to 39, characterized in that the polymer is an acidic or weakly acidic cation exchange resin.
  • Clause 41 The dosage form according to clauses 34 to 40, characterized in that the polymer is a methacrylic acid-divinylbenzene copolymer.
  • Clause 42 The dosage form according to clauses 34 to 41 , characterized in that the polymer is a potassium salt or partial potassium salt of methacrylic acid-divinylbenzene copolymer.
  • Clause 43 The dosage form according to clauses 34 to 42, characterized in that the polymer is a polacrilin potassium.
  • Clause 44 The dosage form according to clauses 34 to 43, characterized in that the polymer is Purolite ® C115KMR
  • Clause 45 The dosage form according to clauses 1 to 44, characterized in that the pharmaceutically acceptable excipients comprise extragranular and intragranular disintegrants selected from polyvinylpolypyrrolidone (crospovidone), cross-linked carboxymethylcellulose (croscarmellose), starch glycolate or mixtures thereof.
  • the pharmaceutically acceptable excipients comprise extragranular and intragranular disintegrants selected from polyvinylpolypyrrolidone (crospovidone), cross-linked carboxymethylcellulose (croscarmellose), starch glycolate or mixtures thereof.
  • Clause 46 The dosage form according to clause 45, characterized in that the total amount of extragranular and intragranular disintegrants are present in an amount from 1 to 35% by weight of disintegrants in the dosage form.
  • Clause 47 The dosage form according to clauses 45 to 46, characterized in that the total amount of extragranular and intragranular disintegrants are present in an amount from 10 to 30% by weight of disintegrants in the dosage form.
  • Clause 48 The dosage form according to clauses 45 to 47, characterized in that the total amount of extragranular and intragranular disintegrants are present in an amount from 20 to 28% by weight of disintegrants in the dosage form.
  • Clause 49 The dosage form according to clauses 45 to 48, characterized in that the disintegrants are present in a weight-to-weight ratio of intragranular to extragranular disintegrants from 14:1 to 1 :14.
  • Clause 50 The dosage form a according to clause 49, characterized in that the disintegrants are present in a weight-to-weight ratio of intragranular to extragranular disintegrant from 13:2 to 2:13.
  • Clause 51 The dosage form a according to clauses 49 to 50, characterized in that the disintegrants are present in a weight-to-weight ratio of intragranular to extragranular disintegrant from 13:2 to 2:13.
  • Clause 52 The dosage form a according to clauses 49 to 51 , characterized in that the disintegrants are present in a weight-to-weight ratio of intragranular to extragranular disintegrant from 2:1 to 1 :4.
  • Clause 53 A process for the preparation of the solid oral dosage form as defined in any of the clauses 1 to 52 which comprises:
  • step (c) granulating the mixture of step (b) by the addition of the liquid mixture of step (a) to obtain wet granules;
  • step (d) drying the wet granules obtained in step (c) to obtain dry granules
  • step (e) mixing the dry granules obtained in step (d) with one or more lubricants and optionally with one or more diluents, binders, disintegrants, sweeteners and flavours, or other excipients or carriers;
  • step (f) compressing the mixture obtained in step (e) to form tablets.
  • Clause 54 The process according to clause 53, characterized in that the polymer of step (a) is an ion exchange resin.
  • Clause 55 The process according to clauses 53 to 54, characterized in that the polymer of step (a) is a cation exchange resin.
  • Clause 56 The process according to clauses 53 to 55, characterized in that the polymer of step (a) is an acidic or weakly acidic cation exchange resin.
  • Clause 57 The process according to clauses 53 to 56, characterized in that the polymer of step (a) is an acidic or weakly acidic cation exchange resin.
  • Clause 58 The process according to clauses 53 to 57, characterized in that the polymer of step (a) is a methacrylic acid-divinylbenzene copolymer
  • Clause 59 The process according to clauses 53 to 58, characterized in that the polymer of step (a) is a potassium salt or partial potassium salt of methacrylic acid-divinylbenzene copolymer.
  • Clause 60 The process according to clauses 53 to 59, characterized in that the polymer of step (a) is a polacrilin potassium.
  • Clause 61 The process according to clauses 53 to 60, characterized in that the one or more disintegrants of step (b) and (e) are selected from polyvinylpolypyrrolidone (crospovidone), cross-linked carboxymethylcellulose (croscarmellose), starch glycolate or mixtures thereof.
  • the one or more disintegrants of step (b) and (e) are selected from polyvinylpolypyrrolidone (crospovidone), cross-linked carboxymethylcellulose (croscarmellose), starch glycolate or mixtures thereof.
  • Clause 62 A solid oral dosage form as defined in any of the clauses 1 to 52 obtainable by the process as defined in any of the clauses 53 to 61.
  • Clause 63 A solid oral dosage form as defined in any of the clauses 1 to 52 and 62 for use in the treatment of lower urinary tract symptoms associated to overactive bladder syndrome.
  • Clause 64 A solid oral dosage form for use according to clause 63 characterized in that the lower urinary tract symptoms associated to overactive bladder syndrome are selected from the group consisting of urge incontinence, increased urinary frequency and increased urinary urgency.

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  • Life Sciences & Earth Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

La présente invention concerne une forme posologique orale solide pharmaceutique comprenant de la solifénacine ou un sel pharmaceutiquement acceptable de celle-ci, une résine échangeuse d'anions, et un ou plusieurs excipients ou véhicules pharmaceutiquement acceptables, la solifénacine et la résine échangeuse d'ions formant une matrice et la forme posologique présentant un profil de dissolution selon lequel : (i) après 5 minutes à un pH de 6,5 à 7,5, moins de 10 % en poids de la teneur en solifénacine est dissoute, et (ii) après 30 minutes à un pH de 1,0 à 1,6, plus de 80 % en poids de la teneur en solifénacine est dissoute. L'invention concerne également un procédé pour sa préparation, et l'utilisation de la forme posologique orale solide pharmaceutique dans le traitement de symptômes du bas appareil urinaire associés au syndrome de la vessie hyperactive.
PCT/EP2019/055666 2018-03-08 2019-03-07 Forme posologique orale solide pharmaceutique de solifénacine WO2019170795A1 (fr)

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MX2020009204A MX2020009204A (es) 2018-03-08 2019-03-07 Una forma de dosificacion oral solida farmaceutica de solifenacina.
JP2020546137A JP2021526504A (ja) 2018-03-08 2019-03-07 ソリフェナシンの医薬固形経口剤形

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1728791A1 (fr) 2004-03-25 2006-12-06 Astellas Pharma Inc. Composition pour la preparation pharmaceutique solide de solifenacine ou des sels de cette derniere
EP1787640A1 (fr) 2004-04-30 2007-05-23 Astellas Pharma Inc. Composition pharmaceutique granulaire du type à libération limitée dans le temps en vue d'une administration orale et comprimé à désintégration rapide intra orale contenant la composition
WO2008128028A2 (fr) * 2007-04-11 2008-10-23 Dr. Reddy's Laboratories Ltd. Compositions à base de solifénacine
US20110288118A1 (en) * 2010-05-19 2011-11-24 Astellas Pharma Inc. Pharmaceutical composition comprising solifenacin

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1728791A1 (fr) 2004-03-25 2006-12-06 Astellas Pharma Inc. Composition pour la preparation pharmaceutique solide de solifenacine ou des sels de cette derniere
EP1787640A1 (fr) 2004-04-30 2007-05-23 Astellas Pharma Inc. Composition pharmaceutique granulaire du type à libération limitée dans le temps en vue d'une administration orale et comprimé à désintégration rapide intra orale contenant la composition
WO2008128028A2 (fr) * 2007-04-11 2008-10-23 Dr. Reddy's Laboratories Ltd. Compositions à base de solifénacine
US20110288118A1 (en) * 2010-05-19 2011-11-24 Astellas Pharma Inc. Pharmaceutical composition comprising solifenacin

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EADALA P.: "Quantifying the ''hidden'' lactose in drugs used for the treatment of gastrointestinal conditions", ALIMENT PHARMACOL. THER., vol. 29, 2009, pages 677 - 687
EUROPEAN PHARMACOPEIA, vol. 6.0, pages 263
EUROPEAN PHARMACOPEIA, vol. 6.0, pages 278 - 279
EUROPEAN PHARMACOPEIA, vol. 6.0, pages 750
KRAUWINKEL W.J.J.: "Effect of age on the pharmacokinetics of solifenacin in men and women", INT J CLIN PHARMACOL THER., vol. 43, 2005, pages 227 - 238
PAWAR S.: "Issues in the formulation of drugs for oral use in children: Role of excipients", PAEDIATR DRUGS, vol. 4, no. 6, 2002, pages 371 - 379
PAWAR S.: "Issues in the formulation of drugs for oral use in children: Role of excipients", PAEDIATR. DRUGS, vol. 4, no. 6, 2002, pages 371 - 379
PH. EUR., vol. 6.0, pages 278 - 279
RAMI REDDY B. V.: "Development and Validation of a Specific Stability Indicating High Performance Liquid Chromatographic Methods for Related Compounds and Assay of Solifenacin Succinate", JOURNAL OF CHEMISTRY, vol. 2013, 2013, pages 7
RAMI REDDY B. V.: "Development and Validation of a Specific Stability Indicating High Performance Liquid Chromatographic Methods for Related Compounds and Assay of Solifenacin Succinate", JOURNAL OF CHEMISTRY, vol. 2013, pages 7

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UY38137A (es) 2019-07-31

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