WO2019170795A1

WO2019170795A1 - A pharmaceutical solid oral dosage form of solifenacin

Info

Publication number: WO2019170795A1
Application number: PCT/EP2019/055666
Authority: WO
Inventors: Ana PURÓN VILLARREAL; Ainara LECUMBERRI MUNÁRRIZ
Original assignee: Intas Third Party Sales 2005 SL
Current assignee: Intas Third Party Sales 2005 SL
Priority date: 2018-03-08
Filing date: 2019-03-07
Publication date: 2019-09-12
Anticipated expiration: 2020-09-08
Also published as: JP2021526504A; MX2020009204A; TW201938163A; UY38137A

Abstract

The present invention relates to a pharmaceutical solid oral dosage form comprising solifenacin or a pharmaceutically acceptable salt thereof, anion exchange resin, and one or more pharmaceutically acceptable excipients or carriers, wherein the solifenacin 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 than10%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. It also relates to a process for its preparation, and the use of the pharmaceutical solid oral dosage form in the treatment of lower urinary tract symptoms associated to overactive bladder syndrome.

Description

A pharmaceutical solid oral dosage form of solifenacin

This application claims the benefit of the European Patent Application EP18382149.5 filed on March 8^th, 2018 and EP18382472.1 filed on June 26^th, 2018.

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.

Background Art

Solifenacin is represented by the structural formula (I) and its chemical name is

(3R)-1-azabicyclo[2.2.2]octan-3-yl- (1 S)-1 -phenyl-3, 4-dihydro-2(1 H)-isoquinolinecarboxylate.

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). On the other hand, 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. However, 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]). Unfortunately, such

requirements are difficult to be industrially applied and may not result cost-effective.

Additionally, although tablets as disclosed in the patent reduce dissolution of solifenacin in the buccal cavity, they do not assure its total suppression.

On the other hand, stability of pharmaceutical compositions of solifenacin is known to be a matter of concern in the prior art. For example, document 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]).

It has been reported that the main degradation product of solifenacin is 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

1 -phenyl-3, 4-dihydroisoquinoline-2(1 H)-carboxylate.

Solifenacin N-oxide has been identified as the main non-pharmacologically active metabolite of solifenacin. In the multiple-dose, open-label cross-over study by Krauwinkel et al. (Krauwinkel 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.

Therefore, the development of orodispersible solid dosage forms of solifenacin that overcome the problems derived from partial dissolution of the active ingredient in the buccal cavity (e.g. bad taste, local numbness, etc.), and at the same time can be manufactured by conventional and cost-effective pharmaceutical processes that prevent the formation of the main degradation product of solifenacin, still remains as an unsolved challenge. Furthermore, the requirement of new formulations of solifenacin to be bioequivalent to the originator’s drug product (Vesicare^®, film coated tablet) makes the development of new orodispersible solid dosage forms an even more difficult task.

Summary of the invention

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.

Furthermore, 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). In particular, 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.

For the purpose of the invention, the disintegration time was measured using a European Pharmacopeia disintegration apparatus A, placing the dosage form in a phosphate buffer having pH=7, at 37°C and 30 cycles per minute.

The inventors have also found that despite the teachings of EP 1 728 791 A1 , which 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. Hence, 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.

Thus, 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. under the suitable pH conditions, at 37°C and stirring at 50 revolutions per minute. 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 obtained in step (e) to form a solid oral dosage form.

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 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.

Particularly, an aspect of the invention relates to an orodispersible pharmaceutical solid dosage form comprising 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, characterized in that 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.

Brief description of the drawings

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).

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).

Detailed description of the invention

The term“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,

ethanesulfonic acid, or glutamic acid.

The term“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. The term 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.

The term“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.

The term“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 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.

The term“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.

The term“polacrilin 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. Hereinafter, the terms “partialpolacrilin potassium is commercialized under several commercial names such as Purolite^® C1 15KMR, Amberlite^® IRP88, amongst others.

The term“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. Particularly, wherein the polymer is an ion exchange resin, the solifenacin or the pharmaceutically acceptable salts thereof are primarily bound by electrostatic interactions. More particularly, wherein the polymer is a cation exchange resin, solifenacin is primarily bound by electrostatic interactions to the negatively charged functional groups of the cation exchange resin. More particularly, wherein the polymer is an acidic cation exchange resin, solifenacin is primarily bound by electrostatic interactions to the negatively charged acidic functional groups of the acidic cation exchange resin. Even more particularly, wherein the polymer is methacrylic acid-divinylbenzene copolymer, 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. In accordance with this definition the term 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.

The term“buccal 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.

The term“gastric 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.

The term“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.

The term“complete disintegration” as used herein 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.

The term“dissolution profile” as used herein refers to dissolution over time of solifenacin from the dosage form of the invention. Hereinafter, 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). Unless otherwise stated, hereinafter, 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.

The term“polacrilin 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,

Amberlite^® IRP88, amongst others.

The term“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. Hereinafter the amorphous content is given in weight percentage (% w/w).

The term“normal storage conditions” as used herein is defined as conditions of temperature from 20 to 30°C and relative humidity from 55 to 65%.

The term“intragranular” as used herein is referred to the components of the formulation added in the process steps before granulating.

The term“extragranular” as used herein is referred to the components added in the process steps after granulating.

The terms“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.

The International Council for Harmonisation of Technical Requirements for

Pharmaceuticals for Human use (ICH) establishes in its Guidelines for Impurities in New Drug Products Q3B(R2) thresholds for degradation products. In the case of solifenacin N- oxide as degradation product of solifenacin, 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 % and the reporting threshold is 0.1 %.

Hereinafter, the amount of 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).

The term“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.

The term“friability” as used herein 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.

As it is mentioned above, an aspect of the invention relates to 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: (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; characterized in that: the solid oral dosage form is an

orodispersible solid dosage form, and the polymer is an ion exchange resin.

In an embodiment, 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.

In an embodiment, 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.

In an embodiment, 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.

In an embodiment, 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.

In an embodiment, 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

(a) at pH from 6.5 to 7.5

(i) after 5 minutes, less than 10% of the solifenacin content is dissolved and,

(ii) after 15 minutes, less than 20% of the solifenacin content is dissolved and,

(iii) after 30 minutes, less than 45% of the solifenacin content is dissolved and,

(b) at pH from 1.0 to 1.6

(i) after 30 minutes, more than 80% of the solifenacin content is dissolved.

(a) at pH from 6.5 to 7.5

(i) after 5 minutes, less than 5% of the solifenacin content is dissolved and,

(ii) after 15 minutes, less than 10% of the solifenacin content is dissolved and,

(iii) after 30 minutes, less than 40% of the solifenacin content is dissolved and,

(b) at pH from 1.0 to 1.6

(i) after 30 minutes, more than 80% of the solifenacin content is dissolved.

(a) at pH from 6.5 to 7.5

(i) after 5 minutes, less than 3% of the solifenacin content is dissolved and,

(ii) after 15 minutes, less than 6% of the solifenacin content is dissolved and,

(iii) after 30 minutes, less than 25% of the solifenacin content is dissolved and,

(b) at pH from 1.0 to 1.6

(i) after 30 minutes, more than 80% of the solifenacin content is dissolved. In an embodiment, 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

(a) at pH from 6.5 to 7.5

(i) after 5 minutes, less than 2% of the solifenacin content is dissolved and,

(ii) after 15 minutes, less than 3% of the solifenacin content is dissolved and,

(iii) after 30 minutes, less than 10% of the solifenacin content is dissolved and,

(b) at pH from 1.0 to 1.6

(i) after 30 minutes, more than 80% of the solifenacin content is dissolved.

In an embodiment, 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 85% of the solifenacin content is dissolved.

In an embodiment, 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.

In an embodiment, 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.

In an embodiment, 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.

(a) at pH from 6.5 to 7.5

(i) after 5 minutes, less than 10% of the solifenacin content is dissolved and,

(b) at pH from 1.0 to 1.6

(i) after 30 minutes, more than 85% of the solifenacin content is dissolved.

(a) at pH from 6.5 to 7.5

(i) after 5 minutes, less than 5% of the solifenacin content is dissolved and,

(b) at pH from 1.0 to 1.6

(i) after 30 minutes, more than 85% of the solifenacin content is dissolved.

(a) at pH from 6.5 to 7.5

(i) after 5 minutes, less than 3% of the solifenacin content is dissolved and,

(iii) after 30 minutes, less than 25% of the solifenacin content is dissolved and, (b) at pH from 1.0 to 1.6

(i) after 30 minutes, more than 85% of the solifenacin content is dissolved.

(a) at pH from 6.5 to 7.5

(i) after 5 minutes, less than 2% of the solifenacin content is dissolved and,

(b) at pH from 1.0 to 1.6

(i) after 30 minutes, more than 85% of the solifenacin content is dissolved.

In an embodiment, 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.

In another embodiment the polymer of the invention is selected from sulfonated styrene- divinylbenzene copolymers and methacrylic acid-divinylbenzene copolymers. In another embodiment, 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. In a particular embodiment, the polymer is polacrilin potassium.

In an embodiment, 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.

In an embodiment, 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. In an embodiment, 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.

In an embodiment, 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.

In an embodiment, 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. In an embodiment, the solid oral dosage form of the invention is a tablet. In another embodiment, the solid oral dosage form of the invention is an orodispersible tablet. In another embodiment, the solid oral dosage form of the invention is a chewable tablet. In yet another embodiment, 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.

In an embodiment, 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.

In an embodiment, 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.

In an embodiment, 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. In an embodiment, 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.

In an embodiment, 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.

In an embodiment, 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 inventors have also found that for some embodiments of the dosage form, the dosage form comprises an amorphous content of solifenacin or other pharmaceutically acceptable salts thereof higher than 77%. Furthermore, despite the teachings of EP 1 728 791 A1 , which 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. Hence, 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. For measuring the crystalline structure of a drug at a lower content in a mixture composition with other components, in particular, the crystalline structure is preferably measured by solid NMR or NIR spectrometry. 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.

In an embodiment, 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%. In a particular embodiment, the dosage form of the invention comprises an amorphous content of solifenacin or other pharmaceutically acceptable salts thereof higher than 99%.

Interestingly, the inventors have also found that when 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.

In an embodiment, 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%. In a particular embodiment, 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 99%.

In an embodiment, 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%.

In another embodiment, 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%.

In another embodiment, 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%.

In another embodiment, 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%.

In another embodiment, 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%.

In another embodiment, 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%.

The amount of 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.

Hereinafter, all the percentages related to the amount of a certain component in the dosage form are given as the ratio between the weight of the component and the total weight of the dosage form and are expressed by the term“% by weight of the component in the dosage form”.

In another embodiment, 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.

In another embodiment, 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.

In another embodiment, 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.

In another embodiment, 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.

In another embodiment, 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.

In another embodiment, 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%.

In another embodiment, 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%.

In another embodiment, 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%.

In another embodiment, 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%.

In another embodiment, 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.

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.

In another embodiment, 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%.

In another preferred embodiment, 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.

In another embodiment, 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.

In another embodiment, 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%.

In another preferred embodiment, 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.

In an embodiment, the disintegrant may be selected from starches, clays, celluloses, algins, gums and cross-linked disintegrants. In a preferred embodiment, the disintegrant is selected from cross-linked disintegrants such as cross-linked carboxymethylcellulose (croscarmellose), cross-linked polyvinylpolypyrrolidone (crospovidone) or starch glycolate, amongst others.

In another embodiment, 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%.

In another embodiment, 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%.

In another embodiment, the solid oral dosage form of the invention comprises

crospovidone or croscarmellose or mixtures thereof in an amount from 1 to 35% by weight of crospovidone or croscarmellose or mixtures thereof in the dosage form, preferably from 10 to 30% and, more preferably from 20 to 28%. In another embodiment, 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%.

In a preferred embodiment 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.

In another preferred embodiment 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.

In another preferred embodiment 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.

In an embodiment, 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. In this regard, the reference product of the invention, Vesicare^®, contains 107.5 mg of lactose monohydrate for the 5 mg tablets and 102.5 mg of lactose monohydrate for the 10 mg tablets. Reducing the amount of lactose in tablets may result in a higher tendency of these to break, chip or crumble. However, 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.

It should be noted that 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.

In another embodiment, 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).

In another embodiment, 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%.

In an embodiment, 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.

In an embodiment, 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.

In another embodiment, 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.

In an embodiment, 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%. In an embodiment, after an oral single-dose administration, the composition of the present invention 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_. The term "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.

In an embodiment, after an oral single-dose administration, the composition of the present invention 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. The term "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.

In an embodiment, after an oral single-dose administration, 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.

In an embodiment, after an oral single-dose administration, the composition of the present invention exhibits an area under the time/plasma concentration curve from time 0 to infinity (AUC₀-~) 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.

The term "AUC" refers to the area under the time/plasma concentration curve after an oral single-dose administration of the composition of the present invention. AUC₀-~ 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.

In an embodiment, after an oral single-dose administration, the composition of the present invention 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. The term "half-life (T_1/2)" refers to the time taken by solifenacin to lose half of its pharmacological activity.

Thus, the inventors have found that the solid oral dosage forms of the invention show equivalent pharmacokinetic parameters on bioavailability (e.g. C_max, T_max, AUCo-t, AUC₀-~ 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^**). Thereby, 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).

In an embodiment, 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;

(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 obtained in step (e) to form a solid oral dosage form.

All the embodiments disclosed above for the solid oral dosage form of the invention apply also for the preparation process.

In a preferred embodiment, 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. In another embodiment, 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.

In a preferred embodiment, 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. The drying

temperature and the duration of drying process depend on the nature of the active ingredient and the level of moisture required for the successful production of satisfactory tablets. Generally, shelf or tray drier and fluidized-bed drier can be used for this purpose. In an embodiment, 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.

Generally, the term“vacuum conditions” refers to a pressure from 0.5 mbar to 3 mbar; preferably comprised from 1 to 2 mbar.

It is also part of the invention a pharmaceutical solid oral dosage form obtainable by the process as defined above. For the purposes of the invention the expressions "obtainable", "obtained" and equivalent expressions are used interchangeably, and in any case, the expression "obtainable" encompasses the expression "obtained". All embodiments disclosed above for steps (a)-(f) of the process of the invention also apply for the solid oral dosage form obtainable by this process.

In an embodiment, the pharmaceutical solid oral dosage form as defined above is a wet granulation pharmaceutical solid oral dosage form. In wet granulation processes, the powder particles are aggregated through the use of a liquid phase called binder. In the wet granulation process for the preparation of the pharmaceutical solid oral dosage form of the present invention as defined above, 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).

Throughout the description and claims the word "comprise" and variations of the word, are not intended to exclude other technical features, additives, components, or steps.

Furthermore, the word“comprise” encompasses the case of“consisting of”. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples and drawings are provided by way of illustration, and they are not intended to be limiting of the present invention. Reference signs related to drawings and placed in parentheses in a claim, are solely for attempting to increase the intelligibility of the claim, and shall not be construed as limiting the scope of the claim. Furthermore, the present invention covers all possible combinations of particular and preferred

embodiments described herein.

Examples

Example 1 : Manufacturing process of tablets

Solifenacin succinate is dissolved in water under stirring. Once the entire Active

Pharmaceutical Ingredient (API) is dissolved and 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).

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. The samples were measured in a Bruker D8 Advance diffractometer using Cu radiation with a primary monochromator (l = 1.54066 A) and a scintillation detector. The measurement conditions used are specified in Table 2.

Table 2: Measurement conditions of the PXRD Diffractometer.

Example 3: Stability of formulations of the invention

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.

N/A stands for not available

In all the cases the content of solifenacin N-oxide was well below the qualification threshold (0.5%) that ICH establishes for degradation products in its Guidelines for Impurities in New Drug Products Q3B(R2).

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.

Table 5: Experimental conditions of the dissolution profiles 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.

Table 7: Experimental conditions of the dissolution profiles at gastric pH.

Example 6: Disintegration and palatability test

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.

Disintegration time was measured following Test A of the European Pharmacopeia (Ph. Eur. 6.0, page 263), pH=7, 37°C, 30 cycles per minute.

In accordance with the definition given by the European Pharmacopeia for orodispersible tablets, these should disintegrate in the mouth within three minutes before being swallowed.

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.

Formulations 5 and 6 as described in Table 9 and formulations 7 and 8 as described in Table 1 were tested for disintegration time following Test A of the European

Pharmacopeia (Ph. Eur. 6.0, page 263), pH=7 phosphate buffer, 37°C, 30 cycles per minute.

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.

N/A stands for not available

As shown in Table 10, all the tablets of Formulations 5,6 and 8 complied with the requirement of having a friability of less than 1 % in according with guidelines of the European Pharmacopeia.

Example 8: Bioavailabilitv test

The bioavailability of the solid oral dosage forms of the present invention was studied.

A. Methodology

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. In each study period, 30 blood samples, including one pre-dose blood sample, were collected from each subject except for the

discontinued/withdrawn subjects and missing samples to analyze the pharmacokinetic profile of the test as well as the reference product.

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.

B. Number of subjects (planned and analysed):

Table 1 1 : Number of subjects (planned and analysed)

^*Due to pre-dose withdrawal, the study was conducted on 61 subjects instead of 62 subjects.

C. Diagnosis and main criteria of inclusion:

Non-smoking, normal healthy, adult, human volunteers between 18 to 45 years of age (both inclusive), having a Body Mass Index (BMI) between 18.5 and 30.0 kg / m2 (both inclusive), that were able to understand and comply with the study procedures and having given their written informed consent were checked in for the study. They did not have any significant diseases or clinically significant abnormal findings during screening, medical history, clinical examination, laboratory evaluations, 12-lead ECG and chest X-ray (posterior-anterior view) recordings.

D. Samples

The samples used in the bioavailability test are the following:

a) Test sample: The formulation 8 of Table 1 of example 1.

b) Reference test: Vesicare^® 10 mg, film coated tablet.

E. Test Method

For test sample:

After an overnight fast of at least 10 hours, 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.

For reference sample:

After an overnight fast of at least 10 hours, 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.

Sampling:

At initial time and at each time point after administration, 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. Immediately after collection of blood, the collection tube (vacutainer) was inverted gently several times to ensure the mixing of tube contents (i.e. anticoagulant). For precaution purpose, 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. For precaution purpose, 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).

All the samples were stored upright in a freezer at a temperature -65 ± 10°C for interim storage till transfer of the same to the bio-analytical department.

F. Pharmacokinetic results

The pharmacokinetic parameters of Solifenacin for Test Product-T and Reference

Product-R are summarized in the following table:

Table 12: Descriptive statistics of formulation means for solifenacin (N=53)

^#T _max is represented in median (min-max) value.

^*N=50

The relative bioavailability analyses (i.e. geometric least squares means, ratio, 90% confidence interval, intra subject CV and power) of Test Product-T vs. Reference Product- R for Solifenacin are summarized in the following table:

Table 13: Relative Bioavailability Results for Solifenacin (N = 53)

^*N=50

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.

Citation List

European Pharmacopeia 6.0, page 750

European Pharmacopeia 6.0, page 263

European Pharmacopeia 6.0, pp. 278-279

ICH Guidelines for Impurities in New Drug Products Q3B(R2)

EP 1787640 A1 EP 1728791 A1

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, 2013, vol.2013, Art. ID 412353, p.7

Krauwinkel W.J.J., Effect of age on the pharmacokinetics of solifenacin in men and women, Int J Clin Pharmacol Ther., 2005; vol. 43, pp. 227-238

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

Eadala P., Quantifying the“hidden” lactose in drugs used for the treatment of

gastrointestinal conditions, Aliment Pharmacol. Ther., 2009, vol. 29, pp. 677-687

For reasons of completeness, various aspects of the invention are set out in the following numbered clauses:

Clause 1. 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

(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.

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

(i) after 5 minutes at pH from 6.5 to 7.5, less than 5% 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

Clause 1 1. The dosage form according to clauses 1 to 10, characterized in that 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% w/w of the solifenacin content is dissolved, and

Clause 12. The dosage form according to clauses 1 to 11 , characterized in that 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% w/w of the solifenacin content is dissolved, and

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.

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:

(a) preparing a mixture of solifenacin or a pharmaceutically acceptable salt thereof and a polymer in water;

(d) drying the wet granules obtained in step (c) to obtain dry granules;

(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.

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.

Claims

1. An orodispersible pharmaceutical solid dosage form comprising 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, characterized in that 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

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.

2. The dosage form according to claim 1 , characterized in that the ion exchange resin is a methacrylic acid-divinylbenzene copolymer.

3. The dosage form according to claims 1 to 2, characterized in that the ion exchange resin is a polacrilin potassium.

4. The dosage form according to claims 1 to 3, characterized in that the dosage form comprises one or more disintegrants in an amount from 1 to 35% w/w.

5. The dosage form according to claim 4, characterized in that the one or more

disintegrants are cross-linked disintegrants.

6. The dosage form according to claims 1 to 5, characterized in that the dosage form is an orodispersible tablet.

7. The dosage form according to claim 6, characterized in that the dosage form shows a hardness equal to or below 70N, preferably equal to or below 60N, more preferably equal to or below 50N.

8. The dosage form according to claims 1 to 7, characterized in that the dosage form disintegrates 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, wherein the disintegration time was measured using a European Pharmacopeia disintegration apparatus A, placing the dosage form in a phosphate buffer having pH=7, at 37°C and 30 cycles per minute.

9. The dosage form according to claims 1 to 8, characterized in that the dosage form exhibits a dissolution profile according to which

10. The dosage form according to claims 1 to 9, characterized in that the dosage form exhibits a dissolution profile according to which

1 1. The dosage form according to claims 1 to 10, characterized in that the dosage form comprises lactose in a weight-to-weight ratio of solifenacin to lactose from 1 :1 to 1 :10 and the dosage form shows a friability below 1%.

12. The dosage form according to claims 1 to 1 1 , characterized in that the dosage form comprises an amorphous content of solifenacin or other pharmaceutically acceptable salts thereof higher than 77% w/w.

13. The dosage form according to claim 12, 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.

14. The dosage form according to claims 12 to 13, 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.

15. The dosage form according to claims 1 to 14, characterized in that the ion exchange resin is in a weight-to-weight ratio of solifenacin or pharmaceutically acceptable salts thereof to the ion exchange resin of 1 :2.

16. A process for the preparation of the solid oral dosage form as defined in any of the claims 1 to 15 which comprises:

(a) preparing a mixture of solifenacin or a pharmaceutically acceptable salt thereof and a ion exchange resin 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;

17. The process according to claim 16, wherein drying step (d) is performed under vacuum conditions.

18. A solid oral dosage form as defined in any of the claims 1 to 15 for use in the treatment of lower urinary tract symptoms associated to overactive bladder syndrome.