EP3558272A1

EP3558272A1 - Oral pharmaceutical composition with improved taste-masking properties

Info

Publication number: EP3558272A1
Application number: EP17825506.3A
Authority: EP
Inventors: Verena GARSUCH; Josef HAALA
Original assignee: Hermes Arzneimittel GmbH
Current assignee: Hermes Pharma GmbH
Priority date: 2016-12-23
Filing date: 2017-12-20
Publication date: 2019-10-30
Also published as: WO2018115130A1

Abstract

The invention provides a pharmaceutical composition for the taste-masking of poorly soluble drug substances wherein a melt of a poorly tasting drug is sorbed by water- dispersible, at least partially hydrophilic polymeric carrier particles. Prior to oral consumption, these drug-melt-treated polymeric carrier particles can be dispersed easily in water, yielding a drink suspension with a neutral taste. Alternatively, the drug-melt-treated polymeric carrier particles may be mixed with further excipients such as sugars, sweeteners or flavourants to provide a dosage form which upon dispersion lends a pleasant taste to the aqueous dispersion medium. The invention further provides an improved process for the preparation of these taste-masked compositions and dosage forms, for instance in heatable vacuum granulators.

Description

Title: ORAL PHARMACEUTICAL COMPOSITION WITH IMPROVED TASTE- MASKING PROPERTIES

FIELD OF THE INVENTION

The present invention relates to the field of pharmaceutics, and concerns taste- masked oral drug formulations, their manufacture and their use.

BACKGROUND OF THE INVENTION

Most patients prefer to take orally administered medicaments over other routes of administration. However, in order to be acceptable to patients, an oral drug product must be easily swallowed and without unpleasant or bitter taste or other undesirable organoleptic properties.

Many drug substances, also commonly referred to as active pharmaceutical ingredients (API), exhibit a rather poor taste, including ibuprofen, paracetamol, diclofenac, acetylsalicylic acid, chinin derivatives, racecadotril, epinephrine, cetirizine, famotidine, dextromethorphan, theophylline and others. A poor taste often involves a significant level of bitterness - likely due to a natural mechanism averting possible toxin ingestion - but may also involve other unpleasant sensations such as distinct acidity or saltiness, a burning, stinging, metallic, or astringent mouthfeel.

While taste masking is generally rather easy to achieve with a conventional tablet which may be coated with a suitable polymeric coating, and also in the case of a capsule formulation wherein the capsule shell itself provides a barrier which prevents contact between the active ingredient and the oral mucosa of the patient during administration, it is much more challenging to mask the taste of a compound having a poor taste when formulated as a dispersible, effervescent, or orally disintegrating dosage form or as granules for direct oral administration ('direct-to-mouth granules'), because in these cases the dosage unit is not swallowed as a whole, but the

formulations - and potentially discrete drug particles dispersed therein - come into substantial contact with the oral mucosa, and usually so for a longer time span than required for swallowing a tablet or capsule.

In addition, dosage forms for direct oral administration, or 'direct-to-mouth' administration, require smaller particle sizes, preferably in the range of not more than about 500 μηι, in order to reduce, or minimize, any unpleasant grittiness or foreign body sensations of the dosage forms when placed in the mouth and/or on the tongue. These smaller powder or granule particles exhibit a larger surface-to-volume ratio (A/V) than e.g. tablets and/or capsules, and this larger A/V-ratio also

unfavourably affects taste-masking approaches.

Further challenges may arise if the API in a dispersible dosage form is poorly wettable upon adding water, or other aqueous ingestible liquids, to the dry

formulation in order to disperse it. Oftentimes, this leads to inhomogeneous dispersions in which the drug particles self-agglomerate and/or float on the surface of the liquid, which is detrimental to the taste-masking, e.g. if concentrated drug agglomerates get in contact with the tongue or the oral mucosa.

Oftentimes taste-masking polymeric coatings are applied to drug particles or drug containing cores, serving as a physical barrier layer between the active ingredient and the patient's taste buds and olfactory receptors. For instance,

US 5,489,436 A describes chewable tablets of ibuprofen, in which the drug is covered with a taste-masking coating comprising a mixture of dimethylaminoethyl

methacrylate and neutral methacrylic acid ester and a cellulose ester such as cellulose acetate.

WO 0197801 A2 describes Eudragit^® NE-coated racecadotril granules; together with apricot aroma and sucrose these granules are commercially available as Tiorfan^® granules for preparing drink suspensions but have been reported by users to exhibit a noticeable bitter (after)taste despite such Eudragit^® NE-coatings, which is likely due to the particularly intense bitter taste of this drug.

US 5,939,099 Al describes solid dispersion compositions in the form of tablets, pellets, granules or capsules, more specifically melt-extrudates which are obtained by jointly melt-extruding an active compound together with a polymer mixture of two different polymers (e.g. two hydroxypropyl-cellulose grades); one water-soluble and thermoplastically processable, and the other water-insoluble. The melt-extrudates are intended to be applicable to a wide variety of more than two hundred different active compounds, including a few with poor taste. The melt-extrusion ensures melting, mixing and compaction of the drug-polymer blend (using the thermoplastically processable polymer as a sort of melt-binder), before extruding it through a die, or nozzle. US 5,939,099 Al is silent on the drug melting during the extrusion process, or any general requirement for such drug melting. Although, the melt-extrudates exhibit delayed release, an additional customary coating on top of the melt-extrudates or dosage forms comprising the extrudates is suggested to improve the taste (e.g. a coated tablet).

A further drawback of coatings, in particular for hydrolysis-sensitive drugs like esters (e.g. racecadotril), is that they typically are applied using aqueous coating dispersions, thereby increasing the risk of product instabilities. Moreover, many polymeric coating systems show curing effects, i.e. their properties may change over time, so that the drug dissolution behaviour may become compromised during storage. A disadvantage of coatings based on organic solvents, on the other hand, is their need for special equipment and their negative impact on the environment.

In principle, a water-free lipid or wax coating may also be applied to drug particles or drug containing cores by various thermal processing methods such as hot- melt coating, spray congealing, and the like, with the advantage that they do not require a solvent. For instance, WO 2008/071407 A2 and US 5,891,476 disclose cefpodoxime pellets and acetaminophen granules, respectively, which are taste- masked with a carnauba wax coating. On the other hand, lipid or wax coatings, due to the poor water solubility of their main constituents, also tend to have a retardation effect on the drug's release profile which is undesirable for drugs like ibuprofen, a pain relief medication, or racecadotril, an antidiarrheal medication; i.e. drugs for which rapid drug release and onset of effect is required. In addition, lipids may alter during storage due to e.g. polymorphism, which could further affect the drug release.

It is an object of the invention to provide an improved pharmaceutical composition for the taste-masking of poorly soluble drug substances, especially of hydrophobic drug substances with a relatively low melting point in the range of about 115 °C or below, preferably of about 100 °C or below. Moreover, it is an object to provide an improved taste-masked dosage form for such drug substances which exhibits easy dispersibility in water or aqueous media. It is further an object to provide an improved process for the preparation of these taste-masked compositions and dosage forms.

These and other objects are achieved by the subject-matter as defined in the independent claims below, with particular embodiments outlined in the dependent claims.

SUMMARY OF THE INVENTION

According to a first aspect the invention provides, a taste-masked

pharmaceutical composition for dispersion in water or an aqueous medium, the composition being provided in the form of a dry, flowable powder or granules, wherein the powder or granule particles comprise:

(a) a poorly water-soluble drug exhibiting a poor taste and a melting point Ti, and

(b) a water-dispersible, at least partially hydrophilic polymeric carrier in the form of powders or granules, the carrier exhibiting a melting or decomposition temperature T2 which is higher than Ti, and optionally a porous structure;

wherein the drug is at least partially sorbed by the polymeric carrier particles in the form of a solidified melt.

In a second aspect, the present invention provides a process for the preparation of a taste-masked pharmaceutical composition, for instance for a taste-masked pharmaceutical composition as described above, the process comprising the steps of:

(a) providing at least

al) a poorly water-soluble drug exhibiting a poor taste and a melting temperature Ti,

a2) a water-dispersible, at least partially hydrophilic polymeric carrier in the form of powders or granules, the carrier exhibiting a melting or decomposition temperature T2, and optionally a porous structure,

and optionally

a3) a further pharmaceutically accepted excipient;

(b) mixing all components provided according to step a) and melting the drug at a product temperature T3 above temperature Ti and below temperature T2

(Ti < T₃ < T2), until the molten drug is sorbed at least partially by the polymeric carrier; and (c) allowing the mixture to cool down to ambient temperature (i.e. about 20 ± 3 °C) and the at least partially sorbed molten drug to solidify with the polymeric carrier.

In a third aspect, the invention also provides a taste-masked pharmaceutical composition for dispersion in water or an aqueous medium provided in the form of a dry, flowable powder or granules which is obtainable by the process described above.

The inventors found, that by sorbing a molten poorly soluble drug with a poor taste to at least partially hydrophilic, and optionally porous, polymeric carrier particles, the taste is successfully masked upon oral administration of said particles in the form of drink suspensions without the need for further provisions, such as taste masking coatings. In other words, after dispersing the drug-melt-treated polymeric carried particles in water, a drink suspension of neutral taste is provided. The taste- masked pharmaceutical composition may also be dispersed in an aqueous medium such as juice, if a specific taste is preferred.

Alternatively, further excipients such as sugars, sugar alcohols, sweeteners, flavourants, or colourants may be added to the taste-masked pharmaceutical composition, e.g. if a specific taste, aroma and/or colour is desired. Hence, in a fourth aspect, the invention provides a pharmaceutical dosage form which is also provided as a dry, flowable powder or granules for dispersion in water or an aqueous medium, and which comprises the taste-masked pharmaceutical composition described above as well at least one pharmaceutically accepted excipient selected from sugars, sugar alcohols, sweeteners, flavourants, or colourants which are admixed with the taste- masked pharmaceutical composition.

Since the drug requires melting, the invention is in particular suited to drugs with low melting points, such as about 115 °C or below or preferably about 100 °C or below. However, as long as the drug is not heat-sensitive and exhibits a melting temperature Ti below the melting or decomposition temperature T2 of the polymeric carrier particles, and as long as these particles sorb the molten drug, it is expected that the invention works over a broad range of poorly soluble drugs and water-dispersible, at least partially hydrophilic polymeric carriers. The product temperature T3 which has to fall in between Ti and T2 (i.e. Ti < T3 < T2) should preferably be at least 10 °C below the melting or decomposition temperature T2 of the polymeric carrier particles, in order to keep the carrier intact, or in other words to preserve both the chemical and physical / structural, integrity of the polymeric carrier particles.

In a fifth aspect, the invention provides a taste-masked aqueous dispersion for oral administration of a poorly water-soluble drug exhibiting a poor taste and a melting point Ti, comprising either the taste masked pharmaceutical composition described above, or the pharmaceutical dosage form described above, dispersed in water or an aqueous medium. Such aqueous dispersions for oral administration are also referred to as drink suspensions.

DEFINITIONS The following terms or expressions as used herein should normally be interpreted as outlined in this section, unless defined otherwise by the description or unless the specific context indicates or requires otherwise:

The words 'comprise', 'comprises' and 'comprising' and similar expressions are to be construed in an open and inclusive sense, as 'including, but not limited to' in this description and in the claims.

Singular forms such as 'a', 'an' and 'the' should be understood as to include plural referents unless the context clearly indicates or requires otherwise. In other words, all references to singular characteristics or limitations of the present disclosure shall include the corresponding plural characteristic or limitation, and vice versa, unless explicitly specified otherwise or clearly implied to the contrary by the context in which the reference is made. The terms 'a', 'an' and 'the' hence have the same meaning as 'at least one' or as 'one or more' unless defined otherwise.

The expressions, 'one embodiment', 'an embodiment', 'a specific embodiment' and the like mean that a particular feature, property or characteristic, or a particular group or combination of features, properties or characteristics, as referred to in combination with the respective expression, is present in at least one of the

embodiments of the invention, but not necessarily in all embodiments. The occurrence of expressions such as 'in one embodiment' in various places throughout this description does thus not necessarily refer to the very same embodiment. Moreover, the particular features, properties or characteristics may be combined in any suitable manner in one or more embodiments. In other words, particular features, properties or characteristics described for one embodiment may be combined with one or more other embodiments unless there is a clear teaching away from such a combination and/or such combination would clearly provide a non-working embodiment.

As used herein, all percentages, parts and/or ratios in the context of numbers should be understood as relative to the total number of the respective items, unless otherwise specified, or indicated or required by the context. Furthermore, all percentages parts and/or ratios are intended to be by weight of the total weight; i.e. '%' should be read as 'wt.-%', unless otherwise specified, or indicated or required by the context.

Terms like 'about', 'approximately' or 'circa' (ca.) with respect to components of pharmaceutical compositions, formulations or dosage forms are meant to compensate for variability allowed for in the pharmaceutical industry and inherent in

pharmaceutical products, such as differences in content due to manufacturing variation and/or time-induced product degradation. Drugs are often also referred to as pharmaceutically active compound or active pharmaceutical ingredient (API) or active principle.

With respect to drug solubility, the term 'poorly water-soluble' as used herein refers to drugs which are sparingly soluble in water according to the definitions of the European Pharmacopoeia (Ph. Eur.) or less soluble; in other words, 1 g of drug/solute requires 30 mL or more of water or an aqueous medium in order to dissolve completely at temperatures between 15 °C and 25 °C, leaving no residues.

As described above, the term 'poor taste' - while obviously being a subjective perception for each consumer - commonly refers to a significant and thus unpleasant level of bitterness (likely due to a natural mechanism averting possible toxin ingestion), but may also involve, and refer to, other unpleasant sensations such as distinct acidity, saltiness or a burning, stinging, metallic, or astringent mouthfeel.

The term 'pharmaceutically acceptable' means that the compound or mixture is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for human pharmaceutical use. Further, with respect to the polymeric carriers of the invention, the term 'at least partially hydrophilic' as used herein refers to polymers which are wettable by water or aqueous media; and/or which are readily dispersible in water or aqueous media. The wettability may, for instance, be assessed by determining the wetting angle of contact, or contact angle; for wettable polymers, this contact angle (formed between a droplet of water or an aqueous medium and the compound's surface) is commonly 90° or smaller.

The term 'swelling' as used herein refers to the volume increase of a solid body, or solid material, caused by an influx, or diffusion process of water or an aqueous medium accompanied by hydration, i.e. wetting and absorption of moisture. Swelling may be assessed, for instance, by optically measuring the size/volume increase of the swollen material (either visually or using automated image analysis systems), or by measuring the weight increase of the swollen material gravimetrically (so-called water-uptake studies).

The terms 'moderate swelling' or 'slightly swelling' as used herein refer more specifically to a low degree of swelling which does not cause:

i. issues in dispersibility of the swelling/swollen material (such as stickiness, lump formation, or the like, leading to a significantly reduced dispersibility), and/or

ii. a tangible or visually noticeable viscosity increase in the aqueous dispersion medium due to addition of the swelling material.

Unless mentioned otherwise, the particle size values provided herein (either measured or calculated/derived from measured values) are determined by dynamic image analysis; for instance, using a Camsizer^® XT device (Retsch Technology GmbH, Haan, Germany) equipped with an X-Jet plug-in cartridge and its related software. The system uses images of dispersed particles (more specifically of their shadows, or projections) as recorded by two digital cameras to analyse them for size and shape as required e.g. by ISO norm 13322-2; e.g. the width of the particle (i.e. the shortest chord of the measured set of maximum chords of a particle's projection). The particle width is most closely related to physical screening using sieving manoeuvres; a particle with a width smaller than a sieve aperture is able to pass the sieve even if the length of such particle is potentially larger than the width. Thus, the terms 'particle size', 'particle diameter' and 'sieve diameter' are used synonymously, or interchangeably, herein. The 'mean particle size' as used herein is a weighted arithmetic mean value as measured by dynamic image analysis, such as according to ISO 13322-2. When referring to the particle size measurements, all percentages provided herein (such as 'at least 90 % of the particles exhibit a particle size of ...') are to be understood as volume-percentages, as calculated by the software of the dynamic image analysis device.

The terms 'substantially free' or 'essentially free' mean that the respective composition contains less than a functional amount of the respective ingredient, typically less than 1 wt.-%, preferably less than 0.1 wt.-% or even 0.01 wt.-%, and also including zero percent by weight of the respective ingredient. The terms 'substantially consist of or 'essentially consist of mean that no further components are added to a composition or dosage form other than those listed. Nevertheless, very small amounts of other materials may potentially be present, such as material inherent impurities. Furthermore, when referring to e.g. 'essentially consisting of A, B, C and optionally D.' this means that no further components are added to a composition or dosage form other than A, B, C and D, with D being an optional component (i.e. not mandatory) in said composition or dosage form.

The expressions 'immediate release' or 'fast release' of a drug, or active ingredient, refer to drug release profiles in which at least 75 % of the drug, or active ingredient, is released in 45 minutes or less, as determined using a USP Dissolution Apparatus type 2 (paddle apparatus) in 900 mL of an aqueous medium at a pH value at which the active ingredient may be soluble and stable at 37 °C, preferably 0.1 N hydrochloride acid, and at a stirring speed of 100 rpm. Of course, release profiles in which more than 75 % of the drug is released in 45 min would thus also be considered immediate release. DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the present invention provides a taste-masked pharmaceutical composition for dispersion in water or an aqueous medium, the composition being provided in the form of a dry, flowable powder or granules, wherein the powder or granule particles comprise:

wherein the drug is at least partially sorbed by the polymeric carrier particles in the form of a solidified melt. The taste-masked pharmaceutical composition is provided in the form of a dry, flowable powder or granules to allow for easy dispersion in water or an aqueous medium. In that regard, the provision that the water-dispersible, at least partially hydrophilic polymeric carrier is 'in the form of powders or granules' as of point (b), requires that the polymeric carrier as such is provided as solid powder or granules particles; rather than, for instance, solid particles of a water-dispersible, at least partially hydrophilic polymer being comprised in carrier powders or carrier granules. In other words, the taste-masked pharmaceutical composition is provided in the form of dry, flowable powder or granules because the water-dispersible, at least partially hydrophilic polymeric carrier itself is in the form of powders or granules. In order to be able to sorb, or at least partially sorb the molten drug, the polymeric carrier particles must preserve both their chemical and

physical / structural, integrity; hence, the melting or decomposition temperature T2 of the polymeric carrier must be higher than the melting point Ti of the poorly water- soluble drug. In other words, the polymeric carrier particles shall preferably remain solid, or rigid, or glassy; and not, for instance, undergo thermoplastic deformation during the while being contacted, or mixed, with the molten drug in said temperature range. This is also important because thermoplastic deformation of the powder or granules of the water-dispersible, at least partially hydrophilic polymeric carrier would typically result in the formation of polymeric matrices in which the drug would be embedded and/or coated; often to such an extent that its release is delayed. And as indicated above, such delayed release would not be desirable for drugs requiring an early onset of effect such as pain relievers or antidiarrheal medications.

One of the advantages of the taste-masked pharmaceutical composition of the present invention is that it obviates the need for additional, dedicated taste-masking coatings and/or delayed release coatings on the dry, flowable powder or granules.

Accordingly, in preferred embodiments, the taste-masked pharmaceutical composition of the present invention does not comprise a coating. Also, in view of the above, the expression 'melting or decomposition

temperature T₂' as used herein, should be understood as referring both to polymeric carriers that melt at a temperature T₂ (or thermoplastically deform at T₂; and then typically decompose at a temperature higher than T₂), and to polymeric carriers that do not melt, or thermoplastically deform, but instead will decompose at a temperature T₂. Hence, for polymeric carriers that melt or thermoplastically deform before decomposing, the melting point is considered to be T₂; whereas for polymeric carriers that do not melt or thermoplastically deform and instead only decompose, the decomposition temperature is considered to be T₂. The expression 'melting or decomposition temperature ΊΥ should thus not be misconstrued in such a way that for polymeric carriers which exhibit both a melting temperature T₂ and a decomposition temperature, any of the two parameters may be compared with the drug's melting point Ti.

The expression 'sorbed' in the context of the invention encompasses both absorption and adsorption phenomena. It furthermore refers to the drug melt solidifying at, or on, the external surface of the polymeric carrier particles as well as the drug melt being wicked, or soaked, into the polymeric carrier particles' porous structure (if applicable); in the latter case sorbing to the particles' internal surface. The molten drug is sorbed by the polymeric carrier particles without the need for further additives such as binders (e.g. aqueous polymer solutions) or melt-binders (e.g. lipids, waxes, or polymers that melt or thermoplastically deform at the melting point Ti of the drug).

Further, the expression 'at least partially sorbed' intends to acknowledge the fact that it is virtually impossible for all the drug melt (100 wt.-% of the melt) to be sorbed by the polymeric carrier particles; i.e. a small fraction may also solidify as pure drug particles without intimate, or direct, contact to the polymeric carrier particles' surface and/or solidify at, or on, the surfaces of the device used for preparation. As used herein, the term 'at least partially sorbed' hence refers to at least 70 wt.-% of the drug being sorbed by the polymeric carrier particles, preferably at least 75 wt.-%, or at least 80 wt.-%, or at least 85 wt.-%, or at least 90 wt.-%, or at least 95 wt.-%, or at least 97 wt.-%, or at least 99 wt.-%.

With respect to the polymeric carrier particles, the term 'water-dispersible' as used herein refers to polymers which are (a) readily dispersible and (b) either water- insoluble, or at least partially water-insoluble. A polymer is considered 'readily dispersible' if it can be dispersed, or suspended, homogeneously in water or aqueous media by simple manual stirring for up to 2 minutes without the polymer particles forming lumps or agglomerates, or without forming lumps or agglomerates whose homogeneous incorporation would necessitate, stirring durations of more than 2 minutes or automatic stirring (i.e. stirring at higher intensities than usually employed manually). Further, a polymer is considered 'at least partially water- insoluble' when besides water-insoluble or at best sparingly soluble polymer fractions, there are also polymer fractions which may dissolve in water or aqueous media. An example for an 'at least partially water-insoluble' polymer is starch, a polysaccharide comprising about 75-80 wt.-% water-insoluble amylopectin and about 20-25 wt.-% water-soluble amylose.

Manually stirring such partially water-insoluble polymers into water or aqueous media (as, for instance, the consumer of a pharmaceutical composition or dosage form would do) results in dispersions; hence the term 'water-dispersible'.

In addition, the term 'water-dispersible' as used herein also refers to readily dispersible polymers which are - strictly speaking - water-soluble but which either a) require more than 15 minutes for complete dissolution (as assessed visually) in water or an aqueous medium after an initial homogenous dispersion was obtained by manual stirring; and/or

b) of which if at least 70 wt.-%, or at least 80 wt.-%, or at least 90 wt.-% is not yet dissolved after 5 minutes in an initially homogeneous dispersion obtained by manual stirring (as assessed gravimetrically).

The inventors surprisingly found that these compositions - when dispersed manually in water or an aqueous medium and consumed as a drink suspension - provide effective taste-masking to a variety of poorly-soluble, meltable drugs; without the need to apply e.g. a subsequent taste-masking coating on the drug-melt-treated polymeric carrier particles (i.e. the dry, flowable powder or granules of the

pharmaceutical composition according to the first aspect of the invention). Without wishing to be bound by theory, it is currently believed that the taste- masking may involve one or both of the following two mechanisms:

(a) sorption of the molten drug to the external surfaces of the polymeric carrier particles, thereby agglomerating the particle and forming small, powder-like granules in which the polymeric carrier particles 'sterically shield' the solidified drug melt, and/or

(b) if the polymeric carrier particles exhibit a porous structure, by physically

'trapping' the poorly soluble drug within the pores of these particles by sorption of the molten drug in said porous structure,

such that (i) less drug gets in direct contact with the taste buds in the mouth and/or on the tongue, and/or (if) access of saliva is slightly hindered or delayed, resulting in a slower dissolution of the drug within the mouth (i.e. slower than it would occur without sorption by the polymeric carrier particles).

Optionally, the taste-masked pharmaceutical composition for dispersion in water or an aqueous medium may be provided in the form of a dry, flowable powder or granules, wherein the powder or granule particles essentially consist of:

wherein the drug is at least partially sorbed by the polymeric carrier particles in the form of a solidified melt. It shall be understood that said option - i.e. the powder or granule particles consisting of a) the drug and b) the polymeric carrier only - is applicable to any of the specific drug/polymeric carrier-combinations described herein, unless where the explicit presence of a further component indicates otherwise.

In one embodiment, the taste-masked pharmaceutical composition for dispersion in water or an aqueous medium may be provided in the form of a dry, flowable powder or granules, wherein the powder or granule particles comprise, or essentially consist of:

(b) one, or a single, water-dispersible, at least partially hydrophilic polymeric carrier in the form of powders or granules, the carrier exhibiting a melting or decomposition temperature T2 which is higher than Ti, and optionally a porous structure; wherein the drug is at least partially sorbed by the polymeric carrier particles in the form of a solidified melt. In a specific embodiment, the powder or granule particles forming the taste-masked pharmaceutical composition consist of:

(a) a poorly water-soluble drug exhibiting a poor taste and a melting point Ti, and (b) one, or a single, water-dispersible, at least partially hydrophilic polymeric carrier in the form of powders or granules, the carrier exhibiting a melting or decomposition temperature T2 which is higher than Ti, and optionally a porous structure, and (c) at least one pharmaceutically accepted excipient selected from colourants, antioxidants, flavourants, or sweeteners;

In an alternative embodiment, the taste-masked pharmaceutical composition for dispersion in water or an aqueous medium may be provided in the form of a dry, flowable powder or granules, wherein the powder or granule particles comprise, or essentially consist of:

(b) two or more water-dispersible, at least partially hydrophilic polymeric carriers in the form of powders or granules, wherein all of the carriers exhibiting a melting or decomposition temperature T₂ which is higher than Ti, and optionally a porous structure;

In a specific embodiment, the powder or granule particles forming the taste-masked pharmaceutical composition essentially consist of:

(b) two or more water-dispersible, at least partially hydrophilic polymeric carriers in the form of powders or granules, wherein all of the carriers exhibiting a melting or decomposition temperature T2 which is higher than Ti, and optionally a porous structure, and

(c) a pharmaceutically accepted excipient selected from colourants, antioxidants, flavourants, or sweeteners;

wherein the drug is at least partially sorbed by the polymeric carrier particles in the form of a solidified melt. In other words, in some preferred embodiments, the taste-masked

pharmaceutical composition is substantially free of polymers, or polymeric carriers (including water-dispersible, at least partially hydrophilic polymers, or polymeric carriers) which exhibit a melting or decomposition temperature T₂ which is lower than the melting point Ti of the drug, such that the drug can be sorbed, or at least partially sorbed, by the polymeric carrier particles in the form of a solidified melt. This means that the taste-masked pharmaceutical composition is substantially free of polymers, or polymeric carriers, that would melt or thermoplastically deform at the melting point Ti of the drug. Furthermore, since the molten drug is preferably sorbed by the polymeric carrier particles without the need for further additives such as melt-binders, as described above, the taste-masked pharmaceutical composition in some preferred embodiments is also substantially free of lipids or waxes that melt or

thermoplastically deform at the melting point Ti of the drug. For oral consumption, the taste-masked pharmaceutical composition be dispersed in water (yielding a neutral tasting drink suspension), but may also be dispersed in an aqueous medium such as juice, if a specific taste is preferred.

While, in preferred embodiments, no additional binders are employed to sorb the molten drug with the polymeric carrier particles, as mentioned above, some of the molten drug melt may solidify 'between' two or more polymeric carrier particles, thereby forming solidified 'bridges' and larger granules of the polymeric carrier particles. However, extensive granulation of the polymeric carrier particles with molten drug is at risk of unfavourably increasing the particle size of the resulting dry, flowable powder or granules of the taste-masked pharmaceutical composition, and should preferably be limited, or controlled, in order to avoid particle sizes larger than 500 μ ι which could cause an unpleasant gritty sensation in the mouth when dispersed in water and ingested orally. The amounts of drug and polymeric carrier are, thus, preferably selected such as to limit, or control, the granulation and/or to ensure that the powder or granule particles of the taste-masked pharmaceutical composition do not become too large (as will be detailed further below).

In one of the preferred embodiments, the dry, flowable powder or granules of the taste-masked pharmaceutical composition exhibit a mean particle size in the range of from about 30 μηι to about 250 μηι; or from about 35 μηι to about 220 μηι; or from about 40 μηι to about 190 μηι; or from about 45 μηι to about 160 μηι; for instance, in the range of 100 ± 50 μηι.

Alternatively, or in addition, to these mean particle sizes, not more than

10 vol.-% of the dry, flowable powder or granules of the taste-masked pharmaceutical composition exhibit a sieve diameter of 500 μηι or more; or 400 μηι or more; or 350 μ ι or more; or 300 μηι or more; or 250 μηι or more; or 200 μηι or more. In other words, the D90 value of the dry, flowable powder or granules of the taste-masked pharmaceutical composition does not exceed 500 μηι, or 400 μηι, or 350 μηι, or 300 μηι, or 250 μηι, or 200 μηι, respectively.

Further alternatively, or in addition, to these mean particle sizes and/or D90- values, not more than 10 vol.-% of the dry, flowable powder or granules of the taste- masked pharmaceutical composition exhibit a sieve diameter of 15 μηι or less; or 20 μ ι or less; or 25 μηι or less; or 30 μηι or less; or 35 μηι or less; or 40 μηι or less. In other words, the D10 value of the dry, flowable powder or granules of the taste- masked pharmaceutical composition does not fall below 15 μηι, or 20 μηι, or 25 μηι, or 30 μηι, or 35 μηι or 40 μηι, respectively.

In other words, the dry, flowable powder or granules of the taste-masked pharmaceutical composition are a small-grained yet not fine-powdered dry-bulk. The small particle sizes are preferred in that they help to reduce, or minimize, any unpleasant gritty, grainy, sandy and/or foreign body sensations in the mouth and/or on the tongue when dispersed in water and ingested orally.

It is to be understood that the particle size - or rather the particle size distribution (PSD) - of the dry, flowable powder or granules of the taste-masked pharmaceutical composition is controlled at least partially (or even predominantly) by the inherent particle size, or PSD, of the polymeric carrier particles. For instance, in one specific embodiment, the water-dispersible, at least partially hydrophilic polymeric carrier in the taste-masked pharmaceutical composition is Lycatab^® PGS, and the dry, flowable powder or granules of the taste-masked pharmaceutical composition exhibit a mean particle size in the range of from about 80 μηι to about 180 μ ι; or from about 90 μηι to about 170 μηι; or from about 100 μηι to about 160 μ ι; for instance, in the range of 125 ± 15 μηι. In an alternative specific embodiment, the water-dispersible, at least partially hydrophilic polymeric carrier in the taste-masked pharmaceutical composition is C PolarTex^®, and the dry, flowable powder or granules of the taste-masked pharmaceutical composition exhibit a mean particle size in the range of from about 60 μηι to about 160 μηι; or from about 70 μηι to about 150 μηι; or from about 80 μηι to about 140 μηι; or from about 90 μηι to about 130 μ ι; for instance, in the range of 110 ± 15 μηι. In a further alternative specific embodiment, the water-dispersible, at least partially hydrophilic polymeric carrier in the taste-masked pharmaceutical composition is a low substituted hydroxypropyl cellulose (L-HPC; such as the LH-21 grade from ShinEtsu), and the dry, flowable powder or granules of the taste-masked pharmaceutical composition exhibit a mean particle size in the range of from about 30 μηι to about 100 μηι; or from about 35 μηι to about 85 μηι; or from about 40 μηι to about 70 μηι; or from about 45 μηι to about 65 μ ι; for instance, in the range of 50 ± 15 μηι.

In one embodiment, the dry, flowable powder or granules of the taste-masked pharmaceutical composition exhibit a mean particle size in the range of from about 30 μ ι to about 160 μηι (e.g. 115 ± 30 μηι). In a specific embodiment, not more than 10 % of these dry, flowable powder or granules exhibit a sieve diameter of 350 μηι or more. In a more specific embodiment, not more than 10 vol.-% of these dry, flowable powder or granules exhibit a sieve diameter of 350 μηι or more; and not more than 10 vol.-% of these dry, flowable powder or granules exhibit a sieve diameter of 20 μηι or less.

In one embodiment, the water-dispersible, at least partially hydrophilic polymeric carrier in the taste-masked pharmaceutical composition is Lycatab^® PGS, and the dry, flowable powder or granules of the taste-masked pharmaceutical composition exhibit a mean particle size in the range of from about 100 μηι to about 160 μ ι (e.g. 125 ± 15 μηι). In a specific embodiment, not more than 10 vol.-% of these dry, flowable powder or granules exhibit a sieve diameter of 350 μηι or more. In a more specific embodiment, not more than 10 vol.-% of these dry, flowable powder or granules exhibit a sieve diameter of 350 μηι or more; and not more than 10 vol.-% of these dry, flowable powder or granules exhibit a sieve diameter of 30 μηι or less.

In further preferred embodiments, the taste-masked pharmaceutical composition exhibits immediate release of the drug. In a yet further the taste-masked pharmaceutical composition exhibits immediate release of the drug and does not comprise a coating. As defined herein, immediate release, or fast release, means a drug release profile in which at least 75 % of the drug, or active ingredient, is released in 45 minutes or less, as determined using a USP Dissolution Apparatus type 2 (paddle apparatus) in 900 mL of an aqueous medium at a pH value at which the active ingredient may be soluble and stable at 37 °C, preferably 0.1 N hydrochloride acid, and at a stirring speed of 100 rpm. This embodiment is particularly preferred for pain relief drugs or anti diarrheal drugs, for instance (such as ibuprofen or racecadotril, respectively); i.e. drugs for which a fast onset of effect is desirable or required.

Without wishing to be bound by theory, it is currently believed that the solidified drug melt is 'sterically shielded' and/or 'trapped' in pores of the polymeric carrier, as described above, which appears to hinder the instant access of water or aqueous media to the solidified drug melt (e.g. when dispersed and placed in the mouth and/or on the tongue). However, once the ingested drink suspension of the taste-masked pharmaceutical composition is in prolonged contact with water or aqueous media, e.g. for periods longer than about 5 minutes, or longer than about 10 minutes (such as after oral ingestion and in the gastrointestinal tract), this 'steric shield' wears down and the water or aqueous media will dissolve the drug melt.

The above mentioned additional provision, that the water-dispersible polymers also encompass certain water-soluble polymers (e.g. with dissolution times of more than 15 minutes), is made with respect to the proposed mechanism of action. Since the taste-masked aqueous drink suspensions are intended to be prepared freshly prior to each consumption and then consumed within a short time frame of not more than about 2 to 5 min on average, preferably within 30 seconds or within 1 minute, a very slowly dissolving but readily dispersible polymer is expected to provide a similar taste-masking by sorption of the drug melt as is obtained with water insoluble polymers or partially water-insoluble polymers.

In one embodiment, the water-dispersible, at least partially hydrophilic polymeric carrier in the taste-masked pharmaceutical composition exhibits moderate swelling in water or an aqueous medium; or in other words, the polymeric carrier takes up water or aqueous media but without causing a tangible or visually noticeable viscosity increase and/or dispersibility issues (such as stickiness, lump formation). Alternatively, or in addition, the water-dispersible, at least partially hydrophilic polymeric carrier is a polysaccharide. In other words, the water-dispersible, at least partially hydrophilic polymeric carrier is a polysaccharide and/or exhibits moderate swelling in water or an aqueous medium. The moderate swelling may further improve the taste masking effect (by providing a diffusion barrier between solidified drug melt and the taste buds), as well as potentially stabilise the taste-masked aqueous drink suspension (e.g. preventing floatation).

In a more specific embodiment, the polysaccharide is selected from starches, modified starches such as pregelatinised or partially pregelatinised starches, or low substituted cellulose ethers such as low substituted hydroxypropyl cellulose (L-HPC) or low substituted hydroxypropymethyl cellulose (L-HPMC) or low substituted carmellose sodium (L-Na-CMC). Examples of suitable polymeric carriers include but are not limited to pregelatinised or partially pregelatinised starches, such as

Lycatab^® PGS or Lycatab^® C, respectively (e.g. commercially available from Roquette), other modified starches such as C PolarTex^® (a highly stable hydroxypropylated starch, as commercially available from Cargill), or low substituted hydroxypropyl cellulose such as the L-HPC LH-21 grade (as commercially available from ShinEtsu). In one of the preferred embodiments, the water-dispersible, at least partially hydrophilic polymeric carrier in the taste-masked pharmaceutical composition is Lycatab^® PGS. In another preferred embodiment, the water-dispersible, at least partially hydrophilic polymeric carrier is low substituted hydroxypropyl cellulose, such as the L-HPC LH-21 grade of ShinEtsu. In yet another preferred embodiment, the water-dispersible, at least partially hydrophilic polymeric carrier is a modified starch, or more specifically a hydroxypropylated starch such as C PolarTex^®.

As shown in more detail in the examples, the compositions have been employed successfully to taste-mask a variety of poorly soluble drugs, such as ibuprofen, dexibuprofen, ketoprofen and racecadotril. Since the drug requires melting, the invention is in particular suited to drugs with low melting points, such as about 115 °C or preferably about 100 °C or below. However, as long as the drug is not heat-sensitive and exhibits a melting temperature Ti which is sufficiently below the melting or decomposition temperature T2 of the polymeric carrier particles, and as long as these polymeric carrier particles sorb the molten drug, it is expected that the invention works over a broad range of poorly soluble drugs and water-dispersible, at least partially hydrophilic polymeric carriers. In this context, 'sufficiently below' means that the two temperatures Ti and T2 should allow for a practically appropriate process range for the product temperature T3 which has to fall in between Ti and T2

(i.e. Ti < T3 < T2) and should preferably be at least 10 °C below the melting or decomposition temperature T2 of the polymeric carrier particles, in order to keep the carrier intact, or in other words to preserve both the chemical and physical, or structural, integrity of the polymeric carrier particles.

In that regard, the invention differs from e.g. hot-melt extrusion processes where typically the situation is vice versa; i.e. at least one low-melting polymeric carrier is chosen to melt, or at least soften, and then incorporate the drug particles therein. In hot-melt extrusion processes and their resulting products, it is oftentimes not desirable for the drug to melt and/or dissolve in the polymeric carrier(s) because re- crystallisation phenomena during storage could occur and negatively affect the properties of the hot-melt extrudates, e.g. their drug release, their taste-masking properties.

In one embodiment, the drug comprised in the taste-masked pharmaceutical compositions of the invention exhibits a melting point Ti of about 115 °C or lower; or about 110 °C or lower; or about 105 °C or lower; or about 100 °C or lower; or about 95 °C or lower; or about 90 °C or lower; or about 85 °C or lower; or about 80 °C or lower. It should be understood that in order for the drug to be sorbed by the solid polymeric carrier particles as a solidified drug melt - as required for the present invention - the drug's melting point Ti must at least be higher than ambient temperature (i.e. about 20 ± 3 °C); and preferably at least 30 °C or higher; or at least 35 °C or higher; or at least 40 °C or higher; or at least 45 °C or higher; or at least 50 °C or higher; or at least 55 °C or higher; or at least 60 °C or higher; or at least 65 °C or higher; or at least 70 °C or higher. In one of the preferred embodiments, the drug comprised in the taste-masked pharmaceutical compositions of the invention exhibits a melting point Ti in the range of from about 40 °C to about 110 °C; or from about 45 °C to about 105 °C; or from about 50 °C to about 100 °C.

In one embodiment, the drug comprised in the taste-masked pharmaceutical compositions of the invention is selected from racemic ibuprofen (M_p about 75-78 °C), dexibuprofen (M_p about 49-53 °C), ketoprofen (M_p about 94 °C),

racecadotril (M_p about 75 °C), fenofibrat (M_p about 78-82 °C), chinin trihydrate (M_p about 57 °C), gemfibrozil (M_p about 62 °C), chloroquine (M_p about 87- 92 °C), N-acetylcysteine (M_p about 106 °C), cetirizine HC1 (M_p about 110-115 °C), dextromethorphan (M_p about 111 °C). In a specific embodiment, the drug is selected from racemic ibuprofen, dexibuprofen, ketoprofen and racecadotril. In a more specific embodiment, the drug is racecadotril.

In one embodiment, the composition comprises the drug racecadotril, and pregelatinised starch as the polymeric carrier, for instance Lycatab^® PGS. In a specific embodiment, the composition comprises the drug racecadotril, pregelatinised starch as the polymeric carrier (for instance Lycatab^® PGS), and a pharmaceutically accepted excipient selected from colourants, antioxidants, flavourants, or sweeteners. In a more specific embodiment, the composition essentially consists of the drug racecadotril, pregelatinised starch as the polymeric carrier (for instance Lycatab^® PGS), and a pharmaceutically accepted excipient selected from colourants, antioxidants, flavourants, or sweeteners. In one embodiment, the composition essentially consists of the drug

racecadotril, and pregelatinised starch as the polymeric carrier, for instance

Lycatab^® PGS. Considering the particularly intense bitter taste of this drug (which was not even completely masked by e.g. polymer coatings such as in the commercially available Tiorfan^® product), it is surprising that satisfactory taste-masking could be obtained by the taste-masked pharmaceutical composition of the present invention.

In one embodiment, the composition comprises a non-steroidal antiinflammatory drug, such as ketoprofen, ibuprofen, or dexibuprofen, and pregelatinised starch as the polymeric carrier, for instance Lycatab^® PGS. In a specific embodiment, the composition essentially consists of a non-steroidal anti-inflammatory drug, such as ketoprofen, ibuprofen, or dexibuprofen, and pregelatinised starch as the polymeric carrier, for instance Lycatab^® PGS.

Since the molten drug is intended to be at least partially sorbed by the polymeric carrier particles (at least 70 wt.-% of the molten drug sorbed, preferably more, as mentioned above), it is understood that the specific amount of drug which can be sorbed by this carrier (i.e. its sorption capacity or drug loading capacity) will typically be dependent on numerous factors, including e.g. the flow properties of the melt (in terms of e.g. viscosity and surface tension), the porosity of the polymeric carrier particles (in terms of e.g. number, size and tortuosity of pores), or specific

physiochemical drug-carrier-interactions which may potentially occur. The upper limit for the drug loading (for a specific drug and a specific polymeric carrier) is commonly assessed by gradually increasing the amount of drug which is added to, and melted with, a given amount of polymeric carrier; when the sorption capacity is exceeded, this would be noticeable by an increasing plasticity in the production vessel in the beginning (often accompanied by increasing fractions of larger-sized granules, such as granules with a particle size of >500 μηι); and then an increasing liquefaction when the sorption capacity is exceeded even further. After solidification such Over- loaded' compositions would not form into a dry, flowable composition, but to somewhat lumpy, inhomogeneous masses which oftentimes cannot be dispersed properly in water or other aqueous media anymore.

In one embodiment, the taste-masked pharmaceutical composition comprises 1 to 35 wt.-% drug and 50 to 99 wt.-% polymeric carrier. In a specific embodiment, the composition essentially consists of 1 to 35 wt.-% drug and 65 to 99 wt.-% polymeric carrier.

In a more specific embodiment, the taste-masked pharmaceutical composition comprises 5 to 30 wt.-% drug and 55 to 95 wt.-% polymeric carrier; for instance, the taste-masked pharmaceutical composition may essentially consist of 5 to 30 wt.-% drug and 70 to 95 wt.-% polymeric carrier.

In a yet further specific embodiment, the taste-masked pharmaceutical composition comprises 7 to 28 wt.-% drug and 60 to 90 wt.-% polymeric carrier; for instance, the taste-masked pharmaceutical composition may essentially consist of 10 to 28 wt.-% drug and 72 to 90 wt.-% polymeric carrier. In one embodiment, the composition comprises 1-20 wt.-% racecadotril and

80-99 wt.-% of a polymeric carrier selected from pregelatinised starch (for instance Lycatab^® PGS), low-substituted hydroxypropyl cellulose L-HPC (for instance L- HPC LH-21) or modified starch (for instance C PolarTex^®, a highly stable

hydroxypropylated starch), for instance, 10 wt.-% racecadotril and 90 wt.- % polymeric carrier. In a specific embodiment, the taste-masked pharmaceutical composition essentially consists of 10 wt.-% racecadotril and 90 wt.-% pregelatinised starch (for instance Lycatab^® PGS). In another specific embodiment, the taste-masked pharmaceutical composition essentially consists of 10 wt.-% racecadotril and 90 wt.- % low-substituted hydroxypropyl cellulose L-HPC (for instance L-HPC LH-21). In yet another specific embodiment, the taste-masked pharmaceutical composition essentially consists of 10 wt.-% racecadotril and 90 wt.-% modified starch (for instance C PolarTex^®, a highly stable hydroxypropylated starch). In another embodiment, the composition comprises 10-30 wt.-% of a nonsteroidal anti-inflammatory drug (NSAID), such as ketoprofen, ibuprofen, or dexibuprofen; and 70-90 wt.-% of a polymeric carrier selected from pregelatinised starch (for instance Lycatab^® PGS), low-substituted hydroxypropyl cellulose L-HPC (for instance L-HPC LH-21) or modified starch (for instance C PolarTex^®, a highly stable hydroxypropylated starch), for instance 27 wt.-% NSAID and

73 wt.-% polymeric carrier.

In a specific embodiment, the composition comprises 15-30 wt.-% of a nonsteroidal anti-inflammatory drug (NSAID), such as ketoprofen, ibuprofen, or dexibuprofen; and 70-85 wt.-% of a polymeric carrier selected from pregelatinised starch (for instance Lycatab^® PGS), low-substituted hydroxypropyl cellulose L-HPC (for instance L-HPC LH-21) or modified starch (for instance C PolarTex^®, a highly stable hydroxypropylated starch); or 20-30 wt.-% of a non-steroidal antiinflammatory drug (NSAID), such as ketoprofen, ibuprofen, or dexibuprofen; and 70- 80 wt.-% of a polymeric carrier selected from pregelatinised starch (for instance Lycatab^® PGS), low-substituted hydroxypropyl cellulose L-HPC (for instance L- HPC LH-21) or modified starch (for instance C PolarTex^®, a highly stable

hydroxypropylated starch); for instance 27 wt.-% NSAID and 73 wt.-% polymeric carrier.

In a more specific embodiment, the taste-masked pharmaceutical composition essentially consists of 27 wt.-% NSAID and 73 wt.-% pregelatinised starch (for instance Lycatab^® PGS). In another specific embodiment, the taste-masked

pharmaceutical composition essentially consists of 27 wt.-% NSAID and 73 wt.-% low- substituted hydroxypropyl cellulose L-HPC (for instance L-HPC LH-21). In yet another specific embodiment, the taste-masked pharmaceutical composition essentially consists of 27 wt.-% NSAID and 73 wt.-% modified starch (for instance C PolarTex^®, a highly stable hydroxypropylated starch). In one embodiment, the powder or granule particles forming the taste-masked pharmaceutical composition further comprise a pharmaceutically accepted excipient selected from colourants, antioxidants, flavourants, or sweeteners (i.e. in addition to the above mentioned drug and polymeric carrier). These are examples of excipients which are usually employed at a lower content, or amount, than the drug, and thus will most likely have only a limited effect on the sorption capacity of the polymeric carrier particles.

It is to be understood that, besides the drug, also these further optional components of the taste-masked composition may - but not necessarily have to - be sorbed by the polymeric carrier particles, preferably sorbed by the internal surface of porous polymeric carrier particles (if applicable). This may, for instance, be

advantageous in order to provide a specific colour not only to the aqueous dispersion medium of a drink suspension but also to the dispersed, solid polymeric carrier particle fraction (i.e. the taste-masked pharmaceutical composition); such as red for a drink suspension of red berry taste, yellow for a drink suspension with lemon taste, orange for a drink suspension with orange or apricot taste, or the like.

In one embodiment, the composition comprises 7 to 10 wt.-% racecadotril, 70 to 80 wt.-% pregelatinised starch (for instance Lycatab^® PGS), low-substituted hydroxypropyl cellulose L-HPC (for instance L-HPC LH-21) or modified starch (for instance C PolarTex^®, a highly stable hydroxypropylated starch), and 10 to 23 wt.-% of a pharmaceutically accepted excipient selected from colourants, antioxidants, flavourants or sweeteners. In a specific embodiment, the composition comprises 8 to 9 wt.-% racecadotril, 73 to 77 wt.-% pregelatinised starch (for instance

Lycatab^® PGS), low-substituted hydroxypropyl cellulose L-HPC (for instance L- HPC LH-21) or modified starch (for instance C PolarTex^®, a highly stable

hydroxypropylated starch), and 14 to 19 wt.-% of a pharmaceutically accepted excipient selected from colourants, antioxidants, flavourants or sweeteners. In a more specific embodiment, the composition comprises 8 to 9 wt.-% racecadotril,

73 to 77 wt.-% pregelatinised starch (for instance Lycatab^® PGS), low-substituted hydroxypropyl cellulose L-HPC (for instance L-HPC LH-21) or modified starch (for instance C PolarTex^®, a highly stable hydroxypropylated starch), and 14 to 19 wt.-% of a blend of two or more pharmaceutically accepted excipients selected from colourants, antioxidants, flavourants or sweeteners. In a further specific embodiment, the composition essentially consists of 8.26 wt.-% racecadotril, 74.35 wt.-% Lycatab^® PGS, and 17.39 wt.-% of a blend of beet root powder, riboflavin sodium and cochenille natural red (E120) as pharmaceutically accepted colourants.

In another embodiment, the composition comprises 10-25 wt.-% of a nonsteroidal anti-inflammatory drug (NSAID), such as ketoprofen, ibuprofen, or dexibuprofen,

55 to 70 wt.-% pregelatinised starch (for instance Lycatab^® PGS), low-substituted hydroxypropyl cellulose L-HPC (for instance L-HPC LH-21) or modified starch (for instance C PolarTex^®, a highly stable texturizing hydroxypropylated starch), and 5 to 35 wt.-% of a pharmaceutically accepted excipient selected from colourants, antioxidants, flavourants or sweeteners. In a specific embodiment, the composition essentially consists of 20 wt.-% NSAID, 70 wt.-% Lycatab^® PGS, and 10 wt.-% of a blend of two or more pharmaceutically accepted excipients selected from colourants, antioxidants, flavourants or sweeteners.

While in theory it would be possible to add a number of yet further components to the taste-masked pharmaceutical compositions, in particular those with a higher amount than the drug (e.g. sugars or sugar alcohols), this would mean that

a) yet further melting points would have to be considered for the preparation

process,

b) the drug loading capacity, or sorption capacity, of the polymeric carrier particles would potentially be reduced due to other molten substances being sorbed; and c) the loading of drug and polymeric carrier particles in a production vessel would often have to be reduced in favour of e.g. these sugars or sugar alcohols.

Thus, in most cases, it appears economically more reasonable to add any components (such as sugars or sugar alcohols) after the preparation of the taste- masked composition of the invention, for instance to provide a dosage form which can be dispersed in water to form pleasant tasting drink suspension, as will be described in more detail further below.

The same applies to any components whose intended function would be impeded if they were incorporated in the melt and sorbed at least partially by the polymeric carrier (even if used in smaller amounts than the drug); for instance, flow improving excipients such as fumed silica or the like which could be added to the taste-masked pharmaceutical composition in the form of a dry, flowable powder or granules.

In a second aspect, the present invention provides a process for the preparation of a taste-masked pharmaceutical composition in the form of a dry, flowable powder or granules for dispersion in water or an aqueous medium, preferably a taste-masked pharmaceutical composition as described above, the process comprising the steps of: (a) providing at least

a2) a water-dispersible, at least partially hydrophilic polymeric carrier in the form of powders or granules, the carrier exhibiting a melting or decomposition temperature T₂, and optionally a porous structure,

and optionally

a3) a further pharmaceutically accepted excipient;

(b) mixing all components provided according to step a) and melting the drug at a product temperature T3 above temperature Ti and below temperature T₂

(Ti < T3 < T₂), until the molten drug is sorbed at least partially by the polymeric carrier; and

(c) allowing the mixture to cool down to ambient temperature (i.e. about 20 ± 3 °C) and the at least partially sorbed molten drug to solidify with the polymeric carrier.

Again, same as described for the first aspect of the invention, the polymeric carrier particles must preserve both their chemical and physical / structural, integrity during the preparation process in order to be able to sorb, or at least partially sorb, the molten drug; hence, the melting or decomposition temperature T₂ of the polymeric carrier must be higher than the melting point Ti of the poorly water-soluble drug. In other words, the polymeric carrier particles shall preferably remain solid, or rigid, or glassy, and not, for instance, undergo thermoplastic deformation during or after the process.

In one embodiment, the pharmaceutically accepted excipient of a3) is selected from colourants, antioxidants, flavourants, or sweeteners. In a specific embodiment, the pharmaceutically accepted excipient of a3) is selected from colourants, antioxidants, or sweeteners. In a more specific embodiment, the pharmaceutically accepted excipient of a3) is selected from colourants. In one embodiment, the water-dispersible, at least partially hydrophilic polymeric carrier provided for this process exhibits moderate swelling.

Optionally, water is removed from the polymeric carrier in a drying step prior to step (a), and/or during step (b). In other words, water may be removed from the components of the composition either before combining them for mixing and melting in step (b), usually in a separate device; and/or it can be removed during step (b), i.e. while mixing. The removal of water can be helpful in order to improve the storage stability of the taste-masked pharmaceutical composition, both in microbial and hydrolytic terms. This step is particularly advisable when working with hydrolysis- sensitive drugs such as esters (e.g. racecadotril), and/or when working with polymeric carriers with a known inherent water-content, such as pregelatinised starches (e.g. Lycatab^® PGS has an inherent water-content of about 10 wt.-%).

In addition, the removal of water from the polymeric carrier is also useful in ensuring the required chemical and physical / structural, integrity of the polymeric carrier particles during the preparation process, since water commonly acts as a plasticizer. In other words, the risk of the polymeric carrier particles to

unintentionally melt, or at least soften, during the process at temperature T3 (i.e. while being subjected to elevated temperatures and the molten drug) is advantageously decreased when drying the polymeric carrier. For polymeric carriers exhibiting a porous structure, the drying step may further be useful for removing water from the pores and thus 'vacate' them for the molten drug to be sorbed therein. This is particularly true for hydrophobic drugs which would interact less with humid polymeric carriers.

In one embodiment, the optional drying step involves vacuum conditions. In a specific embodiment, said vacuum conditions are employed during step (b), and optionally during step (c) using the same equipment as for mixing all components provided and for melting the drug. The term 'vacuum conditions' as used herein means to reduce absolute pressure to about 30 mbar, preferably to about 15 mbar. In a preferred embodiment, step (b), and optionally during step (c), are performed at an absolute pressure in the range of about 30 to about 15 mbar which may be kept constant or which may vary during the different process steps as defined above. In a further specific embodiment, the vacuum conditions are employed from the start of step (b); i.e. the water is removed before, or in the early stages of, the drug melting. This approach resulted in a slightly more homogeneous composition when working with racecadotril and the pregelatinised starch Lycatab^® PGS, assumingly because water is removed more easily from the Lycatab^® PGS as long as no or little molten drug is sorbed by the polymeric carrier particles yet. Alternatively, though, the mixing and melting step (b) may also be performed first, with the vacuum drying being initiated at the end of step (b). The choice between these options may be made independently for each specific drug/polymer/excipient composition, keeping in mind e.g. processing times and homogeneity of the resulting composition.

In one embodiment, the process is performed in a device equipped with

(i) means for mixing any components provided in the product vessel; (ii) means for heating the product vessel, such as water- or oil filled heating jackets, electric or infrared heating devices; and optionally (iii) means for evacuating the product vessel to provide vacuum conditions. For instance, in one embodiment the process may be performed in a vacuum granulator. In a specific embodiment, the granulator is a TOPO granulation system (Hermes Pharma, Germany).

In one embodiment, the process for the preparation of a taste-masked pharmaceutical composition in the form of a dry, flowable powder or granules for dispersion in water or an aqueous medium, preferably a taste-masked pharmaceutical composition as described above, essentially consists of the steps of:

(a) providing

al) a poorly water-soluble drug exhibiting a poor taste and a melting

temperature Ti,

and optionally

a3) a further pharmaceutically accepted excipient;

(b) mixing and drying all components provided according to step a) in a vacuum granulator, and melting the drug at a product temperature T₃ above temperature Ti and below temperature T₂ (Ti < T3 < T₂), until the molten drug is sorbed at least partially by the polymeric carrier; and (c) allowing the mixture to cool down to ambient temperature (i.e. about 20 ± 3 °C) and the at least partially sorbed molten drug to solidify with the polymeric carrier. In a specific embodiment, the pharmaceutically accepted excipient of a3) is selected from colourants, antioxidants, flavourants, or sweeteners; for instance, from colourants.

In one embodiment, the product temperature T3 while performing step (b) of the process is kept at least 10 °C below the melting or decomposition temperature T₂, preferably at least 15 °C below T₂, in order to prevent melting or decomposition of the polymeric carrier particles and thus allow for sorption of the molten drug by the solid particles. Else, the decision of the product temperature will mainly be guided by the melting temperature of the drug to be incorporated.

For instance, in one embodiment, the product temperature T3 while performing step (b) is kept between 50 °C and 130 °C, or between 70 °C and 125 °C, or between 80 °C and 110 °C.

In a specific embodiment, the drug is racecadotril and the product

temperature T3 while performing step (b) is kept between 80 °C and 90 °C, preferably between 80 °C and 85 °C; for instance, at around 82 °C.

In a specific embodiment, the drug is racemic ibuprofen and the product temperature T3 while performing step (b) is kept between 80 °C and 90 °C, preferably between 80 °C and 85 °C; for instance, at around 82 °C.

In another embodiment, the drug is ketoprofen and the product temperature T3 while performing step (b) is kept between 100 °C and 130 °C, preferably between 115 °C and 130 °C; for instance, at around 125 °C. When operating the process in a device equipped with a heat-jacketed product vessel, this product temperature requires oil-heating rather than water-heating in order to provide sufficient temperatures.

In yet another embodiment, the drug is dexibuprofen, and the product temperature T3 while performing step (b) is kept between 50 °C and 100 °C, preferably between 60 °C and 90 °C; for instance, at around 70 °C. In a third aspect, the invention provides a taste-masked pharmaceutical composition for dispersion in water or an aqueous medium, the composition being provided in the form of a dry, flowable powder or granules obtainable by a process as described above.

In a fourth aspect, the invention provides a pharmaceutical dosage form provided as a dry, flowable powder or granules for dispersion in water or an aqueous medium comprising the taste-masked pharmaceutical composition described above as the first aspect of the invention, and in admixture thereto at least one

pharmaceutically accepted excipient selected from sugars, sugar alcohols, sweeteners, flavourants, or colourants.

These excipients are not necessarily required for the taste-masking as such, but they can be admixed to the taste-masked pharmaceutical composition described above in order to influence the taste of water or an aqueous medium upon dispersion of the pharmaceutical dosage form therein. For instance, when dispersing the taste-masked pharmaceutical composition described above in water without any added sugars, sugar alcohols, sweeteners or flavourants, the resulting drink suspension are taste- masked but may potentially have a rather bland, neutral taste, which in particular paediatric patients may object to. Therefore, the preparation of a pharmaceutical dosage form comprising the taste-masked pharmaceutical composition described above and an admixture of e.g. sugars, sweeteners and/or flavourants may be advisable to improve consumer acceptance and compliance.

In one embodiment, a single dose unit of the dosage form comprises about 400 mg to 4000 mg, the single dose optionally being provided in the form of stick packs, sachets, ampoules or vials.

In a specific embodiment, the dosage form comprises sucrose as the sugar;

sucralose as a sweetener; raspberry aroma as a flavourants; and beet root powder, riboflavin sodium and cochenille as colourants. It is easily understood, that various other combinations of sugars, sugar alcohols, sweeteners, flavourants, or colourants can be used, depending on the desired taste of the drink suspensions prepared from the dosage form. In one embodiment, the dosage form comprises 0.2 to 10 wt.-% drug,

70 to 90 wt.-% sugar, 8 to 20 wt.-% polymeric carrier, 0.2 to 2 wt.-% sweetener, 0.4 to 4 wt.-% flavourants and 1 to 5 wt.-% colourants.

In one embodiment, the dosage form comprises 0.2 to 3 wt.-% racecadotril, 70 to 90 wt.-% sucrose, 8 to 20 wt.-% pregelatinised starch, 0.2 to 2 wt.-% sweetener, 0.4 to 4 wt.-% flavourants and 1 to 5 wt.-% colourants.

In a more specific embodiment, the pharmaceutical dosage form comprises, or essentially consist of, 1.5 wt.-% racecadotril, 80.7 wt.-% sucrose, 13.5 wt.-%

pregelatinised starch (e.g. Lycatab® PGS), 0.3 wt.-% sucralose, 0.8 wt.-% raspberry aroma and 3.2 wt.-% colourants selected from beet root powder, riboflavin sodium and cochenille (E120).

In one embodiment, the dosage form comprises 2 to 10 wt.-% of an NSAID drug such as ketoprofen, ibuprofen, or dexibuprofen, 70 to 90 wt.-% sucrose, 8 to 20 wt.-% pregelatinised starch, 0.2 to 2 wt.-% sweetener, 0.4 to 4 wt.-% flavourants and

1 to 5 wt.-% colourants.

In a fifth aspect, the invention provides a taste-masked aqueous dispersion for oral administration of a poorly water-soluble drug exhibiting a poor taste and a melting point Ti, comprising the taste masked pharmaceutical composition described above as the first aspect of the invention, or the pharmaceutical dosage form described above as the third aspect of the invention, dispersed in water or an aqueous medium. Such aqueous dispersions for oral administration are also referred to as drink suspensions.

As described above, it is presently assumed that the taste masking of these aqueous dispersions is caused by the dispersed polymeric carrier particles either trapping the solidified melt of the poorly tasting drug (e.g. ibuprofen, ketoprofen, racecadotril) inside their porous structure, and/or by 'sterically shielding' the solidified drug melt with the polymeric carrier particles in the form of small, powderlike granules; thereby preventing the drug from getting in direct contact with the oral taste-buds and delaying, or hindering, drug dissolution to at least such a degree that only very little dissolved drug molecules are present in the oral cavity. In addition, if the polymeric carrier particles exhibit moderate swelling this may help to stabilise the aqueous dispersions, e.g. by preventing poorly water-soluble drug such as racecadotril from floating. This suspension stabilisation is effective at least for the time that it commonly takes to prepare and ingest the aqueous dispersions. Both factors - the stabilised dispersions in water as well as the sorption of the solidified drug melt by the polymeric carrier particles -reduce the local concentration of the drug in the mouth and/or on the tongue and hence limit the taste perception.

Further embodiments, options, and/or preferences are illustrated by the following examples.

EXAMPLES

Example 1: Taste masked pharmaceutical compositions of different drugs Water-dispersible pregelatinised starch (Lycatab^® PGS) powder and one of the drugs as listed in Table 1 below were weighed into aluminium dishes to yield a drug content of 10 wt.-% in powder blend, manually mixed and stored for 2 h at 15 mbar and 95 °C (or 125 °C for ketoprofen only) in a vacuum drying oven (VT 6060 P;

Heraeus), in order to a) remove water from the pregelatinised starch powder, b) melt the drug and c) allow the molten drug to be sorbed by the pregelatinised starch powder.

Ex. Drug

la Ketoprofen

lb Ibuprofen (acid; racemic)

lc Dexibuprofen

Id Racecadotril

Table 1

After cooling down to ambient temperature (about 20 ±3 °C; optionally also under vacuum), the pulverulent mixtures were loosened up to dry, flowable compositions by gentle stirring and/or shaking. All mixtures resulted in dry, flowable powder-like compositions and appeared homogeneous upon visual inspection.

Then, about 300 mg mixture were stirred into about 200 mL water using a tea spoon to test the mixtures' behaviour with respect to wettability and dispersibility in water, their sedimentation or flotation tendencies as well as their taste (preliminary evaluation by 4 volunteers). All tested samples could be dispersed easily in water, with the mixtures being readily wetted and forming homogenous dispersions without noticeable lump, or agglomerate, formation. After about 1-2 minutes without stirring, all dispersions showed only moderate sedimentation and limited flotation; and both phenomena could be easily reversed when stirring again. In other words, all mixtures tested were suited to form

homogenous drink suspensions in water.

Upon oral ingestion of these drink suspensions, none of the 4 volunteers reported a noticeable bitterness for any of the four tested drugs, despite the fact that no other pharmaceutically accepted excipients, such as sugars, sweeteners, flavourants (e.g. aroma), were added to the water yet.

Example 2: Taste masked pharmaceutical compositions of different polymeric carriers In a further test, racecadotril and one of the polymeric carriers described in

Table 2 below were weighed into aluminium dishes to yield a drug content of about 8.3 wt.-% in the powder blend, manually mixed and stored for 2 h at 15 mbar and 95 °C in a vacuum drying oven (VT 6060 P; Heraeus), similar to the procedure described in Example 1 above. The mixtures further comprised a blend of colourants (comprising beet root powder, riboflavin sodium and cochenille for a red colour) at a total colourant content of about 3.2 wt.-% in the powder blend, to test whether the colourants get sorbed by the (optionally porous) polymeric carrier particles as well.

After cooling down to ambient temperature (about 20 ± 3 °C; optionally also under vacuum), the pulverulent mixtures were loosened up to dry, flowable compositions by gentle stirring and/or shaking. All mixtures resulted in dry, flowable powder-like compositions and appeared homogeneous upon visual inspection.

However, when dispersing about 360 mg of the mixtures in about 200 mL water (stirring with a tea spoon), large differences were noted in the mixtures' behaviour with respect to wettability and dispersibility in water as well as their sedimentation or flotation tendencies. The results are summarised in Table 2 below.

Ex. Polymeric carrier Dispersibility / Sedimentation Flotation

wettability after 1 min after 1 min

2a Water-dispersible Very easily Moderate Minor flotation pregelatinised starch dispersed and sedimentation

(Lycatab^® PGS) wetted

2b Low-substituted Very easily Moderate Minor flotation

Hydroxypropyl cellulose, dispersed and sedimentation, but

L-HPC wetted quicker than with

(Shin-Etsu LH-21) the PGS

Modified starch /

2c Easily dispersed Moderate Moderate

hydroxypropylated starch

and wetted sedimentation, flotation

(Cargill's C PolarTex^®)

similar to PGS

2d Maltodextrin Poor wettability; n/a Pronounced

(Kleptose^® Linecaps 17) then dissolving in (carrier dissolved) flotation (drug) water

2e MCC Poor wettability Pronounced Pronounced

(Avicel® PH-112) sedimentation flotation (drug)

(MCC)

2f Hydroxypropylmethyl Impossible due to n/a Floating gelled cellulose, HPMC 15,000 immediate lump at surface

(AnyAddy®) formation of a

gelled 'lump"

Table 2 As can be seen from Table 2, water-dispersible polymeric carriers with a higher degree of hydrophilicity, such as the two starches or the low-substituted

hydroxypropyl cellulose (L-HPC), appear to work best for the present invention, providing easily wettable and dispersible compositions which showed only moderate sedimentation and only minor floatation when left unstirred for about 1-2 minutes. The moderate swelling of the two starches or the low-substituted hydroxypropyl cellulose (L-HPC) is further considered beneficial for the dispersion stability and the reduced floating of the drug racecadotril.

Upon oral ingestion of the respective drink suspensions (about 360 mg dispersed in 200 mL water), none of the 4 volunteers reported a noticeable bitterness for the compositions using the two starches or the low-substituted hydroxypropyl cellulose (L-HPC), despite the fact that no other pharmaceutically accepted excipients, such as sugars, sweeteners, flavourants (e.g. aroma), were added to the water yet.

Interestingly, it was observed that the colourants were also sorbed (at least partially) by the polymeric carrier particles, thus giving a red colour not only to the water upon dispersion but also to the drug-carrier-particles, as was visible with the minor amounts of floating red particles when stirring was stopped for longer than 2 minutes.

In contrast, when using microcrystalline cellulose (MCC) - a water-insoluble polymer with almost no swelling in aqueous media and a lower degree of

hydrophilicity compared to the starches and the L-HPC - the dispersibility of the composition was poor, requiring more pronounced stirring. In addition, the composition seemed to separate, with the MCC particles sedimenting quickly and most of the racecadotril particles floating at the surface of the water very soon after stopping to stir; yielding a drink suspension with a distinct bitter taste. This could potentially be an indication of insufficient sorption of the drug melt by the MCC carrier particles.

Also, water-soluble polymers with a far higher degree of swelling in aqueous media compared to the starches and the L-HPC were not successful in that they could not be dispersed properly. The composition employing HPMC 15,000 gelled into a floating lump immediately when dropped into the water and could not be dispersed or dissolved homogeneously by stirring with a spoon in a time frame appropriate for preparing and administering a pharmaceutical drink suspension.

More readily water-soluble carriers with a low polymer content such as maltodextrin did not provide successful taste-masking compositions, either. While the drug melt appeared to have been sorbed by the maltodextrin powder, the water- soluble maltodextrin then dissolved quickly upon dispersion and released the drug into the water, yielding a drink suspension with lots of floating racecadotril particles and a distinct bitter taste. Example 3: Taste masked compositions with different levels of ibuprofen

In a further test, the drug loading capacity, or sorption capacity, of water- dispersible pregelatinised starch (Lycatab^® PGS) was tested for racemic ibuprofen. Four mixtures (270 mg of the polymeric carrier + 60 mg, 100 mg, 200 mg or 400 mg ibuprofen) were weighed into aluminium dishes to yield the various drug contents in the powder blend as shown in Table 3; then manually mixed and stored for 2 h at 15 mbar and 95 °C in a vacuum drying oven (VT 6060 P; Heraeus), similar to the procedure described in Example 1 above.

Ex. Drug loading in wt.-% Dispersibility / Sedimentation Flotation

based on total weight wettability after 1 min after 1 min

3a 18.2 Very easily dispersed Moderate Moderate flotation and wetted sedimentation

3b 27.0 Very easily dispersed Moderate Moderate flotation and wetted sedimentation

3c 42.5 n/a n/a n/a

3d 59.7 n/a n/a n/a

Table 3

After cooling down to ambient temperature (about 20 ± 3 °C; optionally also under vacuum), the pulverulent mixtures were loosened up to dry, flowable compositions by gentle stirring and/or shaking if possible. The compositions with an ibuprofen content up to 27 wt.-%, resulted in dry, flowable powder-like compositions, appeared homogeneous upon visual inspection and were easily dispersible in water with only moderate sedimentation or flotation occurring 1 minute after dispersion.

Upon oral ingestion of the respective drink suspensions (about 300 mg dispersed in 200 mL water), none of the 4 volunteers reported a noticeable bitterness for the compositions with an ibuprofen content up to 27 wt.-%.

In contrast, compositions with ibuprofen contents of 42.5 wt.-% or larger turned out sticky and formed lumps, or agglomerates, or even suspensions of the polymeric carrier within the solidified drug melt. They were thus above the sorption capacity of water-dispersible pregelatinised starch (Lycatab^® PGS) for ibuprofen. Example 4: Taste masked pharmaceutical compositions of racecadotril prepared in a granulator

Using a TOPO granulator (equipped with heating jackets and means to evacuate the product vessel), the following components were mixed to homogeneity under vacuum conditions (15 mbar) and at a product temperature of about 82 °C which causes the drug racecadotril to melt (melting point about 75 °C). The heating-jacket was tempered with hot water and provided an operating temperature of up to about 93 °C. Subsequently the mixture was allowed to cool down to ambient temperature (about 20 ± 3 °C), thereby allowing the sorbed molten drug particles to solidify.

Components wt.-% in the composition

Racecadotril 8.26

Water-dispersible, pregelatinised starch (Lycatab^® PGS) 74.35

Beet root powder 16.52

Riboflavin sodium 0.04

Cochenille nat. (E120) 0.83

Table 4

After cooling down to ambient temperature (about 20 ±3 °C), the pulverulent, dry, flowable mixture emptied from the granulator appeared to be homogeneous upon visual inspection.

Upon oral ingestion of the respective drink suspensions (about 360 mg of the particles dispersed in 200 mL water), none of the 4 volunteers reported a noticeable bitterness for the composition.

Subsequently, the taste-masked pharmaceutical composition was incorporated into pharmaceutical dosage forms by mixing them, e.g. in a regular free fall mixing device, together with sugars, sweeteners, flavourants (e.g. aroma). The composition of these pharmaceutical dosage forms is shown in Table 5 below: Components of dosage form wt.-% in the composition

Taste-masked racecadotril composition (see Table 4) 18.16

Sucrose 80.74

Aroma (raspberry) 0.75

Sucralose 0.35

Table 5

As expected, upon oral ingestion of the respective drink suspensions

(e.g. 2000 mg of the dosage form dispersed in 200 mL water), none of the 4 volunteers reported a noticeable bitterness for the composition; instead they reported positively on the pleasant taste and colour of the drink suspension.

Example 5: Taste masked pharmaceutical compositions of further drugs

In analogy to Example 1, water-dispersible pregelatinised starch (Lycatab^® PGS) powder and one of the further drugs as listed in Table 6 below were weighed into aluminium dishes to yield a drug content of 10 wt.-% in powder blend, manually mixed and stored for 1 h at 15 mbar and 90 °C in a vacuum drying oven (VT 6060 P; Heraeus), in order to a) remove water from the pregelatinised starch powder, b) melt the drug and c) allow the molten drug to be sorbed by the pregelatinised starch powder.

Ex. Drug

5a Fenofibrat

5b Gemfibrozil

Table 6

After cooling down to ambient temperature (about 20 ±3 °C; optionally also under vacuum), the pulverulent mixtures were loosened up to dry, flowable compositions by gentle stirring and/or shaking. All mixtures resulted in dry, flowable powder-like compositions and appeared homogeneous upon visual inspection. Then, about 300 mg mixture were stirred into about 200 mL water using a tea spoon to test the mixtures' behaviour with respect to wettability and dispersibility in water, their sedimentation or flotation tendencies as well as their taste (preliminary evaluation by 4 volunteers). Both tested samples could be dispersed easily in water, with the mixtures being readily wetted and forming homogenous dispersions without noticeable lump, or agglomerate, formation. While both drugs exhibited floatation without the pregelatinised starch, none of the two samples floated anymore once sorbed by the solid polymeric carrier particles in the form of a solidified drug melt.

Example 6: Particle size distributions of taste masked pharmaceutical compositions

The particle size distribution of the taste masked pharmaceutical compositions prepared in analogy to Examples 1 to 5 were measured in a Camsizer^® XT device (Retsch Technology GmbH, Haan, Germany) equipped with an X-Jet plug-in cartridge, and analysed with its related software. The results are shown in the table 7 below:

Table7

Claims

1. A taste-masked pharmaceutical composition for dispersion in water or an

aqueous medium, the composition being provided in the form of a dry, flowable powder or granules, wherein the powder or granule particles comprise:

a. a poorly water-soluble drug exhibiting a poor taste and a melting point Ti, and

b. a water-dispersible, at least partially hydrophilic polymeric carrier in the form of powders or granules, the carrier exhibiting a melting or

decomposition temperature T2 which is higher than Ti, and optionally a porous structure;

2. The composition according to claim 1, wherein the dry, flowable powder or

granules of the taste-masked pharmaceutical composition exhibit a mean particle size in the range of from about 30 μηι to about 250 μηι; or from about 35 μηι to about 220 μηι; or from about 40 μηι to about 190 μηι; or from about 45 μηι to about 160 μ ι;

and/or

wherein not more than 10 vol.-% of the dry, flowable powder or granules of the taste-masked pharmaceutical composition exhibit a sieve diameter of 500 μηι or more; or 400 μηι or more; or 350 μηι or more; or 300 μηι or more; or 250 μηι or more; or 200 μηι or more.

3. The composition according to claims 1 to 2, wherein the water-dispersible, at least partially hydrophilic polymeric carrier is a polysaccharide and/or exhibits moderate swelling in water or an aqueous medium.

4. The composition according to claims 1 to 3, wherein the polysaccharide is selected from starches, modified starches such as pregelatinised or partially pregelatinised starches, or low substituted cellulose ethers such as low substituted

hydroxypropyl cellulose (L-HPC) or low substituted hydroxypropymethyl cellulose (L-HPMC) or low substituted carmellose sodium (L-Na-CMC).

5. The composition according to any of claims 1 to 4, wherein the drug exhibits a melting point Ti of about 115 °C or lower; or about 110 °C or lower; or about 105 °C or lower; or about 100 °C or lower; or about 95 °C or lower; or about 90 °C or lower; or about 85 °C or lower; or about 80 °C or lower.

6. The composition according to any of claims 1 to 5, wherein the drug is selected from racemic ibuprofen, dexibuprofen, ketoprofen and racecadotril.

7. The composition according to any of claims 1 to 6, wherein the powder or granule particles further comprise a pharmaceutically accepted excipient selected from colourants, antioxidants, flavourants, or sweeteners.

8. The composition according to any of claims 1 to 7 comprising 1 to 35 wt.-% drug and 50 to 99 wt.-% polymeric carrier.

9. The composition according to any of claims 1 to 8 comprising 7 to 10 wt.-%

racecadotril;

70 to 80 wt.-% pregelatinised starch; and

10 to 23 wt.-% of a pharmaceutically accepted excipient selected from colourants, antioxidants, flavourants or sweeteners.

10. The composition according to any of claims 1 to 9, wherein the composition

exhibits immediate release of the drug.

11. The composition according to any of claims 1 to 10, wherein the composition is substantially free of polymers, or polymeric carriers, which exhibit a melting or decomposition temperature T2 which is lower than the melting point Ti of the drug.

12. A process for the preparation of a taste-masked pharmaceutical composition in the form of a dry, flowable powder or granules for dispersion in water or an aqueous medium, preferably a taste-masked pharmaceutical composition according to any of claims 1 to 11, the process comprising the steps of:

a. providing at least

a2) a water-dispersible, at least partially hydrophilic polymeric carrier in the form of powders or granules, the carrier exhibiting a melting or

decomposition temperature T₂, and optionally a porous structure and optionally

a3) a further pharmaceutically accepted excipient;

b. mixing all components provided according to step a) and melting the drug at a product temperature T3 above temperature Ti and below temperature T₂ (Ti < T3 < T₂), until the molten drug is sorbed at least partially by the polymeric carrier; and

c. allowing the mixture to cool down to ambient temperature and the at least partially sorbed molten drug to solidify with the polymeric carrier.

13. The process according to claim 12, wherein the pharmaceutically accepted

excipient of a3) is selected from colourants, antioxidants, flavourants, or sweeteners.

14. The process according to claims 12 to 13, wherein optionally water is removed from the polymeric carrier in a drying step prior to step (a), and/or during step (b); optionally involving vacuum conditions in this drying step.

15. The process according to claims 12 to 14, wherein the process is performed in a device equipped with

i. means for mixing any components provided in the product vessel ii. means for heating the product vessel, such as water- or oil filled heating jackets, electric or infrared heating devices;

and optionally

iii. means for evacuating the product vessel to provide vacuum conditions; optionally in a vacuum granulator, such as a TOPO granulation system.

16. The process according to any of claims 12 to 15, wherein the product

temperature T3 while performing step (b) is kept at least 10 °C below the melting or decomposition temperature T₂, preferably at least 15 °C below T₂; and optionally between 50 °C and 130 °C, or between 70 °C and 125 °C, or between 80 °C and 110 °C.

17. A pharmaceutical dosage form provided as a dry, flowable powder or granules for dispersion in water or an aqueous medium comprising the taste-masked pharmaceutical composition of any of claims 1 to 11 and in admixture thereto at least one pharmaceutically accepted excipient selected from sugars, sugar alcohols, sweeteners, flavourants, or colourants;

the pharmaceutical dosage form optionally being provided in the form of stick packs, sachets, ampoules or vials.

18. The pharmaceutical dosage form according to claim 17, wherein the dosage form comprises 0.2 to 3 wt.-% racecadotril, 70 to 90 wt.-% sucrose, 8 to 20 wt.-% pregelatinised starch, 0.2 to 2 wt.-% sweetener, 0.4 to 4 wt.-% flavourants and

1 to 5 wt.-% colourants.

19. A taste-masked aqueous dispersion for oral administration of a poorly water- soluble drug exhibiting a poor taste and a melting point Ti, comprising the taste masked pharmaceutical composition according to any of claims 1 to 11 or the pharmaceutical dosage form according to any of claims 17 to 18 dispersed in water or an aqueous medium.

20. A taste-masked pharmaceutical composition for dispersion in water or an

aqueous medium, the composition being provided in the form of a dry, flowable powder or granules obtainable by a process according to any of claims 12 to 16.