Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
  • A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids

Definitions

• the present invention relates to the field of pharmaceutics, and concerns taste- masked oral drug formulations, their manufacture and their use.
• 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.
• 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.
• 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 ⁇ , 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
• API in a dispersible dosage form is poorly wettable upon adding water, or other aqueous ingestible liquids, to the dry
• 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
• 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.
• 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.
• 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.
• 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 is their need for special equipment and their negative impact on the environment.
• 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.
• thermal processing methods such as hot- melt coating, spray congealing, and the like.
• 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.
• 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.
• lipids may alter during storage due to e.g. polymorphism, which could further affect the drug release.
• the invention provides, a taste-masked
• compositions 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 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;
• the drug is at least partially sorbed by the polymeric carrier particles in the form of a solidified melt.
• 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:
• step a) mixing all components provided according to step a) and melting the drug at a product temperature T3 above temperature Ti and below temperature T2
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• aqueous dispersions for oral administration are also referred to as drink suspensions.
• Drugs are often also referred to as pharmaceutically active compound or active pharmaceutical ingredient (API) or active principle.
• 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.
• 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.
• 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.
• 'swelling 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 particle size values provided herein 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.
• 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.
• 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.
• 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.
• release profiles in which more than 75 % of the drug is released in 45 min would thus also be considered immediate release.
• 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:
• 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;
• 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.
• the water-dispersible, at least partially hydrophilic polymeric carrier is 'in the form of powders or granules' as of point (b)
• 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.
• 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.
• the polymeric carrier particles 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
• the melting or decomposition temperature T2 of the polymeric carrier must be higher than the melting point Ti of the poorly water- soluble drug.
• 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.
• taste-masked pharmaceutical composition of the present invention obviates the need for additional, dedicated taste-masking coatings and/or delayed release coatings on the dry, flowable powder or granules.
• 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 T 2 ' should be understood as referring both to polymeric carriers that melt at a temperature T 2 (or thermoplastically deform at T 2 ; and then typically decompose at a temperature higher than T 2 ), and to polymeric carriers that do not melt, or thermoplastically deform, but instead will decompose at a temperature T 2 .
• the melting point is considered to be T 2 ; whereas for polymeric carriers that do not melt or thermoplastically deform and instead only decompose, the decomposition temperature is considered to be T 2 .
• 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).
• 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.
• 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.-%.
• 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).
• 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.
• 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
• the taste- masking may involve one or both of the following two mechanisms:
• 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:
• 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;
• the drug is at least partially sorbed by the polymeric carrier particles in the form of a solidified melt.
• 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.
• 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:
• the powder or granule particles forming the taste-masked pharmaceutical composition consist of:
• a poorly water-soluble drug exhibiting a poor taste and a melting point Ti
• at least one pharmaceutically accepted excipient selected from colourants, antioxidants, flavourants, or sweeteners
• the drug is at least partially sorbed by the polymeric carrier particles in the form of a solidified melt.
• 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:
• the drug is at least partially sorbed by the polymeric carrier particles in the form of a solidified melt.
• the powder or granule particles forming the taste-masked pharmaceutical composition essentially consist of:
• the drug is at least partially sorbed by the polymeric carrier particles in the form of a solidified melt.
• 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 T 2 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.
• T 2 melting or decomposition temperature
• 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.
• the taste-masked pharmaceutical composition in some preferred embodiments is also substantially free of lipids or waxes that melt or
• 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.
• 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.
• 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 ⁇ ⁇ 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).
• the dry, flowable powder or granules of the taste-masked pharmaceutical composition exhibit a mean particle size in the range of from about 30 ⁇ to about 250 ⁇ ; or from about 35 ⁇ to about 220 ⁇ ; or from about 40 ⁇ to about 190 ⁇ ; or from about 45 ⁇ to about 160 ⁇ ; for instance, in the range of 100 ⁇ 50 ⁇ .
• 10 vol.-% of the dry, flowable powder or granules of the taste-masked pharmaceutical composition exhibit a sieve diameter of 500 ⁇ or more; or 400 ⁇ or more; or 350 ⁇ ⁇ or more; or 300 ⁇ or more; or 250 ⁇ or more; or 200 ⁇ or more.
• the D90 value of the dry, flowable powder or granules of the taste-masked pharmaceutical composition does not exceed 500 ⁇ , or 400 ⁇ , or 350 ⁇ , or 300 ⁇ , or 250 ⁇ , or 200 ⁇ , respectively.
• not more than 10 vol.-% of the dry, flowable powder or granules of the taste- masked pharmaceutical composition exhibit a sieve diameter of 15 ⁇ or less; or 20 ⁇ ⁇ or less; or 25 ⁇ or less; or 30 ⁇ or less; or 35 ⁇ or less; or 40 ⁇ or less.
• the D10 value of the dry, flowable powder or granules of the taste- masked pharmaceutical composition does not fall below 15 ⁇ , or 20 ⁇ , or 25 ⁇ , or 30 ⁇ , or 35 ⁇ or 40 ⁇ , respectively.
• 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.
• 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.
• 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 ⁇ to about 180 ⁇ ⁇ ; or from about 90 ⁇ to about 170 ⁇ ; or from about 100 ⁇ to about 160 ⁇ ⁇ ; for instance, in the range of 125 ⁇ 15 ⁇ .
• the water-dispersible, at least partially hydrophilic polymeric carrier in the taste-masked pharmaceutical composition is C PolarTex ®
• the dry, flowable powder or granules of the taste-masked pharmaceutical composition exhibit a mean particle size in the range of from about 60 ⁇ to about 160 ⁇ ; or from about 70 ⁇ to about 150 ⁇ ; or from about 80 ⁇ to about 140 ⁇ ; or from about 90 ⁇ to about 130 ⁇ ⁇ ; for instance, in the range of 110 ⁇ 15 ⁇ .
• 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 ⁇ to about 100 ⁇ ; or from about 35 ⁇ to about 85 ⁇ ; or from about 40 ⁇ to about 70 ⁇ ; or from about 45 ⁇ to about 65 ⁇ ⁇ ; for instance, in the range of 50 ⁇ 15 ⁇ .
• L-HPC low substituted hydroxypropyl cellulose
• the dry, flowable powder or granules of the taste-masked pharmaceutical composition exhibit a mean particle size in the range of from about 30 ⁇ ⁇ to about 160 ⁇ (e.g. 115 ⁇ 30 ⁇ ). In a specific embodiment, not more than 10 % of these dry, flowable powder or granules exhibit a sieve diameter of 350 ⁇ 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 ⁇ or more; and not more than 10 vol.-% of these dry, flowable powder or granules exhibit a sieve diameter of 20 ⁇ or less.
• 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 ⁇ to about 160 ⁇ ⁇ (e.g. 125 ⁇ 15 ⁇ ). In a specific embodiment, not more than 10 vol.-% of these dry, flowable powder or granules exhibit a sieve diameter of 350 ⁇ or more.
• not more than 10 vol.-% of these dry, flowable powder or granules exhibit a sieve diameter of 350 ⁇ or more; and not more than 10 vol.-% of these dry, flowable powder or granules exhibit a sieve diameter of 30 ⁇ or less.
• the taste-masked pharmaceutical composition exhibits immediate release of the drug.
• the taste-masked pharmaceutical composition exhibits immediate release of the drug and does not comprise a coating.
• 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.
• 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).
• this 'steric shield' wears down and the water or aqueous media will dissolve the drug melt.
• 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.
• certain water-soluble polymers e.g. with dissolution times of more than 15 minutes
• 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).
• the water-dispersible, at least partially hydrophilic polymeric carrier is a polysaccharide.
• 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).
• 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).
• 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).
• the water-dispersible, at least partially hydrophilic polymeric carrier in the taste-masked pharmaceutical composition is Lycatab ® PGS.
• the water-dispersible, at least partially hydrophilic polymeric carrier is low substituted hydroxypropyl cellulose, such as the L-HPC LH-21 grade of ShinEtsu.
• the water-dispersible, at least partially hydrophilic polymeric carrier is a modified starch, or more specifically a hydroxypropylated starch such as C PolarTex ® .
• the compositions have been employed successfully to taste-mask a variety of poorly soluble drugs, such as ibuprofen, dexibuprofen, ketoprofen and racecadotril.
• 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.
• the invention works over a broad range of poorly soluble drugs and water-dispersible, at least partially hydrophilic polymeric carriers.
• '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
• 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.
• 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.
• 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.
• 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.
• 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.
• 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),
• the drug is selected from racemic ibuprofen, dexibuprofen, ketoprofen and racecadotril. In a more specific embodiment, the drug is racecadotril.
• the composition comprises the drug racecadotril, and pregelatinised starch as the polymeric carrier, for instance Lycatab ® PGS.
• 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.
• 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.
• the composition essentially consists of the drug
• 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.
• 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.
• a non-steroidal antiinflammatory drug such as ketoprofen, ibuprofen, or dexibuprofen
• pregelatinised starch as the polymeric carrier, for instance Lycatab ® PGS.
• 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
• 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 ⁇ ); 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.
• 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.
• 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.
• 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
• 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 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
• the taste-masked pharmaceutical composition essentially consists of 10 wt.-% racecadotril and 90 wt.-% pregelatinised starch (for instance Lycatab ® PGS).
• 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).
• 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).
• 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
• NSAID nonsteroidal anti-inflammatory drug
• 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)
• NSAID
• hydroxypropylated starch for instance 27 wt.-% NSAID and 73 wt.-% polymeric carrier.
• 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
• the pharmaceutical composition essentially consists of 27 wt.-% NSAID and 73 wt.-% low- substituted hydroxypropyl cellulose L-HPC (for instance L-HPC LH-21).
• 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).
• 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.
• 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
• 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.
• 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.
• 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
• the composition comprises 8 to 9 wt.-% racecadotril,
• pregelatinised starch for instance Lycatab ® PGS
• low-substituted hydroxypropyl cellulose L-HPC for instance L-HPC LH-21
• modified starch for instance C PolarTex ® , a highly stable hydroxypropylated starch
• 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.
• the composition comprises 10-25 wt.-% of a nonsteroidal anti-inflammatory drug (NSAID), such as ketoprofen, ibuprofen, or dexibuprofen,
• NSAID nonsteroidal anti-inflammatory drug
• pregelatinised starch for instance Lycatab ® PGS
• low-substituted hydroxypropyl cellulose L-HPC for instance L-HPC LH-21
• modified starch for instance C PolarTex ® , a highly stable texturizing hydroxypropylated starch
• a pharmaceutically accepted excipient selected from colourants, antioxidants, flavourants or sweeteners.
• 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.
• 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.
• 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
• step a) mixing all components provided according to step a) and melting the drug at a product temperature T3 above temperature Ti and below temperature T 2
• 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 T 2 of the polymeric carrier must be higher than the melting point Ti of the poorly water-soluble drug.
• the polymeric carrier particles shall preferably remain solid, or rigid, or glassy, and not, for instance, undergo thermoplastic deformation during or after the process.
• 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.
• water is removed from the polymeric carrier in a drying step prior to step (a), and/or during step (b).
• 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.-%).
• 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
• 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.
• the optional drying step involves vacuum conditions.
• 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.
• 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.
• 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.
• 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.
• the process is performed in a device equipped with
• the process may be performed in a vacuum granulator.
• the granulator is a TOPO granulation system (Hermes Pharma, Germany).
• 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:
• step a) mixing and drying all components provided according to step a) in a vacuum granulator, and melting the drug at a product temperature T 3 above temperature Ti and below temperature T 2 (Ti ⁇ T3 ⁇ T 2 ), 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.
• the pharmaceutically accepted excipient of a3) is selected from colourants, antioxidants, flavourants, or sweeteners; for instance, from colourants.
• the product temperature T3 while performing step (b) of the process is kept at least 10 °C below the melting or decomposition temperature T 2 , preferably at least 15 °C below T 2 , 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.
• the decision of the product temperature will mainly be guided by the melting temperature of the drug to be incorporated.
• 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.
• 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.
• 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.
• 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.
• this product temperature requires oil-heating rather than water-heating in order to provide sufficient temperatures.
• the drug is dexibuprofen
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• the dosage form comprises sucrose as the sugar
• the dosage form comprises 0.2 to 10 wt.-% drug,
• 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.
• 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 0.3 wt.-% sucralose
• 0.8 wt.-% raspberry aroma 0.8 wt.-% raspberry aroma
• 3.2 wt.-% colourants selected from beet root powder, riboflavin sodium and cochenille (E120).
• 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
• 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.
• aqueous dispersions for oral administration are also referred to as drink suspensions.
• 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.
• the poorly tasting drug e.g. ibuprofen, ketoprofen, racecadotril
• 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.
• 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.
• 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.
• 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.
• MCC microcrystalline cellulose
• 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.
• 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
• 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.
• 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
• Example 5 Taste masked pharmaceutical compositions of further drugs
• 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.
• VT 6060 P Heraeus
• Example 6 Particle size distributions of taste masked pharmaceutical compositions

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