MX2007004260A - Taste-masking pharmaceutical compositions - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for oral administration suitable for the preparation of a ready-to-use suspension comprising coated particles comprising an active substance having an unpleasant and/or bitter taste, such as clarithromycin, and a suspension base comprising an osmotically active substance capable of providing a high osmolality to the admixture of the suspension base with an aqueous suspending medium in the ready-to-use suspension. Said ready-to-use suspension maintains its palatability over a prolonged period of time by those defined osmotic conditions.

Description

PHARMACEUTICAL COMPOSITIONS WITH FLAVOR MASKING FIELD OF THE INVENTION The present invention relates to a pharmaceutical composition for oral administration, comprising an active substance, which has an unpleasant and / or bitter taste when administered orally. More particularly, the present invention relates to a pharmaceutical composition comprising flavored masking coated particles comprising a macrolide antibiotic, preferably clarithromycin, which is in the form of a suspension that maintains its good taste for a prolonged period of time. time through defined osmotic conditions. In addition, the present invention relates to a process for preparing said composition.

BACKGROUND OF THE INVENTION Oral administration of pharmaceutically active substances in conventional solid forms, such as tablets or capsules, is usually problematic in groups of special patients who have difficulty swallowing such whole solid corms, for example, children and elderly patients. For these patients, the appropriate dosage forms for drugs they can be, for example, liquid forms, for example, solutions, suspensions, syrups or emulsions, or alternative solid forms such as chewable tablets, effervescent tablets or soluble tablets. These dosage forms usually do not prevent a noticeable degree of exposure of the active substance to flavors, which is a great problem when the active substance has an unpleasant and / or bitter taste. In such cases, the active substance has to be masked in the flavor, so that the dosage form becomes good taste, thus reducing the risk that patients refuse to take the medication. It is a great challenge to mask the taste of extremely bitter active substances, such as macrolides, for example, erythromycin or clarithromycin, especially when they are included in suspensions. Conventional techniques for masking flavor, such as the addition of sweeteners, such as sugar, artificial sweeteners, fruit flavors, thickeners and amino acids, usually fail to provide an acceptable taste to the pharmaceutical composition. It is very likely that the portion of the active substance in such dosage forms, which is dissolved in the saliva and / or in the liquid for administration, will generate the unpleasant taste. To overcome this problem, it is common to influence the solubility of said active substance in such a way that only a small portion of said substance, or even none at all, will dissolve in a suspension, or in the mouth. This is usually obtained by imbibing the bitter-tasting active substance in a special imbibition material or covering said drugs. However, these techniques present their limitations and usually prove effective only for moderately bitter drugs. The imbibition and / or coating techniques can also adversely impact the desired release of the active substance into the digestive tract to achieve good bioavailability. To ensure sufficient bioavailability of the active substance, covers, for example, lipid and / or wax coatings which retard the dissolution of the active substance for a short period of time, or slightly retard polymer films or the like can be used. However, these coatings can only provide a satisfactory taste masking if said suspensions are administered just after reconstitution, ie, after dispersion in an aqueous medium. Patent application WO 93/12771 discloses another technique for masking flavor by coating core particles comprising, for example, clarithromycin, with a polymeric shell layer comprising a fraction of prolamin derived from grain proteins, preferably zein, and plasticizers preferably being fatty acids, wherein said cover layer is relatively thick. Another technique is described in International Application WO 00/76479 A1, wherein the bitter taste active substance is embedded in a taste masking matrix composed of a combination of two enteric polymers, ie, a copolymer of methacrylic acid and a phthalate polymer, which is optionally covered. Most taste masking techniques fail to provide a satisfactory taste masking in a suspension that is required to maintain its pleasant taste for an extended period of time, for example, for at least 1 to 2 weeks as a reconstituted suspension. . This means that the pH value in the suspension is adjusted to a value at which the film-forming component, for example, the film-forming polymer, comprised in the film cover, is not soluble. The pH value changes after administration, and depending on the cover material used, the active substance will be released either into the stomach, in case the shell is soluble in acid, or into the intestines, for example, the small intestine, in the case of enteric coatings of soluble or gastro-resistant base. International application WO 91/16043 describes the application of a polymeric coating that is soluble only at a pH of 5 or more to a core particle, and the addition of an acidic compound to the formulation to reduce or prevent the dissolution of the membrane of cover in the oral cavity. However, the proportion of said film covers is critical: film covers, which are too strong and / or thick, can slow the release rate of the film. drug in the gastrointestinal tract to a degree that could be unacceptable for conventional immediate release formulations. Another problem is that the aforementioned film covers, for example, polymer covers, are never completely "leak proof", which means that even with intact film covers, a portion of the active substance is always released from the film. the particles covered through diffusion to the suspension, which is called "spill" here. This can lead to the sensation of a bitter taste after ingestion.

Generally, the pH value of the liquid component of the pharmaceutical compositions, such as suspensions, is adjusted to a value that will ensure that the cover will not dissolve and / or burn. However, if the active substance with masked taste has a good solubility at this pH scale, it will, in turn, increase the diffusion of the active substance with unpleasant taste and, in this way, cause a spill towards the suspension and / or in the mouth after oral administration. In addition, conventional techniques for preparing a good-tasting liquid dosage form, comprising a drug of unpleasant and / or bitter taste, may involve very expensive and complicated preparation methods. Accordingly, it is an object of the present invention to provide a liquid dosage form, particularly a suspension, comprising covered particles containing a pharmaceutically active substance of unpleasant and / or bitter taste, which is of good taste and which maintains its good flavor even for a prolonged period of time after being reconstituted, for example, through the addition of water. In addition, said suspension must exhibit satisfactory bioavailability, i.e., rapid release of the active substance in the gastro-intestinal tract after oral administration.

BRIEF DECSRIPTION OF THE INVENTION The inventors hereby surprisingly have found that the flavor of the suspension can be considerably improved by adjusting the osmolarity within the reconstituted suspension, more specifically, of the mixture of the suspension base mixed with an aqueous suspension medium, at a high level of not less than about 2000 mosmol per kg of suspension medium, for example, per liter of water, and maintaining the osmolarity within the specified scale. This can be achieved by adding the "osmotically active" substances described herein to the suspension base. The high osmolarity thus obtained when said suspension base is mixed with an aqueous suspension medium presumably reduces the spillage of the active substance from the coated particles suspended in the suspension ready for use after reconstitution, for example, with water.

Thus, in one aspect, the invention provides a pharmaceutical composition for oral administration suitable for the preparation of a suspension ready for use comprising: a) coated particles comprising at least one pharmaceutically active substance having an unpleasant taste and / or bitter and optionally at least one excipient, and b) a suspension base comprising at least one osmotically active substance, which is capable of providing a high osmolarity to the mixture of said suspension base with an aqueous suspension medium in the suspension ready for use, and c) optionally at least one pharmaceutically acceptable excipient, wherein said high osmolarity is not less than 2000 mosmol per kg of suspension medium. Preferably, the coated particles have masked taste. Preferably, the aqueous suspension medium is water. Preferably, the osmolarity of the mixture of the suspension base with an aqueous suspension medium is not less than 2500 mosmol per kg of the suspension medium, for example, per liter of water. Preferably, the osmolarity of the mixture of the suspension base with an aqueous suspension medium is from about 2500 to about 3500 mosmol per kg of suspension medium, for example, per liter of water. Preferably, the osmotically active substance is selects from the group consisting of sucrose, erythritol, xylitol, sorbitol, maltodextrin, cyclodextrin, potassium phosphate, sodium phosphate, sodium sulfate and sodium chloride, and mixtures thereof. Most preferably, the "osmotically active" substance is sucrose. Preferably, said covered particles comprise a functional cover, more particularly, a functional cover that is semi-permeable. Preferably, the shell is an enteric shell, that is, a gastro-resistant shell. The active substances comprised in the coated particles are preferably macrolide antibiotics, such as erythromycin and its derivatives, clarithromycin, azithromycin or roxithromycin, most preferably clarithromycin. The invention further provides a pharmaceutical composition for oral administration in the form of a suspension ready for use, as described above, which is preferably essentially free of acidic or basic additives. In yet another aspect, the invention provides a method for preparing a pharmaceutical composition for oral administration, suitable for the preparation of a suspension ready for use, which comprises the steps of: a) mixing coated particles comprising at least one pharmaceutically active having an unpleasant and / or bitter taste and optionally at least one excipient, with a suspension base comprising at least one osmotically active substance selected from the group consists of sucrose, sorbitol, xylitol, erythritol ', maltodextrin, cyclodextrin, potassium phosphate, sodium phosphate, sodium sulfate and sodium chloride, and mixtures thereof, and optionally at least one pharmaceutically acceptable excipient, to obtain a mixture of dry suspension, wherein the amount of osmotically active substance is sufficient to provide a high osmolarity to the mixture of said suspension base with an aqueous suspension medium in the suspension ready for use, and b) optionally filling a container with the suspension mixture obtained in step a). In another aspect, the present invention provides a method for preparing a suspension ready for use, comprising the steps of: a) mixing coated particles comprising at least one pharmaceutically active substance having an unpleasant and / or bitter taste and optionally so minus one excipient, with a suspension base comprising at least one osmotically active substance selected from the group consisting of sucrose, sorbitol, xylitol, erythritol, maltodextrin, cyclodextrin, potassium phosphate, sodium phosphate, sodium sulfate and sodium chloride. sodium, and mixtures thereof, and optionally at least one pharmaceutically acceptable excipient, to obtain a dry suspension mixture, wherein the amount of osmotically active substance is sufficient to provide a high osmolality to the mixture of said suspension base with a medium of suspension water in the suspension ready for use, and b) adding water to the dry suspension mixture obtained in step a) to form a suspension ready for use, and c) optionally filling a container with the suspension ready for use. The ready-to-use suspension of the invention is of pleasant taste for at least 1 week, preferably at least 2 weeks. In addition, the pharmaceutical compositions of the invention, for example, the suspension ready for use, show a rapid and quantitatively sufficient release of the active substance under ambient conditions such as those found in the gastrointestinal tract, which means good bioavailability. A further advantage of the pharmaceutical compositions of the invention is the omission of acidic components, which offer a greater freedom of aromatization selection, which means that many flavors, otherwise incompatible with an acidic flavor, can be used, for example , for the suspensions of the invention. In addition, there is also no need for the addition of basic (ie alkaline) additives to the suspension base and / or the dry suspension mixture in cases where film covers are used, which are soluble in an acid medium, in the covered particles, said basic additives making the aromatization more difficult.

Finally, the suspension of the invention can be prepared through a simple production method, thus avoiding very expensive and complicated preparation methods for masking the taste of the prior art compositions.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the effect of high osmolarity within a suspension ready for use, as compared to the effect of the pH value only on the clarithromycin spill from the particles covered within the suspension for use. Figure 2 shows the effect of the presence of different osmotically active substances in the clarithromycin effusion within a suspension.

DETAILED DESCRIPTION OF THE INVENTION "Suspension", as used herein, means, unless otherwise indicated, a liquid formulation for oral administration, which comprises coated, eg, masked flavor particles, comprising at least one pharmaceutically active substance, and at least one pharmaceutically acceptable excipient, and which is prepared by dissolving or suspending a dry slurry mixture as described herein, for example, in the form of a dry powder, in a vehicle aqueous, referred to herein as the "suspension medium", before being used for oral administration. Preferably, the suspension medium is water. The term "suspension base", as used herein, means a dry mixture of components comprising, for example, at least one osmotically active substance and optionally at least one pharmaceutically acceptable excipient, which itself can be mixed with , for example masked flavored coated particles, comprising an active ingredient of unpleasant and / or bitter taste, to form a "dry slurry mixture". Said "dry suspension mixture" can subsequently be dissolved or suspended in a suspension medium. The term "suspension medium", as used herein, means the medium that is added to a dry suspension mixture to obtain the suspension ready for use, which subsequently can be administered to the patient. Preferably, the suspension medium is aqueous, preferably water. The term "reconstituted suspension", as used herein, is understood to be synonymous with the "ready-to-use" suspension. The terms "functional cover" and "functional film cover", as used herein, are understood to include covers that are soluble at a defined pH value, i.e., that are soluble in an environment having an acid pH value , or neutral, or basic. Said functional covers comprise enteric covers or gastro-resistant covers, and in addition they may have properties of taste masking. Said functional covers may be semi-permeable, wherein the term "semi-permeable", as used herein, is understood to be selectively permeable, ie, allows certain molecules to pass through the shell through diffusion. The term "particles", as used herein, refers to free-flowing substances of any form, which are larger than a powder, such as crystals, beads (smooth, round or spherical particles), pellets, spheres and granules . The term "masked taste", as used herein, refers to any substance or particle, or oral pharmaceutical composition comprising a pharmaceutically active substance of unpleasant taste, which has been treated to make it taste good and / or does not release substantially the pharmaceutically active substance in the mouth, but rather, for example, in the stomach or intestinal tract. "An unpleasant and / or bitter taste", as used herein, means that a majority of human patients judge that said pharmaceutical composition or active substance comprised therein, has an unpleasant and / or bitter, and / or extremely bitter flavor, after of ingestion. The coated particles, which are comprised in the suspension of the invention can be prepared according to known methods, for example, through conventional granulation techniques or roller extrusion and compaction techniques, applying, for example, a high shear mixer, a compulsive mixer, for example, of the Diosna Mollet Gral type, a roller compactor, for example of the Alexander Hutt type, or an extruder, for example, of the Werner &; Pfleiderer or Theyson, and subsequently it can be covered. Alternatively, said particles can be obtained by applying imbibition techniques such as roll compaction or melt extrusion. Said particles comprise at least one pharmaceutically active substance, which has an unpleasant taste and / or a bitter taste. Such active substances include, but are not limited to, antibiotics such as macrolides, e.g., erythromycin, clarithromycin, roxithromycin or azithromycin, fluoroquinolones such as ciprofloxacin or norfloxacin, cephalosporins, e.g., cefuroxime, ceftriaxone, or tetracyclic antibiotics such as chloramphenicol. or chlorpromazine, or other antibacterial agents such as penicillin or ampicillin, analgesics, antihistamines, decongestants, anti-inflammatory drugs, hypnotics, sedatives, tranquilizers, vitamins, enzymes, nutritional supplements, hormones, and the like, including their pharmaceutically acceptable salts and esters. Those with an extremely bitter taste, such as macrolide antibiotics, especially erythromycin and clarithromycin, are particularly suitable for the present invention. Therefore, said active substance is preferably a macrolide antibiotic, such as erythromycin or one of its derivatives. Most preferably, the active substance is clarithromycin Said particles optionally further comprise at least one pharmaceutically acceptable excipient. The term "excipient" as used herein, refers to any substance that can be combined with an active ingredient to prepare convenient dosage forms, including, for example, wetting agents, diluents, binders, lubricants, disintegrating agents, colorants, flavors and sweeteners, and others as is known in the art. Examples of wetting agents are, for example, polyoxyethylene-polyoxypropylene block polymers, such as Poloxamer. Suitable binders for use in the formulation of the invention include, but are not limited to, synthetic gums, such as hydroxypropylmethylcellulose, polyvinylpyrrolidone (povidone), carboxymethylcellulose, ethylcellulose and methylcellulose, starch., pre-gelatinized starch, pre-gelatinized starch, gelatin, sugars (e.g., melasas) and natural gums (e.g., acacia gum, sodium alginate, panwar gum). Preferably, povidone (especially, Povidone USP) is used as the binder. The particles mentioned herein can be covered with coatings or covers, preferably functional covers, for example, functional film covers, which can be soluble in an environment of acid pH value, or neutral or basic. Preferably said covers, for example, film covers, they will begin to dissolve at a pH value of more than about 4.5, for example, said covers are enteric or gastro-resistant coats. Alternatively, said covers, for example, film covers, can be of an independent pH. The covered operation can be performed by applying a cover mixture to the particles through conventional methods, for example, by spraying said cover mixture over the particles. The cover, and optional drying, is preferably carried out in a fluid bed coater, for example, of the Glatt Wurster or Huttlin Coater type. The cover mixture may comprise a shell component dissolved, dispersed or suspended in water or in an organic solvent, and optionally at least one excipient. Preferably, the shell component is a functional film-forming component, preferably an enteric film-forming component selected from the group comprising phthalates, such as cellulose phthalates, for example, chemically modified cellulose phthalates, such as hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, or acetate-succinate dehydropropylmethylcellulose, or poly (meth) acrylates, for example, methacrylic polymers and copolymers, such as these commercially available under the tradename Eudragit®, manufactured and sold by Rohm GmbH & Co KG, Darmstadt, Germany. Examples of said methacrylic acid copolymers are described in USP / NF as "Methacrylic Acid Copolymer, Type A), such as that commercially available under the trade name of Eudragit®, L30 D55 (previously also named as Eudragit® L30 D), which is a copolymer of methacrylic acid and sodium acetate. ethyl at a ratio of 1: 1. The functional film shell can be soluble at an acidic pH value, i.e. it can comprise a soluble film forming component at an acid pH value, for example, polymers such as these commercially available under the trade name of Eudragit® E and Eudragit® EPO Optionally, the cover mixture may further comprise at least one excipient, for example, a plasticizer, for example, triethyl citrate In a specific embodiment of the invention, Coated particles are prepared according to the following method: The particles were produced by agglomeration by spraying clarithromycin and poloxamer, for example, in accordance n the method described under the chapter "Fluidized Bed Granules", in the Encyclopedia of Pharmaceutical Technology, Volume 7, Eds., James Swarbrick, James C. Boylan, 1993, pages 136 to 140. The average particle size for the cover it may vary between 200 and 400 p.m., for example, between 250 and 350 p.m., for example, between 280 and 320 p.m., for example, between 290 and 310 p.m., for example, it may be approximately 300 p.m. Alternatively, the average particle size for the cover it can be up to about 500 p.m., for example, it may vary between 200 and 500 p.m. The cover can be applied according to conventional methods, for example, in a fluid bed system, from an aqueous dispersion. In Table 1, below, a typical composition of covered particles is described: TABLE 1 The preparation of said particles and their use for the preparation of the suspension of the invention are described in the following Examples. The coated particles used in the compositions of the present invention may comprise the active substance in pharmaceutically acceptable amounts, wherein said pharmaceutically effective amounts will depend on the active substance used. The term "pharmaceutically effective", as used herein, is understood to include doses of said active substance that provides a desired pharmacological effect.

Preferably, said covered particles comprise a macrolide, most preferably, clarithromycin in an amount of from about 5% to about 60% w / w, such as from about 10% to about 50% w / w, for example, about 15% to 45% w / w, such as about 20 % to approximately 40% w / w in relation to the particle covered. The suspension of the invention can be prepared as follows: the coated particles are mixed with a suspension base comprising at least one osmotically active substance and optionally at least one pharmaceutically acceptable excipient, to form a dry mixture, i.e. the mixture of dry suspension. The term "osmotically active substance", as used herein, is understood to mean a substance that dissociates in solution, for example, when mixed with an aqueous suspension medium, for example, with water, to form osmotically active particles. The osmotically active substances used for the invention are pharmaceutically acceptable. Preferably, said osmotically active substance is characterized by being able to reduce the diffusion of the molecules of the active substance from the coated particles, having a high solubility, for example, in water, and being physiologically, pharmacologically and orally acceptable. Preferably, said osmotically active substance may comprise, for example, a polysaccharide, for example, maltodextrin, or for example, a cyclic polysaccharide, for example, a cyclodextrin such as, for example, β-cyclodextrin, an oligosaccharide, a disaccharide, eg, sucrose, a monosaccharide, by > example, fructose or glucose, a carbohydrate-related compound such as tetritol, e.g., erythritol, a pentahydric alcohol, e.g., xylitol, or a hexahydric alcohol, e.g., sorbitol, or an inorganic salt such as potassium phosphate, phosphate of sodium, sodium sulfate or sodium chloride, or mixtures thereof. Most preferably, the osmotically active substance is sucrose. Preferably, said osmotically active substances are present in an amount of from about 6% to 100% w / w, for example, from 20% to 90% w / w, for example from 40% to 80% w / w, for example from 50% to 60% p / p, in relation to the suspension medium. Preferably, showers osmotically active substances are present in an amount of about 85% to about 95% w / w, most preferably about 89% w / w relative to the suspending medium. Preferably, said osmotically active substances may be present in amounts of from about 3% to about 90%, for example from about 15% to about 80%, such as from about 20% to about 70%, for example from about 30% to about 60%, such as from about 40% to about 50% w / w relative to the suspension mixture dry Most preferably, the osmotically active substances are present in amounts of about 70% to about 80% w / w in the case of carbohydrates, and from about 3% to about 30% in the case of inorganic salts. Optionally, the resuspension base and / or the dry suspension mixture can further comprise at least one pharmaceutically acceptable excipient such as: sugars, for example, chemically modified, for example, including fructose, glucose, sugar alcohols, sweeteners, for example , nutritious and artificial, for example, sodium saccharin, including aspartame, flow promoters, for example, including, silicon dioxides, eg, colloidal, such as aerosils®, - binders, eg, polyvinylpyrrolidones, celluloses, flavoring agents , such as organic acids, for example, citric acid, NaCl, natural and artificial flavors, preservatives, such as potassium sorbate, sodium benzoate, pigments (dyes) such as Ti02, and fillers, surfactants, pH regulating substances , or other pharmaceutically acceptable excipients. The dry suspension mixture, for example, in the form of a powder, can then optionally be placed as a filler in bottles or containers. The dry suspension mixture can be suspended or dissolved in a suspension medium. Preferably, the suspension medium is aqueous, most preferably, water. The resulting reconstituted suspension, i.e., the suspension ready for use, can optionally be placed as a filler in containers, for example, bottles. The amount of active substance, incorporated in the coated particles present in the ready-to-use suspension can be from about 1% to about 20% w / w, for example, from about 2% to about 15% w / w, such as from about 3% to about 10% w / w, for example about 4% to 8% w / w in relation to the suspension ready for use. The ready-to-use suspension, more particularly, the mixture of the suspension base with the aqueous suspension medium, for example, with water, shows a high osmolarity of not less than about 2000 mosmol per kg of suspension medium, preferably per liter of water. The "high osmolarity", as used herein, is understood to mean an osmolarity of more than 2000 mosmol per kg of suspension medium, for example per liter of water. Preferably, the osmolarity of said mixture of the suspension base with the aqueous suspension medium is not less than 2200 mosmol, eg, more than about 2300 mosmol, eg, more than about 2400 mosmol per kg of suspension medium, example, per liter of water. Very preferably The osmolarity is more than 2500 mosmol per kg of suspension medium, for example, per liter of water. Preferably, the osmolarity of said mixture of the suspension base with the aqueous suspension medium is from about 2000 to about 4000 mosmol, such as from about 2200 to about 3800 mosmol, most preferably, from about 2500 to about 3500 mosmol per kilogram of the suspension medium, for example, per liter of water. Alternatively, the osmolarity can be up to 4500 mosmol per kg of suspension medium. The term "osmolarity", as used herein, is understood to mean the concentration of osmotically active particles of an osmotically active substance, ie, a solute, for example, molecules or ions thereof, in solution, ie, in the liquid phase of a suspension ready for use, said liquid phase consisting essentially of the suspension base being mixed, i.e., dissolved or dispersed, in the suspension medium as described herein. The osmolarity is generally expressed in moles of said solute per kg of the solvent medium, for example, in the present case, per kg of the suspension medium, preferably per liter of water. An osmolarity unit is 1 mosmol, indicating the amount of substance that dissociates in solution to form 1 mol of osmotically active particles. Osmolarity can be measured according to known methods, such as those that they use a vapor pressure osmolarity meter, a freezing point depression osmolarity meter, or a colloidal osmolarity meter, according to the methods described in Physikalisch CEIME, Martin et al., ed. H. Stricker, Wissenschaftliche Verlagsgesellsc aft, 1987. Osmolarity can also be calculated according to the following calculation scheme: Osmolarity [mosmol] = g of substance dissolved in 1000 g of solvent medium divided by the molecular weight of said substance, the resulting quotient is first multiplied by the number of particles in which the dissolved substance is dissociated and then multiplied by 1000. In the present invention, the dissolved substance means all the substances that dissolve in the liquid phase obtained after mixing the base of suspension with the suspension medium, for example water, that is, it comprises osmotically active substances, as defined herein, and optionally other dissolved substances, for example, as derived from the excipients described herein. Preferably, the pharmaceutical compositions of the invention are provided either as a dry slurry mixture that will be used to prepare aqueous suspensions or dispersions, or as suspensions ready for use. However, it is contemplated within the scope of the invention that the dry slurry mixture can also be used to prepare other dosage forms such as chewable preparations, tablets soluble or effervescent tablets or similar, or small sacks with a single dose. The ready-to-use suspension of the invention is of pleasant taste and maintains its good flavor even for a prolonged period of time, i.e., for at least 1 week, preferably at least 2 weeks, e.g., 4 weeks, after of its reconstitution with, for example, water, preferably, for example, during the whole therapy. The degree of good taste of the suspension can be measured indirectly by determining the amount of active substance, for example, clarithromycin, which is dissolved in the suspension at room temperature according to known methods, applying HPLC, for example, as described in European Pharmacopoea, 3a. Edition, and Supplement 2000. Said amount of active substance dissolved directly correlates with the bitterness of the suspension as can be seen, for example, in WO 93/12771. Alternatively, good taste can be judged by flavor-trained specialists, for example, as described in the aforementioned patent application. Without wishing to be limited by theory, the inventors believe that the considerable improvement in flavor, which is observed with the suspensions of the invention, is due to the high osmolality of the liquid medium surrounding the suspended particles which seems to lead to a reduction in the diffusion of the active substance towards the mixture of the suspension base with the suspension medium, is say, to a reduction and / or elimination of spillage of the active substance. Surprisingly, the inventors have found that the omission of certain conventional additives, such as acidic and / or basic additives from the suspensions of coated particles, for example, enteric coated particles, can substantially improve the taste of the suspensions comprising said particles, possibly due to reduced diffusion. The high level of osmolarity within the suspension avoids the need for an adjustment of the pH value of the suspension by adding acids, bases and / or acid or basic salts (depending on the type of functional cover used) to protect the masking covers from flavor of the solution. Despite the fact that the cover is actually soluble at the pH value of the suspension, it does not dissolve; again without pretending to be limited by theory, it is believed that this is due to the fact that there are no ions available for salt formation, which is necessary for dissolution. Therefore, the pharmaceutical compositions of the invention, as described above, may also be essentially free of acidic or basic additives, such as organic acids, for example, citric acid. The lack of acidic or basic additives in the pharmaceutical compositions of the invention allows much better conditions for successful aromatization, as compared to conventional compositions comprising said additives.

Preferably, the suspension of the present invention shows a rapid dissolution at a pH level of 6.8, which means 80% of the active substance dissolves in 15 minutes, measured through the dissolution test according to US Pharmacopoea USP 27 - NF 22 S2, 2004. This means that the active substance is released in a sufficient amount at an acceptable rate in the gastrointestinal tract, which generally indicates a good bioavailability. The following Table 2 shows how osmolarity can be adjusted using mixtures of different osmotically active substances as mentioned above (osmolarity is calculated as described above): TABLE 2 * Concentration related to the solution ** Concentration related to the suspension medium The pharmaceutical compositions of the invention can be used as a medicament. In one aspect, the pharmaceutical compositions of the invention can be used in the preparation of a medicament for the treatment and / or prophylaxis of infectious diseases. In a further aspect, the present invention provides a method for the treatment and / or prophylaxis of infectious diseases, especially microbial diseases, such as bacterial diseases and venereal diseases, and certain complications thereof, in a human or mammal that is not a human being, comprising administering a therapeutically effective, non-toxic amount of the active substance comprised in the pharmaceutical composition of the invention, to a human or mammal that is not a human being with the need thereof. Said active substance is preferably a macrolide, most preferably clarithromycin. The term "therapeutically effective," as used herein, is understood to include amounts of said active substance that provide a therapeutic effect desirable. In the treatment and / or prophylaxis of infectious diseases and certain complications thereof, the suspension of the invention may comprise a pharmaceutically effective amount of the active substance as described herein, preferably clarithromycin, in the dose scale usually used for the treatment. prophylaxis and / or treatment of infectious diseases. The suspension of the invention is particularly suitable for patients who have difficulty swallowing, such as children and the elderly patient. The present invention also provides a team of parts, which comprises: a component a) comprising covered particles comprising at least one pharmaceutically active substance having an unpleasant and / or bitter taste and optionally at least one excipient, and a component b) comprising a suspension base which it comprises at least one osmotically active substance which is capable of providing a high osmolarity to the mixture of said suspension base with an aqueous suspension medium in the ready-for-use suspension, and optionally, a component c) comprising at least one pharmaceutically acceptable excipient, for separate, sequential or simultaneous administration. Said equipment of parts may further comprise a component d) which is a means of suspension watery, for example water. Components a), b), c) and d) can be packed in a single container or container or in 2 or more separate containers. When stored in separate containers, components a), b), c) and d) can be mixed before administration. The following Examples are provided to further illustrate the invention without, however, limiting the invention.

EXAMPLES Coated particles were produced through spray agglomeration of clarithromycin and poloxamer. The average particle size for the covers varies between 200 and 400 p.m. The cover is applied in a fluid bed system from an aqueous dispersion. The composition of the particles can be seen in Table 1: TABLE 1 The suspensions of Examples 1 to 6 were prepared as follows: Coated particles, such as those of Table 1, were mixed with the ingredients listed later in Table 3 or Table 4, to form a dry suspension mixture, which was subsequently suspended through the addition of the radical amount of water. The portion of active substance that dissolved in the aqueous suspension was determined at different times in time via HPLC. The amount of said dissolved portion correlates with the bitter taste experienced by the patients after having ingested said suspension.

Examples of Group A: The composition of the suspension for Examples 1 to 4 is found in the following Table 3: TABLE 3 The values are quantities in g.

* The flavor used was mixed with fruit powder flavor, commercially available as 204264 H &R ** The citric acid was dissolved in water and added to titrate to the desired pH value desired. The impact of the osmotic conditions on the enteric coat, that is, the taste masking coat of the particles in Table 1, was determined by measuring the amount of clarithromycin dissolved at room temperature. This is a measure of the tightness of said cover as well as directly a measure of the bitterness of the suspension. The results are shown in Figure 1, which shows that the presence of 2.4 g of sucrose per 5 ml of suspension drastically reduces the clarithromycin spillage of the coated particles when compared to suspensions without sucrose. Dissolved clarithromycin means less bitter taste of the suspension, ie it means that the suspension is of good taste. Surprisingly, an acid pH value only, which is generally believed to prevent dissolution of the enteric coating, does not, however, prevent clarithromycin from spilling into the suspension. The presence of high osmolarity (see Example 1), however, is sufficient to prevent the spill of clarithromycin without considering the pH value in the scale seen in Figure 1.

Examples of Group B The composition of the suspension for Examples 5 to 7 is found in Table 4 below: TABLE 4 Example 5 6 7 The values are in quantities in g The impact of the osmotic conditions on the enteric coat, that is, the taste masking coat of the particles in Table 1, was again determined by measuring the amount of clarithromycin dissolved at room temperature; the results are shown in Figure 2, which shows that the addition of sucrose or a mixture of glucose and fructose prevents clarithromycin from spilling out of the coated particles. This is believed to be due to the high osmolarity of the corresponding suspensions, more particularly, of the mixture of the suspension base with water, which is more than 2500 mosmol per liter of water.

Claims (27)

1. - A pharmaceutical composition for oral administration suitable for the preparation of a suspension ready for use, comprising: a) coated particles comprising at least one pharmaceutically active substance having an unpleasant and / or bitter taste and optionally at least one excipient, and b) a suspension base comprising at least one osmotically active substance, which is capable of providing a high osmolarity to the mixture of said suspension base with an aqueous suspension medium in the suspension ready for use, and c) optionally at least one pharmaceutically acceptable excipient, wherein said high osmolarity is not less than 2000 mosmol per kg of suspension medium.

2. - The pharmaceutical composition according to claim 1, wherein the coated particles are masked taste.

3. The pharmaceutical composition according to claim 1 or 2, wherein said high osmolarity is not less than 2500 mosmol per kg of suspension medium.

4. - The pharmaceutical composition according to any of claims 1 to 3, in the form of a dry powder.

5. - A pharmaceutical composition in the form of a suspension ready for use, which is prepared by suspending the The pharmaceutical composition according to any of claims 1 to 4 in an aqueous suspension medium.

6. - The pharmaceutical composition according to any of claims 1 to 5, wherein the aqueous suspension medium is water.

7. - The pharmaceutical composition according to any of the preceding claims, wherein the osmotically active substance is selected from the group consisting of sucrose, sorbitol, xylitol, erythritol, maltodextrin, cyclodextrin, potassium phosphate, sodium phosphate, sodium sulfate, sodium and sodium chloride, and mixtures thereof.

8. - The pharmaceutical composition according to any of the preceding claims, wherein the amount of osmotically active substance is from about 6% to about 100% w / w relative to the suspension medium.

9. - The pharmaceutical composition according to claim 8, wherein the amount of the osmotically active substance is from about 85% to about 95% w / w relative to the suspension medium.

10. The pharmaceutical composition according to claim 9, wherein the amount of the osmotically active substance is about 89% w / w relative to the suspension medium.

11. The pharmaceutical composition according to any of claims 6 to 10, wherein the suspending medium aqueous is water and where the osmolarity of the mixture of the suspension base with water is not less than 2000 mosmol per liter.

12. - The pharmaceutical composition according to claim 11, wherein the osmolarity of the mixture of the suspension base with water is not less than 2500 mosmol per liter.

13. - The pharmaceutical composition according to any of the preceding claims, wherein the cover of said covered particles is a functional cover.

14. - The pharmaceutical composition according to claim 13, wherein said functional cover is an enteric shell.

15. - The pharmaceutical composition according to any of the preceding claims, wherein said suspension ready for use is of good taste.

16. The pharmaceutical composition according to claim 15, wherein the suspension ready for use maintains its good taste for at least 2 weeks.

17. - The pharmaceutical composition according to any of the preceding claims, wherein the pharmaceutically active substance having an unpleasant and / or bitter taste is a macrolide antibiotic.

18. - The pharmaceutical composition according to claim 17, wherein the macrolide antibiotic is clarithromycin.

19.- The pharmaceutical composition according to any of the preceding claims, which is essentially free of an acidic and / or basic additive.

20. - A method for preparing a pharmaceutical composition according to any of claims 1 to 4, which comprises the steps of: a) mixing covered particles with a suspension base comprising at least one osmotically active substance selected from the group consists of sucrose, sorbitol, xylitol, erythritol, maltodextrin, cyclodextrin, potassium phosphate, sodium phosphate, sodium sulfate and sodium chloride, and mixtures thereof, and optionally at least one pharmaceutically acceptable excipient, to obtain a suspension mixture dry, wherein the amount of osmotically active substance is sufficient to provide a high osmolarity to the mixture of said suspension base with an aqueous suspension medium in the suspension ready for use, and b) optionally fill a container with the obtained suspension mixture. in step a).

21. - A method for preparing a pharmaceutical composition according to any of claims 1 to 5, comprising the steps of: a) mixing covered particles with a suspension base comprising at least one osmotically active substance selected from the group that consists of sucrose, sorbitol, xylitol, erythritol, maltodextrin, cyclodextrin, potassium phosphate, phosphate sodium, sodium sulfate and sodium chloride, and mixtures thereof, and optionally at least one pharmaceutically acceptable excipient, to obtain a dry suspension mixture, wherein the amount of osmotically active substance is sufficient to provide a high osmolality to the mixture of said suspension base with an aqueous suspension medium in the suspension ready for use, and b) adding water to the dry suspension mixture obtained in step a) to form a suspension ready for use, and c) optionally filling a container with the suspension ready for use.

22. A method according to claim 20 or 21, wherein the pharmaceutically active substance is clarithromycin.

23. - A pharmaceutical composition according to any of claims 1 to 19 for use as a medicament.

24. - A pharmaceutical composition according to any of claims 1 to 19 for use in the preparation of a medicament for the treatment and / or prophylaxis of infectious diseases.

25. A method for the treatment and / or prophylaxis of infectious diseases, which comprises administering the pharmaceutical composition according to any of claims 1 to 19 to a human or mammal that is not a human being with the need thereof. .

26. A method according to claim 25, wherein The mammal being a human is a child or an elderly patient.

27. - A piece of equipment comprising a component a) and a component b) and optionally a component c) as defined in claim 1, for separate, sequential or simultaneous administration.