CN1744881A - Pharmaceutical compositions having reduced bitter taste - Google Patents

Abstract

Masking the taste possessed by bitter agents in dispersible compositions is difficult. A new formulation of a dispersible composition has been found in which the bitterness of the active ingredient is reduced and the lipid content of the composition is minimized, thereby reducing the lipid's effect on the release of the active ingredient from the composition. out the delay effect. In particular, the invention relates to basic bitter agents such as macrolide antibiotics, especially erythromycin, roxithromycin, azithromycin, and clarithromycin.

Description

Pharmaceutical composition with reduced bitterness

field of invention

The present invention relates to masking the taste of bitter medicinal agents. In particular, the present invention relates to taste masking of dispersible compositions containing bitter basic active ingredients, especially macrolide antibiotics such as erythromycin, roxithromycin , azithromycin, clarithromycin, etc.

Background technique

Overcoming the bitter taste of certain pharmaceutical active ingredients presents an ongoing challenge for pharmacists. Dispersible pharmaceutical compositions present even greater challenges than other types of formulations such as capsules and non-dispersible tablets. Dispersible pharmaceutical compositions have the advantage of being easier to swallow than capsules or tablets. This advantage is particularly advantageous for pediatric and geriatric patients who prefer easy-to-swallow formulations.

Various methods are known for masking the bitter taste of active ingredients in oral pharmaceutical powders, granules and dispersible tablets. These methods include coating powders or granules, microencapsulating the active ingredient, and complexing the active ingredient. However, these methods may be limited by the number of excipients required, the amount of each component required, the complexity of the preparation method, and the use of volatile organic solvents. In addition, these complex technologies also involve mass production issues.

French Patent No. FR 2793690 (Dominique) describes the use of high concentrations (up to 20%) of sweeteners instead of sugar in dispersible macrolide compositions. However, sweeteners such as aspartame, saccharin and ammonium glycerrhizinate have a distinctive and undesirable taste after tasting. Each of them also has other side effects when used in high concentrations. These traditional sweeteners cannot effectively mask the taste of active pharmaceutical ingredients such as azithromycin with a strong bitter taste anyway.

US Patent No. 5,609,909 (Meyer) discloses the use of water-insoluble oils or waxes as plasticizers to coat prolamin moieties on drug cores. This approach limits the immediate release of the macrolide suspension. This method also requires an organic coating material as well as equipment such as a Glatt-Wurster fluid bed coater.

US Patent No. 6,153,220 (Cumming) discloses spray drying active pharmaceuticals to mask taste with cationic copolymers synthesized from dimethylaminoethyl methacrylate and methacrylates. Organic solvents are used in this method. In addition, this method has limitations on the dose of drug that can be used, eg a drug to polymer ratio of at most 1:6.

To mask taste, pH-dependent polymers are often used in enteric coatings or in delayed-release formulations. US Patent No. 5,409,711 (Mapelli) discloses the use of polymeric films soluble above pH 5 for taste masking of granules. To prevent the film from dissolving in the mouth, acidic substances are added to the composition. Dispersible granules obtained by this method are released only above pH5.

An important disadvantage of formulations prepared by encapsulation and spray drying methods is that various volatile organic solvents such as dichloromethane, chloroform, cyclohexane, carbon tetrachloride, methyl ethyl ketone, acetone, ethanol are required in order to dissolve the coating agent , methanol or isopropanol. Such solvents are considered environmentally unfavorable, and therefore they need to be removed from the product in order to reduce their content to acceptable levels.

In drug mixtures, the use of alkaline substances has been evaluated to reduce drug release from encapsulating microcapsules. US Patent No. 4,656,027 (Sjoovist) discloses the encapsulation of basic substances with drugs and hydrophobic polymers to mask the taste of bitter substances. Also for environmental reasons, the use of organic solvents for encapsulation is not suitable. In addition, this also constitutes a limitation on the loading of the drug, thereby making mass production difficult.

US Patent No. 5,633,006 (Catania) uses alkaline earth metal oxides, alkaline earth metal hydroxides, and alkali metal hydroxides to mask the taste of bitter pharmaceutical compositions containing the macrolide antibiotic azithromycin. Azithromycin is readily absorbed by alkaline earth metal oxides, making the composition less bitter. In some instances, however, this absorption alters the release kinetics of the drug. Dosage forms suggested for this approach are limited to chewable tablets and oral suspensions.

To obtain taste-masked products, pharmacists working on macrolide antibiotics have used various functional polymers and basic oxides. US Patent No. 5,707,646 (Yajima) discloses the use of functional polymers in combination with low melting point substances, a basic oxide, and sugar alcohols to mask taste. However, this method requires a spray-drying process, and the low loading of drug, while also requiring a high content of fatty acid esters, makes this method limited.

US Patent No. 5,792,373 (Yajima) uses gastric juice soluble polymers and monoglycerides in the β-crystalline form to mask the taste of oral pharmaceutical compositions. However, the high ratio of monoglycerides relative to the active ingredient delayed the release of the drug. Limiting factors of this approach include the use of functional polymers that are unstable at high temperatures, low drug loading, and the spray-drying method.

A taste-masked granule containing a complex of clarithromycin and carbomer is described in US Patent No. 4,808,411 (Lu). Aqueous granules of this complex of clarithromycin and carbomer are described in US Patent No. 5,919,489 (Gerhardt). However, this approach is also less than ideal due to the multi-step drug processing required, such as compounding, granulation, and drying.

Various taste-masking formulations are characterized by the incorporation of lipids such as fatty acid esters. However, the lipid proportion is quite high in known taste-masked formulations, typically 20% by weight of the active ingredient.

For example, US Patent No. 5,635,200 (Douglas) describes a taste-masked composition of ranitidine drug substance in which the ranitidine core is coated with a lipid. The amount of lipid used was greater than 20% by weight. It is well known that the amount of lipid required to disperse a drug through a lipid is much higher than that required to simply coat a drug core with lipid. Thus, if it is desired to disperse ranitidine through lipids, much higher than 20% by weight of lipids in the composition may be required.

US Patent No. 5,380,535 (Geyer) describes a chewable tablet in which an unpalatable drug is dispersed or dissolved in a lipid. The amount of lipid used is 5-50% by weight of the composition. However, the above weight ratios of the compositions correspond to much higher weight ratios than the active ingredients. Dispersible formulations generally require higher lipid levels relative to chewable tablets.

The main purpose of using lipids in taste-masking formulations is to limit the release or dissolution of the active ingredient in the mouth (in the case of chewable tablets), and to limit the time when water is added to the active ingredient or when it is located in a place where the taste can be discerned. The release or dissolution behavior of the active ingredient in the mouth (for dispersible compositions). Therefore, a minimum level of lipids of 20% of the composition is generally required. However, the consequence of containing a high concentration of lipids is to delay the release of the drug from the composition, resulting in a delayed absorption of the active ingredient in the bloodstream. Accordingly, there is a need for a dispersible composition which, when administered by a patient, masks the bitter taste of certain active ingredients without causing a problem of delayed release of the active ingredient from the composition.

The applicants have now discovered a new simple and reproducible drug delivery system for dispersible pharmaceutical compositions which reduces the bitterness of bitter basic drugs while containing unexpectedly low levels of lipids.

The present invention relates to the use of lipids such as fatty acid esters, alkaline substances and surfactants to form a particulate matrix for reducing the bitter taste of active ingredients. Dispersible compositions contain granules of the active ingredient and granules of a rapidly disintegrating diluent.

It is an object of the present invention to provide a dispersible pharmaceutical composition with a low lipid content which masks the taste of bitter active ingredients at least to some extent, or at least provides a useful alternative.

Summary of invention

The first aspect of the present invention provides a kind of dispersible pharmaceutical composition, it comprises:

(i) bitter active ingredients;

(ii) a lipid granulating agent in an amount of 1-16% by weight of the active ingredient; and

(iii) an alkaline agent in an amount of 1-20% by weight of the active ingredient;

Wherein the bitter taste of the active ingredient is partially or completely masked.

Preferably, the bitter active ingredient is a macrolide antibiotic, more preferably the macrolide antibiotic is selected from erythromycin, clarithromycin, roxithromycin, and azithromycin, including any solvates or hydrates thereof. The azithromycin used is preferably the isomorphic pseudopolymorph disclosed in Croatian Patent Application No. P20020231 A with excellent dissolution properties.

The content of the lipid granulation agent is preferably 2-8% by weight of the active ingredient.

The lipid granulation agent can be any fatty acid ester, oil, fat or wax. Of course, the lipid granulating agent is preferably selected from glycerol mono-, di- and tri-stearate, glycerol mono-, di- and tri-palmitoyl stearate, glycerol mono-, di- and tri- - behenate, glyceryl mono-, di- and tri-oleate, hydrogenated castor oil, polycetorol emulsifying wax, carnubawax, cetyl alcohol and cetyl esters.

Preferably, the content of the alkaline agent is 2-12% by weight of the active ingredient. Various alkaline agents can be used, but preferably the alkaline agent is selected from sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide and potassium hydroxide.

Preferably the composition further comprises a surfactant in an amount not exceeding 2% by weight of the active ingredient. The surfactant is preferably selected from sodium lauryl sulfate, sodium docusate, polysorbate and sorbitan fatty acid esters.

It is also preferred that the composition further contains a diluent in an amount of 5-60% by weight of the total composition. The diluent is preferably selected from cellulose, microcrystalline cellulose, lactose, mannitol, sorbitol, starch, calcium carbonate, calcium hydrogen phosphate, silicon dioxide and pregelatinized starch.

The diluent is preferably prepared in granular form with a combination of microcrystalline cellulose and starch in a ratio of 1:3 to 3:1 and water-insoluble cellulose. The water-insoluble cellulose is preferably ethyl cellulose in an amount of 2-10% by weight of the granules. The ratio of microcrystalline cellulose to starch is preferably from 1.25:1 to 2:1.

It is further preferred that the composition contains a disintegrant in an amount of 1-12% by weight of the total composition. The disintegrating agent is preferably selected from carmellose sodium, croscarmellose sodium, sodium starch glycolate, polyvinylpolypyrrolidone, aminoalkyl acrylate copolymer E and Polacrillin potassium.

In a preferred embodiment of the present invention, the disintegrant is cationic polymer aminoalkyl methacrylate copolymer E.

It is also preferred that the composition further comprises a sweetener in an amount of 1-10% by weight of the total composition. The sweetener is preferably selected from aspartame, coated aspartame, ammonium glycerrhizinate, sodium saccharin, acesulfam potassium, and sugars.

Preferably the composition further comprises one or more flavoring agents in an amount of 1-6% by weight of the total composition. The one or more flavoring agents are preferably selected from flavoring agents having a vanilla, banana, cherry, pineapple, chocolate, caramel, or mint aroma.

Preferably the composition also contains a lubricating system consisting of lubricants, glidants and flow agents. The lubricant is preferably selected from magnesium stearate, calcium stearate, stearic acid and polyoxyethylene stearate. A preferred glidant is talc, and preferred flow agents are selected from silicon dioxide, fatty acid esters and sodium lauryl sulfate.

A second aspect of the present invention provides a method of preparing a composition according to claim 1, comprising the steps of:

(i) mixing the bitter active ingredient with a lipid granulating agent and an alkaline agent to obtain a granular matrix;

(ii) further optionally mixing the granular base with one or more of a disintegrant, a sweetener, a flavoring agent and a flow agent.

Preferably the granular substrate is prepared by hot melt spiral granulation. The hot-melt spiral granulation method can be carried out at any suitable temperature, preferably at a temperature lower than 80°C.

In one embodiment of the method, the composition is compressed to obtain a water dispersible tablet. In alternative embodiments, the composition is not compressed to obtain water dispersible granules or powders.

Detailed description of the invention

The present invention relates to dispersible compositions containing bitter basic drugs, including macrolide antibiotics, alone or in combination with other active substances, and processes for the preparation of such compositions.

As used herein, the term "dispersible composition" refers to any solid dosage form, including tablets, granules, pills and powders, which is dispersed in water (including cold water) to form a suspension for drinking.

The present invention is applicable to any kind of bitter basic medicine or combination of bitter medicines. Of course, the present invention particularly relates to macrolide antibiotics, especially erythromycin, roxithromycin, azithromycin and clarithromycin. Drugs are usually in the form of stable hydrates, solvates or salts, but may also be in any crystalline or amorphous form. The azithromycin used is preferably the isomorphic pseudopolymorph disclosed in Croatian Patent Application No. P20020231 A with excellent dissolution properties.

Compositions of the invention include any dispersible composition, especially granules, powders and tablets. Although tablets and capsules are simple and convenient to take, they are not easy for children and elderly patients to swallow. For high doses of drugs, size is also a limitation. Thus, dispersible pharmaceutical compositions appear convenient and easy to administer. The dispersible pharmaceutical composition can also be used for titration if desired by the patient.

When a dispersible composition of a bitter drug is dispersed in water, the bitter taste of the resulting oral suspension is difficult to mask. Dispersible pharmaceutical compositions prepared according to the present invention are less bitter and do not interfere with the dissolution profile of the drug (even after being tabletted). The composition meets the requirements of the British Pharmacopoeia for dispersible pharmaceutical compositions including dispersible tablets.

Particulate matrices for dispersible pharmaceutical compositions can be prepared in a number of ways. A preferred method is hot melt spiral granulation. It is known that it is possible to form granules while reducing bitterness using conventional fluid bed dryers. Other devices, such as intensifier mixers and mixing devices with a supply of hot air, can also be used for this purpose. When using fatty acid esters such as glyceryl distearate or glyceryl distearate, the drying temperature of the powder bed can be maintained between 65°C and 70°C.

Hot-melt spiral granulation has advantages over spray drying, microcapsules, and granule coating or encapsulation techniques that require special equipment. This technique is environmentally friendly, renewable and scalable.

The granulating agent used to form the granular matrix by hot melt granulation is a lipid. The lipids may be waxes, oils, fatty acids, fatty alcohols, monoglycerides, diglycerides or triglycerides. Carbon chain lengths are typically C12-C30, and they can be saturated or unsaturated. Examples include glyceryl monostearate, glyceryl distearate, glyceryl behenate, glyceryl distearate and glyceryl palmitoyl behenate. The lipid may also be hydrogenated castor oil, polycetorol emulsifying wax, carnauba wax, cetyl alcohol or cetyl esters. It is contemplated that suitable mixtures of two or more lipids may also be used.

Preferred lipids are generally solid at room temperature (18-22°C), but readily melt upon application of an appropriate temperature (ie about 55-95°C). Also included are mixtures in which the melting points of the individual components are outside the above-mentioned temperature ranges, but the average melting points are within the above-mentioned ranges.

Applicants have surprisingly found that the preferred lipid content can be as low as 1-16%, preferably 2-8%, by weight of the active pharmaceutical ingredient. The main advantage of keeping the lipid content as low as possible is to reduce the impact on drug dissolution/release, while also reducing the bitterness of the drug.

The incorporation of a wetting agent such as sodium lauryl sulfate (not to exceed 2% for the bitter-tasting granules) is preferred. Other humectants include docusate sodium, polysorbate and sorbitan fatty acid esters. Wetting agents are dispersing aids. When used in small amounts, wetting agents generally aid in tablet dispersion and dissolution.

To stabilize the pH of the composition, an alkaline substance such as sodium carbonate or trisodium phosphate is added in an amount of 1-20%, preferably 2-14%, by weight of the active pharmaceutical ingredient. The evaluation found that both intragranular and extragranular addition of alkaline material reduced the bitterness of the dispersible composition. When the dispersible composition is added to water, the rapidly dissolving alkaline material helps to form a uniform dispersion. Common alkaline agents include sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, and potassium hydroxide.

To improve the flow properties of the dispersible composition, other excipients may be added alone or in combination. These diluents include cellulose, microcrystalline cellulose, mannitol, sorbitol, starch, pregelatinized starch, gelatinized starch, directly compressible microcrystalline cellulose, lactose, calcium carbonate, silicon dioxide, and phosphoric acid hydrogen calcium.

A preferred composition of the present invention employs dilute granules consisting of a mixture of microcrystalline cellulose and corn starch in varying ratios from 1:3 to 3:1, preferably in the range of 1.25:1.0 to 1.75:1.0. For dilute granules, the granulating agent can be used in the form of an aqueous dispersion of ethylcellulose (2-10%) and a plasticizer (eg Surelease ^™ ). The excipient combination was evaluated for the compressibility of the resulting mixture when mixed with the reduced bitter granular base. If these dilute granules are used, the disintegration and flow properties of the dispersible pharmaceutical composition of the present invention can be improved.

The granular matrix of the bitter active ingredient can be further processed into dispersible dosage forms using diluting granules and other diluting substances. The granules of the diluent have good flowability, compressibility and disintegration properties. Surprisingly, studies have found that cationic aminoalkyl methacrylate copolymer E (Eudragit ^™ E, EPO) is a suitable disintegrant in this dispersible dosage form composition. Aminoalkylmethacrylate copolymer E is poly(butylmethacrylate, (2-dimethylaminoethyl)methacrylate, methylmethacrylate 1:2:1). Other disintegrants include sodium carmellose, croscarmellose sodium, sodium starch glycolate, polyvinylpolypyrrolidone, and Polacrillin potassium.

Sweeteners such as aspartame, ammonium glycerrhizinate (eg, magnasweet ^™ ), sodium saccharin and other sugars, acesulfame potassium or mannitol are preferably mixed in as the second sweetener. The use of high doses of sweeteners is inadvisable as this can lead to an unpleasant aftertaste and also generally avoid unnecessary dosage of additives to the patient. In the present invention, in order to obtain sweetness, it is preferable to add a low content (2-5%) of sweetener. Aspartame is preferred as a sweetener in dispersible compositions such as tablets.

It is difficult to choose a suitable flavoring agent for basic bitter medicines. Citrus flavors are not suitable as they impart bitterness, however other flavors such as mint and vanilla can synergistically reduce the bitterness of the formulation. The flavors evaluated were vanilla, banana, cherry, pineapple, caramel, chocolate, mint and related flavoring compounds.

Formulations with acceptable taste can also be obtained with mild flavoring or if no flavoring is added.

Preferably a lubricant is incorporated, such as magnesium stearate or calcium stearate or related pharmaceutically acceptable lubricant compounds. Magnesium stearate is a preferred lubricant since it is most commonly used in pharmaceutical compositions. It is also preferred to use flow agents such as silicon dioxide, antiadherents (glidants) such as purified talc in the dispersible compositions of the invention.

The invention may be better understood by reference to the following examples of dispersible compositions. However, these examples are for illustrative purposes only, and it should be understood that the present invention is not limited by these examples.

Example

Example 1: Granular Substrate with Reduced Bitter Taste Element mass (mg) Composition (%w/w) Azithromycin (isomorphic pseudopolymorph) 500mg Azithromycin 528.26 89.63 Sodium dodecyl sulfate 3.00 0.51 Trisodium Phosphate (Anhydrous) 36.98 6.27 Glyceryl Dibehenate 21.13 3.59 gross weight 589.37 100.00

A granular matrix was prepared using azithromycin, glyceryl dibehenate, and sodium lauryl sulfate. Trisodium phosphate can be added intra-granularly in the granular matrix or externally in the dispersible composition. Granular substrates were examined using scanning electron microscopy (SEM).

The components are mixed and then granulated using the fluidized bed method for screw granulation attachment. These granules are then used to prepare dispersible compositions.

Example 2: Granular Substrate with Reduced Bitter Taste Element mass (mg) Composition (%w/w) Azithromycin (isomorphic pseudopolymorph) 500mg Azithromycin 528.26 86.53 Sodium dodecyl sulfate 3.00 0.49 Trisodium Phosphate, Anhydrous 36.98 6.06 Glyceryl Dibehenate 42.22 6.92 gross weight 610.46 100.00

A granular matrix was prepared by adding glyceryl dibehenate inside the granules to obtain a matrix containing 8% by weight of glyceryl dibehenate. These granules with a higher content of fatty acid esters showed good taste-masking properties. The granules are used directly in dispersible compositions without compression.

Example 3: Granular Substrate with Reduced Bitter Taste Element mass (mg) Composition (%w/w) Azithromycin (isomorphic pseudopolymorph) 500mg Azithromycin 528.26 89.63 Sodium dodecyl sulfate 3.00 0.51 Trisodium Phosphate (Anhydrous) 36.98 6.27 Glyceryl Distearate 21.13 3.59 gross weight 589.37 100.00

The above-mentioned granules are prepared by using trisodium phosphate on the outside or inside of the granules. Glyceryl distearate was used as a granulating agent. These particles can be used to form a variety of dispersible compositions.

Example 4: Diluted Particles Element mass (g) Composition (%w/w) Microcrystalline Cellulose (Avicel PH101) 240.00 57.69 starch (corn starch) 160.00 38.46 Ethylcellulose (Surelease) 16.00 3.85 gross weight 416.00 100.00

Dilute granules were prepared using microcrystalline cellulose (Avicel ^™ PH 101) and corn starch. The granulating agent used was an aqueous dispersion of ethylcellulose (Surelease ^™ ). The granules were dried at 60°C. Rapidly disintegrating and flowing granules are obtained after dry granules are sized.

Example 5: Eudragit ^™ EPO as a disintegrant/dispersant in dispersible tablets

The granular base from Example 2 was mixed with the diluted granulation from Example 4. The granules are sieved (40#) and mixed with other excipients: aspartame, disintegrant/dispersant, trisodium phosphate, anhydrous colloidal silicon dioxide and talc. The mixture is then lubricated with magnesium stearate. The following disintegrants/dispersants were used: aminoalkylmethacrylate copolymer E (Eudragit ^™ EPO), sodium carmellose, sodium starch glycolate and polacrillin potassium.

Granules of the dispersible composition were compressed into tablets and the tablets were evaluated for ease of dispersion by dropping into 60 ml of water at 25°C in a 150 ml glass beaker.

Unsatisfactory results were obtained with carmellose, sodium starch glycolate and polacrillin potassium. Some aggregated tablet clumps were observed in the beaker during the last 3 minutes.

Good tablet dispersibility was observed if 100 mg of Eudragit ^™ EPO per tablet was used (see table below). These tablets meet tablet disintegration tests for dispersible tablets and uniformity of dispersion.

Evaluation of Eudragit ^TM EPO as a disintegrating/dispersing agent Content (mg) of Eudragit ^™ EPO in the preparation of embodiment 6 Observation results 0 Incomplete tablet dispersion within 3 minutes 50 Tablet dispersibility improved, but not completely within 3 minutes 100 Tablet disperses completely within 1-3 minutes 150 Tablet disperses completely within 1-3 minutes

Example 6: Dispersible pharmaceutical compositions such as tablets Element Mass/tablet (mg) Composition (%w/w) Reduced bitterness granular matrix (for 500 mg azithromycin) 552.41 43.33 dilute granules 523.59 41.07 aspartame 30.00 2.35 Aminoalkyl Methacrylate Copolymer E (Eudragit ^TM E, EPO) 100.00 7.84 Trisodium Phosphate (Anhydrous) 40.00 3.14 Anhydrous Colloidal Silica 5.00 0.39 talc 12.00 0.94 Magnesium stearate 12.00 0.94 Tablet weight 1275.00 100.00

The granular base from Example 1 was mixed with the diluted granulation from Example 4. The granules were sieved (40#) and mixed with other excipients: aspartame, aminoalkylmethacrylate copolymer E (Eudragit ^™ EPO), trisodium phosphate, anhydrous colloidal silicon dioxide and talc. The mixture is then lubricated with magnesium stearate.

Granules of the dispersible composition were compressed into tablets and evaluated for taste, uniformity of dispersion, and other compendial tests. The reconstitution tablets were found to be acceptable in terms of taste and other tablet characteristics such as dissolution, assay, hardness, friability and ease of reconstitution.

Example 7: Demonstration of masking of bitter taste

The composition used to evaluate taste included azithromycin 500 mg, dilute granules (granules of starch and microcrystalline cellulose), aminoalkyl methacrylate copolymer E (Eudragit ^™ EPO), talc, colloidal silicon dioxide and stearin Granules of Magnesium Oxide. The content of fatty acid esters in the reduced bitter granules varied (as shown in the table below). Trisodium phosphate and aspartame were also present in different amounts (as shown in the table below). Compositions were evaluated on 5 volunteers. Element Composition Trials for Testing Taste I II III IV V VI VII VIII Glyceryl Dibehenate 4% 4% 4% 4% 4% Trisodium Phosphate Anhydrous 7% 7% 7% 7% 7% Aspartame (mg) 30 100 30 100 30 100 Priority Rating for Taste Evaluation f f f E. f E. B C

Percentages are relative to the weight of azithromycin (anhydrous form).

The above compositions were respectively dispersed into 60 ml of water, and taste was evaluated immediately after dispersion.

Taste Evaluation:

A: Palatable and acceptable preparation

B: Palatable and acceptable formulation with very little bitterness and very low aftertaste

C: Palatable and acceptable formulation with a slightly bitter taste and low aftertaste

D: Palatable and acceptable formulation with slightly bitter and unacceptable aftertaste

E: Non-palatable formulation because the aftertaste is bitter and the taste is also bitter

F: Not a palatable preparation because the taste is extremely bitter

Compositions VII and VIII containing the fatty acid ester glycerol dishenate, the alkaline buffer salt sodium phosphate and the sweetener aspartame were significantly better than I-VI. Composition VIII was too sweet and had a bitter aftertaste.

Example 8: Evidence for Bitter Masking

The composition used to evaluate taste included azithromycin 500 mg, dilute granules (granules of starch and microcrystalline cellulose), aminoalkyl methacrylate copolymer E (Eudragit ^™ EPO), talc, colloidal silicon dioxide and stearin Granules of Magnesium Oxide. The levels of fatty acid esters in the less bitter granules and the level of aspartame were fixed (as shown in the table below). The content of trisodium phosphate is fixed, except that it is used outside the granules in XI, and the rest are used inside the granules. Compositions were evaluated on 5 volunteers. components Composition Trials for Testing Taste VII IX x XI Glyceryl Dibehenate 4% 4% 4% 4% Trisodium Phosphate Anhydrous 7% 7% 7% 7% (in granules) Aspartame (mg) 30 30 30 30 Vanilla (mg) - 25 - - Banana (mg) - - 25 - preferred rating B C C B

Percentages are relative to the weight of azithromycin (anhydrous form).

In the table below, composition XII is equivalent to VII without azithromycin. The taste of the dispersion was compared to Composition VII without the drug azithromycin. This composition is labeled XII.

Compositions VII, IX, X and XI were rated by preference ratings obtained by 20 volunteers. Volunteer ID Compositions for taste testing VII IX x XI XII 1 B C D. B A 2 B C C B A 3 B C D. A A 4 B D. C B A 5 C D. D. B A 6 B C C B A 7 B D. D. B A 8 B C C B A 9 B D. D. B B 10 B C C A A 11 B C C B A 12 B D. D. B A 13 B C C B A 14 B D. D. B A 15 A C D. B A 16 B C C B A 17 B C C B A 18 B C C B A 19 B C C A A 20 B D. D. B A preferred rating B C C B A

Taste Evaluation:

A: Palatable and acceptable preparation

B: Palatable and acceptable formulation with very little bitterness and very low aftertaste

C: Palatable and acceptable formulation with a slightly bitter taste and low aftertaste

D: Palatable and acceptable formulation with slightly bitter and unacceptable aftertaste

E: Non-palatable formulation because the aftertaste is bitter and the taste is also bitter

F: Not a palatable preparation because the taste is extremely bitter

Observation results:

Volunteer evaluations showed acceptable levels for the azithromycin formulations described above. Compositions without flavoring components were more acceptable than compositions with flavoring components such as vanilla and banana, indicating that flavoring is not necessary for such formulations. Slightly better acceptability was shown when anhydrous trisodium phosphate and fatty acid ester were used inside the granules.

Although the present invention has been described by way of example, it should be understood that various changes and modifications can be made therein without departing from the scope of the claims. Furthermore, where there are known equivalents for a specific feature, these equivalents are incorporated as if they were cited in this specification.

Claims (31)

1. A dispersible pharmaceutical composition comprising: (i) bitter active ingredients; (ii) a lipid granulating agent in an amount of 1-16% by weight of the active ingredient; and (iii) An alkaline agent in an amount of 1-20% by weight of the active ingredient; wherein the bitter taste of the active ingredient is partially or completely masked. 2. Composition according to claim 1, wherein said bitter active ingredient is a macrolide antibiotic. 3. The composition according to claim 2, wherein said macrolide antibiotic is selected from the group consisting of erythromycin, clarithromycin, roxithromycin and azithromycin, including and preferably in the form of isomorphic pseudopolymorphs with excellent dissolution properties Azithromycin in the form of Azithromycin (as disclosed in Croatian Patent Application No. P20020231 A). 4. Composition according to any one of claims 1-3, wherein the lipid granulating agent is present in an amount of 2-8% by weight of the active ingredient. 5. The composition according to any one of claims 1-4, wherein the lipid granulating agent is a wax, a fatty acid, a fatty alcohol, or a mono-, di- or tri-glyceride of one or more fatty acids . 6. The composition according to claim 5, wherein the lipid granulating agent is selected from the group consisting of glyceryl mono-, di- and tri-stearate, glycerol mono-, di- and tri-palmitoyl stearate, Glyceryl Mono-, Di- and Tri-Behenate, Glyceryl Mono-, Di- and Tri-Oleate, Hydrogenated Castor Oil, Cecitor Glycol Emulsifying Wax, Carnauba Wax, Cetyl Alcohol, and Cetyl Alcohol Alkyl esters. 7. Composition according to any one of claims 1-6, wherein the alkaline agent is present in an amount of 2-12% by weight of the active ingredient. 8. The composition according to any one of claims 1-7, wherein the alkaline agent is selected from the group consisting of sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide and potassium hydroxide. 9. A composition according to any one of claims 1-8, further comprising a surfactant in an amount not exceeding 2% by weight of the active ingredient. 10. The composition according to claim 9, wherein the surfactant is selected from the group consisting of sodium lauryl sulfate, sodium docusate, polysorbate and sorbitan fatty acid esters. 11. The composition according to any one of claims 1-10, further comprising a diluent in an amount of 5-60% by weight of the total composition. 12. The composition according to claim 11, wherein said diluent is selected from the group consisting of cellulose, microcrystalline cellulose, lactose, mannitol, sorbitol, starch, calcium carbonate, calcium hydrogen phosphate, silicon dioxide and pregelatinized starch. 13. The composition according to claim 11, wherein the granules of the diluent are prepared using a combination of microcrystalline cellulose and starch and water-soluble cellulose in a ratio of 1:3 to 3:1. 14. The composition according to claim 13, wherein the water-soluble cellulose is ethyl cellulose in an amount of 2-10% by weight of the granules. 15. The composition according to claim 13, wherein the ratio of microcrystalline cellulose and starch is from 1.25:1 to 2:1. 16. The composition according to any one of claims 1-15, further comprising a disintegrant in an amount of 1-12% by weight of the total composition. 17. The composition according to claim 16, wherein the disintegrant is selected from the group consisting of sodium carmellose, croscarmellose sodium, sodium starch glycolate, polyvinylpolypyrrolidone, aminoalkyl methacrylate copolymer Compound E and Polacrillin potassium. 18. The composition according to claim 17, wherein the disintegrant is the cationic polymer aminoalkyl methacrylate copolymer E. 19. A composition according to any one of claims 1-18, further comprising a sweetener in an amount of 1-10% by weight of the total composition. 20. The composition according to claim 19, wherein the sweetener is selected from the group consisting of aspartame, coated aspartame, ammonium glycerrhizinate, sodium saccharin, acesulfame potassium, and sugars. 21. A composition according to any one of claims 1-20, further comprising one or more flavoring agents in an amount of 1-6% by weight of the total composition. 22. A composition according to claim 21, wherein said one or more flavoring agents are selected from flavoring agents having a vanilla, banana, cherry, pineapple, chocolate, caramel or mint aroma. 23. The composition according to any one of claims 1-22, further comprising a lubricating system consisting of lubricants, glidants and flow agents. 24. A composition according to claim 23, wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, stearic acid and polyoxyethylene stearate. 25. The composition according to claim 23, wherein the glidant is talc. 26. The composition according to claim 23, wherein said flow agent is selected from the group consisting of silicon dioxide, fatty acid esters and sodium lauryl sulfate. 27. A method of preparing a composition according to claim 1, comprising the steps of: (i) mixing the bitter active ingredient with a lipid granulating agent and an alkaline agent to obtain a granular matrix; and (ii) optionally mixing a wetting agent and further mixing the granular base with one or more of a disintegrant, a sweetener, a flavoring agent and a flow agent. 28. The method according to claim 27, wherein said granular substrate is prepared by hot melt spiral granulation. 29. A method according to claim 28, wherein the hot melt spiral granulation is carried out at a temperature below 80°C. 30. A method according to any one of claims 27-29, wherein the composition is compressed to obtain a water dispersible tablet. 31. A method according to any one of claims 27-29, wherein the composition is not compressed to obtain a water dispersible granule or powder.