JP2006514968A - Pharmaceutical composition having reduced bitterness - Google Patents

Abstract

Masking the taste of a bitter-tasting pharmaceutical composition in a dispersible composition is difficult. New formulations for dispersible compositions have been found, the bitter taste of the active ingredient is reduced, the amount of lipid in the formulation is minimized, and the delay that the lipid has for the release of the active ingredient from the composition The impact can be reduced. The present invention relates in particular to bitter-tasting antibiotics such as macrolide antibiotics, especially erythromycin, roxithromycin, azithromycin, clarithromycin.

Description

  The present invention relates to taste masking of a bitter-tasting pharmaceutical composition. In particular, the present invention relates to taste masking of dispersible compositions comprising basic active ingredients having a bitter taste, especially macrolide antibiotics such as erythromycin, loxithromycin, azithromycin, clarithromycin and the like.

  Overcoming the bitterness of certain pharmaceutically active ingredients is an ongoing challenge for prescribing scientists. This challenge is even greater for dispersible pharmaceutical compositions as opposed to other types of formulations such as capsules, non-dispersible tablets and the like. Dispersible pharmaceutical compositions have the advantage of being easier to swallow than capsules and tablets. This advantage is particularly advantageous for pediatric and elderly patients who prefer formulations that are easy to swallow.

  A number of techniques are known for masking the bitter taste of active ingredients in pharmaceutical powders, granules, dispersible tablets intended for oral use. These include powder or granule coating, microencapsulation of the active ingredient, complexation of the active ingredient. However, these techniques may be limited by the number of excipients required, the amount of each component required, the degree of complexity of the manufacturing process, and the use of volatile organic solvents. Scale-up problems associated with these complex technologies often arise.

  French Patent No. 2793690 (Dominique) describes the use of sweeteners other than sugars in dispersible macrolide compositions at high concentrations (up to 20 percent). However, sweeteners such as aspartame, saccharin, and ammonium glycerritinate have a unique and unpleasant aftertaste. They also have other side effects when used at high concentrations. These traditional sweeteners are in any case not effective in masking the bitter taste of intensely bitter pharmaceutically active ingredients such as azithromycin.

  US Pat. No. 5,609,909 (Meyer) discloses the use of applying a prolamin fraction of cereal protein as a coat around the core by using a water insoluble oil or wax as a plasticizer. This method is applicable only to immediate release macrolide suspensions. An organic coating is required for this process, along with equipment such as a Glatt-Wurster liquid bed coater.

US Pat. No. 6,153,220 (Cumming) discloses spray drying an active agent with a cationic copolymer to mask taste. This copolymer is synthesized from dimethylaminoethyl methacrylate and methacrylic acid esters.
There is also a limit to the amount of drug that organic solvents can be used in this process, in addition, for example, the ratio of drug to polymer can be up to 1: 6.

  PH-dependent polymers used in enteric coatings, delayed release formulations have been used for taste masking. US Pat. No. 5,409,711 (Mapelli) describes the use of a polymer membrane, soluble above pH 5, for taste masking of granules. An acidic substance is added to the composition to avoid dissolution of the membrane in the mouth. The dispersible granules obtained in this process release the drug only above pH 5.

  An important disadvantage of formulations prepared by encapsulation and spray drying is that volatile organic solvents such as methylene chloride, chloroform, cyclohexane, carbon tetrachloride, methyl ethyl ketone, acetone, ethyl alcohol, methyl alcohol, or isopropyl alcohol are used as coating agents. It may be necessary to dissolve. Such solvents are considered environmentally friendly and need to be removed from the product or reduced to an acceptable amount.

  Alkaline substances used to reduce drug release from encapsulated microcapsules have been evaluated in pharmaceutical mixtures. US Pat. No. 4,656,027 (Sjoovist) describes the use of an alkaline substance and a hydrophobic polymer encapsulated with a drug to mask the taste of a substance having a bitter taste. Again, the use of organic solvents for encapsulation is undesirable for environmental reasons. Furthermore, the capacity of the drug is limited and it is difficult to produce in large batches.

  US Pat. No. 5,633,006 (Catania) uses alkaline earth oxides and alkaline earth hydroxides and alkaline hydroxides to mask the bitter taste of the macrolide antibiotic azithromycin. Azithromycin tends to adsorb alkaline earth oxides, thereby reducing the bitter taste of the composition. However, such adsorption can alter drug release kinetics and the suggested dosage forms for this method are limited to chewable tablets or oral suspensions.

  Prescription scientists engaged in macrolide antibiotic research have used functional polymers with basic oxides to deliver taste masked products. U.S. Pat. No. 5,707,646 (Yajima) discloses the use of functional polymers in conjunction with substances having a low melting point, basic oxides, sugar alcohols for taste masks. However, the low capacity of the drug and the large amount of fatty acid ester, which are requirements of the spray drying technique, are limitations of this method.

  U.S. Pat. No. 5,792,373 (Yajima) utilizes a polymer soluble in the stomach along with beta crystalline monoglycerides to mask the taste of pharmaceutical compositions for oral administration. However, if the ratio of monoglyceride to the active ingredient is high, drug release is delayed. Limitations of this method include the use of functional polymers that are unstable at high temperatures, low drug volumes, and spray drying processes.

  Taste masked granules comprising a complex between clarithromycin and carbomer are described in US Pat. No. 4,808,411 (Lu). Aqueous granules of clarithromycin-carbomer complex are described in US Pat. No. 5,919,489 (Gerhardt). However, numerous pharmaceutical manufacturing processes and required techniques, such as complexation, granulation, and drying, make this method undesirable.

  A feature of many taste mask formulations is the introduction of lipids such as fatty acid esters. However, the proportion of lipid in known taste mask formulations is quite high, typically more than 20% by weight of the active ingredient.

  For example, US Pat. No. 5,635,200 (Douglas) describes a taste masking composition for a ranitidine drug wherein the drug core of ranitidine is coated with a lipid. The amount of lipid used is 20% by weight or more. It is well known that the amount of lipid used to disperse the drug through the lipid is much higher than if the drug core is simply wrapped with lipid. Therefore, when dispersing ranitidine through lipids, much greater than 20% by weight of lipid in the composition will be required.

US Pat. No. 5,380,535 (Geyer) describes a chewable tablet in which a non-tasting drug is dispersed or dissolved in a lipid. The amount of lipid used is 5-50% by weight of the composition. However, these ratios in weight percent of the composition correspond to much greater than the weight ratio of the active ingredient. Typically, dispersible formulations require a much higher amount of lipid compared to chewable tablets.
French Patent No. 2793690 (Dominique) US Pat. No. 5,609,909 (Meyer) US Pat. No. 6,153,220 (Cumming) US Pat. No. 5,409,711 (Mapelli) US Pat. No. 4,656,027 (Sjoovist) US Pat. No. 5,633,006 (Catania) US Pat. No. 5,707,646 (Yajima) US Pat. No. 5,792,373 (Yajima) US Pat. No. 5,919,489 (Gerhardt) US Pat. No. 5,635,200 (Douglas) US Pat. No. 5,380,535 (Geyer)

  The main purpose of including a lipid in a taste masking formulation is in the part where it is tasted, i.e. in the mouth in the case of chewable tablets, in water or in the mouth in the case of dispersible compositions. Limiting the release and dissolution of active ingredients. Thus, a minimum level of 20% lipid is typically required in the composition. However, as a result of high lipid levels, drug release from the composition is slow and absorption of the active ingredient into the bloodstream is slow. Thus, there is a need for a dispersion composition that effectively masks the bitter taste of certain active ingredients and does not have the problem of delayed release of the active ingredient from the composition upon use by a patient. Applicants have identified a surprisingly low level of lipids for a simple, reproducible and novel drug delivery system for dispersible pharmaceutical compositions with reduced bitterness for bitter-tasting alkaline drugs. I found something that contains.

  The present invention relates to the formation of a granular matrix that reduces the bitter taste of active ingredients by the use of lipids such as fatty acid esters, alkaline substances and surfactants. The dispersible composition comprises granules of the active ingredient and granules of a rapidly disintegrating diluent.

  The object of the present invention is to provide a dispersible pharmaceutical composition comprising low levels of lipids, or at least a useful alternative thereof, having at least some effect on the taste mask of bitter tasting active ingredients. It is in.

In the first aspect of the present invention,
(i) bitter active ingredients;
(ii) a lipid granulating agent in an amount of 1 to 16% by weight of the active ingredient; and
(iii) an alkaline agent in an amount of 1 to 20% by weight of the active ingredient;
And a dispersible pharmaceutical composition is provided wherein the bitter taste of the active ingredient is partially or completely masked.

  The bitter-tasting active ingredient is preferably a macrolide antibiotic, more preferably selected from erythromycin, clarithromycin, roxithromycin, azithromycin, or a solvate or hydrate thereof. The azithromycin selected is preferably an isomorphic pseudopolymorph exhibiting excellent solubility, as disclosed in Croatian patent application No. P20020231A. The lipid granulating agent is preferably in the range of 2 to 8% by weight of the active ingredient.

  The lipid granulating agent may be a fatty acid ester, oil, fat, or wax. However, the lipid granulating agent is preferably glycerol mono-, di- and tri-stearate, mono-, di- and tri-palmitoglycerol glycerol, mono-, di- and tri-behen. Glyceric acid, mono-, di-, and tri-oleic acid glycerol, hydrogenated castor oil, cetomacrogol emulsified wax, carnauba wax, cetyl alcohol, and cetyl ester.

  The alkaline agent is preferably 2 to 12% by weight of the active ingredient. Various alkaline agents may be used. However, the alkaline agent is preferably 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 of 2% by weight or less of the active ingredient. The surfactant is preferably selected from sodium lauryl sulfate, docusate sodium, polysorbates, and sorbitan fatty acid esters.

  The composition further comprises a diluent in an amount of 5 to 60% by weight of the total composition. The diluent is preferably selected from cellulose, microcrystalline cellulose, lactose, mannitol, sorbitol, starch, calcium carbonate, dicalcium phosphate, silica and pregelatinized starch.

  Preferably, the diluent is prepared in the form of granules using 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 to 10% by weight of the granule. The ratio of microcrystalline cellulose and starch is preferably a ratio of 1.25: 1 to 2: 1.

  The composition preferably comprises a disintegrant in an amount of 1 to 12% by weight relative to the total composition. The disintegrant is preferably selected from carmellose sodium, croscarmellose sodium, starch glycolate sodium, crospovidone, aminoalkyl methacrylate copolymer E, and polylacrilline potassium.

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

  Moreover, it is preferable that a composition contains 1-10 weight% of a sweetener further in the whole composition. The sweetener is preferably selected from aspartame, coated aspartame, ammonium glycerritinate, sodium saccharin, acesulfame potassium, and sugars.

  The composition preferably further comprises one or more fragrances at 1-6% by weight of the total composition. The one or more perfumes are preferably selected from agents having a vanilla, banana, cherry, pineapple, chocolate, caramel, or mint flavor.

  The composition also includes a lubricant system including a lubricant, a lubricant (glidant), a flow agent. The lubricant is selected from magnesium stearate, calcium stearate, stearic acid, and polyoxyethylene stearates. A preferred lubricant (talent) is talc, and a preferred flow agent is selected from silicon dioxide, fatty acid esters, and sodium lauryl sulfate.

In the 2nd aspect of this invention, the manufacturing method of the composition which concerns on Claim 1 including the following processes is shown.
(i) obtaining a granule matrix by mixing the bitter active ingredient with a lipid granulating agent and an alkaline agent;
(ii) Optionally, the granule matrix is further mixed with one or more disintegrants, sweeteners, flavors, and flow agents.
Preferably the granule matrix is prepared by hot melt spiral granulation. Hot melt spiral granulation may be performed at any suitable temperature, but is preferably performed at a temperature below 80 ° C.

  In one embodiment of the method, the composition is compressed and supplied with dispersible tablets in water. In an alternative embodiment, the composition is not compressed and is provided with dispersible granules or powder in water.

[Detailed description]
The present invention relates to dispersible compositions containing bitter-tasting alkaline drug substances, including macrolide antibiotics, alone or in combination with other active substances, as well as methods for making these compositions.

  As used herein, a “dispersible composition” is any solid dosage form including tablets, granules, pellets, and powders that are dispersed in water, including cold water, to form a drinking suspension. Say.

  Any bitter-tasting alkaline drug or formulation of any bitter-tasting drug is contemplated in the present invention. However, the present invention is particularly concerned with macrolide antibiotics, especially erythromycin, roxithromycin, azithromycin, and clarithromycin. The drug is typically a stable hydrate, solvate or salt and may be in any crystalline or amorphous form. The azithromycin used is preferably an isomorphic pseudopolymorph having excellent solubility, as disclosed in Croatian patent application No. P20020231A.

  The compositions of the present invention include any dispersible composition, particularly granules, powders, and tablets. Tablets and capsules are simple and convenient to administer, but children and the elderly create difficulties when swallowed. For larger doses, size is a constraint. Dispersible pharmaceutical compositions can also be titrated according to patient requirements.

  The bitter taste of the mouth suspension formed when a dispersible composition of a bitter drug is dispersed in water is very difficult to mask. The dispersible pharmaceutical composition used according to the present invention, even when compressed, reduces bitterness and does not impair the dissolution properties of the drug substance. The composition meets the requirements set forth in the British Pharmacopoeia for dispersible pharmaceutical compositions, including “dispersible tablets”.

  The granular matrix of dispersible pharmaceutical composition can be prepared by a number of methods. One preferred method is a hot melt spiral granulation method. The use of traditional fluidized bed dryers is known as a method of growing “granules with reduced bitterness”. Other devices such as a high intensity mixer and a mixing device with hot air supply may be used for the same purpose. When fatty acid esters such as glycerol dibehenate or glycerol distearate are used in the description of the present invention, the drying temperature of the powder layer may be kept between 65 ° C and 70 ° C.

  Hot melt spiral granulation is advantageous for spray drying, microencapsulation, and uniform particle coating or encapsulation techniques that require special equipment. This technology is environmentally friendly, reproducible and scaleable.

  The granulating agent used to form the granule matrix in hot melt granulation is a lipid. The lipid may be a wax, oil, fatty acid, fatty alcohol, monoglyceride, diglyceride, or triglyceride. The carbon chain length is typically C12-C30 and may be saturated or unsaturated. Examples include glycerol monostearate, glycerol distearate, glycerol behenate, glycerol dibehenate, and glycerol palmitostearate. The lipid may also be hydrogenated castor oil, cetomacrogol emulsified wax, carnauba wax, cetyl alcohol, or cetyl ester. Any suitable combination of two or more lipids may be used.

  Preferred lipids are usually solid at room temperature (18-22 ° C.), but it is desirable that they dissolve easily by gentle application of temperature (ie, 55-95 ° C.). Mixtures having an average melting point within this range are also included above, even if the melting temperature of the individual composition is outside this temperature range.

  Applicants have surprisingly found that the preferred amount of lipid is 1-16% by weight, preferably 2-8% by weight, based on the active pharmaceutical ingredient. The main advantage of keeping the amount of lipid as low as possible is that it can minimize the impact on drug dissolution / release while reducing the bitter taste of the drug.

  A wetting agent such as sodium lauryl sulfate is also preferably included (2% or less for granules with reduced bitterness). Other wetting agents include docusate sodium, polysorbate, sorbitan fatty acid ester. The wetting agent is a dispersion aid. When used in small amounts, wetting agents generally assist tablet dispersion and dissolution.

  In order to stabilize the pH of the composition, sodium carbonate or tribasic sodium phosphate is preferably added in an amount of 1 to 20% by weight, preferably 2 to 14% by weight, based on the active pharmaceutical ingredient. Evaluate the intragranular and extragranular addition of alkaline materials, both reducing the bitter taste of the dispersible composition. Alkaline materials that dissolve rapidly when the dispersible composition is added to water help to form a uniform dispersion. Typical alkaline agents are sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, and potassium hydroxide.

  Other excipients used alone or in admixture are also added to improve the flowability of the dispersible composition. These diluents include cellulose, microcrystalline cellulose, mannitol, sorbitol, starch, pregelatinized starch, directly compressible microcrystalline cellulose, lactose, calcium carbonate, silica, and dicalcium phosphate.

  Preferred compositions of the present invention are microcrystalline cellulose and corn starch in various ratios of 1: 3 to 3: 1, with a preferred range of 1.25: 1.0 to 1.75: 1.0. Utilizing dilutable granules containing the mixture. Along with a plasticizer (eg, Surelease®), ethylcellulose (2-10%) in a dispersion in water may be used as a granulating agent for dilutable granules. For excipient formulation, the compressibility of the mixture formed when mixed with a granular matrix with reduced bitterness was investigated. The disintegration and fluidity of the dispersible pharmaceutical composition of the present invention is improved when these dilutable granules are used.

  The granular matrix of the bitter active ingredient is processed into a dispersible dosage form using dilutable granules and other diluting materials. Diluent granules have good flow properties, compressibility and disintegration properties. Surprisingly, studies have shown that the cationic polymer, aminoalkyl methacrylate copolymer E (Eudragit® E, EPO) is a suitable disintegrant in dispersible dosage compositions. Aminoalkyl methacrylate copolymer E is poly (butyl methacrylate), (2-dimethylamino ethyl) methacrylate, methyl methacrylate (1: 2: 1). Other disintegrants include carmellose sodium, croscarmellose sodium, starch glycolate sodium, crospovidone, and Polacrilline potassium.

  Aspartame, ammonium glycerritinate (eg Magnus Sweet®), sodium saccharin and other sugars, acesulfame potassium, mannitol may be included as secondary sweeteners. The use of sweeteners at high doses is undesirable and has an unpleasant aftertaste, generally to avoid giving the patient unnecessary amounts of additives. In the present invention, a low level of sweetener (2-5%) is preferably added to impart sweetness. Aspartame is preferred as a sweetener for dispersible compositions such as tablets.

  The selection of a fragrance for a drug with an alkaline bitter taste is difficult. Citrus flavors are not useful because they add bitterness, whereas other flavors such as mint and vanilla synergistically reduce the bitterness of the formulation. The perfumes evaluated are vanilla, banana, cherry, pineapple, caramel, chocolate, mint and related perfume compounds. Formulations with an acceptable taste are realized when the fragrance is mild and when no fragrance is added.

  It is preferred to mix a lubricant such as magnesium stearate or calcium stearate, or a related pharmaceutically acceptable lubricant compound. Magnesium stearate is preferred as the most commonly used drug in pharmaceutical compositions. A fluidizing agent such as silicon dioxide and an anti-adhesive agent (lubricant (glidant)) such as purified talc are also preferable as those included in the dispersible composition of the present invention.

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

  [Example]

Example 1: Granular matrix with reduced bitterness

  A granule matrix was prepared with azithromycin, glycerol dibehenate, and sodium lauryl sulfate. Tribasic sodium phosphate is added in the granule matrix, within the granules, or added extragranularly to the dispersible composition. The granule matrix was examined using a scanning electron microscope (SEM).

  The ingredients were mixed and granulated using a fluid bed processor, with accessories for spiral granulation. A dispersible composition was prepared using these granules.

  Example 2: Granular matrix with reduced bitterness

  A granular matrix was prepared by adding glycerol dibehenate into the granules to obtain a matrix containing 8% by weight of glycerol dibehenate. These granules with a high content of fatty acid esters showed good taste masking properties. This granule was used for a dispersible composition without compression.

  Example 3: Granular matrix with reduced bitterness

  These granules were prepared by using tribasic sodium phosphate intragranular or extragranular. Glycerol distearate was used as a granulating agent. These granules can be used to form various dispersible compositions.

  Example 4: Dilutable granules

  Dilutable granules were prepared using microcrystalline cellulose (Avicel® PH 101) and corn starch. The granulating agent used was an aqueous dispersion of ethyl cellulose (Surelease®). The granule was dried at 60 ° C., and the dried granule was sized to become a granule having fast disintegration and fluidity.

Example 5: Eudragit® EPO as disintegrant / dispersant in dispersible tablets
The granular matrix of Example 2 and the dilutable granules of Example 4 were mixed. The granules were sieved (40 #) and mixed with other excipients: aspartame, disintegrant / dispersant, sodium triphosphate, anhydrous colloidal silica, and talc. The mixture was lubricated with magnesium stearate. The following disintegration / dispersing agents were used: aminoalkyl methacrylate copolymer E (Eudragit® EPO), carmellose sodium, starch glycolate sodium, and polylacrilline potassium. Each dispersion obtained by compressing the tablets with granules of the dispersible composition and placing each tablet in 60 ml of 25 ° C. water in a 150 ml glass beaker was evaluated.

  The results for carmellose cellulose, starch glycolate sodium, and polylacrilline potassium were not satisfactory. Several clumped tablet aggregates were observed after 3 minutes in the beaker.

  Eudragit® EPO was used at a rate of 100 mg per tablet. A good tablet dispersion was observed (see table below). These tablets meet the disintegration test for tablets in terms of dispersible tablets and uniformity of dispersion.

  Evaluation of Eudragit® EPO as a disintegrant / dispersant

  Example 6: Dispersible pharmaceutical composition such as tablets

  The granular matrix of Example 1 and the dilutable granules of Example 4 were mixed. The granules were sieved (40 #) and mixed with other excipients: aspartame, aminoalkylmethacrylate copolymer E (Eudragit® EPO), sodium triphosphate, anhydrous colloidal silica, and talc. The mixture was lubricated with magnesium stearate.

  Tablets were compressed with granules of the dispersible composition and evaluated for taste, uniformity of dispersion and other pharmaceutical formulation tests. The reconstituted tablets were confirmed to be acceptable for taste as well as for dissolution, potency assay, hardness, brittleness, and ease of reconstitution.

Example 7: Evidence for masking bitterness The composition for taste evaluation comprises granules containing 500 mg azithromycin, dilutable granules (starch and microcrystalline cellulose granules), talc, colloidal silica, and magnesium stearate. It was. The level of fatty acid ester in the granule with reduced bitterness is different as shown in the table below. Trisodium phosphate and aspartame levels were also varied as shown in the table below. The composition was evaluated by 5 volunteers.

  The composition was dispersed in 60 ml of water and was evaluated for taste immediately after dispersion.

Taste rating:
A: Good taste and acceptable formulation
B: Tasteful and acceptable formulation, but with very low bitterness and very low aftertaste
C: Tasteful and acceptable formulation with low bitterness and low aftertaste
D: Good taste and acceptable formulation, but with low bitterness and unacceptable aftertaste
E: Bitter aftertaste and bitterness, not a good-tasting formulation,
F: Because of the great bitter taste, it cannot be said to be a good-tasting formulation

Compositions VII and VIII, which contained glycerol dibehenate, a fatty acid ester, sodium phosphate, an alkaline buffer salt, and aspartame, a sweetener, were significantly better than compositions I-VI.
Composition VIII was too sweet and showed a bitter aftertaste.

Example 8: Evidence for masking bitterness A composition for taste evaluation comprises granules containing 500 mg of azithromycin, dilutable granules (starch and microcrystalline cellulose granules), aminoalkyl methacrylate copolymer E (Eudragit®) ) EPO), talc, colloidal silica, and magnesium stearate. The levels of fatty acid esters and aspartame in the granules with reduced bitterness were constant as can be seen in the table. Although the level of tribasic sodium phosphate was constant, it was used extragranular except for XI used intragranularly. The composition was evaluated by 5 volunteers.

  In the table below, composition XII was the same as VII without azithromycin. The taste of the dispersion was compared to Composition VII without the azithromycin drug. This composition was marked XII.

Taste rating:
A: Good taste and acceptable formulation
B: Tasteful and acceptable formulation, but with very low bitterness and very low aftertaste
C: Tasteful and acceptable formulation with low bitterness and low aftertaste
D: Good taste and acceptable formulation, but with low bitterness and unacceptable aftertaste
E: Bitter aftertaste and bitterness, not a good-tasting formulation
F: Because of the great bitter taste, it cannot be said to be a good-tasting formulation

Observation:
Volunteers showed acceptance for these azithromycin prescriptions.
The higher acceptance for a composition without a fragrance than that for a composition having a fragrance composition such as vanilla or banana indicates that the fragrance is not essential in this type of formulation. Anhydrous sodium triphosphate showed barely good acceptance when used in the granules with fatty acid esters. Although the invention has been described by way of examples, it should be recognized that variations or modifications can be made without departing from the scope of protection of the claims of the invention. Further, where there are equivalent known aspects of certain aspects, such aspects and the like are to be referred to and included in this specification.

Claims (31)

(i) bitter active ingredients;
(ii) a lipid granulating agent in an amount of 1 to 16% by weight of the active ingredient; and
(iii) an alkaline agent in an amount of 1 to 20% by weight of the active ingredient;
Including
A dispersible pharmaceutical composition wherein the bitter taste of the active ingredient is partially or completely masked.   The composition of claim 1 wherein the bitter tasting active ingredient is a macrolide antibiotic.   The macrolide antibiotic is selected from erythromycin, clarithromycin, roxithromycin and azithromycin, preferably the same pseudo-polymorph showing excellent solubility, similar to that disclosed in Croatian patent application No. P20020231A 3. A composition according to claim 2 comprising azithromycin.   4. The composition according to any one of claims 1 to 3, wherein the lipid granulating agent is in the range of 2 to 8% by weight of the active ingredient.   The composition according to any one of claims 1 to 4, wherein the lipid granulating agent is a wax, a fatty acid, an aliphatic alcohol, or a mono-, di-, or triglyceride of one or more fatty acids.   The lipid granulating agent comprises glycerol mono-, di- and tri-stearate glycerol, mono-, di- and tri-palmito stearate glycerol, mono-, di- and tri-behenate glycerol, mono 6. A composition according to claim 5 selected from-, di- and tri-oleate glycerol, hydrogenated castor oil, cetomacrogol emulsified wax, carnauba wax, cetyl alcohol and cetyl ester.   The composition according to any one of claims 1 to 6, wherein the alkaline agent is 2 to 12% by weight of the active ingredient.   The composition according to any one of claims 1 to 7, wherein the alkaline agent is selected from sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, or potassium hydroxide.   9. A composition according to any one of the preceding claims comprising a surfactant in an amount of 2% or less by weight of the active ingredient.   The composition according to claim 9, wherein the surfactant is selected from sodium lauryl sulfate, docusate sodium, polysorbates, and sorbitan fatty acid esters.   11. A composition according to any preceding claim, further comprising a diluent in an amount of 5 to 60% by weight of the total composition.   12. A composition according to claim 11 wherein the diluent is preferably selected from cellulose, microcrystalline cellulose, lactose, mannitol, sorbitol, starch, calcium carbonate, dicalcium phosphate, silica, and pregelatinized starch. .   12. The composition of claim 11 wherein the diluent granules are prepared using a combination of microcrystalline cellulose and starch in a ratio of 1: 3 to 3: 1 and water-insoluble cellulose.   The composition according to claim 13, wherein the water-insoluble cellulose is ethylcellulose in an amount of 2 to 10% by weight of the granules.   14. The composition of claim 13, wherein the ratio of microcrystalline cellulose and starch is a ratio of 1.25: 1 to 2: 1.   The composition according to any one of claims 1 to 15, further comprising a disintegrant in an amount of 1 to 12% by weight relative to the total composition.   The composition according to claim 16, wherein the disintegrant is selected from carmellose sodium, croscarmellose sodium, starch glycolate sodium, crospovidone, aminoalkyl methacrylate copolymer E, and polylacrilline potassium.   The composition of claim 17, wherein the disintegrant is an aminoalkyl methacrylate copolymer E which is a cationic polymer.   The composition according to any one of claims 1 to 18, further comprising a sweetener in an amount of 1 to 10% by weight relative to the total composition.   20. The composition of claim 19, wherein the sweetener is selected from aspartame, coated aspartame, ammonium glycerritinate, sodium saccharin, acesulfame potassium, and sugars.   21. The composition according to any one of claims 1 to 20, further comprising one or more fragrances in an amount of 1 to 6% by weight of the total composition.   22. The composition of claim 21, wherein the one or more fragrances are selected from reagents having a flavor of vanilla, banana, cherry, pineapple, chocolate, caramel, or mint.   23. The composition of claim 21, further comprising a lubricant system comprising a lubricant, a lubricant (gliant), and a flow agent.   24. The composition of claim 23, wherein the lubricant is selected from magnesium stearate, calcium stearate, stearic acid, and polyoxyethylene stearates.   24. The composition of claim 23, wherein the lubricant is talc.   24. The composition of claim 23, wherein the flow agent is selected from silicon dioxide, fatty acid esters, and sodium lauryl sulfate. A method for producing a composition according to claim 1, comprising:
(I) a step of obtaining a granular matrix by mixing the bitter active ingredient with the lipid granulating agent and the alkaline agent; and (ii) optionally adding a wetting agent, and further adding one or more granular matrices. The manufacturing method including the process of mixing with a disintegrating agent, a sweetener, a fragrance | flavor, and a flow agent.   28. The method of claim 27, wherein the granule matrix is prepared by hot melt spiral granulation.   29. The method of claim 28, wherein the hot melt spiral granulation is performed at a temperature less than 80C.   30. A method according to any one of claims 27 to 29, wherein the composition is compressed to provide a dispersible tablet in water. 30. A method according to any one of claims 27 to 29, wherein the composition provides dispersible granules or powder in water without being compressed.