KR101122096B1 - Pharmaceutical composition of clarithromycin and its manufacturing method for taste masking and increasing dissolution rate - Google Patents

Abstract

The present invention is to improve the dissolution rate while shielding the bitter taste of clarithromycin, characterized in that the core particles containing clarithromycin and hydroxypropyl cellulose of 10 to 60% of the weight of clarithromycin is coated with an enteric base The pharmaceutical composition, which has a bitter taste and excellent dissolution rate, ensures drug efficacy, and thus, formulations such as dry syrups, suspensions, powders, granules or chewed tablets for children or the elderly who have difficulty in taking solids such as tablets and capsules. It is possible to develop with.

Clarithromycin, hydroxypropylcellulose, bitter taste, dissolution rate, core particles, enteric base.

Description

Pharmaceutical composition of clarithromycin with excellent dissolution rate while masking bitter taste and its preparation method {PHARMACEUTICAL COMPOSITION OF CLARITHROMYCIN AND ITS MANUFACTURING METHOD FOR TASTE MASKING AND INCREASING DISSOLUTION RATE}

The present invention is intended to improve the dissolution rate while masking the bitter taste of clarithromycin, specifically, the pharmaceutical composition of clarithromycin coated with an enteric base and using hydroxypropylcellulose as a binder in clarithromycin It is about how to.

Clarilidemycin, a macrolide antibiotic, has high activity against a wide range of bacterial infections, such as upper ear infections such as otitis media, pharyngitis, tonsillitis, lower respiratory tract infections such as bronchitis, and pneumonia, and mycobacterial infections. It is very useful for treating conventional infections. However, because clarithromycin has a very bitter taste and causes discomfort when taken orally, it is difficult to take it in a solid state such as children or the elderly, and therefore, when administered in the form of suspensions, powders, granules, and chewed tablets, The disadvantage is that it causes severe rejection.

As a method for effectively masking this bitter taste of clarithromycin, a method of coating clarithromycin with a pH dependent material may be sought first. However, at pH 5.5 or higher, the wettability of clarithromycin is poor, and the decomposition of the drug occurs in a lower pH environment. Therefore, when clarithromycin is coated with gastric disintegrating substance under acidic conditions, the rapid degradation occurs under acidic conditions, thereby reducing the therapeutic effect and causing deviations in the efficacy according to the residence time of the stomach. There is a risk of causing severe deviations in the effects. On the other hand, when clarithromycin is coated with an enteric material, it exhibits a rapid drop in dissolution rate and a decrease in treatment effect due to poor wettability of clarithromycin in a pH environment in which the film collapses.

The Korean Standards Standard for Antibiotic Drugs specifies that the dissolution rate for clarithromycin dry syrup is 80% or higher at pH 6.8. In other words, in order to ensure the therapeutic effect of clarithromycin, it is very important to solve the problem of poor wettability at pH 5.5 or higher, and in particular, to improve the wettability of clarithromycin in the small intestine in a pH 6.8 environment, thereby rapidly dissolving the drug. To achieve this is a problem to be solved by the present invention.

Korean Laid-Open Patent Publication No. 1999-67265 describes an aqueous granulation method of clarithromycin using a carbomer, and a product which masks the bitter taste by applying an enteric coating to the granules thus prepared is currently clariside ^R (technical raw material source). : ABBOTT) is commercially available under the trade name. This product is characterized by the production of clarithromycin granules in order to mask the bitter taste, and then to form a coating with an enteric substance dissolved at pH 5.5 or higher. That is, by using a carbomer is a method of securing the dissolution rate by improving the physical properties of clarithromycin difficult to secure a rapid dissolution rate due to poor wettability in an environment of pH 5.5 or more, and also to prepare the aqueous granules without using an organic solvent. This method has the advantage of covering the bitter taste with clarithromycin coated with an enteric material to ensure dissolution rate at pH 6.8, as well as to protect the drug in low pH environments where the drug is unstable.

However, aqueous granulation methods using carbomers have the disadvantage of producing quality differences depending on the rate and amount of water addition, the granulation temperature and time. That is, there is a limitation that the blending step with the carbomer must be performed in a vessel having a head space maintained at a temperature of about 0 to 70 ° C. In addition, there is a disadvantage that the yield is low, such as fine powder is generated during the granulation process to undergo a re-granulation process.

Korean Patent Registration No. 218700 discloses Eudragit E ^R (methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer) and AEA (polyvinylacetan diethyl) for basic drugs with an unpleasant taste. A technique of masking the bitter taste by dispersing or dissolving a functional polymer compound selected from amino acetate) and mixtures thereof in a low melting point material having a melting point of 40 to 120 ° C. and spray-cooling is described. In addition, the Republic of Korea Patent No. 404293 discloses a pharmaceutical composition consisting of a drug having an unpleasant taste, gastric soluble high molecular material and β-crystalline monoglycerides.

In the prior art, waxes of low melting point are mainly used, which not only has the disadvantage that the physical properties change with the temperature rise during the distribution after the manufacture of the product, and also the decomposition of the clarithromycin is easy because the film collapses under acidic conditions. There is a problem of exposure to the environment. That is, the above-mentioned conventional technique using gastric polymers and waxes as a method for masking the bitter taste of clarithromycin may solve the wettability problem of clarithromycin, but releases the drug in an acidic environment in which the drug is degraded. There are disadvantages.

Meanwhile, Korean Unexamined Patent Publication No. 2001-0006251 discloses a method of preparing a sustained release formulation using clarithromycin and a water-soluble polymer composition. That is, an object of the present invention is to delay drug release through a composition of clarithromycin and a water-soluble polymer, which is contrary to the object of the present invention to increase the dissolution rate of drugs. In particular, the present invention employs a composition coated with an enteric base to mask the bitter taste of clarithromycin and to protect the drug from gastric acid, which is different from the above technique.

The clarithromycin can be effectively masked by bitterness when coated with an enteric base, and can be expected to increase the therapeutic effect by protecting the drug from an unstable acidic environment. However, in spite of these advantages, in the environment of pH 5.5 or higher in which the enteric coating collapses to release the drug, the dissolution rate is sharply lowered due to the poor wettability of clarithromycin, which is the most important and difficult task in product development. can do.

In the conventional method, the clarithromycin is coated with an enteric material to shield the bitter taste and the dissolution rate is secured. Since the granules prepared by the clarithromycin granules are manufactured in a very complicated equipment and process, they contain a considerable amount of powder. There is a problem in that it requires an additional regranulation process and the yield is lowered.

An object of the present invention is to solve the problem of clarithromycin, which causes severe rejection when administered in dosage forms such as suspensions, powders, granules and chewable tablets to children or the elderly and very strong unpleasant taste, clarithromycin The present invention provides a pharmaceutical composition of clarithromycin capable of achieving rapid drug release in a pH 6.8 environment with poor wettability while being coated with an enteric material to mask the bitter taste of the present invention.

The pharmaceutical composition of the present invention for achieving the above object is characterized in that the core particles comprising clarithromycin and hydroxypropyl cellulose of 10 to 60% by weight of clarithromycin is coated with an enteric base.

Method for producing a pharmaceutical composition comprising the clarithromycin of the present invention for achieving the above another object, the liquid dissolved 10% to 60% of hydroxypropyl cellulose in the solvent of clarithromycin in association with clarithromycin And then granulating and drying to prepare the core particles, and coating the core particles with an enteric base.

Here, the hydroxypropyl cellulose is preferably 10 to 30% of the weight of clarithromycin, and the enteric base is preferably coated in an amount of 80 to 200% with respect to the core particles.

In general, hydroxypropyl cellulose is used as a binder of tablets, it is known to use 2 to 6%, 15 to 35% for the purpose of developing a long-acting formulation to delay drug release (HAND BOOK of PHARMACEUTICAL EXCIPIENTS , 3th EDITION, p244). In the course of studying the composition and preparation method of clarithromycin-coated particles, the inventors of the present invention, on the contrary, to the contrary to the general theory, when the particles are prepared using an excess amount of hydroxypropyl cellulose in excess of 2 to 6% of the conventional binder, It was found that the dissolution rate was further improved at pH 6.8. Accordingly, the core particles prepared by associating 10 to 60%, preferably 10 to 30%, of hydroxypropylcellulose with clarithromycin with a binder dissolved in a solvent are coated with an enteric base. A pharmaceutical composition of clarithromycin with excellent dissolution rate and masked bitter taste without complicated equipment and equipment has been prepared. Herein, when the amount of hydroxypropyl cellulose is less than 10% of clarithromycin, the dissolution rate improvement effect is insufficient, and when the amount of hydroxypropyl cellulose is more than 60%, the association is difficult, causing problems in manufacturing.

That is, in the present invention, the core particles are prepared using hydroxypropyl cellulose, and then coated with an enteric material to provide coated particles of clarithromycin capable of securing dissolution rate at pH 6.8 while masking bitter taste. Although the granulation method using a conventional carbomer is manufactured under complex apparatus and process conditions, unlike the fine granules generated during the granulation process and undergoing re-granulation, the present invention not only uses a very simple process and apparatus, It provides the core particles of clarithromycin in high yield with little generation of fines in the process.

In the present invention, in order to secure an excellent dissolution rate of clarithromycin at pH 6.8, an excess amount of hydroxypropyl cellulose is used than a conventional amount, which may be difficult to stir due to an increase in viscosity during the binder manufacturing process. However, the present inventors solved this problem by dividing the hydroxypropyl cellulose several times to produce a binder, and then repeated association, granulation, drying and grinding operations, and evaluated the dissolution rate of the prepared core particles in one process. There was no difference from the prepared core particles. For example, in the case of associating 15% of hydroxypropyl cellulose with clarithromycin, 7.5% of hydroxypropyl cellulose is first dissolved in a solvent to perform the association, granulation, drying and grinding processes. The core particles may be prepared by adding a binder in which 7.5% of the remaining hydroxypropyl cellulose is dissolved in a solvent and repeating the process from association to grinding.

As a solvent for dissolving hydroxypropyl cellulose in the production method of the present invention, water and ethanol may be used alone or in combination. The amount of the solvent can be changed according to various factors such as the type of solvent, the lot size, the associative group to be used, the amount of hydroxypropyl cellulose, and the amount of the solvent that can be maintained in a pharmaceutically conventional association state is used.

The combination produced by mixing hydroxypropylcellulose binder solution with clarithromycin is granulated with a conventional granulator such as an Alexander granulator and then dried. The drying process is carried out using a conventional dryer.

With the dried product obtained by the above process, a core particle of 40 to 200 mesh can be obtained by using a sieve or a pulverizer or a pulverizer commonly used in the pharmaceutical field. Preferably, the pulverizer is pulverized to 50 mesh or less and then 40 to 200 mesh of core particles are prepared in a fluid bed granulator. Specifically, 40 to 200 mesh core particles can be produced in very good yield by spraying a solvent while flowing the powder in a fluidized bed granulator, or by forming particles while spraying a liquid in which a water-soluble polymer is dissolved in a solvent. . Here, as the water-soluble polymer, cellulose, derivatives of cellulose, polyvinylpyrrolidone, starch, and the like can be used alone or in combination, but are not limited to these in the nature of the present invention. As a solvent of the water-soluble polymer, water and ethanol may be used alone or in combination, and the amount of the water-soluble polymer is preferably used in an amount of less than 10%, preferably less than 5% based on the pulverized product.

Coated particles may be prepared while spraying a solution obtained by dissolving or dispersing an enteric base in a solvent while flowing the core particles prepared as described above in a fluidized bed granulator. As a solvent, water and ethanol may be used alone or in combination, and as an enteric base, a water-soluble polymer and a water-insoluble polymer known in the pharmaceutical art may be used alone or in combination. Although these enteric bases are Eudragit L30 D-55 suitable coating materials in terms of ease of operation, other enteric bases known in the art, for example hydroxypropylmethylcellulose phthalate HP 50 (HPMCP-HP 50) , Hydroxypropylmethylcellulose phthalate HP 55 (HPMCP-HP 55) and hydroxypropylmethylcellulose phthalate HP 55S (HPMCP-HP 55S), polyvinyl acetate phthalate, cellulose acetate phthalate, or mixtures thereof. The nature of the invention is not limited to these.

The amount to coat the core particles may vary depending on the enteric base, but usually 80 to 200% is preferred for the core particles to be coated. The amount of coating varies depending on the size of the particles. In the core particles of 40 to 200 mesh as in the present invention, when the amount of coating is 80% or more, complete coating is possible, and thus bitterness shielding is also possible.

The enteric coating may optionally contain a plasticizer. In the preparation method of the clarithromycin particles according to the present invention, the plasticizer is not particularly limited, and triethyl citrate, diethyl phthalate, triacetin, tributyl sebate, polyethylene glycol, or mixtures thereof commonly used in the art. Can be used. In addition, talc, magnesium stearate, hard silicic acid, and the like may be added to the coating liquid or the material to be flowed in order to prevent adhesion or adhesion between the coater wall and particles during coating, but is not limited thereto.

Pharmaceutical compositions comprising clarithromycin prepared according to the present invention can be prepared in the form of dry syrups, suspensions, powders, granules or chewable tablets by the addition of excipients conventionally acceptable in the art of the manufacture of a medicament.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these Examples are only illustrative of the present invention, and the scope of the present invention is not limited thereto.

Comparative Example 1

500 g of clarithromycin was added to the coalescing machine, and 25 g of hydroxypropyl cellulose was combined using a solution dissolved in 400 ml of ethanol, and then granulated and dried through No. 12 sieve. The dried product was passed through No. 16 sieve and No. 30 sieve, and then screened to prepare 40 to 200 mesh core particles.

Comparative Example 2

500 g of clarithromycin was added to the associator, and 37.5 g of hydroxypropyl cellulose was dissolved using 400 ml of ethanol, and then granulated and dried through No. 12 sieve. The dried product was passed through No. 16 sieve and No. 30 sieve, and then screened to prepare 40 to 200 mesh core particles.

Example 1

500 g of clarithromycin was added to the coalescer, and 50 g of hydroxypropyl cellulose was dissolved in 400 ml of ethanol. The dried product was passed through No. 16 sieve and No. 30 sieve, and then screened to prepare 40 to 200 mesh core particles.

Example 2

500 g of clarithromycin was added to the coalescer, and 75 g of hydroxypropyl cellulose was dissolved in 400 ml of ethanol. The dried product was passed through No. 16 sieve and No. 30 sieve, and then screened to prepare 40 to 200 mesh core particles.

Example 3

500 g of clarithromycin was added to the associator, and 37.5 g of hydroxypropyl cellulose was dissolved using 400 ml of ethanol, and then granulated and dried through No. 12 sieve. The dried product was pulverized and re-aggregated with a solution of 37.5 g of hydroxypropyl cellulose dissolved in 400 ml of ethanol in an associated machine, and then granulated and dried through No. 12 sieve. The dried product was passed through No. 16 sieve and No. 30 sieve, and then screened to prepare 40 to 200 mesh core particles.

Example 4

500 g of clarithromycin was added to the coalescer, and 50 g of hydroxypropyl cellulose was dissolved in 400 ml of ethanol. The dried product was pulverized and fed again using a liquid obtained by dissolving 50 g of hydroxypropyl cellulose in 400 ml of ethanol in an associated machine, and then granulated and dried through No. 12 sieve. The dried product was passed through No. 16 sieve and No. 30 sieve, and then screened to prepare 40 to 200 mesh core particles.

Example 5

500 g of clarithromycin was added to the coalescer, and 50 g of hydroxypropyl cellulose was dissolved in 400 ml of ethanol. The dried product was pulverized and fed again using a liquid obtained by dissolving 50 g of hydroxypropyl cellulose in 400 ml of ethanol in an associated machine, and then granulated and dried through No. 12 sieve. The dried product was pulverized and again fed together using a solution in which 50 g of hydroxypropyl cellulose was dissolved in 400 ml of ethanol in an associated machine, and then granulated and dried through No. 12 sieve. The dried product was passed through No. 16 sieve and No. 30 sieve, and then screened to prepare 40 to 200 mesh core particles.

Example 6

500 g of clarithromycin was added to the coalescing machine, and 50 g of hydroxypropyl cellulose was dissolved using 400 ml of ethanol, followed by granulation through a No. 12 sieve and dried. While the dry matter is pulverized to 50 mesh or less and the pulverized product is flowed in a fluidized bed granulator, a binder in which 5% of hydroxypropyl cellulose is dissolved in 500 ml of water is sprayed on the pulverized product to flow the core particles of 40 to 200 mesh. Prepared.

Example 7

500 g of clarithromycin was added to the coalescer, and 75 g of hydroxypropyl cellulose was dissolved in 400 ml of ethanol. The dried product was pulverized to 50 mesh or less and water was sprayed while flowing the pulverized product in a fluidized bed granulator to prepare core particles of 40 to 200 mesh.

Example 8

500 g of clarithromycin was added to the coalescer, and 37.5 g of hydroxypropyl cellulose was dissolved in 400 ml of ethanol. The dried product was pulverized and re-aggregated with a solution of 37.5 g of hydroxypropyl cellulose dissolved in 400 ml of ethanol in an associated machine, and then granulated and dried through No. 12 sieve. The dried product was pulverized to 50 mesh or less and water was sprayed while flowing the pulverized product in a fluidized bed granulator to prepare core particles of 40 to 200 mesh.

Example 9

500 g of clarithromycin was added to the associator, and 37.5 g of hydroxypropyl cellulose was dissolved using 400 ml of ethanol, and then granulated and dried through No. 12 sieve. The dried product was pulverized and re-aggregated with a solution of 37.5 g of hydroxypropyl cellulose dissolved in 400 ml of ethanol in an associated machine, and then granulated and dried through No. 12 sieve. While the dry matter is pulverized to 50 mesh or less and the pulverized product is flowed in a fluidized bed granulator, a binder in which 3% of hydroxypropyl cellulose is dissolved in 500 ml of water is sprayed on the pulverized product to flow the core particles of 40 to 200 mesh. Prepared.

Example 10

500 g of clarithromycin was added to the associator, and 37.5 g of hydroxypropyl cellulose was dissolved using 400 ml of ethanol, and then granulated and dried through No. 12 sieve. The dried product was pulverized and re-aggregated with a solution of 37.5 g of hydroxypropyl cellulose dissolved in 400 ml of ethanol in an associated machine, and then granulated and dried through No. 12 sieve. 40 to 200 mesh core particles are sprayed with a binder in which 5% of hydroxypropyl cellulose is dissolved in 500 ml of water, while the dried product is pulverized to 50 mesh or less and the pulverized product is flowed in a fluidized bed granulator. Was prepared.

Example 11

500 g of clarithromycin was added to the coalescer, and 50 g of hydroxypropyl cellulose was dissolved in 400 ml of ethanol. The dried product was pulverized and fed again using a liquid obtained by dissolving 50 g of hydroxypropyl cellulose in 400 ml of ethanol in an associated machine, and then granulated and dried through No. 12 sieve. While the dry matter is pulverized to 50 mesh or less and the pulverized product is flowed in a fluidized bed granulator, a binder in which 3% of hydroxypropyl cellulose is dissolved in 500 ml of water is sprayed on the pulverized product to flow the core particles of 40 to 200 mesh. Prepared.

Example 12

500 g of clarithromycin was added to the coalescer, and 50 g of hydroxypropyl cellulose was dissolved using 400 ml of ethanol. The mixture was granulated and passed through No. 12 sieve and dried. The dried product was pulverized and fed again using a liquid obtained by dissolving 50 g of hydroxypropyl cellulose in 400 ml of ethanol in an associated machine, and then granulated and dried through No. 12 sieve. The dried product was pulverized and fed again using a liquid obtained by dissolving 50 g of hydroxypropyl cellulose in 400 ml of ethanol in an associated machine, and then granulated and dried through No. 12 sieve. While the dried product was pulverized to 50 mesh or less and the pulverized product was flowed in a fluidized bed granulator, a binder in which 2% of hydroxypropyl cellulose was dissolved in 500 ml of water was sprayed on the pulverized product to flow the core particles of 40 to 200 mesh. Prepared.

Preparation Example: Preparation of Enteric Coated Particles

While 500 g of the core particles prepared in Examples 1 to 12 were flowed in a fluidized bed granulator, 120 g of triethyl citrate and 150 g of talc were added to a solution of 4 kg of Eudragit L30 D-55 and 8 kg of purified water. The core particles were coated while spraying the coating solution prepared by addition and suspension. The coating particles were taken when the amount of Eudragit to the core particles was coated with 80%, 100%, 120%, 140%, 160%, 180% and 200% as the solid component during enteric coating.

Dissolution Test

Each core particle and enteric-coated particle was taken in an amount corresponding to 250 mg with clarithromycin, and then 50 ml at 37 ± 0.5 ° C. with 900 ml of 0.05 mol / L potassium dihydrogen phosphate buffer (pH 6.8) as eluent. The test was carried out according to the Dissolution Test Method No. 2 of the Korean Pharmacopoeia General Test Method. 45 minutes after the start of the elution, a certain amount of the eluate was taken out, filtered through a membrane filter of 0.45 μm or less, and diluted to contain 0.2 mg per ml as a mobile phase to obtain a sample solution. Separately, about 50 mg of commercial standard clarithromycin was precisely weighed and dissolved in methanol to make exactly 25 ml. 5 ml of this solution was taken and a mobile phase was added to make exactly 50 ml. The peak areas A _T and A _S of clarithromycin were determined by testing the liquid chromatograph method with 20 μl of the sample solution and the commercial standard solution under the following conditions.

-Liquid chromatography conditions

Detector: ultraviolet absorbance photometer (wavelength 210 nm)

Column: 4.6 mm inside diameter and 150 mm length column filled with octadecylsilylated 5 μm silica gel

Mobile phase: A solution in which a mixture of methanol and 0.067 mol / L potassium dihydrogen phosphate solution (65:35) was adjusted to pH 4.0 with phosphoric acid

Flow rate: 1.0 ml per minute

Dissolution Rate (%) =

Table 1 shows coating particles coated with 80%, 100%, 120%, 140%, 160%, 180% and 200% of the core particles and enteric base prepared according to Comparative Examples 1 and 2, and Examples 1 to 12 The dissolution rate measurement result of is shown.

Coating amount 0% 80% 100% 120% 140% 160% 180% 200% Comparative Example 1 54% - - - - - - - Comparative Example 2 58% - - - - - - - Example 1 88% 90% 89% 92% 91% 88% 89% 92% Example 2 90% 91% 93% 90% 92% 91% 89% 90% Example 3 92% 93% 92% 95% 91% 92% 92% 93% Example 4 92% 90% 93% 92% 91% 91% 91% 90% Example 5 93% 92% 93% 93% 90% 89% 91% 89% Example 6 91% 92% 90% 91% 92% 90% 93% 92% Example 7 94% 91% 92% 90% 89% 90% 92% 93% Example 8 90% 90% 91% 93% 91% 92% 92% 90% Example 9 92% 91% 91% 90% 91% 92% 90% 89% Example 10 89% 90% 90% 92% 92% 93% 92% 91% Example 11 92% 92% 92% 90% 93% 89% 88% 90% Example 12 90% 92% 91% 93% 92% 90% 89% 91%

As shown in Table 1 above, in the compositions of Examples 1 to 12 in which the amount of hydroxypropyl cellulose is 10% or more of clarithromycin, all of the dissolution rates at pH 6.8 exceeded 80%, and thus the standard was used. The same was true when coated with. On the other hand, in Comparative Examples 1 and 2 where the amount of hydroxypropyl cellulose was 5% and 7.5% of clarithromycin, the dissolution rates at pH 6.8 were 54% and 58%, respectively, well below the baseline 80%. Can be.

In addition, in Examples 1 to 12, complete coating was possible in all cases when the coating amount of the enteric base was 80% to 200% of the core particles, and the bitterness was also masked.

As described above, since the composition containing clarithromycin prepared according to the present invention is secured because the bitter taste is shielded and the dissolution rate is excellent, it is difficult for children or the elderly to take solid agents such as tablets and capsules. It is possible to develop into formulations such as dry syrups, suspensions, powders, granules or chewable tablets.

Claims (14)

A pharmaceutical composition, characterized in that the core particles comprising clarithromycin and clarithromycin 10 to 60% by weight of hydroxypropylcellulose are coated with an enteric base. delete delete delete The method of claim 1 wherein the enteric base is Eudragit L30 D-55, hydroxypropylmethylcellulose phthalate HP 50 (HPMCP-HP 50), hydroxypropylmethylcellulose phthalate HP 55 (HPMCP-HP 55), hydroxypropyl Methylcellulose phthalate HP 55S (HPMCP-HP 55S), polyvinyl acetate phthalate, cellulose acetate phthalate, or mixtures thereof. The composition of claim 1, further comprising a plasticizer selected from the group consisting of triethyl citrate, diethyl phthalate, triacetin, tributyl sebcate, polyethylene glycol, or mixtures thereof. delete The solution of 10 to 60% of the hydroxypropyl cellulose in the weight of clarithromycin dissolved in water, ethanol, or mixtures thereof is combined with clarithromycin, and the granulated and dried dry matter is pulverized to 50 mesh or less and flowed in a fluidized bed granulator. Spraying water, ethanol, or mixtures thereof alone, or dissolving a water-soluble polymer selected from celluloses, derivatives of celluloses, polyvinylpyrrolidones, starches, or mixtures thereof in water, ethanol, or mixtures thereof. Method for producing a pharmaceutical composition comprising clarithromycin characterized in that the core particles are prepared by spraying the solution. delete delete delete 10. The method of claim 8, wherein the water soluble polymer is used in an amount of less than 10% relative to the milled product. delete delete