JP2006232789A - Composition for oral formulation and process thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a composition for oral formulation which can mask unpleasant taste such as bitterness even though it contain a macrolide antibiotic and which has medicinal properties with high elution ability, and a process thereof. <P>SOLUTION: In the composition for oral formulation in which a powdery composition comprising at least the macrolide antibiotic is coated with a polymer composition comprising a pH-independent and water-insoluble polymer and a polymer soluble in stomach, a ratio of the pH-independent and water-insoluble polymer to the polymer soluble in stomach (weight ratio) is adjusted to 1/1-1/20. The pH-independent and water-insoluble polymer may be, for example, a cellulose derivative (e.g. ethyl celluloses) and a (meth)acrylic polymer or the like. The macrolide antibiotic may be, for example, a 14-membered ring compound like clarithromycin. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a composition for oral preparation containing a macrolide antibiotic such as clarithromycin and a method for producing the same.

  Macrolide antibiotics such as clarithromycin are frequently used as antibiotics such as streptococcal pharyngitis and pneumococcal pneumonia. However, since macrolide antibiotics exhibit an unpleasant taste such as a bitter taste, they are used by masking the unpleasant taste, particularly when used for children. Therefore, a method for masking the unpleasant taste of such macrolide antibiotics has been proposed.

  For example, Japanese Patent Laid-Open No. 6-116138 (Patent Document 1) discloses a basic substance such as a gastric polymer compound and a macrolide constituent material to a hot-melted low-melting-point material (stearyl alcohol, glycerin stearate, etc.). An oral pharmaceutical composition containing a complex obtained by dispersing a drug, a sugar alcohol, and a basic oxide is disclosed. WO 96/34628 (Patent Document 2) discloses a composition for oral administration comprising a drug exhibiting an unpleasant taste such as a macrolide antibiotic, a gastric soluble polymer compound, and a β-crystal form monoglyceride. ing.

  However, since these compositions use fatty acid or ester thereof, which is a low melting point substance, the thermal stability is lowered and odor is generated. Moreover, since a low melting point substance is used, manufacturing conditions must be strictly controlled, making it difficult to handle. Furthermore, since it contains a fatty acid component, its dispersibility in water is low and it is not suitable for applications that require dispersibility in water, such as dry syrups.

  In addition, JP 2004-315424 A (Patent Document 3) granulates a drug having a bitter taste mixed with a forming component using 2 to 40% of ethyl cellulose as a binder based on the weight of the whole granule. An immediate release drug-containing granule with reduced bitterness is disclosed. However, this granule cannot sufficiently mask the bitterness of the drug, and therefore cannot be used in applications where the bitterness must be highly masked, such as a pediatric preparation.

Furthermore, Japanese Patent Application Laid-Open No. 57-58631 (Patent Document 4) discloses a gastric or intestinal fluid-insoluble polymer coating or enteric polymer coating, and a gastric polymer coating or water-soluble polymer coating. A coating composition comprising a molecular coating is disclosed. In this document, the ratio of the gastric or intestinal fluid-insoluble polymer coating or enteric polymer coating to the gastric or water-soluble polymer coating is 100: 5 to 50. In the examples, drugs such as doxycycline hydrochloride, ampicillin, cephalexin are coated. However, when a drug is coated with this coating composition, the drug elution is lowered, and the behavior of a sustained-release preparation is exhibited, so that it is not suitable for an immediate-release preparation.
JP-A-6-116138 (Claim 1, paragraph numbers [0012] to [0014], Examples) WO96 / 34628 (Claim 1, Example) JP-A-2004-315424 (Claim 1, Example) JP-A-57-58631 (Claims 1 and 2, Examples)

  Accordingly, an object of the present invention is to provide a composition for oral preparations that can mask an unpleasant taste such as bitter taste and has a high dissolution property of a medicinal component and a method for producing the same even if it contains a macrolide antibiotic. There is.

  Another object of the present invention is a composition for oral preparations which has high heat stability, suppresses the generation of odor, and is excellent in handleability such as productivity and processability even if it contains a macrolide antibiotic. And a manufacturing method thereof.

  As a result of intensive studies to achieve the above-mentioned problems, the present inventors have coated a macrolide antibiotic with a polymer composition in which a pH-independent water-insoluble polymer and a gastric polymer are combined at a specific ratio. The present inventors have found that, even if a macrolide antibiotic is contained, unpleasant tastes such as bitterness can be masked and the medicinal components are highly soluble, and the present invention has been completed.

  That is, in the composition for oral preparation of the present invention, a granular composition composed of at least a macrolide antibiotic is coated with a polymer composition composed of a pH-independent water-insoluble polymer and a gastric polymer. Wherein the ratio (weight ratio) of the pH-independent water-insoluble polymer to the gastric soluble polymer is pH-independent water-insoluble polymer / gastric soluble polymer = 1/1 to 1 / 20. The pH-independent water-insoluble polymer may be, for example, a cellulose derivative (for example, ethyl cellulose) or a (meth) acrylic polymer. The ratio (weight ratio) of the pH-independent water-insoluble polymer and the gastric soluble polymer is about pH-independent water-insoluble polymer / gastric-soluble polymer = 1 / 1.5 to 1/15. The granular composition may be composed of a macrolide antibiotic and an additive such as a binder, an excipient, a disintegrant, and a coating agent. The macrolide antibiotic may be, for example, a 14-membered ring compound such as clarithromycin. The ratio of the polymer composition is, for example, about 1 to 150 parts by weight with respect to 100 parts by weight of the granular composition. The average particle diameter of the composition for oral preparation is, for example, about 30 to 300 μm.

  The present invention also includes a dry syrup containing the composition for oral preparation.

  In addition, the present invention includes a method for producing the composition for oral preparation, in which a granular composition composed of at least a macrolide antibiotic is coated with the polymer composition. In this production method, the granular composition is a granular composition granulated using a macrolide antibiotic, an additive such as a binder, an excipient, a disintegrant, a coating agent, and a solvent. (Particularly, a granular composition obtained by drying and then pulverizing a granulated product containing a macrolide antibiotic, the additive, and a solvent).

  The present invention also includes a method for masking the bitterness of a macrolide antibiotic, and a method of coating a granular composition composed of at least a macrolide antibiotic with the polymer composition.

  Furthermore, the present invention provides a dry syrup preparation method in which the composition for oral preparation is formed into a dry syrup by a fluidized bed granulation method, wherein the dry syrup preparation is granulated by spraying an aqueous dispersion containing an excipient. Also included in the manufacturing method.

  In the present invention, since the macrolide antibiotic is coated with a polymer composition in which a water-insoluble polymer and a gastric polymer are combined at a specific ratio, unpleasant taste such as bitterness can be masked and elution of medicinal ingredients The nature is also high. Furthermore, since it does not contain low melting point components such as fats and oils, the thermal stability is high, the generation of odors is suppressed, and the handleability such as productivity and workability is excellent.

  In the composition for oral preparation of the present invention, a granular composition composed of at least a macrolide antibiotic is coated with a polymer composition in which a pH-independent water-insoluble polymer and a gastric polymer are combined in a specific ratio. Has been.

[Powdered composition]
The granular composition is composed of at least a macrolide antibiotic, and in particular, may be composed of a macrolide antibiotic and an additive such as a binder, an excipient, a disintegrant, and a coating agent. Good.

(Macrolide antibiotics)
Macrolide antibiotics include, for example, 14-membered ring compounds (erythromycin, erythromycin ethyl succinate, erythromycin stearate, erythromycin lactobionate, roxithromycin, clarithromycin, etc.), 15-membered ring compounds (such as azithromycin), 16-membered ring system compounds (acetyl spiramycin, josamycin, josamycin propionate, kitasamycin, acetyl kitasamycin, kitasamycin tartrate, midecamycin, midecamycin acetate, rokitamycin, etc.) and the like. In addition, these macrolide antibiotics may be physiologically or pharmacologically acceptable salts, derivatives (prodrugs) such as esters, optical isomers, and the like. These macrolide antibiotics can be used alone or in combination of two or more.

  Of these macrolide antibiotics, the composition for oral preparation of the present invention is effective when used for 14-membered ring compounds such as erythromycin and clarithromycin, particularly clarithromycin having a strong bitter taste.

(Additive)
The macrolide antibiotic is preferably used in combination with pharmacologically acceptable additives such as a binder, an excipient, a disintegrant, and a coating agent from the viewpoint of improving fluidity and adhesion.

  As the binder, conventional binders such as sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose (for example, HPC-L manufactured by Nippon Soda Co., Ltd.), carboxymethylcellulose (carmellose) , Crystalline cellulose / sodium carboxymethylcellulose (for example, Avicel RC manufactured by Asahi Kasei Co., Ltd.), polyvinylpyrrolidone, pullulan, dextrin, tragacanth, sodium alginate, pregelatinized starch and the like. These binders can be used alone or in combination of two or more.

  Examples of the excipient include starches such as crystalline cellulose and corn starch, lactose, powdered sugar, granulated sugar, glucose, mannitol, light anhydrous silicic acid, talc, magnesium oxide, magnesium carbonate, calcium carbonate and the like. These excipients can be used alone or in combination of two or more.

  Examples of the disintegrant include carmellose calcium (eg, Nichirin Chemical Co., Ltd., ECG505), carmellose sodium, croscarmellose sodium (eg, FMC, Akzizol), cross-linked polyvinyl pyrrolidone (eg, BASF). Product, Kollidon CL), low-substituted hydroxypropyl cellulose (for example, L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd.), starches and the like. These disintegrants can be used alone or in combination of two or more.

  Examples of the coating agent include a pH-independent water-insoluble polymer and a gastric polymer described later. These coating agents can be used alone or in combination of two or more.

  Among these additives, binders (hydroxyalkylcelluloses such as hydroxypropylcellulose and hydroxypropylmethylcellulose), excipients (starches such as corn starch, mannitol, etc.), coating agents (cellulose ethers such as ethylcellulose) , Methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer, and the like).

  The ratio of these additives can be selected from the range of about 1 to 300 parts by weight with respect to 100 parts by weight of the macrolide antibiotic, and is usually 5 to 200 parts by weight, preferably 10 to 150 parts by weight, and more preferably. Is about 20 to 100 parts by weight (especially 25 to 40 parts by weight).

  The powder composition may further comprise other conventional pharmacologically acceptable additives such as lubricants (magnesium stearate, talc, stearic acid, calcium stearate, etc.), fluidizing agents or antistatic agents ( For example, non-ionics such as light anhydrous silicic acid), surfactants (eg, anionic surfactants such as sodium alkyl sulfate, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, and polyoxyethylene castor oil derivatives) Surfactants), coloring agents (eg tar pigments, caramels, bengara, titanium oxides), corrigents (eg sweeteners (sucrose, lactose, mannitol, xylitol, saccharin, saccharin sodium, aspartame, stevioside, etc.)) Fragrances, etc.], wetting agents [eg polyethylene Glycol (macrogol), glycerine, propylene glycol, etc.], fillers, extenders, adsorbents, preservatives such as preservatives, buffering agents, may contain such disintegrating extender. These other conventional additives can be used alone or in combination of two or more. These components are not particularly limited in content in the final formulation.

  The average particle diameter of the granular composition is, for example, about 5 to 100 μm, preferably 5 to 70 μm, and more preferably about 5 to 50 μm (particularly 7 to 30 μm).

(Preparation method of granular composition)
As a method for preparing the granular composition, a dry granulation method may be used. Usually, a macrolide antibiotic, an additive such as a binder, an excipient and a disintegrant, and a solvent are used. A method of granulating is used. Such granulation methods include conventional wet granulation methods such as extrusion granulation, tumbling granulation, fluidized bed granulation, mixing / stirring granulation, spray drying granulation, vibration granulation Although a method may be used, a method of pulverizing and granulating a granulated product containing a macrolide antibiotic, the additive and the solvent can be preferably used. In such a method, since the granulated product is used after being pulverized, the particle size of the macrolide antibiotic used is not limited, and a fine particle preparation can be produced at low cost.

  In the preparation of the granulated product, the mixing method of the macrolide antibiotic, the additive and the solvent may be, for example, a method in which the macrolide antibiotic, the additive and the solvent are mixed together. In some cases, a part of the additive may be mixed into the macrolide antibiotic and then mixed with a solution containing the remaining additive.

  As a method for mixing and granulating the macrolide antibiotic, the additive and the solvent, conventional methods and apparatuses can be used. The granulated product is usually pulverized after drying. For pulverization, a pulverizer usually used for pulverization of pharmaceuticals, such as an atomizer (sample mill, hammer mill, etc.), pin mill, jet mill, ball mill, etc., can be used.

The solvent is not particularly limited, but water, lower alcohols (for example, C _1-4 alcohols such as ethanol, isopropanol, etc.), aliphatic ketones (for example, acetone, etc.) or a mixed solvent thereof are widely used and are safe. From the aspect, water and / or ethanol (for example, ethanol or a mixed solvent of water and ethanol) can be preferably used. The proportion of the solvent can be selected from the range of, for example, about 1 to 200 parts by weight, and is usually 3 to 100 parts by weight, preferably 5 to 100 parts by weight with respect to the total of 100 parts by weight of the macrolide antibiotic and the additive. It is about 70 parts by weight, more preferably about 10 to 50 parts by weight (particularly 15 to 40 parts by weight).

[Composition for oral preparation]
In the composition for oral preparation of the present invention, the powdery granular composition is coated with a polymer composition composed of a pH-independent water-insoluble polymer and a gastric polymer.

(PH-independent water-insoluble polymer)
Examples of pH-independent water-insoluble polymers include cellulose derivatives [cellulose ethers (eg, cellulose alkyl ethers such as ethyl cellulose, ethyl methyl cellulose, ethyl propyl cellulose, isopropyl cellulose, butyl cellulose, cellulose aralkyl ethers such as benzyl cellulose, cyano Cellulose fatty acid esters such as cellulose cyanoalkyl ethers such as ethyl cellulose), cellulose esters (eg, cellulose acetate butyrate, cellulose acetate, cellulose propionate, cellulose butyrate, cellulose acetate propionate, hydroxymethyl cellulose acetate succinate) , Cellulose acetate phthalate, hydroxypropyl methylcellulose Cellulose aromatic carboxylic acid esters such as phthalates)], (meth) acrylic polymers [for example, (meth) acrylic monomers ((meth) acrylic acid, (meth) acrylic acid ester monomers, etc.) ) Homopolymer or copolymer, (meth) acrylic monomer and copolymerizable monomer (vinyl ester monomer, N, N-dialkylaminoethyl (meth) acrylate, heterocyclic vinyl monomer) And a copolymer with a vinyl monomer such as a polymerizable unsaturated dicarboxylic acid or a derivative thereof].

  Among these, the pH-independent water-insoluble polymer may be composed of at least one selected from cellulose derivatives (for example, ethyl celluloses) and (meth) acrylic polymers. Moreover, at least one selected from ethyl celluloses, cellulose acetate butyrate and (meth) acrylic polymers, particularly ethylcelluloses and (meth) acrylic polymers were selected from the point of little change in solubility due to pH. At least one type is desirable. Examples of ethyl celluloses include ethyl cellulose, ethyl methyl cellulose, and ethyl propyl cellulose. Among these, ethyl cellulose can be preferably used. As the (meth) acrylic polymer, trade names Eudragit RSPO, Eudragit NE30D, Eudragit RS30D, Eudragit RL30D, and the like are imported and sold by Degussa Japan. Of these, Eudragit RSPO can be preferably used.

(Gastric soluble polymer)
The gastric polymer is not particularly limited as long as it is a polymer that dissolves under acidic conditions (pH 5 or lower) in the stomach. As a particularly preferred gastric polymer, a methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer is available from Degussa Japan Co., Ltd., an importer and distributor, under the trade names Eudragit E100 and Eudragit EPO. Acetal diethylaminoacetate is available from Sankyo Co., Ltd. under the trade name AEA.

  These gastric polymers can be used alone or in combination of two or more. Of these, Eudragit E100 and Eudragit EPO are particularly preferred.

  The ratio (weight ratio) between the pH-independent water-insoluble polymer and the gastric-soluble polymer can be selected, for example, from the range of pH-independent water-insoluble polymer / gastric-soluble polymer = 1/1 to 1/20, It is about 1 / 1.5 to 1/15, preferably 1 / 1.5 to 1/10, more preferably about 1 / 1.5 to 1/8 (particularly 1 / 1.5 to 1/5). When the ratio of both is in this range, it is possible to achieve both uncomfortable taste masking such as bitterness and high dissolution of medicinal ingredients.

  Such a polymer composition may also contain the additive exemplified in the section of the granular composition. These additives can also be used alone or in combination of two or more, and the content in the final preparation is not limited.

  In this composition, the ratio of the polymer composition can be selected from a range of, for example, about 1 to 300 parts by weight, for example, 1 to 150 parts by weight, preferably 10 to 100 parts per 100 parts by weight of the granular composition. Part by weight, more preferably about 20 to 80 parts by weight (particularly 30 to 60 parts by weight).

  The average particle size of the composition for oral preparation is, for example, about 30 to 300 μm, preferably 40 to 250 μm, and more preferably about 50 to 200 μm (particularly 60 to 150 μm). The ratio of the average particle diameter of the granular composition before and after coating is, for example, average particle diameter before coating / average particle diameter after coating = 1 / 1.1 to 1/50, preferably 1 / 1.5 to It is about 1/30, more preferably about 1/2 to 1/20 (particularly 1/3 to 1/10).

[Method for producing composition for oral preparation]
The composition for oral preparation of this invention can be manufactured by coating the said granular composition with the said polymer composition. In the present invention, coating is usually performed using a solution composed of a polymer composition and a solvent.

The solution containing the polymer composition is not particularly limited, but is a solution using water and a lower alcohol (for example, C _1-4 alcohol such as ethanol or isopropanol), an aliphatic ketone (acetone) or a mixed solvent thereof, safety From this point of view, an ethanol solution can be preferably used. The concentration of the polymer composition in the solution can be selected from the range of about 1 to 30% by weight, preferably 2 to 20% by weight, more preferably 3 to 15% by weight (particularly 5 to 10% by weight).

  As the coating method, a coating method using a fluidized bed coating machine, a rolling coating machine, a rolling fluidized coating machine, a pan coating machine or the like can be applied, and among these, a coating method using a fluidized bed coating machine is preferable.

  In addition, although coating with a polymer composition is performed on the surface of a granular composition, it is preferable to coat | cover the whole surface especially.

  In the production method of the present invention, an environmentally friendly solvent is used as described above, and the production process is simple and the composition for oral preparation can be produced easily.

[Dry syrup preparation]
The composition for oral preparation of the present invention can be used for various oral preparations. The oral preparation only needs to contain at least the composition for oral preparation, and may be various oral preparations such as pills, solutions, powders, troches, dry syrups, tablets, capsules, suspensions and the like. Good. Among these oral preparations, the composition for oral preparation of the present invention has a high masking property and dissolution property, so that it is particularly effective to use it as a dry syrup agent.

  The dry syrup may be composed of at least an oral preparation composition, and may be a granular preparation obtained by further granulating the oral preparation composition. The granular preparation may further contain the pharmacologically acceptable additive in addition to the composition for oral preparation. Among the additives mentioned above, the additives contained in the granular preparation include, in particular, excipients (mannitol, magnesium oxide, etc.), binders (hydroxypropylcellulose, etc.), disintegrating agents (carmellose sodium, etc.), antistatic agents. (Light anhydrous silicic acid and the like), sweetener (such as saccharin sodium), wetting agent (such as macrogol), and colorant (such as tar dye) are preferable.

  The ratio of these additives is 10 to 1000 parts by weight of the excipient (preferably 50 to 500 parts by weight, more preferably 100 to 400 parts by weight) with respect to 100 parts by weight of the composition for oral preparation. To 200 parts by weight (preferably 3 to 100 parts by weight, more preferably 5 to 50 parts by weight), 0 to 10 parts by weight (especially 0.1 to 5 parts by weight) of an antistatic agent, and 0 to 5 parts by weight of a sweetener ( Especially 0.05 to 3 parts by weight), 0 to 10 parts by weight (especially 0.1 to 5 parts by weight) of a wetting agent, and 0 to 10 parts by weight (particularly 0.1 to 5 parts by weight) of a colorant.

  The method for producing a granular preparation is exemplified by a conventional granulation method using a composition for oral preparation and additives such as excipients and / or binders, for example, in the section of the granular composition. Granulation method and the like. In the present invention, among these granulation methods, the composition for oral preparation and additives (excipients, binders, sweeteners, etc.) are fluidly mixed in advance using a fluidized bed granulator, and the additives (shaped) A fluidized bed granulation method in which an aqueous dispersion containing an agent, a binder, a sweetener, etc.) is sprayed and granulated is preferred. Specifically, the composition for oral preparation and an additive containing at least an excipient are fluidly mixed in advance with a fluidized bed granulator, and granulated by spraying an aqueous dispersion in which at least the excipient is dispersed. May be. Examples of excipients include sugar alcohols such as mannitol, sorbitol and xylitol, oligosaccharides such as sucrose and trehalose, and starches such as corn starch. These excipients can be used alone or in combination of two or more. Of these excipients, sugar alcohols such as mannitol and sucrose are preferred. In the aqueous dispersion to be sprayed, an excipient and a binder (such as hydroxypropylcellulose) may be combined, and the ratio (weight ratio) between the two is, for example, excipient / binder = 100/0 It is about 1/99, preferably 99.99 / 0.01 to 10/90, more preferably about 99.9 / 0.1 to 30/70 (particularly 99/1 to 50/50). The aqueous dispersion to be sprayed may further contain a sweetening agent. Examples of the sweetening agent include saccharin or artificial sweeteners such as saccharin sodium and aspartame. Although the ratio of a sweetening agent changes with kinds, it is 0.01-10 weight part with respect to 100 weight part of excipient | fillers, for example, Preferably it is about 0.1-5 weight part. In the present invention, the composition for oral preparation and the excipient are mixed in advance with a fluidized bed granulator, and the excipient is sufficiently dispersed in the solvent to be sprayed, whereby the composition for oral preparation is sufficiently added. And can be granulated firmly. After granulation, it may be further dried and classified by classification or sieving.

  INDUSTRIAL APPLICABILITY The present invention can be used as a composition for oral preparations containing macrolide antibiotics (such as clarithromycin) that are antibiotics such as streptococcal pharyngitis and pneumococcal pneumonia, and can mask unpleasant tastes such as bitterness. Therefore, it is particularly useful as a pediatric preparation such as a dry syrup.

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.

  First, a granular composition containing clarithromycin was prepared as described in the following production examples, and the operability in coating of the obtained granular composition was evaluated.

Production Example 1
After mixing 2034 g of clarithromycin, 366 g of corn starch, 200 g of ethyl cellulose and 200 g of hydroxypropyl cellulose with a high speed mixer (Fukae Pautech Co., Ltd., FS-GS-10, agitator 300 rpm), a mixed solvent of purified water and ethanol ( 750 g of purified water / ethanol = 1/1 (weight ratio) was added and stirring granulation was performed. Then, after wet-regulating with a power mill and drying, it was pulverized with a sample mill (manufactured by Fuji Powder Co., Ltd., screen diameter φ1.5 mm) to obtain a granular composition A containing clarithromycin. The average particle size was about 12 μm.

Production Example 2
After mixing 2034 g of clarithromycin, 300 g of corn starch, 60 g of ethyl cellulose, 200 g of a gastric polymer (Eudragit EPO) and 200 g of hydroxypropyl cellulose with a high speed mixer (FS-GS-10, manufactured by Fukae Powtech Co., Ltd., agitator 300 rpm) Then, 610 g of a mixed solvent of purified water and ethanol (purified water / ethanol = 1/1 (weight ratio)) was added and granulated with stirring. Then, after wet-regulating with a power mill and drying, it was pulverized with a sample mill (manufactured by Fuji Powder Co., Ltd., screen diameter φ1.5 mm) to obtain a granular composition B containing clarithromycin. The average particle size was about 15 μm.

Production Example 3
After mixing 101.7 g of clarithromycin, 30 g of corn starch, 30 g of hydroxypropylmethylcellulose and 100 g of D-mannitol with a high speed mixer (Fukae Pautech Co., Ltd., FS-MINI, agitator 300 rpm), mixing of purified water and ethanol 75 g of a solvent (purified water / ethanol = 1/1 (weight ratio)) was added and granulated with stirring. Then, after wet sizing with a power mill and drying, a powder composition C containing clarithromycin is obtained by pulverizing with a sample mill (Fuji Powder Co., Ltd., screen diameter φ1.5 mm). It was. The average particle size was about 20 μm.

Production Example 4
After mixing 101.7 g of clarithromycin, 15 g of corn starch, 10 g of hydroxypropylmethylcellulose, 10 g of a gastric polymer (Eudragit EPO) and 3 g of ethylcellulose with a high speed mixer (FS-MINI, manufactured by Fukae Powtech Co., Ltd., agitator 300 rpm) Then, 36 g of a mixed solvent of purified water and ethanol (purified water / ethanol = 1/1 (weight ratio)) was added to carry out stirring granulation. Thereafter, the powder is wet-sized in a power mill, dried, and then pulverized in a sample mill (made by Fuji Powder Co., Ltd., screen diameter φ1.5 mm) to obtain a granular composition D containing clarithromycin. It was. The average particle size was about 14 μm.

Production Example 5
After mixing 203.4 g of clarithromycin and 60 g of ethyl cellulose with a high speed mixer (Fukae Pautech Co., Ltd., FS-MINI, agitator 300 rpm), a mixed solvent of purified water and ethanol (purified water / ethanol = 1/1 ( (Weight ratio)) 91 g was added, and stirring granulation was performed. Thereafter, wet sizing with a power mill and drying are performed, followed by pulverization with a sample mill (made by Fuji Powder Co., Ltd., screen diameter φ1.5 mm) to obtain a granular composition E containing clarithromycin. It was. The average particle size was about 14 μm.

Production Example 6
After mixing 200 g of clarithromycin and 60 g of hydroxypropyl methylcellulose with a high speed mixer (Fukae Pautech Co., Ltd., FS-MINI, agitator 300 rpm), a mixed solvent of purified water and ethanol (purified water / ethanol = 1/1 ( (Weight ratio)) 91 g was added, and stirring granulation was performed. Thereafter, the powder is wet-sized in a power mill, dried, and then pulverized in a sample mill (made by Fuji Powder Co., Ltd., screen diameter φ1.5 mm) to obtain a granular composition F containing clarithromycin. It was. The average particle size was about 27 μm.

[Coating operability of granular composition]
Since the obtained granular compositions A to F are used by granulating or modifying (modifying) the clarithromycin drug substance with a polymer additive, the fluidity and adhesion of the clarithromycin powder are improved. Thus, the coating operation described later was easy. On the other hand, 100 g of clarithromycin powder (average particle size of about 9 μm) is charged in a fluidized bed granulator (Freund Co., Ltd., FLO-MINI, supply air temperature 60 ° C.) and coated. The coating property was poor and the coating operation was difficult.

  A dry syrup preparation was prepared by the following method using the obtained granular composition. In addition, the evaluation method of the obtained dry syrup preparation is shown below.

[Bitter taste test]
Three healthy adult men were allowed to take 0.5 g of each sample, and a sensory test for bitterness was performed.

[Simple test of bitterness]
A 10 mL Spitz tube (with a stopper) is fixed to the outer periphery of a drum of a friability tester (Toyama Sangyo Co., Ltd., TFT-120, drum diameter φ30 cm), and 9 mL of purified water at about 37 ° C. is placed in the Spitz tube. After putting 0.5 g of each specimen into the stopper and plugging the Spitz tube, the friability tester is rotated at 25 rpm for 30 seconds. Then, after filtering with a PVDF filter (manufactured by WHATMAN, pore size 0.45 μm), the elution amount of clarithromycin was measured using high performance liquid chromatography (HPLC). As the amount of clarithromycin eluted increases, the bitterness tends to increase.

[Dissolution test]
A test was conducted according to the dissolution test method of 14 Japanese Pharmacopoeia, and the dissolution rate after 90 minutes was measured using HPLC. Furthermore, the dissolution property was evaluated in comparison with the reference standard (the dissolution rate after 90 minutes is 75% or more).

Each sample amount: 0.5g
Test solution: pH 5.5 McIlvaine buffer Paddle rotation speed: 50 rpm.

[Particle size distribution]
The particle size distribution was determined by classification with a sieve.

Example 1
504 g of the powdered granular composition A was charged into a fluidized bed granulator (manufactured by Paulec Co., Ltd., MP-01 fluidized bed specification, air supply temperature 40 ° C.), 241.2 g of a gastric polymer (Eudragit E100) and 57.6 g of ethyl cellulose ( The coating was carried out for about 13 hours by spraying an ethanol solution containing a mixing ratio of 4.2: 1) at about 4.3 g / min. After coating, 3.6 g of light anhydrous silicic acid was added after classification with a No. 30 stainless steel sieve. The average particle size of the obtained fine particle preparation was about 100 μm.

  Next, 224 g of this clarithromycin fine particle preparation, 207 g of D-mannitol, 10 g of carmellose sodium and 10 g of magnesium oxide were added to a fluidized bed granulator (manufactured by Pauleck Co., Ltd., MP-01 fluidized bed specification, air supply temperature 40-50) C.) and granulated by spraying a solution of 515 g of D-mannitol, 20 g of hydroxypropylcellulose and 10 g of sodium saccharin in purified water at about 11 g / min. After the granulation was completed, the dried product was dried, and 3 g of light anhydrous silicic acid and a small amount of aroma were added to the granular material classified and sieved with a No. 22 stainless steel sieve to produce a dry syrup preparation. The results of evaluating this dry syrup are shown in Table 1. Furthermore, Table 2 shows the results of measuring the particle size distribution of the dry syrup.

  About the obtained dry syrup agent, the result of having image | photographed the photograph (60 time) of the state of the granulated material with a microscope is shown in FIG. From the result of FIG. 1, this dry syrup is uniformly granulated.

Example 2
503 g of the powdered granular composition B was charged into a fluidized bed granulator (manufactured by Paulec Co., Ltd., MP-01 fluidized bed specification, air supply temperature 40 ° C.), 181.4 g of a gastric polymer (Eudragit E100) and 121 g of ethyl cellulose (mixing ratio) Coating was carried out for about 17 hours by spraying an ethanol solution of 3: 2) at about 3.8 g / min. After coating, 3.6 g of light anhydrous silicic acid was added after classification with a No. 30 stainless steel sieve. The average particle size of the obtained fine particle preparation was about 80 μm.

  Next, 224.8 g of this clarithromycin microparticle preparation, 57.3 g of D-mannitol, 10 g of carmellose sodium and 10 g of magnesium oxide were added to a fluidized bed granulator (manufactured by Paulec Co., Ltd., MP-01 fluidized bed specification, air supply The temperature was 40 to 50 ° C., and granulated by spraying a solution obtained by dispersing 664 g of D-mannitol, 20 g of hydroxypropylcellulose and 10 g of sodium saccharin in purified water at about 11 g / min. After the granulation was completed, the dried product was dried, and 3 g of light anhydrous silicic acid and a small amount of aroma were added to the granular material classified and sieved with a No. 22 stainless steel sieve to produce a dry syrup preparation. The results of evaluating this dry syrup are shown in Table 1.

Example 3
503 g of the powdered granular composition B was charged into a fluidized bed granulator (manufactured by Paulec Co., Ltd., MP-01 fluidized bed specification, air supply temperature 40 ° C.), 242 g of a gastric polymer (Eudragit E100) and 60.4 g of ethyl cellulose (mixing ratio) The coating was carried out for about 14 hours by spraying an ethanol solution of 4: 1) at about 4.3 g / min. After coating, 3.6 g of light anhydrous silicic acid was added after classification with a No. 30 stainless steel sieve. The average particle size of the obtained fine particle formulation was about 75 μm.

  Next, 224.8 g of this clarithromycin microparticle preparation, 57.3 g of D-mannitol, 10 g of carmellose sodium and 10 g of magnesium oxide were added to a fluidized bed granulator (manufactured by Paulec Co., Ltd., MP-01 fluidized bed specification, air supply The temperature was 40 to 50 ° C., and granulated by spraying a solution obtained by dispersing 664 g of D-mannitol, 20 g of hydroxypropylcellulose and 10 g of sodium saccharin in purified water at about 11 g / min. After the granulation was completed, the dried product was dried, and 3 g of light anhydrous silicic acid and a small amount of aroma were added to the granular material classified and sieved with a No. 22 stainless steel sieve to produce a dry syrup preparation. The results of evaluating this dry syrup are shown in Table 1.

Example 4
Powdered composition C100 g was charged into a fluidized bed granulator (Freund Co., Ltd., FLO-MINI, air supply temperature 60 ° C.), 40 g of gastric soluble polymer (Eudragit E100) and 10 g of ethyl cellulose (mixing ratio 4: 1). Coating was performed for about 10 hours by spraying the ethanol solution at about 0.8 g / min. After coating, the average particle size of the fine particle preparation obtained after classification with No. 30 stainless steel sieve was about 100 μm.

  Next, 39.3 g of this clarithromycin fine particle preparation, 54.4 g of D-mannitol, 1 g of carmellose sodium, 2 g of magnesium oxide and 2 g of hydroxypropyl cellulose were mixed into a fluidized bed granulator (Freund Corporation, FLO-MINI, Granulation was carried out by spraying an aqueous solution in which 0.2 g of sodium saccharin was dissolved at a rate of about 1.8 g / min. After the granulation was completed, the dried product was dried, and 1 g of light anhydrous silicic acid and a small amount of perfume were added to the granular material classified and sieved with No. 22 stainless steel sieve to produce a dry syrup preparation.

Example 5
100 g of powdered granular composition B was charged into a fluidized bed granulator (Freund Co., Ltd., FLO-MINI, supply air temperature 60 ° C.), 40 g of gastric soluble polymer (Eudragit EPO) and 33.3 g of water insoluble polymer (Eudragit RS30D). Coating was carried out for about 13 hours by spraying an aqueous dispersion containing (solid content 10 g) (mixing ratio 4: 1), 4 g sodium lauryl sulfate and 2.5 g triethyl citrate at about 0.6 g / min. . After coating, the average particle size of the fine particle preparation obtained after classification with No. 30 stainless steel sieve was about 100 μm.

  Next, 21.86 g of this clarithromycin fine particle preparation, 72.84 g of D-mannitol, 1 g of carmellose sodium, 1 g of magnesium oxide and 2 g of hydroxypropylcellulose were mixed into a fluidized bed granulator (Freund Corporation, FLO-MINI, Granulation was performed by spraying an aqueous solution in which 0.2 g of saccharin sodium was dissolved at a rate of about 1.5 g / min. After the granulation was completed, the dried product was dried, and 1 g of light anhydrous silicic acid and a small amount of perfume were added to the granular material classified and sieved with No. 22 stainless steel sieve to produce a dry syrup preparation.

Example 6
100 g of the powdered granular composition B was charged into a fluidized bed granulator (Freund Co., Ltd., FLO-MINI, supply air temperature 60 ° C.), 40 g of a gastric polymer (Eudragit EPO) and 33.3 g of an aqueous dispersion of ethyl cellulose (solid) Coating was carried out for about 13 hours by spraying at about 0.6 g / min with an aqueous dispersion of 10 g min) (mixing ratio 4: 1) and 4 g sodium lauryl sulfate and 2.5 g triethyl citrate. After coating, the average particle size of the fine particle preparation obtained after classification with No. 30 stainless steel sieve was about 100 μm.

  Next, 21.86 g of this clarithromycin microparticle preparation, 72.8 g of D-mannitol, 1 g of carmellose sodium, 1 g of magnesium oxide and 2 g of hydroxypropylcellulose were mixed into a fluidized bed granulator (Freund Corporation, FLO-MINI, Granulation was performed by spraying an aqueous solution in which 0.2 g of saccharin sodium was dissolved at a rate of about 1.5 g / min. After the granulation was completed, the dried product was dried, and 1 g of light anhydrous silicic acid and a small amount of perfume were added to the granular material classified and sieved with No. 22 stainless steel sieve to produce a dry syrup preparation.

Comparative Example 1
Powdered composition D100 g was charged into a fluidized bed granulator (Freund Co., Ltd., FLO-MINI, supply air temperature 60 ° C.) and sprayed with an ethanol solution of 50 g of a gastric polymer (Eudragit E100) at about 2 g / min. Coating for about 4 hours. After coating, the average particle size of the fine particle preparation obtained after classification with No. 30 stainless steel sieve was about 75 μm.

  Next, 21 g of this clarithromycin fine particle preparation, 72.3 g of D-mannitol, 1 g of carmellose sodium, 2 g of magnesium oxide and 2 g of hydroxypropylcellulose were mixed into a fluid bed granulator (Freund Corporation, FLO-MINI, air supply). The mixture was granulated by spraying at about 1.5 g / min with an aqueous solution in which 0.2 g of saccharin sodium was dissolved. After the granulation was completed, the dried product was dried, and 1 g of light anhydrous silicic acid and a small amount of perfume were added to the granular material classified and sieved with No. 22 stainless steel sieve to produce a dry syrup preparation. The results of evaluating this dry syrup are shown in Table 1.

Comparative Example 2
Powdered composition E100g was charged into a fluidized bed granulator (Freund Co., Ltd., FLO-MINI, air supply temperature 60 ° C), ethyl cellulose 32g and gastric soluble polymer (Eudragit E100) 8g (mixing ratio 4: 1). Coating was carried out for about 11 hours by spraying the ethanol solution at about 0.8 g / min. After coating, the average particle size of the fine particle preparation obtained after classification with No. 30 stainless steel sieve was about 100 μm.

  Next, 18.44 g of this clarithromycin microparticle preparation, 75.26 g of D-mannitol, 1 g of carmellose sodium, 2 g of magnesium oxide and 2 g of hydroxypropylcellulose were mixed into a fluidized bed granulator (Freund Corporation, FLO-MINI, Granulation was performed by spraying an aqueous solution in which 0.2 g of saccharin sodium was dissolved at a rate of about 1.5 g / min. After the granulation was completed, the dried product was dried, and 1 g of light anhydrous silicic acid and a small amount of perfume were added to the granulated material classified and saved with No. 22 stainless steel sieve to produce a dry syrup preparation. The results of evaluating this dry syrup are shown in Table 1.

Comparative Example 3
100 g of powdered granular composition A was charged into a fluidized bed granulator (Freund Co., Ltd., FLO-MINI, air supply temperature 60 ° C.), and 27 g of ethyl cellulose and 13 g of a gastric polymer (Eudragit E100) (mixing ratio 2: 1) Coating was performed for about 13 hours by spraying the ethanol solution at about 0.7 g / min. After coating, the average particle size of the fine particle preparation obtained after classification with No. 30 stainless steel sieve was about 100 μm.

  Next, 22.4 g of this clarithromycin fine particle preparation, 20 g of D-mannitol, 1 g of strong rumellose sodium and 1 g of magnesium oxide were fluidized bed granulator (Freund Co., Ltd., FLO-MINI, air supply temperature 50 ° C.). Then, 52.3 g of D-mannitol, 2 g of hydroxypropylcellulose and 1 g of sodium saccharin were dispersed in purified water and granulated by spraying at about 1.8 g / min. After the granulation was completed, the dried product was dried, and 0.2 g of light anhydrous silicic acid and a small amount of perfume were added to the granular material classified and sieved with No. 22 stainless steel sieve to produce a dry syrup preparation. The results of evaluating this dry syrup are shown in Table 1.

Example 7
224 g of clarithromycin fine particle preparation before dry syrup in Example 1, 722 g of D-mannitol, 10 g of carmellose sodium and 10 g of magnesium oxide were fluidized bed granulator (manufactured by Paulec Co., Ltd., MP-01 fluidized bed specification, supply) The mixture was granulated by spraying at about 10 g / min with an aqueous solution in which 20 g of hydroxypropylcellulose and 10 g of sodium saccharin were dissolved. After the granulation was completed, the product was dried, and 3 g of light anhydrous silicic acid and a small amount of perfume were added to the granular material classified and sieved with a No. 22 stainless steel comb to produce a dry syrup preparation. Table 2 shows the results of measuring the particle size distribution of the obtained dry syrup.

  About the obtained dry syrup preparation, the result of having photographed the state of the granulated material with a microscope (60 times) is shown in FIG.

  As is clear from the results in Table 1, the dry syrups of the examples have no bitter taste and high elution properties. On the other hand, the dry syrup preparation of Comparative Example 1 has a bitter taste, and the dry syrup preparations of Comparative Examples 2 and 3 are not sufficiently soluble.

  From the results of Table 2, Example 1 shows a sharp particle size distribution, but Example 7 has variations. As is clear from the results of FIGS. 1 and 2, the clarithromycin fine particle formulation is granulated more strongly in Example 1 than in Example 7.

1 is a photomicrograph (60 ×) of the dry syrup obtained in Example 1. FIG. FIG. 2 is a photomicrograph (60 ×) of the dry syrup obtained in Example 7.

Claims (15)

  A composition for oral preparations, wherein a powdery granular composition composed of at least a macrolide antibiotic is coated with a polymer composition composed of a pH-independent water-insoluble polymer and a gastric polymer, wherein the pH The composition for oral preparations, wherein the ratio (weight ratio) between the non-dependent water-insoluble polymer and the gastric soluble polymer is pH-independent water-insoluble polymer / gastric soluble polymer = 1/1 to 1/20.   The composition for oral preparation according to claim 1, wherein the pH-independent water-insoluble polymer is composed of at least one selected from cellulose derivatives and (meth) acrylic polymers.   The composition for oral preparation according to claim 2, wherein the cellulose derivative is ethylcellulose.   2. The oral preparation according to claim 1, wherein the ratio (weight ratio) between the pH-independent water-insoluble polymer and the gastric-soluble polymer is pH-independent water-insoluble polymer / gastric-soluble polymer = 1 / 1.5 to 1/15. Composition.   The composition for oral preparation according to claim 1, wherein the granular composition comprises a macrolide antibiotic and at least one additive selected from a binder, an excipient, a disintegrant and a coating agent. .   The composition for oral preparation according to claim 1, wherein the macrolide antibiotic is a 14-membered ring compound.   The composition for oral preparation according to claim 1, wherein the macrolide antibiotic is clarithromycin.   The composition for oral preparation according to claim 1, wherein the ratio of the polymer composition is 1-150 parts by weight with respect to 100 parts by weight of the granular composition.   The composition for oral preparation according to claim 1, wherein the average particle size is 30 to 300 µm.   A dry syrup comprising the composition for oral preparation according to claim 1.   2. The method for producing a composition for oral preparation according to claim 1, wherein the granular composition composed of at least a macrolide antibiotic is coated with a polymer composition composed of a pH-independent water-insoluble polymer and a gastric polymer. .   As a granular composition, a granular composition granulated using a macrolide antibiotic, at least one additive selected from a binder, an excipient, a disintegrant and a coating agent, and a solvent is used. The manufacturing method of Claim 11.   A powder obtained by drying a granulated product containing a macrolide antibiotic, at least one additive selected from a binder, an excipient, a disintegrant, and a coating agent, and a solvent, and then grinding the powder The manufacturing method of Claim 12 using a granular composition.   A method for masking the bitterness of a macrolide antibiotic, wherein a powdery composition composed of at least a macrolide antibiotic is coated with the polymer composition according to claim 1.   A method for producing a dry syrup preparation, wherein the composition for oral preparation according to claim 1 is made into a dry syrup by a fluidized bed granulation method, and granulated by spraying an aqueous dispersion containing an excipient.