JP6176840B2 - Fexofenadine granule preparation and method for producing the same - Google Patents

Description

  The present invention relates to a granule preparation containing fexofenadine or a pharmaceutically acceptable salt thereof (hereinafter sometimes simply referred to as “fexofenadine”) and a method for producing the same. More specifically, the present invention relates to a fexofenadine granule preparation masked for bitterness, particularly a dry syrup preparation. More specifically, the present invention relates to a fexoso obtained by forming a drug layer containing fexofenadine on the surface of a core particle by a layering method, and further applying a film coating to the obtained spherical elementary granule. It relates to a phenazine granule preparation.

Fexofenadine is a 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzene acetate known from US Pat. No. 4,254,129. And an effective antihistamine which is an H1 receptor antagonist.
As for fexofenadine, an oral tablet or an orally disintegrating tablet (OD tablet) is marketed in Japan under the trade name: Allegra (registered trademark). Currently in Japan, Allegra® is a tablet containing 30 mg or 60 mg of fexofenadine hydrochloride that is indicated for allergic rhinitis, urticaria and pruritus associated with skin diseases in adults and children over 7 years of age. OD tablets containing 60 mg of fexofenadine hydrochloride are commercially available.

  Fexofenadine is a medically used drug because of its powerful pharmacological action. Fexofenadine drug substance itself has a very strong bitter taste, and has an unpleasant and strong bitter aftertaste. Therefore, when used as an oral preparation, it is necessary to reduce the bitterness by coating the surface of the tablet. is there. However, when an oral preparation is produced by a normal technique, there is a practical problem that the bitterness in the oral cavity is not sufficiently concealed or blocked in the oral cavity at the time of taking, resulting in discomfort to the user.

  In general, solid preparations such as tablets are difficult to take for children and elderly people with weak swallowing ability. Although an OD tablet has been developed as a dosage form that is easy to swallow, it cannot be said that it is always easy to swallow for the elderly or the like whose saliva secretion amount has decreased. Liquid preparations such as syrups are easy to take, but are more inconvenient for patients to carry, as compared to solid preparations, they require more time for dispensing at pharmacies and hospitals. In addition to improving these points, granule preparations that mask the bitter taste of fexofenadine drug substance and improve the ingestion to pediatric patients and the elderly with allergic diseases, especially dry syrups, are available for pediatric patients and elderly patients. It is very useful for a person.

So far, several dosage forms are known for formulations containing fexofenadine.
Patent Document 1 discloses that tablets and capsules were prepared as pharmaceutical compositions for piperidinoalkanol compounds typified by fexofenadine. These tablets and capsules can improve bioavailability by making specific formulations containing croscarmellose sodium, microcrystalline cellulose, lactose, pregelatinized starch, gelatin and magnesium stearate with fexofenadine. ing.
Patent Document 2 discloses an orally dispersible tablet containing a mixture of coated granules of fexofenadine and an excipient comprising at least one disintegrant, a soluble diluent, and a lubricant. A granule coated with phenazine, a method for its preparation, and a method for using the mouth dispersible tablet are described, and taste masking of fexofenadine is performed by coating finely divided microcrystals of fexofenadine with one or more polymers. It is described.
Patent Document 3 discloses an oral pharmaceutical suspension composition containing a mixture of compressed fexofenadine and plain fexofenadine, which has a masking ability for the bitter taste of a drug, and quickly. It is described that the drug is in a form that can be dissolved in Further, as a specific example of the suspension composition, a compressed product of a mixture of compressed fexofenadine and plain fexofenadine or a slug pulverized product is mixed with sucrose, xanthan gum, etc. to form granules, An example of preparing fexofenadine hydrochloride powder for suspension by mixing a fragrance and aspartame is disclosed.
Patent Document 4 discloses a fexofenadine-containing film coating oral preparation having an effect of improving stability to heat and light, and specifically discloses a tablet coated with a coating agent not containing a plasticizer. .

Japanese National Patent Publication No. 11-501028 JP 2005-513008 A Special table 2009-503058 gazette JP 2011-162531 A

Patent Document 3 discloses a composition for suspending powder containing fexofenadine and a composition containing a sweetener. However, it is necessary to take it without feeling the bitterness of fexofenadine. It is not considered sufficient.
Therefore, the present invention is a preparation containing fexofenadine or a pharmaceutically acceptable salt thereof as an active ingredient, has a dosage form that is easy to take even for children and the elderly, and when taken Fexofenadine can suppress the bitterness peculiar to fexofenadine, is excellent in the release of active ingredients from the formulation, has good stability over time, does not cause degradation during storage, and has little change in formulation. The purpose is to develop phenazine preparations.

  The present inventors have studied means for solving the above problems, and surprisingly, a coating layer (drug layer) containing fexofenadine is preferably formed on the surface of inert fine core particles, preferably by a layering method. It was found that the above problems can be solved by a granule preparation obtained by forming a polymer membrane capable of releasing a drug (film coating) by coating on the obtained spherical elementary granules. Was completed.

That is, this invention relates to the following 1-18 invention.
1. A coating base having a drug layer containing fexofenadine or a pharmaceutically acceptable salt thereof on a pharmaceutically inert core particle, and further capable of releasing the drug after administration on the drug layer A fexofenadine granule preparation containing a coated granule having a coating layer.
2. 2. The fexofenadine granule preparation according to 1 above, wherein the coating base-containing coating layer is a coating layer containing ethyl cellulose.
3. 3. The fexofenadine granule preparation according to 2 above, wherein the coating base-containing coating layer further contains a water-soluble polymer.
4). 4. The fexofenadine granule preparation according to 3 above, which contains hypromellose as a water-soluble polymer.
5. 5. The fexofenadine granule preparation according to 3 or 4 above, wherein the content of the water-soluble polymer in the coating layer is 1 to 40% with respect to ethyl cellulose.
6). 6. The fexofenadine granule preparation according to any one of 1 to 5 above, wherein the drug layer is a layer formed of fexofenadine or a pharmaceutically acceptable salt thereof alone.
7). The fexofenadine granule preparation according to any one of 1 to 6 above, wherein the drug layer is a layering layer formed of a layering solution containing no binder.
8). 8. The fexofenadine granule preparation according to any one of 1 to 7 above, wherein the core particle is D-mannitol.

9. 9. The fexofenadine granule preparation according to any one of 1 to 8 above, wherein the average particle diameter of the core particles is 50 to 1000 μm.
10. 10. The fexofenadine granule preparation according to any one of 1 to 9 above, wherein the coated granule is an overcoat granule having an overcoat layer further containing a sugar alcohol, a high-intensity sweetener, and a water-soluble polymer.
11. The fexofenadine granule preparation according to any one of 1 to 10 above, which is a dry syrup preparation.
12 The fexofenadine granule preparation according to any one of 1 to 11 above, wherein the fexofenadine or a pharmaceutically acceptable salt thereof is fexofenadine hydrochloride.
13. 12. The fexofenadine granule preparation according to any one of 1 to 11 above, wherein the coating base-containing coating layer further contains a plasticizer and talc.
14 The content ratio of ethyl cellulose, water-soluble polymer, talc and plasticizer in the coating base-containing coating layer is 5 to 40 parts by mass of water-soluble polymer and 30 to 80 parts by mass of talc with respect to 100 parts by mass of ethyl cellulose. 14. The fexofenadine granule preparation according to the above 13, wherein the plasticizer is 0.5 to 5 parts by mass.

15. A step of forming a drug layer from a drug solution containing fexofenadine or a pharmaceutically acceptable salt thereof on a pharmaceutically inert core particle, and a coating base-containing coating on the outside of the formed drug layer A method for producing a fexofenadine granule preparation having a drug layer and a coating base-containing coating layer on the core particle, the method comprising using a liquid to form a coating base-containing coating layer capable of releasing the drug after administration .
16. A layer in which the inert core particle is a sugar alcohol and the step of forming a drug layer is formed by spraying a layering solution in which fexofenadine or a pharmaceutically acceptable salt thereof is dissolved in ethanol onto the core particle. 16. The method for producing a fexofenadine granule preparation according to the above 15, which is a ring method and the coating base-containing coating solution is a coating solution containing both ethylcellulose and hypromellose.
17. 16. Production of fexofenadine granule preparation according to 15 above, wherein the content of fexofenadine or a pharmaceutically acceptable salt thereof in the layering solution is 0.1 to 20% by weight based on the total amount of the layering solution. Method.
18. 18. The method according to any one of 15 to 17, further comprising a step of forming an overcoat layer with an overcoat solution containing a sugar alcohol, a high-intensity sweetener, and a water-soluble polymer after the coating layer is formed. A method for producing a xofenazine granule preparation.

According to the present invention, although it is a fexofenadine granule preparation having a dosage form that is easy to take for children, the elderly, etc., the initial elution can be suppressed and the bitterness peculiar to fexofenadine drug substance can be suppressed. At the same time, the release of the active ingredient from the subsequent preparation is excellent. In addition, it is possible to obtain a fexofenadine granule preparation with good stability over time, with no degradation during storage and with little change in formulation. For example, the fexofenadine granule preparation of the present invention has excellent storage stability that prevents decomposition of active ingredients and does not cause elution delay even when stored under high temperature, high temperature and high humidity, and irradiation of light. Show. Furthermore, when the granule preparation of the present invention is a dry syrup preparation, a fexofenadine preparation with excellent dosing properties that does not develop bitterness can be obtained.
Therefore, the fexofenadine-containing film-coated granule preparation of the present invention is extremely useful as a pharmaceutical product, and has an advantage that a pharmaceutical product that is excellent in terms of improving the quality of life (QOL) of a patient can be provided.

The fexofenadine used in the granule preparation of the present invention is fexofenadine (4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -α, α-dimethylbenzene. Acetate) or a pharmaceutically acceptable salt thereof (hereinafter referred to as “fexofenadine” unless otherwise indicated). In the granule preparation of the present invention, it is preferable to use fexofenadine hydrochloride.
In this specification, “granule preparation” means “granule” as defined in the 16th revision Japanese Pharmacopoeia.

  The fexofenadine granule preparation of the present invention is a spherical granule obtained by forming a drug layer containing fexofenadine on the surface of a pharmaceutically inert core particle (hereinafter simply referred to as “core particle”). And a fexofenadine granule preparation obtained by further film coating. The fexofenadine granule preparation of the present invention can be suitably used as a preparation for suspension in water, particularly as a dry syrup preparation.

  As a first step for producing the fexofenadine granule preparation of the present invention, a drug layer containing fexofenadine or a pharmaceutically acceptable salt thereof is formed on pharmaceutically inert core particles. Any method can be used to form the drug layer, but the layering method is preferred. The process of forming a drug layer by layering is hereinafter referred to as “layering process”.

  In the layering method in the present invention, the core particles are coated with a drug-containing coating layer (drug layer) by spraying a layering solution containing a drug, a binder, or the like onto the core particles. It is a method of manufacturing. Specifically, there are a method in which a drug powder and an aqueous binder solution are simultaneously supplied to coat, a method in which a drug particle suspension is supplied for coating, a method in which a drug-dissolved solution is supplied, and a method for coating. In the layering method, it is known that spherical particles having a high sphericity and a narrow particle size distribution can be obtained by using spherical core particles having a high sphericity and a narrow particle size distribution. However, in the present invention, a substance generally used as a pharmaceutical excipient or the like can be used as a core particle as it is. It is preferable to use core particles having a narrow particle size distribution as much as possible. Spherical granules obtained by layering are suitable as film coating granules.

  Pharmaceutically inactive core particles used in the fexofenadine granule preparation of the present invention include sugars such as glucose, fructose, sucrose and lactose; sugar alcohols such as D-mannitol, xylitol and erythritol; corn Core particles which are pharmaceutically inert ingredients such as starch; crystalline cellulose; and mixtures thereof.

  In some cases, the core particles may contain other pharmaceutical additives in addition to the above components, and may be processed into spherical core particles for layering. Other pharmaceutical additives include excipients, binders, coating bases, surfactants (emulsifiers), and other additives such as talc, magnesium stearate, magnesium aluminate metasilicate, titanium oxide And other additives such as silicic anhydride, crystalline cellulose and carmellose sodium.

  Examples of excipients that the core particles may contain include powdered cellulose, calcium hydrogen phosphate, glucose, fructose, sucrose, lactose, PCS (partially pregelatinized starch) and the like.

Examples of the binder that the core particles may contain include hydroxypropylcellulose, povidone (polyvinylpyrrolidone), xanthan gum, gum arabic powder, polyvinyl alcohol, methylcellulose, gelatin, pullulan and the like.
Examples of the coating base that may be contained in the core particles include hydroxypropylmethylcellulose, methacrylic acid copolymer LD, and ethylcellulose aqueous dispersion.
Examples of the surfactant (emulsifier) that the core particles may contain include sucrose fatty acid ester, glycerin fatty acid ester, sodium lauryl sulfate, polysorbate 80, and the like.

  The core particles used in the present invention include sugar alcohols, dextrins and dextrins that do not have reducibility from the viewpoint of dispersibility in water when used as a dry syrup and reactivity with other components such as Maillard reaction. Cyclodextrin and the like are preferable. In some cases, the core particle may be processed into a core particle for layering by adding the above-mentioned additives. In the present invention, the core particle is usually sold as a pharmaceutical excipient or the like. Sugar alcohol, dextrin, cyclodextrin and the like can be used as core particles as they are. In the present invention, D-mannitol can be mentioned as a preferable core particle, and β-crystal D-mannitol is more preferable.

The particle size of the core particles usually used for layering is an average particle size of about 50 to 1000 μm. In the present invention, any of these particle sizes can be used. In the present invention, the preferable average particle size of the core particles is about 50 to 300 μm, more preferably about 70 to 250 μm, and still more preferably 100 to 200 μm. The sharper particle size distribution is preferable, and the particle size distribution is preferably not more than half and not less than 10% of the average particle size. The bulk density of the core particles depends on the balance between strength and water retention, but is usually about 0.2 to 2.0 g / cm ³ , preferably 0.4 to 1 g / cm ³ . Further, it is preferable that the mechanical strength of the core particle is high. Examples of D-mannitol that meets the above conditions include Granitol (registered trademark) R and Nonparel (registered trademark) -108 (both manufactured by Freund Sangyo Co., Ltd.).

  As a layering method for forming a drug layer containing fexofenadine in the present invention, a method of forming a coating layer (drug layer) by spraying a layering solution containing fexofenadine onto core particles. preferable. The layering solution can be obtained by dispersing or dissolving fexofenadine in a medium together with various additives as required.

The medium of the layering solution is not particularly limited as long as it is a medium that can dissolve or disperse fexofenadine. For example, organic solvents that can be used in the field of food or medicine such as water and ethanol, and mixtures thereof. Can be used.
In the present invention, a medium that dissolves fexofenadine is preferable, and ethanol is the most preferable in that it dissolves fexofenadine and allows fexofenadine to adhere to the core particles without a binder and to form a drug layer well. preferable.

  If necessary, an additive may be further added to the layering solution used in the present invention. Any additive can be used as long as it is used in the field of pharmaceuticals and foods. For example, binders (including film coating bases) used in pharmaceuticals and foods, surfactants (emulsifiers) , Excipients, disintegrants and the like can be used in combination.

  As the binder that can be added to the layering solution, known binders can be used. Specific examples thereof include cellulose derivatives such as methylcellulose, ethylcellulose, hydroxylpropylcellulose, hydroxypropylmethylcellulose, carboxymethylethylcellulose; Non-cellulose polysaccharides such as xanthan gum and locust bean gum; and synthetic polymers such as polyethylene oxide, acrylic acid polymer, polyvinyl alcohol, and polyvinylpyrrolidone.

  Usually, the binder is added to the layering solution in order to bind the drug to the core particles. In the present invention, it is preferable to use an ethanol solution as the layering solution, and the binder is preferably an ethanol-soluble binder. An example is hydroxypropylmethylcellulose.

  In addition, as described above, an additive other than the binder can be added to the layering solution as desired. Specific examples of the additive include those that may be added to the core particles. The same can be mentioned. In the present invention, it is usually unnecessary to include these additives.

Surprisingly, in the present invention, as described above, when ethanol is used as a solvent for the layering solution, fexofenadine can be attached to the core particles without a binder as described above. Therefore, an embodiment that does not include a binder is more preferable.
Although an embodiment in which a binder is added is possible, the purity stability of the fexofenadine granule preparation may be reduced.
In the most preferred embodiment of the present invention, the layering solution is an ethanol solution of fexofenadine containing no binder.

  The content of fexofenadine contained in the layering solution can be appropriately selected depending on the intended granule preparation. The content of fexofenadine in the layering solution is not particularly limited, but is about 0.1 to 20% by mass, preferably about 1 to 15% by mass with respect to the total amount of the layering solution. is there.

  In order to form a drug layer on the surface of the core particles using the layering solution, the drug layer may be formed while spraying the fexofenadine-containing layering solution, spraying the core particles, and drying.

  As an apparatus used in the layering step, any apparatus can be used as long as it can form a drug layer containing fexofenadine on the outside of the core particles by the above-described method. For example, fluidized bed type coating An apparatus (sometimes called a fluidized bed dryer or a fluidized bed granulator) can be used. In addition to the normal fluidized bed type, the fluidized bed coating apparatus includes a spouted bed type having a guide tube (Worster column) inside, a rolling fluidized bed type having a rotating mechanism at the bottom, and the like. Specific examples of such devices include "Flow coater" and "Spiraflow" manufactured by Freund Corporation, "WST / WSG series" and "GPCG series" manufactured by Glatt, and "Numeralizer" manufactured by Fuji Powder Corporation. ”,“ Multiplex ”manufactured by POWREC Co., Ltd., and the like.

By the above layering method, spherical elementary granules having a fexofenadine drug layer on the surface of the core particles (hereinafter simply referred to as “spherical elementary granules”) are obtained. The “spherical shape” of the “spherical elementary granule” in the present invention does not mean a true spherical shape, but is used to include all shapes close to a spherical shape formed by layering.
The content of fexofenadine in the spherical elementary granule is usually 1 to 30% by mass, preferably 1 to 20% by mass, more preferably 3 to 15% by mass with respect to the total amount of core particles in the spherical elementary granule. Range.

The obtained spherical granules are sized as necessary, and then subjected to film coating for the purpose of sustained release, enteric properties, bitterness mask, etc. (hereinafter, this process is referred to as “film coating process”). . By this step, spherical granules are film-coated, and the granule preparation of the present invention can be obtained.
In the present invention, since fexofenadine is unpleasant and has a very strong bitterness and aftertaste, the film coating can mask bitterness and has a release property of fexofenadine after taking. Good ones are preferred.

The film coating can be carried out by any known film coating method, for example, by the fluidized bed granulation method using the same apparatus as used in the layering method. Can do.
As the film coating solution to be used, a known enteric film coating base, and if necessary, a coating solution in which a water-soluble coating base or a film coating additive is dissolved or dispersed can be used.

Specific examples of the coating base that can be used in the film coating solution of the present invention include, for example, ethyl cellulose, low-viscosity methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), hydroxypropyl methylcellulose acetate succinate. , Cellulose derivatives such as hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose and cellulose acetate phthalate, starches, polyvinylpyrrolidone, poly (meth) acrylic acid and its esters, polyvinyl alcohol and its derivatives, polyoxyethylene hydrogenated castor oil, etc. It is done. These components may be used alone or in combination of two or more as long as they contain at least one coating base.
Among the above, ethyl cellulose or a copolymer of poly (meth) acrylic acid and its ester is preferable. In particular, the coated granule coated with a coating agent containing ethylcellulose is more preferable because it has excellent storage stability.
Examples of commercially available products of poly (meth) acrylic acid and esters thereof include Eudragit (all registered trademarks) RL, Eudragit RS, and Eudragit NE-30D (both are Evonik Degussa Japan), etc. Examples of ethyl cellulose include ETHOCEL (registered trademark).

  Etosel is ethyl cellulose produced industrially by Dow Chemical Company, and when used in the present invention, it is desirable to use a pharmaceutical grade.

As the film coating base in the present invention, it is preferable to use ethyl cellulose and a water-soluble coating base in combination. By using ethyl cellulose and a water-soluble coating base in combination, elution during suspension in water can be suppressed, and the elution rate after administration can be improved. Specific examples of the water-soluble coating base (also referred to as “water-soluble polymer”) include hypromellose, hydroxypropylcellulose, low-viscosity methylcellulose, polyvinyl alcohol, and polyvinylpyrrolidone (povidone). Most preferably, ethyl cellulose and hypromellose are used in combination as a film coating base. In the present specification, unless otherwise specified, “water-soluble” means “slightly soluble” or higher in the above pharmacopoeia, and usually corresponds to “easily soluble” or “very soluble”. Is preferred.
The amount of water-soluble coating base, preferably hypromellose, used in combination with ethyl cellulose is preferably 1 to 40% by mass, more preferably 5 to 40% by mass, based on ethyl cellulose. When there is too much content of the water-soluble coating base in a coating film, the strong bitterness of fexofenadine may be expressed at the time of taking, and it is not preferable.

  The medium of the film coating solution is not particularly limited, and organic solvents that can be used in the field of food or pharmaceuticals such as water and ethanol, and mixtures thereof can be used, but from the viewpoint of preservation of the working environment and the natural environment, An aqueous solvent composed of water or a mixture of water and an organic solvent is preferred. Moreover, when using ethylcellulose as a film coating base, it is preferable to use ethanol or a mixed solvent of water and ethanol. As a medium of the film coating solution, a mixed solvent of water and ethanol is more preferable, ethanol is 60 to 99% by mass, more preferably 75 to 95% by mass, and a mixed solvent in which the balance is water is particularly preferable.

  In addition to the above coating base, one or more film coating additives selected from the group consisting of plasticizers, surfactants, sweeteners, colorants, and fragrances are further added to the coating liquid used in the present invention. be able to.

  In the coating solution used in the present invention, talc is preferably added as an additive since antistatic effects, solubility adjustment, caking prevention, fluidization and light stabilization can be expected. The amount of talc added to the coating solution is at most about 100% by weight, preferably 10 to 90% by weight, more preferably 20 to 70% by weight, and still more preferably 30 to 60% by weight based on the total amount of the coating base. % Is preferably used. Moreover, it is preferable to use a talc in the ratio of 30-80 mass parts with respect to 100 mass parts of ethylcellulose in a coating base.

  The plasticizer that may be added to the coating liquid is not particularly limited as long as it can be used as a pharmaceutical additive. For example, triacetin, triethyl citrate, acetyl tributyl citrate, tributyl citrate, diethyl phthalate, polyethylene glycol , Polysorbate, monoacetylated glyceride, diacetylated glyceride and the like, and triacetin is preferably used as a plasticizer. In the present invention, it is preferable to use a plasticizer at a ratio of at most about 10% by mass, preferably 0.1 to 5% by mass, based on the total amount of the coating base. Moreover, it is preferable to use a plasticizer in the ratio of 0.5-5 mass parts with respect to 100 mass parts of ethylcellulose in a coating base.

  The surfactant that may be added to the coating liquid is not particularly limited as long as it can be used as a pharmaceutical additive. For example, an anionic surfactant, a cationic surfactant, a nonionic surfactant, and Examples of the amphoteric surfactant include sucrose fatty acid ester, glycerin fatty acid ester, sodium lauryl sulfate, polysorbate 80 and the like. When a surfactant is used, it is used at a ratio of at most about 20% by mass, preferably 5 to 15% by mass, based on the total amount of the coating base. In the present invention, it may not be included.

  The sweetener that may be added to the coating solution is not particularly limited as long as it is a high-intensity sweetener that can be used as a pharmaceutical additive. For example, saccharin salts such as sodium saccharin, aspartame, glycyrrhizic acid, and dipotassium glycyrrhizinate Glycyrrhizic acid salts such as acesulfame potassium and stevia. These sweeteners may be used alone or in combination of two or more.

The colorant that may be added to the coating solution is not particularly limited as long as it can be used as a pharmaceutical additive, and examples thereof include iron sesquioxide, yellow iron sesquioxide, and caramel.
Examples of the fragrance that may be added to the coating liquid include those used in pharmaceuticals, foods, etc., such as apple flavor, orange extract, orange oil, orange essence, spearmint oil, mint oil, vanilla flavor, lemon oil, Examples include l-menthol, peach flavor, grapefruit flavor, and strawberry essence.

What is necessary is just to select suitably the content rate of solid content in a film coating liquid according to manufacturing conditions, and is about 1-30 mass% with respect to the total amount of a film coating liquid, Preferably it is about 3-20 mass%.
The content ratio of the film coating base with respect to the total solid content in the film coating solution is usually about 20 to 100% by mass, preferably about 40 to 90% by mass, and the balance is an additive for film coating.

A coating layer is formed on the outer side of the spherical elementary granule by the solid content comprising the film coating base and the film coating additive contained in the film coating solution.
What is necessary is just to adjust suitably the mass ratio of the coating layer with respect to a spherical elementary granule according to the objective of film coating, and is about 3-30 mass% with respect to a spherical elementary granule, Preferably it is about 5-25 mass%.

As the granule preparation of the present invention, the film-coated granule obtained above can be used as it is as a granule preparation.
Usually, it is preferable to further form an overcoat layer on the surface of the film-coated granule in order to improve the drug formulation, in particular, to improve the dissolution of the drug and the taste at the time of taking.
Hereinafter, the step of forming the overcoat layer is referred to as “overcoat step”, and the granule in which the overcoat layer is further formed on the film-coated granule is referred to as “overcoat granule”.

The overcoat step in the present invention may be any overcoat layer as long as the above object can be achieved, but in the present invention, an overcoat with a water-soluble sweetener is preferable.
For example, the overcoat layer may be formed on the surface of the film-coated granule using the same apparatus as used in the layering step.

  The medium for the overcoat liquid is not particularly limited, and water, ethanol, and other organic solvents that can be used in the field of food or pharmaceuticals and mixtures thereof can be used, but water or an aqueous solvent composed of a mixture of water and an organic solvent. Are preferred, and water is particularly preferred.

Excipients contained in the overcoat liquid include, for example, water-soluble saccharides such as sucrose, glucose, fructose, starch syrup, and lactose; water-soluble sugar alcohols such as D-mannitol, sorbitol, xylitol, and erythritol; corn starch, potato Examples thereof include starches such as starch and partially pregelatinized starch; water-soluble oligosaccharides such as dextrin and cyclodextrin; crystalline cellulose; organic acid salts such as calcium citrate; inorganic salts such as calcium hydrogen phosphate and calcium sulfate. One or two or more kinds of excipients can be used.
The excipient contained in the overcoat liquid of the present invention is preferably at least one selected from water-soluble sugar alcohols and oligosaccharides (for example, dextrin and cyclodextrin), more preferably water-soluble sugar alcohols, and D-mannitol. Is more preferable.
In the overcoat solution, a sugar alcohol or oligo corresponding to “easily soluble” (1 g of solute is dissolved in 10 ml or less) or “very soluble” (1 g of solute is dissolved in 1 ml or less) in the above pharmacopoeia. It is preferred that sugar be included. In the present invention, sugar alcohol is preferable as an excipient contained in the overcoat liquid, and D-mannitol is more preferable.

Examples of the binder that can be added to the overcoat liquid include compounds described as binders that may be added to the spherical core particles. The overcoat solution of the present invention may not contain a binder, but it is usually preferred to contain a binder. As the binder, any water-soluble polymer can be used. More preferably, hydroxypropylcellulose is used. The content of the binder is usually 0 to 50% by mass, preferably 5 to 40% by mass, and more preferably 10 to 30% by mass with respect to the total amount of the sweetener.
Examples of the high-intensity sweetener that can be added to the overcoat liquid include high-intensity sweeteners described as sweeteners that may be added to the film coating liquid. The overcoat solution of the present invention preferably contains the high-intensity sweetener. The high-intensity sweetener is a sweetener whose sweetness is several tens of times that of sucrose, for example, 30 times or more, and there is no particular upper limit. In the present invention, the high-intensity sweetener is preferably a sweetener having a sweetness of 50 times or more, preferably 100 times or more and about 800 times or less that of sucrose. More preferably, the high-intensity sweetener preferably contains at least one of a saccharin salt such as saccharin sodium and aspartame, and more preferably contains both saccharin sodium and aspartame.

The content ratio of the excipient (preferably sugar alcohol) and the high-intensity sweetener contained in the overcoat liquid is a ratio of 5 to 100 parts by mass of the sugar alcohol with respect to 1 part by mass of the high-intensity sweetener, The ratio is preferably 10 to 90 parts by mass, and more preferably 15 to 50 parts by mass. When both saccharin sodium and aspartame are contained, the amount of aspartame is usually 0.5 to 10 parts by mass, preferably 1 to 5 parts by mass with respect to 1 part by mass of saccharin sodium.
As the fragrance and colorant that can be added to the overcoat liquid, the fragrance and colorant described as additives that may be added to the film coating agent can be used. In some cases, it is preferable to add caramel to the overcoat solution. When using a colorant, preferably caramel, the content is usually 0.01 to 3% by mass, preferably about 0.05 to 1% by mass, based on the solid content of the overcoat liquid. Trace amount.
The overcoat solution used in the present invention preferably contains both the sugar alcohol and the high-intensity sweetener. Furthermore, the aspect containing a binder and / or a coloring agent is more preferable, and the aspect including both is particularly preferable.

The solid content contained in the overcoat liquid is appropriately adjusted according to the purpose, but is usually about 2 to 50% by mass, more preferably about 5 to 40% by mass with respect to the film coating particles. Thus, it is preferably contained in the overcoat liquid.
Moreover, what is necessary is just to select suitably the content rate of the solid content with respect to the total amount of overcoat liquid according to manufacturing conditions, and is about 1-30 mass% normally with respect to the total amount of overcoat liquid, Preferably it is about 2-20 mass%. is there.
The content ratio of the sugar alcohol with respect to the total amount of the solid content in the overcoat liquid is usually about 50 to 99% by mass, preferably about 85 to 98% by mass, and the remainder is other additives, preferably the above binder. , Colorants and high intensity sweeteners.

  For the film-coated granule or the overcoat granule that is the granule preparation of the present invention, a sweetener such as a saccharide, a sugar alcohol, or a high-intensity sweetener, and a fluidizing agent for the purpose of further enhancing the dosing property and commercial value. (Lubricants), disintegrants, binders, flavoring agents (fragrances), coloring agents, surfactants (solubilizing agents), and other various pharmaceutical additives commonly used in the field of normal pharmaceutical formulation technology (Hereinafter, this step is referred to as “final mixing step”). Usually, in this final mixing step, it is preferable that a sweetener and a fluidizing agent are further mixed with the granule.

  Examples of sweeteners that may be mixed in the final mixing step include the high-intensity sweeteners described as sweeteners that may be added to the film coating solution. In the granule preparation of the present invention, it is preferable to mix one or more selected from stevia, acesulfame potassium and aspartame in the final mixing step, and it is more preferable when two or more of these are mixed. The amount of the high-intensity sweetener mixed in the final mixing step is usually about 0.05 to 10% by mass and about 0.1 to 5% by mass with respect to the total amount of the granule preparation of the present invention. It is preferable.

  The fluidizing agent (lubricant) that may be mixed in the final mixing step is not particularly limited as long as it can be used as a pharmaceutical additive. For example, stearic acid such as magnesium stearate or a salt thereof, sodium stearyl Examples include fumarate, finely divided polyoxyethylene glycol, sodium benzoate, hydrous silicon dioxide, sucrose fatty acid ester, fumaric acid, sodium stearyl fumarate, and polyethylene glycol. In the granule preparation of the present invention, it is preferable to use magnesium stearate in the final mixing step. The amount of the fluidizing agent mixed in the final mixing step is usually about 0.01 to 5% by mass and about 0.01 to 3% by mass with respect to the total amount of the granule preparation of the present invention. Preferably, it is about 0.05-3 mass%.

As saccharides or sugar alcohols that may be mixed in the final mixing step, any sugars and sugar alcohols that are usually used as excipients in the field of pharmaceutical preparation technology can be mixed. Examples thereof include saccharides such as sucrose, glucose, fructose, starch syrup, and lactose, and sugar alcohols such as D-mannitol, with sugar alcohol being more preferred and D-mannitol being more preferred.
As a disintegrating agent, a binder, a fragrance, a colorant, and a surfactant that may be mixed in the final mixing step, an additive that may be added to the spherical core particles or a film coating agent may be added. Disintegrants, binders, fragrances, colorants and surfactants described as good additives can each be used.

  In the final mixing step, for example, additives such as calcium citrate, calcium hydrogen phosphate, and calcium sulfate may be mixed as necessary, but it is not usually necessary to mix and it is preferable not to mix them.

  About 0.1-10 mass% is preferable with respect to the total amount of the granule formulation of this invention, and, as for the addition amount of these pharmaceutical additives in a final mixing process, about 0.1-5 mass% is more preferable.

  The granule preparation of the present invention can be taken as an oral granule preparation as it is, filled into a capsule or the like to form a capsule, or can be made into a suspension preparation to be taken in suspension in water or the like. . The granule preparation of the present invention is preferably used as a suspension preparation that is suspended in an aqueous medium such as water. A preferable suspending preparation includes a dry syrup. Like the usual dry syrup, the granule preparation of the present invention, preferably the granule preparation that has undergone the final mixing step, can be drunk in water or an aqueous beverage at the time of taking. Here, the dry syrup preparation is a “syrup preparation” described in the 16th revised Japanese Pharmacopoeia, and in the present invention, it is a dry solid preparation that is suspended and used.

About the granule formulation of this invention obtained above, the preferable content rate of each layer when a core particle is 100 mass parts is as follows approximately. In addition, all "parts" represent a mass part.
Fexofenadine-containing coating layer: 1 to 20 parts, more preferably 3 to 15 parts.
Coating base-containing coating layer: 1-120 parts, more preferably 5-60 parts.
Optional overcoat layer: 2-120 parts, more preferably 5-70 parts.
Additives to be arbitrarily mixed in the final mixing step (preferably high intensity sweetener and fluidizer): 0.1 to 20 parts, more preferably 0.1 to 10 parts.

Preferred embodiments of the present invention include the following embodiments (I) to (VII).
(I) (i) A drug by spraying a layering solution obtained by dissolving fexofenadine hydrochloride in ethanol on spherical core particles having a D-mannitol content of 80% or more, preferably 100% And (ii) a fexofenadine granule preparation obtained through a step of forming a coating film using a coating solution containing both ethylcellulose and a water-soluble polymer on the outside of the coating layer. .
(II) A fexofenadine granule preparation obtained through a step of forming an overcoat layer using an overcoat liquid containing a sugar alcohol on the fexofenadine granule formulation described in (I) above.
(III) The granule preparation according to (II), wherein the sugar alcohol in step (iii) is D-mannitol, and the overcoat solution further contains a binder and a high-intensity sweetener.
(IV) Fexo obtained by the step of further mixing (iv) a high-intensity sweetener and a fluidizing agent with the fexofenadine granule preparation according to any one of (I) to (III) above. Phenazine dry syrup.
(V) The granule preparation or dry syrup preparation according to any one of (I) to (IV) above, wherein the layering solution in step (i) is a layering solution containing no binder.
(VI) The granule preparation or dry syrup preparation according to any one of (I) to (V) above, wherein the water-soluble polymer in step (ii) is hydroxypropylmethylcellulose.
(VII) Granule preparation according to any one of (I) to (VI) above, wherein steps (i), (ii) and (iii) are all carried out in a fluid bed granulator Or dry syrup.

  Although the preferable specific example of this invention is described below, this invention is not limited to the following specific example.

Example 1
<Layering process>
A layering solution was prepared by dissolving 60.0 g of fexofenadine hydrochloride in 750.0 g of ethanol (anhydrous ethanol: manufactured by Gansu Chemical Industry Co., Ltd.). In a fluidized bed type coating device (multiplex FD-MP-01D / SPC type, manufactured by POWREC Co., Ltd.), 600.0 g of D-mannitol (Granitol (registered trademark) R: manufactured by Freund Sangyo Co., Ltd.) is added and layered. The layered spherical granules were obtained by drying while spraying the solution. The obtained layered spherical granule was sized by sieving with 42M sieve.

<Film coating process>
In 1578.90 g of ethanol, 75.00 g of ethyl cellulose (product name Etocel Standard 7 Premium ethyl cellulose: manufactured by Dow Chemical Co., Ltd.) was dissolved, and 25.0 g of hypromellose (product name TC-5E: manufactured by Shin-Etsu Chemical Co., Ltd.) was dispersed. Thereafter, 296.10 g of purified water and 1.50 g of triacetin (manufactured by Daihachi Chemical Industry Co., Ltd.) were mixed and dissolved. A film coating solution was prepared by dispersing 48.50 g of talc (manufactured by Matsumura Sangyo Co., Ltd.) in the solution. The layered sphere elementary granule obtained by the above-mentioned particle size regulation was put into the fluidized bed type coating apparatus used in the layering step, and dried while spraying the film coating solution to obtain a film coated granule.

<Overcoat process>
Purified water (1770.0 g), D-mannitol (manufactured by Food Science Co., Ltd.) 166.5 g, hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., trade name HPC-L) 1.0 g, saccharin sodium hydrate (Daiwa Kasei Co., Ltd.) An overcoat solution was prepared by dissolving 2.0 g of company) and 5.0 g of aspartame (manufactured by Ajinomoto Co., Inc.). The film-coated granule obtained above was put into the same fluidized bed type coating apparatus used in the film coating process, and dried while spraying the overcoat liquid to obtain an overcoat granule.

<Final mixing process>
To the overcoat granule obtained above, Stevia extract purified product (product name Stevi MZ: manufactured by Maruzen Pharmaceutical Co., Ltd.) 5.00 g, acesulfame potassium (product name Sanet (registered trademark): manufactured by Neutrinova) 10.0 g and 0.5 g of magnesium stearate (magnesium stearate (vegetable): manufactured by Taihei Sangyo Co., Ltd.) was mixed to obtain the granule preparation of the present invention as a dry syrup.

Example 2
In the film coating process, except that 77.77 g of ethyl cellulose, 22.23 g of hypromellose, 1.50 g of triacetin and 48.50 g of talc were used, the same operation as in Example 1 was performed, and the granule preparation of the present invention was dried syrup. Obtained as an agent.

Example 3
In the film coating process, 80.0 g of ethylcellulose, 20.0 g of hypromellose, 1.50 g of triacetin, and 48.50 g of talc were used. In the overcoat process, 180.5 g of D-mannitol and 1 hydroxypropylcellulose were used. 1.0 g, 1.0 g of saccharin sodium hydrate and 5.0 g of aspartame, and in the final mixing step, 1.0 g of stevia extract and purified product, 1.0 g of acesulfame potassium, and 0.5 g of magnesium stearate The granule preparation of the present invention was obtained as a dry syrup preparation in the same manner as in Example 1.

Example 4
In the overcoat step, 156.5 g of D-mannitol, 1.0 g of hydroxypropyl cellulose, 2.0 g of sodium saccharin hydrate, and 5.0 g of aspartame were used, and the obtained overcoat granules were used in the final mixing step. The same operation as in Example 1 was performed except that 5.0 g of stevia extract and 10.0 g of acesulfame potassium, 10.0 g of aspartame (manufactured by Ajinomoto Co., Inc.) and 0.5 g of magnesium stearate were mixed. The inventive granule formulation was obtained as a dry syrup.

Example 5
Except having used the following components etc. in each process of Example 1, operation similar to Example 1 was performed and the granule formulation of this invention was obtained as a dry syrup agent. In the layering step, a layering solution in which 60.0 g of fexofenadine hydrochloride and 3.0 g of hydroxypropylcellulose (manufactured by Nippon Soda Co., Ltd., product name HPC-L) was dissolved in 750.0 g of ethanol was used. In the film coating step, after dissolving 50.0 g of ethyl cellulose in 789.45 g of ethanol, a film coating solution in which 24.25 g of talc was dispersed in a solution in which 148.05 g of purified water and 0.75 g of triacetin were mixed and dissolved. Using. In the overcoat process, 255.50 g of D-mannitol, 1.0 g of hydroxypropylcellulose, 1.0 g of sodium saccharin hydrate, and 2.0 g of aspartame were used. In the final mixing step, 1.0 g of stevia extract and purified product, 1.0 g of acesulfame potassium, and 0.5 g of magnesium stearate were used.

Example 6
In the film coating process, 77.77 g of ethyl cellulose, 22.23 g of hypromellose, 1.50 g of triacetin and 48.50 g of talc were used. In the overcoating process, 141 g of D-mannitol, 1.0 g of hydroxypropyl cellulose, and saccharin sodium Stevia extraction and purification was performed on the overcoat granules obtained in the final mixing step using 2.0 g of hydrate, 5.0 g of aspartame, and a small amount (0.5 g) of caramel (manufactured by Semba Saccharification Co., Ltd.). Except for mixing 1.0 g of product, 10.0 g of acesulfame potassium, 30.0 g of aspartame (manufactured by Ajinomoto Co., Inc.), and a trace amount of magnesium stearate (0.5 g), the same operation as in Example 1 was carried out. A granule formulation was obtained as a dry syrup.

  Table 1 below shows the components blended in each step and the blending amount [mg / g] per 1 g of the obtained dry syrup for each preparation. In addition, in Table 1, the solvent in a layering liquid, a coating base containing coating liquid, and an overcoat liquid is not described. Moreover, since the addition amount of the caramel and magnesium stearate in the granule preparation of Example 6 is very small (0.5 mg for caramel and 0.5 mg for magnesium stearate), it is not included in the total in Table 1 below.

Test Example 1 (Purity test)
1.0 g of layered spherical elementary granules prepared and sized according to the layering process in Example 1 were packaged in aluminum sachets and stored for 2 weeks in an environment of 40 ° C. and RH 75%. After storage, the purity test was performed on the layered spherical granules taken out from the aluminum package.
In the purity test, fexofenadine and its related substances were quantified for each sample immediately after production and after the storage test, and the content ratio of the related substances relative to fexofenadine was used as an indicator of stability.

<Method for measuring related substances>
Based on the amount of raw material used at the time of preparing the layered spheroid granules, an amount of layered spheroid granules corresponding to 30 mg of fexofenadine hydrochloride was taken, and the following mobile phase was added to make 30 mL and shaken. This solution was centrifuged, and the supernatant was used as a sample solution. 1 mL of this sample solution was accurately weighed, and a mobile phase was added thereto to make exactly 100 mL, which was used as a standard solution. 20 μL of each of the obtained sample solution and standard solution was accurately weighed and measured by liquid chromatography under the following conditions. From the measurement results of each solution, the peak areas of fexofenadine and its related substances were calculated by the automatic integration method. Purity stability was evaluated by the ratio of the total amount of the peak areas of the related substances to the peak area of the obtained fexofenadine.

<Test conditions>
Detector: UV absorptiometer (measurement wavelength: 220 nm)
Column: A column in which a stainless steel tube having an inner diameter of 4.6 mm and a length of 25 cm is filled with phenylsilylated silica gel for liquid chromatography having a particle diameter of 5 μm.
Column temperature: constant temperature around 40 ° C.
Mobile phase: Dissolve 7.51 g of sodium dihydrogen phosphate dihydrate and 0.84 g of sodium perchlorate in 1000 mL of water, add phosphoric acid to adjust the pH to 2.0, take 650 mL, A mobile phase was prepared by adding 350 mL of acetonitrile and 3 mL of triethylamine to this solution.
Flow rate: Adjusted so that the retention time of fexofenadine was about 9 minutes.
Area measurement range: about 5 times the retention time of fexofenadine. However, for the standard solution, the range is about 1.2 times the retention time of fexofenadine.
(For related substances, the total area was calculated assuming that a new peak not detected in the standard solution was the peak of the related substance. At that time, the peak of the peak having a relative retention time of about 1.6 with respect to fexofenadine. The area was a value obtained by multiplying the area obtained by the automatic integration method by a sensitivity coefficient of 1.42.)

In Table 2 above, the value of “related substance (%)” represents the percentage of the total peak area of the related substance with respect to the peak area of fexofenadine. “Initial” is a value of the layered spherical elementary granule immediately after production and before the storage test.
As is apparent from the results in Table 2, the layered spherical granules obtained by forming the coating layer containing fexofenadine on the spherical core particles obtained in the production process of the fexofenadine granule preparation of the present invention has a temperature of 40 ° C. and RH of 75%. Even after being stored for 2 weeks in this environment, almost no related substances were produced, and the purity stability was good.

Test example 2 (initial dissolution test)
The fexofenadine hydrochloride dry syrup of the present invention obtained in Examples 1, 2, and 3 was subjected to a dissolution test.
For each dry syrup of each example, accurately measure the amount corresponding to 60 mg of fexofenadine hydrochloride, put it in a container, put 50 mL of purified water there, and shake it once a second, Suspended for 1 minute. 10 mL or more was taken from the suspension and filtered with a membrane filter having a pore size of 0.45 μm or less. Except for 5 mL of the first filtrate, 1 mL of the next filtrate was accurately weighed. 17 mL of purified water was added to 1 mL of the measured filtrate for dilution. 1 mL of the diluted solution was accurately weighed, and 1 mL of the following mobile phase and 2 mL of 0.001 mol / L hydrochloric acid were accurately added to 1 mL of the measured diluted solution to obtain a sample solution.
On the other hand, 33 mg of fexofenadine hydrochloride for quantification (a separate moisture was measured) was accurately weighed and dissolved in the following mobile phase to make exactly 50 mL. 5 mL of this liquid was accurately weighed and the following mobile phase was added to make exactly 50 mL. 1 mL of this solution was accurately weighed, and 3 mL of 0.001 mol / L hydrochloric acid was accurately added to obtain a standard solution. The sample solution and the standard solution were each accurately weighed by 10 μL and measured by liquid chromatography under the following measurement conditions. From the measurement result, the sample solution and standard solutions fexofenadine peak area A _T and A _S was calculated.

Than the measured value of A _T and _{A S,} the dissolution rate to the content of fexofenadine hydrochloride after the dry syrup was suspended for one minute in water of each example _{(C 32 H 39 NO 4 ·} HCl), The following calculation formula was used.
Elution rate (%) = (W _S / W _T ) × (A _T / A _S ) × (1 / C) × 180
W _S : Weighed amount of fexofenadine hydrochloride for determination in terms of dehydrated product (mg)
W _T : Weighed amount of dry syrup preparation of each Example (g)
C: Content of fexofenadine hydrochloride in 1 g of the dry syrup preparation of each Example (mg)

<Measurement conditions for liquid chromatography>
Detector: UV absorptiometer (measurement wavelength: 220 nm)
Column: A column filled with octadecylsilylated silica gel for liquid chromatography having a particle diameter of 5 μm in a stainless steel tube having an inner diameter of 4.6 mm and a length of 15 cm.
Column temperature: constant temperature around 40 ° C. Mobile phase: 3.8 g of sodium dihydrogen phosphate dihydrate and 1.9 g of sodium perchlorate were dissolved in 1000 mL of water, and 1 mL of phosphoric acid was further added. 400 mL was taken from the obtained liquid, and 600 mL of acetonitrile was added to this liquid to prepare a mobile phase.
Flow rate: Adjusted so that the retention time of fexofenadine was about 3 minutes.
Area measurement range: about 1.2 times the retention time of fexofenadine.
The results of the initial dissolution test of Test Example 2 are shown in Table 3.

  As apparent from the results in Table 3, the fexofenadine granule preparation of the present invention was a granule preparation in which the initial dissolution of fexofenadine was suppressed when suspended in water for 1 minute. Since the bitterness at the time of taking is suppressed by suppressing the initial elution, the fexofenadine granule preparation of the present invention is considered to be a preparation with improved feeling of taking.

Test Example 3 (Sensory test)
A sensory test was conducted by 10 subjects. The dry syrup preparation 0.5g obtained in Example 4 was included in the mouth, and sweetness, bitterness, aftertaste, and comprehensive evaluation were evaluated in five stages according to each scoring standard. The scoring criteria are shown below. Table 4 below shows the evaluation of each subject, the average and standard deviation (SD) for each evaluation item.
<Scoring criteria>
Sweetness: 1 (insufficient sweetness), 2 (middle of 1 and 3), 3 (just right), 4 (middle of 3 and 5), 5 (too sweet)
Bitterness: 1 (no bitterness), 2 (between 1 and 3), 3 (bitterness doesn't matter much), 4 (between 3 and 5), 5 (bitter)
Aftertaste: 1 (I want to drink water), 2 (between 1 and 3), 3 (I can stand without drinking water), 4 (between 3 and 5), 5 (I don't feel the need to drink water) )
Comprehensive: 1 (drink with patience), 2 (between 1 and 3), 3 (drink without patience), 4 (between 3 and 5), 5 (delicious)

As is clear from the results in Table 4, the sweetness was moderate, with an average evaluation of 3.4. The average bitterness of fexofenadine was 2.2, and the fexofenadine granule preparation of the present invention had no bitterness or could be taken without concern. The average of the aftertaste evaluation was 3.4, which was an aftertaste that could be tolerated without drinking water. The average of the overall evaluation was 3.5, and although the drug substance of fexofenadine had a strong bitter taste, it was evaluated that the fexofenadine granule preparation of the present invention could be taken without patience.
Therefore, it was found that the fexofenadine granule preparation of the present invention has a good sweetness and has a sufficient masking effect, so that the bitterness and aftertaste at the time of taking are hardly felt, and the preparation is excellent in taking feeling.

Test Example 4 (Purity test)
<Sample>
The purity test was performed as follows for each of the layered spherical granules (sized with 42M sieve) and the film-coated granules obtained in Example 3.
1.0 g of each of the layered sphere granules and the film-coated granules were packaged in aluminum sachets and stored for 2 weeks in an environment of 40 ° C. and RH 75%. After storage, the purity test was performed on the layered spherical elementary granules and the film-coated granules taken out from the aluminum package.

<Method for measuring related substances>
An amount corresponding to 30 mg of fexofenadine hydrochloride is taken in a container, and a mixture of sodium dihydrogen phosphate / sodium perchlorate solution and acetonitrile for liquid chromatography (1 1) was added to the container to make 30 mL and shaken. This solution was centrifuged, and the supernatant was used as a sample solution. 1 mL of this sample solution was accurately weighed, and the following mobile phase was added to make exactly 100 mL to obtain a standard solution. 20 μL of each of the obtained sample solution and standard solution was accurately weighed and measured by liquid chromatography under the following conditions. From the measurement results of each solution, the peak areas of fexofenadine and its related substances were calculated by the automatic integration method. However, the peak area having a relative retention time of about 1.6 relative to fexofenadine was a value obtained by multiplying the area obtained by the automatic integration method by a sensitivity coefficient of 1.42. Purity stability was evaluated by the ratio of the total amount of the peak areas of the related substances to the peak area of the obtained fexofenadine.

<Measurement conditions>
Detector: UV absorptiometer (measurement wavelength: 220 nm)
Column: A column in which a stainless steel tube having an inner diameter of 4.6 mm and a length of 25 cm is filled with phenylsilylated silica gel for liquid chromatography having a particle diameter of 5 μm.
Column temperature: constant temperature around 25 ° C.
Mobile phase: A mobile phase was prepared by adding 350 mL of acetonitrile and 3 mL of triethylamine to 650 mL of a sodium dihydrogen phosphate / sodium perchlorate solution.
Flow rate: Adjusted so that the retention time of fexofenadine was about 9 minutes.
Area measurement range: After the solvent peak, up to about 6 times the retention time of fexofenadine. However, the standard solution and the solution used for confirmation of system suitability are in the range of about 1.2 times the retention time of fexofenadine.

The numerical values in Table 5 above represent the percentage of the total peak area of related substances relative to the peak area of fexofenadine. “Initial” is a value of each preparation after production and before a storage test.
As is clear from the results in Table 5, the layered sphere-shaped granules and the film-coated granules are excellent in storage stability. In particular, the film-coated granules of the present invention showed excellent storage stability.

Test Example 5 (Storage stability of dry syrup in aluminum packaging)
1.0 g of the fexofenadine hydrochloride dry syrup of the present invention obtained in Example 3 was packaged in an aluminum sachet and stored in an environment of 40% RH 75% for 2 weeks and 4 weeks. After storage, a purity test was conducted on the dry syrup taken from the aluminum package.
The purity test was performed in the same manner as in Test Example 4 except that the amount of dry syrup of Example 3 corresponding to 30 mg of fexofenadine hydrochloride was used. The results of the purity test are shown in Table 6 below.

The numerical value of the item “related substance (%)” in Table 6 above represents the percentage of the total peak area of the related substance with respect to the peak area of fexofenadine, and “initial” is a dry syrup preparation after production and before the storage test. Is the value of
As is apparent from the results in Table 6, the fexofenadine hydrochloride dry syrup of the present invention produced a small amount of related substances even after being stored under accelerated conditions of 40 ° C. and RH 75% for 2 weeks and 4 weeks. Purity stability was good.

Test Example 6 (Storage stability under dry syrup release)
The fexofenadine hydrochloride dry syrup of the present invention obtained in Example 6 was spread on a glass petri dish and stored for one month in an open state in an environment of 25 ° C. and RH 60%. A purity test was performed on the dry syrup immediately after production and on the dry syrup taken from the glass petri dish after storage. The measurement method and measurement conditions for fexofenadine and its related substances in the purity test were set in the same manner as in Test Example 5.
Moreover, about each dry syrup agent immediately after manufacture and a storage test, the elution test was done by the following method.

<Dissolution test>
Based on the blending amounts shown in Table 1, an amount corresponding to 60 mg of fexofenadine hydrochloride was accurately weighed for each dry syrup. Each weighed dry syrup is put into 900 mL of the first solution of the 16th revised Japanese Pharmacopoeia dissolution test, which has been degassed, and the dissolution test method No. 2 (Paddle method) described in the general test method of the 16th revised Japanese Pharmacopoeia The dissolution test was conducted at 50 revolutions per minute. After 30 minutes from the start of the dissolution test, 10 mL or more of the eluate was collected and filtered through a membrane filter having a pore size of 0.45 μm or less. Except for 4 mL of the first filtrate, the next filtrate was used as a sample solution.
On the other hand, about 30 mg of fexofenadine hydrochloride for quantitation (separately measure the water content) was taken and weighed accurately, then dissolved in 5 mL of methanol, and water was added to make exactly 100 mL. . 10 mL of this solution was accurately weighed and water was added to make exactly 50 mL as a standard solution.
The sample solution and the standard solution were each accurately weighed 20 μL, and measured by liquid chromatography under the following measurement conditions. From the measurement result, the sample solution and standard solutions fexofenadine peak area A _T and A _S was calculated.

Than the measured value of A _T and _{A S,} the dissolution rate to the content of fexofenadine hydrochloride _{(C 32 H 39 NO 4 ·} HCl) in the eluate of each dry syrup was calculated by the following calculation formula.
Elution rate (%) = (W _S / W _T ) × (A _T / A _S ) × (1 / C) × 180
W _S : Weighed amount of fexofenadine hydrochloride for determination in terms of dehydrated product (mg)
W _T : Weighed amount of each dry syrup (g)
C: Content of fexofenadine hydrochloride in 1 g of each dry syrup (mg)

<Measurement conditions for liquid chromatography>
Detector: UV absorptiometer (measurement wavelength: 220 nm)
Column: A column in which a stainless steel tube having an inner diameter of 4.6 mm and a length of 25 cm is filled with phenylated silica gel for liquid chromatography having a particle diameter of 5 μm.
Column temperature: constant temperature around 35 ° C. Mobile phase: To 1000 mL of diluted acetic acid (100) (17 → 10000) solution, 15 mL of triethylamine / acetonitrile mixture (1: 1) was added, and phosphoric acid was added to adjust the pH to 5. Adjusted to 25. The resulting mixed solution and acetonitrile were mixed at a volume ratio of 16: 9 to prepare a mobile phase.
Flow rate: Adjusted so that the retention time of fexofenadine was about 6 minutes.
Area measurement range: about 1.2 times the retention time of fexofenadine.

The results of the dissolution test and the purity test after the storage test of Test Example 6 are shown in Table 7 below.

In Table 7, the numerical value of the item “elution rate (%)” represents the elution rate relative to the content of fexofenadine hydrochloride, and the numerical value of the item “related substance (%)” has the same meaning as in Table 6 above. Represent. “Initial” is each value of the preparation after production and before the storage test.
As is apparent from the results in Table 7, the fexofenadine hydrochloride dry syrup of the present invention has a small amount of related substances and good purity stability even after storage for 1 month at 25 ° C. and RH 60%. And had good dissolution properties that were not different from those before the storage test.

Test Example 7 (Storage stability of dry syrup in a bottle)
100 g of the fexofenadine hydrochloride dry syrup of the present invention obtained in Example 6 was placed in a plastic bottle (manufactured by Shingo Chemical Co., Ltd., product name SK-200), and the cap was closed. % In an environment. After storage for 1 month, 3 months and 6 months from the start of the test, each dry syrup taken from the bottle was subjected to a purity test and a dissolution test. The measurement method and measurement conditions for the content of fexofenadine and its related substances in the purity test were set in the same manner as in Test Example 5, and the test conditions for the dissolution test were set in the same manner as in Test Example 6. The results are shown in Table 8. In Table 8, numerical values in the items of “elution rate (%)” and “related substances (%)” and “initial” have the same meaning as in Table 7. As apparent from Table 8, the preparation of the present invention showed no increase in related substances after 1 month, and its content was only 0.16% even after 6 months.

As a comparative object, commercially available oral tablets of fexofenadine hydrochloride (trade name Allegra Tablets 60 mg, fexofenadine hydrochloride 60 mg, manufactured by Sanofi-aventis Co., Ltd.) (hereinafter also referred to as “normal tablets”) are used. Similarly, a purity test was conducted on each of the preparation before the storage test and the preparation after being stored for 1 month in a PTP-packed form in an environment of 40 ° C. and RH 75%. As a result, the content of related substances was 0.27% at initial, and increased to 0.34% after 1 month storage.
Similarly, orally disintegrating tablets (product of Sanofi-aventis Co., Ltd., trade name Allegra OD tablets 60 mg, fexofenadine hydrochloride 60 mg) (hereinafter also referred to as “OD tablets”), In addition, a purity test was performed on each of the preparations that had been PTP-wrapped in an environment of 40% RH 75%, further packed in an aluminum pillow, and stored in a paper box for 6 months. As a result, the content of related substances was 0.38% initial, and 0.45% after 6 months storage.

Test Example 8 (Photostability of dry syrup)
The fexofenadine hydrochloride dry syrup of the present invention obtained in Example 6 was spread on a glass petri dish. Without covering the glass petri dish, 3000 lx light was continuously irradiated from above the glass petri dish using a fluorescent lamp. After 200 hours (cumulative irradiation amount 600,000 lx · hr) and 400 hours (cumulative irradiation amount 1,200,000 lx · hr) from the start of irradiation, a purity test and a dissolution test were performed on the dry syrup taken from the glass petri dish.
As a comparison object, a commercially available oral tablet of fexofenadine hydrochloride (manufactured by Sanofi-aventis Co., Ltd., trade name Allegra Tablet 60 mg, containing fexofenadine hydrochloride 60 mg) (hereinafter also referred to as “normal tablet”). The tablet was irradiated with light in the same manner as described above, and a purity test was performed on the tablet after the irradiation. The normal tablets to be compared were not packaged.
The measurement method and test conditions for the content of fexofenadine and its related substances in the purity test were set in the same manner as in Test Example 5, and the test conditions for the dissolution test were set in the same manner as in Test Example 6.

The results of Test Example 8 are shown in Table 9 below.

In Table 9, the numerical values in the items of “elution rate (%)” and “related substances (%)” and “initial” have the same meaning as in Table 7.
As is apparent from the results in Table 9, the fexofenadine hydrochloride dry syrup of the present invention had a good dissolution property with little increase in the amount of related substances produced even after irradiation with light.

The fexofenadine granule preparation of the present invention is easy to take even for children and the elderly, and at the time of taking, the initial elution can be suppressed, and the bitterness peculiar to fexofenadine drug substance can be suppressed. It is a granule preparation having good release of active ingredients from the preparation, excellent stability over time of the preparation, no degradation product during storage, and little change in formulation. For example, the fexofenadine granule preparation of the present invention is excellent in storage stability even in storage under high temperature, high temperature and high humidity, and light irradiation.
Therefore, the present invention has an advantage that a pharmaceutical excellent in QOL (Quality of Life) can be provided for a patient.

Claims (17)

A coating base having a drug layer containing fexofenadine or a pharmaceutically acceptable salt thereof on a pharmaceutically inert core particle, and further capable of releasing the drug after administration on the drug layer A fexofenadine granule preparation containing a coated granule having a containing coating layer ,
Fexofenadine granule preparation which is a dry syrup.   The fexofenadine granule preparation according to claim 1, wherein the coating base-containing coating layer is a coating layer containing ethylcellulose.   The fexofenadine granule formulation according to claim 2, wherein the coating base-containing coating layer further contains a water-soluble polymer.   The fexofenadine granule preparation according to claim 3, comprising hypromellose as a water-soluble polymer.   The fexofenadine granule preparation according to claim 3 or 4, wherein the content of the water-soluble polymer in the coating layer is 1 to 40% with respect to ethylcellulose.   The fexofenadine granule preparation according to any one of claims 1 to 5, wherein the drug layer is a layer formed of fexofenadine or a pharmaceutically acceptable salt thereof alone.   The fexofenadine granule preparation according to any one of claims 1 to 6, wherein the drug layer is a layering layer formed of a layering solution containing no binder.   The fexofenadine granule preparation according to any one of claims 1 to 7, wherein the core particle is D-mannitol.   The fexofenadine granule preparation according to any one of claims 1 to 8, wherein the average particle diameter of the core particles is 50 to 1000 µm.   The fexofenadine granule formulation according to any one of claims 1 to 9, wherein the coated granule is an overcoat granule having an overcoat layer further containing a sugar alcohol, a high-intensity sweetener, and a water-soluble polymer. . Fexofenadine or fexofenadine granular formulation according to any one of claims 1 to 1 0 a pharmaceutically acceptable salt thereof fexofenadine hydrochloride.   The fexofenadine granule preparation according to any one of claims 1 to 11, wherein the coating base-containing coating layer further contains a plasticizer and talc. The content ratio of ethyl cellulose, water-soluble polymer, talc and plasticizer in the coating base-containing coating layer is 5 to 40 parts by mass of water-soluble polymer and 30 to 80 parts by mass of talc with respect to 100 parts by mass of ethyl cellulose. , fexofenadine granular formulation according to claim 1 2 plasticizer is 0.5 to 5 parts by weight.   A step of forming a drug layer from a drug solution containing fexofenadine or a pharmaceutically acceptable salt thereof on a pharmaceutically inert core particle, and a coating base-containing coating on the outside of the formed drug layer A method for producing a fexofenadine granule preparation having a drug layer and a coating base-containing coating layer on the core particle, the method comprising using a liquid to form a coating base-containing coating layer capable of releasing the drug after administration . A layer in which the inert core particle is a sugar alcohol and the step of forming a drug layer is formed by spraying a layering solution in which fexofenadine or a pharmaceutically acceptable salt thereof is dissolved in ethanol onto the core particle. a ring method, a manufacturing method of fexofenadine granular formulation according to claim 1 4 coating base-containing coating liquid is a coating liquid containing both of ethylcellulose and hypromellose. The fexofenadine granule preparation according to claim 15 , wherein the content of fexofenadine or a pharmaceutically acceptable salt thereof in the layering solution is 0.1 to 20% by weight based on the total amount of the layering solution. Manufacturing method. After forming a coating layer, further, a sugar alcohol, an overcoat solution containing a high intensity sweetener agent and a water-soluble polymer, in any one of claims 1 4 to 1 6 comprising the step of forming an overcoat layer The manufacturing method of the fexofenadine granule formulation of description.