JP5819680B2 - Small sustained release formulation of ambroxol hydrochloride - Google Patents

Description

  The present invention relates to miniaturized sustained-release granules of ambroxol hydrochloride, capsule-filled preparations thereof, and compression-molded tablets.

  Ambroxol hydrochloride is a drug that has the effect of promoting the secretion of pulmonary surfactant, the secretion of airway fluid, and the action of promoting ciliary motility. As an expectorant in bronchitis and asthma, it is widely used from children to the elderly. An expectorant is especially useful for children with undeveloped vaginal function or elderly people with reduced vaginal function, and these children and the elderly often have poor swallowing function. Ease is an important factor in compliance.

  Ambroxol hydrochloride, as a solid preparation for oral administration, has already been approved and marketed as a once-daily capsule comprising filled sustained-release granules. This capsule has high patient compliance in terms of once a day. However, capsules are generally harder to drink than tablets, and the main factors are size and adhesion to the oral mucosa. Of these, the size of the capsule depends on the weight of the filled formulation. According to Table 3 of Non-Patent Document 1, the filling amount of the above-mentioned ambroxol hydrochloride capsules (commercially available product) is about 230 mg and 160 mg, and if this filling amount can be reduced, it is easier to drink the capsules. It becomes possible to make it small. The marketed product is a mixed preparation of two types of granules, fast-dissolving granules and slow-dissolving granules, and the core particles of these granules are common. Therefore, theoretically, at least overlap is caused by multiple granulation (single granulation of two types of granules) in which core particles as disclosed in Patent Document 1 are coated concentrically with a slow-dissolving layer and a fast-dissolving layer. It was thought that the weight of the core particles could be reduced. However, multiple granules are generally known to suffer from a slow-dissolving layer at the time of preparation, and it is difficult to unify the granules from the viewpoint of maintaining the same elution characteristics with respect to a mixed preparation of two types of granules. is there.

  On the other hand, tablets of ambroxol hydrochloride have also been approved and marketed. The tablets on the market are superior to capsules in terms of ease of swallowing, but since they are ordinary immediate release preparations, they are once a day in that they need to be administered three times a day. Compared to, compliance is not good.

  In view of the above, in a once-daily sustained release formulation of ambroxol hydrochloride, capsules and tablets that are easy to drink and downsized are desired. In such capsules or tablets, it is necessary to maintain the dissolution characteristics equivalent to the marketed products in order to guarantee the effectiveness and safety as a once-daily ambroxol hydrochloride preparation. Yes, it is a challenge.

  As a sustained-release preparation of ambroxol hydrochloride, in addition to the above-mentioned marketed capsules, Patent Document 2 includes compression-molded granulated granules that are uniformly mixed with an additive containing a water-insoluble polymer such as ethyl cellulose. Sustained release tablets are disclosed. However, the preparation described in Patent Document 2 has a matrix-type drug release mechanism, which is clearly different from the above-mentioned membrane-controlled type of granules of the marketed capsule. Therefore, it is difficult to guarantee the effectiveness and safety as a once-daily administration type ambroxol hydrochloride preparation which is one of the problems of the present invention.

  Patent Document 3 discloses a membrane-controlled granule of ambroxol hydrochloride comprising an inactive nucleus, an inner multilayer containing ambroxol hydrochloride, and an outer layer not containing a pharmaceutically active substance. However, the weight of granules per unit weight of ambroxol hydrochloride is about 186 mg (granule) / 45 mg (ambroxol hydrochloride), which is a commercial product (160 mg (granule) / 45 mg (ambroxol hydrochloride)), and there is no description or suggestion regarding miniaturization or tableting of capsules.

JP 62-103012 A JP 2008-201706 A JP-A-5-320044

PHARM TECH JAPAN Vol.22 No.8, p73-78 (2006)

  The object of the present invention is to reduce the size of ambroxol hydrochloride, which is easy to drink even for children and elderly people with reduced swallowing function, and is guaranteed effective and safe as a once-daily sustained-release preparation. Providing a solid formulation.

  In view of the above problems, as a result of intensive studies, the present inventors have found that the first layer that exhibits a fast-dissolving action for the core particles, a slow-dissolving action, compared to the prior art using two types of granules of fast-dissolving and slow-dissolving. Granules per unit weight of ambroxol hydrochloride by using a single granule, a granule having a layered structure of at least three layers, sequentially coated with a second layer presenting and a third layer exhibiting a fast dissolving action The present invention was completed by finding that a reduced solid dosage form of ambroxol hydrochloride, which can reduce the amount, and assured effectiveness and safety as a once-daily sustained-release preparation, was obtained. did.

That is, the present invention relates to the following.
[1] Granules containing ambroxol hydrochloride as a medicinal ingredient and having a layered structure of at least three layers,
(1) nuclear particles,
(2) a first layer covering the core particles, comprising ambroxol hydrochloride, a disintegrant, and a binder;
(3) a second layer comprising a water-insoluble polymer and a water-soluble polymer,
(4) Granules comprising a third layer comprising ambroxol hydrochloride and a binder.
[2] The granule according to [1], wherein the core particle is crystalline cellulose.
[3] The granule according to [1] or [2], wherein the water-insoluble polymer is at least one selected from the group consisting of ethyl cellulose, a (meth) acrylic acid copolymer of an aminoalkyl methacrylate copolymer, and polyvinyl acetate. .
[4] The water-soluble polymer is hydroxypropylcellulose, hypromellose, carmellose sodium, methylcellulose, hydroxyethylcellulose, pregelatinized starch, sodium alginate, xanthan gum, guar gum, gum arabic, carrageenan, carboxyvinyl polymer, polyethylene oxide, vinylpovidone acetate polymer The granule according to any one of [1] to [3], which is at least one selected from the group consisting of a matrix, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene glycol, and pullulan.
[5] The granule according to any one of [1] to [4], wherein the granule has an average particle size of 300 to 800 μm.
[6] A protective coating layer containing a water-soluble polymer is further provided between the second layer and the third layer, and the third layer further contains an excipient and a plasticizer [1] to [5] The granule according to any one of the above.
[7] The granule according to any one of [1] to [6], further comprising a pH adjuster in the first layer and / or the second layer.
[8] A drug sustained-release solid preparation comprising the granule according to any one of [1] to [7].
[9] The drug sustained-release solid preparation of [8], which is a tablet or capsule.
[10] A sustained-release drug tablet obtained by compression molding only the granules according to [6].

  The miniaturized solid preparation of ambroxol hydrochloride of the present invention provides a preparation that is easy to drink for a wide range of patients including children and elderly people whose swallowing function has been reduced, and that is administered once a day and has high compliance. The

It is a figure which shows the elution profile implemented according to the 15th revision Japanese Pharmacopoeia general test method 6.10 elution test method paddle method (test solution: water, rotation speed: 50 rpm) of the capsule obtained in Example 1. FIG. Fifteenth revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method of Capsule obtained in Example 1 Dissolution profile carried out according to paddle method (test solution: JP1 solution (pH 1.2), rotation speed: 50 rpm) FIG. Elution carried out in accordance with the 15th revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method Paddle Method (Test Solution: McIlvine Buffer (pH 4.0), Rotation Speed: 50 rpm) of Capsule Obtained in Example 1 It is a figure which shows a profile. Fifteenth revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method of Capsule obtained in Example 1 Dissolution performed according to the paddle method (test solution: McIlvine buffer (pH 7.5), rotation speed: 50 rpm) It is a figure which shows a profile. Fifteenth revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method of Capsule obtained in Example 1 Dissolution performed according to paddle method (test solution: McIlvine buffer (pH 7.5), rotation speed: 100 rpm) It is a figure which shows a profile. Fifteenth revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method of Capsules obtained in Example 1 Dissolution performed according to the paddle method (test solution: McIlvine buffer (pH 7.5), rotation speed: 200 rpm) It is a figure which shows a profile. The 15th revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method of Capsule obtained in Example 1 was carried out according to the rotating basket method (test solution: McIlvine buffer (pH 7.5), rotation speed: 100 rpm). It is a figure which shows an elution profile. The 15th revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method of Capsule obtained in Example 1 was carried out according to the rotating basket method (test solution: McIlvine buffer (pH 7.5), rotation speed: 200 rpm). It is a figure which shows an elution profile. It is a figure which shows the dissolution profile implemented according to the 15th revision Japanese Pharmacopoeia general test method 6.10 dissolution test method paddle method (test liquid: water, rotation speed: 50 rpm) of the tablet obtained in Example 2. FIG. 15th revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method of Tablet obtained in Example 2 Dissolution profile carried out according to paddle method (test solution: JP1 solution (pH 1.2), rotation speed: 50 rpm) Show. Fifteenth revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method Dissolution profile of the tablet obtained in Example 2 according to the paddle method (test solution: McIlvaine buffer (pH 4.0), rotation speed: 50 rpm) FIG. Fifteenth revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method Dissolution profile of the tablet obtained in Example 2 according to the paddle method (test solution: McIlvine buffer (pH 7.5), rotation speed: 50 rpm) FIG. Fifteenth revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method Dissolution profile of the tablet obtained in Example 2 according to the paddle method (test solution: McIlvine buffer (pH 7.5), rotation speed: 100 rpm) FIG. Fifteenth revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method Dissolution profile of the tablet obtained in Example 2 according to the paddle method (test solution: McIlvine buffer (pH 7.5), rotation speed: 200 rpm) FIG. Fifteenth revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method of Tablet obtained in Example 2 Dissolution performed according to the rotating basket method (test solution: McIlvine buffer (pH 7.5), rotation speed: 100 rpm) It is a figure which shows a profile. Fifteenth revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method Dissolution of the tablet obtained in Example 2 was performed according to the rotating basket method (test solution: McIlvine buffer (pH 7.5), rotation speed: 200 rpm). It is a figure which shows a profile. Fifteenth revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method of Tablets Obtained in Example 2 Paddle Method (Test solution: McIlvine buffer (pH 7.5) containing 1 w / v% PSB80, rotation speed: 100 rpm) FIG. Fifteenth revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method of Capsule obtained in Reference Example 1 Dissolution profile carried out according to paddle method (test solution: JP1 solution (pH 1.2), rotation speed: 50 rpm) FIG. Fifteenth revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method Elution Profile of Capsule Obtained in Reference Example 1 (Test Solution: JP2 Solution (pH 6.8), Rotation Speed: 50 rpm) FIG. It is a figure which shows the elution profile implemented according to the 15th revision Japanese Pharmacopoeia general test method 6.10 elution test method paddle method (test liquid: water, rotation speed: 50 rpm) of the capsule obtained in Reference Example 2. Fifteenth revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method Elution Profile of Capsule Obtained in Reference Example 2 (Test Solution: JP1 Solution (pH 1.2), Rotation Speed: 50 rpm) FIG. Elution carried out according to the 15th revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method Paddle Method (Test Solution: McIlvaine Buffer (pH 4.0), Rotation Speed: 50 rpm) of Capsule Obtained in Reference Example 2 It is a figure which shows a profile. Fifteenth revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method of Capsule obtained in Reference Example 2 Dissolution performed according to the paddle method (test solution: McIlvine buffer (pH 7.5), rotation speed: 50 rpm) It is a figure which shows a profile. It is a figure which shows the elution profile implemented according to the 15th revision Japanese Pharmacopoeia general test method 6.10 elution test method paddle method (test liquid: water, rotation speed: 50 rpm) of the capsule obtained in Reference Example 3. Fifteenth revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method Elution Profile of Capsule Obtained in Reference Example 3 (Test Solution: JP1 Solution (pH 1.2), Rotation Speed: 50 rpm) FIG. Elution carried out according to the 15th revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method Paddle Method (Test Solution: McIlvaine Buffer (pH 4.0), Rotation Speed: 50 rpm) of Capsule Obtained in Reference Example 3 It is a figure which shows a profile. 15th revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method of Capsule obtained in Reference Example 3 Dissolution performed according to the paddle method (test solution: McIlvine buffer (pH 7.5), rotation speed: 50 rpm) It is a figure which shows a profile. It is a figure which shows the elution profile implemented according to the 15th revision Japanese Pharmacopoeia general test method 6.10 elution test method paddle method (test liquid: water, rotation speed: 50 rpm) of the capsule obtained in Reference Example 4. Fifteenth revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method Elution profile of capsule obtained in Reference Example 4 (Test solution: JP1 solution (pH 1.2), rotation speed: 50 rpm) FIG. Elution carried out according to the 15th revised Japanese Pharmacopoeia General Test Method 6.10 Elution Test Method Paddle Method (Test Solution: McIlvaine Buffer (pH 4.0), Rotation Speed: 50 rpm) of Capsule Obtained in Reference Example 4 It is a figure which shows a profile. Fifteenth revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method of Capsules obtained in Reference Example 4 Dissolution performed according to the paddle method (test solution: McIlvine buffer (pH 7.5), rotation speed: 50 rpm) It is a figure which shows a profile. 15th revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method Elution profile of capsule obtained in Reference Example 5 according to paddle method (test solution: JP1 solution (pH 1.2), rotation speed: 50 rpm) FIG. Fifteenth revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method Elution profile of capsule obtained in Reference Example 6 according to paddle method (test solution: JP1 solution (pH 1.2), rotation speed: 50 rpm) FIG. Fifteenth revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method Elution profile of capsule obtained in Reference Example 7 according to paddle method (test solution: JP1 solution (pH 1.2), rotation speed: 50 rpm) FIG.

  In the granule of the present invention, ambroxol hydrochloride is contained in the first layer and the third layer of the present invention, and the content ratio is usually 2 to 8: 1, preferably 4 to 6: 1.

  The content of ambroxol hydrochloride used in the first layer of the present invention is usually 30 to 80% by weight, preferably 50 to 70% by weight, based on the total weight of the first layer. If it is higher than 80% by weight, the dissolution characteristics are poor, and if it is less than 30% by weight, the granule weight per unit weight of ambroxol hydrochloride increases, which is not preferable.

  The content of ambroxol hydrochloride used in the third layer varies depending on whether or not compression molding is applied for final formulation. When compression molding is not performed, that is, when the final formulation is a granule or a capsule. Is preferably so high that the layer can be formed by the binder contained in the third layer. Specifically, the content of ambroxol hydrochloride used in the third layer when compression molding is not performed is 80 to 99% by weight based on the weight of the third layer, and the final formulation is a tablet. In some cases, it is 1 to 20% by weight.

  In the granule of the present invention, the core particle can become a core when preparing the granule. Specifically, for example, crystalline cellulose or a mixture of sugar and starch can be used alone or in combination. Of these, crystalline cellulose is preferable. In particular, crystalline cellulose spherical granules having an average particle size of about several tens to several hundreds of μm are preferable. For example, SELFIA <registered trademark> CP-203 (Asahi Kasei Chemicals Corporation) (particle size 150 to 300 [mu] m) and SELFIA <registered trademark> CP- 305 (Asahi Kasei Chemicals Corporation) (particle size 300-500 μm). SELPHYA CP-203 is preferable from the viewpoint of miniaturization and tableting of granules, and SELPHYA 305 is preferable from the viewpoint of manufacturability.

  In the granule of the present invention, as the disintegrant of the first layer, corn starch, sodium carboxymethyl starch, partially pregelatinized starch, pregelatinized starch, or derivatives thereof; carmellose, croscarmellose sodium, carmellose calcium Or cellulose derivatives such as low-substituted hydroxypropyl cellulose (L-HPC); or crospovidone, light silicic anhydride, or crystalline cellulose can be used alone or in combination. Among them, those that exhibit a disintegrating action by swelling with a small amount of water are preferable, and L-HPC is particularly preferable.

  In the granule of the present invention, the content of the disintegrant in the first layer depends on the type thereof, the type and amount of the water-soluble polymer in the second layer, the type of solvent used for coating the second layer, and the like. Although it is different, 5 to 50% by weight is preferable with respect to the total weight of the first layer, and more preferably 20 to 40% by weight.

  The first layer of the granules of the present invention further comprises a binder. As such a binder, for example, hydroxypropylcellulose, polyvinylpyrrolidone, hypromellose, or polyethylene glycol is used alone or in combination. Of these, hydroxypropylcellulose is preferred. The content of the binder is usually 1 to 20% by weight, preferably 5 to 10% by weight, based on the total weight of the first layer, although it depends on the type.

  In the granule of the present invention, the method for coating the core particles with the first layer is not particularly limited, but in particular, the suspension is prepared by spraying an suspension of ambroxol hydrochloride or a solution on the core particles by a stirring rolling fluidized bed granulation method. Is preferred. By coating the core particles with the first layer, fast-dissolving granules are obtained. At the time of granulation, when the exhaust relative humidity is 70 to 95%, preferably 85 to 95%, the raw material in the suspension or solution is laminated on the core particles almost as theoretically. When the exhaust relative humidity is 70% or less, the rate of scattering as powder is increased without being laminated, and when the exhaust relative humidity is 95% or more, the rate of occurrence of agglomerates is increased. When the exhaust relative humidity is 70% or less or 95% or more, the elution characteristics are poor.

  In the granule of the present invention, the total weight of the second layer depends on the type of solvent used for coating the second layer, the type of water-soluble polymer in the second layer, and the content ratio of the second layer to the second layer. However, it is usually 10 to 40% by weight, preferably 15 to 30% by weight, based on the weight of the fast-dissolving granules coated with the first layer. When the proportion of the second layer is less than 10% by weight, the dissolution characteristics are poor, and the physical strength of the granules is low, which is not preferable. When the ratio is more than 40% by weight, the dissolution characteristics are poor, and ambroxol hydrochloride The granule weight per unit amount is increased, which is not preferable.

  In the granule of the present invention, as the water-insoluble polymer of the second layer, for example, a (meth) acrylic acid copolymer such as ethyl cellulose or an aminoalkyl methacrylate copolymer, or polyvinyl acetate is used alone or in combination. be able to. Of these, ethyl cellulose is preferable.

  In the granule of the present invention, the content of the water-insoluble polymer in the second layer varies depending on the type and the size, shape and weight of the granule coated with the first layer, but the total weight of the second layer. The content is preferably 60 to 90% by weight.

  In the granule of the present invention, the water-soluble polymer of the second layer includes, for example, cellulose derivatives such as hydroxypropylcellulose, hypromellose, carmellose sodium, methylcellulose, or hydroxyethylcellulose, pregelatinized starch, sodium alginate, xanthan gum, guar gum, Gum arabic, carrageenan, carboxyvinyl polymer, polyethylene oxide, vinyl acetate povidone polymer matrix, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene glycol, or pullulan can be used alone or in combination. Of these, hydroxypropylcellulose, hypromellose, methylcellulose, and polyethylene glycol are preferable, and a combination of hypromellose and polyethylene glycol is particularly preferable. There are various viscosity grades of hypromellose, and the viscosity grade in the present invention is a grade in which the viscosity of a 2 (w / w)% aqueous solution at 20 ° C. is about 80 to about 120 mPa · s, about 3000 to about 5600 mPa · s. Grades from about 11250 to about 21000 mPa · s, or from about 75000 to about 140000 mPa · s. As the hypromellose, one of the above four viscosity grades can be used alone, or 2 to 4 types can be mixed and used at an arbitrary weight ratio. There are various grades of polyethylene glycol having different average molecular weights. In the present invention, for example, those having an average molecular weight of 4000 can be used.

  In the granule of the present invention, the content of the water-soluble polymer in the second layer varies depending on the type and the type of the disintegrant in the first layer, but it depends on the type of solvent used for coating the second layer. It depends heavily. When dichloromethane is contained in the solvent, the content of the water-soluble polymer in the total weight of the second layer is preferably about 30% by weight. When the solvent is a mixed solution of ethanol and water, depending on the mixing ratio, good elution characteristics can be obtained with an amount of about 1/20 that of dichloromethane. When the solvent is a mixed solution of ethanol and water, the range of 0.5 to 22% by weight is usually preferable with respect to the total weight of the second layer from the viewpoint of good elution characteristics.

  In the granule of the present invention, the method for coating the fast-dissolving granule having the first layer with the second layer is not particularly limited, and for example, a stirring rolling fluidized bed granulation method can be used. As the solvent for granulation, dichloromethane, ethanol, or water is preferably used alone or in combination of a plurality of types, and a mixed solution of ethanol and water is particularly preferable. The mixing ratio of ethanol and water is preferably 7: 3 to 9: 1. If the ethanol ratio is lower than this, the elution characteristics are poor, and if it is higher, the elution characteristics and production costs are not preferred. An organic solvent containing dichloromethane is generally used as a coating solvent for ethyl cellulose, but there is a concern about environmental burden and safety to humans, and usually, a device on the manufacturing apparatus is devised. When dichloromethane is included as a solvent during granulation, adding a pH adjusting agent to the first layer and / or the second layer, particularly the first layer in the granule of the present invention can maintain the dissolution property. Is preferable. Although the kind is not specifically limited, A phosphoric acid type compound is preferable especially and sodium monohydrogen phosphate is preferable. The content is preferably 1 to 10% by weight, more preferably 5 to 10% by weight, based on ambroxol hydrochloride. The fast-dissolving granules are obtained by coating the fast-dissolving granules with the second layer. At the time of granulation, when the exhaust relative humidity is 20 to 60%, preferably 30 to 50%, the raw materials in the solution are laminated on the core particles almost as theoretical values. When the exhaust relative humidity is 20% or less, the rate of scattering as powder without being stacked increases, and when the exhaust relative humidity is 60% or more, the rate of occurrence of agglomerates increases. When the exhaust relative humidity is 20% or less or 60% or more, the elution characteristics are poor. Furthermore, granule moisture is important for precisely controlling the elution characteristics. When the granule moisture at the time of granulation is 2 to 4%, preferably 2.5 to 3.5%, a certain elution characteristic can be obtained.

  The granule of the present invention further has a third layer that exhibits a fast-dissolving action on the outer layer of the second layer that exhibits a slow-dissolving action. Compared to the prior art (Non-Patent Document 1), which is a mixed preparation of two types of granules, by making a multilayer structure comprising the first to third layers, per unit amount of ambroxol hydrochloride while maintaining its dissolution characteristics A sustained-release capsule can be obtained by filling a certain amount of capsules with a sustained-release granule having a reduced granule weight or only the granule of the present invention which is a multilayer granule thereof.

  In the granule of the present invention, the binder of the third layer is not particularly limited, and for example, hydroxypropylcellulose, polyvinylpyrrolidone, hypromellose, or polyethylene glycol can be used alone or in combination.

  In the granule of the present invention, the content of the binder in the third layer varies depending on the type, but is preferably low enough that the third layer of ambroxol hydrochloride can form a layer. It is usually 1 to 20% by weight based on the total weight.

  In the granule of the present invention, the method for coating the granule having the second layer by the third layer is not particularly limited, and for example, a stirring rolling fluidized bed granulation method can be used. At the time of granulation, when the exhaust relative humidity is 60 to 80%, preferably 65 to 75%, the raw material in the suspension or solution is laminated on the core particles almost as theoretically. When the exhaust relative humidity is 60% or less, the rate of scattering as powder without being stacked increases, and when the exhaust relative humidity is 80% or more, the rate of occurrence of agglomerates increases.

  When the granules of the present invention are compression-molded into tablets, a protective coating layer is further provided between the second layer and the third layer, and an excipient and a plasticizer are further added to the third layer. It is preferable. This protective coating layer has a role of protecting the granules so as to withstand the compressive force when the granules of the present invention are compression-molded without changing the characteristics and functions relating to the elution of the second layer. Therefore, the protective coating that can be used in the present invention is not particularly limited as long as it can fulfill this role, but is a water-soluble polymer such as hypromellose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, polyethylene glycol, or gelatin; Acid soluble polymers such as alkyl methacrylate copolymers or polyvinyl acetal diethylaminoacetate; hardened oils; fatty alcohols; polyolefins; glycerides; or for example fatty acids can be used alone or in combination. Of these, hydroxypropylcellulose or polyethylene glycol is preferably used alone or in combination. In addition to these essential components, components such as a plasticizer can be blended in the protective coating layer. Here, the method for coating the protective film is not particularly limited, and for example, an aqueous solution of these components may be sprayed onto the granules having the second layer.

  By adding excipients and plasticizers to the third layer, they are not contained in the third layer, and compared with the case where they are compressed and formed into tablets, the hydrochloride hydrochloride for each tablet at the time of manufacture is compared. Segregation of the sole content can be suppressed. Moreover, since mixing with an excipient | filler is not required at the time of compression molding, a compression molding process becomes easy. The excipient is not particularly limited, and sugars such as lactose, sucrose, glucose, fructose, trehalose, mannitol, sorbitol, xylitol, maltitol, or erythritol; wheat starch, corn starch, potato starch, partially pregelatinized starch, dextrin , Starches such as hydroxypropyl starch or carboxymethyl starch; celluloses such as crystalline cellulose; or inorganic salts such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate, or calcium phosphate, alone or A plurality of types can be used in combination. Of these, mannitol is preferable. Although it does not specifically limit as a plasticizer, For example, polyethyleneglycol, triethyl citrate, propylene glycol, polysorbate 80, or glyceryl monostearate can be used individually or in combination of multiple types. Of these, polyethylene glycol is preferred.

  The granule of the present invention has an average particle size of 300 to 800 μm, more preferably 300 to 600 μm, and further 300 to 500 μm, and according to the prior art (1200 μm or 800 μm in Non-Patent Document 1, 600 to 1500 μm in Patent Document 3). On the other hand, it is small. In addition, the average particle diameter in this invention uses the sieve of diameter 76mm 600, 500, 425, 355, and 300 micrometers according to the 15th revision Japanese Pharmacopoeia general test method 3.04 particle size measurement method 2nd method sieving method. The particle size distribution was measured and calculated using lognormal probability paper.

  According to the granule of the present invention, the granule weight per unit weight of ambroxol hydrochloride is 50 to 150 mg (granule) / 45 mg (ambroxol hydrochloride), and the prior art (230 mg or 160 mg (granule) in Non-Patent Document 1) is used. / 45 mg (Ambroxol hydrochloride), about 310 mg (granule) / 75 mg (Ambroxol hydrochloride) in Patent Document 3) is achieved.

  The method of compression-molding the granule of the present invention into tablets is not particularly limited, and can be produced by general-purpose equipment. The granule of the present invention can be used as a lubricant, for example, in a small amount of magnesium stearate, talc, or monostearic acid. Tableting may be performed by adding glycerin. The tablet can be further formed into a film coating or a sugar-coated tablet by a commonly used method.

  The granule of the present invention can be used as a granule as it is, or filled into a capsule to form a capsule. In the case of a capsule, the filling amount may be adjusted according to the dose of ambroxol hydrochloride. For example, when the dose is 45 mg, the granule of the present invention is 50 to 150 mg, and if necessary, a trace amount of lubricant such as stearin. It can be manufactured by filling a No. 4 or No. 5 capsule together with magnesium acid.

  The once-daily dosage form of ambroxol hydrochloride sustained-release preparation to be achieved by the preparation of the present invention is ensured in accordance with the guidelines for bioequivalence testing of generic drugs. When implemented, the dissolution rate of the marketed product (Mucosolvan (registered trademark) L capsule) as a standard formulation is 30%, 50%, and 80% at 3 time points, and the dissolution rate of the standard product is ± 15%. (In the range of similarity standards), preferably in the range of ± 10% (in the range of equivalence standards).

Details of the medicines and devices used in this example are as follows.
Ambroxol hydrochloride; Boehringer Ingelheim hydroxypropyl cellulose (HPC): Nippon Soda Co., Ltd., trade name: HPC-L
Low-substituted hydroxypropyl cellulose (L-HPC): manufactured by Shin-Etsu Chemical Co., Ltd., trade name: LH-31
Crystalline cellulose grain: manufactured by Asahi Kasei Chemicals Corporation, trade name: SELPHYA CP-203
Hypromellose: Shin-Etsu Chemical Co., Ltd., trade name: TC-5 R
Macrogol 4000 (PEG4): manufactured by NOF Corporation Macrogol 6000 (PEG6): manufactured by NOF Corporation, trade name: Macrogol 6000P
Ethyl cellulose: manufactured by The Dow Chemical Company, trade name: ETHOCEL STANDARD 10 PREMIUM
Triethyl citrate: manufactured by Morimura Shoji Co., Ltd., trade name: Citroflex 2
Combined granulation coating equipment: Freund Sangyo Co., Ltd., Spiraflow SFC-50
Mixer: Meiwa Kogyo Co., Ltd., cross rotary mixer CM-10
Rotary tableting machine: HT-AP6SS-U, manufactured by Hata Plant

[Example 1] Manufacture of capsules and evaluation of dissolution properties <Fast-dissolving granules>
11.445 kg of ambroxol hydrochloride was added to 45.950 kg of purified water and homogenized. This operation was repeated 4 times to obtain a total of 229.736 kg of ambroxol hydrochloride suspension. 1.683 kg of hydroxypropylcellulose was added to 83.700 kg of purified water and dissolved. This operation was repeated four times to obtain a total of 341.232 kg of hydroxypropylcellulose solution. 28.200 kg of ambroxol hydrochloride suspension and 41.850 kg of hydroxypropylcellulose solution were mixed to form a uniform suspension, and then 3.079 kg of low-substituted hydroxypropylcellulose was dispersed. This operation was repeated 8 times to obtain a total of 585.032 kg of an active ingredient layering (first layer coating) solution.
Using a composite granulation coating device, 21.000 kg of crystalline cellulose particles were used as core particles, and 567.650 kg of the active ingredient layering solution was sprayed and laminated to produce fast-dissolving granules.

<Granules having second layer>
After 30.460 kg of hypromellose and 0.216 kg of macrogol 4000 were dispersed in 31.460 kg of absolute ethanol (Wako Chemical Co., Ltd .: the same applies in this example), 7.870 kg of purified water was added and dissolved. 573 kg of hypromellose macrogol solution was obtained. After 1.665 kg of ethyl cellulose and 0.126 kg of triethyl citrate were dispersed in 7.712 kg of purified water, 30.850 kg of absolute ethanol was added and dissolved. This operation was repeated 4 times to obtain a total of 161.444 kg of ethyl cellulose / triethyl citrate solution. Hypromellose / macrogol solution (9,950 kg) and ethylcellulose / triethyl citrate solution (40.361 kg) were mixed to obtain a uniform solution. This operation was repeated four times to obtain a total of 201.244 kg of sustained-release membrane (second layer) coating solution.
Using a composite granulation coating apparatus, 400.000 kg of fast-dissolving granules were sprayed and coated with 197.250 kg of sustained-release membrane coating solution to produce granules having a second layer.

<Granules having a third layer>
The amount of lamination was corrected so that the ratio of the active ingredient contained in the first layer to the active ingredient contained in the third layer was 5: 1.
Hydroxypropylcellulose solution was added and dissolved in 11.570 kg of purified water to obtain a hydroxypropylcellulose solution. Ambroxol hydrochloride 3.647 kg was added to purified water 14.590 kg and homogenized to obtain an ambroxol hydrochloride suspension. 11.896 kg of the hydroxypropyl cellulose solution and 17.450 kg of ambroxol hydrochloride suspension were mixed to obtain a uniform suspension to obtain 29.346 kg of the outer layer main agent layering solution.
Using a composite granulation coating apparatus, 27.500 kg of the outer-layer main ingredient layering solution was sprayed and laminated on 40.000 kg of the slow-dissolving granules to produce granules having a third layer.

<Average particle size>
The obtained granule having the third layer is sieved with a diameter of 76 mm, 600, 500, 425, 355, and 300 μm in accordance with the 15th revised Japanese Pharmacopoeia General Test Method 3.04 Particle Size Measurement Method Second Method Screening Method. The particle size distribution was measured, and the average particle size was calculated using log-normal probability paper.

<Capsule filling>
The filling amount was set so that the content of the active ingredient per capsule was 45 mg. A capsule having a third layer of 105.17 mg was filled into a hypromellose capsule. Table 1 shows the weight (mg) of each component per capsule.

<Elution evaluation>
Dissolution tests were performed on capsules prepared in capsule filling. The test was conducted on December 22, 1997, from the notice of the Pharmaceutical Administration Bureau No. 487, Pharmaceutical Safety Bureau Examination Management Section / Appendix “Biological Equivalence Test Guidelines for Generic Drugs”, Chapter 3B. I. 2. It carried out according to the criteria shown in. The elution profiles are shown in FIGS. 1A-1H. The elution curves of the obtained capsules were all within the range of similarity specifications. In addition, the similarity specification upper limit / lower limit shown in FIG. 1 indicates a range of ± 15% with respect to the dissolution rate of Mucosolvan (registered trademark) L capsules, and the same applies to the following examples.

[Example 2] Manufacture of tablets and evaluation of dissolution <fast dissolving granules>
The fast dissolving granules produced in Example 1 were used.

<Granules having second layer>
After 30.460 kg of hypromellose and 0.216 kg of macrogol 4000 were dispersed in 31.460 kg of absolute ethanol (Wako Chemical Co., Ltd .: the same applies in this example), 7.870 kg of purified water was added and dissolved. 573 kg of hypromellose macrogol solution was obtained. After dispersing 1.665 kg of ethyl cellulose and 0.126 kg of triethyl citrate in 7.720 kg of purified water, 30.850 kg of absolute ethanol was added and dissolved. This operation was repeated 4 times to obtain a total of 161.444 kg of ethyl cellulose / triethyl citrate solution. Hypromellose / macrogol solution (9,950 kg) and ethylcellulose / triethyl citrate solution (40.361 kg) were mixed to obtain a uniform solution. This operation was repeated four times to obtain a total of 201.244 kg of sustained-release membrane (second layer) coating solution.
Using a composite granulation coating apparatus, 400.000 kg of fast-dissolving granules were sprayed and coated with 197.250 kg of sustained-release membrane coating solution to produce granules having a second layer.

<Granule with protective coating layer>
5.849 kg of macrogol 6000 was added to 52.650 kg of purified water and dissolved. This operation was repeated twice to obtain a total of 116.998 kg of the protective coating layer coating solution. Using a composite granulation coating apparatus, 40.000 kg of granules having the second layer were sprayed and coated with 111.450 kg of the protective coating layer coating solution to produce granules having a protective coating layer (buffer film-coated granules).

<Granules having a third layer>
The amount of lamination was corrected so that the ratio of the active ingredient contained in the first layer to the active ingredient contained in the third layer was 5: 1.
0.261 kg of hydroxypropylcellulose was added to 9.300 kg of purified water and dissolved to obtain 9.561 kg of hydroxypropylcellulose solution. 2.929 kg of ambroxol hydrochloride was added to 11.720 kg of purified water and homogenized to obtain 14.649 kg of ambroxol hydrochloride suspension. 9.561 kg of hydroxypropylcellulose solution and 14.010 kg of ambroxol hydrochloride suspension were mixed to form a uniform suspension to obtain an active ingredient layering solution. Hydroxypropyl cellulose (3.039 kg) and 2.199 kg of macrogol 6000 were added to 95.550 kg of purified water and dissolved to obtain 100.788 kg of a hydroxypropyl cellulose / macrogol solution. 11.359 kg of D-mannitol (Mitsubishi Corporation Foodtech Co., Ltd., trade name: Mannit P) was added to 32.060 kg of the hydroxypropylcellulose macrogol solution to obtain a uniform suspension. This operation was repeated three times to obtain a total of 130.257 kg of compression-molded layer layering solution. Using a composite granulation coating device, spraying and laminating 40.000 kg of buffer film-coated granules in the order of 22.050 kg of the active ingredient layering solution and 124.050 kg of the compression molding layer layering solution to produce granules having the third layer did.

<Tablet>
The tablet weight was set so that the content of the active ingredient per tablet was 45 mg. Using a mixer, 6000.0 g of the granule having the third layer and 1.2 g of magnesium stearate (MALLINCKRODT) were mixed and then compression molded using a rotary tableting machine. The molding conditions were tableting with a tablet weight of 228 mg and a diameter of Φ8.0 mm12R so that the hardness was about 58.8N. Table 2 shows the weight (mg) of each component per tablet.

<Elution evaluation>
Dissolution tests were performed on tablets produced in tableting. The test was conducted on December 22, 1997, from the notice of the Pharmaceutical Administration Bureau No. 487, Pharmaceutical Safety Bureau Examination Management Section / Appendix “Biological Equivalence Test Guidelines for Generic Drugs”, Chapter 3B. I. 2. It carried out according to the criteria shown in. The elution profile is shown in FIG. The elution curves of the obtained capsules were within the range of similarity specifications in all tests shown in FIGS. 2A to 2I.

  In the following Reference Examples 1 to 7, for the convenience of preparation, mixing fast-dissolving granules (granules having a first layer) and slow-dissolving granules (granules having a second layer coated on fast-dissolving granules) The capsule filled with the granule was used for the evaluation of dissolution as being equivalent to the single granule of the present invention. In the granule of the present invention, since the third layer is fast-dissolving, the active ingredient in the third layer elutes to the 0th order. Therefore, a capsule-filled mixed granule of fast-dissolving granules and slow-dissolving granules is slow in its action. This is because the dissolution property is equivalent to a tablet obtained by compression-molding a granule obtained by coating a soluble granule with a third layer. Therefore, the components of the first layer and the second layer in the slow-soluble granule used for the mixed granule and the blending amounts thereof are the same as those in the first layer and the second layer in the granule having a three-layered structure of the present invention. It can be considered that it is each component of this layer, and its compounding quantity. About each component and its compounding quantity in the fast dissolving granule used for a mixing granule, what remove | excluded the core particle and the disintegrating agent from the fast dissolving granule of the 3rd layer in the granule which has the layered structure of 3 layers of this invention It can be regarded as an ingredient and its blending amount.

[Reference Example 1] Production of capsules and evaluation of dissolution properties: Solvent at the time of coating the second layer is dichloromethane and contains a pH regulator <Fast-dissolving granules>
291.7 g of ambroxol hydrochloride was added to 1155.1 g of purified water and homogenized to obtain 1446.8 g of ambroxol hydrochloride suspension. Hydroxypropyl cellulose (27.2 g) was added to purified water (427.0 g) and dissolved to obtain 454.2 g of hydroxypropyl cellulose solution. After 19.4 g of anhydrous sodium monohydrogen phosphate (Taihei Chemical Industry Co., Ltd.) was added to 1164.5 g of purified water and dissolved, 75.9 g of low-substituted hydroxypropyl cellulose, 434.2 g of hydroxypropyl cellulose solution, and ambro hydrochloride 1377.8 g of xol suspension was added to make a uniform suspension. A total of 3071.8 g of the active ingredient layering solution was obtained.
Using a composite fluidized bed granulator (Dalton Co., Ltd., Pneumaticizer NQ-125), spraying and laminating 3067.9 g of the active ingredient layering solution on 200.0 g of crystalline cellulose granules produced fast-dissolving granules. .

<Granules having second layer>
To anhydrous ethanol (Wako Pure Chemical Industries, Ltd., grade: Japanese Pharmacopoeia) 768.7 g and dichloromethane (Wako Pure Chemical Industries, Ltd., grade: for high performance liquid chromatograph) 767.7 g, hypromellose 19.7 g, 5 .6 g of macrogol 4000, 57.6 g of ethyl cellulose, and 4.4 g of triethyl citrate were added and dissolved. A total of 1623.7 g of sustained-release membrane coating solution was obtained.
Using a combined fluidized bed granulator (Dalton Co., Ltd., Pneumaticizer NQ-125), spray-coating the sustained-release membrane coating solution 1559.8g on 200.0g of fast-dissolving granules to produce slow-dissolving granules did.

<Capsule filling>
A capsule was prepared by filling 16.2 mg of fast-dissolving granules and 101.3 mg of granules having the second layer (using the sample at the time of spraying of the sustained-release membrane coating solution 935.9 g) into a hypromellose capsule. did. Table 3 shows the weight (mg) of each component per capsule.

<Elution evaluation>
Dissolution tests were performed on capsules prepared in capsule filling. The test was conducted according to the 15th revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method Paddle Method. As a test solution, the dissolution test first solution (pH 1.2) and the dissolution test second solution (pH 6.8) are used, and the dissolution profiles in the respective dissolution test solutions are shown in FIGS. 3A and 3B. The dissolution curve of the obtained capsule was within the range of the similarity standard in any dissolution test.

[Reference Example 2] Capsule preparation and dissolution evaluation: The ratio of the water-soluble polymer in the total weight of the second layer is 22%, and the ratio of the total weight of the second layer to the total weight of the fast-dissolving granules is 17% <fast dissolving granules>
2125.0 g of ambroxol hydrochloride was added to 8500.1 g of purified water and homogenized to obtain 10625.1 g of ambroxol hydrochloride suspension. 308.1 g of hydroxypropyl cellulose was added to 589.11 g of purified water and dissolved to obtain 615.4 g of a hydroxypropyl cellulose solution. To 9641.1 g of purified water, 1138.9 g of low-substituted hydroxypropylcellulose, 584.1 g of hydroxypropylcellulose solution, and 10416.5 g of ambroxol hydrochloride suspension were added to obtain a uniform suspension. A total of 27030.6 g of the active ingredient layering solution was obtained.
Using a composite fluidized bed granulator (Dalton Co., Ltd., Pneumaticizer NQ-230), 20.00.0 g of the active ingredient layering solution was sprayed and laminated on 1000.0 g of crystalline cellulose granules to produce fast-dissolving granules. .

<Granules having second layer>
Ethylcellulose 195.3 g and triethyl citrate (Morimura Shoji Co., Ltd.) 14.9 g were added to 5559.9 g of absolute ethanol (Wako Pure Chemical Industries, Ltd., Grade: Japanese Pharmacopoeia) and dissolved to obtain a total of 5770.1 g. An ethyl cellulose / triethyl citrate solution was obtained. Hypromellose 48.7 g and 13.4 g of macrogol 4000 were added and dissolved in 656.6 g of purified water to obtain a total of 718.7 g of hypromellose macrogol solution. Hypromellose / macrogol solution (676.3 g) was added to ethyl cellulose / triethyl citrate solution (5770.1 g) to obtain a uniform solution to obtain a sustained-release membrane coating solution.
Using a combined fluidized bed granulator (Dalton Co., Ltd., Pneumatic Melizer NQ-230), spray-coating 5138.0 g of the sustained-release membrane coating solution onto 1000.0 g of fast-dissolving granules, and coating the second layer. A granule having the above was made.

<Capsule filling>
16.3 mg of fast-dissolving granules and 94.9 mg of granules having the second layer (the sample at the time of spraying of the sustained-release membrane coating solution 4029.0 g was used) were filled into hypromellose capsules to prepare capsules. Table 4 shows the weight (mg) of each component per capsule.

<Elution evaluation>
Dissolution tests were performed on capsules prepared in capsule filling. The test was conducted according to the 15th revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method Paddle Method. As test solutions, water, dissolution test first solution (pH 1.2), McIlvaine buffer solution (pH 4.0), and McIlvine buffer solution (pH 7.5) were used, and elution profiles in the respective dissolution test solutions are shown in FIGS. Shown in FIG. 4D. The elution curves of the obtained capsules were all within the range of similarity specifications.

[Reference Example 3] Production of capsule and evaluation of dissolution property: The ratio of the water-soluble polymer in the total weight of the second layer is 22%, and the ratio of the total weight of the second layer to the total weight of the fast-dissolving granules is 25% <fast dissolving granules>
502.5 g of ambroxol hydrochloride was added to 2012.5 g of purified water and homogenized to obtain 2515.7 g of ambroxol hydrochloride suspension. 70.3 g of hydroxypropylcellulose was added to 935.8 g of purified water and dissolved to obtain 1006.2 g of hydroxypropylcellulose solution. 262.0 g of low-substituted hydroxypropylcellulose, 958.4 g of hydroxypropylcellulose solution, and 2395.7 g of ambroxol hydrochloride suspension were added to 2156.8 g of purified water to obtain a uniform suspension. A total of 5732.9 g of the active ingredient layering solution was obtained.
Using a composite fluidized bed granulator (Dalton Co., Ltd., Pneumaticizer NQ-125), 570.0 g of the active ingredient layering solution was sprayed and laminated on 230.0 g of crystalline cellulose particles to produce fast-dissolving granules. .

<Granules having second layer>
31.1 g of ethyl cellulose and 3.0 g of triethyl citrate were dissolved in 1112.1 g of absolute ethanol (Wako Pure Chemical Industries, Ltd., grade: Japanese Pharmacopoeia). A total of 1154.2 g of ethyl cellulose / triethyl citrate solution was obtained. Hypromellose 9.7 g and 2.7 g of macrogol 4000 were added to 131.3 g of purified water and dissolved. A total of 143.7 g of hypromellose macrogol solution was obtained. 135.3 g of a hypromellose / macrogol solution was added to 1154.2 g of an ethyl cellulose / triethyl citrate solution to obtain a uniform solution to obtain a sustained-release membrane coating solution.
Using a combined fluidized bed granulator (Dalton Co., Ltd., Pneumaticizer NQ-125), 200.0 g of fast-dissolving granules were sprayed and coated with 1208.7 g of the sustained-release membrane coating solution, and the second layer was coated. A granule having the above was made.

<Capsule filling>
A capsule was prepared by filling 16.3 mg of fast-dissolving granules and 101.7 mg of granules having the second layer into a hypromellose capsule. Table 5 shows the weight (mg) of each component per capsule.

<Elution evaluation>
Dissolution tests were performed on capsules prepared in capsule filling. The test was conducted according to the 15th revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method Paddle Method. As the test solution, water, dissolution test first solution (pH 1.2), McIlvaine buffer solution (pH 4.0), and McIlvine buffer solution (pH 7.5) were used, and the dissolution profiles in each dissolution test are shown in FIGS. Shown in 5D. The dissolution curve of the obtained capsule was within the range of equivalence standards in any dissolution test.

[Reference Example 4] Production of capsule and evaluation of dissolution property: The ratio of the water-soluble polymer in the total weight of the second layer is 20%, and the ratio of the total weight of the second layer to the total weight of the fast-dissolving granules is 30% <Fast-dissolving granules>
4250 g of ambroxol hydrochloride was added to 17000 g of purified water and homogenized. This operation was repeated 5 times to obtain a total of 106250 g of ambroxol hydrochloride suspension. 3058 g of hydroxypropylcellulose was added to 58188 g of purified water and dissolved to obtain 61251 g of hydroxypropylcellulose solution. 2278 g of low-substituted hydroxypropylcellulose, 11667 g of hydroxypropylcellulose solution, and 20833 g of ambroxol hydrochloride suspension were added to 19282 g of purified water to obtain a uniform suspension. This operation was repeated 5 times to obtain a total of 270300 g of the active ingredient layering solution.
Using a combined fluidized bed granulator (Dalton Co., Ltd., Pneumaticizer NQ-500), spray and laminate the entire amount of the active ingredient layering solution on 10000 g of crystalline cellulose granules (Asahi Kasei Chemicals Co., Ltd.) to quickly dissolve granules Made.

<Granules having second layer>
To 36498 g of absolute ethanol (Wako Pure Chemical Industries, Ltd., Grade: Japanese Pharmacopoeia: the same applies in the present Examples), 1305 g of ethyl cellulose and 100 g of triethyl citrate were added and dissolved to give a total of 37903 g of ethyl cellulose / triethyl citrate solution. I was obtained. Ethylcellulose 1057 g and triethyl citrate 80 g were added to and dissolved in 29551 g of absolute ethanol to obtain a total 30688 g of ethylcellulose / triethyl citrate solution II. In 4251 g of purified water, 294 g of hypromellose and 81 g of macrogol 4000 were added and dissolved to obtain a total of 4626 g of hypromellose macrogol solution I. In 3476 g of purified water, 241 g of hypromellose and 66 g of macrogol 4000 were added and dissolved to obtain a total of 3783 g of hypromellose macrogol solution II. A sustained-release membrane coating solution I was obtained by adding 412 g of hypromellose / macrogol solution I to 37903 g of ethyl cellulose / triethyl citrate solution I. 3572 g of hypromellose / macrogol solution II was added to 30688 g of ethyl cellulose / triethyl citrate solution II to obtain a uniform solution to obtain a sustained-release membrane coating solution II.
Using a combined fluidized bed granulator (Dalton Co., Ltd., Pneumaticizer NQ-500), 10000 g of fast-dissolving granules are mixed with the sustained-release membrane coating liquids I and II, and 72520 g of the mixed liquid is sprayed and coated. To produce granules having a second layer.

<Capsule filling>
A capsule was prepared by filling 16.3 mg of fast-dissolving granules and 105.8 mg of granules having a second layer into a hypromellose capsule. Table 6 shows the weight (mg) of each component per capsule.

<Elution evaluation>
Dissolution tests were performed on capsules prepared in capsule filling. The test was conducted according to the 15th revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method Paddle Method. As the test solution, water, dissolution solution first solution (pH 1.2), McIlvine buffer solution (pH 4.0), and McIlvine buffer solution (pH 7.5) were used, and the dissolution profiles in the respective dissolution test solutions are shown in FIGS. Shown in 6D. The dissolution curve of the obtained capsule was within the range of the similarity standard in any dissolution test.

[Reference Example 5] Capsule preparation and dissolution evaluation: The ratio of the water-soluble polymer in the total weight of the second layer is 29%, and the ratio of the total weight of the second layer to the total weight of the fast-dissolving granules is 17% <fast dissolving granules>
The fast dissolving granules produced in Reference Example 4 were used.

<Granules having second layer>
To 4943.1 g of absolute ethanol (Wako Pure Chemical Industries, Ltd., Grade: Japanese Pharmacopoeia), 177.5 g of ethyl cellulose and 13.5 g of triethyl citrate were added and dissolved to obtain a total of 514.1 g of ethyl cellulose / triethyl citrate. A solution was obtained. Hypromellose 65.1 g and 17.9 g of macrogol 4000 were added to and dissolved in 1312.7 g of purified water to obtain a total of 1395.7 g of hypromellose macrogol solution. Hydromellose / macrogol solution 1313.6 g was added to 514.1 g of ethylcellulose / triethyl citrate solution to obtain a uniform solution to obtain a sustained-release membrane coating solution.
Using a combined fluidized bed granulator (Dalton Co., Ltd., Pneumaticizer NQ-230), spray-coating 5945.0 g of the sustained-release membrane coating solution onto 1000.0 g of fast-dissolving granules, and coating the second layer. A granule having the above was made.

<Capsule filling>
16.3 mg of fast-dissolving granules and 94.9 mg of granules having the second layer (the sample at the time of spraying of the sustained-release membrane coating solution 4029.0 g was used) were filled into hypromellose capsules to prepare capsules. Table 7 shows the weight (mg) of each component per capsule.

<Elution evaluation>
Dissolution tests were performed on capsules prepared in capsule filling. The test was conducted according to the 15th revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method Paddle Method. As a test solution, a first dissolution test solution (pH 1.2) was used. The elution profile is shown in FIG. The elution curve of the obtained capsule was outside the range of the similarity standard.

[Reference Example 6] Production of capsule and evaluation of dissolution property: The proportion of the water-soluble polymer in the total weight of the second layer is 23%, and the ratio of the total weight of the second layer to the total weight of the fast-dissolving granules is 30% <Fast-dissolving granules>
The fast dissolving granules produced in Reference Example 4 were used.

<Granules having second layer>
To 36513 g of absolute ethanol (Wako Pure Chemical Industries, Ltd., Grade: Japanese Pharmacopoeia: the same applies in the present Examples), 1259 g of ethyl cellulose and 96 g of triethyl citrate were added and dissolved to obtain a total of 37868 g of ethyl cellulose / triethyl citrate solution. I was obtained. To 29537 g of absolute ethanol, 1018 g of ethyl cellulose and 78 g of triethyl citrate were added and dissolved to obtain a total of 30633 g of ethyl cellulose / triethyl citrate solution II. Hypromellose 336 g and 93 g of macrogol 4000 were added to 4248 g of purified water and dissolved to obtain 4677 g of hypromellose macrogol solution I in total. 275 g of hypromellose and 76 g of macrogol 4000 were added to 3475 g of purified water and dissolved to obtain a total of 3826 g of hypromellose / macrogol solution II. A sustained-release membrane coating solution I was obtained by adding 4463 g of hypromellose / macrogol solution I to 37868 g of ethyl cellulose / triethyl citrate solution I. A uniform solution was obtained by adding 3613 g of hypromellose / macrogol solution II to 30633 g of ethyl cellulose / triethyl citrate solution II to obtain sustained-release membrane coating solution II.
Using a combined fluidized bed granulator (Dalton Co., Ltd., Pneumaticizer NQ-500), 10000 g of fast-dissolving granules are mixed with the sustained-release membrane coating liquids I and II, and 72522 g of the mixed liquid is sprayed and coated. To produce granules having a second layer.

<Capsule filling>
A capsule was prepared by filling 16.3 mg of fast-dissolving granules and 105.8 mg of granules having a second layer into a hypromellose capsule. Table 8 shows the weight (mg) of each component per capsule.

<Elution evaluation>
Dissolution tests were performed on capsules prepared in capsule filling. The test was conducted according to the 15th revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method Paddle Method. As a test solution, a first dissolution test solution (pH 1.2) was used. The elution profile is shown in FIG. The elution curve of the obtained capsule was outside the range of the similarity standard.

[Reference Example 7] Capsule preparation and dissolution evaluation: The ratio of the water-soluble polymer in the total weight of the second layer is 26%, and the ratio of the total weight of the second layer to the total weight of the fast-dissolving granules is 30% <Fast-dissolving granules>
The fast dissolving granules produced in Reference Example 4 were used.

<Granules having second layer>
Anhydrous ethanol (Wako Pure Chemical Industries, Ltd., grade: Japanese pharmacopoeia: the same applies in the present examples) 36504 g of ethyl cellulose 1210 g and triethyl citrate 92 g were added and dissolved to obtain a total of 37806 g of ethyl cellulose / triethyl citrate solution I. Obtained. To 36487 g of absolute ethanol, 1210 g of ethyl cellulose and 92 g of triethyl citrate were added and dissolved to obtain a total of 37789 g of ethyl cellulose / triethyl citrate solution II. Hypromellose 379 g and 105 g of macrogol 4000 were added to 4248 g of purified water and dissolved to obtain a total of 4732 g of hypromellose macrogol solution I. Hypromellose 378 g and 104 g of macrogol 4000 were added to 4248 g of purified water and dissolved to obtain a total of 4730 g of hypromellose macrogol solution II. A sustained-release membrane coating solution I was obtained by adding 4514 g of hypromellose / macrogol solution I to 37806 g of ethyl cellulose / triethyl citrate solution I. Hypromellose / macrogol solution II (4514 g) was added to 37789 g of ethyl cellulose / triethyl citrate solution II to obtain a uniform solution to obtain a sustained-release membrane coating solution II.
Using a combined fluidized bed granulator (Dalton Co., Ltd., Pneumaticizer NQ-500), 10000 g of fast-dissolving granules are mixed with sustained-release membrane coating liquids I and II, and 72520 g of the mixed liquid is sprayed and coated. Slowly soluble granules were produced.

<Capsule filling>
16.3 mg of fast-dissolving granules and 105.8 mg of granules having a second layer (the sample at the time of spraying of the sustained-release membrane coating solution 72520 g) were filled into a hypromellose capsule to prepare a capsule. Table 9 shows the weight (mg) of each component per capsule.

<Elution evaluation>
Dissolution tests were performed on capsules prepared in capsule filling. The test was conducted according to the 15th revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method Paddle Method. As a test solution, a first dissolution test solution (pH 1.2) was used. The elution profile is shown in FIG. The elution curve of the obtained capsule was outside the range of the similarity standard.

  The granule of the present invention is a miniaturized version of ambroxol hydrochloride that is easy to drink for children and elderly people with reduced swallowing function and that is guaranteed effective and safe as a once-daily sustained release formulation. It is useful in the manufacture of pharmaceutical preparations.

Claims (10)

A granule comprising ambroxol hydrochloride as a medicinal ingredient and having a layered structure of at least three layers,
(1) core particles of crystalline cellulose ,
(2) a first layer covering the core particles, comprising ambroxol hydrochloride, a disintegrant, and a binder;
(3) a second layer comprising a water-insoluble polymer and a water-soluble polymer,
(4) A granule comprising a third layer comprising ambroxol hydrochloride and a binder. A granule comprising ambroxol hydrochloride as a medicinal ingredient and having a layered structure of at least 4 layers,
(1) nuclear particles,
(2) a first layer covering the core particles, comprising ambroxol hydrochloride, a disintegrant, and a binder;
(3) a second layer comprising a water-insoluble polymer and a water-soluble polymer,
(4) a granule comprising a third layer comprising ambroxol hydrochloride and a binder ,
A granule having a protective coating layer further comprising a water-soluble polymer between the second layer and the third layer, wherein the third layer further comprises an excipient and a plasticizer. A granule comprising ambroxol hydrochloride as a medicinal ingredient and having a layered structure of at least three layers,
(1) nuclear particles,
(2) a first layer covering the core particles, comprising ambroxol hydrochloride, a disintegrant, and a binder;
(3) a second layer comprising a water-insoluble polymer and a water-soluble polymer,
(4) a granule comprising a third layer comprising ambroxol hydrochloride and a binder ,
A granule further comprising a pH adjusting agent in the first layer and / or the second layer. The granule according to claim 2 or 3 , wherein the core particle is crystalline cellulose. The granule according to any one of claims 1 to 4 , wherein the water-insoluble polymer is ethyl cellulose. The granule according to any one of claims 1 to 5 , wherein the water-soluble polymer is hypromellose. The granule according to any one of claims 1 to 6 , wherein the granule has an average particle size of 300 to 800 µm.   A drug sustained-release solid preparation comprising the granule according to any one of claims 1 to 7.   The drug sustained-release solid preparation according to claim 8, which is a tablet or a capsule. A sustained-release drug tablet obtained by compression molding only the granules according to claim 2 .

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