JP6396719B2 - 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-mentioned problems, the present inventors have intensively studied. As a result, as compared with the prior art using two types of granules, which are fast-dissolving and slow-dissolving, the first particle that contains ambroxol hydrochloride as the core particle exhibits a fast-dissolving action. A granule having a layered structure of at least three layers, sequentially coated with a layer, a second layer exhibiting a slow-dissolving action, and a third layer exhibiting a fast-dissolving action that may include ambroxol hydrochloride By using a single granule having a specific range of the ratio of the amount of ambroxol hydrochloride contained in the first layer and the amount of ambroxol hydrochloride contained in the third layer, the unit of ambroxol hydrochloride The amount of granules per weight can be reduced, and furthermore, it has been found that a miniaturized solid preparation of ambroxol hydrochloride, which is guaranteed effective and safe as a once-daily sustained-release preparation, The present invention has been completed.

That is, the present invention is as follows.
[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) comprising a third layer which may comprise ambroxol hydrochloride and comprises a binder;
When the third layer contains ambroxol hydrochloride, granules in which the amount of ambroxol hydrochloride contained in the first layer is at least 5 times the amount of ambroxol hydrochloride contained in the third layer.
[2] The granule according to [1], wherein the third layer contains ambroxol hydrochloride.
[3] The granule according to [2], wherein the amount of ambroxol hydrochloride contained in the first layer is 25 times or more of the amount of ambroxol hydrochloride contained in the third layer.
[4] The granule according to [2], wherein the amount of ambroxol hydrochloride contained in the first layer is 40 times or more of the amount of ambroxol hydrochloride contained in the third layer.
[5] The granule according to [2], wherein the amount of ambroxol hydrochloride contained in the first layer is 44 times or more the amount of ambroxol hydrochloride contained in the third layer.
[6] The granule according to any one of [1] to [5], wherein the core particle is crystalline cellulose.
[7] The granule according to any one of [1] to [6], wherein the water-insoluble polymer is ethyl cellulose.
[8] The granule according to any one of [1] to [7], wherein the water-soluble polymer is hydroxypropylcellulose.
[9] The granule according to any one of [1] to [8], wherein the granule has an average particle size of 300 to 800 μm.
[10] 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 [9] The granule according to any one of the above.
[11] The granule according to any one of [1] to [10], further comprising a pH adjuster in the first layer and / or the second layer.
[12] A drug sustained-release solid preparation comprising the granule according to any one of [1] to [11].
[13] The sustained-release drug solid preparation according to [12], which is a tablet or capsule.
[14] A sustained-release drug tablet obtained by compression molding only the granule according to [10].

  The miniaturized solid preparation of ambroxol hydrochloride of the present invention is easy to drink for a wide range of patients including children and elderly people with reduced swallowing function. Is guaranteed.

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 the Example. 15th revised Japanese Pharmacopoeia General Test Method 6.10 Dissolution Test Method of Tablets Obtained in Examples According to the paddle method (test solution: McIlvine buffer (pH 7.5), rotation speed: 200 rpm) FIG.

  In the granule of the present invention, ambroxol hydrochloride may be contained in the third layer in addition to being contained in the first layer. The content ratio when the ambroxol hydrochloride is also contained in the third layer (first layer / third layer) is also related to the maximum blood concentration, so that the efficacy and / or safety It is important for guarantee and is greater than 5, preferably 25 or greater, more preferably 40 or greater, and most preferably 44 or greater.

  The content of ambroxol hydrochloride used in the first layer of the present invention is usually 30 to 80% by weight, preferably 65 to 80% by weight, based on the total weight of the first layer. If it is more 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 is undesirably increased.

  Ambroxol hydrochloride may not be present in the third layer, but it is preferable that it is present at all in terms of manufacturability. In this case, the content of ambroxol hydrochloride varies depending on whether or not compression molding is applied for final formulation, and the third content is obtained when compression molding is not performed, that is, when the final formulation is a granule or capsule. It is preferable that the layer is high enough to form a layer with the binder contained in the layer. Specifically, the content of ambroxol hydrochloride used in the third layer when not subjected to compression molding is preferably 80 to 99% by weight based on the weight of the third layer, and the final formulation When is a tablet, it is preferably 0.01 to 10% 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 Co., Ltd., particle size 150-300 μm) and SELFIA <registered trademark> CP-305. (Asahi Kasei Chemicals Corporation, particle size of 300 to 500 μm). Selfia CP-203 is preferable from the viewpoint of miniaturization and tableting of granules, and Selfia CP-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 it exceeds 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 1 to about 20 mPa · s, about 80 to about 120 mPa · s. Grades of about 3000 to about 5600 mPa · s, grades of about 11250 to about 21000 mPa · s, or grades of about 75000 to about 140000 mPa · s, among which about 1 to about 20 mPa · s Is preferred.

  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. In this case, 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, it is necessary to further add a pH adjusting agent to the first layer and / or the second layer, particularly the first layer in the granule of the present invention in order to maintain the dissolution property. 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 to allow the third layer to form a layer, and is based on the total weight of the third layer. Usually 1 to 20% by 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. The exhaust relative humidity during granulation is 40 to 70%, preferably 45 to 70%, more preferably 45 to 55%. When the exhaust relative humidity is 45 to 70%, the raw material in the suspension or solution is laminated on the core particles almost as theoretically. When the exhaust relative humidity is 40% or less, the rate of scattering as powder is increased without being laminated, and when the exhaust relative humidity is 70% or more, the rate of occurrence of agglomerates is increased. When the exhaust relative humidity is 60 to 70%, the filling accuracy into the capsule and the filling accuracy into the mortar of the tableting machine when compressed into a tablet are lowered. Further, when a tablet is formed by compression molding, the tableting pressure for obtaining an appropriate tablet hardness is increased, which may adversely affect the dissolution characteristics.

  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, preferably 400 to 700 μm, more preferably 400 to 600 μm, and prior art (1200 μm or 800 μm in Non-Patent Document 1, 600 to 1500 μm in Patent Document 3). Is smaller than In addition, the average particle diameter in this invention uses the sieve of diameter 76mm, 600, 500, 425, 355, and 300 micrometers of diameter according to the 15th revision Japanese Pharmacopoeia general test method 3.04 particle size measuring 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
D-mannitol: manufactured by Mitsubishi Corporation Food Tech Co., Ltd., trade name: Mannit P
Magnesium stearate: Taihei Chemical Industry Co., Ltd. composite granulation coating device: Dalton Co., Ltd., Newmerizer NQ-500 type mixer: Tsukasa Kogyo Co., Ltd., cross rotary mixer SCM-200
Rotary tableting machine: HT-X20SS-UW, manufactured by Hata Works

[Production of fast-dissolving granules]
34.318 kg of absolute ethanol (Wako Chemical Co., Ltd .: same in the present example) was added to 30.433 kg of purified water (Yoshida Pharmaceutical Co., Ltd .: the same in the present example) to obtain a mixed solution. 0.735 kg of cellulose and 5.250 kg of ambroxol hydrochloride were added and dissolved. This operation was repeated 5 times to obtain a total of 353.680 kg of ambroxol hydrochloride / hydroxypropylcellulose solution. 1.760 kg of low-substituted hydroxypropyl cellulose was dispersed in 43.367 kg of ambroxol hydrochloride / hydroxypropyl cellulose solution to obtain a uniform suspension. This operation was repeated 8 times to obtain a total of 361.016 kg of an active ingredient layering (first layer coating) solution.
Using a composite granulation coating apparatus, the core cellulose layering solution 350.500 kg was sprayed and laminated using 12.000 kg of crystalline cellulose particles as core particles to produce fast-dissolving granules.

[Manufacture of tablets and evaluation of dissolution]
The fast dissolving granules produced above were used.

<Granules having second layer>
Hypromellose 0.251 kg and 0.053 kg of macrogol 4000 were dispersed in 7.686 kg of absolute ethanol, and 1.921 kg of purified water was added and dissolved to obtain a total of 9.911 kg of hypromellose macrogol solution. After dispersing 1.613 kg of ethyl cellulose and 0.122 kg of triethyl citrate in 7.472 kg of purified water, 29.889 kg of absolute ethanol was added and dissolved to obtain a total of 39.096 kg of ethyl cellulose / triethyl citrate solution. 9.635 kg of hypromellose / macrogol solution and 39.096 kg of ethyl cellulose / triethyl citrate solution were mixed to obtain a uniform solution, and a total of 48.731 kg of sustained-release membrane (second layer) coating solution was obtained. Using a composite granulation coating apparatus, 10.6.4 kg of fast-dissolving granules were sprayed and coated with 46.411 kg of a sustained-release membrane coating solution to produce granules having a second layer.

<Granule with protective coating layer>
5.144 kg of absolute ethanol was added to 4.562 kg of purified water to obtain a mixed solution. The macrogol 6000 2.427 kg was added and melt | dissolved in this, and the protective film layer coating liquid of the total 12.133 kg was obtained. Using a composite granulation coating apparatus, 10.005 kg of granules having the second layer were sprayed and coated with 10.551 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>
It was manufactured such that the ratio of the active ingredient contained in the first layer to the active ingredient contained in the third layer was 44: 1. 0.942 kg of absolute ethanol was added to 0.842 kg of purified water to obtain a mixed solution. To this, 0.145 kg of ambroxol hydrochloride was added and dissolved to obtain a total of 1.936 kg of the active ingredient layer coating solution. Hydroxypropylcellulose 0.105 kg, macrogol 60000.525 kg, and D-mannitol 9.794 kg were added to and dissolved in purified water 59.068 kg to obtain a total of 69.492 kg compression molding layer layering solution. Spraying and laminating 0.968 kg of the active ingredient coating liquid and 66.183 kg of the compression molding layer layering liquid in this order to 10.000 kg of the buffer film-coated granules using a composite granulation coating apparatus to produce granules having a third layer. .

<Tablet>
The tablet weight was set so that the content of the active ingredient per tablet was 45 mg. Using a mixer, 19000.0 g of the granule having the third layer and 1.9 g of magnesium stearate were mixed and then compression molded using a rotary tableting machine. The molding conditions were tableting with a tablet weight of 275.6 mg and a φ of 7.5 mmWR so that the hardness was about 58.8N. Table 1 shows the weight (mg) of each component per tablet.

<Elution evaluation>
A dissolution test was conducted on the tablets produced in the table of 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 FIGS. The dissolution curve of the obtained tablets was within the range of similarity standards in all tests for the marketed product “Mucosolvan L Capsule 45 mg”.

<Bioequivalence>
An in vivo bioequivalence test of the preparation produced in the tabletting section confirmed bioequivalence to the marketed product “Mucosolvan L Capsule 45 mg”.

  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 (9)

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 third layer comprising ambroxol hydrochloride and a binder, and
(5) comprising a protective coating layer containing a water-soluble polymer between the second layer and the third layer ;
A sustained-release drug tablet obtained by compression-molding granules in which the amount of ambroxol hydrochloride contained in the first layer is 25 times or more the amount of ambroxol hydrochloride contained in the third layer. The tablet according to claim 1 , wherein the amount of ambroxol hydrochloride contained in the first layer is 40 times or more of the amount of ambroxol hydrochloride contained in the third layer. The tablet according to claim 1 , wherein the amount of ambroxol hydrochloride contained in the first layer is 44 times or more of the amount of ambroxol hydrochloride contained in the third layer. The tablet according to any one of claims 1 to 3 , wherein the core particle is crystalline cellulose. The tablet according to any one of claims 1 to 4 , wherein the water-insoluble polymer is ethyl cellulose. The tablet according to any one of claims 1 to 5 , wherein the water-soluble polymer is hypromellose. The tablet according to any one of claims 1 to 6 , wherein the granule has an average particle size of 300 to 800 µm. The tablet according to any one of claims 1 to 7 , wherein the third layer further comprises an excipient and a plasticizer. The tablet according to any one of claims 1 to 8 , further comprising a pH adjusting agent in the first layer and / or the second layer.

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