Granules with unpleasant taste masked and method for producing the same

Abstract

To provide a granule in which an unpleasant taste is masked and quick release of an active ingredient is maintained and to provide a method for producing the same, in particular, to provide a granule containing zinc acetate as an active ingredient having an unpleasant taste and to provide a method for producing the same.SOLUTION: There is provided a method for producing a granule in which an unpleasant taste is masked and quick release of an active ingredient is maintained, which comprises: (1) a step of obtaining core particles containing an active ingredient having an unpleasant taste; (2) a step of coating the surface of the core particles obtained in the step (1) with ethyl cellulose; and (3) a step of heat-treating the particles obtained in the step (2) in a closed state.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a granule in which an unpleasant taste of an active ingredient is masked and the rapid release property of the active ingredient is maintained, and a method for producing the same. In particular, the present invention relates to a granule containing zinc acetate as an active ingredient having an unpleasant taste and a method for producing the same.

Background Art

[0002] Generally, as the saying goes, "Good medicine tastes bitter." There are drugs that have excellent therapeutic effects but very unpleasant tastes. For example, zinc acetate, which is used as a therapeutic agent for Wilson's disease and has recently been clinically applied as a therapeutic agent for zinc supplementation therapy for patients with hypozincemia, has a very unpleasant taste.

[0003] Therapeutic agents containing zinc acetate that have been used so far are capsule preparations or film-coated tablets, so the problem regarding the unpleasant taste of the active ingredient during administration has not been manifested. However, since zinc acetate preparations are used for patients of a wide range of ages from children to the elderly, a granule-form preparation that is easier to take and allows for easier dosage adjustment is desired.

[0004] Here, when making a granule of an active ingredient having a very unpleasant taste such as zinc oxide, since the preparation dissolves in the mouth during administration and the unpleasant taste of the active ingredient is directly felt, there is a need for masking. On the other hand, in order to sufficiently obtain the effect of the drug, it is necessary for a drug such as zinc acetate to be absorbed into the living body early after administration. Therefore, in order to make a drug such as zinc acetate into a granule, it is necessary to simultaneously overcome the conflicting problems of masking the unpleasant taste and maintaining the rapid release property.

[0005] Patent Document 1 discloses a method for producing a rapidly releasable granular preparation with masked unpleasant taste, in which ethyl cellulose and hydroxypropyl cellulose are dissolved in hydrous ethanol with respect to a core containing a pharmacologically active substance, and this is coated on the core granules at 60 to 100%.

[0006] Patent Document 2 discloses a coating method without using an organic solvent, which uses an ethyl cellulose aqueous suspension. Patent Document 2 discloses a method of coating a core containing a pharmacologically active substance with an ethyl cellulose aqueous suspension and then performing a heat treatment under a certain humidity.

[0007] Patent Document 3 discloses a technique for masking an unpleasant taste and achieving rapid release. In this technique, for a core containing a pharmacologically active substance, first, a water-soluble polymer is coated as an intermediate layer, and then, an ethyl cellulose aqueous suspension containing a certain amount of a plasticizer is coated at 20 to 40%.

Prior Art Documents

Patent Documents

[0008]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0009] As described above, in a granule containing an active ingredient having an unpleasant taste such as zinc acetate, it is necessary to simultaneously overcome the conflicting problems of masking the unpleasant taste and maintaining rapid release properties.

[0010] However, in the inventions described in Patent Documents 1 to 3, it was not possible to obtain a granule that masked the unpleasant taste of the active ingredient while maintaining rapid release properties. Also, although the heating step of the granule is usually performed in an open system to avoid positive pressure, it was not possible to obtain a granule that masked the unpleasant taste of the active ingredient while maintaining rapid release properties by this method either.

[0011] The present invention has been made in view of the above circumstances, and an object thereof is to provide a granule in which an unpleasant taste of an active ingredient is masked and the rapid release property of the active ingredient is maintained, and a method for producing the same.

Means for Solving the Problems

[0012] In order to solve the above problems, the present inventors diligently studied the heat treatment in the coating process in the conventional release system. Surprisingly, by performing this heating process in a sealed state contrary to common technical knowledge, the problems were solved and the present invention was achieved. That is, by heat-treating core particles sprayed with an aqueous ethylcellulose suspension in a sealed state, an unpleasant-tasting active ingredient is not released in the mouth after administration, but an amount or thickness of coating that allows the active ingredient to be immediately released in the stomach after swallowing was successfully obtained, and the present invention was achieved. In this specification, the term "core particle" is used to mean the central particle of each particle constituting the granule. Also, the term "rapid release property" is used to mean that the active ingredient is released early in the stomach after swallowing.

[0013] That is, the present invention includes (1) a step of obtaining core particles containing an active ingredient having an unpleasant taste, (2) a step of coating the surface of the core particles obtained in step (1) with ethylcellulose, and (3) a step of heat-treating the particles obtained in step (2) in a sealed state, and is a method for producing a granule in which an unpleasant taste of an active ingredient is masked and the rapid release property of the active ingredient is maintained.

[0014] The present invention is also a granule obtained by the production method described in this specification, in which an unpleasant taste of an active ingredient is masked and the rapid release property of the active ingredient is maintained.

[0015] Furthermore, the present invention is a granule in which core particles containing an active ingredient having an unpleasant taste are coated with a film containing 2 to 12% by weight of ethylcellulose with respect to the core particles, and an unpleasant taste of the active ingredient is masked and the rapid release property of the active ingredient is maintained.

[0016] That is, the present invention provides a granule in which core particles containing an active ingredient having an unpleasant taste are coated with a film containing 2 to 12% by weight of ethyl cellulose with respect to the core particles, and the dissolution value of the active ingredient after 5 minutes is 80% or less and the dissolution value after 15 minutes is 85% or more according to the second dissolution test method of the Japanese Pharmacopoeia (paddle method, test solution: water, test solution volume: 900 mL, 50 rpm).

Effect of the Invention

[0017] According to the present invention, it is possible to provide a granule in which the unpleasant taste of the active ingredient is masked and the rapid release property of the active ingredient is maintained, and a method for producing the same. In particular, it is possible to provide a granule containing zinc acetate as an active ingredient having an unpleasant taste and a method for producing the same.

Brief Description of the Drawings

[0018]

Figure 1

Figure 2

Figure 3

Modes for Carrying Out the Invention

[0019] Hereinafter, the present invention will be described in detail.

[0020] Examples of the active ingredient having an unpleasant taste that can be used in the present invention include various substances having unpleasant flavors such as bitterness and astringency. However, it is particularly effective for water-soluble substances that have been difficult to maintain rapid release while masking the taste. For example, zinc acetate can be mentioned. Zinc acetate may be an anhydride or a hydrate, and is more preferably a dihydrate.

[0021] In one aspect of the present invention, step (1) can be a step of spraying a solution or suspension of the active ingredient onto the particles that serve as the core of the core particles to coat the particles with the active ingredient.

[0022] The particles that serve as the core of the core particles are not particularly limited as long as they are particles mainly composed of a substance having disintegrability in the body, such as saccharides and / or crystalline cellulose. For example, sucrose (refined white sugar in the Japanese Pharmacopoeia) or particles mainly composed of sucrose and corn starch, particles composed of lactose and crystalline cellulose, spherical particles composed of D-mannitol, granulated sugar, etc. can be used.

[0023] Also, the shape of the particles that serve as the core of the core particles is not particularly limited, but preferably substantially spherical particles can be used. The closer the shape of the particles is to spherical, the more uniform the coating of the active ingredient and the like becomes, and the quality becomes stable.

[0024] In one aspect of the present invention, step (1) can be a step of coating a binder in addition to the active ingredient. The binder may be contained in the solution or suspension of the active ingredient and sprayed together with the active ingredient, or may be prepared as a separate solution from the solution or suspension of the active ingredient and sprayed simultaneously or individually with the active ingredient. By coating the binder together with the active ingredient, the bond between the active ingredient and the core particles can be made stronger.

[0025] The binder may be any one generally used in the pharmaceutical field. Examples include hydroxypropylcellulose, polyvinyl alcohol, hydroxypropylmethylcellulose, methylcellulose, gum arabic, gelatin, starch, etc., and hydroxypropylcellulose is preferred.

[0026] The blending amount of the binder may be an amount sufficient for the core particles and the active ingredient to be sufficiently bonded, and can be set as appropriate.

[0027] In one aspect of the present invention, step (1) can be a step of coating a disintegrant in addition to the active ingredient. The disintegrant may be contained in a solution or suspension of the active ingredient and sprayed together with the active ingredient, or may be prepared as a separate solution from the solution or suspension of the active ingredient and sprayed simultaneously or separately with the active ingredient.

[0028] The disintegrant may be any commonly used in the pharmaceutical field, and examples include partially pregelatinized starch, carboxymethyl cellulose, croscarmellose sodium, crospovidone, etc., and preferably partially pregelatinized starch.

[0029] The amount of the disintegrant can be appropriately adjusted so as to achieve a desired dissolution rate.

[0030] In the present invention, either the binder or the disintegrant may be coated on the particles together with the active ingredient, or both of them may be coated on the particles together with the active ingredient. When coating the binder and the disintegrant simultaneously, the binder and the disintegrant may be blended in a solution or suspension of the active ingredient and sprayed together with the active ingredient, or a solution of the binder and the disintegrant may be prepared separately from the solution or suspension of the active ingredient and sprayed simultaneously or separately with the active ingredient.

[0031] In one aspect of the present invention, step (1) can be a step of pulverizing a granulated product obtained by granulating an active ingredient having an unpleasant taste together with a formulation aid such as an excipient and sieving it to have a certain particle size.

[0032] Examples of the excipient include saccharides such as lactose, sucrose, and mannitol, starches such as corn starch and potato starch, binders such as hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, and polyvinyl alcohol. According to a conventional method, after granulation, a product sieved to 100 to 600 μm, preferably 200 to 500 μm, can be used as core particles having the active ingredient.

[0033] In one aspect of the present invention, step (2) can be a step of spray-coating an aqueous dispersion of ethyl cellulose suspension.

[0034] The coating amount of ethyl cellulose is 2 to 12% by weight based on the core particles, preferably 5 to 9% by weight, and more preferably 5 to 7% by weight.

[0035] In one aspect of the present invention, step (2) can be a step of coating with a plasticizer together with ethyl cellulose. By coating ethyl cellulose together with a plasticizer, particles can be more completely formed into a film.

[0036] The plasticizer may be any one generally used in the pharmaceutical field, and examples thereof include triethyl citrate, polyethylene glycol, propylene glycol, and triacetin.

[0037] The amount of the plasticizer can be appropriately selected and used. For example, when coating granules having a particle size of 200 to 1000 μm, an amount of about 5 to 20% by weight based on ethyl cellulose may be used.

[0038] In the present invention, the heat treatment in step (3) is performed by heating the particles in a sealed state so as to prevent, to some extent, the moisture contained in the particles from being released outside the system due to overheating. "Heating the particles in a sealed state" means heating the particles under closed conditions, and any conditions that can prevent, to some extent, the moisture contained in the particles from being released outside the system are acceptable. For example, it means putting the particles obtained in step (2) into a sealed container and heating them. The heating in step (3) is preferably performed under so-called airtight conditions where there is no entry or exit of liquid, and more preferably under so-called sealed conditions where there is no entry or exit of water vapor, air, or other gases. The heating may be under conditions sufficient to form a film with the ethyl cellulose coated on the particle surface. For example, the temperature can be 70 to 100°C and the treatment time can be 15 to 180 minutes.

[0039] In a preferred embodiment, during the heating step in step (3), a fluidizing agent can be added to the particles obtained in step 2 in advance. By adding the fluidizing agent, adhesion and aggregation of the particles during the heating step can be prevented.

[0040] The fluidizing agent may be any one generally used in the pharmaceutical field, and examples thereof include light anhydrous silicic acid.

[0041] The addition amount of the fluidizing agent may be an amount sufficient to disperse the particles. Specifically, about 0.5 to 1% by weight may be used with respect to the particles.

[0042] In the present invention, the term "the unpleasant taste of the active ingredient is masked and the rapid release property of the active ingredient is maintained" means that the active ingredient does not elute in the initial stage of administration of the granule (the time when the granule is present in the oral cavity), and a sufficient amount of the active ingredient elutes after a certain period of time (the early time point after swallowing). For example, when a test is conducted according to the second dissolution test method of the Japanese Pharmacopoeia (paddle method, test solution: water, test solution volume: 900 mL, 50 rpm), it is a granule having a performance that the 5-minute dissolution value of the active ingredient is 80% or less and the 15-minute dissolution value is 85% or more, and preferably a granule having a performance that the 5-minute dissolution value of the active ingredient is 70% or less and the 15-minute dissolution value is 90% or more.

[0043] In a preferred embodiment, the production method according to the present invention includes step (1): spraying a solution or suspension containing an active ingredient and a binder onto substantially spherical particles mainly composed of saccharides and / or crystalline cellulose, and then spraying a solution or suspension of a disintegrant; step (2): spraying a water-dispersed ethylcellulose suspension containing a plasticizer; and step (3): adding a fluidizing agent and heating in a sealed state at 70 to 100°C for 15 to 180 minutes, which can be sequentially performed.

[0044] One embodiment of the granule of the present invention is a granule obtained by a method including the above-mentioned step (1), step (2), and step (3).

[0045] Also, one aspect of the granule of the present invention is a granule in which core particles containing an active ingredient having an unpleasant taste are coated with a coating containing 2 to 12% by weight of ethyl cellulose with respect to the core particles, the unpleasant taste of the active ingredient is masked, and the sustained-release property of the active ingredient is maintained. Such granules can be produced, for example, by the method described above.

[0046] One aspect of the granule of the present invention is a granule in which core particles containing an active ingredient having an unpleasant taste are coated with a coating containing 2 to 12% by weight of ethyl cellulose with respect to the core particles, and the dissolution 5-minute value of the active ingredient by the second dissolution test method (paddle method, test solution: water, test solution volume: 900 mL, 50 rpm) of the Japanese Pharmacopoeia is 80% or less, and the dissolution 15-minute value is 85% or more. Such granules can be produced, for example, by the method described above.

[0047] Examples of the active ingredient having an unpleasant taste that can be used in the granule of the present invention include the above-mentioned active ingredients, for example, zinc acetate. Zinc acetate may be an anhydride or a hydrate, and is more preferably a dihydrate.

[0048] The particle size of the granule of the present invention can be appropriately selected and is not particularly limited. For example, the particle size can be about 200 to 700 μm. By using a particle size of this degree, a formulation that is easy to take for children and the elderly can be obtained.

Examples

[0049] The present invention will be described below with specific embodiments, but the present invention is not limited to the embodiments, and various changes and modifications therein can be carried out by those skilled in the art without departing from the scope or spirit of the present invention defined in the appended claims.

[0050] Example 1, Comparative Example 1: Confirmation of the effect under sealed conditions

[0051] (1) Preparation of granules 1,300 g of spherical particles with a particle size of 355 to 500 μm composed of refined sugar and corn starch (product name: Nonpareil (registered trademark)-101, manufactured by Freund Industry Co., Ltd.) were charged into a rolling fluidization device, and under the condition of an air supply temperature of 65°C, a drug substance dissolution solution and a disintegrant suspension with the following compositions were sprayed in sequence to obtain drug substance-coated core particles. Drug substance dissolution solution: A solution prepared by dissolving 338.6 g of zinc acetate hydrate (C4H6O4Zn·2H2O) in 1,183 g of a 6% hydroxypropyl cellulose solution. Disintegrant suspension: A suspension prepared by adding 41.1 g of partially pregelatinized starch to 352 g of a 6% hydroxypropyl cellulose solution.

[0052] (Example 1) To 1,500 g of the obtained drug substance-coated core particles, 450 g of a 20% ethyl cellulose suspension containing about 2% triethyl citrate was sprayed, and sieved using an 18-mesh sieve to obtain ethyl cellulose-coated particles. To the obtained ethyl cellulose-coated particles, 0.7% equivalent of light anhydrous silicic acid was added and mixed, and then placed in a sealed container and heated at 80°C for 2 hours (hereinafter referred to as "heated granules under sealed conditions").

[0053] (Comparative Example 1) For comparison, the above ethyl cellulose-coated particles mixed with 0.7% equivalent of light anhydrous silicic acid were placed in an open container and heated at 80°C for 2 hours to obtain particles (hereinafter referred to as "heated granules under open conditions").

[0054] (2) Dissolution test According to the second method of the dissolution test in the Japanese Pharmacopoeia (paddle method, test solution: water, test solution volume: 900 mL, 50 rpm), for the prepared granules (heated granules under sealed conditions and heated granules under open conditions), the dissolution 5-minute value, dissolution 15-minute value, and dissolution 30-minute value of the active ingredient were measured. Quantification was performed using an ultraviolet-visible spectrophotometer (detection reagent: 1-(2-hydroxycarbonylphenyl)-5-(2-hydroxy-5-sulfophenyl)-3-phenylformazan, measurement wavelength: 620 nm). The results are shown in Figure 1 (Comparison of the dissolution rates of the active ingredient in the heated preparation under sealed conditions and the heated preparation under open conditions) and Table 1 (Results of the dissolution test).

[0055]

Table 1

[0056] As shown in Fig. 1 and Table 1, for the elution 15-minute value, both the heat-treated granules under sealed conditions and the heat-treated granules under release conditions showed almost 100% values, and no difference was observed between the two. From this result, it was confirmed that both the heat-treated granules under sealed conditions and the heat-treated granules under release conditions had sufficient rapid release properties of the active ingredient. On the other hand, for the elution 5-minute value, the heat-treated granules under sealed conditions had a significantly suppressed elution compared to the heat-treated granules under release conditions. This result indicates that by performing the heat treatment under sealed conditions, the elution of the active ingredient in the early stage after administration is significantly suppressed, effectively masking the unpleasant taste.

[0057] From the above results, it was confirmed that by using the production method of the present invention, that is, a production method including performing the heat treatment in the coating step under sealed conditions, granules can be produced in which the unpleasant taste of the active ingredient is masked and the rapid release property of the active ingredient is maintained.

[0058] Example 2: Coating amount of ethyl cellulose

[0059] The amount of the 20% ethyl cellulose suspension containing about 2% triethyl citrate sprayed on the drug-coated core particles was adjusted so that the coating amount (the coating amount of ethyl cellulose on the drug-coated core particles) was 5, 6, and 7% by weight. Otherwise, the same operations as in Example 1 were performed to prepare heat-treated granules under sealed conditions, and the elution amount of the active ingredient was confirmed by the same test method as in Example 1. The results are shown in Fig. 2 (relationship between the coating amount of ethyl cellulose and the elution rate of the active ingredient).

[0060] As shown in Figure 2, the elution value at 15 minutes showed a value of 85% or more for the granules with all coating amounts. From this result, it was confirmed that the rapid release property of the active ingredient was maintained in all the granules. Also, the elution value at 5 minutes showed a good value of less than 70% for the granules with all coating amounts. From this result, it was confirmed that the unpleasant taste was masked in all the granules.

[0061] Example 3: Examination of the amount of plasticizer added

[0062] The same operations as in Example 1 were carried out except that the amount of plasticizer incorporated into the ethylcellulose suspension was adjusted to be 7, 9, and 11% by weight based on ethylcellulose, and heat-sealed granules were prepared. The elution amount of the active ingredient was confirmed by the same test method as in Example 1. The results are shown in Figure 3 (relationship between the amount of plasticizer added and the elution rate of the active ingredient).

[0063] As shown in Figure 3, almost no change was observed in the elution behavior of the active ingredient in the granules when the plasticizer was 7 - 11%.

Industrial Applicability

[0064] According to the present invention, it becomes possible to provide granules in which the unpleasant taste of the active ingredient is masked and the rapid release property of the active ingredient is maintained, and in particular, it becomes possible to provide granules that are easier to take and whose dosage can be easily adjusted for patients of a wide range of ages from children to the elderly.

Claims

1. (1) A step of obtaining core particles containing zinc acetate as an active ingredient having an unpleasant taste; (2) A step of coating the surface of the core particles obtained in step (1) with ethyl cellulose; and (3) A step of adding a fluidizing agent to the particles obtained in step (2) and performing a heat treatment in a sealed state 、 A method for producing a granule in which the unpleasant taste of the active ingredient is masked and the rapid release property of the active ingredient is maintained, comprising: Step (2) is A step of spray-coating a water-dispersed ethyl cellulose suspension on the surface of the core particles obtained in step (1); A step of coating the surface of the core particles obtained in step (1) with a plasticizer together with ethyl cellulose, and the amount of the plasticizer is 5 to 20% by weight based on ethyl cellulose, and A step of spray-coating the core particles obtained in step (1) with a water-dispersed ethyl cellulose suspension containing a plasticizer A step selected from, and the granule obtained in step (3) has an elution 5 minute value of the active ingredient of 80% or less and an elution 15 minute value of 85% or more by the second dissolution test method of the Japanese Pharmacopoeia (paddle method, test solution: water, test solution volume: 900 mL, 50 rpm). Manufacturing method.

2. Step (1) is a step of coating an active ingredient on particles mainly composed of saccharides and / or crystalline cellulose, The production method according to claim 1.

3. Step (1) is a step of coating a binder and / or a disintegrant together with an active ingredient on particles mainly composed of saccharides and / or crystalline cellulose, The production method according to claim 1 or 2.

4. Step (1) is a step of spraying an active ingredient-containing solution or an active ingredient-containing suspension on particles mainly composed of saccharides and / or crystalline cellulose to coat the particles with the active ingredient, The production method according to any one of claims 1 to 3.

5. The particles mainly composed of saccharides and / or crystalline cellulose are substantially spherical particles, The production method according to any one of claims 2 to 4.

6. Step (1) is a step of pulverizing a granulated product obtained by granulating an active ingredient having an unpleasant taste together with a pharmaceutical adjuvant and sieving it to have a certain particle size, The production method according to claim 1.

7. The amount of the plasticizer is 7 to 11% based on ethyl cellulose, The production method according to any one of claims 1 to 6.

8. The coating amount of ethyl cellulose in step (2) is 5 to 9% by weight based on the core particles, The production method according to any one of claims 1 to 7.

9. ​ ​ ​ ​ The coating amount of ethyl cellulose in step (2) is 5 to 7-fold by weight based on the core particles, and the production method according to claim 8.

10. The amount of the fluidizing agent is 0.5 to 1% by weight based on the particles, and any one of claims 1 to 9 The production method according to the above.

11. Step (3) is a step of heat-treating the particles obtained in step (2) under conditions of a sealed state and 70 to 100 °C for 15 to 180 minutes, and the production method according to any one of claims 1 to 10.

12. A granule obtained by the method according to any one of claims 1 to 11, in which the unpleasant taste of the active ingredient is masked and the rapid release property of the active ingredient is maintained. ​