Granule having masked unpleasant taste and method for producing the same

Abstract

To provide a granule in which an unpleasant taste of an active ingredient is masked and immediate release of the active ingredient is maintained, and a method for producing the granule, in particular, to provide a granule containing zinc acetate as an active ingredient having an unpleasant taste, and a method for producing the granule.SOLUTION: Provided is a method for producing a granule in which an unpleasant taste of an active ingredient is masked and immediate release of the active ingredient is maintained. The method includes a step (1) of obtaining a core particle containing an active ingredient having an unpleasant taste, a step (2) of coating a surface of the core particle obtained in the step (1) with ethylcellulose, and a step (3) of subjecting the particle obtained in the step (2) to a heat treatment in a closed state.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention provides a granule that masks the unpleasant taste of an active ingredient and maintains the immediate release of the active ingredient. In particular, the present invention relates to a pharmaceutical composition containing zinc acetate as an active ingredient having an unpleasant taste and a method for producing the same. The present invention relates to a granule and a method for producing the same. [Background technology]

[0002] Generally speaking, as the saying goes, good medicine tastes bitter, and there are drugs that have excellent therapeutic effects but have a very unpleasant taste. For example, it is used as a treatment for Wilson's disease, and in recent years, it has been used as a treatment for hypozincemia. Zinc acetate, which is clinically used as a treatment for zinc replacement therapy for people with diabetes, is very unpleasant. Has a taste.

[0003] The therapeutic agents containing zinc acetate that have been used so far are capsules and film-coated. Since the drug is a tablet, there has been no problem with the unpleasant taste of the active ingredient when taken. However, zinc acetate preparations are used in a wide range of patients, from children to the elderly, and therefore There is a demand for a granular formulation that is easy to take and allows easy dosage adjustment.

[0004] Here, when making granules of an active ingredient with a very unpleasant taste, such as zinc oxide, Sometimes the formulation dissolves in the mouth, causing the unpleasant taste of the active ingredient to be felt directly. Masking is necessary. On the other hand, in order to obtain the full effect of the drug, it is necessary to use drugs such as zinc acetate. It is necessary for drugs such as zinc acetate to be absorbed into the body as soon as possible after administration. To make a granule, it is necessary to simultaneously address the conflicting issues of masking the unpleasant taste and maintaining rapid release. Sometimes you have to overcome it.

[0005] Patent Document 1 discloses a method for producing an immediate-release granular preparation that masks unpleasant tastes, in which a core containing a pharmacologically active substance is coated with 60 to 100% of a solution of ethyl cellulose and hydroxypropyl cellulose dissolved in hydroethanol. For the core containing the pharmacologically active substance, ethyl cellulose and hydroxypropyl cellulose are dissolved in hydroethanol, and this is coated on the granules at 60 to 100%. A method is disclosed.

[0006] Patent Document 2 discloses a coating method that does not use an organic solvent, namely, a method using an ethyl cellulose aqueous suspension. In Patent Document 2, a method is disclosed in which a core containing a pharmacologically active substance is coated with an ethyl cellulose aqueous suspension and then heat-treated under a certain humidity. For the core containing the pharmacologically active substance, it is coated with an ethyl cellulose aqueous suspension, and then heat-treated under a certain humidity. A method is disclosed.

[0007] Patent Document 3 discloses a technique for masking unpleasant tastes and achieving rapid release. First, a water-soluble polymer is coated on a core containing a pharmacologically active substance, and then an ethyl cellulose aqueous suspension containing a certain amount of a plasticizer is coated at 20 to 40%. For the core containing the 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%. A method is disclosed.

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 granular preparation containing an active ingredient having an unpleasant taste such as zinc acetate, the unpleasant ​​​It is necessary to simultaneously overcome the conflicting problems of masking unpleasant tastes 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. Further, the heating step of the granule is usually carried out in an open system in order to avoid positive pressure, but even this method could not obtain a granule that masked the unpleasant taste of the active ingredient while maintaining rapid release properties.

[0011] The present invention has been made in view of the above circumstances, and an object thereof is 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.

Means for Solving the Problems

[0012] In order to solve the above problems, the present inventors earnestly studied the heat treatment in the coating step in the conventional open system, and surprisingly, by performing this heating step 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 dispersion of ethylcellulose in a sealed state, a granule having a coating of an amount or thickness that enables the active ingredient with an unpleasant taste not to be released in the mouth after ingestion but 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. Further, the term "rapid release property" is used to mean that the active ingredient is rapidly released in the stomach after swallowing.

[0013] ​​​​​​​​​​​​​That is, the present invention 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 step (1) with ethyl cellulose; and (3) a step of heat-treating the particles obtained in step (2) in a sealed state, and 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 . .

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

[0015] Furthermore, the present invention relates to 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 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 coats core particles containing an active ingredient having an unpleasant taste with a film containing 2 to 12% by weight of ethyl cellulose with respect to the core particles, and the dissolution of the active ingredient by the second method of the dissolution test of the Japanese Pharmacopoeia (paddle method, test solution: water, test solution volume: 900 mL, 50 rpm) has a dissolution 5-minute value of 80% or less and a dissolution 15-minute value of 85% or more . It is a granule

Advantages 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

Embodiments for Carrying Out the Invention

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

[0020] As the active ingredient having an unpleasant taste that can be used in the present invention, there are various substances having unpleasant flavors such as bitterness and astringency, but 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 it is more preferably the 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 serving as the core of the core particles to coat the particles with the active ingredient.

[0022] The particles serving 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 (purified 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] ​​​​​​​​​In addition, the shape of the particle serving as the core of the core particle is not particularly limited, but preferably substantially spherical particles can be used. The closer the shape of the particle is to spherical, the more uniform the coating of the active ingredient and the like becomes, and the quality is stabilized.

[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 a solution or suspension of the active ingredient and sprayed together with the active ingredient, or prepared as a separate solution from the solution or suspension of the active ingredient and sprayed simultaneously with or individually from the active ingredient. By coating the binder together with the active ingredient, the binding between the active ingredient and the particle serving as the core can be made stronger.

[0025] The binder may be any one generally used in the pharmaceutical field. For example, hydroxypropyl cellulose, polyvinyl alcohol, hydroxypropyl methylcellulose, methylcellulose, gum arabic, gelatin, starch, etc. can be mentioned, and hydroxypropyl cellulose is preferably used.

[0026] The blending amount of the binder may be an amount sufficient for the particle serving as the core and the active ingredient to be sufficiently bound, and can be appropriately set.

[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 prepared as a separate solution from the solution or suspension of the active ingredient and sprayed simultaneously with or individually from the active ingredient.

[0028] The disintegrant may be any one generally used in the pharmaceutical field. For example, partially pregelatinized starch​​​ Dextrin, carboxymethyl cellulose, croscarmellose sodium, crospovidone etc., and preferably 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 these may be coated on the particles together with the active ingredient at the same time. When coating the binder and the disintegrant at the same time, 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 with or separately from the active ingredient.

[0031] In one aspect of the present invention, step (1) may be a step of pulverizing the 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 acetate. According to a conventional method, after granulation, the product sieved to 100 to 600 μm, preferably 200 to 500 μm can be used as the core particles having the active ingredient.

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

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

[0035] In one embodiment of the present invention, step (2) comprises coating a plasticizer with ethyl cellulose. By coating the ethyl cellulose together with a plasticizer, the process can be completed more completely. The particles can be completely deposited.

[0036] The plasticizer may be any one commonly used in the pharmaceutical field, for example, trichloroethylene. Examples of such glycols include polyethylene glycol, propylene glycol, and triacetin. do.

[0037] The amount of plasticizer can be appropriately selected. For example, the particle size is 200 to 1000 μm. When coating granules, use 5 to 20% by weight of ethyl cellulose. It is sufficient to use the degree amount.

[0038] In the present invention, the heat treatment in step (3) is carried out to remove moisture contained in the particles by overheating. To prevent some of the particles from being released outside the system, the particles are heated in a sealed environment. "Heating particles in a closed state" means heating particles under closed conditions. The conditions are such that the moisture contained in the particles can be prevented to some extent from being released outside the system. For example, the particles obtained in step (2) may be placed in a sealed container and heated. The heating in step (3) is carried out under so-called airtight conditions, i.e., under conditions where no liquid flows in or out. It is preferable to use a so-called sealed state, which is a condition where there is no inflow or outflow of water vapor, air, or other gases. It is more preferable to carry out by heating. The heating should be carried out under conditions sufficient to form a film with ethyl cellulose coated on the particle surface. For example, the temperature can be 70 - 100 °C and the treatment time can be 15 - 180 minutes. It is sufficient if it is a condition sufficient to form a film, for example, the temperature can be 70 - 100 °C and the treatment time can be 15 - 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. By adding the fluidizing agent, adhesion and aggregation of the particles during the heating step can be prevented.

[0040] The fluidizing agent may be one generally used in the pharmaceutical field. For example, light anhydrous silicic acid etc. can be mentioned.

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

[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 carried out by 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. Preferably, it is 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 manufacturing method according to the present invention comprises 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 ethyl cellulose suspension containing a plasticizer; step (3): adding a fluidizing agent and heating in a closed state at 70 to 100 °C for 15 to 180 minutes, which can be carried out sequentially.

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

[0045] Another embodiment 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 above-mentioned method.

[0046] Another embodiment 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 of the Japanese Pharmacopoeia (paddle method, test solution: water, test solution volume: 900 mL, 50 rpm) is 80% or less, and the dissolution 15-minute value is 85% or more. Such granules can be produced, for example, by the above-mentioned method.

[0047] The active ingredient having an unpleasant taste that can be used in the granule of the present invention includes the above-mentioned active ​​​​​​​​​​​​​Examples of components include zinc acetate. Zinc acetate may be anhydrous or hydrated, and more preferably is the dihydrate.

[0048] The particle size of the granules 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 can be obtained even for children and the elderly.

Examples

[0049] The present invention will be described below by giving specific embodiments, but the present invention is not limited to those 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. This is understood.

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

[0051] (1) Preparation of granules 1300 g of spherical particles (product name: Nimparel (registered trademark)-101, manufactured by Freund Industry Co., Ltd.) having a particle size of 355 to 500 μm and consisting of refined sugar and corn starch 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 having the following compositions were sprayed in this order to obtain drug substance-coated elementary particles. Drug substance dissolution solution: A solution prepared by dissolving 338.6 g of zinc acetate hydrate (C4H6O4Zn·2H2O) in 1183 g of a 6% hydroxypropyl cellulose solution. Disintegrant suspension: A solution prepared by adding 41.1 g of partially gelatinized starch to 352 g of a 6% hydroxypropyl cellulose solution and suspending it.

[0052] (Example 1) To 1500 g of the obtained active ingredient-coated fine particles, 450 g of a 20% ethyl cellulose suspension containing about 2% triethyl citrate was sprayed, sieved using an 18-mesh sieve, and ethyl cellulose-coated particles were obtained. To the obtained ethyl cellulose-coated particles, 0.7% equivalent of light anhydrous silicic acid was added and mixed, and the mixture was placed in a sealed container and heated at 80°C for 2 hours (hereinafter referred to as "sealed-condition heated granules"). For comparison, the above-mentioned 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 "open-condition heated granules").

[0053] (Comparative Example 1)

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

[0055]

Table 1

[0056] As shown in Fig. 1 and Table 1, for the 15-minute dissolution value, both the sealed-condition heated granules and the open-condition For both the conditioned heating granules, almost 100% values were shown, and no difference was observed between them. This result confirmed that both the sealed-condition heating granules and the release-condition heating granules have sufficient rapid release properties of the active ingredient. On the other hand, for the 5-minute elution value, the sealed-condition heating granules showed a significantly suppressed elution compared to the release-condition heating granules. 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

[0058] Example 2: Coating amount of ethyl cellulose

[0059] Except that the amount of a suspension liquid containing about 2% triethyl citrate and 20% ethyl cellulose sprayed on the drug-coated core particles was adjusted so that the coating amount (coating amount of ethyl cellulose on the drug-coated core particles) became 5, 6, and 7% by weight, the same operations as in Example 1 were carried out to prepare sealed- condition heating granules, 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

[0060] As shown in Fig. 2, the 15-minute elution values were 85% or more in the granules of 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 5-minute elution value was in all the granules of all and showed good values of less than 70%. From these results, it was confirmed that in all the granules, the unpleasant taste was masked.

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

[0062] The amount of plasticizer to be blended in the ethyl cellulose suspension was adjusted to 7, 9, and 11% by weight with respect to ethyl cellulose, and the same operations as in Example 1 were carried out to prepare granules under heating in a sealed condition, 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. 3 (Relationship between the amount of plasticizer added and the elution rate of the active ingredient).

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

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, for a wide range of ages from children to the elderly, it becomes possible to provide granules that are easier to take and whose dosage can be easily adjusted. ​

Claims

1. (1) obtaining core particles containing an active ingredient having an unpleasant taste; (2) a step of coating the surfaces of the core particles obtained in the step (1) with ethyl cellulose; and (3) The particles obtained in step (2) are subjected to a condition in which there is no water vapor, air, or other gases entering or leaving the particles. and a heat treatment step for masking the unpleasant taste of the active ingredient and achieving rapid release of the active ingredient. The method for producing a granule in which the above-mentioned condition is maintained, wherein the step (2) comprises: The surface of the core particles obtained in step (1) is spray-coated with a water-dispersed ethyl cellulose suspension. a step of applying the A step of coating the surfaces 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 the ethyl cellulose; and A water-dispersed ethyl cellulose suspension containing a plasticizer is sprayed onto the core particles obtained in step (1). The manufacturing method is a step selected from the step of coating.

2. Step (1) comprises coating an active ingredient onto particles whose main components are sugars and / or crystalline cellulose. The method according to claim 1, wherein the step of:

3. The step (1) comprises adding a binder and / or a binder to particles mainly composed of sugars and / or crystalline cellulose. The method according to claim 1 or 2, wherein step (b) is a step of coating the disintegrant together with the active ingredient.

4. The step (1) is a step of adding an active ingredient-containing solution to particles mainly composed of sugars and / or crystalline cellulose.

3. A process of coating the particles with the active ingredient by spraying a liquid or suspension containing the active ingredient. The method for producing a compound according to any one of 1 to 3.

5. Claim 2, wherein the particles mainly composed of sugars and / or crystalline cellulose are approximately spherical particles.

5. The manufacturing method according to any one of claims 1 to 4.

6. The step (1) comprises granulating an active ingredient having an unpleasant taste together with a formulation aid, pulverizing the granulated product, and 2. The method according to claim 1, further comprising the step of sieving the powder to a predetermined particle size.

7. Any of claims 1 to 6, wherein the amount of plasticizer is 7 to 11% relative to ethyl cellulose. The manufacturing method according to claim 1.

8. The coating amount of ethyl cellulose in step (2) is 5 to 9 times the amount of the core particles. The method according to any one of claims 1 to 7, wherein the amount of the hydroxybenzoate is 100% by weight.

9. The coating amount of ethyl cellulose in step (2) is 5 to 7 times that of the core particles. The method according to claim 8, wherein the content is in the range of 0.01 to 0.1% by weight.

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