KR20190117469A - Granule formulation - Google Patents

Abstract

The present invention provides granule formulations comprising isoleucine, leucine and valine with improved dosage. The present invention relates to a granule formulation comprising isoleucine, leucine and valine as active ingredients, and to a granule formulation comprising a gelling agent.

Description

Granule formulation

The present invention relates to granule formulations. Specifically, the present invention relates to granule formulations comprising isoleucine, leucine and valine.

As medicines containing isoleucine, leucine, and valine, Libact (registered trademark, the same applies hereinafter), which is a therapeutic drug effective for liver disease, is commercially available.

Liebt-containing granules contain 4 g of active ingredient in one packet (4.15 g), and are used to improve hypoalbuminemia in non-target cirrhosis patients who exhibit hypoalbuminemia despite a sufficient amount of meal intake (Non-Patent Document 1) ).

Attached document Branched chain amino acid preparation Japanese Pharmacopoeia Isoleucine, leucine, valine granules Libact (registered trademark) combination granules April, 2016 revision (17th edition)

Since Reacted granules are granule preparations containing a large amount of amino acid components, further improvement of the feeling of taking such as bitterness derived from amino acids and the mouth residue of granules is required.

The problem to be solved by the present invention is to provide a granule preparation comprising isoleucine, leucine and valine with improved feeling of taking.

MEANS TO SOLVE THE PROBLEM As a result of earnestly examining, the present inventors discovered that the said subject could be solved by mix | blending a gelling agent in the granule formulation containing isoleucine, leucine, and valine, and completed this invention.

That is, this invention is as follows.

(One)

A granule formulation comprising isoleucine, leucine and valine as active ingredients, the granule formulation comprising a gelling agent.

(2)

The granule formulation according to (1), wherein the gelling agent is a carboxyvinyl polymer or polyethylene oxide.

(3)

The granule formulation according to (1) or (2), wherein the gelling agent is a polyethylene oxide having an average molecular weight of 500,000 or more.

(4)

The granule formulation according to any one of (1) to (3), wherein the gelling agent is powdered.

(5)

The granule formulation according to any one of (1) to (4), which contains 0.05 to 2% of a gelling agent based on the total amount of the granule formulation.

(6)

The granule preparation according to any one of (1) to (5), which is included in a weight ratio of isoleucine / leucine / valine = 1 / 1.9 to 2.2 / 1.1 to 1.3.

(7)

The granule formulation according to any one of (1) to (6), which contains 80% or more of isoleucine, leucine and valine relative to the total amount of granule formulation.

(8)

The granule formulation according to any one of (1) to (7), further comprising a binder and / or a mating agent.

(9)

As a method for producing a granule formulation containing isoleucine, leucine and valine as active ingredients,

A manufacturing method of adding a gelling agent to granules containing isoleucine, leucine and valine.

(10) The manufacturing method as described in (9) which powder-adds a gelling agent.

According to the present invention, it is possible to provide granule preparations comprising isoleucine, leucine and valine with improved dosage.

1 shows the results in the dissolution test of the granule formulation of Example 1. FIG.
The result in the dissolution test of the granule formulation of the comparative example 1 is shown.

Although this invention is demonstrated concretely by the form for implementing this invention, this invention is not limited to the form for implementing the following invention, It can variously deform and implement.

The granule formulation of the present invention contains isoleucine, leucine and valine as active ingredients, and includes a gelling agent.

In the granule preparation of the present invention, isoleucine, leucine and valine used as active ingredients are amino acids known as branched chain amino acids.

In the present invention, each of D and L forms may be used, a mixture of any of D and L forms may be used, and DL may be used.

Isoleucine, leucine and valine may each be a chemical synthetic product or a fermented product.

It is preferable to use the thing which satisfy | fills the specification described as L-isoleucine, L-leucine, and L-valine in Revision 17 of the Japanese Pharmacopoeia (pages 483, 1711-1712, 1248 respectively).

In the present invention, the inclusion of isoleucine, leucine and valine as active ingredients means that isoleucine, leucine, and valine are included as components that exert an efficacy effect when the granule preparation of the present invention is used as a medicine. .

As a potent effect of a drug containing isoleucine, leucine and valine as active ingredients, in Japan, a potent effect of a commercially available Ribect compounded granule is `` of a non-target cirrhosis patient who exhibits hypoalbuminemia despite a sufficient food intake. Improvement of hypoalbuminemia ”is known, but the efficacy effect of the granule preparation which contains the isoleucine, leucine, and valine of this invention as an active ingredient is not limited only to such an efficacy effect.

In the present invention, other active ingredients may be included as active ingredients, but only isoleucine, leucine and valine are preferable.

The granule formulation of the present invention can be used as a pharmaceutical granule formulation by containing isoleucine, leucine and valine as active ingredients.

In the granule preparation of the present invention, the content ratio of isoleucine, leucine and valine is not particularly limited, but is preferably isoleucine / leucine / valine = 1 / 1.9 to 2.2 / 1.1 to 1.3 as weight ratio.

Although content of isoleucine, leucine, and valine is set suitably, it is preferable that it is 80% or more as a lower limit of the content as mass% with respect to the granule preparation whole quantity, It is more preferable that it is 90% or more, It is further more preferable that it is 95% or more.

Although it does not specifically limit as an upper limit of content of isoleucine, leucine and valine, It is preferable that content of isoleucine, leucine and valine is less than 100%, It is more preferable that it is 99% or less, It is still more preferable that it is 98% or less, It is 97% or less Even more preferred.

Content of isoleucine, leucine, and valine should just be the range which combined each value described as a preferable value as an upper limit and a lower limit.

Granule formulations of the present invention include a gelling agent.

In the present invention, the gelling agent means a preparation additive which is a base material which is gelled by containing water.

Although it does not specifically limit as a gelling agent, For example, hypromellose, methylcellulose, hydroxypropyl cellulose, carboxyvinyl polymer, sodium alginate, carrageenan, xanthan gum, tamarind gum, pectin, locust bean gum, gellan gum, agar And polyethylene oxides.

From the viewpoint of gelling ability and gelling rate, carboxyvinyl polymer and polyethylene oxide are preferable, and polyethylene oxide is more preferable. A gelling agent may be used by 1 type, and may be used as 2 or more types of mixtures.

The average molecular weight of the gelling agent is appropriately set according to the type of gelling agent from the viewpoint of the index such as gelling ability and gelling rate.

The gelling ability can be confirmed, for example, by observing the appearance when the gelling agent is dissolved in water at high or low concentration.

In addition, a gelation rate can be confirmed by adding a gelling agent to water, stirring after dissolution, and observing the gelation condition over time.

As a measurement density | concentration of a gelation ability, high density | concentration (10w / v%) and low density | concentration (1w / v%) are 10w / v% etc. as a measurement density | concentration of a gelation rate, for example.

In polyethylene oxide, as a lower limit of the average molecular weight, it is preferable to have an average molecular weight of 150,000 or more, It is more preferable to have an average molecular weight of 500,000 or more, It is further more preferable to have an average molecular weight of 1 million or more, 2 million It is still more preferable to have the above average molecular weight.

Although it does not specifically limit as an upper limit of the average molecular weight of polyethylene oxide, It is preferable that it is 10 million or less, and, as for the average molecular weight of polyethylene oxide, it is more preferable that it is 5 million or less.

The average molecular weight of polyethylene oxide should just be a range which combined each value described as a preferable value as an upper limit and a lower limit.

Although the value displayed on a product may be sufficient as the average molecular weight of a gelling agent in this invention, it can measure as a viscosity average molecular weight by measuring the viscosity of the solution of a gelling agent.

It is preferable that the gelling agent contained in the granule preparation of this invention exists in powder addition.

Powder addition of the gelling agent is performed on the small granules containing isoleucine, leucine and valine. With respect to the small granules, the gelling agent is added to the granules by the powder addition, and the gelling agent is present on the surface of the granules in the state where the gelling agent is added.

In the granule formulation of the present invention, when the gelling agent is powdered, since the gelling agent is present in the powdered state, the granulation formulation of the present invention is so-called coated granules (coated granules), and the gelling agent is coated on the granule surface. It is different from the granule formulation.

In the coated granules, the microgranules including isoleucine, leucine and valine are coated by the coating liquid. In this case, the gelling agent is included in the coating liquid.

In the granule formulation, it is not particularly limited that the gelling agent is added by powder, but it can be confirmed by evaluating the gelling ability of the powder obtained by, for example, separating by sieve classification or the like. It is also possible to confirm that the gelling agent is added by powder by spectral image observation or the like.

Although content of a gelling agent is set suitably according to the kind of gelling agent, it is preferable that it is 0.01 to 5% as mass% with respect to the granule formulation whole quantity from a viewpoint of a gelling ability and a gelation rate, and it is more preferable that it is 0.05 to 2%. It is preferable and it is more preferable that it is 0.05 to 1%. The content of the gelling agent may be 0.1% or more within the above range.

The granule formulation of the present invention can be prepared by adding a gelling agent to granules containing isoleucine, leucine and valine, prepared by a conventionally known method.

In the present invention, isoleucine, leucine and valine may be mixed and pulverized with solid raw material amino acids that are isoleucine, leucine and valine by the method described in Japanese Patent No. 3328288.

Mixed pulverization may use both the method of preliminarily mixing isoleucine, leucine, and valine, or the method of grinding while mixing isoleucine, leucine and valine.

Although it does not specifically limit in mixing of a solid raw material amino acid, For example, stirring stirring by rotation of the container rotation type mixers, such as a container type mixer, and fluidized-bed mixer, stirring blade, and stirring ribbon, and powder transportation A feeder type mixer which is provided in a raw material supply port such as a line mixer or a pulverizer that is mixed in a line can be used.

The pulverization of the solid raw material amino acid is not particularly limited, but, for example, impact type (high-speed rotary) pulverizers such as hammer mills and pin mills, tumbler type (medium) pulverizers such as ball mills or fluids such as jet mills ( Air type grinder can be used.

In the production of granules containing the isoleucine, leucine and valine of the present invention, it is not particularly limited, but for example, a high speed stirring granulator, a fluidized bed granulator, a planetary mixer, a dry pelletizer granulator, Crushing granulators, extrusion granulators, electric granulators, spray dried granulators or coated granulators can be used.

It is preferable to produce granules using a high speed stirring granulator or an extrusion granulator.

Although it does not specifically limit as an extrusion granulator, For example, a pre extrusion granulator, a disk pellet granulator, a ring die granulator, a basket granulator, an oscillating granulator, a cylindrical granulator, etc. are mentioned.

In the case of producing granules, known additives that can be used as medicaments satisfying standards such as the Japanese Pharmacopoeia or the pharmaceutical additive standard can be blended. Although it does not specifically limit as an additive, For example, additives known as a binder, a lubricating agent, a coloring agent, a plasticizer, surfactant, a sweetener, a copper, a flavourant, a fragrance | flavor, etc. are mentioned, Especially, a binder and / or a mating agent are preferable.

An additive may be used by 1 type and may be used as 2 or more types of mixtures.

Although it does not specifically limit as a binder, For example, cellulose derivatives, such as methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, starches, such as corn starch and wheat starch, polyvinylpyrrolidone Synthetic polymers such as (povidone), polyvinyl alcohol and acrylic acid polymers, and natural polymers such as gum arabic and gelatin.

Although it does not specifically limit as a mating agent, For example, citric acid, tartaric acid, aspartame, saccharin, saccharin sodium, erythritol, xylitol, mannitol, stevia, etc. are mentioned. The mating agent also includes an additive known as a sweetener.

Although it does not specifically limit as a malodorant and a fragrance | flavor, For example, menthol, lemon flavor, sugarless, sweet flavor, strawberry oil, etc. are mentioned.

In the present invention, for the granules preferably containing isoleucine, leucine and valine, the mating agent and / or the caustic agent are adhered to the surface of the granules by the method described in Japanese Patent No. 3405342.

The particle size of the granule to which the mating agent and / or the corpuscle is adhered is not particularly limited as long as it can easily maintain a fluid state in a normal fluidized bed value, but is generally 100 to 2000 µm, preferably 200 to 1700. About μm.

Although it does not specifically limit as a fluidizing apparatus for attaching a mating agent and / or an aviding agent to granules, For example, the fluidized-bed granulation of the fluid drying apparatus "flow drier" made by Freundt Sankyo Co., Ltd., and the Freundt Sankyo Co., Ltd. make Coating apparatus "flow coater", "Gratt GPCG" by Faurex, "Marumeiser" by Dalton, "Multiprocessor" by Kikusui Seisakusho, etc. are mentioned.

In the present invention, a gelling agent is mixed with granules containing isoleucine, leucine and valine, preferably granules with a mating agent and / or a coring agent attached thereto.

In the present invention, it is preferable to add a gelling agent to the granules containing isoleucine, leucine and valine, preferably to the granules to which the mating agent and / or the corpuscle is attached, and to mix them.

The mixing method is not particularly limited as long as it is a method capable of mixing substantially uniformly. For example, a general container rotary mixer (eg, V-type, double cone, rotary swing type, etc.), container fixed mixer (eg, ribbon) Die, conical screw type, or the like, or a method using a mixer such as an air-flow stirring mixer.

You may use the method of adding the prescribed amount of each preparation to the predetermined container by a distributor, etc., and mixing.

By adding the gelling agent to the granules containing isoleucine, leucine and valine, the granulation formulation in which the gelling agent is present in the powder added state is mixed.

Although the granule preparation of this invention contains granules which added the gelling agent, these granules are granules prescribed | regulated by the Japanese Pharmacopoeia (refer page 11 if Japanese Pharmacopoeia 17 revision).

In the present invention, the particle size of the granule formulation is generally 100 to 2000 µm, and preferably about 200 to 1700 µm.

In this invention, particle size means the average particle diameter of particle | grains, but can measure it by the general test method 3.04 "particle size measurement method" 2nd method "sieve classification method" of the JP 17th revision (pages 95-97). In addition, you may measure by the general test method 6.03 "particle size test method of preparation" of the Japanese Pharmacopoeia 17 revision (page 135).

The granule formulation of the present invention may be a granule formulation obtained by the method for producing a granule formulation of the present invention.

In the granule preparation of the present invention, the feeling of taking such as bitterness derived from the amino acid and the residue in the mouth of the granule is improved.

In the present invention, a method for improving the feeling of taking a granule preparation containing isoleucine, leucine and valine as active ingredients by adding a gelling agent in powder is provided. Examples of the improvement in the feeling of taking include improvement in bitterness derived from amino acids, improvement in mouth residue of granule preparations, and the like.

Example

EMBODIMENT OF THE INVENTION Hereinafter, although this invention is demonstrated concretely based on an Example, this invention is not limited to this at all. Those skilled in the art can change the present invention in various aspects without departing from the meaning of the present invention, and such changes are included in the scope of the present invention.

Example 1

Based on the prescription shown in Table 1, granule formulations were prepared.

To a mixture of L-isoleucine, L-leucine and L-valine, an aqueous solution of povidone (collidone, 90F), polyvinylalcohol (partially saponified), tartaric acid and sodium saccharin hydrate was added and granulated by stirring granulator Small granules were obtained by sizing, drying and drying.

The granules were prepared by powder-adding polyethylene oxide (average molecular weight: 5 million) after the fragrance was granulated for the small granules.

Comparative Example 1

Based on the prescription shown in Table 1, granule formulations were prepared.

In the same manner as in Example 1, small granules were obtained.

The granules were prepared by coating the small granules with an aqueous solution of povidone (collidone, 90F) and then scenting the fragrances.

Using the granule preparation prepared in Example 1 and Comparative Example 1, sensory evaluation was performed by making it easy to swallow, difficulty of leaving granules, and weakness of bitter taste. (n = 9)

For ease of swallowing, both granule formulations at the time of taking were compared and the one which is easy to swallow was selected.

For the difficulty of leaving the granules, the granules at the time of taking were compared, and the one which was hard to remain in the mouth was selected.

About the weakness of bitterness, the granule preparation of both was compared and the one with the weaker bitterness was selected. The results are shown in Table 2.

It was found that the granule formulation of Example 1 was a granule formulation having an excellent feeling of taking from the granule formulation of Comparative Example 1, which is a prescription of the compounded granules, in terms of ease of swallowing, difficulty in leaving granules, and bitter taste.

Using the granule preparation prepared in Example 1 and Comparative Example 1, the dissolution property was evaluated by the dissolution test by the paddle method using the dissolution test second liquid in the JP 17th Amendment (p. 141 to 145 General) Test Method 6.10 Dissolution Test Method).

The results are shown in FIGS. 1 and 2.

The granule formulation of Example 1 was confirmed to have a low dissolution property in the initial stage (5 minutes value) with respect to the granule formulation of Comparative Example 1, but after 15 minutes, both formulations showed an almost 100% dissolution ability. It became. It was thought that the granule formulation of Example 1 also exhibited the same effect as the compound compound granules.

Examples 2-4

A granule formulation was prepared in the same manner as in Example 1 except that the content of polyethylene oxide (average molecular weight: 5 million) was 0.1%, 1%, or 2% based on the total amount of the granule formulation.

Examples 5-7

A granule formulation was prepared in the same manner as in Example 1 except that polyethylene oxide having an average molecular weight of 500,000, 1 million, or 2 million was used.

Using the granule preparation prepared in Examples 1-7, the sensory evaluation was performed using foreign matter, bitterness, and swallowability as an index. (n = 10)

For each index, scores were given as not feeling: 1 point, not feeling very much: 2 points, and managing feeling: 3 points, feeling: 4 points, and the average value was obtained. The results are shown in Table 3.

Since the granule preparation of this invention is considered to have the improved dose property with respect to the compound of the present compound, it has industrial applicability as a pharmaceutical granule preparation.

Claims (10)

A granule formulation comprising isoleucine, leucine and valine as active ingredients, the granule formulation comprising a gelling agent. The granule formulation of claim 1, wherein the gelling agent is a carboxyvinyl polymer or polyethylene oxide. The granule formulation according to claim 1 or 2, wherein the gelling agent is polyethylene oxide having an average molecular weight of 500,000 or more. The granule formulation according to any one of claims 1 to 3, wherein the gelling agent is powdered. The granule formulation according to any one of claims 1 to 4, which contains 0.05 to 2% of a gelling agent based on the total amount of the granule formulation. The granule formulation according to any one of claims 1 to 5, comprising a weight ratio of isoleucine / leucine / valine = 1 / 1.9 to 2.2 / 1.1 to 1.3. The granule formulation according to any one of claims 1 to 6, which contains 80% or more of isoleucine, leucine and valine, based on the total amount of the granule formulation. 8. Granule formulation according to any one of the preceding claims, further comprising a binder and / or a mating agent. As a method for producing a granule formulation containing isoleucine, leucine and valine as active ingredients,
A manufacturing method of adding a gelling agent to granules containing isoleucine, leucine and valine. The production method according to claim 9, wherein the gelling agent is added in powder.

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