JP2023183350A - Lacosamide solid preparation - Google Patents

Abstract

To provide a lacosamide solid preparation that has suppressed bitterness and also has photostability.SOLUTION: A lacosamide solid preparation contains lacosamide and an amino alkyl methacrylate copolymer. Preferably, the lacosamide solid preparation should be in a form of a granule where a core particle containing the lacosamide is provided with a coating layer containing the amino alkyl methacrylate copolymer, or a tablet containing the same. Also preferably, the granule has an overcoat layer at an outside the coating layer.SELECTED DRAWING: None

Description

The present invention relates to lacosamide solid formulations.

Lacosamide, i.e. (2R)-2-acetamido-N-benzyl-3-methoxypropanamide, is an antiepileptic drug, and tablets, dry syrups, and injections containing it are sold under the name Vimpad (registered trademark). has been done.

Lacosamide is known to have a bitter taste. When formulating an active ingredient that has a bitter taste, it is required to mask the bitter taste from the viewpoint of patient medication adherence. As a method for masking the unpleasant taste of active ingredients, there is a method of coating granules or tablets containing the active ingredients with a water-insoluble polymer. A method of coating ethylcellulose, an insoluble polymer, is disclosed.

Japanese Patent Application Publication No. 2021-138775

However, in producing a solid preparation having lacosamide as an active ingredient, the present inventors have discovered that when core particles containing lacosamide are coated with ethylcellulose, a new problem arises in that photostability is reduced.
The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a solid preparation of lacosamide that has suppressed bitterness and has photostability.

The present inventors have found that photostability is improved by using an aminoalkyl methacrylate copolymer instead of ethyl cellulose, and have completed the present invention.

The present invention has the following aspects.
[1] A lacosamide solid preparation containing lacosamide and an aminoalkyl methacrylate copolymer.
[2] The lacosamide solid preparation according to [1], which is a granule in which a coating layer containing the aminoalkyl methacrylate copolymer is provided on the core particle containing the lacosamide.
[3] The lacosamide solid preparation according to [1], which is a tablet comprising granules in which the core particles containing the lacosamide are provided with a coating layer containing the aminoalkyl methacrylate copolymer.
[4] The lacosamide solid preparation according to [2] or [3], wherein the granules have an overcoat layer on the outside of the coating layer.

According to the present invention, it is possible to provide a lacosamide solid preparation with suppressed bitterness and photostability.

The present invention will be explained in detail below.
The lacosamide solid preparation (hereinafter sometimes simply referred to as solid preparation) of the present invention contains lacosamide and an aminoalkyl methacrylate copolymer.

Lacosamide is not particularly limited, and any commercially available lacosamide can be used, and may be in crystalline or amorphous form.
As the aminoalkyl methacrylate copolymer, aminoalkyl methacrylate copolymer E type, which is commercially available for pharmaceutical use, can be used. Aminoalkyl methacrylate copolymers E type include the commercially available Eudragit® E100, Eudragit® EPO, and Collicoat®, which are copolymers of methyl methacrylate, butyl methacrylate, and dimethylaminoethyl methacrylate. Smart Seal 30D, Collicoat (registered trademark) Smart Seal 100P, etc. can be used.

In addition to lacosamide and the aminoalkyl methacrylate copolymer, the solid preparation of the present invention contains any additives that can be used in the pharmaceutical field, such as excipients, binders, disintegrants, surfactants, colorants, sweeteners, and flavoring agents. may also be included if necessary.

Examples of excipients include D-mannitol, crystalline cellulose, lactose hydrate, anhydrous lactose, refined white sugar, potato starch, pregelatinized starch, and one or more of these may be used as necessary. However, it is preferable to use D-mannitol in terms of taste and ease of granulation.

Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, stearyl alcohol, ammoniomethacrylate copolymer, polyvinyl acetal diethylaminoacetate, dextrin, starch syrup, and the like. Although the above can be used, it is preferable to use hydroxypropylcellulose because the stability of the lacosamide solid preparation is excellent and the production of related substances can be suppressed.

Examples of disintegrants include croscarmellose sodium, carmellose calcium, carmellose, low-substituted hydroxypropyl cellulose, crospovidone, corn starch, sodium starch glycolate, partially pregelatinized starch, hydroxypropyl starch, etc. One or more types can be used.

Examples of the surfactant include sodium lauryl sulfate and polysorbate 80, and one or more of these can be used.
Examples of the coloring agent include yellow iron sesquioxide, iron sesquioxide, food yellow No. 4, food yellow No. 5, food red No. 2, food red No. 3, food red No. 102, and one of these. You can use the above.

Examples of sweeteners include acesulfame potassium, aspartame, sucralose, thaumatin, sucrose, saccharin or a salt thereof, glycyrrhizic acid or a salt thereof, stevia or a salt thereof, and one or more of these may be used.
Fragrances include orange essence, orange oil, caramel, camphor, cinnamon oil, spearmint oil, strawberry essence, chocolate essence, cherry flavor, spruce oil, pine oil, peppermint oil, vanilla flavor, bitter essence, fruit flavor, peppermint essence, Examples include mixed flavor, mint flavor, l-menthol, lemon powder, lemon oil, rose oil, etc., and one or more of these can be used.

Other additives include lubricants (stearate metal salts such as magnesium stearate and calcium stearate, fatty acid esters such as glycerin fatty acid ester and sucrose fatty acid ester, sodium stearyl fumarate, talc, etc.), and for film coating. Examples include base materials (hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc.), light silicic anhydride, titanium oxide, carnauba wax, etc., and one or more of these can be used.

The form of the solid preparation of the present invention is not particularly limited, and examples include granular preparations (granules, dry syrup, fine granules, etc.), tablets (immediate release tablets, orally disintegrating tablets, etc.), and the like.

<Granular preparation>
When the solid preparation of the present invention is a granular preparation, it is preferably a granule in which a coating layer containing an aminoalkyl methacrylate copolymer is provided on a core particle containing lacosamide. An overcoat layer may be provided on the outside of the coating layer depending on the purpose. By providing an overcoat layer, a specific function can be imparted, such as preventing granules from sticking to each other.
Examples of the form of core particles include granules containing lacosamide and additives, layered particles in which a drug substance layer containing lacosamide is formed on the surface of additive particles, and even particulates containing lacosamide. Bye.

The content of lacosamide in the solid preparation of the present invention can be set as appropriate, but when the solid preparation is a granular preparation, it may be set to, for example, 1 to 30% by mass when the granular preparation is 100% by mass. The amount is preferably 2 to 20% by weight, more preferably 5 to 15% by weight.
Further, when the core particle is 100% by mass, the content of lacosamide in the core particle can be, for example, 5 to 35% by mass, preferably 8 to 25% by mass, and 10 to 20% by mass.

In addition to lacosamide, the core particles may optionally contain additives such as those exemplified above, and may contain at least an excipient such as D-mannitol and a binder such as hydroxypropyl cellulose. preferable.
When the granular preparation is 100% by mass, the content of excipients can be, for example, 40 to 70% by mass, preferably 45 to 65% by mass, and more preferably 50 to 60% by mass.
When the core particle is 100% by mass, the content of the excipient in the core particle can be, for example, 60 to 90% by mass, preferably 70 to 90% by mass, more preferably 75 to 85% by mass. be.
When the granular preparation is 100% by mass, the content of the binder can be, for example, 1 to 15% by mass, preferably 2 to 10% by mass, and more preferably 3 to 8% by mass.
When the core particle is 100% by mass, the content of the binder in the core particle can be, for example, 3 to 20% by mass, preferably 4 to 15% by mass, more preferably 5 to 10% by mass. .

The content of the aminoalkyl methacrylate copolymer in the solid preparation of the present invention can be set as appropriate, but when the solid preparation is a granular preparation, the content of the aminoalkyl methacrylate copolymer can be set, for example, from 1 to 30% by mass when the granular preparation is 100% by mass. It is preferably 2 to 20% by weight, more preferably 5 to 15% by weight.
Further, when the coating layer is 100% by mass, the content of the aminoalkyl methacrylate copolymer in the coating layer is preferably at least 80% by mass, more preferably 90% by mass or more, and even more preferably 100% by mass. .
In addition to the aminoalkyl methacrylate copolymer, the coating layer may optionally contain additives such as those exemplified above and water-insoluble polymers other than the aminoalkyl methacrylate copolymer.

When providing an overcoat layer on the outside of the coating layer, the components constituting the overcoat layer can be selected depending on the purpose. For example, when the purpose is to prevent granules from sticking to each other, D-mannitol, sorbitol, xylitol, It is preferable to provide an overcoat layer made of sugar alcohol such as maltitol. In addition, sweeteners may be used in the overcoat layer for the purpose of enhancing the feeling of taking the drug, and titanium oxide, coloring agents, etc. may be used for the purpose of imparting photostability. The overcoat layer may contain a water-soluble polymer such as hydroxypropyl methylcellulose or hypromellose as a base material for forming the layer.

The mass ratio of the core particles to the coating layer is, for example, 1 to 50 parts by mass, preferably 5 to 30 parts by mass, and more preferably 10 to 20 parts by mass, based on 100 parts by mass of the core particles.
When providing an overcoat layer, the mass proportion of the overcoat layer can be appropriately set depending on the purpose, but it is, for example, 2 to 100 parts by mass, preferably 10 to 60 parts by mass, when the core particles are 100 parts by mass. parts, more preferably 20 to 40 parts by weight.

As mentioned above, the granular preparation can contain additives as appropriate, but preferably contains a sweetener in at least one of the core particles, the coating layer, and the overcoat layer.

When the solid preparation is a granular preparation, it can be manufactured by the following method.
First, lacosamide and additives such as excipients are mixed to make a granulation composition, and a solution of a binder dissolved in a solvent such as water is added to the granulation composition, followed by fluidized bed granulation, stirring granulation, etc. It is granulated by a known method such as granulation. Next, a solution prepared by dissolving an aminoalkyl methacrylate copolymer in a solvent such as ethanol is sprayed onto the obtained granules (core particles) and dried to form a coating layer on the outside of the granules. Then, if necessary, a solution prepared by dissolving D-mannitol or the like in water is sprayed and dried to form an overcoat layer.
In addition, particles made of excipients such as D-mannitol and lactose hydrate are prepared, and a liquid containing lacosamide is sprayed onto the surface of the particles to form a drug substance layer, and the resulting layering particles are used as core particles. May be used.
The solid preparation of the present invention, which is a granular preparation, can be produced by the method described above.
Note that one or more layers may be further formed outside the overcoat layer depending on the purpose.

<Tablets>
When the solid preparation of the present invention is a tablet (immediate release tablet, orally disintegrating tablet, etc.), it is a tablet containing granules in which a coating layer containing an aminoalkyl methacrylate copolymer is provided on a core particle containing lacosamide. It is preferable that there be. In this case as well, an overcoat layer depending on the purpose may be provided on the outside of the coating layer, and one or more layers depending on the purpose may be further formed on the outside of the overcoat layer.
Such tablets can be manufactured by adding additives to granules as needed and then tableting.
Another preferred form of the tablet is a form in which a plain tablet containing lacosamide and optionally additives is obtained, and a film coating layer containing an aminoalkyl methacrylate copolymer is formed on the outside of the plain tablet.
The form of the tablet can be determined as appropriate depending on whether the tablet is an immediate release tablet or an orally disintegrating tablet.

As explained above, since the solid preparation of the present invention contains lacosamide and an aminoalkyl methacrylate copolymer, bitterness is suppressed and it also has photostability.

The present invention will be specifically explained below using examples.
[Example 1, Example 2]
A dry syrup, which is a granular preparation, was produced according to the formulation shown in Table 1 below.
Specifically, first, among the components listed in the granulated product column of Table 1, components other than hydroxypropylcellulose are mixed to prepare a granulation composition, and a solution in which hydroxypropylcellulose is dissolved in water is prepared. was sprayed onto the granulation composition and subjected to fluidized bed granulation to obtain granules (core particles). Next, a solution prepared by dissolving the components listed in the coating layer column of Table 1 in ethanol was sprayed onto the obtained granules and dried to form a coating layer. An overcoat layer was formed by spraying and drying a solution in which the components listed in the column were dissolved in water.
Thereafter, the mixture was sized by passing through an 18 mesh screen to obtain dry syrup formulations of Examples 1 and 2 containing each component in the proportions shown in Table 1.
A purity test (evaluation of photostability) was conducted on each of the obtained dry syrups by the following method.
The results are shown in Table 2.

<Purity test (light stability evaluation)>
In an open system, each dry syrup agent was continuously irradiated with 3000 lx of light, and the total amount of related substances after 400 hours (total irradiation amount: 1.2 million lx/hr) from the start of irradiation and the total amount of related substances before irradiation were measured. A purity test was conducted by: Specifically, 500 mg of dry syrup is dissolved in 10 mL of a 9:1 mixture of water and methanol, the resulting solution is centrifuged at 3000 rpm for 5 minutes, the supernatant is collected and used as a sample solution, and this is subjected to high-performance liquid chromatography. The analysis was carried out using an automatic analysis method using graphography.
The numerical value of the total amount of related substances listed in Table 2 is the ratio of the sum of peak areas due to a plurality of observed related substances to the peak area derived from lacosamide, expressed as a percentage.

As shown in Table 2, the dry syrup of Example 1 using aminoalkyl methacrylate copolymer E in the coating layer suppressed the increase in the total amount of related substances due to light irradiation compared to the dry syrup of Example 2 using ethyl cellulose. It had excellent photostability.
In addition, no sticking was observed in the dry syrups of Examples 1 and 2 even after they were stored in an open system at 50°C and 60°C for one week.

Claims (4)

A lacosamide solid preparation comprising lacosamide and an aminoalkyl methacrylate copolymer. The lacosamide solid preparation according to claim 1, which is a granule in which a coating layer containing the aminoalkyl methacrylate copolymer is provided on the core particle containing the lacosamide. The lacosamide solid preparation according to claim 1, which is a tablet comprising granules in which the core particles containing the lacosamide are provided with a coating layer containing the aminoalkyl methacrylate copolymer. The lacosamide solid preparation according to claim 2 or 3, wherein the granules have an overcoat layer on the outside of the coating layer.