JP2021134168A - Solid preparation and method for producing the same - Google Patents

Abstract

To provide a solid preparation having sufficient hardness without impairing collapsibility, and a method for producing the same.SOLUTION: A solid preparation contains levetiracetam with a particle size of 50 μm or more, and a water-soluble additive. A solution of the water-soluble additive is added to the levetiracetam.SELECTED DRAWING: None

Description

The present invention relates to a solid preparation containing levetiracetam and a method for producing the same.

Levetiracetam is a compound having the chemical name (2S) -2- (2-oxopyrrolidine-1-yl) butyramide represented by the following formula (1). Levetiracetam is currently used in combination with antiepileptic drugs for partial epilepsy in patients with epilepsy (including secondary generalized seizures) and tonic seizures in patients with epilepsy who are not sufficiently effective with other antiepileptic drugs. It is used in.

Patent Document 1 discloses a levetiracetam-containing pharmaceutical composition using a levetiracetam drug substance having an average particle size of 50 μm or less in order to improve strength and disintegration property. Further, Patent Document 1 discloses that the average particle size of levetiracetam is preferably 5 μm or more in terms of excellent handling during production.

Japanese Unexamined Patent Publication No. 2017-206454

However, as disclosed in Patent Document 1, it has been difficult to control the degree of pulverization of the API to prepare the desired particle size. In general, a drug substance having an average particle size of 50 μm or less tends to have adhesiveness and scattering property to manufacturing equipment due to static electricity, and the fluidity required in the process of preparing a pharmaceutical product tends to be inferior. As disclosed in Patent Document 1, in order to secure the hardness by reducing the average particle size of the drug substance to 50 μm or less, it is necessary to consider the fluidity of the drug substance and the like. In particular, since the amount of drug substance in one levetiracetam tablet is large and there is little room for adding an additive, it has been difficult to ensure fluidity and hardness by adding an additive.

Therefore, an object of the present invention is to provide a solid preparation containing levetiracetam, which has improved hardness without impairing disintegration, and a method for producing the same. Another object of the present invention is to provide a solid preparation having good fluidity and less adhesiveness and scattering of a drug substance in the manufacturing process, and a method for producing the same.

As a result of diligent studies to solve the above problems, the present inventor has found that by adding a solution of a water-soluble additive to levetiracetam, a solid preparation having excellent hardness can be obtained without impairing disintegration property. rice field. In addition, the present inventor has found that by adding a solution of a water-soluble additive to levetiracetam, a solid preparation having good fluidity and less adhesion and scattering of the drug substance in the manufacturing process can be obtained. ..

That is, the present invention relates to the following.
(1) A solid preparation containing levetiracetam having a particle size of 50 μm or more and a water-soluble additive, which is obtained by adding a solution of the water-soluble additive to levetiracetam.
(2) The water-soluble additive is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinylpyrrolidone, sodium carboxymethyl cellulose, cyclodextrin, lactose, mannitol, erythritol, sorbitol, xylitol, martitol and isomalt. The solid preparation according to (1), which is one type or two or more types.
(3) The solid preparation according to (1) or (2), wherein the water-soluble additive is one or more selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and polyvinylpyrrolidone.
(4) The solid preparation according to any one of (1) to (3), which is a tablet.
(5) The solid preparation according to any one of (1) to (4), which further has a film coating.
(6) A method for producing a solid preparation containing levetiracetam having a particle size of 50 μm or more and a water-soluble additive, which comprises adding a solution of the water-soluble additive to levetiracetam. Method.
(7) The water-soluble additive is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinylpyrrolidone, sodium carboxymethyl cellulose, cyclodextrin, lactose, mannitol, erythritol, sorbitol, xylitol, martitol and isomalt. The method for producing a solid preparation according to (6), which is one type or two or more types.
(8) Production of the solid preparation according to (6) or (7), wherein the water-soluble additive is one or more selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and polyvinylpyrrolidone. Method.
(9) The method for producing a solid preparation according to any one of (6) to (8), wherein the solid preparation is a tablet.
(10) The method for producing a solid preparation according to any one of (6) to (9), which is coated with a film coating.

In the solid preparation of the present invention and the method for producing the same, by adding a solution of a water-soluble additive to levetiracetam, the surface of levetiracetam can be modified to enhance the binding force. As a result, the solid preparation containing levetiracetam has sufficient hardness without impairing the disintegration property.

The solid preparation of the present invention is prepared by adding a solution of a water-soluble additive to levetiracetam having a particle size of 50 μm or more.

The solid preparation used in the present invention is not particularly limited as long as it is a solid preparation. For example, tablets, capsules, granules, powders, etc. in the general formulation rules described in the Japanese Pharmacopoeia can be mentioned, but tablets are preferable.

In the present invention, as levetiracetam, a compound represented by the above formula (1), an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or the like can be used. Further, as levetiracetam, a crystalline type, an amorphous type or a mixture thereof can be used.
As such levetiracetam, one produced by a known method may be used, or a commercially available product may be used.

The particle size (D50) of levetiracetam is not particularly limited as long as it is 50 μm or more, but is preferably more than 50 μm and 500 μm or less, more preferably 70 to 400 μm, and particularly preferably 80 to 300 μm.

By keeping the particle size (D50) within the above range, a solid preparation having excellent hardness can be produced.
Further, if the particle size (D50) of levetiracetam is less than 50 μm, the particles become bulky, the adhesiveness is increased, the fluidity is inferior, and the handling at the time of manufacturing may be inferior. On the other hand, if it exceeds 500 μm, the hardness of the produced solid preparation may be inferior.

Here, the particle size (D50) means a volume average particle size as measured by, for example, a laser diffraction / scattering type particle size distribution measuring device. In principle, it means the particle size at the time when particles having a certain volume are sieved in order from the smallest one and the particles corresponding to 50% of the volume are separated. The particle size can be measured by using a known method or measuring device, and can be easily measured by, for example, a laser light scattering method particle size distribution measurement or a dynamic light scattering method particle size distribution measurement.

Examples of the method for preparing the particle size (D50) of levetiracetam include a method using a jet mill, a pin mill, a feather mill, a ball mill, a hammer mill, a mortar and the like.

The content of levetiracetam in the solid preparation is not particularly limited, but levetiracetam is preferably 70 to 98% by mass, more preferably 80 to 97% by mass, and particularly preferably 90 to 96% by mass with respect to the total mass of the solid preparation. Can be included in the range.

The water-soluble additive used in the present invention is an additive having a solubility in water at 25 ° C. of 20% or more. The water-soluble additive is not particularly limited, and examples thereof include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinylpyrrolidone, sodium carboxymethyl cellulose, cyclodextrin, lactose, mannitol, erythritol, sorbitol, xylitol, maltitol, and isomalt. .. These may be used alone or in combination of two or more. Of these, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and polyvinylpyrrolidone are preferable from the viewpoint of imparting stability of the preparation and desired hardness.

The type of solvent used in the solution for dissolving the water-soluble additive is not particularly limited as long as it is a liquid that facilitates the dissolution of the water-soluble additive, and is, for example, water, methanol, ethanol, isopropanol, acetone, or any of these. Two or more types can be used in combination. Water is preferable from the viewpoint of ease of operation and the like.

The amount of the water-soluble additive added is not particularly limited, but is preferably 0.1 to 20% by mass, more preferably 0.3 to 10% by mass, and particularly preferably 0.7, based on the total mass of the solid preparation. It can be in the range of ~ 3% by mass. Within this range, the solid preparation can be given a desired hardness without impairing the disintegration property.

The solid preparation of the present invention may contain various additives usually used in the field of preparation, and the amount of the addition can be appropriately selected in an amount usually used in the production of the preparation. Such additives include, for example, excipients, binders, disintegrants, lubricants, flavoring agents, foaming agents, sweeteners, flavors, colorants, fluidizers, dispersants, stabilizers and solubilizers. Agents and the like can be mentioned. These additives may be used in combination of one or more.

Examples of the disintegrant include crospovidone, carboxymethyl cellulose, hydroxypropyl starch, starches, crystalline cellulose, carmellose calcium, croscarmellose sodium, polyvinylpolypyrrolidone and the like. These may be used individually by 1 type, or may be used in combination of 2 or more type.
Of these, croscarmellose sodium is preferable because its hardness and disintegration can be ensured with an appropriate striking pressure.

The content of the disintegrant can be preferably in the range of 1 to 30% by mass, more preferably 2 to 10% by mass, and particularly preferably 3 to 5% by mass with respect to the total mass of the solid preparation.

Examples of excipients include starches, crystalline cellulose, corn starch, sodium starch glycolate, lactose, sucrose, gelatin, sugars, sugar alcohols, dextrin, precipitated calcium carbonate, calcium silicate, sodium chloride, calcium hydrogen phosphate and the like. Be done. These may be used individually by 1 type, or may be used in combination of 2 or more type.

Examples of the binder include polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium starch glycolate, hydroxyethyl cellulose, gelatin, purulan, methyl cellulose, sodium carboxymethyl cellulose, gum arabic, starches, corn starch, alginate, and the like. Examples thereof include polyethylene glycol, crystalline cellulose, sucrose, mannitol, sorbitol and the like. These may be used individually by 1 type, or may be used in combination of 2 or more type.

The content of the binder is preferably in the range of 0.01 to 15% by mass, more preferably 0.1 to 10% by mass, and particularly preferably 1 to 8% by mass with respect to the total mass of the solid preparation. Can be done.

Examples of the fluidizing agent include synthetic aluminum silicate, light anhydrous silicic acid, hydrous silicon dioxide, magnesium hydroxide alumina and the like. These may be used individually by 1 type, or may be used in combination of 2 or more type.
Of these, light silicic anhydride is preferable because it prevents particles from adhering to each other and improves fluidity.

The content of the fluidizing agent is preferably in the range of 0.01 to 10% by mass, more preferably 0.05 to 7% by mass, and particularly preferably 0.1 to 5% by mass with respect to the total mass of the solid preparation. Can be included in.

Examples of the lubricant include glycerin monostearate, stearyl sodium fumarate, sucrose fatty acid ester, carnauba wax, L-leucine, talc, magnesium stearate, calcium stearate and the like. These may be used individually by 1 type, or may be used in combination of 2 or more type.
Of these, magnesium stearate is preferable because it can ensure hardness and disintegration with an appropriate striking pressure.

The content of the lubricant is preferably 0.01 to 5.0% by mass, more preferably 0.05 to 3.0% by mass, and particularly preferably 0.1 to 1% by mass, based on the total mass of the solid preparation. It can be contained in the range of 1.5% by mass.

Examples of the stabilizer include sodium edetate, tocopherol, nicotinic acid amide, cyclodextrin and the like.

The solid preparation of the present invention can be used as it is (or uncoated tablets in the case of tablets) after being formed into an appropriate shape, but it can reduce the influence of external light, air (humidity, oxygen), etc., and has a taste, bitterness, etc. If necessary, a film coating using a commonly used coating agent can be applied in order to seal off odors and enhance the beauty of the appearance.

Examples of the coating agent include hydroxypropylmethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, ethyl acrylate / methyl methacrylate copolymer, aminoalkyl methacrylate copolymer, carboxyvinyl polymer, purulan, polyvinylpyrrolidone, stearyl alcohol, cetanol, cellac, triacetin, and macro. Gol, polysorbate, polyvinyl alcohol, talc, titanium oxide, iron oxide, carnauba wax, pigments and the like can be mentioned. These may be used individually by 1 type, or may be used in combination of 2 or more type.

In the method for producing a solid preparation of the present invention, a solution of a water-soluble additive is added to levetiracetam to obtain levetiracetam-containing particles.

The method of adding the solution of the water-soluble additive is not particularly limited, and examples thereof include a method of dropping, spraying, spray coating, preferably further granulating and drying the solution on levetiracetam.

Examples of the granulation include extrusion granulation, rolling granulation, stirring granulation, fluidized bed granulation, spray granulation, spray drying and the like.
The granulation conditions can be appropriately selected according to the purpose.

The method for producing a solid preparation of the present invention may further include pulverization, sizing, mixing, tableting, coating and other steps, if necessary.

In the pulverization step, the obtained levetiracetam-containing particles can be pulverized with a pulverizer to obtain a pulverized powder having a desired particle size.

In the sizing step, the obtained particles or crushed powder can be sized with a sizing machine to obtain sizing powder.

In the mixing step, the obtained particles, crushed powder or sized powder and additives such as excipients, binders and fluidizing agents are weighed, respectively, and a known mixing device such as a V-type mixer is used. Can be mixed to obtain a mixed powder.

In the case of molding into tablets, the obtained particles, crushed powder, sized powder, and mixed powder can be tableted to obtain an uncoated tablet in the tableting step.
For locking, a hydraulic hand press machine, a single-shot locking machine, a rotary locking machine, or the like can be used. The conditions for tableting can be appropriately set according to the mass of the tablet and the like.

The obtained particles, crushed powder, sized powder, mixed powder or uncoated tablets can be coated with a coating agent using a coating machine, if necessary.

The hardness of the obtained tablet is not particularly limited, but in the case of an uncoated tablet, it is preferably about 50N to 150N, and in the case of a film-coated tablet, it is preferably about 120N to 250N, for example.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited to the following Examples.

(Example 1)
8 g of polyvinylpyrrolidone was dissolved in 72 g of water to prepare a polyvinylpyrrolidone solution. This polyvinylpyrrolidone solution was sprayed, granulated, and dried on 500 g of levetiracetam (particle size (D50) 100 μm) to obtain levetiracetam-containing particles.
To 254 parts of levetiracetam-containing particles, 11.7 parts of croscarmellose sodium, 1.3 parts of light anhydrous silicic acid, and 3 parts of magnesium stearate were added and mixed to prepare a mixed powder.
The mixed powder was locked with a force of 1 ton to obtain an oval-shaped uncoated tablet having a mass of 270 mg and a major axis of 12.8 mm and a minor axis of 6 mm.

(Comparative Example 1)
230 g of water was sprayed on 500 g of levetiracetam (particle size (D50) 100 μm), granulated, and dried to obtain levetiracetam-containing particles.
After mixing 11.7 parts of croscarmellose sodium, 4 parts of polyvinylpyrrolidone and 1.3 parts of light anhydrous silicic acid with 250 parts of levetiracetam-containing particles, 3 parts of magnesium stearate was added and mixed, and the mixed powder was mixed. Prepared.
The mixed powder was locked with a force of 1 ton to obtain an oval-shaped uncoated tablet having a mass of 270 mg and a major axis of 12.8 mm and a minor axis of 6 mm.
The compositions of Example 1 and Comparative Example 1 are shown in Table 1 below.

(Example 2)
8 g of polyvinylpyrrolidone was dissolved in 72 g of water to prepare a polyvinylpyrrolidone solution. This polyvinylpyrrolidone solution was sprayed, granulated, and dried on 500 g of levetiracetam (particle size (D50) 100 μm) to obtain levetiracetam-containing particles.
To 254 parts of levetiracetam-containing particles, 11 parts of croscarmellose sodium, 2.5 parts of macrogol and 5.2 parts of light anhydrous silicic acid are mixed, and then 0.3 part of magnesium stearate is added and mixed, and mixed. The powder was prepared.
The mixed powder was locked with a force of 1 ton to obtain an uncoated tablet having a mass of 273 mg and a diameter of 9 mm.
The composition of Example 2 is shown in Table 2 below.

(Comparative Example 2)
For 250 parts of levetiracetam (particle size (D50) 100 μm), 4 parts of polyvinylpyrrolidone, 11 parts of croscarmellose sodium, 2.5 parts of macrogol, 5.2 parts of light anhydrous silicic acid, and 0.3 parts of magnesium stearate were added. It was added and mixed to prepare a mixed powder.
The mixed powder was locked with a force of 1 ton to obtain an uncoated tablet having a mass of 273 mg and a diameter of 9 mm.
The composition of Comparative Example 2 is shown in Table 3 below.

(Example 3)
600 g of polyvinylpyrrolidone was dissolved in 5.40 kg of water to prepare a polyvinylpyrrolidone solution. 37.5 kg of levetiracetam (particle size (D50) 100 μm) was charged into a fluidized bed granulator, and the polyvinylpyrrolidone solution was sprayed, granulated, and dried while flowing to obtain levetiracetam-containing particles.
Using a diffusion mixer, 11.7 parts of croscarmellose sodium, 1.3 parts of light anhydrous silicic acid, and 3 parts of magnesium stearate were added to 254 parts of levetiracetam-containing particles and mixed to prepare a mixed powder. ..
Using a rotary locking machine, the mixed powder was locked with a force of 1 ton to obtain an oval-shaped uncoated tablet having a mass of 270 mg per tablet and a major axis of 12.8 mm and a minor axis of 6 mm.
1.09 kg of polyvinyl alcohol, 315 g of talc, 63.0 g of macrogol 6000, and a trace amount of dye were dissolved and dispersed in 28.4 kg of water to prepare a coating liquid.
Using a coating machine, the obtained uncoated tablets were coated with a coating liquid, dried and cooled, and then 3 g of carnauba wax was added for polishing to obtain a coated tablet having a mass of 277 mg per tablet. The composition of Example 3 is shown in Table 4 below.

(Example 4)
600 g of polyvinylpyrrolidone was dissolved in 5.40 kg of water to prepare a polyvinylpyrrolidone solution. 37.5 kg of levetiracetam (particle size (D50) 100 μm) was charged into a fluidized bed granulator, and the polyvinylpyrrolidone solution was sprayed, granulated, and dried while flowing to obtain levetiracetam-containing particles.
Using a diffusion mixer, 11.7 parts of croscarmellose sodium, 1.3 parts of light anhydrous silicic acid, and 3 parts of magnesium stearate were added to 254 parts of levetiracetam-containing particles and mixed to prepare a mixed powder.
Using a rotary locking machine, the mixed powder was locked with a force of 1 ton to obtain an oval-shaped uncoated tablet having a mass of 270 mg per tablet and a major axis of 12.8 mm and a minor axis of 6 mm.
840 g of polyvinyl alcohol, 468 g of titanium oxide, 311 g of talc, 424 g of macrogol 4000, and a trace amount of dye were dissolved and dispersed in 8.4 kg of water to prepare a coating liquid.
Using a coating machine, the obtained uncoated tablets were coated with a coating liquid, dried and cooled, and then 3 g of carnauba wax was added for polishing to obtain a coated tablet having a mass of 277 mg per tablet.
The composition of Example 4 is shown in Table 4 below.

The hardness and disintegration property of each of Experimental Examples 1 to 4 and Comparative Examples 1 and 2 were measured according to the following methods.

(hardness)
The hardness of the uncoated tablets of Experimental Examples 1 and 2, the coated tablets of Examples 3 and 4 and the uncoated tablets of Comparative Examples 1 and 2 was measured using a digital hardness tester. Table 5 shows the results of measuring the average hardness of each of the three tablets.

(Collapse)
The disintegration time of the uncoated tablets of Experimental Examples 1 and 2, the coated tablets of Examples 3 and 4 and the uncoated tablets of Comparative Examples 1 and 2 was measured using a disintegration tester. Purified water (about 37.5 ° C.) was used as the test solution, and no auxiliary board was used. Table 5 shows the results of measuring the average of each of the three tablets.

From the results in Table 5, Examples 1 and 2 were able to obtain sufficient hardness as compared with Comparative Examples 1 and 2. The disintegration time of Examples 1 and 2 was about 5 minutes, which was very rapid, and was almost the same as that of Comparative Examples 1 and 2. That is, in Examples 1 and 2, the hardness was improved and the disintegration property was not impaired.
Further, in Examples 1 and 2 and Comparative Examples 1 and 2, the fluidity of the powder was good at the time of weighing the drug substance, preparing and mixing the preparation, and tableting in the manufacturing process, and adhesion to the device was observed. I couldn't.

The coated tablets of Examples 3 to 4 had sufficient hardness, and the disintegration time was about 5 minutes, which was very rapid. That is, Examples 3 to 4 also had improved hardness and did not impair disintegration as compared with Comparative Examples 1 and 2.
Further, in Examples 3 to 4, the fluidity of the powder was good at the time of weighing the drug substance, preparing / mixing the preparation, and tableting in the manufacturing process, and no adhesion to the device was observed.

Claims (10)

A solid preparation containing levetiracetam having a particle size of 50 μm or more and a water-soluble additive.
A solid preparation characterized by adding a solution of a water-soluble additive to levetiracetam. One of the water-soluble additives selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinylpyrrolidone, sodium carboxymethyl cellulose, cyclodextrin, lactose, mannitol, erythritol, sorbitol, xylitol, martitol and isomalt. The solid preparation according to claim 1, which is two or more kinds. The solid preparation according to claim 1 or 2, wherein the water-soluble additive is one or more selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and polyvinylpyrrolidone. The solid preparation according to any one of claims 1 to 3, which is a tablet. The solid preparation according to any one of claims 1 to 4, further comprising a film coating. A method for producing a solid preparation containing levetiracetam having a particle size of 50 μm or more and a water-soluble additive.
A method for producing a solid preparation, which comprises adding a solution of a water-soluble additive to levetiracetam. One water-soluble additive selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinylpyrrolidone, sodium carboxymethyl cellulose, cyclodextrin, lactose, mannitol, erythritol, sorbitol, xylitol, maltitol and isomalt. The method for producing a solid preparation according to claim 6, which is two or more kinds. The method for producing a solid preparation according to claim 6 or 7, wherein the water-soluble additive is one or more selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and polyvinylpyrrolidone. The method for producing a solid preparation according to any one of claims 6 to 8, wherein the solid preparation is a tablet. The method for producing a solid preparation according to any one of claims 6 to 9, which is coated with a film coating.