JP7300725B2 - Solid formulation and its manufacturing method - Google Patents

Description

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

Levetiracetam is a compound with the chemical name (2S)-2-(2-oxopyrrolidin-1-yl)butyramide represented by the following formula (1). Levetiracetam is currently used in combination therapy with antiepileptic drugs for partial-onset seizures (including secondary generalized seizures) in epileptic patients and for tonic-clonic seizures in epileptic patients for whom other antiepileptic drugs are not sufficiently effective. used for

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

JP 2017-206454 A

However, as disclosed in Patent Document 1, it has been difficult to control the degree of pulverization of the drug substance to prepare the desired particle size. In general, drug substances with a small average particle size of 50 μm or less tend to adhere to manufacturing equipment and scatter due to static electricity, and have poor fluidity, which is required in the process of preparing formulations. As disclosed in Patent Document 1, in order to ensure hardness by setting the average particle size of the drug substance to 50 μm or less, it was necessary to consider the fluidity of the drug substance and the like. In particular, since levetiracetam tablets have a large amount of drug substance per tablet and little room for adding additives, it has been difficult to secure fluidity and hardness by adding additives.

Accordingly, an object of the present invention is to provide a solid preparation containing levetiracetam, which has improved hardness without impairing disintegration properties, and a method for producing the same. Another object of the present invention is to provide a solid preparation which has good fluidity and less adhesion and scattering of drug substances during the production process, and a method for producing the same.

As a result of intensive studies aimed at solving the above problems, the present inventors have found that a solid preparation with excellent hardness can be obtained without impairing disintegration properties by adding a solution of water-soluble additives to levetiracetam. rice field. In addition, the present inventors have found that by adding a solution of water-soluble additives to levetiracetam, a solid preparation with good fluidity and less sticking and scattering of the drug substance during 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 hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose, cyclodextrin, lactose, mannitol, erythritol, sorbitol, xylitol, maltitol and isomalt; The solid preparation according to (1), which is one or two or more.
(3) The solid preparation according to (1) or (2), wherein the water-soluble additive is one or more selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, 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 hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose, cyclodextrin, lactose, mannitol, erythritol, sorbitol, xylitol, maltitol and isomalt; The method for producing a solid preparation according to (6), which is one or two or more.
(8) Manufacture of the solid preparation according to (6) or (7), wherein the water-soluble additive is one or more selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, 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 film coating.

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

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

The solid formulation used in the present invention is not particularly limited as long as it is a solid formulation. Examples thereof include tablets, capsules, granules, powders and the like in the general rules for formulations described in the Japanese Pharmacopoeia, with tablets being preferred.

In the present invention, the compound represented by the above formula (1), its isomers, their pharmaceutically acceptable salts, their solvates, etc. can be used as levetiracetam. Also, levetiracetam can be used in a crystalline form, an amorphous form, or a mixture thereof.
Such levetiracetam may be produced by a known method or may be commercially available.

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 in the range of 70 to 400 μm, particularly preferably in the range of 80 to 300 μm.

By setting the particle size (D50) within the above range, a solid preparation with excellent hardness can be produced.
If the particle size (D50) of levetiracetam is less than 50 µm, the particles may become bulky, resulting in increased adhesion and poor fluidity, which may lead to poor handling during production. On the other hand, if it exceeds 500 µm, the hardness of the produced solid preparation may deteriorate.

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

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

The content of levetiracetam in the solid preparation is not particularly limited, but is preferably 70 to 98% by weight, more preferably 80 to 97% by weight, and particularly preferably 90 to 96% by weight, based on the total weight 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 of 20% or more at 25°C. The water-soluble additive is not particularly limited, but includes hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose, cyclodextrin, lactose, mannitol, erythritol, sorbitol, xylitol, maltitol, and isomalt. . These may be used individually by 1 type, and can also be used in combination of 2 or more type. Among them, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone are preferable from the viewpoint of imparting stability and desired hardness to the formulation.

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. Examples include water, methanol, ethanol, isopropanol, acetone, or Two or more kinds 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, particularly preferably 0.7%, based on the total mass of the solid preparation. It can be in the range of up to 3% by mass. Within this range, the desired hardness can be imparted to the solid preparation without impairing its disintegration properties.

The solid preparation of the present invention may contain various additives commonly used in the pharmaceutical field, and the amount to be added can be appropriately selected from the amount commonly used in the production of the preparation. Such additives include, for example, excipients, binders, disintegrants, lubricants, flavoring agents, foaming agents, sweeteners, flavoring agents, coloring agents, fluidizing agents, dispersing agents, stabilizing agents and solubilizing agents. agents and the like. These additives may be used in combination of one or more.

Examples of disintegrants include crospovidone, carboxymethylcellulose, hydroxypropyl starch, starches, crystalline cellulose, carmellose calcium, croscarmellose sodium, polyvinylpolypyrrolidone and the like. These may be used individually by 1 type, and may be used in combination of 2 or more type.
Among them, croscarmellose sodium is preferable because it can ensure hardness and disintegration properties with an appropriate pressing pressure.

The content of the disintegrant is preferably 1 to 30% by mass, more preferably 2 to 10% by mass, particularly preferably 3 to 5% by mass, relative 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, and may be used in combination of 2 or more type.

Binders include, for example, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium starch glycolate, hydroxyethylcellulose, gelatin, pullulan, methylcellulose, sodium carboxymethylcellulose, gum arabic, starches, corn starch, alginate, polyethylene glycol, crystalline cellulose, sucrose, mannitol, sorbitol and the like. These may be used individually by 1 type, and may be used in combination of 2 or more type.

The binder content is preferably 0.01 to 15% by mass, more preferably 0.1 to 10% by mass, and particularly preferably 1 to 8% by mass, relative to the total mass of the solid preparation. can be done.

Fluidizing agents include, for example, synthetic aluminum silicate, light anhydrous silicic acid, hydrated silicon dioxide, and magnesium alumina hydroxide. These may be used individually by 1 type, and may be used in combination of 2 or more type.
Among them, light anhydrous silicic acid is preferable from the viewpoint of preventing adhesion between particles and improving fluidity.

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

Lubricants include, for example, glyceryl monostearate, sodium stearyl 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, and may be used in combination of 2 or more type.
Among them, magnesium stearate is preferable because it can ensure hardness and disintegration properties with an appropriate pressing pressure.

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

Stabilizers include, for example, sodium edetate, tocopherol, nicotinamide, cyclodextrin, and the like.

The solid preparation of the present invention can be used as it is (uncoated tablets in the case of tablets) after being formed into an appropriate shape. Film coating using a commonly used coating agent can be applied, if necessary, in order to seal off odors and enhance the beauty of the appearance.

Coating agents include, for example, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, ethyl acrylate/methyl methacrylate copolymer, aminoalkyl methacrylate copolymer, carboxyvinyl polymer, pullulan, polyvinylpyrrolidone, stearyl alcohol, cetanol, shellac, triacetin, macro Gall, polysorbate, polyvinyl alcohol, talc, titanium oxide, iron oxide, carnauba wax, pigments, and the like. These may be used individually by 1 type, and 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, but includes a method of dropping, spraying, spray coating, preferably further granulating and drying the solution onto levetiracetam.

Examples of granulation include extrusion granulation, tumbling granulation, stirring granulation, fluidized bed granulation, spray granulation, and spray drying.
Granulation conditions can be appropriately selected depending on the purpose.

The method for producing the 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 pulverized powder can be sieved with a sizing machine to obtain sieved powder.

In the mixing step, the obtained particles, pulverized powder or sieved powder, and additives such as excipients, binders and fluidizing agents are weighed, and a known mixing apparatus such as a V-type mixer is used. to obtain a mixed powder.

In the case of molding into tablets, the resulting particles, pulverized powder, sized powder and mixed powder can be tableted to obtain uncoated tablets in the tableting step.
For tableting, a hydraulic hand press machine, a single tableting machine, a rotary tableting machine, or the like can be used. The tableting conditions can be appropriately set according to the weight of the tablet and the like.

The obtained particles, pulverized powder, sieved powder, mixed powder or uncoated tablet can be coated with a coating agent using a coating machine, if necessary.

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

EXAMPLES The present invention will be described in more detail with reference to examples below, but the scope of the present invention is not limited by the following examples.

(Example 1)
A polyvinylpyrrolidone solution was prepared by dissolving 8 g of polyvinylpyrrolidone in 72 g of water. This polyvinylpyrrolidone solution was sprayed onto 500 g of levetiracetam (particle size (D50): 100 µm), granulated and dried 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 tableted with a force of 1 t to obtain an oval-shaped uncoated tablet with a tablet weight of 270 mg and a major axis of 12.8 mm and a minor axis of 6 mm.

(Comparative example 1)
Levetiracetam-containing particles were obtained by spraying 230 g of water onto 500 g of levetiracetam (particle size (D50): 100 μm), granulating and drying.
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 obtained. prepared.
The mixed powder was tableted with a force of 1 t to obtain oval-shaped tablets with a mass of 270 mg per tablet 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)
A polyvinylpyrrolidone solution was prepared by dissolving 8 g of polyvinylpyrrolidone in 72 g of water. This polyvinylpyrrolidone solution was sprayed onto 500 g of levetiracetam (particle size (D50): 100 µm), granulated and dried to obtain levetiracetam-containing particles.
After mixing 11 parts of croscarmellose sodium, 2.5 parts of macrogol and 5.2 parts of light anhydrous silicic acid with 254 parts of levetiracetam-containing particles, 0.3 parts of magnesium stearate was added and mixed. powder was prepared.
The mixed powder was tableted with a force of 1 t to obtain uncoated tablets with 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)
4 parts of polyvinylpyrrolidone, 11 parts of croscarmellose sodium, 2.5 parts of macrogol, 5.2 parts of light silicic anhydride, and 0.3 parts of magnesium stearate are added to 250 parts of levetiracetam (particle size (D50) 100 μm). They were added and mixed to prepare a mixed powder.
The mixed powder was tableted with a force of 1 t to obtain uncoated tablets with 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 put into a fluid bed granulator, and the polyvinylpyrrolidone solution was sprayed while fluidizing, granulated and dried 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 tableting machine, the mixed powder was tableted with a force of 1 t to obtain oval-shaped uncoated tablets with a mass of 270 mg per tablet and a major axis of 12.8 mm and a minor axis of 6 mm.
In 28.4 kg of water, 1.09 kg of polyvinyl alcohol, 315 g of talc, 63.0 g of macrogol 6000 and a trace amount of pigment were dissolved and dispersed to obtain a coating liquid.
Using a coating machine, the obtained uncoated tablets were coated with a coating liquid, dried, cooled, and polished by adding 3 g of carnauba wax to obtain coated tablets weighing 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 put into a fluid bed granulator, and the polyvinylpyrrolidone solution was sprayed while fluidizing, granulated and dried 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 tableting machine, the mixed powder was tableted with a force of 1 t to obtain oval-shaped uncoated tablets with a mass of 270 mg per tablet and a major axis of 12.8 mm and a minor axis of 6 mm.
In 8.4 kg of water, 840 g of polyvinyl alcohol, 468 g of titanium oxide, 311 g of talc, 424 g of macrogol 4000 and a trace amount of pigment were dissolved and dispersed to obtain a coating liquid.
Using a coating machine, the obtained uncoated tablets were coated with a coating liquid, dried, cooled, and polished by adding 3 g of carnauba wax to obtain coated tablets weighing 277 mg per tablet.
The composition of Example 4 is shown in Table 4 below.

For each of Experimental Examples 1-4 and Comparative Examples 1-2, hardness and disintegration properties 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 were measured using a digital hardness tester. Table 5 shows the results of measuring the average hardness of each of the three tablets.

(Collapsible)
The disintegration times 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 were measured using a disintegration tester. Purified water (about 37.5° C.) was used as the test liquid, and no auxiliary plate was used. Table 5 shows the results of measuring the average of 3 tablets each.

From the results in Table 5, Examples 1 and 2 were able to obtain sufficient hardness compared to Comparative Examples 1 and 2. The disintegration time of Examples 1 and 2 was very rapid, about 5 minutes, 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.
In addition, in Examples 1 and 2 and Comparative Examples 1 and 2, the flowability of the powder was good during the weighing of the drug substance, preparation and mixing of the formulation, and tableting in the manufacturing process, and no adhesion to the equipment was observed. I couldn't.

The coated tablets of Examples 3 and 4 had sufficient hardness, and their disintegration time was about 5 minutes, which was very rapid. That is, Examples 3-4 also had improved hardness compared to Comparative Examples 1-2, and did not impair disintegration properties.
In addition, in Examples 3 and 4, the flowability of the powder was good during the weighing of the drug substance, preparation and mixing of the formulation, and tableting in the manufacturing process, and no adhesion to the equipment was observed.

Claims (6)

Levetiracetam having a particle size (D50) of 80 to 100 μm, one or more water-soluble additives selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone, and a disintegrant. A tablet containing
A tablet obtained by adding a solution of a water-soluble additive to levetiracetam and granulating it. A tablet according to claim 1, wherein the water-soluble excipient is polyvinylpyrrolidone. 3. The tablet according to claim 1 or 2 , wherein the disintegrant is croscarmellose sodium . Levetiracetam having a particle size (D50) of 80 to 100 μm, one or more water-soluble additives selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone, and a disintegrant. A method for producing a tablet containing
A method for producing tablets, which comprises adding a solution of a water-soluble additive to levetiracetam and granulating the mixture. 5. The method for producing tablets according to claim 4, wherein the water-soluble additive is polyvinylpyrrolidone. 6. The method for producing a tablet according to claim 4 or 5 , wherein the disintegrant is croscarmellose sodium .