JP7264711B2 - Method for producing pharmaceutical composition containing levetiracetam - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing a pharmaceutical composition containing levetiracetam with excellent dissolution properties, and a pharmaceutical solid formulation containing the composition.

Levetiracetam has the chemical name (−)-(S)-ethyl-(2-oxo-1-pyrrolidine)acetamide (molecular formula C ₈ H ₁₄ N ₂ O ₂ , molecular weight 170.21) and has the following chemical formula (1). is the compound represented.

Levetiracetam is a white to off-white crystalline powder that is highly water soluble.

Levetiracetam is used as a therapeutic/preventive drug for epilepsy, and is effective against partial seizures (including secondary generalized seizures) in epileptic patients. It is also sometimes used in combination with other antiepileptic drugs.

As a method for producing pharmaceutical preparations (tablets, granules, etc.) containing levetiracetam, there is a production method including a step of adding a binder to a composition containing levetiracetam and granulating (hereinafter also referred to as a "granulating step"). known (Patent Documents 1 to 5).

Japanese Patent Publication No. 2009-502835 Japanese Patent Publication No. 2011-513372 JP 2017-206454 A JP 2017-206467 A JP 2018-70534 A

Pharmaceutical preparations containing levetiracetam may pose a problem of delayed dissolution of levetiracetam over time.

As a solution to such problems, there has been a method of blending a disintegrant selected from the group consisting of polyvinylpolypyrrolidone and croscarmellose sodium into a pharmaceutical preparation containing levetiracetam at a predetermined ratio (for example, patent Document 1), a method of blending hydroxypropyl cellulose as a retardant (eg, Patent Document 4), a method of blending sodium stearyl fumarate (eg, Patent Document 5), and the like have been reported.

However, in pharmaceutical formulations containing levetiracetam, even if various additives such as those described above are added, the effect of suppressing dissolution delay may not be sufficiently exhibited depending on the manufacturing method of the pharmaceutical formulation. Along with this, there is a possibility that sufficient dissolution properties cannot be obtained.

The present invention has been made in view of the above points, and the main object thereof is to provide a method for producing a pharmaceutical composition containing levetiracetam with sufficiently suppressed dissolution delay and excellent dissolution properties. do.

According to one aspect of the present invention, a method for producing a pharmaceutical composition containing levetiracetam comprises granulating a composition containing levetiracetam under conditions in which the water content in the composition is maintained substantially at 0.5% or less. characterized by including a step of

In the production method, the composition containing levetiracetam preferably contains an excipient.

Furthermore, the excipient is preferably at least one selected from the group consisting of sugar, sugar alcohol, and crystalline cellulose.

In the above production method, the resulting pharmaceutical composition containing levetiracetam was stored under conditions of 40°C and 75% RH for 2 weeks, and then levetiracetam was dissolved for 10 minutes according to the paddle method of the dissolution test described in the Japanese Pharmacopoeia. is preferably 90% or more.

According to the present invention, it is possible to provide a method for producing a levetiracetam-containing pharmaceutical composition with excellent dissolution properties.

Embodiments according to the present invention will be described below, but the present invention is not limited to these.

A method for producing a pharmaceutical composition containing levetiracetam of the present embodiment includes a step of granulating a composition containing levetiracetam under conditions in which the water content in the composition is maintained substantially at 0.5% or less. It is characterized by

As long as the method for producing the pharmaceutical composition of the present embodiment includes the granulation step, other steps are not particularly limited.

The levetiracetam-containing composition to be subjected to the granulation step of the present embodiment contains levetiracetam as an active ingredient. Levetiracetam is a compound having the chemical name of (−)-(S)-ethyl-(2-oxo-1-pyrrolidine)acetamide represented by the following formula (1).

This levetiracetam is marketed in Japan as an antiepileptic drug under the product name of "E Keppra (registered trademark) Dry Ship 50%" or "E Keppra (registered trademark) tablet 250 mg/E Keppra (registered trademark) tablet 500 mg".

The amount of levetiracetam in the pharmaceutical composition produced by the production method of the present embodiment is such that the daily dose of levetiracetam for human patients is usually about 300 to 3000 mg per day (in one dose or in divided doses). Quantity is preferred.

Therefore, the pharmaceutical composition of this embodiment usually contains 150 to 1500 mg, preferably 150 to 1000 mg of levetiracetam, although it varies depending on dosage forms. The actual dosage suitable for each patient can be appropriately determined depending on the patient's age, body weight, symptoms, and the like.

The particle size of levetiracetam used in the present embodiment is not particularly limited, and for example, levetiracetam having a particle size (D50) of 100 to 300 μm can be used. Examples of the method for measuring the particle diameter (D50) include a laser diffraction particle size distribution measuring method, and specific examples include a method using a laser diffraction scattering particle size distribution measuring apparatus (Mastersizer 3000 manufactured by Malvern). be done.

The composition containing levetiracetam to be subjected to the granulation step of the present embodiment may contain various additives (such as excipients) used for granulation, in addition to the levetiracetam.

The excipient is not particularly limited as long as it is an excipient that is usually used for dry syrups, tablets, etc. Examples include sugar, sugar alcohol, crystalline cellulose, dextrin, corn starch, anhydrous calcium hydrogen phosphate, and the like. can be used. These may be used individually by 1 type, and it is also possible to use them in combination of 2 or more type.

In particular, the excipient is preferably at least one selected from the group consisting of sugar, sugar alcohol, and crystalline cellulose. Among them, it is preferable to use at least one selected from the group consisting of mannitol, lactose hydrate, and crystalline cellulose as the excipient of the present embodiment.

The content of excipients in the pharmaceutical composition of the present embodiment varies depending on the dosage form. It is preferably up to 90% by mass, more preferably 5 to 70% by mass. In the case of tablets, when the total amount of the drug substance (levetiracetam) and excipients in the tablet granules is 100% by mass, it is preferably 5 to 90% by mass, more preferably 5 to 70% by mass. is more preferable.

In the pharmaceutical composition of the present embodiment, in addition to the active ingredient levetiracetam and the excipient, pharmaceutically acceptable additives may be added as appropriate within a range that does not impair the effects of the present invention. can be compounded.

Specific additives include, for example, pregelatinized starch, carmellose sodium, hydroxypropylcellulose, polyvinyl alcohol, alginates, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, binders such as methylcellulose; light silicic anhydride, Hydrous silicic acid, magnesium aluminometasilicate, talc, calcium stearate and other fluidizing agents; starch, crospovidone, carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium starch glycolate, partial Disintegrants such as pregelatinized starch; sweeteners such as astelpalm, acesulfame potassium, saccharin, sucralose, stevia, sucrose; fragrances such as I-menthol, yogurt micron, pineapple micron, peppermint micron, lemon micron, orange micron; titanium oxide , Food Yellow No. 4, Food Yellow No. 4 Aluminum Lake, Food Yellow No. 5, Food Red No. 2, Food Red No. 3, Food Red No. 102, Black Iron Oxide, Iron Oxide, Yellow Iron Oxide, Blue No. 2 Aluminum Colorants/light-shielding agents such as lakes; lubricants such as magnesium stearate, calcium stearate, stearic acid, magnesium silicate, magnesium oxide, sucrose fatty acid esters, glyceryl behenate and talc; granules such as sucrose and gelatin A binding agent or the like can be added.

As described above, the method for producing the pharmaceutical composition of the present embodiment is not particularly limited for other steps as long as it includes the granulation step. will be described.

First, the case where the pharmaceutical composition of this embodiment is a tablet will be described. For tablets, for example, levetiracetam is granulated using excipients and, if necessary, other additives, dried, and sized to obtain sized powder (granules). Examples of the granulation method include a fluidized bed granulation method and an agitation granulation method, preferably a fluidized bed granulation method.

In this granulation step, it is important to granulate under conditions in which the water content of the composition containing levetiracetam is maintained substantially at 0.5% or less. After that, it is possible to obtain a pharmaceutical composition containing levetiracetam in which delay in dissolution that may occur over time is sufficiently suppressed (especially, it has sufficient dissolution even after humidified storage).

In the present embodiment, the "moisture content" is a value obtained by measuring the loss on drying when the granulated product is dried for 30 seconds at a temperature of 80 ° C. using an electronic moisture meter. is a value (% by mass) calculated assuming that the amount of granulated substance in is 100%.

Conditions for maintaining the water content substantially at 0.5% or less are not particularly limited, and the water content is adjusted by appropriately setting each parameter of the granulating apparatus to be used and the like. For example, when granulating by a fluidized bed granulation method, the water content can be adjusted by slowing down the liquid feeding speed in the fluidized bed granulator or by raising the air supply temperature. The liquid feeding speed and the temperature of the supplied air are appropriately set according to the production amount of the composition and the equipment used for granulation. Therefore, the water content of the composition containing levetiracetam is periodically measured during the granulation process, and the liquid feeding rate and air supply temperature are adjusted according to the measured value. In the granulator to be used, after finding the conditions (liquid feeding rate, air supply temperature, etc.) for maintaining the water content substantially at 0.5% or less, the conditions are applied to obtain the water content. It is also possible to carry out the granulation step without periodically measuring is not limited to performing moisture content measurements during granulation.

Tablets can be produced by mixing the granules obtained as described above with an external additive, followed by tableting. Alternatively, a film-coated tablet may be obtained by subjecting a tablet (uncoated tablet) obtained by tableting to a film-coated tablet.

Tableting is preferably carried out by compression molding. A lock machine or the like can be used. The tableting pressure can be appropriately set according to the tablet weight of the tablet to be manufactured.

Although tablets have been described above, the dosage form of the pharmaceutical composition obtained by the production method of the present embodiment is not particularly limited, and may be dry syrup formulations, powders, granules, tablets, capsules, and the like. Preferred are tablets or dry syrup formulations.

In addition, although it is necessary to adjust the water content during the granulation, the water content in the pharmaceutical composition finally obtained by the production method of the present embodiment is not particularly limited, and is, for example, 3.0% or less. It is preferably 1.0% or less, more preferably 1.0% or less.

The pharmaceutical composition containing levetiracetam obtained by the production method of the present embodiment was stored under conditions of 40° C. and 75% RH for 2 weeks, and then dissolved for 10 minutes according to the paddle method of the dissolution test described in the Japanese Pharmacopoeia. The dissolution rate is preferably 90% or more, and the present invention also includes pharmaceutical solid preparations containing the composition.

That is, the solid pharmaceutical preparation of the present embodiment is a solid pharmaceutical preparation containing a composition having a water content of 0.5% or less in the granulation step of a composition containing levetiracetam.

The levetiracetam-containing pharmaceutical composition of the present embodiment can be effectively used as an antiepileptic agent. In addition, the levetiracetam-containing pharmaceutical composition of the present embodiment can obtain sufficient dissolution even after the passage of time after production (specifically, even after storage for 2 weeks under conditions of 40°C and 75% RH). long-term storage is possible.

The shape of the tablet of the present embodiment is not particularly limited, but may be disk-shaped, doughnut-shaped, polygonal plate-shaped, spherical, elliptical, or the like.

The hardness of the tablet is not particularly limited, but for uncoated tablets, it is preferably about 70N to 200N, and for film-coated tablets, it is preferably about 120N to 300N.

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

First, each reagent used in this example is shown.
・Microcrystalline cellulose: Ceolus (registered trademark) manufactured by Asahi Kasei Corporation
・ Low-substituted hydroxypropyl cellulose: manufactured by Shin-Etsu Chemical Co., Ltd. ・ Low-substituted hydroxypropyl cellulose: manufactured by Shin-Etsu Chemical Co., Ltd. ・ Bovidone: Kollidon 30 manufactured by BASF Japan Co., Ltd.
・Magnesium stearate: manufactured by Nitto Kasei Co., Ltd. ・Magnesium stearate: manufactured by Taihei Chemical Industry Co., Ltd. ・Hypromellose: manufactured by Shin-Etsu Chemical Co., Ltd. ・Hydroxypropyl cellulose: manufactured by Nippon Soda Co., Ltd. ・Talc: manufactured by Hayashi Kasei Co., Ltd. Tarkan Hayashi (registered trademark)
・ Blue No. 2 aluminum lake: manufactured by Kishi Kasei Co., Ltd. ・ Yellow ferric oxide: manufactured by Kishi Kasei Co., Ltd. ・ Iron sesquioxide: manufactured by Kishi Kasei Co., Ltd.

<Production of film-coated (FC) tablets>
(Example 1: FC tablet 500 mg tablet)
500.0 g of levetiracetam and 31.0 g of low-substituted hydroxypropyl cellulose were placed in a fluid bed granulator (MP-01 manufactured by Powrex Co., Ltd.) and mixed. Next, a 1.0% by mass aqueous solution containing 5.0 g of povidone was separately prepared as a binder solution, and 505.0 g of this binder solution was sprayed to the mixture to granulate (granulation conditions: supply air temperature 75 ° C. , liquid feeding rate 4.5 to 5.5 g/min). In this granulation step, the granulation conditions are set as described above so that the moisture content of the granulation powder (loss on drying obtained by the moisture content measurement method described later) is 0.5% by mass or less during the granulation step. It was adjusted. Further, when the water content of the granulated powder (composition to be granulated) was measured every 10 minutes from the start of granulation for a total granulation time of 100 minutes, the maximum water content was 0.35%. rice field.

After granulation, the mixture was dried in a fluidized bed granulator so that the exhaust temperature was 50° C. or higher (drying conditions: supply air temperature 70° C., supply air volume about 1.0 m ³ /min). A drying time of 3 minutes was required.

The resulting granules were sieved through a sieve with an opening of 500 µm to size the particles. Magnesium stearate was added to the resulting granules in an amount of 0.37% by mass based on the granules and mixed in a bag.

The resulting mixture was tableted with a rotary tableting machine (VIRGO manufactured by Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 18 kN to produce uncoated tablets of 538.0 mg per tablet.

Then, the obtained uncoated tablet is put into a tablet coating machine (HCT-LABO manufactured by Freund Corporation), and 112.01 g of hypmelose, 14.0010 g of hydroxypropyl cellulose, 14.0008 g of talc, and 0 yellow iron sesquioxide. 121.8 g of a film-coating liquid containing 0.0150 g of iron sesquioxide and 1200.08 g of purified water was sprayed to obtain 552 mg of film-coated tablets per tablet.

(Example 2: FC tablet 500 mg)
Process 1
25.00 kg of levetiracetam, 1270 g of low-substituted hydroxypropyl cellulose, and 270.0 g of crystalline cellulose were placed in a fluid bed granulator (FLO-30 manufactured by Freund Co., Ltd.) and mixed. Next, a 1.0% by mass aqueous solution containing 250.0 g of povidone was separately prepared as a binder solution, and 25.25 kg of this binder solution was granulated while being sprayed on the mixture (air supply temperature: 73 ° C., liquid feeding speed: 60.0-70.0 g/min). In this granulation step, the granulation conditions are set as described above so that the moisture content of the granulated powder (loss on drying obtained by the moisture content measurement method described later) is 0.5% by mass or less during the granulation step. It was adjusted. Further, when the water content of the granulation powder (composition to be granulated) was measured every 60 minutes from the start of granulation for a total granulation time of 390 minutes, the maximum water content was 0.16%. rice field.

After granulation, the powder was dried in a fluidized bed granulator so that the exhaust temperature was 50° C. or higher (drying conditions: supply air temperature 75° C., supply air volume about 8.1 Nm ³ /min). Drying time required 4 minutes. The operation of the above step 1 was performed twice and combined to obtain a granule.

The obtained granules were sized with a sizing machine (QC-197S manufactured by Powrex Co., Ltd.). Magnesium stearate in an amount of 0.37% by mass based on the granules was added to the obtained granules and mixed in a diffusion mixer (CB-200 manufactured by Kit Co., Ltd.).

The resulting mixture was tableted together with magnesium stearate in a rotary tableting machine (VIRGO manufactured by Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 20 kN to produce uncoated tablets of 538.0 mg per tablet.

The obtained uncoated tablet is put into a tablet coating machine (FZ-100 manufactured by Freund Corporation), and 2240.03 g of hypmelose, 280.05 g of hydroxypropyl cellulose, 280.09 g of talc, and 6.000 g of yellow iron sesquioxide. , 0.301 g of iron sesquioxide and 16.64 kg of a film-coating liquid containing 32.00 kg of purified water were sprayed to obtain 552 mg of film-coated tablets per tablet.

(Example 3: FC tablet 250 mg)
25.00 kg of levetiracetam, 1270 g of low-substituted hydroxypropyl cellulose, and 270.0 g of crystalline cellulose were placed in a fluid bed granulator (FLO-30 manufactured by Freund Co., Ltd.) and mixed. Next, a 1.0% by mass aqueous solution containing 250.0 g of povidone was separately prepared as a binder solution, and 25.25 kg of this binder solution was granulated while being sprayed on the mixture (granulation conditions: supply air temperature 73 ° C. , liquid feeding rate 60.0 to 70.0 g/min). In this granulation step, the granulation conditions are set as described above so that the moisture content of the granulated powder (loss on drying obtained by the moisture content measurement method described later) is 0.5% by mass or less during the granulation step. It was adjusted. Further, when the water content of the granulated powder (composition to be granulated) was measured every 60 minutes from the start of granulation for a total granulation time of 390 minutes, the maximum water content was 0.39%. rice field.

After granulation, the powder was dried in a fluidized bed granulator so that the exhaust temperature was 50° C. or higher (drying conditions: supply air temperature 75° C., supply air volume about 8.1 Nm ³ /min). Drying time required 4 minutes.

The obtained granules were sized with a sizing machine (QC-197S manufactured by Powrex Co., Ltd.). Magnesium stearate in an amount of 0.37% by mass based on the granules obtained is put into a diffusion mixer (PM-100 manufactured by Hiroshima Metal & Machinery Co., Ltd.) and mixed. bottom.

The resulting mixture was tableted together with magnesium stearate in a rotary tableting machine (VIRGO manufactured by Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 20 kN to produce uncoated tablets of 269.0 mg per tablet.

The obtained uncoated tablets were placed in a tablet coating machine (HCT-80N manufactured by Freund Corporation), and coated with 1280.01 g of hypmelose, 160.01 g of hydroxypropyl cellulose, 160.00 g of talc, and blue No. 2 aluminum lake3. 001 g and 18,000 g of purified water, 7940 g of the film coating liquid was sprayed to obtain 277 mg of film-coated tablets per tablet.

(Comparative Example 1: FC tablet 500 mg tablet)
The granulation conditions were changed to an air supply temperature of 65 ° C. and a liquid feeding rate of 9.5 to 10.5 g / min, and the moisture content of the granulated powder (loss on drying value obtained by the moisture content measurement method described later) was granulated. Film-coated tablets of 552 mg per tablet were obtained in the same manner as in Example 1, except that the content was adjusted to exceed 0.5% by mass during the process. In addition, when the water content of the granulation powder (composition to be granulated) was measured every 10 minutes from the start of granulation in the granulation process for a total granulation time of 50 minutes, the maximum water content was 1 .12%.

Table 1 summarizes the prescribed amount (% by mass) of each example.

<Evaluation method>
(elution test)
A dissolution test was performed using 900 mL of water as a test liquid according to the dissolution test method (paddle method/immediate release preparation) of the 17th revision of the Japanese Pharmacopoeia. Details are as follows.

After setting the container containing the test solution in the dissolution test device, put one tablet to be tested, operate the device at a rotation speed of 50 rpm, and run it for a specified time (0 minutes, 5 minutes, 10 minutes , 15 minutes).

The amount of levetiracetam in the sampled test solution was measured using high performance liquid chromatography (HPLC), and the percentage of the indicated amount (the amount of levetiracetam shown in Table 1) was determined as the dissolution rate (%).

This dissolution test was performed on each tablet after left for two weeks (2W) under initial (initial state) and humidified conditions (temperature 40° C., humidity 75% RH, open).

(Disintegration test)
The disintegration property was evaluated according to the disintegration test method of the 17th revision of the Japanese Pharmacopoeia without an auxiliary plate. Details are as follows.

One sample was placed in each of the six glass tubes of the tester, and the tester was operated at 37±2° C. with the test liquid (water) without using the auxiliary plate. The decay time was defined as the time when the residue of the sample was no longer visible inside the glass tube. The samples were tablets after being left for Initial, 3 days (3D), 1 week (1W), and 2 weeks (2W) under humidified conditions (temperature 40°C, humidity 75% RH, open). .

(moisture content measurement)
The moisture content of the granulated powder is a value obtained by measuring the loss on drying when about 5.0 g of the granulated powder is dried at 80 ° C. using an electronic moisture meter. is a value (% by mass) calculated as 100%.

Test Method: Thermogravimetric Analysis Approximately 5 g of sample was spread evenly on the test dish of the meter. Heating was continued at the set temperature, and the measurement was terminated when the rate of change in the specimen weight became 0.05% or less. The water content was calculated assuming that all changes in weight were due to evaporation of water.

Moisture measurement conditions:
・Moisture measuring instrument: MOC-120H
・ Specimen weight: 5 g ± 0.25 g
・Set temperature: 80℃
・Termination condition: The amount of change in 30 seconds is 0.05% or less

<Results and discussion>
The results of the dissolution test for Example 1 and Comparative Example 1 are shown in Table 2 (Initial) and Table 3 (after standing at a temperature of 40° C. and a humidity of 75% RH for 2 weeks).

By comparing the results in Tables 2 and 3, even with the same formulation, the FC tablet of Comparative Example 1, in which the water content during the granulation process exceeded 0.5%, tended to delay dissolution, especially after humidified storage. (After standing for 2 weeks at a temperature of 40° C. and a humidity of 75% RH), it can be seen that the elution retardation occurs remarkably. On the other hand, the FC tablet of Example 1, in which the water content during the granulation process was 0.5% or less, had better dissolution properties than the FC tablet of Comparative Example 1, and even after humidified storage, tableting within 10 minutes It was confirmed that 90% or more of the levetiracetam contained therein has an excellent dissolution property.

Next, Table 4 shows the dissolution test results (10 minutes, 15 minutes) of Examples 2 and 3.

From the results in Table 4, even in the FC tablets of Examples 2 and 3, which have different formulations from Example 1, the water content during the granulation process was 0.5% or less, so after humidified storage (temperature 40 °C and humidity of 75% RH for 2 weeks), 90% or more of the levetiracetam in the tablet was dissolved within 10 minutes, demonstrating excellent dissolution properties.

Next, with respect to disintegration properties, Table 5 shows the test results of Example 1 and Comparative Example 1, Table 6 shows the test results of Example 2, and Table 7 shows the test results of Example 3.

From the results in Tables 5 to 7, by setting the moisture content during the granulation process to 0.5% or less, the delay in disintegration of the FC tablet was suppressed (disintegration after standing for 2 weeks at a temperature of 40 ° C and a humidity of 75% RH It was also found that the time could be within ±1 minute of the initial decay time).

From the above, it was confirmed that the production method of the present invention sufficiently suppressed dissolution delay and provided a levetiracetam-containing pharmaceutical composition with excellent dissolution properties.

Claims (4)

granulating a composition containing levetiracetam under conditions that maintain the water content in the composition substantially at 0.5% or less ;
The moisture content is the loss on drying when the composition is dried at a temperature of 80 ° C. until the change in weight of the composition for 30 seconds is 0.05% or less. A method for producing a pharmaceutical composition containing levetiracetam, which is a value (% by mass) calculated using the mass of the composition before measurement as 100%. 2. A method for producing a pharmaceutical composition comprising levetiracetam according to claim 1, wherein said composition comprising levetiracetam comprises an excipient. 3. The method for producing a pharmaceutical composition containing levetiracetam according to claim 2, wherein the excipient is at least one selected from the group consisting of sugar, sugar alcohol, and crystalline cellulose. In the resulting pharmaceutical composition containing levetiracetam,
Any one of claims 1 to 3, wherein the dissolution rate of levetiracetam is 90% or more when dissolution is performed for 10 minutes according to the paddle method of the dissolution test described in the Japanese Pharmacopoeia after storage at 40°C and 75% RH for 2 weeks. 2. A method for producing a pharmaceutical composition containing levetiracetam according to 1.