KR102065090B1 - A sustained release formulation including levetiracetam or pharmaceutically acceptable salt thereof, and Method preparing the same - Google Patents

Abstract

The present invention provides a sustained release formulation comprising levetiracetam or a pharmaceutically acceptable salt thereof. The sustained-release preparation of the present invention uses a water-soluble polymer as a release control material so that the active ingredient levetiracetam is slowly released at a constant rate so that the blood concentration of levetiracetam can be kept constant even with a single dose, so that the patient's medication Convenience can be significantly improved.

Description

A sustained release formulation including levetiracetam or pharmaceutically acceptable salts, and Method preparing the same}

The present invention relates to a sustained release preparation comprising levetiracetam or a pharmaceutically acceptable salt thereof and a method for preparing the same. More specifically, the present invention relates to a daily-release sustained-release preparation comprising levetiracetam or a pharmaceutically acceptable salt thereof and an improved method of preparing the preparation in an easier process. .

Leveretiracetam is a white to white crystalline powder with molecular formula C ₈ H ₁₄ N ₂ O ₂ , chemical name (S)-(-)-ethyl-2-oxo-1-pyrrolidine acetamide, 170.21 It has a molecular weight. Levetiracetam is the Biopharmaceutics Classification because it has high solubility (1.04 g / ml), high permeability (F> 90%) and releases more than 85% of the drug within 15 minutes in three different pH media. Molecule belonging to class I.

Revetiracetam is used for adjunctive therapy in the treatment of partial seizure outbreaks in adults with epilepsy. It is also used as an adjunct therapy for the treatment of myoclonus attacks in adults with pediatric myoclonus epilepsy and adolescents 12 years of age and older. It may also be used as an adjunct therapy for the treatment of primary tension hepatic seizures in adults with idiopathic epilepsy and children over 6 years of age. In addition, levetiracetam has potential benefits in treating mental and neurological conditions, such as Alzheimer's disease, as well as Tourette syndrome, Autism, Bipolar and Anxiety disorders. Have

Revetiracetam is rapidly absorbed and has an oral bioavailability of 100%. The degree of absorption of levetiracetam in vivo is not affected by food, but decreases C _max by 20% and delays T _max by 1.5 hours. The pharmacokinetics of levetiracetam are linear within the dosage range of 500-5000 mg, and dosing at twice the daily dose, then take two days to reach steady state kinetcs. The levetiracetam binds up to 10% of the plasma protein and has a plasma loss half-life of 7 ± 1 hours at a volume of distribution of 0.6 L / Kg. The total body clearance is 0.9 ml / min / kg and the renal clearance is 0.6 ml / min / kg. The release correlates with creatinine clearance and has no age, gender, race or circadian effect.

Revetiracetam is marketed in the United States as the 250 mg, 500 mg, 750 mg and 1000 mg tablets and 100 mg / mL solution under the trade name Keppra.

Leveretiracetam has relatively low toxicity and a relatively high therapeutic index. Although twice daily prescriptions for immediate-release levetiracetam tablets have a good effect, some neuropsychiatric adverse events, such as drowsiness and fatigue, difficulty coordinating behavior and abnormal behavior, occur. These adverse events occur in proportion to the blood concentration of the drug and require a once-daily regimen of prolonged release of levetiracetam.

The preparation of sustained release formulations of levetiracetam has many difficulties due to the high solubility of levetiracetem. Sustained release patterns require the use of large amounts of excipients for controlled release, resulting in an increase in the size of the dosage form. And this can reduce patient compliance.

Republic of Korea Patent Publication No. 10-2008-0030546 (2008.04.04)

It is an object of the present invention to provide a levetiracetam-containing sustained release formulation having sustained release properties so that a useful therapeutic effect can be expressed even when taken once daily.

Another object of the present invention is to provide a method for preparing a sustained release formulation containing levetiracetam.

In order to achieve the above object, the present invention provides a sustained-release preparation containing levetiracetam or a pharmaceutically acceptable salt thereof and a water-soluble polymer as a release control material as an active ingredient.

The sustained release formulation according to the present invention can release the active ingredient levetiracetam over a long time at a constant rate. The sustained-release preparation according to the present invention is 25-40 wt% in 2 hours, 40-65 wt% in 4 hours and 75- in 8 hours from administration of the formulation with respect to the total weight of levetiracetam or salt thereof contained in the formulation. The active ingredient levetiracetam or a salt thereof can be released at a constant rate of 90% by weight.

For example, the sustained-release preparation of the present invention is characterized by the degree of dissolution of levetiracetam or a pharmaceutically acceptable salt thereof in a paddle method (USP Apparatus 2) at 37 ° C. ± 0.5 ° C. and 50 rpm in 900 ml of artificial intestinal fluid (pH 6.8). When tested, the total weight of levetiracetam or salts thereof contained in the formulation was constant and stable, between 35 and 2 wt% at the start of elution, 40 to 65 wt% at 4 hours and 75 to 90 wt% at 8 hours. Dissolution rate

In the present invention, the levetiracetam or a pharmaceutically acceptable salt thereof is a racemate, optical isomer, polymorph, hydrate or solvate of levetiracetam or a pharmaceutically acceptable salt thereof. All of them are referred to.

In the present invention, the levetiracetam or a pharmaceutically acceptable salt thereof is included in 50 to 90% by weight, preferably 60 to 80% by weight, more preferably 65 to 75% by weight of the total weight of the total formulation. Can be.

In the present invention, the sustained-release preparation may include the amount of 500 ~ 750mg per unit formulation of the levetiracetam or a pharmaceutically acceptable salt thereof in terms of levetiracetam.

In the present invention, the sustained release formulation may include 20 to 50% by weight, preferably 25 to 45% by weight, more preferably 30 to 40% by weight of the water-soluble polymer in the total weight of the total formulation. When the sustained release formulation of the present invention contains a water-soluble polymer in the above content, it is possible to prepare a sustained release formulation in which the sustained release formulation exhibits a desired dissolution pattern.

The sustained-release preparation according to the present invention includes two or more kinds of water-soluble polymers different from each other as a release controlling substance. According to the present invention, two kinds of water-soluble polymers are used on two species so that the active ingredient levitaracetam or salts thereof may be released slowly in pharmaceutical compositions containing levitaracetam or salts thereof without the use of enteric or water-insoluble polymers. I can regulate it.

The water-soluble polymer according to the present invention may be a water swellable polymer. The water-swellable polymer forms a viscous gel layer upon contact with a fluid such as artificial intestinal fluid (pH 6.8) or artificial gastric fluid (pH 2), and expands over time to gradually erode the surface, resulting in the active ingredient levetiracetam. It can be released at a constant rate in slow contact with the aqueous solution.

In the present invention, the water swellable polymer is methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyvinylacetate, Carbopol, polyethylene oxide, magnesium aluminum silicate, starch derivative, polysaccharide, polyacrylate, copolymer of acrylic acid and methacrylic acid ester, polyethylene, polyamide, polyvinylchloride, polyacrylic acid, acrylic resin, acrylic latex dispersion , Cellulose acetate phthalate, polyvinylacetate phthalate, or two or more different materials selected from the above materials. Preferably, the emission control material may include two or more kinds of water-soluble polymers different from each other, and more preferably, may include both hydroxyethyl cellulose and hydroxypropyl cellulose.

When the sustained release formulation of the present invention includes both hydroxyethyl cellulose and hydroxypropyl cellulose as the release controlling substance, the hydroxyethyl cellulose and the hydroxypropyl cellulose may be used in a weight ratio of 1: 1 to 1: 3. The preparation of the present invention comprising hydroxyethyl cellulose and hydroxypropyl cellulose in the above weight ratio as a release controlling substance can slowly release levetiracetam or a salt thereof at a constant rate. For example, the formulation of the present invention comprising hydroxyethyl cellulose and hydroxypropyl cellulose in a weight ratio of 1: 1 to 1: 3 may contain 35 weights of levetiracetam or a salt thereof contained in the formulation at 2 hours after the formulation administration. Percentages can be released at 40-65 wt% in 4 hours and 75-90 wt% in 8 hours.

In the present invention, when hydroxypropyl cellulose is used as the emission control material, the viscosity of the hydroxypropyl cellulose may be 50 to 600 mPa · s in an aqueous solution of 2w / v% (g / mL), preferably It may be 100 to 500 mPa · s, more preferably 150 to 400 mPa · s.

When hydroxyethyl cellulose is used as the emission control material in the present invention, the viscosity of the hydroxyethyl cellulose is 1,000 to 80,000 mPa · s, preferably 3,000 to 8,000 in an aqueous solution of 1 w / v% (g / mL). 6,000 mPa · s, more preferably 3,500 to 5,500 mPa · s.

When the hydroxypropyl cellulose and the hydroxyethyl cellulose have the above viscosity, it is properly eroded upon contact with a fluid such as artificial intestinal fluid (pH 6.8) or artificial gastric juice (pH 2) to stably stabilize the active ingredient at a constant rate. It can release the setam.

The sustained-release preparation according to the present invention comprises levetiracetam or a pharmaceutically acceptable salt thereof as an active ingredient; Release control agents include hydroxyethylcellulose and hydroxypropylcellulose, levetiracetam or salts thereof 25-40% by weight, based on the total weight of levetiracetam or salts thereof in the formulation, 2 hours from administration of the formulation. , Dissolution rate of 40 to 65% by weight in 4 hours, 75 to 90% by weight in 8 hours.

The sustained-release preparation according to the present invention comprises levetiracetam or a pharmaceutically acceptable salt thereof as an active ingredient; The release controlling substance includes hydroxyethylcellulose and hydroxypropylcellulose in a weight ratio of 1: 1 to 1: 3, and levetiracetam or a salt thereof is based on the total weight of levetiracetam or a salt thereof included in the formulation. Elution rates of 25-40 wt% at 2 hours, 40-65 wt% at 4 hours, and 75-90 wt% at 8 hours can be indicated.

For example, the sustained-release preparation of the present invention is characterized by the degree of dissolution of levetiracetam or its pharmaceutically acceptable salt in the paddle method (USP Apparatus 2) at 37 ° C. ± 0.5 ° C. and 50 rpm in 900 ml of artificial intestinal fluid (pH 6.8). When tested, the total weight of levetiracetam or salt thereof contained in the formulation was constant at about 35% by weight in 2 hours, 40-65% in 4 hours and 75-90% in 8 hours from the start of elution. It shows a stable dissolution rate.

Sustained release formulations of the present invention may further comprise a pharmaceutically acceptable excipient in addition to the components mentioned above.

The pharmaceutically acceptable excipients include fillers such as lactose, corn starch, microcrystalline cellulose, polyethylene glycol or dicalcium phosphate, microcrystalline cellulose, highly disperse silica, mannitol, sugars such as lactose, highly disperse silica, mannitol, Binders such as lactose or polyethylene glycol, coating agents such as colloidal silicon oxide, talc, stearic acid, magnesium stearate, sodium stearyl fumarate lubricant, ethyl cellulose, hydroxypropylmethyl cellulose and methacrylic acid-alkyl acrylate copolymers; In addition, dissolution aids, solubilizers, colorants, pH adjusting agents, surfactants and emulsifiers may be used, but are not limited thereto, and may be appropriately selected and used in accordance with known techniques in the art.

The dosage of the sustained-release preparation of the present invention may be a content suitable for the treatment or prevention of the subject and / or disease, which is the age, weight, general health, sex and diet, time of administration, type of disease, and disease of the patient. It can be adjusted according to various factors including the severity of, the type and amount of other components contained in the formulation, the type of formulation, the route of administration, the rate of composition of the composition, the duration of treatment and the drug used concurrently. For example, when the subject is an adult, the formulation of the present invention may be administered in a total dose of 500 to 3,000 mg, converted to levetiracetam once daily or when administered.

The sustained-release preparation of the present invention does not contain an excessively high content of levetiracetam, which is an active ingredient per unit formulation, to cause side effects, while maintaining a constant concentration of the active ingredient in plasma and adjusting the number of doses and dosages to be administered. This compliance can be improved, and preferably, the sustained-release preparation of the present invention is provided in a form suitable for administration once a day.

Sustained release formulations of the invention can be prepared in a variety of formulations. For example, the preparation of the present invention may be formulated into tablets, powders, granules or capsules, such as liquids, uncoated tablets, coated tablets, multi-layered tablets or nucleated tablets, and the like, and preferably tablets.

The route of administration of the sustained release preparations of the invention may be suitably controlled but may be administered orally.

The preparation method of the sustained release formulation of the present invention

Preparing a granule by mixing levetiracetam or a pharmaceutically acceptable salt thereof with at least one first water soluble polymer which is a release controlling material; And adding one or more second water-soluble polymers, which are release control substances, to the granules to prepare a mixture.

In the present invention, the granules may be prepared by wet granulation or dry granulation, preferably by wet granulation.

In the preparation method of the sustained-release preparation of the present invention, the first water-soluble polymer and the second water-soluble polymer may be the same or different from each other.

In the present invention, the water-soluble polymer is a water swellable polymer and its physical properties and specific types are as described above.

In the present invention, the first water-soluble polymer and the second water-soluble polymer may be at least one selected from the group consisting of hydroxypropyl cellulose and hydroxyethyl cellulose. As an example, the first water soluble polymer may be hydroxypropyl cellulose and the second water soluble polymer may be hydroxyethyl cellulose or a mixture of hydroethylethyl cellulose and hydroxypropyl cellulose. Alternatively, both the first water soluble polymer and the second water soluble polymer may be a mixture of hydrocyethylcellulose and hydroxypropyl cellulose.

The method of the present invention may further comprise the step of drying the granules to form a sieve by sifting.

The sustained release formulation of the present invention may be a tablet, in which case the preparation method may further comprise the step of tableting the mixture.

The method for producing a sustained release formulation of the present invention can simplify the manufacturing process to improve productivity and ensure excellent quality.

Sustained release formulation according to the present invention is the active ingredient levetiracetam is slowly released from the formulation at a constant rate to maintain a constant concentration of levetiracetam in the body, it is possible to increase the patient's medication compliance due to the reduced number of doses

1 is a view showing the dissolution rate (%) for 12 hours of the active ingredient levetiracetam in the sustained-release preparation according to the present invention.
Figure 2 is a diagram showing the dissolution rate (%) for 12 hours of the active ingredient levetiracetam in the formulation according to the comparative example.

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.

In addition, the reagents and solvents mentioned below were purchased from Sigma-Aldrich Korea, unless otherwise specified.

Example  One

The mixture was prepared by adding 150 g of levetiracetam, 12.1 g of microcrystalline cellulose, and 1.06 g of hard silicic anhydride 200 to a high speed mixer for 5 min at MM-set = 300 rpm and CM-set = 600 rpm. Meanwhile, 1.2 g of hydroxypropyl cellulose (Klucel GXF) was dissolved in 24 mL of fermented liquor to form a binding solution, and then 20.1 g of the prepared binding solution was added to the high speed mixer with a funnel to prepare a mixture. At this time, the granules were prepared by operating a high speed mixer at MM-set = 300rpm and CM-set = 600rpm for 2min 30s. The granules thus prepared were dried at 50 ° C. for 15 minutes with a fluidized bed dryer, and then sieved using a 1 mm sieve.

14.08 g of hydroxyethyl cellulose (NATROSOL HHX250) and 41.04 g of hydroxypropyl cellulose (Klucel GXF) were apologized using No. 18, and these excipients were put together in the plastic bag together with the previously prepared formulation and shaken 400 times. Thereafter, 0.52 g of magnesium stearate was further added to the plastic bag, shaken 200 times to prepare a mixture, and the mixture was compressed in a tablet press to prepare 1100 mg tablets containing 750 mg of levetiracetam per tablet.

Example 2

The mixture was prepared by adding 150 g of levetiracetam, 12.1 g of microcrystalline cellulose, and 1.06 g of hard silicic anhydride 200 to a high speed mixer for 5 min at MM-set = 300 rpm and CM-set = 600 rpm. 1.2 g of hydroxypropyl cellulose (Klucel GXF) was dissolved in 24 mL of fermented liquor to form a binding solution, and then 20.1 g of the binding solution was added to the high speed mixer with a funnel in 1 minute to prepare a mixture as the mixture. At this time, the granules were prepared by operating a high speed mixer at MM-set = 300rpm and CM-set = 600rpm for 2min 30s. The granules thus formed were dried at 50 ° C. for 15 minutes with a fluid bed dryer. A sizing product was prepared by sizing with a sizing machine using a 1 mm sieve.

18.78 g of hydroxyethyl cellulose (NATROSOL HHX250) and 36.34 g of hydroxypropyl cellulose (Klucel GXF) were apologized using No. 18, and these excipients were put together in the plastic bag together with the previously prepared formulation and shaken 400 times. Thereafter, 0.52 g of magnesium stearate was further added to the plastic bag, and shaken 200 times to prepare a mixture. The mixture was compressed in a tablet press to prepare 1100 mg tablets containing 750 mg of levetiracetam per tablet.

Example 3

The mixture was prepared by adding 150 g of levetiracetam, 12.1 g of microcrystalline cellulose, and 1.06 g of hard silicic anhydride 200 to a high speed mixer for 5 min at MM-set = 300 rpm and CM-set = 600 rpm. 1.2 g of hydroxypropyl cellulose (Klucel GXF) was dissolved in 24 mL of fermented alcohol to form a binding solution, and then 20.1 g of the binding solution was added to a high speed mixer with a funnel in 1 minute to prepare a mixture. At this time, the granules were prepared by operating a high speed mixer at MM-set = 300rpm and CM-set = 600rpm for 2min 30s. The granules thus formed were dried at 50 ° C. for 15 minutes with a fluid bed dryer. A sizing product was prepared by sizing with a sizing machine using a 1 mm sieve.

28.16 g of hydroxyethyl cellulose (NATROSOL HHX250) and 26.96 g of hydroxypropyl cellulose (Klucel GXF) were appled using No. 18, and these excipients were put together in the plastic bag together with the previously prepared formulation and shaken 400 times. Thereafter, 0.52 g of magnesium stearate was weighed and placed in a plastic bag together with the grains and shaken 200 times to prepare a mixture. The mixture was compressed in a tablet press to prepare 1100 mg tablets containing 750 mg of levetiracetam per tablet.

Example 4

The mixture was prepared by adding 150 g of levetiracetam, 12.1 g of microcrystalline cellulose, and 1.06 g of hard silicic anhydride 200 to a high speed mixer for 5 min at MM-set = 300 rpm and CM-set = 600 rpm. 1.2 g of hydroxypropyl cellulose (Klucel LXF) was dissolved in 24 mL of fermented alcohol to form a binding solution, and then 20.1 g of the binding solution was added to a high speed mixer with a funnel in 1 minute to prepare a mixture as the mixture. At this time, the granules were prepared by operating a high speed mixer at MM-set = 300rpm and CM-set = 600rpm for 2min 30s. The granules thus prepared were dried at 50 ° C. for 15 minutes with a fluidized bed dryer, and then sieved using a 1 mm sieve.

18.78 g of hydroxyethyl cellulose (NATROSOL HHX250) and 36.34 g of hydroxypropyl cellulose (Klucel LXF) were appled using No. 18, and these excipients were put together in the plastic bag together with the previously prepared formulation and shaken 400 times. Thereafter, 0.52 g of magnesium stearate was placed in a plastic bag and shaken 200 times to prepare a mixture, and the mixture was compressed in a tablet press to prepare a 1100 mg tablet containing 750 mg of levetiracetam per tablet.

Example 5

A mixture was prepared by adding 150 g of levetiracetam, 12.1 g of microcrystalline cellulose, and 1.06 g of hard silicic anhydride 200 to a high speed mixer and operating for 5 min at MM-set = 300 rpm and CM-set = 600 rpm. Hydroxypropyl cellulose (Klucel MXF) 1.2g was dissolved in 24mL fermentation alcohol to make a binding solution, and 20.1g of the binding solution was placed in a high speed mixer with a funnel in 1 minute to prepare a mixture as the mixture. At this time, the granules were prepared by operating a high speed mixer at MM-set = 300rpm and CM-set = 600rpm for 2min 30s. The granules thus prepared were dried at 50 ° C. for 15 minutes with a fluidized bed dryer, and then sieved using a 1 mm sieve.

18.78 g of hydroxyethyl cellulose (NATROSOL HHX250) and 36.34 g of hydroxypropyl cellulose (Klucel MXF) were apologized using No. 18, and these excipients were put together in the plastic bag together with the previously prepared formulation and shaken 400 times. Thereafter, 0.52 g of magnesium stearate was added to the plastic bag together with the grains, shaken 200 times to prepare a mixture, and the mixture was compressed in a tablet press to prepare 1100 mg tablets containing 750 mg of levetiracetam per tablet.

Example 6

Levetiracetam 150 g, microcrystalline cellulose PH101 12.1 g, hydroxypropyl cellulose (Klucel GXF) 18.77 g, hydroxyethyl cellulose (NATROSOL HHX250) 9.39 g, hard silicic anhydride 200 1.06 g The mixture was prepared by 5 min operation at CM-set = 600 rpm. Thereafter, while operating the high speed mixer again for 2 min 30 s at MM-set = 300 rpm and CM-set = 600 rpm, 24 mL of ethanol was added to the High speed mixer with a funnel in 1 minute to prepare granules. The granules thus prepared were dried at 50 ° C. for 15 minutes with a fluidized bed dryer, and then sieved using a 1 mm sieve.

9.39 g of hydroxyethyl cellulose (NATROSOL HHX250) and 18.77 g of hydroxypropyl cellulose (Klucel GXF) were apologized using No. 18, and these excipients were put together in the plastic bag together with the previously prepared formulation and shaken 400 times. Thereafter, 0.52 g of magnesium stearate was placed in a plastic bag and shaken 200 times to prepare a mixture. The mixture was compressed in a tablet press to prepare a 1100 mg tablet containing 750 mg of levetiracetam per tablet.

Example 7

150 g of levetiracetam, 12.1 g of microcrystalline cellulose, 37.54 g of hydroxypropyl cellulose (Klucel GXF), and 1.06 g of hard silicic anhydride 200 are placed in a high speed mixer and operated for 5 min at MM-set = 300 rpm and CM-set = 600 rpm. Thereafter, the high speed mixer was operated again for 2 min 30 s at MM-set = 300 rpm and CM-set = 600 rpm, and 24 mL of ethanol was added to the high speed mixer with a funnel in 1 minute to prepare granules. The granules thus prepared were dried at 50 ° C. for 15 minutes using a fluidized bed dryer, and then sieved using a 1 mm sieve.

18.78 g of hydroxyethyl cellulose (NATROSOL HHX250) was weighed and apologized using No. 18, and these excipients were put together in a plastic bag together with the previously prepared formulation and shaken 400 times. In addition, 0.52 g of magnesium stearate was weighed and placed in a plastic bag with the granules, and shaken 200 times to prepare a mixture. The mixture was compressed in a tablet press to prepare 1100 mg tablets containing 750 mg of levetiracetam per tablet.

The components used in the preparation of the sustained-release tablets of Examples 1 to 7 and the contents of each component are shown in Table 1 below.

Table 1 Components included in the tablets of Examples 1 to 7 and their contents (mg)

Comparative Example 1

The mixture was prepared by adding 150 g of levetiracetam, 21.96 g of microcrystalline cellulose, and 1.06 g of hard silicic anhydride 200 to a high speed mixer and operating for 5 min at MM-set = 300 rpm and CM-set = 600 rpm. 4.5 g of polyvinylpyrrolidone (PVP K30) was dissolved in 60 mL of fermented alcohol to form a binder solution, and then 20.1 g of the binder solution was added to a high speed mixer with a funnel in 1 minute to prepare a mixture. At this time, by operating the high speed mixer at MM-set = 300rpm, CM-set = 600rpm for 2min 30s, granules were prepared, and the granules were dried in a fluid bed dryer at 50 ° C for 15 minutes. A sizing product was prepared by sizing with a sizing machine using a 1 mm sieve.

21.96 g of microcrystalline cellulose PH102 was apologized using No. 18 sieve, and the mixture was put into a plastic bag together with the previously prepared formulation and shaken 400 times. Thereafter, 0.52 g of magnesium stearate was added to a plastic bag and shaken 200 times to prepare a mixture. The mixture was compressed in a tablet press to prepare a 1000 mg tablet containing 750 mg of levetiracetam per tablet.

Comparative Example 2

The mixture was prepared by adding 150 g of levetiracetam, 12.1 g of microcrystalline cellulose, and 1.06 g of hard silicic anhydride 200 to a high speed mixer for 5 min at MM-set = 300 rpm and CM-set = 600 rpm. 1.2 g of hydroxypropyl cellulose (Klucel LXF) was dissolved in 24 mL of fermented alcohol to form a binding solution, and then 20.1 g of the binding solution was added to a high speed mixer with a funnel in 1 minute to prepare a mixture as the mixture. At this time, high speed mixer was operated for 2min 30s at MM-set = 300rpm, CM-set = 600rpm, granules were prepared, and the granules were dried in a fluidized bed dryer at 50 ° C for 15 minutes and then stipulated with a 1mm sieve. Was prepared. It works.

55.12 g of hydroxypropyl cellulose (Klucel LXF) was apologized using a No. 18 sieve, which was mixed with a previously prepared formulation in a plastic bag and shaken 400 times. Thereafter, 0.52 g of magnesium stearate was placed in a plastic bag and shaken 200 times to prepare a mixture. The mixture was compressed in a tablet press to prepare 1100 mg tablets containing 750 mg of levetiracetam per tablet.

Comparative Example 3

The mixture was prepared by adding 150 g of levetiracetam, 12.1 g of microcrystalline cellulose, and 1.06 g of hard silicic anhydride 200 to a high speed mixer for 5 min at MM-set = 300 rpm and CM-set = 600 rpm. 1.2 g of hydroxypropyl cellulose (Klucel GXF) was dissolved in 24 mL of fermented alcohol to form a binding solution, and then 20.1 g of the binding solution was added to a high speed mixer with a funnel in 1 minute to prepare a mixture as the mixture. At this time, the granules were prepared by operating a high speed mixer at MM-set = 300rpm and CM-set = 600rpm for 2min 30s. The granules thus prepared were dried at 50 ° C. for 15 minutes with a fluidized bed dryer, and then sized to a size using a 1 mm sieve to prepare a product.

55.12 g of hydroxypropyl cellulose (Klucel GXF) was apologized using No. 18 sieve, and the mixture was put into a plastic bag together with the previously prepared formulation and shaken 400 times. Thereafter, 0.52 g of magnesium stearate was added to a plastic bag and shaken 200 times to prepare a mixture. The mixture was compressed in a tablet press to prepare a 1100 mg tablet containing 750 mg of levetiracetam per tablet.

Comparative Example 4

The mixture was prepared by adding 150 g of levetiracetam, 12.1 g of microcrystalline cellulose, and 1.06 g of hard silicic anhydride 200 to a high speed mixer for 5 min at MM-set = 300 rpm and CM-set = 600 rpm. 1.2 g of hydroxypropyl cellulose (Klucel MXF) was dissolved in 24 mL of fermented alcohol to make a binding solution, and then 20.1 g of the binding solution was added to a high speed mixer with a funnel in 1 minute to prepare a mixture as the mixture. At this time, the granules were prepared by operating a high speed mixer at MM-set = 300rpm and CM-set = 600rpm for 2min 30s. The granules thus prepared were dried at 50 ° C. for 15 minutes with a fluidized bed dryer, and then sieved using a 1 mm sieve.

55.12 g of hydroxypropyl cellulose (Klucel MXF) was apologized using No. 18 sieve, and the mixture was put into a plastic bag with the previously prepared formulation and shaken 400 times. Thereafter, 0.52 g of magnesium stearate was added to the plastic bag together with the grains and shaken 200 times to prepare a mixture. The mixture was compressed in a tablet press to prepare 1100 mg tablets containing 750 mg of levetiracetam per tablet.

Comparative Example 5

The mixture was prepared by adding 150 g of levetiracetam, 12.1 g of microcrystalline cellulose, and 1.06 g of hard silicic anhydride 200 to a high speed mixer for 5 min at MM-set = 300 rpm and CM-set = 600 rpm. 1.2 g of hydroxypropyl cellulose (Klucel HXF) was dissolved in 24 mL of fermented alcohol to form a binding solution, and then 20.1 g of the binding solution was added to a high speed mixer with a funnel in 1 minute to prepare a mixture as the mixture. At this time, the granules were prepared by operating a high speed mixer at MM-set = 300rpm and CM-set = 600rpm for 2min 30s. The granules thus prepared were dried at 50 ° C. for 15 minutes in a fluidized bed dryer, and then, a sizing unit using a 1 mm sieve was established to prepare a sieved product.

55.12 g of hydroxypropyl cellulose (Klucel HXF) was apologized using a No. 18 sieve, and the mixture was put into a plastic bag with the previously prepared formulation and shaken 400 times. Thereafter, 0.52 g of magnesium stearate was added to the plastic bag together with the grains, and shaken 200 times to prepare a mixture. The mixture was compressed in a tablet press to prepare 1100 mg tablets containing 750 mg of levetiracetam per tablet.

Comparative Example 6

The mixture was prepared by adding 150 g of levetiracetam, 12.1 g of microcrystalline cellulose, and 1.06 g of hard silicic anhydride 200 to a high speed mixer for 5 min at MM-set = 300 rpm and CM-set = 600 rpm. 1.2 g of hydroxyethyl cellulose (NATROSOL HHX250) was dissolved in 24 mL of fermented alcohol to make a binding solution, and then 20.1 g of the binding solution was added to a high speed mixer with a funnel in 1 minute to prepare a mixture. At this time, the granules were prepared by operating a high speed mixer at MM-set = 300rpm and CM-set = 600rpm for 2min 30s. The granules thus prepared were dried at 50 ° C. for 15 minutes in a fluidized bed dryer, and then sieved using a 1 mm sieve.

55.12 g of hydroxyethyl cellulose (NATROSOL HHX250) was apologized using No. 18 sieve, and the mixture was put into a plastic bag with the previously prepared formulation and shaken 400 times. Thereafter, 0.52 g of magnesium stearate was added to the plastic bag together with the grains, and shaken 200 times to prepare a mixture. The mixture was compressed in a tablet press to prepare a 1100 mg tablet containing 750 mg of levetiracetam per tablet.

Comparative Example 7

The mixture was prepared by adding 150 g of levetiracetam, 12.1 g of microcrystalline cellulose, and 1.06 g of hard silicic anhydride 200 to a high speed mixer for 5 min at MM-set = 300 rpm and CM-set = 600 rpm. 1.2 g of hydroxyethyl cellulose (NATROSOL 250MR) was dissolved in 24 mL of fermented alcohol to make a binding solution, and then 20.1 g of the binding solution was added to a high speed mixer with a funnel in 1 minute to prepare a mixture. At this time, the granules were prepared by operating the high speed mixer for 2 min 30 s under the above conditions. The granules thus prepared were dried at 50 ° C. for 15 minutes with a fluidized bed dryer, and then sieved using a 1 mm sieve.

55.12 g of hydroxyethyl cellulose (NATROSOL 250MR) was apologized using No. 18 sieve, and the mixture was put into a plastic bag with the previously prepared formulation and shaken 400 times. Thereafter, 0.52 g of magnesium stearate was added to the plastic bag together with the grains, and shaken 200 times to prepare a mixture. The mixture was compressed in a tablet press to make 1100 mg tablets containing 750 mg of levetiracetam per tablet.

Comparative Example 8

A mixture was prepared by adding levetiracetam 150g, microcrystalline cellulose PH101 12.1g, Polyox 30g, and hard silicic anhydride 200 1.06g in a high speed mixer for 5 min at MM-set = 300 rpm and CM-set = 600 rpm. 1.2 g of hydroxypropyl cellulose (Klucel GXF) was dissolved in 24 mL of fermented alcohol to make a binding solution, and then 20.1 g of the binding solution was placed in a high speed mixer with a funnel in 1 minute to prepare a mixture as the mixture. At this time, the granules were prepared by operating the high speed mixer for 2 min 30 s under the above conditions. The granules thus prepared were dried at 50 ° C. for 15 minutes with a fluidized bed dryer, and then sieved using a 1 mm sieve.

25.12 g of hydroxypropyl cellulose (Klucel GXF) was apologized using No. 18 sieve, and the mixture was put into a plastic bag with the previously prepared formulation and shaken 400 times. Thereafter, 0.52 g of magnesium stearate was added to the plastic bag together with the grains, and shaken 200 times to prepare a mixture. The mixture was compressed in a tablet press to make 1100 mg tablets containing 750 mg of levetiracetam per tablet.

Comparative Example 9

A mixture was prepared by adding levetiracetam 150g, microcrystalline cellulose PH101 12.1g, Polyox 30g, and hard silicic anhydride 200 1.06g in a high speed mixer for 5 min at MM-set = 300 rpm and CM-set = 600 rpm. 1.2 g of hydroxyethyl cellulose (NATROSOL HHX250) was dissolved in 24 mL of fermented alcohol to make a binding solution, and then 20.1 g of the binding solution was added to a high speed mixer with a funnel in 1 minute to prepare a mixture. At this time, the granules were prepared when the high speed mixer was operated at MM-set = 300rpm and CM-set = 600rpm for 2min 30s. The granules thus prepared were dried at 50 ° C. for 15 minutes with a fluidized bed dryer, and then sieved using a 1 mm sieve.

25.12 g of hydroxyethyl cellulose (NATROSOL HHX250) was apologized using No. 18 sieve, and the mixture was put into a plastic bag with the previously prepared formulation and shaken 400 times. Thereafter, 0.52 g of magnesium stearate was added to the plastic bag together with the grains, and shaken 200 times to prepare a mixture. This mixture was compressed in a tablet press to make a 1100 mg tablet containing 750 mg of levetiracetam per tablet.

The components used in the preparation of Comparative Examples 1 to 9 and their contents are shown in Tables 2 and 3 below.

TABLE 2 Components included in the tablets of Comparative Examples 1 to 5 and their contents (mg)

TABLE 3 Components included in the tablets of Comparative Examples 6 to 9 and their contents (mg)

Experimental Example . Over time Dissolution rate  evaluation

The dissolution rate was evaluated for the tablets which are the sustained release pharmaceutical compositions of Examples 1-7 and Comparative Examples 1-9. 900 ml of artificial intestinal fluid (pH 6.8) was used as the dissolution medium, and the degree of elution of levetiracetam or its pharmaceutically acceptable salts was tested in a paddle method (USP Apparatus 2) at 37 ° C ± 0.5 ° C and 50 rpm. 1 and 2 are shown.

Table 4 Evaluation of dissolution rate (%) of the Example and Comparative Example tablets

As shown in Table 4, in the case of tablets prepared by Examples 1 to 7 of the present invention, unlike tablets of Comparative Examples 1 to 9 can effectively control the rate of releasing levetiracetam, constant activity It was confirmed that the component dissolution rate, that is, 25 to 40% at 2 hours, 45 to 60% at 4 hours, 75 to 90% at 8 hours.

Therefore, the pharmaceutical composition according to the present invention can increase the compliance of the subject to be administered through such a stable dissolution rate, and can obtain an improved therapeutic or prophylactic effect of the target disease.

Claims (18)

Wet granules comprising levetiracetam or a pharmaceutically acceptable salt thereof as an active ingredient; And
Hydroxyethyl cellulose and hydroxypropyl cellulose as the release controlling substance, in a weight ratio of 1: 1 to 1: 3,
The levetiracetam or salt thereof is 25-40 wt% in 2 hours, 40-65 wt% in 4 hours, 75-90 wt in 8 hours, based on the total weight of levetiracetam or salt thereof contained in the tablet Sustained-release tablet which shows the dissolution rate of%. delete delete delete The sustained-release tablet of claim 1, wherein the hydroxypropyl cellulose has a viscosity of 50 to 600 mPa · s in a 2w / v (g / mL)% aqueous solution. The sustained-release tablet of claim 1, wherein the hydroxyethyl cellulose has a viscosity of 1,000 to 80,000 mPa · s in a 1 w / v (g / mL)% aqueous solution. The sustained release tablet of claim 1, wherein the dissolution test is performed using a solution of pH 6.0 to 7.0 and 35 ° C. to 39 ° C. 7. The sustained release tablet of claim 1, wherein the dissolution test is performed by paddle method at 40 to 75 rpm. The sustained release tablet of claim 1, wherein the sustained release tablet comprises 50% to 90% by weight of the levetiracetam or a pharmaceutically acceptable salt thereof per unit dosage form based on the total weight of the total tablet. The sustained release tablet of claim 1, wherein the sustained release tablet comprises 20-50 wt% of the release controlling substance per unit dosage form relative to the total weight of the total tablet. delete The sustained-release tablet according to any one of claims 1 to 5, wherein the sustained-release tablet is for once-daily administration. Wet granules comprising, as active ingredients, levetiracetam or a pharmaceutically acceptable salt thereof and at least one first water soluble polymer which is a release controlling substance; And
At least one second water soluble polymer that is an emission control material,
The levetiracetam or salt thereof is 25-40 wt% in 2 hours, 40-65 wt% in 4 hours, 75-90 wt in 8 hours based on the total weight of levetiracetam or salt thereof contained in the tablet The sustained-release tablet which shows the dissolution rate of%,
The first water-soluble polymer and the second water-soluble polymer are each at least one selected from the group consisting of hydroxyethyl cellulose and hydroxypropyl cellulose,
The tablet is a sustained-release tablet containing both hydroxyethyl cellulose and hydroxypropyl cellulose as the release control material. The sustained release tablet of claim 13, wherein the second water soluble polymer is located in addition to the wet granules. Preparing a wet granule by mixing an active ingredient levetiracetam or a pharmaceutically acceptable salt thereof with at least one first water-soluble polymer which is a release controlling substance; And
A method for preparing a sustained-release tablet comprising the step of preparing a mixture by adding at least one second water-soluble polymer which is a release controlling substance to the granules,
The first water-soluble polymer and the second water-soluble polymer are each at least one selected from the group consisting of hydroxyethyl cellulose and hydroxypropyl cellulose,
Wherein said tablet comprises both hydroxyethylcellulose and hydroxypropylcellulose as the release controlling substance. The method of claim 15, wherein the first water soluble polymer is hydroxypropyl cellulose, and the second water soluble polymer is hydroxyethyl cellulose or a mixture of hydroxyethyl cellulose and hydroxypropyl cellulose. The method of claim 15, wherein the first water soluble polymer and the second water soluble polymer are a mixture of hydroxyethyl cellulose and hydroxypropyl cellulose, respectively. The method of claim 15, further comprising the step of sizing the granules using a sieve.

Images