WO2012070785A1

WO2012070785A1 - Sustained-release pharmaceutical composition comprising levetiracetam or pharmaceutically acceptable salt thereof having improved dissolution stability and method for manufacturing the same

Info

Publication number: WO2012070785A1
Application number: PCT/KR2011/008420
Authority: WO
Inventors: Sang-Joon Lee; Kwan-Young Chang; Jae-Soon Ahn; Jae-Min Cho; Kyoung-Un Kang; Hyun-Joo Lee
Original assignee: BIO PHARMARTIS Co Ltd; Hyundai Pharm Co Ltd
Current assignee: BIO PHARMARTIS Co Ltd; Hyundai Pharm Co Ltd
Priority date: 2010-11-23
Filing date: 2011-11-07
Publication date: 2012-05-31
Anticipated expiration: 2013-05-23
Also published as: KR20120055313A

Abstract

The present invention relates to a sustained-release pharmaceutical composition comprising a levetiracetam or a pharmaceutically acceptable salt thereof, and to a method of preparing the same. More specifically, the present invention relates to a sustained-release pharmaceutical composition comprising a levetiracetam or a pharmaceutically acceptable salt thereof with an improved dissolution stability that is constant dissolution rate under various releasing conditions, and to a method of preparing the same in a simple and easy manner.

Description

[DESCRIPTION]

[Invention Title]

SUSTAINED-RELEASE PHARMACEUTICAL COMPOSITION

COMPRISING LEVETIRACETAM OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF HAVING IMPROVED DISSOLUTION STABILITY AND METHOD FOR MANUFACTURING THE SAME

[Technical Field]

The present invention relates to a sustained-release pharmaceutical composition comprising a levetiracetam or a pharmaceutically acceptable salt thereof, and to a method of preparing the same. More specifically, the present invention relates to a sustained-release pharmaceutical composition comprising a levetiracetam or a pharmaceutically acceptable salt thereof with improved dissolution stability that is constant dissolution rate under various releasing conditions, and to a method of preparing the same in a simple and easy process.

[ B ackground Art ]

Levetiracetam is S-enantiomer of (S)-(-)-ethyl-2-oxo-l-pyrolidine acetamide and has a chemical structure of C₈Hi₄N₂0₂ and a molecular weight of 170.21. Levetiracetam is used as a protecting agent for preventing or treating a hypoxic-ischemic attack in central nervous system, and particularly, as an assistant anti-epileptic drug used to treat various types of seizures in adults. The exact mechanism of levetiracetam to take an antiepileptic effect has not been identified, and how the antiepileptic effect is derived from the interaction with the known mechanism of inhibition and excitation of neurotransmission has not been reported.

The pharmaceutical composition including the levetiracetam shows different releasing rate of active ingredient as time goes on, thereby causing the delay in drug release. Thus, it lo wers the stability of the pharmaceutical composition and shortens the storage time.

Meanwhile, a food which is known as another factor affecting the releasing rate does not affect the absorption rate of levetiracetam, but reduces the Cmax by 20% and delays in Tmax by 1.5 hour.

The sustained-release pharmaceutical composition containing water-soluble active ingredients such as levetiracetam is difficult to prepare. When a large amount of an excipient to control the drug release is used for obtaining the dissolution stability of levetiracetam-containing pharmaceutical composition, it increases the dosage size and thus causes the patient's inconvenience in drug administration.

In addition, in a wet granulation process used normally for preparing the pharmaceutical composition containing the levetiracetam as an active ingredient, the levetiracetam can be dissociated due to the contact with liquid phase. The demand for an additional drying step makes the process be complex, requires more time and increases the production cost due to the heat supply for drying.

[Disclosure]

[Technical Problem]

Therefore, the present invention relates to a sustained-release pharmaceutical composition comprising a levetiracetam or a pharmaceutically acceptable salt thereof with an improved dissolution stability that is constant under various releasing conditions. [Technical Solution]

To achieve the object, the present invention provides a sustained-release pharmaceutical composition comprising an active ingredient including a levetiracetam or a pharmaceutically acceptable salt thereof; a sustained-release base material containing a water-swellable polymer; and a pharmaceutically acceptable excipient.

In addition, the present invention provides a method of preparing the sustained-release pharmaceutical composition, comprising the steps of mixing the levetiracetam or pharmaceutically acceptable salt thereof, the water-swellable polymer, and the pharmaceutically acceptable excipient; and lubricating and directly compressing the mixture into a tablet.

The pharmaceutical composition and the method of preparing the same according to an embodiment of the present invention will be described in more detail.

According to an embodiment of the present invention, a sustained-release pharmaceutical composition comprising an active ingredient including a levetiracetam or a pharmaceutically acceptable salt thereof; a sustained-release base material including a water-swellable polymer; and a pharmaceutically acceptable excipient is provided.

The amount of active ingredient may be determined at an amount being sufficiently proper for preventing and/or treating the disease depending upon the subject to be administered, and may be adjusted by various factors, for examples, age, body weight, general health condition and sex of the subject, diet, administering time interval, the kind and severity of disease, the kind and amount of the other components contained the composition, formulation type, administering route, releasing rate of the composition, the treatment period, and co-administered drug. For example, the pharmaceutical composition of the present invention can be administered one to several times daily for adult at a total effective amount of 500 to 3,000 mg.

However, it is well-known to an ordinarily-skilled person that the administering amount or dosage of the active ingredient is determined, so as not to cause the side-effect due to the excess active ingredient. Preferably, in order to consistently maintain a plasma concentration of active ingredient, and to make the drug compliance by reducing the number of administration, the pharmaceutical composition of the present invention can be provided as a proper formulation type to be administered once daily.

Thus, the present inventors researched to provide the pharmaceutical composition in a proper formulation type to be administered once daily. As a result, they found that when the formulation of pharmaceutical composition is prepared to be released slowly by using the sustained-release base material including the water-swellable, it was possible to effectively control the release rate of the levetiracetam or pharmaceutically acceptable salt thereof and to achieve the desired release rate of active ingredient, such as preferably 20-40% in 1 hour, 40-60% in 2 hours, and 80% or more in 6 hours or longer, thereby increasing the subject's compliance and obtaining the improved prevention or treatment effect, and then completed the present invention.

The pharmaceutical composition of an embodiment of the present invention has the proper condition of testing the bioequivalence under the fed condition. When the pharmaceutical composition was stored even for 6 months, it showed the consistent dissolution rate after 6 months and thus had the improved dissolution stability in various dissolution conditions.

The levetiracetam or pharmaceutically acceptable salt thereof may include levetiracetam, a racemate, an enanthiomer, an isomer, a hydrate, solvate and the like.

The levetiracetam or pharmaceutically acceptable salt thereof may be contained at an amount of 50 to 90wt%, and more preferably 60 to 80 wt% with respect to total pharmaceutical composition. When the levetiracetam or pharmaceutically acceptable salt thereof is contained at less than the range, the increased weight of composition itself makes it difficult to be administered and useless for a pharmaceutical composition. When the amount is excessively high, the composition cannot be formulated as a sustained- release type.

To induce the continuous and proper sustained-release of the pharmaceutical composition, the sustained-release base material including the water-swellable polymer is used.

The examples of the water-swellable polymer may be at least one selected from the group consisting of methylcellulose, hydroxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydro xybutylcellulose, hydro yethylmethylcellulose, hypromellose, galactomannans, tragacanth, agar, guar gum, polyfructan, methacrylate copolymer, polyvinylalcohol, polyvinylpyrrolidone, polyvinylpyrrolidone-vinylacetate copolymer(PVP-PVA), a mixture of polyvinylalcohol and polyvinylpyrrolidone, polyethylene oxide, polypropylene oxide, ethylene oxide-propylene oxide copolymer, acrylate polymer, methacrylate copolymer, alginate, carrageenan, acasia, xanthan gum, chitin derivative, sodium carmellose, cecium carmellose, carbomer and a mixture thereof, and preferably, may be at least one selected from the group consisting of polyethylene oxide, hydroxypropyl cellulose, hydroxyethyl cellulose, alginate, carbomer and a mixture thereof.

When the water-swellable polymer contacts with an aqueous liquid, the surface erosion of tablet progresses slowly and expands as time goes on. And then the water-swellable polymer forms the viscous gel layer to control the drug release, and makes the active ingredient release slowly via dispersion.

The release rate of active ingredient is based on the viscosity of water-swellable polymer, and the viscosity of water-swellable polymer may be 50 to 100,000mPa · s, or more preferably 2000 to 15,000mPa · s, when it is measured at 2wt% concentration in water at 20 ^°C, according to the methods disclosed in United States Pharmacopeia, such as Ubbelohde method.

The hydroxypropyl cellulose among the water-swellable polymers can has various viscosities. In order that the active ingredient can be released continuously and stably by being properly wet and easily eroded, the viscosity of the water-swellable polymer can be about 50 to about 10,000mPa · s, or more preferably about 3,000 to about 8,000mPa · s.

The polyethylene oxide to be used can has a viscosity of about 400 to 2O,O0OmPa · s and preferably about 2,000 to 15,000 mPa · s. The hydro xyethyl cellulose can have viscosity of about 150 to 10,000mPa · s and more preferably about 4,500 to 8,000 mPa · s.

When the viscosity of the water-swellable polymer is lower than the ranges, it is difficult to achieve the sufficient sustained release. When the viscosity is excessively high, the release rate is too slow to reach the optimal blood concentration, thereby not showing the sufficient efficacy.

The pharmaceutical composition of the present invention includes the water-swellable polymer at an amount of 5 to 50 wt% preferably, and more preferably 15 to 35 wt%, on the basis of total pharmaceutical composition. When the water-swellable polymer is less than the ranges, the drug release rate gets faster and causes the side-effects such as Dose Dumping. When it exceeds the ranges, the low release rate makes it impossible to reach the optimal blood concentration, thereby not achieving the sufficient efficacy.

The pharmaceutical composition of the present invention may further include pharmaceutically acceptable excipient.

The examples of pharmaceutically acceptable excipients are filling agents such as lactose, corn starch, microcrystalline cellulose, polyethylene glycol and dicalcium phosphate; binders such as micro crystalline cellulose, high dispersible silica, mannitol, sugar such as lactose, and polyethylene glycol; lubricants such as colloidal silica, talc, stearic acid, magnesium stearate, and sodium stearyl fumarate; coating agents such as ethylcellulose, hydroxypropyl methylcellulose and methacrylic acid-alkyl acrylate copolymer; a solubilizing agent, a coloring agent, a pH adjuster, a surfactant, a emulsifying agent and the like, but can be selected properly according to the conventional technology known to an ordinarily-skilled person in the art without limitation.

When the levetiracetam or pharmaceutically acceptable salt thereof of the pharmaceutical composition was tested for dissolution degree in 900ml of pH 6.8 dissolution media at 37 ^°C ± 0.5 ^°C and 80rpm to 120rpm in 40-mesh basket (USP type 1), it shows constant and stable dissolution rate which is preferably 20-40% in 1 hour, 40-60% in 2 hours, 80% or more in 6 hours or longer.

The effective control of the release rate of pharmaceutical composition can increase the subject's compliance, and show the prevention or treatment of the disease of interest.

The pharmaceutical composition can be prepared according to the general preparation method known to ordinarily-skilled person in the art without limitation. But, in the wet granulation method used generally, the active ingredient can be dissociated by contacting with liquid phase, and has high cost and long production time due to the need to additional drying step. Thus, the direct compression method can be used preferably.

An embodiment of the present invention provides a method of preparing the sustained-release pharmaceutical composition comprising the steps of mixing a levetiracetam or a pharmaceutically acceptable salt thereof, a water-swellable polymer and a pharmaceutically acceptable excipient; and lubricating and directly compressing the mixture into a tablet.

The method of preparing the pharmaceutical composition may include a step of coating the tablet with a coating agent after making the tablet.

According to the method of preparing the pharmaceutical composition, it is possible to make pharmaceutical composition simply and easily which is very economical due to saving of time, endeavor and cost, and to improve the effect of prevention or treatment of the disease of interest by preventing the active ingredient dissociating due to the contact with liquid phase .

The effective control of the release rate of pharmaceutical composition can increase the subject's compliance by reducing the number of administration and maintain the plasma concentration of active ingredient, thereby showing the prevention or treatment of the disease of interest. In particular, the pharmaceutical composition satisfies the condition of testing the bio equivalence under the fed condition. When the pharmaceutical composition is stored even for 6 months, it shows the consistent dissolution rate after 6 months. Thus the composition has an improved dissolution stability in various releasing conditions.

According to the method of preparing the pharmaceutical composition, it is possible to make pharmaceutical composition simply and easily which is very economical due to saving of time, endeavor and cost, and to improve the effect of prevention or treatment of the disease of interest by preventing the active ingredient dissociating due to the contact with liquid phase.

[Examples]

The invention is further explained in more detail with reference to the following examples. These examples, however, should not be interpreted as limiting the scope of the invention in any manner. Examples 1 to 4. Preparation of sustained-release pharmaceutical composition including a levetiracetam

According to the components and their amounts, the sustained-release pharmaceutical composition including the levetiracetam was prepared in a table 1.

Specifically, levetiracetam, Polyethylene oxide and polyethylene glycol were sieved with 30-mesh sieve and mixed, and then were lubricated with colloidal silica and magnesium stearate. The lubricated product was directly compressed to produce tablet (KP200/13, Gisan, Korea). The tablet was coated with Opadry (SFC-30F, Sejong Pharmatec, Korea) to obtain final tablet.

[Table 1]

The viscosity of the Polyethylene oxide used in Table 1 were as follows:

Polyox WSR N-60K viscosity: 2,000-4,000 mPa^■ s

Polyox WSR 301 viscosity: 3,300-11,000 mPa · s

Polyox WSR Coagulant viscosity: 1 1 ,000-15,000 mPa · s Examples 5 to 9. Preparation of a sustained-release pharmaceutical composition including levetiracetam

According to the components and their amounts, the sustained-release pharmaceutical composition including the levetiracetam was prepared in a table 2.

Specifically, levetiracetam and hydroxypropyl cellulose (Examples 5 to 7) or hydroxyethyl cellulose(Examples 8 and 9), and polyethyle glycol were sieved with 30 -mesh sieve and mixed, and then was lubiricated with colloidal silica and magnesium stearic acid. The lubricated mixture was compressed directly into tablet (KP200/13, Gisan, Korea). The tablet was coated with opadry (SFC-30F, Sejongpharmatech, Korea) to produce the final tablet.

[Table 2]

The viscosity of hydro xypropyl cellulose used in Table 2 are as follows.

Klucel-HF viscosity 4,000-8,000 mPa · s

Klucel-MF viscosity 3,000-6,500 mPa · s

Natrosol-HR viscosity 5,000-8,000 mPa · s

Natrosol-MR viscosity 4,500-6,500 mPa · s

Examples 10 to 12. Preparation of a sustained-release pharmaceutical composition including levetiracetam

According to the components and their amounts, the sustained-release pharmaceutical composition including the levetiracetam was prepared in a table 3.

Specifically, levetiracetam, carbomer (Examples 10 and 1 1) or sodium alginate (Example 12), and polyethylene glycol were sieved with 30 -mesh sieve and mixed, and then was lubiricated with colloidal silica and magnesium stearic acid. The lubricated mixture was compressed directly into tablet (KP200/13, Gisan, Korea). The tablet was coated with opadry (SFC-30F, Sejongpharmatech, Korea) to produce the final tablet.

[Table 3]

Sum 721 721 721

The viscosity of carbomer used in Table 3 are as follows.

Carbopol 971 P NF viscosity: 4,000-1 1 ,000 mPa · s

Carbopol 974P NF viscosity: 29,400-39,400 mPa · s

Comparative Examples 1 to 3. Preparation of a sustained-release pharmaceutical composition including levetiracetam

According to the components and their amounts, the sustained-release pharmaceutical composition including the levetiracetam was prepared in a table 4.

Specifically, levetiracetam was sieved with 30-mesh sieve, granulated with aqueous polyvinyl pyrrolidone solution, and dried at 50 ^°C . The dried granules were classified with 20-mesh sieve, mixed with hydroxypropyl methylcellulose, lubricated with Magnesium stearate and colloidal silica, and then compressed into tablet. The tablet was coated with aqueous dispersion solution including ethyl cellulose (Comparative Example 1), Opadry(Comparative Example 3), or aqueous dispersion solution including ethylecellulose and Opadry (Comparative Example 2). The coated tablet was cured at 55 ^°C for 1 hour.

[Table 4]

. means a sufficient amount

Test Example 1. Test of dissolution rate at various time

The sustained-release tablets in Examples 1 to 12 and Comparative Examples 1 to 3 were tested for the dissolution of levetiracetam in 900m£ of pH 6.8 phosphate buffer as a dissolving medium at 40-mesh basket (USP type 1) at 37 ^°C and 100 rpm, and the results were shown in Table 5.

[Table 5]

As shown in Table 5, the tablets of Examples 1 to 12 represented the effective control of levetiracetam release, and constant release rate of levetiracetam which was 20-40% in 1 hour, 40-60% in 2 hours, 80% or higher in 6 hours, unlike the tablets of Comparative Examples 1 to 3 levetiracetam.

Therefore, the stable release rate of pharmaceutical composition can increase the subject's compliance and have an improved dissolution stability in various releasing conditions. Test Example 2. Test of dissolution stability in long-term storage

Shortly after the sustained-release tablets of Examples 3 and 1 1 and Comparative Example 3, the tablets were in completely open state without packaging at 40 ^°C and a relative humidity of 75% for 6 months and then were tested for the dissolution of levetiracetam in 900m£ of pH 6.8 phosphate buffer as a dissolving medium at 40-mesh basket (USP type 1) at 37 ^°C and 100 rpm in 1 , 2, 4, 6, 8 and 12 hour. The results were shown in Table 6.

[Table 6]

4 78.5 75.1 72.4 70.1 61. 1 44.8

6 94.5 92.2 86.5 86.4 74.2 56.2

8 102.0 98.4 95.6 96.7 83.9 67.2

12 106.5 102.4 103.0 102.4 94.8 80. 1

As shown in Table 6, the tablets prepared by the direct compressing method in Examples 3 and 1 1 represented nearly constant release rate even after 6 months, but the tablet prepared by wet granulating method in Comparative Example 3 showed largely-decreased release rate. Thus, the result confirmed that the tablet prepared by the method of present invention maintained still excellent dissolution stability after long-term storage.

Test Example 3. Test of bioequivalence at fed condition

The sustained-release tablet is required to test bioequivalence at fed condition.

The in vitro dissolution test was performed to predict the bioequivalence at fed condition, according to the test method disclosed in the journal of "M. Zahirul I. Khan. International Journal of Pharmaceutics 140(19-6) 131 143 Dissolution testing for sustained or controlled release oral dosage forms and correlation with in vivo data: challenges and opportunities."

Specifically, the sustained-release tablets of Example 3 and Comparative Example 1 were tested for the dissolution degree of levetiracetam by using 900m# of pH 1.2 hydrochloric acid/sodium chloride solution as a dissolving medium, which is similar to the gastrointestinal condition, and by adding the compounds in Table 7 at 40-mesh basket (USP type 1) at 37 ^°C and 100 rpm in 1, 2, 4, 6, 8 and 12 hour. The results were shown in Table 7.

[Table 7] hour, % No addition Polystyrene bead oil Pepsin

Example 3 32.1 35.3 31.6 30.3

1 Comparative Example

1 1.5 24.7 9.7 16.6 1

Example 3 50.8 53.9 49.3 46.8

2 Comparative Example

22.9 42.5 27.5 34.4 1

Example 3 78.4 75.3 73.9 73.4

4 Comparative Example

42.4 63.8 48.8 59.3 1

Example 3 92.9 88.2 89.9 89.7

6 Comparative Example

56.3 78.4 63.4 74.3 1

Example 3 99.2 93.8 99.8 95.5

8 Comparative Example

67.1 88.6 73.6 83.1 1

Example 3 101.6 96.3 107.0 102.4

12 Comparative Example

88.3 97.4 82.4 90.0 1

As shown in Table 7, when the change in dissolution rate for imitate gasterointestinal tract condition after feeding the food was compared with the change in dissolution rate for the general in vitro dissolution condition (no addition group), the dissolution rate of Comparative Example 1 showed larger change than that of Example 3. When the dissolution rate of polystyrene bead addition group was compared with that of no addition group, Comparative Example 1 showed the difference of dissolution rate by 13.2% in 1 hour after adding the polystyrene bead, but Example 3 was only 3.2%». In 2 hours after adding the polystyrene bead, the difference in the dissolution rate was 19.6% for Comparative Example 1 , but 3.1% for Example 3. The pepsin addition group showed largest difference in dissolution rate, but Example 3 showed even 4%. After 6 hours, Comparative Example 1 showed largest difference in dissolution rate, 22.1 % but Example 3 showed only 4.7% of dissolution rate.

As described above, the composition prepared by the Examples of the present invention showed constant dissolution rate which was not affected by the food-feeding, and very excellent dissolution stability.

Claims

[CLAIMS!

1. A sustained-release pharmaceutical composition, comprising

an active ingredient including a levetiracetam or a pharmaceutically acceptable salt thereof;

a sustained-release material including a water-swellable polymer; and a pharmaceutically acceptable excipient.

2. The sustained-release pharmaceutical composition according to claim 1 , wherein the levetiracetam or pharmaceutically acceptable salt thereof is contained at an amount of 50 to 90 wt% with respect to the total pharmaceutical composition.

3. The sustained-release pharmaceutical composition according to claim 1, wherein the water-swellable polymer has 50 to 100,000mPa · s of viscosity which is measured at 2wt% concentration in water at 20 ^°C .

4. The sustained-release pharmaceutical composition according to claim 1, wherein the water-swellable polymer is at least one selected from the group consisting of methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydro xybutylcellulose, hydroxyethylmethylcellulose, hypromellose, galactomannans, tragacanth, agar, guar gum, polyfructan, methacrylate copolymer, polyvinylalcohol, polyvinylpyrrolidone, polyvinylpyrrolidone-vinylacetate copolymer(PVP-PVA), a mixture of polyvinylalcohol and polyvinylpyrrolidone, polyethylene oxide, polypropylene oxide, ethylene oxide-propylene oxide copolymer, acrylate polymer, methacrylate copolymer, alginate, carrageenan, acasia, xanthan gum, chitin derivative, sodium carmellose, cecium carmellose, carbomer and a mixture thereof.

5. The sustained-release pharmaceutical composition according to claim I , wherein the water-swellable polymer is at least one selected from the group consisting of polyethylene oxide, hydroxypropyl cellulose, hydroxyethyl cellulose, alginate, carbomer and a mixture thereof.

6. The sustained-release pharmaceutical composition according to claim 5, wherein the polyethylene oxide has 400 to 20,000mPa · s of viscosity which is measured at 2wt% concentration in water at 20 ^°C .

7. The sustained-release pharmaceutical composition according to claim 5, wherein the hydroxypropyl cellulose has 50 to 10,000mPa · s of viscosity which is measured at 2wt% concentration in water at 20 ^°C .

8. The sustained-release pharmaceutical composition according to claim 5, wherein the hydroxyethyl cellulose has 150 to 10,000mPa · s of viscosity which is measured at 2wt% concentration in water at 20 ^°C .

9. The sustained-release pharmaceutical composition according to claim 1, wherein the water-swellable polymer is contained at an amount of 5 to 50 wt% with respect to the total pharmaceutical composition.

10. The sustained-release pharmaceutical composition according to claim 1 , wherein the dissolution rate of levetiracetam or pharmaceutically acceptable salt thereof is 20-40% in 1 hour, 40-60% in 2 hour, and 80% or higher in 6 hours or longer which are measured by using 900 ml of dissolution media (pH 6.8) in 40 mesh basket(USP type 1 ) at 37 ^°C ± 0.5 ^°C and 80 rpm to 120 rpm.

1 1. A method of preparing a sustained-release pharmaceutical composition comprising the steps of

mixing a levetiracetam or a pharmaceutically acceptable salt thereof, a water-swellable polymer, and a pharmaceutically acceptable excipient; and

lubricating and directly compressing the mixture into a tablet.