KR20200107586A - Oral tablet composition for constant(zero-order) and sustained release of Rivastigmine - Google Patents

Abstract

In the present invention, disclosed is a sustained-release tablet composition for oral administration of rivastigmine which lowers a maximum blood concentration (C_max) of a drug by having a constant release profile to minimize side effects such as nausea and vomiting, and which maintains an effective drug concentration in the blood for more than 14 hours, while having significantly improved drug compliance by orally taking the composition once a day. The tablet composition according to the present invention can be manufactured by a simple manufacturing method such as a direct tableting method, a dry granulation method, or a wet (granular) compression method.

Description

{Oral tablet composition for constant (zero-order) and sustained release of Rivastigmine}

The present invention relates to a constant (0-order) release type oral sustained-release tablet composition of rivastigmine, and more particularly, by lowering the maximum blood concentration (C _max ) of the drug by having a constant release profile, nausea and vomiting and It relates to an oral sustained-release tablet composition of rivastigmine in which the effective drug concentration is maintained in the blood for more than 14 hours while minimizing the same side effects, and the adherence to the medication is significantly improved by oral administration once a day.

Rivastigmine is (S)-N-ethyl-3-[(1-dimethylamino)ethyl]-N-methylphenyl-carbamate having the structure of the formula:

Rivastigmine is an acetylcholine-degrading enzyme inhibitor and is a drug used in mild to severe Alzheimer's-type dementia or Parkinson's disease. This drug improves symptoms by improving the rate of transmission of the neurotransmitter acetylcholine to the central nervous system.

Rivastigmine has a short half-life in the blood of about 1 to 1.5 hours, making it difficult to develop a sustained-release preparation. The current commercially available oral rivastigmine formulation is taken twice a day as the basic dosage, and nausea and vomiting are very common side effects, so medication compliance is poor. Moreover, since patients with dementia have low adherence to basic medications due to poor memory, there has been a demand for the development of oral sustained-release formulations with low side effects and low intake frequency with a constant release profile.

In conventional sustained-release formulation techniques, a water-soluble polymer matrix system has been used. However, for drugs with high water solubility such as rivastigmine, when using a water-soluble polymer matrix system, it is difficult to control the initial release amount, and the release of the drug was also not constant until about 14 hours when the final drug stays in the digestive tract.

Patent Publication No. 10-2016-0127405 discloses a sustained-release pharmaceutical composition containing rivastigmine, a pH-dependent delayed-release spherical granule comprising an ethylcellulose aqueous dispersion (Surelease) coating layer and a pH-dependent polymer coating layer on the drug layer And, after preparing a sustained-release dry granule containing a drug, and then mixing and tableting them again, a tablet composition is proposed, but the manufacturing process is complicated and requires special equipment, It is a simple sustained-release formulation that does not show a release profile.

Therefore, there is an urgent need to develop an oral sustained-release composition for oral administration of rivastigmine, which can be easily applied to the actual process because it can be manufactured by a simple manufacturing method while having a constant release profile.

Accordingly, the present inventors continued research to develop an oral sustained-release formulation of rivastigmine, as a result, by mixing a hydrophilic polymer (hydroxypropylmethylcellulose) and carrageenan in a specific ratio and using a plastic additive together, a certain ( The present invention has been completed by developing an oral tablet of rivastigmine having a 0-order) release profile and remarkably improved dosage compliance.

Accordingly, it is an object of the present invention to provide a sustained-release tablet composition for oral administration of rivastigmine in a once-a-day dosage that maintains an effective drug concentration in blood for more than 14 hours by having a constant release profile.

Another object of the present invention is to provide a method of treating Alzheimer's-type dementia or Parkinson's disease using the oral sustained-release tablet composition of rivastigmine.

In order to achieve the above object, the present invention provides a constant (0-order) release type oral sustained-release tablet composition of rivastigmine comprising rivastigmine, a hydrophilic polymer, carrageenan, and a plastic additive.

In the present invention,'rivastigmine' may exist as a free base, but may also exist as derivatives such as acid addition salts, hydrates, and solvates. Unless otherwise stated, these derivatives will be included in the designation'rivastigmine'. A preferred acid addition salt of rivastigmine is rivastigmine tartrate.

In the tablet composition of the present invention, labastigmine may be included in an amount of 4.8 to 19.2 mg. The content of rivastigmine may be appropriately included within the above range depending on the mildness or severity of the disease.

Rivastigmine has a peculiar pharmacokinetic property of being rapidly and evenly absorbed in the large intestine and large intestine, so if the drug is formulated to be released regularly and slowly, it can be continuously absorbed until discharged after taking it, thereby exhibiting a medicinal effect.

In the present invention, the term'sustained release' means that the drug is released over a long period of time so that the drug can act over a long period of time.

In the present invention, the term'constant release type' or '0-order release type' means that the drug (rivastigmine) is released at a constant release rate over 14 hours, and is in a straight line form in the cumulative drug dissolution rate graph over time Represents. Preferably, 10 to 25% of the total weight of the drug until 2 hours after the start of dissolution, 30 to 40% up to 4 hours, 40 to 60% up to 6 hours, 60 to 75% up to 10 hours, 80% or more up to 14 hours Means to be released. Most preferably, 14 to 25% of the total weight of the drug until 2 hours after initiation of dissolution after administration, 30 to 38% up to 4 hours, 45 to 55% up to 6 hours, 65 to 75% up to 10 hours, 80% or more up to 14 hours It means that it is released.

The constant (0-order) release type sustained-release formulation maintains a substantially constant release rate over an extended period while maintaining the drug release at a constant rate. Therefore, since it is possible to prevent the plasma drug concentration from becoming a relatively high peak in the early stage, side effects are minimized and constant efficacy of the drug is achieved during a long treatment period. In addition, medication adherence can be improved by reducing the number of times the drug is administered (dosing) over time.

In the present invention, the'hydrophilic polymer' is a hydrophilic polymer having a sustained release property and a viscosity of 4,000 to 100,000 cps or less, and includes hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), and carboxymethyl One or more selected from the group consisting of cellulose (CMC) and mixtures thereof may be used. Most preferably, hydroxypropylmethylcellulose is used.

In the present invention, "Carrageenan" is a red algae derived from molecular weight of 100,000 to 500,000 linear sulfated polysaccharides, has a unit structure as described below, sulfate group (OSO ₃ ^-) in the structure of the unit according to the content of kappa (k) - carrageenan, iota It can be divided into (i)-carrageenan and lambda (λ)-carrageenan.

In the present invention, the three types of carrageenan may be used individually or in combination, and lambda-carrageenan is preferably used.

If carrageenan is not included in the tablet composition of the present invention, the initial release of rivastigmine is not properly suppressed, and if the hydrophilic polymer is not included, rapid release of rivastigmine after 2 hours (Comparative Examples 1 to 4).

In the tablet composition of the present invention, the mixing weight ratio of the hydrophilic polymer and carrageenan is preferably 1:1 to 3:1, and the sum of the weight of the hydrophilic polymer and carrageenan is preferably 57 to 86% by weight. Most preferably, the mixing weight ratio of the hydrophilic polymer and carrageenan is 1:1.

Surprisingly, when the hydrophilic polymer and carrageenan were included in the sum of the weight ratio and weight as described above, the tablet composition of the present invention showed a constant release profile (straight line) up to 14 hours after administration (Examples 1 to 4). Such a remarkable effect is that when the hydrophilic polymer and carrageenan are included in the sum of the weight ratio and weight as described above, the sustained-release property of the hydrophilic polymer, the swelling property of the carrageenan and the ionic interaction between the methyl group present in rivastigmine and the sulfate group present in carrageenan It seems to be due to the complex action of action and the like.

When the mixing weight ratio of the hydrophilic polymer and carrageenan is out of the above range, or the sum of the weights of the hydrophilic polymer and carrageenan is out of the above range, a constant release profile (linear) could not be exhibited (Comparative Examples 5 to 7).

The tablet composition of the present invention contains 2 to 3% by weight of a plastic additive. Plastic additives act as a binder when high molecular weight polymers such as carrageenan are included in a high content to facilitate the formation of tablets of high hardness by enhancing moldability, thereby enhancing the sustained-release properties of the tablet composition to release more consistent drugs. Have a profile (Table 6, Figure 6). As the plastic additive that can be used in the present invention, at least one selected from the group consisting of silica (light anhydrous silicic acid), magnesium oxide, zinc oxide, and mixtures thereof may be used. Most preferably, it is silica.

The tablet composition of the present invention may further include excipients such as diluents, lubricants, and binders (when prepared by wet granulation), which are commonly used in the pharmaceutical field at the time of formulation. Examples of diluents include microcrystalline cellulose, corn starch, lactose, mannitol, sorbitol, arabinose, xylitol, dextrose, sodium carboxymethylcellulose, and xanthan gum, and as lubricants, magnesium stearate, stearic acid, light anhydrous silicic acid , Talc, sodium lauryl sulfate, and the like, and as the binder, polyvinylpyrrolidone or a copolymer thereof (eg povidone, copovidone (V64)), hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxy Ethanol solutions or aqueous solutions of oxypropylmethylcellulose, gum arabic and chitosan may be listed, but are not limited thereto, and one or more may be selected and used as necessary.

In addition, colorants, sweeteners, flavoring agents, preservatives, and the like may be contained as needed.

The amount of the excipients, colorants, sweeteners, flavoring agents, preservatives, and the like may be appropriately selected according to the purpose.

The tablet composition of the present invention may be prepared by a conventional method for preparing tablets, for example, a direct tableting method, a dry granulation method, or a wet (granulation) compression method. That is, a conventional pharmaceutical excipient may be added to prepare a mixture for direct compression, or a granule product through a process such as wet granulation or dry granulation, and then compressed to prepare a tablet.

The average weight of one tablet of the tablet composition according to the present invention is, but is not limited to, 200 to 400 mg, and preferably 350 mg.

The tablet composition according to the present invention can be administered orally once a day.

When tested by the paddle method (proceeding in an environment similar to in vivo gastric juice and intestinal fluid by dissolution time), the tablet composition according to the present invention showed a linear shape over 14 hours in a graph of cumulative dissolution rate of rivastigmine over time, resulting in a constant (0-order) ) It was confirmed that it has a release profile (Test Example 1). Specifically, 10 to 25% of the total weight of rivastigmine until 2 hours of dissolution start, 30 to 40% up to 4 hours, 40 to 60% up to 6 hours, 60 to 75% up to 10 hours, and 80% or more by 14 hours (Table 1, Figs. 1 to 3).

Therefore, the tablet composition according to the present invention has a constant (0-order) release profile, so that when taken orally once a day, the effective drug concentration is maintained in the blood for more than 14 hours, while achieving the drug efficacy, the highest blood concentration of the drug (C _max. ) Can also reduce side effects such as nausea and vomiting.

According to another object of the present invention, there is provided a method for treating Alzheimer's-type dementia or Parkinson's disease comprising the step of orally administering the tablet composition according to the present invention to an individual once a day.

In the present invention, "individual" refers to a subject in need of treatment for the disease, and more specifically refers to a human or non-human primate, mammal, and the like.

The tablet composition according to the present invention has a constant (0-order) release profile of rivastigmine up to 14 hours of dissolution, so it is useful as a once-a-day oral formulation for the treatment of Alzheimer's type dementia or Parkinson's disease.

In addition, the oral sustained-release tablet composition according to the present invention has a constant (0-order) release profile of rivastigmine so that the effective drug concentration is maintained in the blood for more than 14 hours to achieve the medicinal effect while achieving the highest blood concentration of rivastigmine ( C _max ) is also lowered to minimize side effects such as nausea and vomiting.

Since rivastigmine has the property of being rapidly and evenly absorbed in the human small and large intestine, the oral sustained-release tablet composition according to the present invention having a constant release profile is released regularly for 14 hours passing through the digestive tract of the human body after taking It is continuously absorbed and can maintain its medicinal effect.

Due to the characteristics of the tablet composition according to the present invention as described above, ease of administration and patient compliance for Alzheimer-type dementia or Parkinson's disease patients are significantly improved.

In addition, the tablet composition according to the present invention may be prepared by a simple manufacturing method such as a direct tableting method, a dry granulation method, or a wet (granule) compression method.

1 is a graph showing the dissolution pattern of the oral sustained-release tablet composition according to the present invention exhibits a constant (0-order) release profile.
2 is a graph showing the cumulative dissolution rate over time for 24 hours of the tablet compositions of Examples 1 to 3.
3 is a graph showing the cumulative dissolution rate over time for 24 hours of the tablet composition of Example 4.
4 is a graph showing the cumulative dissolution rate over time for 24 hours of the tablet compositions of Comparative Examples 1-4.
5 is a graph showing the cumulative dissolution rate over time for 24 hours of the tablet compositions of Comparative Examples 5-7.
6 is a graph showing the cumulative dissolution rate over time for 24 hours of the tablet composition of Comparative Example 8 compared to Example 1.

The present invention is explained in more detail by the following examples. These examples are intended to illustrate the invention, and the scope of the invention should not be limited by them.

Manufacturing example 1: Dry preparation of the tablet composition according to the present invention

The tablet compositions of Examples 1 to 3 were prepared by a direct tableting method so that each tablet had a composition as shown in Table 1 below.

Specifically, in the case of Example 1, 1.92 g of rivastigmine tartrate and 10 g of lambda-carrageenan (Viscarin® GP 109) were mixed, and then apples were made through a 50 mesh sieve. Then, 10 g of hydroxypropylmethylcellulose 2208 (Metolose® 90SH-100000SR) and 12.03 g of microcrystalline cellulose (Pharmacel® 102) were mixed, 0.7 g of silica (Syloid® 244 FP) and 0.35 g of magnesium stearate were further mixed. Then, 100 tablets were prepared by tableting so that the weight per tablet was 350 mg using a compression tablet press.

In the case of Example 2, lambda-carrageenan (Viscarin® GP 109) 15 g, hydroxypropylmethylcellulose 2208 (Metolose® 90SH-100000SR) 15 g, microcrystalline cellulose (Pharmacel® 102) 2.03 g. In the case of Example 3, lambda-carrageenan (Viscarin® GP 109) 5 g, hydroxypropylmethylcellulose 2208 (Metolose® 90SH-100000SR) 15 g, microcrystalline cellulose (Pharmacel® 102) 12.03 g. , The remaining ingredients were prepared in the same manner as in Example 1 and 100 tablets each.

The tablet compositions of Examples 1 to 3 contain 19.2 mg of rivastigmine tartrate per tablet.

Composition per tablet (content unit mg) ingredient Example 1 Example 2 Example 3 Example 4 Rivastigmine Tartrate 19.2 19.2 19.2 19.2 Lambda-carrageenan 100 150 50 100 Hydroxypropylmethylcellulose 100 150 150 100 Microcrystalline cellulose 120.3 20.3 120.3 113.3 Silica (hard anhydrous silicic acid) 7 7 7 7 Magnesium stearate 3.5 3.5 3.5 3.5 Polyvinylpyrrolidone (binder) - - - 7 total 350 350 350 350

Manufacturing example 2: Wet preparation of the tablet composition according to the present invention

A tablet composition was prepared by a wet (granular) compression method using a polyvinylpyrrolidone K-30 ethanol solution as a binder so as to have the same composition as Example 4 in Table 1 per tablet.

Specifically, 1.92 g of rivastigmine tartrate and 10 g of lambda-carrageenan (Viscarin® GP 109) were mixed, and then apples were made through a 50 mesh sieve. 5% (w/w) polyvinylpyrrolidone K-30 ethanol solution was added, the powder was kneaded, apples were apples through a 14 mesh sieve, and dried to prepare wet granules. To the prepared wet granules, 10 g of hydroxypropylmethylcellulose 2208 (Metolose® 90SH-100000SR) and 11.33 g of microcrystalline cellulose (Pharmacel® 102) were mixed, and 0.7 g of silica (Syloid® 244 FP) and 0.35 g of magnesium stearate After further mixing, 100 tablets were prepared by tableting so that the weight per tablet was 350 mg using a compression tablet press.

Test example 1: dissolution test

The dissolution tests of the tablets of Examples 1 to 4 prepared in Preparation Examples 1 and 2 were performed in an environment similar to gastric juice and intestinal fluid in vivo.

Specifically, for each tablet of Examples 1 to 4, from the start of elution to 2 hours at 37°C, in 750 mL of 0.1N HCl eluate (pH 1.2), and at 2 hours, 250 mL of 0.25M tribasic phosphate buffer was added. After 2 hours, the eluate was changed to neutral pH (pH 6.8) and the dissolution test was carried out for 24 hours by the paddle method under the rotation condition of 50 rpm.

15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours and 24 hours after the start of the dissolution test, the eluate was collected and filtered through a 0.45㎛ membrane filter After analyzing the content of rivastigmine using high performance liquid chromatography under the following conditions, the cumulative rivastigmine dissolution rate for each time was calculated and shown in Table 2 and FIGS. 1 to 3:

Measurement wavelength: 217nm

Column: C18, 4.6 x 250 mm

Temperature: 5℃

Mobile phase: 20 mM potassium phosphate buffer (pH 3): acetonitrile = 70: 30

Flow rate: 1.0 mL/min

Sample injection volume: 20 µl

Cumulative dissolution rate of rivastigmine (%) Time (minutes) 0 15 30 60 120 240 360 480 600 720 840 1440 Example 1 0 8.9 12.4 16.6 22.3 32.3 45.2 54.6 65.7 74.5 82.2 97.8 Example 2 0 2.9 5.9 10.3 14.8 34.6 46.3 57.7 66.5 77.5 84.0 92.1 Example 3 0 5.3 9.4 14.6 19.5 32.7 51.9 67.1 74.9 84.7 88.2 89.8 Example 4 0 5.6 9.4 15.3 24.7 36.7 51.3 62.7 72.3 84.2 90.8 96.0

As shown in Figs. 1 to 3, the tablets of Examples 1 to 4 according to the present invention all have a constant release profile (linear) up to 14 hours, that is, 10 to 25 of the total weight of rivastigmine until 2 hours from the start of dissolution. %, 30 to 40% up to 4 hours, 40 to 60% up to 6 hours, 60 to 75% up to 10 hours, and 80% or more by 14 hours.

Examples 1 and 2 were tablet compositions containing hydroxypropylmethylcellulose and lambda-carrageenan in a 1:1 weight ratio (100mg/100mg, 150mg/150mg, respectively), and showed the most linear dissolution pattern, that is, the most constant release rate. . In addition to the sustained-release action of hydroxypropylmethylcellulose, the action of inhibiting the initial release of the drug of lambda-carrageenan and silica exerts a synergistic effect, indicating the above-described zero-order release profile.

Example 3 is a tablet composition in which the weight ratio of hydroxypropylmethylcellulose and lambda-carrageenan is 3:1 (150mg/50mg), and Example 4 is hydroxypropylmethylcellulose and lambda prepared by a wet (granular) compression method. -A tablet composition in which the weight ratio of carrageenan is 1:1 (100mg/100mg), 10 to 25% of the total weight of rivastigmine based on the 0-order release profile, 30 to 40% for up to 4 hours, 40 to 60 for up to 6 hours %, 60-75% for 10 hours, and 80% or more for 14 hours were satisfied.

It is known that rivastigmine is rapidly and evenly absorbed in the ileum, jejunum, and ascending colon, as well as in the duodenum of humans (J Clin Pharmacol, 2004).The tablets of Examples 1 to 4 having a constant release profile affect the digestive tract of the human body after administration. During the passing of 14 hours, it can be released constantly and continuously absorbed to show medicinal effects.

Manufacturing example 3: Comparative example Preparation of 1 to 8 tablet compositions

For comparison, 100 tablets of each of the tablet compositions of Comparative Examples 1 to 8 were prepared in the same manner as in Preparation Example 1 by a direct tableting method, except that each tablet was composed of the composition shown in Table 3 and Table 4 below. .

Specifically, the tablet compositions of Comparative Examples 1 and 2 (without lambda-carrageenan) were 1.92 g of rivastigmintartrate, hydroxypropylmethylcellulose 2208 (Metolose® 90SH-100000SR) 10 g or 20 g, microcrystalline cellulose (Pharmacel® 102) 22.03 g or 12.03 g, silica (Syloid® 244 FP) 0.7 g, and magnesium stearate 0.35 g were mixed and then tableted to a weight of 350 mg per tablet, and 100 tablets were prepared.Rivastigmintart per tablet It contains 19.2mg rate.

The tablet compositions of Comparative Examples 3 and 4 (hydroxypropylmethylcellulose not included) 1.92 g of rivastigmintartrate and 10 g or 20 g of lambda-carrageenan (Viscarin® GP 109), microcrystalline cellulose (Pharmacel® 102) After mixing 22.03 or 12.03 g, 0.7 g of light anhydrous silicic acid, and 0.35 g of magnesium stearate, 100 tablets were prepared by tableting so that the weight of each tablet was 350 mg, and 19.2 mg of rivastigmine tartrate was contained.

The tablet composition (not containing silica) of Comparative Example 8 was 1.92 g of rivastigmintartrate, 10 g of lambda-carrageenan (Viscarin® GP 109), 10 g of hydroxypropylmethylcellulose 2208 (Metolose® 90SH-100000SR), After mixing 12.73 g of microcrystalline cellulose (Pharmacel® 102) and 0.35 g of magnesium stearate, each tablet was tableted to a weight of 350 mg to prepare 100 tablets, and 19.2 mg of rivastigmine tartrate was contained per tablet.

Composition per tablet (content unit mg) ingredient Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 8 Rivastigmine Tartrate 19.2 19.2 19.2 19.2 19.2 Lambda-carrageenan - - 100 200 100 Hydroxypropylmethylcellulose 100 200 - - 100 Microcrystalline cellulose 220.3 120.3 220.3 120.3 127.3 Silica (hard anhydrous silicic acid) 7 7 7 7 - Magnesium stearate 3.5 3.5 3.5 3.5 3.5 total 350 350 350 350 250

The tablet compositions of Comparative Examples 5 to 7 were prepared by 100 tablets each in the same manner as in Preparation Example 1 by the direct tableting method, except that the tablet compositions of Comparative Examples 5 to 7 were composed of the composition shown in Table 4 per tablet. I did.

Composition per tablet (content unit mg) ingredient Comparative Example 5 Comparative Example 6 Comparative Example 7 Rivastigmine Tartrate 19.2 19.2 19.2 Lambda-carrageenan 50 50 50 Hydroxypropylmethylcellulose 50 100 200 Microcrystalline cellulose 220.3 170.3 70.3 Silica (hard anhydrous silicic acid) 7 7 7 Magnesium stearate 3.5 3.5 3.5 total 350 350 350

Test example 2: Comparative dissolution test

The dissolution test of the tablets of Comparative Examples 1 to 7 prepared in Preparation Example 3 was carried out for 24 hours by the paddle method under the same conditions as in Test Example 1, and the high performance liquid chromatography was used under the same conditions. After analyzing the content, the cumulative rivastigmine dissolution rate for each time was calculated and shown in Table 5, FIGS. 4 and 5.

Cumulative dissolution rate of rivastigmine (%) Time (minutes) 0 15 30 60 120 240 360 480 600 720 840 1440 Comparative Example 1 0 11.5 17.1 24.4 35.5 49.5 59.9 65.5 71.0 77.2 80.5 93.7 Comparative Example 2 0 8.6 13.5 19.2 28.9 41.1 49.6 56.4 61.8 68.9 74.5 87.6 Comparative Example 3 0 6.0 12.0 23.4 48.4 74.9 87.5 89.1 91.4 92.6 93.3 96.2 Comparative Example 4 0 4.4 7.4 14.9 32.1 59.5 83.9 95.6 100.1 101.5 99.9 99.8 Comparative Example 5 0 5.9 11.2 17.9 24.4 52.5 63.4 72.0 77.2 86.9 91.4 91.3 Comparative Example 6 0 8.4 11.8 17.5 27.0 40.8 53.7 62.7 70.6 76.9 82.6 96.6 Comparative Example 7 0 8.4 11.3 16.0 24.2 36.5 47.0 56.6 65.0 70.6 76.2 94.9

Comparative Examples 1 and 2, which are tablet compositions that do not contain carrageenan, show sustained release for more than 14 hours depending on the content of hydroxypropylmethylcellulose, but the initial release was not properly suppressed and the release rate of rivastigmine was not constant. The pattern is not straight and is 10 to 25% of the total weight of rivastigmine up to 2 hours from the start of dissolution based on the 0-order release profile, 30 to 40% for up to 4 hours, 40 to 60% for up to 6 hours, 60 to up to 10 hours 75%, did not satisfy the release pattern of 80% or more until 14 hours (Fig. 4).

Comparative Examples 3 and 4, which are tablet compositions not containing hydroxypropylmethylcellulose, suppressed the initial release, but showed rapid release after 2 hours of elution, and did not have a constant release profile of rivastigmine (FIG. 4).

The tablet compositions of Comparative Example 5 (100mg) and Comparative Example 6 (150mg) in which the sum of the weight of hydroxypropylmethylcellulose and carrageenan is less than 57% by weight are also not uniform in the release rate of rivastigmine, so the overall dissolution pattern is not linear. 10 to 25% of the total weight of rivastigmine up to 2 hours from the start of dissolution, which is based on the 0-th release profile, 30 to 40% by 4 hours, 40 to 60% by 6 hours, 60 to 75% by 10 hours, The release pattern of 80% or more was not satisfied until 14 hours (FIG. 5).

The tablet composition of Comparative Example 7 in which the weight ratio of hydroxypropylmethylcellulose and carrageenan was 4:1 (200mg/50mg) showed 76.2% dissolution up to 14 hours, based on the 0-order release profile (Rivasti 10 to 25% of the total weight of Gummin, 30 to 40% up to 4 hours, 40 to 60% up to 6 hours, 60 to 75% up to 10 hours, and 80% or more release aspects up to 14 hours) were not satisfied (Fig. 5 ).

Test example 3: On the hardness and dissolution pattern of the tablet Plastic additive Action analysis

In order to analyze the moldability and dissolution pattern of the tablet according to the addition of the calcined additive, the tablet of Example 1 prepared in Preparation Example 1, and the carrageenan and hydroxypropylmethylcellulose contained the same content and did not contain only real car. The moldability and dissolution patterns of the tablets of Comparative Example 8 prepared in Preparation Example 3 were compared.

During manufacture, the tablet of Example 1 was tableted with a high hardness of 30 kg, but the tablet of Comparative Example 8 was tableted with only a low hardness of 16 kg. Therefore, it can be seen that silica improves the moldability of the tablet, thereby enabling the formation of high hardness tablets.

The dissolution test of the tablet of Comparative Example 8 was carried out for 24 hours by the paddle method under the same conditions as in Test Example 1, and the content of rivastigmine was analyzed using high performance liquid chromatography under the same conditions, and then each time The cumulative rivastigmine dissolution rate was calculated and compared with Example 1 and shown in Table 6 and FIG. 6.

Cumulative dissolution rate of rivastigmine (%) Time (minutes) 0 15 30 60 120 240 360 480 600 720 840 1440 Example 1 0 8.9 12.4 16.6 22.3 32.3 45.2 54.6 65.7 74.5 82.2 97.8 Comparative Example 8 0 6.3 9.8 15.4 24.0 36.7 48.6 60.7 75.5 80.1 86.5 93.4

As shown in Table 6 and FIG. 6, in the tablet of Comparative Example 8 composed of only silica from the tablet composition of Example 1, the dissolution of rivastigmine began to increase from 2 hours to 14 hours. It can be seen that the degree of this is significantly reduced compared to Example 1. Therefore, it can be seen that silica not only affects the moldability of the tablet, but also increases the sustained-release property of the tablet composition, so that the tablet has a zero-order release profile more easily.

Claims (11)

A constant release oral sustained-release tablet composition of rivastigmine containing rivastigmine, a hydrophilic polymer, carrageenan and a plastic additive,
The sum of the weight of the hydrophilic polymer and carrageenan is 57 to 86% by weight and the plastic additive is included in 2 to 3% by weight,
The weight ratio of the hydrophilic polymer and carrageenan is 1:1 to 3:1,
The tablet composition is 10 to 25% of the total weight of rivastigmine up to 2 hours from the start of dissolution, 30 to 40% up to 4 hours, 40 to 60% up to 6 hours, 60 to 75% up to 10 hours, 80% or more up to 14 hours The tablet composition that is eluted.
The method of claim 1, wherein the hydrophilic polymer is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC), and mixtures thereof. A constant release oral sustained-release tablet composition of rivastigmine that is one or more.
According to claim 2, wherein the hydrophilic polymer is hydroxypropylmethylcellulose (HPMC) is a constant-release oral sustained-release tablet composition of rivastigmine.
The constant release oral sustained-release tablet composition of claim 1, wherein the plastic additive is at least one selected from the group consisting of light anhydrous silicic acid, magnesium oxide, zinc oxide, and mixtures thereof.
According to claim 4, wherein the plastic additive is a light anhydrous silicic acid constant release oral sustained-release tablet composition of rivastigmine.
According to claim 1, wherein the carrageenan is lambda-carrageenan constant release oral sustained-release tablet composition of rivastigmine.
The constant release oral sustained-release tablet composition of claim 1, wherein the weight ratio of the hydrophilic polymer and carrageenan is 1:1.
The constant release oral sustained-release tablet composition of claim 1, wherein the ravastigmine is contained in an amount of 4.8 to 19.2 mg.
The oral sustained-release tablet composition of claim 1, wherein the rivastigmine is rivastigmine tartrate.
The method of claim 1, wherein the tablet composition is prepared by any one method selected from the group consisting of a direct tableting method, a dry granulation method, and a wet (granule) compression method. Sex tablet composition.
The oral sustained-release tablet composition of claim 1, wherein the tablet composition is administered once a day.

Images