MX2011005725A - Matrix pharmaceutical composition containing galantamine. - Google Patents

Abstract

The present invention relates to a pharmaceutical composition that enables easy control of a release pattern of galantamine or pharmaceutically acceptable salts thereof as an active ingredient. The pharmaceutical composition in the form of matrix comprises: granules including a therapeutically effective amount of galantamine or pharmaceutically acceptable salts thereof and aminoalkyl methacrylate copolymer; and ethylcellulose polymer particles having average particle diameter of 1 to 450 μm, wherein the amount of the galantamine is 8n mg and the average particle diameter of the ethylcellulose polymer particles is more than 15(n- 1)3 μm and not more than 15n3 μm.

Description

PHARMACEUTICAL COMPOSITION OF MATRIX BACKGROUND OF THE INVENTION Field of the invention The present invention relates to a pharmaceutical composition in the form of a matrix. More specifically, the present invention relates to the pharmaceutical composition in matrix form that allows easy control of a release pattern of galantamine or its pharmaceutically acceptable salts as an active ingredient.

Description of the related art [4aS- (4aa, 6β, 8aR *)] -4a, 5, 9, 10, 11, 12-hexahydro-3-methoxy-11-methyl-6H-benzofuro [3a, 3, 2-ef] [2] Benzazepine-6-ol of the following chemical formula 1 is generally called galantamine. Galantamine is a known acetylcholinesterase inhibitor that is active at nicotinic receptor sites but not at muscarinic receptor sites. [chemical formula 1] U.S. Pat. 4,663,318 discloses that galantamine or its pharmaceutically acceptable salts (for example: galantamine hydrobromide) is used for the treatment of Alzheimer's disease and related dementias.

Furthermore, it is known that galantamine or its pharmaceutically acceptable salts have the potential to treat conditions such as alcoholism (EP 0.449.247), nicotine dependence (O 94/16708), nerve gas poisoning (DE 4,342,174), mania (US 5,336,675), chronic fatigue syndrome (EP 0.515.302) and schizophrenia (US 5,633,238).

Galantamine therapy is considered optimal if effective plasma levels are achieved when necessary. Also, the level of peak values (Cmax) should be as low as possible in order to reduce the incidence and severity of possible side effects. For example, when a patient suffering from Alzheimer's disease is treated with galantamine, optimal efficacy is expected when effective plasma levels are maintained during the day and plasma galantamine levels as low as possible during the night. For the treatment of other conditions, for example: the treatment of breathing-related sleep disorders such as snoring and apnea, you may want to achieve the opposite situation, this is to show effective plasma levels at night and lower levels during the day .

Accordingly, for the treatment of various diseases using galantamine it is very important to reach the effective levels in plasma when necessary by controlling the release pattern of galantamine or its pharmaceutically acceptable salts. Especially, for the benefit of a patient who is generally an elderly person and has difficulty taking a dose, a pharmaceutical dosage form that can be administered only once a day and that shows effective galantamine levels in plasma at a time would be highly desirable. appropriate time Since the desirable plasma levels and release pattern may vary depending on the class or severity of the disease, easy control of the galantamine release pattern is necessary.

Taking into account the requirements, various compositions are suggested which have appropriate release patterns of galantamine or its pharmaceutically acceptable salts.

For example, the publication of U.S. Pat. 2004/0097484 discloses a pharmaceutical composition comprising a therapeutically effective amount of galantamine or its pharmaceutically acceptable salts and a pharmaceutically acceptable carrier that includes at least one gelling agent (eg, xanthan gum, locust bean gum or hydroxyalkyl celluloses).

Also, the publication of the U.S. patent no. 2005/0191349 describes a sustained release formulation comprising galantamine or its pharmaceutically acceptable salts and a material delaying release, wherein said material is an acrylate polymer (for example: methyl methacrylate copolymer) or hydroxyalkyl cellulose (eg example: hydroxypropylmethyl cellulose).

However, the above pharmaceutical compositions or sustained release formulations tend to show irregular patterns of release of galantamine or its pharmaceutically acceptable salts, even when only the amount of active ingredient of galantamine or its salts changes. Therefore, although a formulation has been designed and developed to change the amount of active ingredient taking into account the type of disease or the severity thereof, there remains a need to design and develop additional formulations separately that can release the Active ingredient in a regular and appropriate way.

For example, each of the pharmaceutical formulations comprising 10 mg, 20 mg and 30 mg of active ingredient (ie, galantamine or its pharmaceutically acceptable salts) has different active ingredient release patterns, although each formulation has the same composition ( that is, a composition that includes the same proportion of excipients as the amount of active ingredient).

Therefore, it is necessary to design the formulations separately so that all of them can release the active ingredient in a regular and appropriate manner. In this way, it is difficult to design and prepare the pharmaceutical composition that has optimum therapeutic efficacy.

In addition, a separate design of the pharmaceutical composition is necessary to control or change a little the pattern of release of the active ingredient according to the type of disease or its severity, so that the design and preparation of the pharmaceutical composition having the Therapeutic efficacy is more complicated.

Therefore, there is a continuing need for new pharmaceutical compositions in which the release pattern of galantamine or its pharmaceutically acceptable salts can be easily controlled so that its design and preparation is easy according to the type or severity of the disease.

COMPENDIUM OF THE INVENTION The present invention provides a pharmaceutical composition that allows easy control of a release pattern of galantamine or its pharmaceutically acceptable salts as an active ingredient.

In one embodiment of the present invention, the pharmaceutical composition in matrix form comprises: granules that include a therapeutically effective amount of galantamine or its pharmaceutically acceptable salts and a copolymer of aminoalkyl methacrylate and ethylcellulose polymer particles having an average diameter of particle from 1 to 450 μ?), wherein the amount of galantamine is 8n mg (n = 1 to 4, preferably n = 3) and the average particle diameter of the ethylcellulose polymer particles is greater than 15 (nl. 3 μ ?? and not greater than 15n3 [im.

In another embodiment of the present invention, the matrix pharmaceutical composition may comprise: galantamine in an amount of 8 mg and ethylcellulose polymer particles having an average particle diameter of 1 to 15 μp?; galantamine in an amount of 16 mg and ethylcellulose polymer particles having an average particle diameter of 16 to 120; or the galantamine in an amount of 24 mg and the ethylcellulose polymer particles having an average particle diameter of 125 to 350 μpp.

The present inventors, due to the experiments carried out, surprisingly discovered that said matrix pharmaceutical composition comprising a copolymer of aminoalkyl methacrylate and ethylcellulose polymer particles and satisfying the correlation between the amount of galantamine and the average particle diameter of the ethylcellulose polymer particles allow easy control of the release pattern of active ingredient due to the control of the average particle diameter of the ethylcellulose polymer particles.

Thus, a pharmaceutical composition with a desirable therapeutic efficacy can be easily provided by controlling the release pattern of active ingredient according to the type or severity of the disease and the amount of active ingredient without a substantially separate design of the composition.

DETAILED DESCRIPTION OF THE REALIZATIONS Next, a pharmaceutical composition according to embodiments of the invention will be explained in detail. However, the sole purpose of the following embodiments is to illustrate the present invention and not limit it.

Unless otherwise indicated herein, some terms used in the specification are defined as follows: The terms "comprising (understanding)", "having (having)", "including (including)" and "containing (containing)" shall be construed as open terms (ie, terms "including but not limited to a ") unless otherwise specified.

The term "amount of galantamine" means the amount of galantamine in a pharmaceutical dosage unit administered once (e.g., one tablet). When the pharmaceutical composition or dosage unit includes pharmaceutically acceptable salts of galantamine such as its acid addition salt, "amount of galantamine" means only the amount of galantamine excluding the amount of acid added.

The term "average particle diameter" of ethylcellulose polymer particles means an "average particle diameter by weight", and the average particle diameter of the ethylcellulose polymer particles is measured using a particle size analyzer such as Mastersizer. 2000 manufactured by Malvern Instruments.

In one embodiment of the invention, the pharmaceutical composition in matrix form comprises: granules that include a therapeutically effective amount of galantamine or its pharmaceutically acceptable salts and a copolymer of aminoalkyl methacrylate and ethylcellulose polymer particles having an average particle diameter from 1 to 450 [im, wherein the amount of galantamine is 8n mg (n = 1 to 4, preferably n = 3) and the average particle diameter of the ethylcellulose polymer particles is greater than 15 (n-1) 3 μp? and not more than 15n3.

With the support of the following examples, product of experiments carried out, it is observed that the pharmaceutical composition in matrix form according to an embodiment allows the easy control of the active ingredient release pattern by controlling the average particle diameter of the polymer particles. of ethylcellulose.

More specifically, it is observed that the matrix pharmaceutical composition that meets the specific correlation between the amount of galantamine and the average particle diameter of the ethylcellulose polymer particles can provide an equivalent release pattern despite changes in the amount of active ingredient.

Thus, the matrix pharmaceutical composition according to the embodiment allows easy control of the amount and pattern of release of active ingredient according to the type of disease or its severity without a substantially separate design. In the same compositions (for example: compositions that include different amounts of active ingredient and the same ratio of excipients to active ingredient), when controlling the average particle diameter of the ethylcellulose polymer particles, each of the compositions Pharmaceuticals that include different amounts of active ingredient may show an equivalent release pattern. Therefore, according to the embodiment, it is easy to design and prepare the pharmaceutical composition having the desirable therapeutic efficacy and the appropriate amount of active ingredient according to the type of disease or the severity thereof.

Furthermore, when it is necessary to control or change a little the pattern of release of the active ingredient according to the type of disease or its severity, the pattern of release of the active ingredient can be controlled or easily changed by regulating the amount of galantamine and the average particle diameter of the ethylcellulose polymer particles. Therefore, according to the invention, it is very easy to design and prepare the pharmaceutical composition having effective levels in plasma and the desirable therapeutic efficacy necessary to treat each type of disease according to its severity.

Next, a matrix pharmaceutical composition according to an embodiment of the invention will be explained in detail.

The matrix pharmaceutical composition comprises a therapeutically effective amount of galantamine or its pharmaceutically acceptable salts as the active ingredient. The pharmaceutically acceptable salts of galantamine may include, without limitation, galantamine hydrobromide, a galatamine free base and various pharmaceutically acceptable acid addition salts of galantamine.

Together with the active ingredient, the matrix pharmaceutical composition of the embodiment comprises a copolymer of aminoalkyl methacrylate and ethylcellulose polymer particles. These are water-insoluble polymers with a solubility in water of 0.1 mg / ml or less at room temperature (20 ± 5). The pattern of release of active ingredient in the body can be controlled by the aminoalkyl methacrylate copolymer and the ethylcellulose polymer particles.

In particular, the matrix pharmaceutical composition is in the form of a matrix having the active ingredient dispersed and combined in the water insoluble polymer. Accordingly, the release pattern of the active ingredient is easily controlled and the pharmaceutical composition can be easily manufactured without the need for expensive equipment.

The aminoalkyl methacrylate copolymer can be manufactured by manufacturing methods well known in the art or can be selected from pharmaceutically and commercially available excipients, for example: the Eudragit polymers.

The Eudragit polymers may include Eudragit RS or Eudragit RL, preferably Eudragit RS PO or PL PO.

The aminoalkyl methacrylate copolymer is included in the matrix pharmaceutical composition in the form of granules mixed with the active ingredient. Thus, the pattern of release of active ingredient in the body is appropriately controlled by the aminoalkyl methacrylate copolymer.

Meanwhile, together with the aminoalkyl methacrylate copolymer, the matrix composition of the embodiment comprises the ethylcellulose polymer particles as another water insoluble polymer. The ethylcellulose polymer particles are mixed with said granules including the active ingredient and the aminoalkyl methacrylate copolymer. Thus, the pattern of release of active ingredient in the body is appropriately controlled by the ethyelulose polymer particles together with the aminoalkyl methacrylate copolymer.

In particular, according to the result of the experiments of the present inventors, it is observed that the pharmaceutical composition of matrix that complies with the correlation between the amount of galanthamine of 8n mg (n = 4, preferably n = 3) and the average particle diameter of the ethylcellulose polymer particles is greater than 15 (nl) 3 Jim and not greater than 15n3 [im, can demonstrate an optimal release pattern of the active ingredient to allow dosing once a day.

In other words, when galantamine is used to treat various diseases such as Alzheimer's disease with a daily dosage, it is necessary to reach the effective level in plasma at an appropriate time, for example: during the day in the case of Alzheimer's disease , by controlling the optimal pattern of galantamine release. Based on the following examples, it is noted that if the specific correlation between the amount of galantamine and the average particle diameter of the ethylcellulose polymer particles is met, the matrix pharmaceutical composition can show the optimum release pattern of active ingredient that allows dosing once a day.

Also, it is noted that the matrix pharmaceutical composition fulfilling said correlation can show the equivalent release pattern despite changes in the amount of active ingredient in the same compositions (namely, compositions that include different amounts of active ingredient and the same proportion of excipients in relation to the active ingredient).

Therefore, according to the embodiment, it is easy to design and prepare the pharmaceutical composition having the desirable pattern of release of active ingredient, the desirable therapeutic efficacy and the appropriate amount of active ingredient according to the type of disease or severity Of the same .

Furthermore, when it is necessary to control or change a little the pattern of release of the active ingredient according to the type of disease or its severity, the pattern of release of active ingredient can be controlled or easily changed by regulating the average particle diameter of the ethylcellulose polymer particles within the range of said correlation.

In particular, the changed or controlled active ingredient release pattern can be maintained at an optimum release standard level corresponding to a once-a-day dosage.

Therefore, according to the invention, it is very easy to design and prepare the pharmaceutical composition having the effective plasma levels and the desirable therapeutic efficacy necessary to treat each type of disease according to its severity.

In the meantime, according to one embodiment, a dosage unit of the matrix pharmaceutical composition that is administered at one time may comprise galantamine in an amount of 8 mg and the ethylcellulose polymer particles having the average particle diameter. from 1 to 15 μt?; the galantamine in an amount of 16 mg and the ethylcellulose polymer particles having the average particle diameter of 16 to 120 μp?; or the galantamine in an amount of 24 mg and the ethylcellulose polymer particles having the average particle diameter of 125 to 350 μp? .

Since the matrix pharmaceutical composition meets the correlation between the amount of galantamine and the average particle diameter of the ethylcellulose polymer particles, the matrix pharmaceutical composition can show the optimum release pattern of active ingredient to allow dosing a once a day and has the therapeutic efficacy desirable for several diseases such as Alzeheimer's disease.

Also, despite changes in the amount of active ingredient, the matrix pharmaceutical composition that complies with said correlation can maintain the equivalent level of the release pattern in the same compositions and its release pattern can be easily controlled or changed in a therapeutic range. Therefore, according to the embodiment, it is easy to design and prepare the pharmaceutical composition having the optimal therapeutic efficacy necessary for each type of disease or its severity.

The ethylcellulose polymer particles included in the matrix pharmaceutical composition can have an average particle diameter of 1 to 450 μt? and preferably 1 to 350 μ ?? in a range of said correlation, in order to control the release pattern of the active ingredient in the body.

The ethylcellulose polymer particles can be manufactured by manufacturing methods well known in the art or can be selected from pharmaceutically and commercially available excipients, for example: the Ethocel polymers.

Specifically, Ethocel polymers can include Ethocel Std 7 (average particle diameter: approximately 310 | 1?)), Std 7 FP (average particle diameter: approximately 9.7 [im], Std 10 P (average particle diameter: about 375, 0 μ), Std 10 FP (average particle diameter: about 9.0 μt?), Std 100 FP (average particle diameter: about 45.0 | im).

Also, the average particle diameter of the ethylcellulose polymer particles needed in an embodiment of the invention, that is, the average particle diameter greater than 15 (nl) 3 and not greater than 15n3 | im can be achieved by controlling the degree of polymerization of the ethylcellulose polymer particles or by mixing one or more types of pharmaceutically or commercially available excipients.

Meanwhile, according to one embodiment, the matrix pharmaceutical composition can have a weight ratio in which the weight of galantamine or its pharmaceutically acceptable salts to the total weight of the polymer particles of ethylcellulose and of aminoalkyl methacrylate copolymer is in the range of 1: 4 to 1: 6.

Since the matrix pharmaceutical composition comprises the active ingredient and the two types of water-insoluble polymers in said weight ratio, the matrix pharmaceutical composition can maintain the equivalent level of release pattern and can be easily designed and prepared to have the same optimal therapeutic efficacy despite changes in the amount of active ingredient in the same compositions.

Also, the matrix pharmaceutical composition can have a weight ratio whose weight of aminoalkyl methacrylate copolymer to weight of the ethylcellulose polymer particles is in the range of 1: 0.5 to 1: 2.

Since the matrix pharmaceutical composition comprises in said weight ratio two types of water-insoluble polymer, the matrix pharmaceutical composition can maintain the equivalent level of release pattern despite changes in the amount of active ingredient in the same compositions. Also, the pharmaceutical matrix composition having the optimum therapeutic efficacy is easily designed and prepared by controlling the release pattern of active ingredient by regulating parameters such as the average particle diameter of the ethylcellulose polymer particles.

The pharmaceutical composition of matrix according to embodiment may comprise various amounts of active ingredient, ie, galantamine or its pharmaceutically acceptable salts. For example, the matrix pharmaceutical composition may comprise the active ingredient in an amount of 8 to 32 mg and preferably 8 to 24 mg, and more preferably 8 mg, 16 mg or 24 mg based on the amount of galantamine.

In particular, the matrix pharmaceutical composition can maintain the equivalent level of the release pattern in a therapeutic range in the same compositions. In this way, the pharmaceutical composition including the various amounts of active ingredient can be provided without a substantially separate design. In addition, the required release pattern of active ingredient can be easily controlled or changed by regulating the average particle diameter of the ethylcellulose polymer particles within a range of said correlation.

Therefore, the pharmaceutical matrix composition having a desired release pattern can be designed and prepared by the aforementioned embodiment. Since the pattern of active ingredient can be easily anticipated, the matrix pharmaceutical composition can demonstrate optimal therapeutic efficacy through time control and frequency of administration (for example: once a day).

Since the matrix pharmaceutical composition comprises galantamine or its pharmaceutically acceptable salts as active ingredient, the pharmaceutical composition of matrix can be used for the treatment or prevention of the disease of Alzheimer's, dementia, alcoholism, nicotine dependence, nerve gas poisoning, mania, chronic fatigue syndrome or schizophrenia.

Together with the water insoluble polymer, the matrix pharmaceutical composition of the embodiment may further comprise at least one pharmaceutically acceptable excipient. The excipients are pharmaceutically acceptable inert substances.

Examples of such excipients include, without limitation, 1) diluents such as anhydrous lactose, lactose monohydrate or mannitol; 2) lubricants such as magnesium stearate, sodium stearyl fumarate or talc and 3) conventional colorants or preservatives in the art.

In addition, the matrix pharmaceutical composition can be made in oral dosage form (e.g., tablets) and can be administered once a day.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the active ingredient release pattern of the pharmaceutical composition (tablet) according to Examples 2-l ~ 2-3, Reference Examples 2-1-2-4 and Control 2 (the amount of galantamine: 16 mg).

Figures 2a ~ 2c show the release pattern of the active ingredient of the pharmaceutical composition (tablet) according to Examples 1-2, 2-2 and 3-1, and the control drugs 1 ~ 3 (the amount of galantamine : each 8 mg, 16 mg and 24 mg).

Figure 3 shows the release pattern of the active ingredient of the pharmaceutical composition (tablet) according to Comparative Examples l-1-l-3.

EXAMPLES The following examples provide further illustration of the invention but, of course, in no way should they be construed as limiting the scope thereof.

Reference Laboratories l-l-l-5 and Elas 1-1-1-2: Preparation of a pharmaceutical composition (tablet) including galantamine hydrobromide (amount of galantamine = 8 mg).

As components of Table 1, galantamine hydrobromide, dehydrated lactose by spray and a copolymer of aminoalkyl methacrylate (trade name: Eudragit RS PO) were mixed for 5 minutes using a planetary mixer. The mixture was combined using ethanol as the granulation fluid and converted into wet granules. The wet granules were dried to approximately 50 using a tray dryer and passed through a mesh screen 18. The granules were combined with ethylcellulose polymer particles (trade name: Ethocel Std 7 (average particle diameter approximately 310 [im] or Ethocel Std 7 FP (average particle diameter approximately 9.7μp?)), and then combined with talc and magnesium stearate as lubricants. The resulting mixture compressed to tablets having a weight of 125 mg [Table 1] * In Table 1, the amount of galantamine was 8 mg in 10.25 mg of galantamine hydrobromide.

* In Table 1, the average particle diameter of the ethylcellulose polymer particles is the average particle diameter by weight as measured by a common method using a particle size analyzer produced by Malvern Instruments (Mastersizer 2000).

Reference Examples 2-l ~ 2-4 and Examples 2-l ~ 2-3: Preparation of a pharmaceutical composition (tablet) including galántamine hydrobromide (amount of gallanthamine = 16 mg).

Tablets according to Reference Examples 2-1-4-4 and Examples 2-1-3-3 were obtained in the same manner as described in Reference Examples 1-1-1-5 and Examples 1-1-1-2, except that a mixture of the components of Table 2 having a weight of 250 mg was used.

[Table 2] Tablet / mg Example Component Example % Example Example is weight 0 0 Ref. Ref. Ref. 0 lo Ref. Ref. 2-1 2-2 2-3 Ref. Ref. 2-1 2-2 2-3 2-4 Eudragit 16 40 40 40 40 40 40 40 RS PO Lactose (dehydrates calculated by 49.8 124.5 124.5 124.5 124.5 124.5 124.5 124.5 aspersion ) Hydrobrom uro 8.2 20.5 20.5 20.5 20.5 20.5 20, 5 20.5 Galantami na Ethocel 57,5 46 34.5 28,75 23 11,5 0 Std 7 2. 3 Ethocel 0 11.5 23 28.75 34.5 46.5.5 Std 7 FP Stearate of 1 2.5 2.5 2.5 2.5 2.5 2.5 2.5 Magnesium Talcum 2 5 5 5 5 5 5 5 Ethanol q.s q.s q.s q.s q.s q.s q.s Diameter average from particle of the particle (| im) 296.7 130.3 96.3 67.4 18.6 9.3 8.8 s of polymer from ethylcellul bear Total 100 250 250 250 250 250 250 250 * In Table 2, the amount of galantamine was 16 mg in 20.5 mg of galantamine hydrobromide.

* In Table 2, the average particle diameter of the ethylcellulose polymer particles is the average particle diameter by weight as measured by a common method using a particle size analyzer produced by Malvern Instruments (Mastersizer 2000).

Reference Examples 3-l ~ 3-5 and Examples 3-l ~ 3-2: Preparation of a pharmaceutical composition (tablet) including galantamine hydrobromide (amount of galantamine = 24 mg).

Tablets according to Reference Examples 3-l ~ 3-5 and Examples 3-l ~ 3-2 were obtained in the same manner as described in Reference Examples ll-l-5 and Examples ll ~ 1-2, except that a mixture of the components of Table 3 having a weight of 375 mg was used.

[Table 3] Diámetr 0 average or of partic the one (μ ??) 296.7 130.3 96.3 67.4 18, 6 9.3 8.8 partico those of polymer or of ethylcel ulosa Total 100 375 375 375 375 375 375 375 * In Table 3, the amount of galantamine was 24 mg in 30.75 mg of galantamine hydrobromide.

* In Table 3, the average particle diameter of the ethylcellulose polymer particles is the average particle diameter by weight as measured by a common method using a particle size analyzer produced by Malvern Instruments (Mastersizer 2000).

Comparative Example 1-l-1-3: Preparation of a pharmaceutical composition (tablet) including galantamine hydrobromide (amount of galantamine = each 8 mg, 16 mg and 24 mg).

As components of Table 4, a mixture of galantamine hydrobromide, hydroxypropyl methylcellulose (trade name: Methocel K15M), and microcrystalline cellulose (trade name: Avicel PH102) was combined well for 5 minutes using a planetary mixer. The mixture was combined with stearate magnesium and light anhydrous silicic acid (trade name: Aerosil 200) as lubricants. The resulting mixture was compressed into tablets according to Comparative Examples 1-1-1-3 having a weight of 80 mg, 160 mg and 240 mg, respectively.

[Table 4] * In Table 4, each amount of galantamine was 8 mg, 16 mg, and 24 mg in each 10.25 mg, 20.5 mg, and 30.75 mg of galantamine hydrobromide.

Experiment: Active ingredient release pattern of the pharmaceutical compositions Comparative in vitro dissolution studies were carried out in the tablets according to Examples 1-1-1-2, 2-1-2-3 and 3-1-3-2, Reference Examples 1-1-1-5 , 2-1-2-4 and 3-1-3-5 and Comparative Examples 1-1-1-3 according to Dissolution Test Method 2 (paddle method, Apparatus 2, 50 rpm) indicated in the Korean pharmacopoeia. The average was 900 ml of simulated intestinal juice (pH 6.8) to 37. The results of the dissolution test are summarized in Tables 5 to 8 given below.

[Table 5] The tablet release pattern according to Reference Examples 1-1-1-5 and Examples 1-1-1-2 [Table 6] The pattern of release of the tablets according to Reference Examples 2-1-2-4 and Examples 2-1-2-3 8 100.4 85.8 79.9 80.1 81, 1 67.0 66.0 10 106.1 91.7 87.0 87.1 88.1 75.3 72.8 12 109.3 96.0 92.5 92.7 93.7 80.5 80.2 18 113.7 102.0 102.7 103.8 103.8 94.0 90.7 [Table 7] The pattern of release of the tablets according to Reference Examples 3-l ~ 3-5 and Examples 3-l ~ 3-2 [Table 8] The pattern of release of the tablets according to Comparative Examples l-1-l-3 In addition, the release patterns of tablets of according to Examples 2-l ~ 2-3 and Reference Examples 2-1-2-4 with the Control 2 drug (trade name: REMINYL PR CAP; galantamine 16 mg) having the same amount of galantamine are represented in Figure 1.

In addition, the patterns of release of the tablets according to Examples 1-2, 2-2 and 3-1 are shown in Figures 2a to 2c with the control drugs 1 ~ 3 (trade name: REMINYL PR CAP; one with galantamine 8 mg, 16 mg and 24 mg) having the same amount of galantamine and in Figure 3 the tablet release patterns of Comparative Examples ll ~ l-3 are represented.

As shown in Tables 5 to 7 and Figures 2a ~ 2c, the pharmaceutical compositions of Examples 1-2, 2-2 and 3-1 showed the optimal release pattern (ie, the release pattern that allows the daily dosage, which shows the effective plasma levels and the desirable therapeutic efficacy) of the active ingredient equivalent to Control 1 ~ 3 drugs, which is known to show the desirable release pattern for the treatment of diseases such as Alzheimer's Also, the pharmaceutical compositions of the Examples 1-2, 2-2 and 3-1 fulfilled the specific correlation between the amount of galantamine and the average particle diameter of the ethylcellulose polymer particles (ie, the correlation between the amount of galanthamine of 8n mg and the average particle diameter of the ethylcellulose polymer particles greater than 15 (nl) 3 μp and not greater than 15n3 (im). Therefore, the pharmaceutical compositions showed the equivalent release pattern despite the differences in the amount of galantamine hydrobromide in the same compositions.

Comparatively, as shown in Table 8 and Figure 3, the pharmaceutical compositions of Comparative Examples l-1-l-3 showed different release patterns due to differences in the amount of galantamine hydrobromide in the same compositions.

Moreover, as shown in Tables 5-8 and Figure 1, according to the release pattern of the Reference Examples and the Examples, the active ingredient release pattern can be controlled or changed by regulating the average diameter of particle of the ethylcellulose polymer particles in the same composition and the same amount of the active ingredient.

In particular, as shown in Figure 1, the pharmaceutical composition of Examples 2-l ~ 2-3 which complies with the correlation between the amount of galantamine and the average particle diameter of the ethylcellulose polymer particles showed the optimal release pattern of the active ingredient equivalent to the control drug 2. With this result, it is confirmed that the release pattern of active ingredient can be controlled or changed within the desired range by regulating the average particle diameter of the particles of ethylcellulose polymer.

Comparatively, since the pharmaceutical composition of Reference Examples 2-l ~ 2-4 did not meet the correlation between the amount of galantamine and the average particle diameter of the ethylcellulose polymer particles (ie, the correlation between the amount of galanthamine of 8n mg and the average particle diameter of the ethylcellulose polymer particles greater than 15 (nl) 3 im and not greater than 15n3 p), the release of the active ingredient is too rapid in a short time (Examples of Reference 2-1 and 2-2) or not sufficient after a sufficient time (Reference Examples 2-3 and 2-4). Thus, the pharmaceutical compositions of Reference Examples 2-l ~ 2-4 could not show the optimal release pattern (ie, the release pattern that allows daily dosing, showing effective plasma levels and desirable therapeutic efficacy ).

Accordingly, the pharmaceutical composition having the optimal release pattern of active ingredient is very easily designed and prepared using the composition of the Examples. Especially, it is confirmed that this effect is still obtained despite changes in the amount of active ingredient.

Claims (9)

1. A matrix pharmaceutical composition characterized in that it comprises: granules including a therapeutically effective amount of galantamine or its pharmaceutically acceptable salts and a copolymer of aminoalkyl methacrylate; Y ethylcellulose polymer particles having an average particle diameter of 1 to 450 μt ?; wherein the amount of galantamine is 8n mg (n = 1 to 3) and the average particle diameter of the ethylcellulose polymer particles is greater than 15 (n-1) 3 [im and not greater than 15n3.

2. The matrix pharmaceutical composition according to claim 1, characterized in that the amount of galantamine is 8 mg and the average particle diameter of the ethylcellulose polymer particles is from 1 to 15 | i.

3. The matrix pharmaceutical composition according to claim 1, characterized in that the amount of galantamine is 16 mg and the average particle diameter of the ethylcellulose polymer particles is 16 to 120 μp ?.

4. The matrix pharmaceutical composition according to claim 1, characterized in that the amount of galantamine is 24 mg and the average particle diameter of the ethylcellulose polymer particles is 125 to 350 μp ?.

5. The matrix pharmaceutical composition as claimed in claim 1, characterized in that the weight ratio of galantamine or its pharmaceutically acceptable salts: total weight of the polymer particles of ethylcellulose and of the aminoalkyl methacrylate copolymer is in the range of 1. : 4 to 1: 6.

6. The matrix pharmaceutical composition as claimed in claim 5, characterized in that the ratio of aminoalkyl methacrylate copolymer: ethylcellulose polymer particles is in the range of 1: 0.5 to 1: 2.

7. The matrix pharmaceutical composition as claimed in claim 1, characterized in that it is in the form of a tablet.

8. The matrix pharmaceutical composition as claimed in claim 1, characterized in that it is used for the treatment or prevention of Alzheimer's disease, dementias, alcoholism, nicotine dependence, nerve gas poisoning, hobbies, chronic fatigue syndrome or schizophrenia

9. The matrix pharmaceutical composition as claimed in claim 1, characterized in that it is administered once a day.