RU2390354C2 - Slow-release matrix preparation containing base agent or its salt and method for making thereof - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns medicine and pharmacology, more specifically, drug preparation. There is offered a slow-release matrix composition containing donepezil hydrochloride and/or memantine hydrochloride; an intestine-soluble polymer at least the one chosen from the group consisting of a methacrylic acid copolymer - ethyl acrylate, a methacrylic acid copolymer - methyl acrylate, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose succinate acetate; and a water-insoluble polymer at least the one chosen from the group consisting from ethylcellulose, an aminoalkylmethacrylate RS copolymer and an ethyl acrylate - methyl acrylate copolymer. There is also offered a method for making said composition, including the stage of mixing donepezil hydrochloride and/or memantine hydrochloride, said intestine-soluble polymer and water-insoluble polymer; and the stage of compression moulding of the mixture prepared at the stage of mixing.

EFFECT: implementation of said composition and method provides slow release of the active substance in an organism.

11 cl, 13 tbl, 51 ex, 9 dwg

Description

Technical field

The present invention relates to a sustained release matrix type preparation containing a primary drug or its salt, more particularly, relates to a drug that not only inhibits the initial peak of a drug (rapid drug release immediately after dissolution) in a solubility test, but also in the solubility test provides dissolution with little dependence on the pH of the main drug or its salt at an early stage of dissolution. The present invention also relates to a sustained release matrix-type preparation containing the main drug or its salt, in which the ratio of the dissolution rate of the main drug or its salt in an acidic test solution to the dissolution rate of the main drug or its salt in a neutral test solution (speed dissolution in an acidic test solution / dissolution rate in a neutral test solution) decreases as it dissolves in a late stage of dissolution compared with the early stage of dissolution.

State of the art

Compared to conventional instant drugs, a sustained release preparation containing a physiologically active drug allows the blood drug concentrations to remain at the level of an effective therapeutic concentration for a long time or higher. Thus, when achieving sustained release properties of a drug, it is possible to reduce the number of administrations while providing the same or better therapeutic effect, potentially improving the patient's susceptibility to treatment. With the slow release properties of the drug, a rapid increase in the concentration of the drug in the blood immediately after administration can be avoided, thereby potentially reducing adverse effects, toxicity, and the like. due to the action of the drug.

Basically, sustained release preparations containing a drug that is physiologically active can be divided into two types of drugs: (1) a sustained release preparation with a coating in which the release of the drug is controlled by coating the surface of a core particle or a core tablet containing physiologically active sustained release drug coating; (2) a matrix-type preparation in which the drug and the sustained release base are evenly distributed in the preparation.

Since coating uniformity in sustained release coating preparations affects drug release, delayed release coating parameters need to be strictly controlled, and performance is often low due to long coating times. In addition, when the sustained release coating is applied to the granules, the sustained release coating is typically applied after the drug is applied to a base particle, typically containing crystalline cellulose or sucrose. Therefore, when several layers of coating are applied for sustained release, or when the drug contains a large amount of the drug, the size of the drug is usually large, making it difficult to take orally.

On the other hand, sustained-release matrix-type preparations have a structure in which the drug and the sustained-release base are uniformly distributed in the formulation and do not require such stringent manufacturing conditions as sustained-release coated preparations, and can be obtained by a production technology similar to with the technology for the production of conventional instant drugs. Thus, for sustained release matrix type preparations, high performance can be expected. In addition, a sustained release matrix type preparation is easy to obtain even if it contains a large amount of the drug, and the size of the preparation need not be large. Thus, in terms of productivity and smaller drug size, sustained release matrix type preparations are more suitable than sustained release coated preparations.

However, when the physiologically active drug is the main drug or its salt, upon receipt of the matrix-type drug with a slow release using a water-insoluble base, as a rule, the following problems exist:

The first problem is that in the solubility test of a sustained release matrix type preparation containing the main drug or its salt, the dissolution rate of the main drug or its salt in the main test solution as a rule dissolves much less than in an acidic test solution. This is due to the fact that the solubility of the main drug or its salt in an aqueous solvent in the neutral or alkaline pH range is less than in the acidic pH range. Due to the fact that delayed-release preparations usually contain larger amounts of the drug than the amount of the drug in instant preparations, if the retention time of the drug with delayed release in the stomach is increased, there is a risk of an unexpected increase in the concentration of the main drug or its salt in the blood and side effects. The risk of side effects is especially serious in the case of the main drug or its salt with strong side effects and the main drug and its salt with a narrow safe range of blood concentration.

The second problem is that in the solubility test, the release rate of the main drug or its salt from the matrix type sustained release drug is lower in the late stage of dissolution than in the early stage of dissolution. If, in order to eliminate the first problem described above (i.e., rapidly increase the concentration in the blood due to the long retention time of the drug or its salt in the stomach), the dissolution rate of the main drug or its salt from the drug with delayed release in an acidic test solution is controlled in in the case of a sustained-release drug with a short excretion time from the stomach, this drug is excreted with most of the drug remaining in the drug, thus, decreasing bioavailability and creating another risk that pharmacologically effective concentrations will not be achieved.

This is due to the fact that the water-insoluble matrix does not dissolve in the solution in the solubility test and, therefore, the diffusion length in the matrix, which the drug must pass to release as it dissolves, becomes longer. Thus, if the rate of release of the main drug or its salt at an early stage of dissolution is slowed down too much, there may be an increased risk that the matrix-type drug with delayed release will be excreted from the body with most of the drug remaining in the drug. In addition, since the matrix-type drug with a slow release passes from the stomach into the small intestine, the rate of release of the drug decreases as the surrounding drug becomes neutral or slightly alkaline, thereby increasing the risk that this drug is excreted from the body with the majority of the drug remaining in the drug. This is undesirable, as it reduces the bioavailability of the drug and leads to uncertainty in pharmacological effects.

Documents describing sustained release matrix-type preparations containing the main drug or its salt include the following documents. For example, US Pat. No. 4,792,452 describes a matrix preparation containing a primary drug or a salt thereof, alginic acid or a salt thereof, a pH-independent water-soluble gelling agent, and a binding agent. For example, US Pat. No. 4,968,508 describes a matrix preparation containing cefaclor, an acrylic acid polymer, soluble at a pH of from 5.0 to 7.4, and a hydrophilic polymer. For example, Japanese Patent Application Laid-Open No. H6-199657 describes that a pH-dependent dissolution of a drug with a higher solubility in acetic acid buffer, pH 4.0, than in 1st fluid and 2nd fluid according to Japanese Pharmacopoeia, can be improved by preparing matrix tablets containing a water-soluble polymer, a “carboxyvinyl polymer or a methyl vinyl ester-maleic anhydride copolymer” and an intestinal soluble base. For example, US Pat. No. 6,285,799 describes a matrix preparation containing a basic drug or a salt thereof with a pH-dependent solubility, a pH-independent sustained release base and a pH-dependent additive, such as an intestinal soluble base, an organic acid, and the like. . (which increases the dissolution rate of the drug from the tablet at a pH greater than 5.5).

However, these documents from the scope of the invention relate to sustained-release matrix-type preparations intended only for pH-independent drug release, and their inventors have not necessarily studied how to eliminate or prevent the above risks of adverse events (the first problem described above) and reduced bioavailability due to delayed release properties (second problem described above). Thus, there is no description of a drug that not only inhibits the dissolution of the main drug or its salt in accordance with the environment in the body so that the initial peak of the drug is suppressed (rapid release of the drug immediately after dissolution), but also reliably ensures dissolution with low pH dependence in the early stage of the solubility test, and where as it dissolves in the late stage of dissolution compared to the early stage of dissolution ratio decreases the dissolution rate of the basic drug or its salt in an acidic test solution to the dissolution rate of the basic drug or the salt thereof in neutral test solution (dissolution rate in an acidic test solution / dissolution rate in a neutral test solution).

Description of the invention

Problems to be Solved by the Application of the Invention

Given the pH environment in the body, there is a need for sustained release formulations containing the primary drug that suppress unexpected increases in blood concentrations associated with the rapid dissolution of the primary drug from the preparations and which provide a reduced risk of decreased bioavailability associated with sustained release properties . Thus, there is a need for a sustained release matrix type preparation containing the main drug or its salt, which not only suppresses the initial peak of the drug (quick release of the drug immediately after dissolution) in the solubility test, but also ensures the dissolution of the main drug or its salt with a low pH dependence in the early stage of dissolution, and where, as the solubility test passes, the dissolution rate in a neutral test solution in the late stage of dissolution remains high. Thus, there is a need for a sustained release matrix-type drug containing its main drug or its salt, in which, as it dissolves in a late stage of dissolution compared to the early stage of dissolution, the ratio of the dissolution rate of the main drug or its salt in an acidic test solution to dissolution of the main drug or its salt in a neutral test solution (dissolution rate in acidic test solution / dissolution rate in non tral test solution) is reduced. In particular, there is a need for a sustained release matrix type preparation that is capable of controlling the dissolution of the main drug or its salt so that the solubility of the main drug or its salt decreases strongly from neutral to slightly alkaline with increasing pH.

Troubleshooting tools

In view of these circumstances, the authors of the present invention as a result of extensive research have found that the desired objectives for the implementation of the present invention can be achieved using the following design:

In other words, in one aspect of the present invention, there is provided (I) a sustained release matrix type preparation comprising (1) a major drug or a salt thereof with a greater solubility in 0.1N. a solution of hydrochloric acid and a neutral aqueous solution, pH 6.0, than in the main aqueous solution, pH 8.0; and (2) at least one intestinal soluble polymer. In this aspect, the neutral aqueous solution is 50 mM phosphate buffer and the basic aqueous solution is 50 mM phosphate buffer.

The present invention also relates to (II) a sustained release matrix type preparation according to (I), wherein in a solubility test in accordance with a method using a stirrer according to the Japanese Pharmacopoeia for solubility tests, the ratio of the dissolution rate of the main drug or its salt to 0.1n a solution of hydrochloric acid to the dissolution rate of the main drug or its salt in 50 mm phosphate buffer, pH 6.8, decreases as it dissolves to a dissolution time at which the dissolution rate of the main drug or its salt in 50 mm phosphate buffer, pH 6, 8 is 90%.

In a preferred aspect of the present invention, there is provided (III) a sustained release matrix type preparation according to (I) or (II), wherein in a solubility test according to a method using a stirrer according to the Japanese Pharmacopoeia for solubility tests, the dissolution rate of the main drug or its salt in 0.1n. a solution of hydrochloric acid at a dissolution time of 1 hour does not exceed 60%. More preferably, the dissolution rate of the main drug or its salt in 0.1N. a solution of hydrochloric acid at a dissolution time of 1 hour does not exceed 50%, and more preferably does not exceed 40%.

In a more preferred aspect of the present invention, there is provided (IV) a sustained release matrix type preparation according to any one of (I) to (III), wherein, in a solubility test using a method using a stirrer according to the Japanese Pharmacopoeia for solubility test, the dissolution rate of the main drug funds or its salts in 0.1n. a solution of hydrochloric acid to the dissolution rate of the main drug or its salt in 50 mm phosphate buffer, pH 6.8, with a dissolution time of 3 hours is from 0.3 to 1.5. More preferably, the ratio of dissolution rates is from 0.3 to 1.4, even more preferably from 0.3 to 1.3, most preferably from 0.3 to 1.2.

In an even more preferred aspect of the present invention, there is provided a (V) sustained release matrix type preparation according to any one of (I) to (IV), wherein, in a solubility test using a method using a stirrer according to the Japanese Pharmacopoeia for solubility test, dissolution rate the main drug or its salt in 0.1N. a solution of hydrochloric acid at a dissolution time of 1 hour does not exceed 60%, and the ratio of the dissolution rate of the main drug or its salt in 0.1N. a solution of hydrochloric acid to the dissolution rate of the main drug or its salt in 50 mm phosphate buffer, pH 6.8, with a dissolution time of 3 hours is from 0.3 to 1.5. More preferably, the dissolution rate of the main drug or its salt in 0.1N. a solution of hydrochloric acid at a dissolution time of 1 hour does not exceed 50%, and the ratio of dissolution rates is from 0.3 to 1.4, even more preferably, the dissolution rate of the main drug or its salt in 0.1N. hydrochloric acid solution does not exceed 40%, and the ratio of dissolution rates is from 0.3 to 1.2.

The sustained release matrix type preparation of the present invention may also contain at least one water insoluble polymer. For example, the present invention relates to a sustained release matrix type preparation comprising: (1) a major drug or a salt thereof with a higher solubility of 0.1 N. a solution of hydrochloric acid and 50 mm phosphate buffer, pH 6.0 than in 50 mm phosphate buffer, pH 8.0; (2) at least one intestinal soluble polymer; and (3) at least one water insoluble polymer.

In a more preferred aspect of the present invention, there is provided a sustained release matrix type preparation comprising (1) a main drug or a salt thereof, in which the solubility of the main drug or its salt in a neutral aqueous solution, pH 6.8, is at least twice as large its solubility in a basic aqueous solution, pH 8.0 and does not exceed half of its solubility in a neutral aqueous solution, pH 6.0; and (2) at least one intestinal soluble polymer. Alternatively, the sustained release matrix type preparation also contains (3) at least one water insoluble polymer. In a particularly preferred aspect of the present invention, there is provided a sustained release matrix type preparation comprising (1) a main drug or a salt thereof, in which the solubility of the main drug or its salt in 50 mM phosphate buffer, pH 6.8, is at least double more than its solubility in 50 mM phosphate buffer, pH 8.0, and does not exceed half its solubility in 50 mM phosphate buffer, pH 6.0; and (2) at least one intestinal soluble polymer. Alternatively, the sustained release matrix type preparation also contains (3) at least one water insoluble polymer.

In a particularly preferred aspect of the present invention, there is also provided a sustained release matrix type preparation comprising (1) a main drug or a salt thereof, in which the solubility of the main drug or its salt is 0.1N. a solution of hydrochloric acid and 50 mm phosphate buffer, pH 6.0, is 1 mg / ml or more, and the solubility of the main drug or its salt in 50 mm phosphate buffer, pH 8.0, is 0.2 mg / ml or less ; (2) at least one intestinal soluble polymer. Alternatively, the sustained release matrix type preparation also contains (3) at least one water insoluble polymer.

In a particularly preferred aspect of the present invention, there is also provided a sustained release matrix type preparation comprising (1) a main drug or a salt thereof, in which the solubility of the main drug or its salt is 0.1N. a solution of hydrochloric acid and 50 mm phosphate buffer, pH 6.0, is 1 mg / ml or more, the solubility of the main drug or its salt in 50 mm phosphate buffer, pH 8.0, is 0.2 mg / ml or less, and the solubility of the main drug or its salt in 50 mm phosphate buffer, pH 6.8, at least twice as soluble in 50 mm phosphate buffer, pH 8.0, and does not exceed half its solubility in 50 mm phosphate buffer, pH 6.0; (2) at least one intestinal soluble polymer. Alternatively, the sustained release matrix type preparation also contains (3) at least one water insoluble polymer.

In a particularly preferred aspect of the present invention, there is also provided a sustained release matrix type preparation comprising: (1) a main drug or a salt thereof, in which the solubility of the main drug or its salt is 1 mg / ml or more in 0.1N. a solution of hydrochloric acid and 50 mm phosphate buffer, pH 6.0, and is 0.2 mg / ml or less in 50 mm phosphate buffer, pH 8.0, and the solubility of the main drug or its salt in 50 mm phosphate buffer, pH 6.8, at least twice its solubility in 50 mM phosphate buffer, pH 8.0, and does not exceed half its solubility in 50 mM phosphate buffer, pH 6.0; and (2) at least one intestinal soluble polymer. Alternatively, the sustained release matrix type preparation also contains (3) at least one water insoluble polymer.

Advantageous Effects of the Invention

According to the present invention, in a sustained-release matrix-type preparation containing the main drug or its salt with a higher solubility of 0.1N. a solution of hydrochloric acid and a neutral aqueous solution, pH 6.0 than in the main aqueous solution, pH 8.0, the pH dependence of the dissolution of the drug or its salt is reduced at an early stage of dissolution, and when passing the solubility test, the ratio of the dissolution rate of the drug or its salt in an acidic test solution to the dissolution rate of a drug or its salt in a neutral test solution (dissolution rate in an acidic test solution / dissolution rate in a neutral test solution Thief) decreases as the dissolution (ratio becomes lower at a later stage than the early stage of the dissolution test). Due to this dissolution regimen, the risk of adverse events due to delayed release properties at an early stage of dissolution can be reduced, and the risk of reduced bioavailability can also be reduced. In addition, since 90% or more of the drug contained in the preparation of the present invention can be released in a neutral test solution within 8 hours, which are calculated as the upper limit for reaching the large intestine in humans, the risk of lower bioavailability due to the slow release properties is small , and believe that the preparations of the present invention are very useful. The beneficial effects of the present invention are shown below.

Brief Description of the Drawings

The figure 1 shows the results of the dissolution profiles of donepezil hydrochloride in matrix-type preparations with a sustained release of 0.1 n. the hydrochloric acid solution of examples 2 and 4 of the present invention (control experiment: comparative example 1);

Figure 2 shows the results of the dissolution profiles of donepezil hydrochloride in sustained release matrix preparations in 50 mM phosphate buffer, pH 6.8, from Examples 2 and 4 of the present invention (control experiment: comparative example 1);

The figure 3 shows the results of the dissolution profiles of donepezil hydrochloride in matrix-type preparations with a sustained release of 0.1 n. a solution of hydrochloric acid from examples 14-17 of the present invention;

Figure 4 shows the results of the dissolution profiles of donepezil hydrochloride in sustained release matrix-type preparations in 50 mM phosphate buffer, pH 6.8, from Examples 14-17 of the present invention;

The figure 5 shows the results of the dissolution profiles of donepezil hydrochloride in matrix-type preparations with a sustained release of 0.1 n. hydrochloric acid solution from examples 12 and 13 of the present invention (control experiment: comparative example 2);

Figure 6 shows the results of the dissolution profiles of donepezil hydrochloride in matrix-type sustained release preparations in 50 mM phosphate buffer, pH 6.8, from Examples 12 and 13 of the present invention (control experiment: comparative example 2).

7 shows the results of the dissolution profiles of donepezil hydrochloride in sustained release matrix type preparations in test solution A and test solution B from Example 27 of the present invention.

Figure 8 shows the results of the dissolution profiles of donepezil hydrochloride in sustained release matrix type preparations in test solution A and test solution B of Examples 28 and 29 of the present invention.

Figure 9 shows the results of the dissolution profiles of donepezil hydrochloride in sustained release matrix type preparations in test solution A and test solution B of Examples 30 and 31 of the present invention.

The best way of carrying out the invention

The present invention will be described in detail below by way of examples and comparative examples, but the present invention is not limited to them.

There are no particular restrictions on the essential drug used in the present invention or its salt. For example, the salt of the main drug used in the present invention may be a salt of an organic or inorganic acid. Examples of salts include, but are not limited to, hydrochlorides, sulfates, acetates, phosphates, carbonates, mesylates, tartrates, citrates, tosylates, and the like. Examples of the main drug or salt thereof used in the present invention include, but are not limited to, anti-dementia drugs such as donepezil hydrochloride, galantamine hydrobromide, rivastigmine tartrate, memantine hydrochloride, tacrine and the like; anti-anxiety drugs such as flurazepam hydrochloride, alprazolam, tandospiron citrate, rilmazafone hydrochloride and the like; antihistamines such as diphenylpyraline hydrochloride, chlorpheniramine maleate, cimetidine, isotypendil hydrochloride and the like; drugs that affect the circulatory system, such as phenylephrine hydrochloride, procainamide hydrochloride, quinidine sulfate, isosorbide dinitrate, nicorandil, etc .; antihypertensive drugs such as amlodipine besylate, nifedipine, nicardipine hydrochloride, nilvadipine, atenolol hydrochloride, and the like; antipsychotic drugs such as perospiron hydrochloride and the like; antibacterial agents such as levofloxacin and the like; antibiotics such as cephalexin, cefcapen-pivoxil hydrochloride, ampicillin and the like, as well as sulfamethoxazole, tetracycline, metronidazole, indapamide, diazepam, papaverine hydrochloride, bromhexine hydrochloride, ticlopridin hydrochloride pentanephenylphenethenylphenethenylphenethenylphenethenylphenethenylphenethenylphenylamine, citrate drugs and macrolide antibiotics such as erythromycin, dirithromycin, josamycin, midecamycin, kitasamycin, roxithromycin, roquitamycin, oleandomycin, myocamycin, flurithromycin, rosaramycin, azithromycin N, clarithromycin, etc. One or two or more of these essential drugs or their salts may be contained in a sustained release matrix type preparation of the present invention.

Of these drugs or their salts, anti-dementia drugs are preferred, and donepezil hydrochloride and / or memantine hydrochloride are particularly preferred. The sustained release matrix-type preparation of the present invention may be suitable for essential drugs or their salts, which have a narrow safe range of the drug or which have adverse effects depending on the maximum concentration of the drug in the blood. There are no specific restrictions on the anti-dementia drug contained in the sustained release matrix-type preparation of the present invention, but from the point of view of controlled release, it is effective for essential drugs or their salts, which are less soluble in an alkaline aqueous solution than in acidic aqueous solutions and the solubility of essential drugs or their salts for the pH of an aqueous solution changes near neutral pH. Examples include essential drugs or their salts with pKa from 7.0 to 12, preferably from 7.5 to 11, more preferably from 8.0 to 10.5, even more preferably from 8.5 to 10.5 . For example, donepezil hydrochloride is the main drug with a pKa of 8.90, and memantine hydrochloride is the main drug with a pKa of 10.27.

There are no particular restrictions on the solubility of the main drug or its salt used in the present invention with respect to acidic aqueous solutions, neutral aqueous solutions or basic aqueous solutions, but the solubility of the main drug or its salt in an acidic aqueous solution and a neutral aqueous solution is higher than their solubility in the basic aqueous solution. Herein, for use in preparing these aqueous solutions, examples for such use include, but are not limited to, phosphate buffer (e.g., buffers prepared with a solution of 50 mM sodium phosphate and hydrochloric acid), buffers such as GL Miller buffer, Atkins-Pantin buffer, Good buffer or the like, 0.1 n. hydrochloric acid, 0.1 mol / L sodium hydroxide solution or the like. It should be noted that the solubility used in the present invention refers to solubility, where the temperature of the solution is 25 ° C.

As used in the present invention, the term “solubility in an acidic aqueous solution” means the solubility of the main drug or its salt in a solution exhibiting acidic properties when the main drug or its salt is dissolved in a buffer or the like. Similarly used in the present invention, the term "solubility in a neutral (basic) aqueous solution means the solubility of the main drug or its salt in a solution exhibiting neutral (basic) properties when the main drug or its salt is dissolved in a buffer or the like.

By way of example, the main drug or salt thereof used in the present invention has greater solubility in an acidic aqueous solution, pH 3.0, and a neutral aqueous solution, pH 6.0, than in the basic aqueous solution, pH 8.0. As used herein, the term “solubility in an acidic aqueous solution, pH 3.0” means the solubility of a main drug or its salt in an acidic solution with a pH of 3.0 when the main drug or its salt is dissolved in a buffer or the like. As used herein, the term “solubility in a neutral aqueous solution, pH 6.0” means the solubility of the main drug or its salt in a solution with a pH of 6.0 when the main drug or its salt is dissolved in a buffer or the like. Similarly, as used herein, the term “solubility in a basic aqueous solution, pH 8.0” means the solubility of the main drug or its salt in a solution with a pH of 8.0 when the main drug or its salt is dissolved in a buffer or the like.

As another example, the main drug or its salt used in the present invention has a greater solubility in 0.1N. a solution of hydrochloric acid and a neutral aqueous solution, pH 6.0, than in the main aqueous solution, pH 8.0. As used herein, the term “solubility in a 0.1N hydrochloric acid solution” means the solubility of the main drug or its salt upon dissolution of the main drug or its salt in 0.1N. hydrochloric acid solution. For example, solutions of donepezil hydrochloride and memantine hydrochloride, which dissolve in 0.1N. hydrochloric acid solution, demonstrate a pH range of from about 1 to about 2.

Preferably, the main drug or salt thereof used in the present invention has a solubility of 0.1 N. a solution of hydrochloric acid and a neutral aqueous solution, pH 6.0, higher than in the main aqueous solution, pH 8.0 and solubility in a neutral aqueous solution, pH 6.8, at least two times their solubility mainly aqueous solution, pH 8.0, and not exceeding half its solubility in a neutral aqueous solution, pH 6.0. As used herein, the term “solubility in a neutral aqueous solution, pH 6.8” means the solubility of the main drug or its salt in a solution with a pH of 6.8 when the main drug or its salt is dissolved in a buffer or the like.

More specifically, there are no specific restrictions as long as the solubility of the main drug or its salt in 0.1N. a solution of hydrochloric acid and a neutral aqueous solution, pH 6.0, is 1 mg / ml or more, the solubility of the main drug or its salt in the main aqueous solution, pH 8.0, is 0.2 mg / ml or less, and solubility the main drug or its salt in a neutral aqueous solution, pH 6.8, two or more times its solubility in a basic aqueous solution, pH 8.0, and does not exceed half its solubility in a neutral aqueous solution, pH 6.0. Thus, the solubility of the main drug or its salt in 0.1N. a solution of hydrochloric acid and a neutral aqueous solution, pH 6.0, is not particularly limited, provided that the solubility indicated above is 1 mg / ml or more. The above solubility is usually from 1 to 1000 mg / ml, preferably from 5 to 200 mg / ml, more preferably from 5 to 100 mg / ml, even more preferably from 10 to 80 mg / ml. The solubility of the main drug or its salt in a basic aqueous solution, pH 8.0, is not particularly limited, provided that the solubility indicated above is 0.2 mg / ml or less. The above solubility is usually from 0.0001 to 0.2 mg / ml, preferably from 0.0005 to 0.1 mg / ml, more preferably from 0.001 to 0.05 mg / ml, even more preferably - from 0.002 to 0.03 mg / ml. In addition, the solubility of the main drug or its salt in a neutral aqueous solution, pH 6.8 is not particularly limited, provided that the above solubility is at least twice that of the solubility in the basic aqueous solution, pH 8.0, and does not exceed 1/2 solubility in a neutral aqueous solution, pH 6.0. The above solubility is preferably at least 3 times greater than the solubility in a basic aqueous solution, pH 8.0, and does not exceed 1/3 of the solubility in a neutral aqueous solution, pH 6.0, more preferably at least 5 times the solubility in a basic aqueous solution, pH 8.0, and does not exceed 1/5 of the solubility in a neutral aqueous solution, pH 6.0, even more preferably at least 10 more than the solubility in a basic aqueous solution, pH 8, 0, and does not exceed 1/10 solubility in a neutral aqueous solution, pH 6.0.

As another example, the solubility of the main drug or its salts used in the present invention, in 0.1N. a solution of hydrochloric acid and 50 mm phosphate buffer, pH 6.0, higher than their solubility in 50 mm phosphate buffer, pH 8.0. As used herein, the term “solubility in 50 mM phosphate buffer, pH 6.0” means the solubility of the main drug or its salt in 50 mM phosphate buffer with a pH of 6.0 when the main drug or its salt is dissolved in 50 mM phosphate buffer. Similarly, as used herein, the term “solubility in 50 mM phosphate buffer, pH 8.0” means the solubility of the main drug or its salt in 50 mM phosphate buffer with a pH of 8.0 when the main drug or its salt is dissolved in 50 mM phosphate buffer.

Preferably, the solubility of the main drug or its salt in 0.1N. a solution of hydrochloric acid and 50 mm phosphate buffer, pH 6.0, higher than their solubility in 50 mm phosphate buffer, pH 8.0, and solubility in 50 mm phosphate buffer, pH 6.8, two or more times their solubility in 50 mm phosphate buffer, pH 8.0, and does not exceed half its solubility in 50 mm phosphate buffer, pH 6.0. More specifically, there are no specific restrictions, provided that the solubility of the main drug or its salt in 0.1N. a solution of hydrochloric acid and 50 mm phosphate buffer, pH 6.0, is 1 mg / ml or more, the solubility of the main drug or its salt in 50 mm phosphate buffer, pH 8.0, is 0.2 mg / ml or less, and the solubility of the main drug or its salt in 50 mm phosphate buffer, pH 6.8, two or more times their solubility in 50 mm phosphate buffer, pH 8.0, and does not exceed half its solubility in 50 mm phosphate buffer, pH 6.0. Thus, the solubility of the main drug or its salt in 0.1N. hydrochloric acid solution and 50 mM phosphate buffer, pH 6.0, are not particularly limited, provided that the solubility indicated above is 1 mg / ml or more. The above solubility is usually from 1 to 1000 mg / ml, preferably from 5 to 200 mg / ml, more preferably from 5 to 100 mg / ml, even more preferably from 10 to 80 mg / ml. The solubility of the main drug or its salt in 50 mM phosphate buffer, pH 8.0, is not particularly limited, provided that the solubility indicated above is 0.2 mg / ml or less. The above solubility is usually from 0.0001 to 0.2 mg / ml, preferably from 0.0005 to 0.1 mg / ml, more preferably from 0.001 to 0.05 mg / ml, even more preferably - from 0.002 to 0.03 mg / ml. In addition, the solubility of the main drug or its salt in 50 mm phosphate buffer, pH 6.8, is not specifically limited, provided that the above solubility is at least twice that of solubility in 50 mm phosphate buffer, pH 8, 0, and does not exceed 1/2 solubility in 50 mm phosphate buffer, pH 6.0. The above solubility is preferably at least 3 times greater than the solubility in 50 mM phosphate buffer, pH 8.0, and does not exceed 1/3 of the solubility in 50 mM phosphate buffer, pH 6.0, more preferably at least 5 times greater solubility in 50 mM phosphate buffer, pH 8.0, and not more than 1/5 of solubility in 50 mM phosphate buffer, pH 6.0, even more preferably at least 10 times greater solubility in 50 mM phosphate buffer, pH 8.0, and does not exceed 1/10 solubility in 50 mm phosphate buffer, pH 6.0.

For example, donepezil hydrochloride is characterized by its solubility of 11 to 16 mg / ml in an acidic aqueous solution, pH 3.0, and a neutral aqueous solution, pH 6.0, and 0.1 mg / ml or less in a basic aqueous solution, pH 8 , 0. In addition, donepezil hydrochloride is a weakly basic drug or its salt with one Quaternary amino group, which is widely used in dementia due to Alzheimer's disease, and is characterized by its solubility in a neutral aqueous solution, pH 6.8, at least twice as soluble in a basic aqueous solution, pH 8.0, and not exceeding 1/2 solubility in a neutral aqueous solution, pH 6.0.

Alternatively, donepezil hydrochloride is a weakly basic drug or its salt with one quaternary amino group, which is widely used in dementia due to Alzheimer's disease. Donepezil hydrochloride is characterized by its solubility from 11 to 16 mg / ml in 0.1N. a solution of hydrochloric acid and 50 mm phosphate buffer, pH 6.0, and 0.1 mg / ml or less in 50 mm phosphate buffer, pH 8.0, with solubility in 50 mm phosphate buffer, pH 6.8, at least , twice the solubility in 50 mm phosphate buffer, pH 8.0, and not exceeding 1/2 solubility in 50 mm phosphate buffer, pH 6.0.

There are no specific restrictions on the dose of the weakly basic drug or its salt used in the present invention depending on the type of weakly basic drug and patient characteristics for each disease, but in the case of an acetylcholinesterase inhibitor for dementia like Alzheimer's disease, the dose is from 0.01 to 50 mg /day. More specifically, the dose of donepezil or a pharmaceutically acceptable salt thereof is from 0.01 to 50 mg / day, preferably from 0.1 to 40 mg / day, more preferably from 1 to 30 mg / day, even more preferably from 5 up to 25 mg / day. The dose of rivastigmine or its pharmaceutically acceptable salt is from 0.01 to 50 mg / day, preferably from 0.1 to 30 mg / day, more preferably from 1 to 20 mg / day, even more preferably from 1 to 15 mg /day. The dose of galantamine or its pharmaceutically acceptable salt is from 0.01 to 50 mg / day, preferably from 0.1 to 40 mg / day, more preferably from 1 to 30 mg / day, even more preferably from 2 to 25 mg /day.

In addition, in the case of memantine or a pharmaceutically acceptable salt thereof, which act as an antagonist of the N- methyl-D-aspartate receptor (NMDA), the dose is from 0.5 to 100 mg / day, preferably from 1 to 100 mg / day, more preferably 1 to 40 mg / day; even more preferably 5 to 25 mg / day.

There are no particular restrictions on the gut-soluble polymer used in the present invention, but preferably it should be soluble in some aqueous buffer solutions at a pH in the range of about 5.0 to about 8.0, although the gut-soluble polymer is not soluble in 0.1N. hydrochloric acid solution. At least one gut-soluble polymer can be used, and two or more gut-soluble polymers can be mixed. Examples of intestinal soluble polymers include, but are not limited to, a methacrylic acid-methyl methacrylate copolymer (Eudragit L100, Eudragit S100, etc.: Röhm GmbH & Co. KG, Darmstadt, Germany), a methacrylic acid-ethyl acrylate copolymer (Eudragit L100-55, Eudragit L30D-55, etc.: Röhm GmbH & Co. KG, Darmstadt, Germany), hydroxypropyl methylcellulose phthalate (HP-55, HP-50, etc.: Shin-Etsu Chemical, Japan), hydroxypropyl methylcellulose acetate ( AQOAT, etc .: Shin-Etsu Chemical, Japan), carboxymethyl ethyl cellulose (CMEC: Freund Corporation, Japan), cellulose acetate phthalate and the like, with a methacrylic copolymer of Slots etilaktilata-copolymer, methacrylic acid-methyl methacrylate, hydroxypropylmethylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate are preferable. Most preferred is an intestinal soluble polymer that can dissolve in a buffer solution at a pH in the range of 5.0 to 6.8. Examples of such intestinal soluble polymers include, but are not limited to, a methacrylic acid-ethyl acrylate copolymer and hydroxypropyl methylcellulose acetate succinate. In particular, it is particularly preferred that the methacrylic acid-ethyl acrylate copolymer is L100-55 Eudragit (Röhm GmbH & Co. KG, Darmstadt, Germany), which is a powder and which can dissolve in a buffer solution at a pH in the range of not less than 5.5. In addition, it is particularly preferred that the hydroxypropyl methylcellulose acetate succinate is AQOAT LF (which can dissolve at a pH in the range of at least 5.5; Shin-Etsu Chemical, Japan) or AQOAT MF (which can dissolve at a pH in the range of at least 6.0; Shin-Etsu Chemical, Japan), which are fine powders and an average particle size of about 5 microns. It should be noted that there are no particular restrictions on the average particle size of the gut-soluble polymer used in the present invention, but as a rule, the smaller the better, and the average particle size is preferably from 0.05 to 100 μm, more preferably from 0 , 05 to 70 microns, even more preferably from 0.05 to 50 microns.

The water-insoluble polymer used in the present invention relates to a sustained release base that is not soluble in an aqueous buffer at any pH in the range of 1.0 to 8.0, and is not particularly limited. The sustained-release matrix type preparation of the present invention preferably contains at least one water-insoluble polymer, and two or more water-insoluble polymers may be contained in the sustained-release matrix type preparation.

Examples of water-insoluble polymers include, but are not limited to, cellulose ethers (alkyl cellulose ethers such as ethyl cellulose, ethyl methyl cellulose, ethyl propyl cellulose, isopropyl cellulose, butyl cellulose and the like; aralkyl cellulose ethers such as benzyl cellulose and the like; cyanoalkyl esters such as cyanoethyl cellulose and the like), cellulose esters (cellulose and organic acid esters such as cellulose acetate butyrate, cellulose acetate, cellulose propionate, cellulose butyrate, acetate cellulose propionate and the like), copolymers of methacrylic acid-acrylic acid (trade name: Eudragit RS, Eudragit RL, Eudragit NE, Röhm GmbH & Co. KG, Darmstadt, Germany), etc. Of these polymers, ethyl cellulose, an aminoalkyl methacrylate copolymer RS (Eudragit RL, Eudragit RS) and an ethyl acrylate-methyl methacrylate copolymer (Eudragit NE) are preferred, and ethyl cellulose (ETHOCEL, The Dow Chemical Company, U.S., etc.) is most preferred. There are no particular restrictions on the average particle size of the water-insoluble polymer used in the present invention, but as a rule, the smaller the better. The average particle size is preferably from 0.1 to 100 microns, more preferably from 1 to 50 microns, even more preferably from 3 to 15 microns, most preferably from 5 to 15 microns.

The amount of intestinally soluble polymer in the sustained release matrix type preparation is not particularly limited, but generally ranges from 5 to 90% by weight, preferably from 8 to 70% by weight, more preferably from 10 to 60% by weight most preferably from 15 to 50% by weight, from 100% by weight of a sustained release matrix type preparation. The total amount of water-insoluble polymer and gut-soluble polymer in a sustained release matrix type preparation is not particularly limited, but typically ranges from 25 to 95 wt.%, Preferably from 35 to 95 wt.%, More preferably from 35 to 90 wt.%, Most preferably from 35 to 75 wt.%, From 100 wt.% The drug matrix type with a slow release.

In the sustained release matrix type preparation of the present invention, it is preferred that the water-insoluble polymer is ethyl cellulose and that the intestinally soluble polymer is at least one selected from the group consisting of a methacrylic acid-ethyl acrylate copolymer, a methacrylic acid-methyl methacrylate copolymer and hydroxypropyl methylcellulose acetate succinate. More preferably, the water-insoluble polymer is ethyl cellulose and the intestinally soluble polymer is a copolymer of methacrylic acid-ethyl acrylate and / or hydroxypropyl methylcellulose acetate succinate.

The amount of water-insoluble polymer in a sustained release matrix type preparation is not particularly limited, but generally ranges from 1 to 90 wt.%, Preferably from 3 to 70 wt.%, More preferably from 5 to 50 wt.%, Still more preferably 5 to 35 wt.%, 100 wt.% sustained release matrix type preparation.

The delayed-release matrix-type preparation of the present invention causes such unusual properties that in the solubility test it is possible to ensure the dissolution of the main drug or its salt with a low pH dependence in the early stage of dissolution and that as the solubility test passes, the ratio of the dissolution rate of the main drug or its salt in an acidic solution in a solubility test (hereinafter referred to as an acidic test solution) to the growth rate irradiating the main drug or its salt in a neutral solution in a solubility test (hereinafter referred to as a neutral test solution) (dissolution rate in an acidic test solution / dissolution rate in a neutral test solution) compared to the early dissolution stage as it dissolves into late stage dissolution is reduced. In a sustained release matrix-type preparation of the present invention, by mixing an intestinally soluble polymer with a basic drug or its salt with a greater solubility in an acidic aqueous solution and a neutral aqueous solution than in the basic aqueous solution, as described above, the dissolution of the basic drug can be slowed down means or its salts in acidic and neutral solutions in the solubility test. When mixed with a water-insoluble polymer and an intestinally soluble polymer, the greater the amount of intestinally soluble polymer mixed with the water-insoluble polymer, the greater the decrease in the dissolution rate of the main drug or its salt in acidic and neutral solutions in the solubility test, thus easily providing slow-release matrix-type preparation, where in the solubility test it is possible to ensure the dissolution of the main drug or its low-dependent salt depending on the pH at the early stage of dissolution, and where, as the solubility test passes, the ratio of the dissolution rate of the main drug or its salt in an acidic test solution to the dissolution rate of the main drug or its salt in a neutral test solution (dissolution rate in an acidic test solution / the dissolution rate in a neutral test solution) decreases as it dissolves (in particular, the ratio decreases in the late stage of dissolution compared to the early stage of dissolution).

Herein, the characteristic features of the sustained release matrix-type preparation of the present invention can be specifically demonstrated by dissolution profile in the solubility test in 50 mM phosphate buffer, pH 6.8, as a neutral solution in the solubility test and in 0.1N. hydrochloric acid solution of the acidic solution in the solubility test. Thus, more specifically, when the main drug or its salt is released from the sustained-release matrix-type preparation of the present invention in a solubility test in accordance with a method using a pharmacopoeia mixer of Japan for solubility tests, the dissolution rate ratio of the main drug or its salts in 0.1n. a solution of hydrochloric acid to the dissolution rate of the main drug or its salt in 50 mm phosphate buffer, pH 6.8, decreases as it dissolves to a dissolution time at which the dissolution rate of the main drug or its salt in 50 mm phosphate buffer, pH 6, 8 is 90%. In addition, the present invention relates to a sustained release matrix type preparation, wherein in a solubility test in accordance with a method using a stirrer according to the Japanese Pharmacopoeia for solubility tests, the dissolution rate of the main drug or its salt in 0.1N. a solution of hydrochloric acid at a dissolution time of 1 hour does not exceed 60%, preferably does not exceed 50%, more preferably does not exceed 40%. In addition, at an early stage of dissolution in the solubility test in accordance with the method using a stirrer according to the Japanese Pharmacopoeia for solubility tests, the ratio of the dissolution rate of the main drug or its salt in 0.1N. a solution of hydrochloric acid to the dissolution rate of the main drug or its salt in 50 mm phosphate buffer, pH 6.8, with a dissolution time of 3 hours is from 0.3 to 1.5, preferably from 0.3 to 1.4, more preferably from 0.3 to 1.3, even more preferably from 0.3 to 1.2. It should be noted that the method using the mixer according to the Japanese Pharmacopoeia for solubility tests is described in the 14th edition of the Japanese Pharmacopoeia and the test can be carried out, for example, at a stirrer speed of 50 rpm.

The sustained-release matrix-type preparation of the present invention preferably also contains water-soluble sugar and / or water-soluble sugar alcohol. There are no specific restrictions on water soluble sugar and / or water soluble sugar alcohol. Examples of water soluble sugars include, but are not limited to, lactose, sucrose, glucose, dextrin, pullulan, and the like. Examples of water-soluble sugar alcohols include, but are not limited to, mannitol, erythritol, xylitol, sorbitol, and the like, where lactose and mannitol are preferred. There are no particular restrictions on the amount of water-soluble sugar or water-soluble sugar alcohol in the sustained release matrix-type preparation of the present invention, but the approximate amount is typically from 3 to 70 wt.%, Preferably from 5 to 60 wt.%, More preferably - from 10 to 60 wt.%, even more preferably from 12 to 60 wt.%, from 100 wt.% the drug matrix type sustained release.

The matrix-type sustained release preparation of the present invention, if necessary, further comprises a number of pharmacologically acceptable carriers, such as diluents, lubricants, binders, disintegrating agents and the like, as well as other drug additives, such as preservatives, antioxidants, colorants, sweeteners, plasticizers, etc. The finished matrix-type sustained release preparation can also be provided with a film coating as needed. Examples of diluents include, but are not limited to, starch, pregelatinized starch, crystalline cellulose, colorless anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate, and the like. Examples of lubricants include, but are not limited to, magnesium stearate (Mallinckrodt Baker, Inc. USA), calcium stearate, talc, sodium stearyl fumarate, and the like. Examples of binders include hydroxypropyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone and the like. Examples of disintegrants include, but are not limited to, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, and the like. Examples of preservatives include, but are not limited to, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like. Examples of antioxidants include, but are not limited to, sulfites, ascorbates, and the like. Suitable examples of dyes include, but are not limited to, water-insoluble colorful varnishes, natural pigments (such as β-carotene, chlorophyll and red iron oxide), yellow iron oxide, red iron oxide, black iron oxide dye, and the like. Examples of sweeteners include, but are not limited to, sodium saccharin, dibasic potassium glycyrrhizinate, aspartame, urticaria, and the like. Examples of plasticizers include, but are not limited to, glycerol fatty acid esters (Mivacet brand), triethyl citrate (Citroflex 2 brand), propylene glycol, polyethylene glycol, and the like. Examples of film coating bases include, but are not limited to, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and the like.

The amount of carrier contained in the sustained release matrix type preparation of the present invention is not particularly limited, but, for example, the amount of lubricant is typically 0 to 5 wt.%, Preferably 0.01 to 4 wt.% more preferably 0.1 to 3 wt.%, even more preferably 0.3 to 1 wt.%, 100 wt.% sustained release matrix type preparation. In addition, the amount of binding agent is usually from 0 to 10 wt.%, Preferably from 0.1 to 8 wt.%, More preferably from 0.5 to 6 wt.%, Even more preferably from 1 up to 3 wt.%, from 100 wt.% drug matrix type sustained release.

The sustained release matrix type preparation of the present invention contains, for example, (a) a basic drug or salt thereof, (b) from 5 to 90 wt.% Intestinally soluble polymer and (c) from 3 to 70 wt.% Water soluble sugar alcohol, from 100 wt.% drug matrix type with a slow release. Preferably, the sustained release matrix type preparation of the present invention contains (a) a basic drug or a salt thereof, (b) from 8 to 70 wt.% Intestinally soluble polymer and (c) from 5 to 60 wt.% Water-soluble sugar alcohol , from 100 wt.% drug matrix type sustained release. More preferably, the sustained release matrix-type preparation of the present invention contains (a) a basic drug or a salt thereof, (b) 10 to 60 wt.% Intestinally soluble polymer and (c) 10 to 60 wt.% Water-soluble sugar alcohol, from 100% by weight of a sustained release matrix type preparation. Even more preferably, the sustained release matrix type preparation of the present invention contains (a) a basic drug or a salt thereof, (b) 15 to 50 wt.% Intestinally soluble polymer and (c) 12 to 60 wt.% Water-soluble sugar alcohol , from 100 wt.% drug matrix type sustained release.

Alternatively, the sustained release matrix-type preparation of the present invention contains, for example, (a) a basic drug or its salt, (b) from 5 to 90 wt.% Intestinally soluble polymer, (c) from 3 to 70 wt.% Water-soluble sugar alcohol; and (d) from 1 to 90 wt.% a water-insoluble polymer, from 100 wt.% a sustained release matrix type preparation. Preferably, the sustained release matrix-type preparation of the present invention contains, for example, (a) a basic drug or its salt, (b) from 8 to 70 wt.% Intestinally soluble polymer, (c) from 5 to 60 wt.% water-soluble sugar alcohol and (d) from 3 to 70 wt.% water-insoluble polymer, from 100 wt.% the drug matrix type with a slow release. More preferably, the sustained release matrix-type preparation of the present invention contains, for example, (a) a basic drug or its salt, (b) 10 to 60 wt.% Intestinally soluble polymer, (c) 10 to 60 wt.% Water-soluble sugar alcohol; and (d) from 5 to 50% by weight of a water-insoluble polymer, from 100% by weight of a sustained release matrix type preparation. Even more preferably, the sustained release matrix-type preparation of the present invention contains, for example, (a) a basic drug or its salt, (b) 15 to 50 wt.% Intestinally soluble polymer, (c) 12 to 60 wt.% water-soluble sugar alcohol and (d) from 5 to 35 wt.% water-insoluble polymer, from 100 wt.% the drug matrix type with a slow release.

According to another aspect of the present invention, there is also provided a method for producing a sustained release matrix type preparation comprising the steps of: mixing a basic drug or a salt thereof with a greater solubility of 0.1N. a solution of hydrochloric acid and in 50 mM phosphate buffer, pH 6.0 than in a neutral aqueous solution, pH 8.0, with at least one intestinally soluble polymer; and compression molding the mixture obtained in the mixing step. The present invention also relates to another method for producing a sustained release matrix type preparation comprising the steps of: mixing (1) a basic drug or a salt thereof with a solubility of 0.1 N. hydrochloric acid solution and a neutral aqueous solution, pH 6.0, 1 mg / ml or more, solubility in a basic aqueous solution, pH 8.0, 0.2 mg / ml or less, and solubility in a neutral aqueous solution, pH 6.8, at least two times greater than its solubility in a basic aqueous solution, pH 8.0, and not exceeding half its solubility in a neutral aqueous solution, pH 6.0, s (2) at least , one intestinally soluble polymer; and compression molding the mixture obtained in the mixing step. In a preferred aspect of the process for preparing the sustained release matrix-type preparation of the present invention, a water-insoluble polymer is also admixed in the mixing step.

In yet another aspect of the present invention, there is also provided a method for preparing a sustained release matrix type preparation comprising the steps of: mixing a basic drug or a salt thereof with a greater solubility in 0.1N. hydrochloric acid solution and 50 mM phosphate buffer, pH 6.0 than in 50 mM phosphate buffer, pH 8.0, with at least one intestinal soluble polymer; and compression molding the mixture obtained in the mixing step. The present invention also relates to another method for producing a sustained release matrix type preparation comprising the steps of: mixing (1) a basic drug or a salt thereof with a solubility of 0.1 N. hydrochloric acid solution and 50 mM phosphate buffer, pH 6.0, 1 mg / ml or more, solubility in 50 mM phosphate buffer, pH 8.0, 0.2 mg / ml or less, and with solubility in 50 mm phosphate buffer, pH 6.8, at least twice its solubility in 50 mM phosphate buffer, pH 8.0, and not exceeding half its solubility in 50 mM phosphate buffer, pH 6.0, s (2) at least one intestinally soluble polymer; and compression molding the mixture obtained in the mixing step. In a preferred aspect of the process for preparing the sustained release matrix-type preparation of the present invention, a water-insoluble polymer is also admixed in the mixing step.

In addition, the present invention relates to a method for producing a sustained release matrix type preparation comprising the steps of: mixing (A) a basic drug or a salt thereof with a greater solubility in 0.1N. a solution of hydrochloric acid and 50 mm phosphate buffer, pH 6.0 than in 50 mm phosphate buffer, pH 8.0, the solubility of the main drug or its salt in 50 mm phosphate buffer, pH 6.8, at least two times its solubility in 50 mM phosphate buffer, pH 8.0, and not exceeding half its solubility in 50 mM phosphate buffer, pH 6.0, with (B) at least one intestinally soluble polymer and (C) at least one water insoluble polymer; and compression molding the mixture obtained in the mixing step. In addition, the present invention relates to a method for producing a sustained release matrix type preparation comprising the steps of: mixing (1) a basic drug or a salt thereof with a solubility of 0.1 N. hydrochloric acid solution and 50 mM phosphate buffer, pH 6.0, 1 mg / ml or more, solubility in 50 mM phosphate buffer, pH 8.0, 0.2 mg / ml or less, and with solubility in 50 mm phosphate buffer, pH 6.8, at least twice its solubility in 50 mM phosphate buffer, pH 8.0, and not exceeding half its solubility in 50 mM phosphate buffer, pH 6.0, s (2) at least one intestinally soluble polymer; and (3) with at least one water-insoluble polymer; and compression molding the mixture obtained in the mixing step.

According to a preferred aspect of the present invention, the aforementioned method for producing a sustained release matrix type preparation further comprises granulating the mixture obtained in the mixing step to the compression molding step. Alternatively, in the mixing step, the main drug or salt thereof, an intestinally soluble polymer and a water-insoluble polymer can be mixed. It is clear that other pharmaceutically acceptable additives can also be mixed in the mixing step. In a more preferred aspect of the present invention, the granulation step is a wet granulation step, more preferably the wet granulation step includes the use of a water-soluble binding agent.

In the method for producing a sustained release matrix type preparation of the present invention, a water-soluble sugar and / or water-soluble sugar alcohol may be mixed as necessary in a sustained-release matrix type preparation, and other pharmacologically acceptable additives may also be mixed. Mixing and compression (compression) molding is carried out by generally accepted methods commonly used in the field of production, without specific restrictions. A sustained release matrix type preparation can be prepared by direct compression molding using a tabletting device after the mixing step. A delayed-release matrix-type preparation can also be prepared by a manufacturing method that includes the steps of: granulating the mixture after mixing and before compression molding. For example, any granulation method may be used, including a wet granulation method, a dry granulation method, a fluidized bed granulation method, a wet extrusion method, a spraying and curing method, and the like.

The sustained release matrix type preparation is not particularly limited as long as it is an oral preparation. For example, tablets, granules, fine granules, capsules and the like can be prepared according to the present invention. Capsules may be filled with one or more tablets, granules, or finely divided granules based on the sustained release matrix-type preparation of the present invention. For example, hard capsules can be filled with several small diameter mini-tablets based on a sustained release matrix-type preparation, or granules or fine granules based on a sustained-release matrix-type preparation granules or tablets based on a slow-release matrix preparation and granules, or fine granules on the basis of a sustained release matrix-type preparation. A sustained release matrix type preparation may also be provided with a film coating as needed. It should be noted that the presence or absence of the water-soluble film coating on the sustained release matrix preparation of the present invention has very little effect on the dissolution profile of the main drug or its salt from the sustained release matrix type preparation.

The present invention also relates to a method of decreasing the pH dependence of the dissolution of the main drug or its salt at a dissolution time of 2 to 3 hours, corresponding to the time of the stomach contents removal (at the early stage of the solubility test), by mixing the main drug or its salt, solubility which are higher in 0.1n. a solution of hydrochloric acid and a neutral aqueous solution, pH 6.0 than in the main aqueous solution, pH 8.0, with at least one intestinally soluble polymer, and then compression molding the mixture. A method for producing a sustained release matrix type preparation of the present invention may also include adding at least one water insoluble polymer. Thus, the present invention relates to a method for decreasing the pH dependence of the dissolution of the main drug or its salt at a dissolution time of 2 to 3 hours, corresponding to the time the stomach contents are removed (at an early stage of the solubility test) by mixing the main drug or its salt whose solubility is higher in 0.1n. a solution of hydrochloric acid and a neutral aqueous solution, pH 6.0 than in the main aqueous solution, pH 8.0, with at least one intestinally soluble polymer and at least one water-insoluble polymer, and then compression molding the mixture .

Alternatively, the present invention relates to a method for decreasing the pH dependence of the dissolution of the main drug or its salt at a dissolution time of 2 to 3 hours, corresponding to the time for the stomach contents to be taken out (at an early stage of the solubility test) by mixing the main drug or its salt, the solubility of which is higher in 0.1N. hydrochloric acid solution and 50 mM phosphate buffer, pH 6.0 than in 50 mM phosphate buffer, pH 8.0, with at least one intestinally soluble polymer, and then compression molding the mixture. A method for producing a sustained release matrix type preparation of the present invention may also include adding at least one water insoluble polymer. Thus, the present invention relates to a method for decreasing the pH dependence of the dissolution of the main drug or its salt at a dissolution time of 2 to 3 hours, corresponding to the time the stomach contents are removed (at an early stage of the solubility test) by mixing the main drug or its salt whose solubility is higher in 0.1n. hydrochloric acid solution and 50 mM phosphate buffer, pH 6.0 than in 50 mM phosphate buffer, pH 8.0, with at least one intestinally soluble polymer and at least one water-insoluble polymer, and then compression molding the mixture.

The present invention provides a method for the controlled release of a basic drug or a low pH-dependent salt thereof, comprising the steps of: mixing (1) a basic drug or its salt with a solubility of 0.1 N. hydrochloric acid solution and 50 mM phosphate buffer, pH 6.0, 1 mg / ml or more, solubility in 50 mM phosphate buffer, pH 8.0, 0.2 mg / ml or less, and with solubility in 50 mm phosphate buffer, pH 6.8, at least twice its solubility in 50 mM phosphate buffer, pH 8.0, and not exceeding half its solubility in 50 mM phosphate buffer, pH 6.0, s (2) at least one intestinally soluble polymer; and (3) with at least one water-insoluble polymer; and compression molding the mixture obtained in the mixing step.

For example, the sustained release matrix-type preparation of the present invention can be prepared by the following methods. 130 g of donepezil hydrochloride (Eisai Co. Ltd), 624 g of etocel 10FP (ethyl cellulose, Dow Chemical Company), 780 g of eudragit L100-55 (Röhm GmbH & Co. KG) and 988 g of lactose are mixed in a granulator. Wet granulation is carried out by adding an aqueous solution of 52 g of hydroxypropyl cellulose dissolved in an appropriate amount of purified water, and the obtained granules are heat-dried using a centrifugal dryer and sieved to obtain granules of the desired size. After sizing, 1 g of magnesium stearate (Mallinckrodt Baker, Inc.) is added per 99 g of granules and mixed, and then a rotary tabletting device can be used to produce 8 mm diameter tablets containing 10 mg of donepezil hydrochloride in 200 mg tablets. You can also use a coating device to cover these tablets with a water-soluble film containing hydroxypropyl methylcellulose or the like as its main component.

The sustained release matrix type preparation of the present invention can also be prepared, for example, by the following methods. 20 g memantine hydrochloride (Lachema s.r.o. Czech Republic), 48 g etocel 10FP (ethyl cellulose, Dow Chemical Company), 60 g eudragit L100-55 (Röhm GmbH & Co. KG) and 66 g lactose are mixed in a granulator. Wet granulation is carried out by adding an aqueous solution of 4 g of hydroxypropyl cellulose dissolved in an appropriate amount of purified water, and the obtained granules are heat-dried using a centrifugal dryer and sieved to obtain granules of the desired size. After sizing, add 1 g of magnesium stearate (Mallinckrodt Baker, Inc.) per 99 g of granules and mix, and then you can use a rotary tabletting device to obtain tablets with a diameter of 8 mm containing 20 mg of memantine hydrochloride in 200 mg of granules. You can also use a coating device to cover these tablets with a water-soluble film containing hydroxypropyl methylcellulose or the like as its main component.

Experimental Example 1

In the sustained release matrix type preparation of the present invention, the effects of an intestinal soluble polymer in the presence of a water insoluble dissolution property are evaluated as follows.

Slow-release matrix-type preparations were prepared using donepezil hydrochloride in accordance with comparative example 1 and examples 2 and 4, which are given below, and then solubility tests were performed. It should be noted that sustained-release matrix-type preparations were prepared using ethyl cellulose as a water-insoluble polymer, and L100-55 as an intestinal soluble polymer of eudragit. The ratios of ethyl cellulose to eudragit L100-55 in comparative example 1 and examples 2 and 4 were 25%: 0 wt.%, 25%: 25 wt.% And 25%: 50 wt.%, Respectively. In addition, solubility tests were carried out in the following two types of test solutions at a stirrer speed of 50 rpm in accordance with the solubility testing methods of the Japanese Pharmacopoeia, ed. 14. Solubility tests were performed using test solution A as an acidic test solution and the remaining solution B as a neutral test solution, as described below.

Test solution A: 0.1 N hydrochloric acid solution

Test solution B: 50 mM phosphate buffer, pH 6.8 (buffer from a solution of 50 mM sodium phosphate adjusted to pH 6.75 to pH 6.84 with hydrochloric acid)

It should be noted that the dissolution rate was calculated on the basis of the concentration of donepezil hydrochloride in samples of solutions taken as they dissolve and analyzed by spectrophotometric or HPLC analysis. The spectrophotometric method was carried out under measurement conditions at a measurement wavelength of 315 nm, a reference wavelength of 650 nm. The HPLC analysis method was carried out under measurement conditions with a measuring column: Inertsil ODS-2 (GL Science), mobile phase: water / acetonitrile / 70% aqueous perchloric acid solution = mixture 650/350/1, at a detection wavelength of 271 nm. The comparative results of the solubility tests are shown in figures 1 and 2, and the results of comparative example 1 and examples 2 and 4 in tables 1 and 2.

Table 1 Comparative Example 1 Example 1 Clock Test Solution A Test Solution B Test Solution A / Test Solution B Clock Test Solution A Test Solution B Test Solution A / Test Solution B 1 hour 27% 19% 1.41 1 hour 22% fifteen% 1,52 2 hours 41% 27% 1,50 2 hours 32% 29% 1.13 3 hour fifty% 33% 1,52 3 hour 39% 40% 0.97 4 hour 57% 37% 1,54 4 hour 44% fifty% 0.87 5 hour 63% 41% 1,54 5 hour 47% 58% 0.81 6 hour 67% 44% 1,54 6 hour fifty% 65% 0.76 8 hour 73% 48% 1,53 8 hour 55% 78% 0.71 table 2 Example 2 Example 3 Clock Test Solution A Test Solution B Test Solution A / Test Solution B Clock Test Solution A Test Solution B Test Solution A / Test Solution B 1 hour eighteen% fourteen% 1.28 1 hour 19% 13% 1.42 2 hours 27% 21% 1.29 2 hours 25% 19% 1.36 3 hour 33% 26% 1.27 3 hour thirty% 23% 1.33 4 hour 37% thirty% 1.26 4 hour 34% 26% 1.31 5 hour 41% 33% 1.25 5 hour 37% 29% 1.29 6 hour 44% 36% 1.24 6 hour 40% 31% 1.28 8 hour fifty% 41% 1.23 8 hour 45% 36% 1.24

Example 4 Example 5 Clock Test Solution A Test Solution B Test Solution A / Test Solution B Clock Test Solution A Test Solution B Test Solution A / Test Solution B 1 hour 8% 10% 0.75 1 hour fourteen% 13% 1,07 2 hours eleven% fifteen% 0.69 2 hours twenty% twenty% 0.96 3 hour 12% 19% 0.64 3 hour 23% 25% 0.92 4 hour fourteen% 23% 0.61 4 hour 26% 29% 0.88 5 hour fifteen% 25% 0.59 5 hour 28% 34% 0.84 6 hour 16% 28% 0.57 6 hour thirty% 41% 0.74 8 hour 17% 31% 0.54 8 hour 33% 56% 0.59 Example 6 Clock Test Solution A Test Solution B Test Solution A / Test Solution B 1 hour 17% fifteen% 1.15 2 hours 24% 29% 0.83 3 hour 29% 41% 0.70 4 hour 33% 51% 0.63 5 hour 35% 60% 0.59 6 hour 38% 67% 0.57 8 hour 42% 77% 0.55

In comparative example 1 and examples 2 and 4, the mass fraction of eudragit L100-55 in tablets at a constant 25 wt.% Ethyl cellulose per 100 wt.% Tablets varies (0%, 25%, 50 wt.% Eudragit L100-55 per 100 wt. % of tablets, respectively). As shown in figures 1 and 2, it was confirmed that in solubility tests using the same test solutions under the same conditions, the higher the content (percentage) of the intestinally soluble polymer (Eudragit L100-55), the slower the dissolution of donepezil hydrochloride from matrix sustained release preparation of the present invention.

In the sustained release matrix preparation of the present invention, when both the intestinally soluble polymer and the water-insoluble polymer are mixed in the preparation, the greater the amount of the intestinally soluble polymer mixed with the water-insoluble polymer, the more the dissolution rate is reduced, thereby making the preparation possible sustained release drug.

Experimental Example 2

The following are steps to ensure low pH-dependent dissolution for a sustained-release matrix-type drug, while reducing the ratio of the dissolution rate of the main drug or its salt in an acidic test solution to the dissolution rate in a neutral test solution (dissolution rate in acidic test solution / dissolution rate in a neutral test solution) in the solubility test as the solubility tests pass.

Initially, Eudragit L100-55 was used as a gut-soluble polymer in a sustained release matrix preparation, and ethyl cellulose was used as a water-insoluble polymer.

Slow-release matrix-type preparations were prepared using donepezil hydrochloride in accordance with comparative example 1 and examples 1-11 and 14-17 below, and then solubility tests were performed. Solubility tests were performed to evaluate formulations in which the amounts of donepezil hydrochloride, intestinally soluble polymer, and water-insoluble polymer (in Examples 1-6) were varied, in which the type of diluents (in Examples 5 and 7) were varied, in which wet granulation was carried out using binding agents (in examples 8, 11 and 14-17 and 20) in which the type of ethyl cellulose was changed (in examples 5, 9 and 10) and in which an increase in production was carried out (in examples 11, 14 to 17). It should be noted that, as comparative example 1, a preparation was used containing, as main components, donepezil hydrochloride and a water-insoluble polymer without any intestinal-soluble polymer. The results for comparative example 1 and examples 1, 2-6, 7-11 and 14-17 and 20 are presented in tables 1, 2, 3 and 4, respectively. The results of the comparative solubility test for examples 14-17 are presented in figures 3 and 4.

Table 3 Example 7 Example 8 Clock Test Solution A Test Solution B Test Solution A / Test Solution B Clock Test Solution A Test Solution B Test Solution A / Test Solution B 1 hour fifteen% 16% 0.98 1 hour 17% 13% 1.35 2 hours 22% 24% 0.92 2 hours 25% 26% 0.98 3 hour 26% thirty% 0.86 3 hour 32% 39% 0.83 4 hour 29% 36% 0.81 4 hour 37% 51% 0.73 5 hour 31% 45% 0.68 5 hour 42% 62% 0.68 6 hour 33% 57% 0.59 6 hour 45% 71% 0.63 8 hour 36% 69% 0.53 8 hour 51% 87% 0.59 Example 9 Example 10 Clock Test Solution A Test Solution B Test Solution A / Test Solution B Clock Test Solution A Test Solution B Test Solution A / Test Solution B 1 hour 16% fifteen% 1.06 1 hour 16% fourteen% 1,11 2 hours 22% 28% 0.80 2 hours 22% 27% 0.82 3 hour 26% 39% 0.68 3 hour 26% 37% 0.70 4 hour thirty% 49% 0.61 4 hour thirty% 46% 0.64 5 hour 33% 57% 0.57 5 hour 33% 53% 0.61 6 hour 35% 64% 0.55 6 hour 35% 60% 0.58 8 hour 39% 76% 0.51 8 hour 39% 71% 0.55

Example 11 Clock Test Solution A Test Solution B Test Solution A / Test Solution B 1 hour 25% 16% 1,56 2 hours 37% 33% 1.12 3 hour 46% 52% 0.88 4 hour 53% 69% 0.77 5 hour 59% 83% 0.71 6 hour 64% 92% 0.69 8 hour 70% 99% 0.71

Table 4 Example 14 Example 15 Clock Test Solution A Test Solution B Test Solution A / Test Solution B Clock Test Solution A Test Solution B Test Solution A / Test Solution B 1 hour 36% 32% 1.13 1 hour 21% 13% 1,60 2 hours 56% 65% 0.87 2 hours 31% 27% 1.16 3 hour 69% 87% 0.79 3 hour 40% 47% 0.85 4 hour 76% 99% 0.77 4 hour 46% 63% 0.73 5 hour 81% 101% 0.80 5 hour 52% 76% 0.68 6 hour 84% 101% 0.83 6 hour 57% 86% 0.66 8 hour 63% 95% 0.66 10 hour 68% 97% 0.71

Example 16 Example 17 Clock Test Solution A Test Solution B Test Solution A / Test Solution B Clock Test Solution A Test Solution B Test Solution A / Test Solution B 1 hour 17% eleven% 1.49 1 hour fourteen% 10% 1.37 2 hours 25% 21% 1.17 2 hours 21% 16% 1.27 3 hour 31% 34% 0.90 3 hour 26% 22% 1.18 4 hour 36% fifty% 0.72 4 hour thirty% 28% 1,08 5 hour 41% 63% 0.64 5 hour 34% 36% 0.94 6 hour 45% 75% 0.60 6 hour 37% 47% 0.79 8 hour 51% 90% 0.56 8 hour 43% 68% 0.63 10 hour 56% 97% 0.58 10 hour - 82% - 12 hour 60% 97% 0.61 12 hour - 92% - 14 hour 63% 97% 0.65 14 hour - 98% - Example 20 Clock Test Solution A Test Solution B Test Solution A / Test Solution B 1 hour 32,0 16.7 1.92 2 hours 43.0 27.0 1,59 3 hour 52.0 46.0 1.13 4 hour 58.0 65.3 0.89 5 hour 65.0 80.3 0.81 6 hour 72.0 92.3 0.78 8 hour 79.0 103.0 0.77 10 hour 84.0 104.0 0.81 12 hour 87.0 103.3 0.84 14 hour 90.0 103.7 0.87

In the case of a sustained release matrix type preparation from comparative example 1, which does not contain an intestinal soluble polymer, the ratio of the dissolution rate in the acidic test solution to the dissolution rate in the neutral test solution (dissolution rate in the acidic test solution / dissolution rate in the neutral test solution) at an early stage, it slightly increases in the interval from the dissolution time of 1 hour to the dissolution time from 2 to 3 hours, and subsequently the ratio remains in the amount of approximately But 1.5 with a slight change in the late stage of dissolution. On the other hand, in the preparations of all examples (examples 1-11, examples 14-17), in which the intestinal-soluble polymer eudragit L100-55 was contained, the ratio of the dissolution rate in the interval from dissolution time 1 hour to dissolution time from 2 to 3 hours decreased and continued to decrease gradually as the solubility test was completed until the solubility test was completed or until the dissolution time at which the dissolution rate in the neutral test solution was 90% or more. In these cases, the ratio of dissolution rates ranged from 0.6 to 1.3 with a dissolution time of 3 hours. Thus, by mixing an intestinally soluble polymer into a preparation, the preparation of the present invention can provide a preparation in which the dissolution rate in an acidic test solution at an early stage of dissolution is slowed down (in accordance with the retention period in the stomach) while decreasing the dependence of the main drug or its salts against pH, and when applied at a late stage of dissolution (which is considered to be the corresponding stage of retention in the small intestine), a higher dissolution rate can be achieved eniya neutral test solution relative to the dissolution rate in an acidic test solution. Both effects at the early and late stages of dissolution are confirmed for all preparations in which the amounts of donepezil hydrochloride, intestinally soluble polymer and water-insoluble polymer (in examples 1 to 6) were varied, in which the type of diluents was varied (in examples 5 and 7), in which wet granulation was carried out with a binder (in examples 8, 11, 14-17 and 20), in which the type of ethyl cellulose was varied (in examples 5, 9, 10) and for which the scale of production was changed (in examples 11, 14-17 and twenty). In particular, in Examples 11 and 14-16, due to the fact that 90% or more of the drug was released in 50 mM phosphate buffer, pH 6.8, within 8 hours, which are calculated as the upper limit for reaching the large intestine in humans (Int J. Pharm. Vol. 53, 1989, 107 to 117), the risk of lowering bioavailability due to sustained release properties is small, and these drugs are believed to be very beneficial.

Experimental Example 3

In this experimental example, the types of intestinal soluble and water insoluble polymers were evaluated for a sustained release matrix type preparation. First, experimental examples of sustained release matrix-type preparations are described below, in which hydroxypropyl methylcellulose acetate succinate was used as a soluble polymer and ethyl cellulose was used as a water-insoluble polymer. Slow-release matrix-type preparations were prepared using donepezil hydrochloride in accordance with comparative example 2 and examples 12 and 13, which are set forth below, and then solubility tests were performed. In matrix-type sustained release preparations, hydroxypropyl methylcellulose acetate succinate (AQOAT LF or AQOAT MF; Shin-Etsu Chemical) was used as an intestinal soluble polymer, and ethyl cellulose was used as a water-insoluble polymer. It should be noted that the amount of hydroxypropyl methylcellulose acetate succinate as an intestinally soluble polymer in the preparations was 50% of the total weight of the drug.

As comparative examples 2, a preparation containing the same amounts of donepezil hydrochloride and a water-insoluble polymer as in examples 12 and 13, but a polymer insoluble in the intestine, was used. The comparative results of the solubility tests are shown in figures 5 and 6, and the results for comparative example 2 and examples 12 and 13 are shown in tables 5.

Table 5 Example 12 Example 13 Clock Test Solution A Test Solution B Test Solution A / Test Solution B Clock Test Solution A Test Solution B Test Solution A / Test Solution B 1 hour 12% 22% 0.55 1 hour fourteen% 27% 0.52 2 hours 17% 44% 0.38 2 hours 19% fifty% 0.38 3 hour twenty% 61% 0.32 3 hour 23% 67% 0.34 4 hour 22% 75% 0.30 4 hour 26% 78% 0.34 5 hour 25% 85% 0.29 5 hour 29% 86% 0.33 6 hour 27% 91% 0.29 6 hour 31% 91% 0.34 8 hour thirty% 94% 0.32 8 hour 35% 93% 0.38 Reference Example 2 Clock Test Solution A Test Solution B Test Solution A / Test Solution B 1 hour 71% 53% 0.34 2 hours 92% 70% 0.32 3 hour 96% 76% 1.26 4 hour 97% 80% 1.20 5 hour 97% 83% 1.16 6 hour 97% 86% 1.13 8 hour 97% 88% 1.09

As shown in figures 5 and 6, it was confirmed that as a result of the addition of a matrix type with a slow release of 50% intestinally soluble polymer (AQOAT LF or AQOAT MF; Shin-Etsu Chemical), the rate of dissolution of donepezil hydrochloride in an acidic solution is significantly reduced . The larger the amount of the intestinally soluble polymer mixed with the water-insoluble polymer in the preparation containing the intestinally soluble polymer and the water-insoluble polymer in the matrix sustained release preparation of the present invention, the more the dissolution rate can be reduced, thereby making a sustained release preparation with slow release.

With a delayed-release matrix type preparation from comparative example 2 that did not contain an intestinal-soluble polymer, the dissolution rate in an acidic test solution at a dissolution time of 2 hours reached 90%, and the ratio of the dissolution rate in an acidic test solution to the dissolution rate in a neutral test solution ( the dissolution rate in an acidic test solution / dissolution rate in a neutral test solution) at the early stage of dissolution remained approximately constant, equal to 1.3 (from 1 to 3 hours), although in preparations (examples 12 and 13), in which 50.0% hydroxypropyl methylcellulose acetate succinate (AQOAT LF or AQOAT MF; Shin-Etsu Chemical) was mixed as an intestinal soluble polymer, the dissolution rate ratio was recorded from 0.38 to 0, 55, which was lower than the ratio of dissolution rates in comparative example 2. Thus, the mixture of intestinal soluble polymer had the effect of decreasing the dissolution rate of the drug in acidic and neutral test solutions at an early stage of dissolution, and specifically, significant th reduction in the acidic solution test drug dissolution rate, thus resulting in the dissolution rate of the two solutions close to each other and reducing the dependence on pH. In addition, at a late stage of dissolution, it also had the effect of slowing down dissolution in an acidic test solution while enhancing dissolution in a neutral test solution. This means that it is possible to reduce the risk of adverse events at an early stage of dissolution due to delayed release properties, and in these preparations, the risk of reduced bioavailability can be reduced. Thus, it was confirmed that by establishing the added amount of hydroxypropylcellulose succinate acetate (AQOAT LF or AQOAT MF; Shin-Etsu Chemical) to an appropriate value of 0 to 50%, it is possible to develop a preparation in which a dissolution mode can be achieved with an early stage of dissolution with the ratio of the dissolution rate in an acidic test solution to the dissolution rate in a neutral test solution (dissolution rate in an acidic test solution / dissolution rate in a neutral test solution) of 1 and by a torus, the ratio of dissolution rates can be reduced until, at a late stage of dissolution, the dissolution rate in a neutral solution reaches 90% or more.

Further, Table 6 shows the effects of the combination of ethyl cellulose and Eudragit L100 on the dissolution regimen of the preparation. Compared with comparative example 1, which contains 25% ethyl cellulose, in the case of example 21, which contains 25% ethyl cellulose and 50% eudragit L100, it was confirmed that the ratio of the dissolution rate of the drug or its salt in the acidic test solution to the dissolution rate of the drug or its salts in a neutral test solution (dissolution rate in an acidic test solution / dissolution rate in a neutral test solution) decreases as it dissolves.

Table 6 Example 21 Reference Example 13 Clock Test Solution A Test Solution B Test Solution A / Test Solution B Clock Test Solution A Test Solution B Test Solution A / Test Solution B 1 hour 12% 8% 1,50 1 hour 27% 19% 1.41 2 hours 19% 13% 1.46 2 hours 41% 27% 1,50 3 hour 25% 19% 1.32 3 hour fifty% 33% 1,52 4 hour 29% 23% 1.26 4 hour 57% 37% 1,54 5 hour 32% 26% 1.23 5 hour 63% 41% 1,54 6 hour 35% 29% 1.21 6 hour 67% 44% 1,54 8 hour 39% 34% 1.15 8 hour 73% 48% 1,53 10 hour 43% 38% 1.13 12 hour 46% 41% 1.12 14 hour 49% 44% 1,11

In addition, the effects of eudragit RSPO as a water-insoluble polymer on the dissolution regimen of the drug were also evaluated as follows: as shown in table 7, in comparative example 3, which does not contain intestinal soluble polymer but contains eudragit RSPO, the drug peak mode and lack of effect of sustained release drug properties. However, in Examples 22 and 23, which contain Eudragit L100 and AQOAT LF, respectively, it was confirmed that the dissolution time was increased in Test Solution A and Test Solution B, and the effect of sustained release properties was achieved by mixing the intestinal soluble polymer in these examples. In addition, in examples 22 and 23, the ratio of the dissolution rate of a drug or its salt in an acidic test solution to the dissolution rate of a drug or its salt in a neutral test solution (dissolution rate in an acidic test solution / dissolution rate in a neutral test solution) at time 3 hours dissolution was 0.34 and 0.7, respectively, and it was confirmed that the above ratio of the dissolution rate of the drug or its salt in acidic solution to the dissolution rate of the drug Nogo means or the salt thereof in neutral solution after a dissolution time of 3 chasa decreased as dissolution. In particular, Example 23 shows that 90% or more of the drug was released in 50 mM phosphate buffer, pH 6.8, within 8 hours, which are calculated as the upper limit for reaching the large intestine in humans and suggest that the drugs of Example 23 are very helpful.

Table 7 Example 22 Example 23 Clock Test Solution A Test Solution B Test Solution A / Test Solution B Clock Test Solution A Test Solution B Test Solution A / Test Solution B 1 hour eleven% 12% 0.92 1 hour 10% 21% 0.48 2 hours 17% 22% 0.77 2 hours 16% 41% 0.39 3 hour 21% thirty% 0.70 3 hour 19% 56% 0.34 4 hour 25% 38% 0.66 4 hour 21% 71% 0.30 5 hour 28% 46% 0.61 5 hour 23% 82% 0.28 6 hour thirty% 52% 0.58 6 hour 26% 91% 0.29 8 hour 34% 64% 0.53 8 hour 29% 105% 0.28 10 hour 37% 74% 0.50 10 hour 32% 108% 0.30 12 hour 40% 82% 0.49 12 hour 35% 109% 0.32 14 hour 42% 88% 0.48 14 hour 38% 109% 0.35 Reference Example 30 Clock Test Solution A Test Solution B Test Solution A / Test Solution B 1 hour 68% 88% 0.77 2 hours 94% 98% 0.96 3 hour 97% 101% 0.96 4 hour 97% 101% 0.96 5 hour 97% 102% 0.95 6 hour 98% 102% 0.96 8 hour 97% 102% 0.95 10 hour 98% 102% 0.96 12 hour 98% 102% 0.96 14 hour 98% 103% 0.95

Experimental Example 4

Using the tablets obtained in examples 27-31, solubility tests were performed. The results of the solubility tests are shown in table 8 and in figures 7-9. According to the present invention, it is obvious that the delayed-release matrix-type preparation has properties that provide the dissolution of the main drug or its salt at an early stage of dissolution with a low pH dependence and can reduce the ratio of the dissolution rate of the main drug or its salt in an acidic test solution to the speed dissolution of the main drug or its salt in a neutral test solution (dissolution rate in acidic test solution / speed astvoreniya neutral test solution) at a late stage of dissolution, as the test for solubility. These drugs demonstrated that 90% or more of the drug was released in 50 mM phosphate buffer, pH 6.8, within 8 hours, which are calculated as the upper limit for reaching the large intestine in humans and are believed to be very useful.

Table 8 Example 27 Example 28 Clock Test Solution A Test Solution B Test Solution A / Test Solution B Clock Test Solution A Test Solution B Test Solution A / Test Solution B 1 hour 29% 22% 1.30 1 hour 29% fifteen% 1.87 2 hours 42% 35% 1.20 2 hours 41% 31% 1.32 3 hour 53% 52% 1.01 3 hour fifty% 47% 1.06 4 hour 61% 71% 0.86 4 hour 56% 61% 0.93 5 hour 68% 87% 00.78 5 hour 61% 72% 0.85 6 hour 73% 97% 0.75 6 hour 66% 84% 0.78 8 hour 81% 103% 0.78 8 hour 74% 96% 0.77 10 hour 86% 104% 0.83 10 hour 79% 97% 0.81 12 hour 89% 104% 0.86 12 hour 82% 97% 0.84 14 hour 92% 104% 0.88 14 hour 84% 98% 0.86 Example 29 Example 30 Clock Test Solution A Test Solution B Test Solution A / Test Solution B Clock Test Solution A Test Solution B Test Solution A / Test Solution B 1 hour 31% twenty% 1.51 1 hour 29% twenty% 1.45 2 hours 44% 34% 1.29 2 hours 43% 33% 1.30 3 hour 53% 47% 1.14 3 hour 54% 47% 1.14 4 hour 60% 59% 1,02 4 hour 62% 61% 1.01 5 hour 66% 70% 0.94 5 hour 70% 77% 0.90 6 hour 72% 81% 0.89 6 hour 76% 92% 0.82 8 hour 80% 96% 0.83 8 hour 85% 99% 0.85 10 hour 85% 97% 0.87 10 hour 90% 99% 0.90 12 hour 89% 97% 0.91 12 hour 94% one hundred% 0.94 14 hour 91% 97% 0.94 14 hour 96% one hundred% 0.96

Example 31 Clock Test Solution A Test Solution B Test Solution A / Test Solution B 1 hour 29% 21% 1.39 2 hours 43% 36% 1.20 3 hour 52% 51% 1,03 4 hour 61% 66% 0.93 5 hour 69% 80% 0.86 6 hour 75% 91% 0.82 8 hour 83% one hundred% 0.83 10 hour 88% one hundred% 0.88 12 hour 91% one hundred% 0.91 14 hour 94% one hundred% 0.94

Experimental Example 5

To assess the dissolution regime of the pharmaceutical composition containing memantine hydrochloride, solubility tests were performed using the preparations obtained in the following examples and comparative examples. Solubility tests were carried out in the following two types of test solutions at a stirrer speed of 50 rpm in accordance with Japanese Pharmacopoeia solubility testing methods, ed. 14. Solubility tests were performed using test solution A as an acidic test solution and test solution B as a neutral test solution, as described below.

Test solution A: 0.1 N hydrochloric acid solution

Test solution B: 50 mM phosphate buffer, pH 6.8 (buffer from a solution of 50 mM sodium phosphate adjusted to pH 6.75 to pH 6.84 with hydrochloric acid)

It should be noted that the dissolution rate was calculated based on the concentration of memantine hydrochloride in samples of solutions taken as they dissolve and analyzed by HPLC analysis after fluorescence labeling of memantine hydrochloride with fluorescamine. The conditions for fluorescence labeling and HPLC analysis are typically as follows: After selection as they were dissolved, sample solutions (1 ml) were mixed with borate buffer, pH 9.0 (USP, 9 ml), acetone solution (5 ml) was added containing fluorescamine (1.2 mg / ml) and mixed well. Water (10 ml) was also added to the above solution and mixed to obtain a test sample. The test sample was analyzed by HPLC. HPLC analysis was performed under measurement conditions with a measuring column: CAPCELL PAK UG120 C18 (Shiseido) or a similar column, with a column temperature: 40 ° C, mobile phase: borate buffer, pH 9.0, (USP) / acetonitrile = 60/40 mixture and detection conditions: fluorescence detector (excitation wavelength / detection wavelength = 391 nm / 474 nm).

To assess the effect of an intestinal soluble polymer on preparations containing memantine hydrochloride and ethyl cellulose as a water-insoluble polymer, solubility tests were performed using the tablets obtained in Examples 40-42 and Comparative Example 4.

In comparative example 4, which does not contain an intestinal soluble polymer but contains glucose, it was shown that the dissolution rate of memantine hydrochloride was slowed down to values from 30 to 40% at a dissolution time of 1 hour, but the ratio of the dissolution rate of the drug or its salt in acid test solution to the dissolution rate of the drug or its salt in a neutral test solution (dissolution rate in an acidic test solution / dissolution rate in a neutral test solution) remained constant th unchanged during dissolution. On the other hand, in examples 40-42, which contains an intestinal soluble polymer, it was shown that the dissolution rate of memantine hydrochloride in the early stage of dissolution was much lower than the dissolution rate of memantine hydrochloride in comparative example 4, and it was confirmed that the dissolution rate of memantine hydrochloride in the early stages of dissolution can be slowed down. In addition, these examples also confirm that the ratio of the dissolution rate of a drug or its salt in an acidic test solution to the dissolution rate of a drug or its salt in a neutral test solution (dissolution rate in an acidic test solution / dissolution rate in a neutral test solution) as dissolution decreased.

Table 9 Example 40 Example 41 Clock Test Solution A Test Solution B Test Solution A / Test Solution B Clock Test Solution A Test Solution B Test Solution A / Test Solution B 1 hour 10% 12% 0.91 1 hour 26% twenty% 1.33 2 hours fourteen% eighteen% 0.81 2 hours 39% thirty% 1.32 3 hour eighteen% 22% 0.80 3 hour 49% 39% 1.25 4 hour 19% 27% 0.70 4 hour 57% 46% 1.23 6 hour 22% 34% 0.64 6 hour 67% 56% 1.20 8 hour 23% 41% 0.57 8 hour 77% 63% 1.22 12 hour 28% 49% 0.57 12 hour 87% 70% 1.24 Example 42 Reference Example 4 Clock Test Solution A Test Solution B Test Solution A / Test Solution B Clock Test Solution A Test Solution B Test Solution A / Test Solution B 1 hour 10% 21% 0.49 1 hour 40% 37% 1.09 2 hours fourteen% 32% 0.44 2 hours 57% 51% 1.12 3 hour eighteen% 39% 0.46 3 hour 66% 60% 1.10 4 hour twenty% 44% 0.46 4 hour 74% 69% 1,08 6 hour 25% 59% 0.42 6 hour 86% 80% 1,07 8 hour 29% 64% 0.46 8 hour 91% 84% 1,08 12 hour 35% 68% 0.51 12 hour 97% 94% 1,03

Further, to evaluate the effect of an intestinal soluble polymer on the dissolution regime of preparations containing memantine hydrochloride and RSPO eudragit as a water-insoluble polymer, solubility tests were performed using the tablets obtained in Example 43 and Comparative Example 5.

In comparative example 5, which does not contain an intestinal soluble polymer but contains RSPO eudragit, it was shown that the dissolution rate of memantine hydrochloride in acidic and neutral test solutions was not less than 90% at 2 hours, and the ratio of the dissolution rate of the drug or its salt in an acidic test solution to the dissolution rate of a drug or its salt in a neutral test solution (dissolution rate in an acidic test solution / dissolution rate in a neutral test solution) avalas constant without change during dissolution. On the other hand, in Example 43, which contained an intestinal soluble polymer, it was shown that the dissolution rate of memantine hydrochloride in the early stage of dissolution was much lower than the dissolution rate of memantine hydrochloride in comparative example 5, and it was confirmed that the dissolution rate of memantine hydrochloride in early stages of dissolution can be slowed down. In addition, in example 43, it was also confirmed that the ratio of the dissolution rate of a drug or its salt in an acidic test solution to the dissolution rate of a drug or its salt in a neutral test solution (dissolution rate in an acidic test solution / dissolution rate in a neutral test solution) as dissolution decreased.

Table 10 Example 43 Reference Example 5 Clock Test Solution A Test Solution B Test Solution A / Test Solution B Clock Test Solution A Test Solution B Test Solution A / Test Solution B 1 hour 31% 26% 1.16 1 hour 67% 87% 0.77 2 hours 46% 44% 1,04 2 hours 95% 90% 1.06 3 hour 57% 59% 0.96 3 hour 96% 94% 1,02 4 hour 64% 68% 0.94 4 hour 96% 95% 1.01 6 hour 74% 86% 0.86 6 hour 97% 94% 1,03 8 hour 83% 90% 0.92 8 hour 95% 93% 1,02 12 hour 91% 97% 0.94 12 hour 94% 93% 1.01

Example 1

300 mg of donepezil hydrochloride (Eisai Co. Ltd), 1500 mg of eudragit L100-55 (Röhm GmbH & Co. KG), 1170 mg of lactose and 30 mg of magnesium stearate (Mallinckrodt Baker, Inc.) were mixed in a mortar. 200 mg of this mixture was taken and formed into a tablet using an Autograph AG5000A (Shimazu Corporation) to obtain an 8 mm diameter tablet containing 20 mg of donepezil hydrochloride. The results of the solubility test are shown in table 1.

Example 2

In a mortar, 300 mg of donepezil hydrochloride (Eisai Co. Ltd), 750 mg of etocel 10FP (ethyl cellulose, Dow Chemical Company), 750 mg of Eudragit L100-55 (Röhm GmbH & Co. KG), 1170 mg of lactose and 30 mg of magnesium stearate ( Mallinckrodt Baker, Inc.). 200 mg of this mixture was taken and formed into a tablet using an Autograph AG5000A (Shimazu Corporation) to obtain an 8 mm diameter tablet containing 20 mg of donepezil hydrochloride. The results of the solubility test are shown in table 2.

Example 3

In a mortar, 75 mg of donepezil hydrochloride (Eisai Co. Ltd), 750 mg of etocel 10FP (ethyl cellulose, Dow Chemical Company), 750 mg of eudragit L100-55 (Röhm GmbH & Co. KG), 1395 mg of lactose and 30 mg of magnesium stearate ( Mallinckrodt Baker, Inc.). 200 mg of this mixture was taken and formed into a tablet using an Autograph AG5000A (Shimazu Corporation) to obtain an 8 mm diameter tablet containing 5 mg of donepezil hydrochloride. The results of the solubility test are shown in table 2.

Example 4

300 mg of donepezil hydrochloride (Eisai Co. Ltd), 750 mg of etocel 10FP (ethyl cellulose, Dow Chemical Company), 1500 mg of Eudragit L100-55 (Röhm GmbH & Co. KG), 420 mg of lactose, and 30 mg of magnesium stearate were mixed in a mortar Mallinckrodt Baker, Inc.). 200 mg of this mixture was taken and formed into a tablet using an Autograph AG5000A (Shimazu Corporation) to obtain an 8 mm diameter tablet containing 20 mg of donepezil hydrochloride. The results of the solubility test are shown in table 2.

Example 5

300 mg of donepezil hydrochloride (Eisai Co. Ltd), 375 mg of etocel 10FP (ethyl cellulose, Dow Chemical Company), 1500 mg of Eudragit L100-55 (Röhm GmbH & Co. KG), 795 mg of lactose and 30 mg of magnesium stearate were mixed in a mortar Mallinckrodt Baker, Inc.). 200 mg of this mixture was taken and formed into a tablet using an Autograph AG5000A (Shimazu Corporation) to obtain an 8 mm diameter tablet containing 20 mg of donepezil hydrochloride. The results of the solubility test are shown in table 2.

Example 6

300 mg of donepezil hydrochloride (Eisai Co. Ltd), 183 mg of etocel 10FP (ethyl cellulose, Dow Chemical Company), 1500 mg of Eudragit L100-55 (Röhm GmbH & Co. KG), 987 mg of lactose and 30 mg of magnesium stearate were mixed in a mortar Mallinckrodt Baker, Inc.). 200 mg of this mixture was taken and formed into a tablet using an Autograph AG5000A (Shimazu Corporation) to obtain an 8 mm diameter tablet containing 20 mg of donepezil hydrochloride. The results of the solubility test are shown in table 2.

Example 7

300 mg of donepezil hydrochloride (Eisai Co. Ltd), 375 mg of etocel 10FP (ethyl cellulose, Dow Chemical Company), 1500 mg of Eudragit L100-55 (Röhm GmbH & Co. KG), 795 mg of D-mannitol and 30 mg of stearate were mixed in a mortar magnesium (Mallinckrodt Baker, Inc.). 200 mg of this mixture was taken and formed into a tablet using an Autograph AG5000A (Shimazu Corporation) to obtain an 8 mm diameter tablet containing 20 mg of donepezil hydrochloride. The results of the solubility test are shown in table 3.

Example 8

An appropriate amount of purified water was added and mixed with 300 mg of donepezil hydrochloride (Eisai Co. Ltd), 375 mg of etocel 10FP (ethyl cellulose, Dow Chemical Company), 1500 mg of Eudragit L100-55 (Röhm GmbH & Co. KG), 705 mg of lactose and 90 mg of hydroxypropyl cellulose (HPC-L; Nippon Soda Co., Ltd), and the mixture was heat-dried in a thermostatic chamber. 30 mg of magnesium stearate (Mallinckrodt Baker, Inc.) was added and mixed with dried granules. 200 mg of this mixture was taken and formed into a tablet using an Autograph AG5000A (Shimazu Corporation) to obtain an 8 mm diameter tablet containing 20 mg of donepezil hydrochloride. The results of the solubility test are shown in table 3.

Example 9

300 mg of donepezil hydrochloride (Eisai Co. Ltd), 375 mg of etocel 10STD (ethyl cellulose, Dow Chemical Company), 1500 mg of Eudragit L100-55 (Röhm GmbH & Co. KG), 795 mg of lactose and 30 mg of magnesium stearate were mixed in a mortar Mallinckrodt Baker, Inc.). 200 mg of this mixture was taken and formed into a tablet using an Autograph AG5000A (Shimazu Corporation) to obtain an 8 mm diameter tablet containing 20 mg of donepezil hydrochloride. The results of the solubility test are shown in table 3.

Example 10

300 mg of donepezil hydrochloride (Eisai Co. Ltd), 375 mg of etocel 100FP (ethyl cellulose, Dow Chemical Company), 1500 mg of Eudragit L100-55 (Röhm GmbH & Co. KG), 795 mg of lactose and 30 mg of magnesium stearate (mixed with Mallinckrodt Baker, Inc.). 200 mg of this mixture was taken and formed into a tablet using an Autograph AG5000A (Shimazu Corporation) to obtain an 8 mm diameter tablet containing 20 mg of donepezil hydrochloride. The results of the solubility test are shown in table 3.

Example 11

70 g of donepezil hydrochloride (Eisai), 336 g of etocel 10FP (ethyl cellulose, Dow Chemical Company), 364 g of Eudragit L100-55 (Röhm GmbH & Co. KG) and 588 g of lactose were mixed. Wet granulation was performed by adding to this mixture an aqueous solution of 28 g of hydroxypropyl cellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in a suitable amount of purified water. The resulting granules were heat dried in a centrifugal dryer and sieved to obtain granules of the desired size. After sizing, 1 g of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 99 g of granules and mixed. To form granules into tablets with a diameter of 8 mm containing 10 mg of donepezil hydrochloride in 200 mg of tablets, a rotational tabletting device was used. The results of the solubility test are shown in table 3.

Example 12

300 mg of donepezil hydrochloride (Eisai Co. Ltd), 375 mg of etocel 10FP (ethyl cellulose, Dow Chemical Company), 1500 mg of AQOAT LF (hydroxypropyl methylcellulose acetate succinate, Shin-Etsu Chemical), 795 mg of lactose and 30 mg of magnesium stearate (30 mg) were mixed in a mortar Mallinckrodt Baker, Inc.). 200 mg of this mixture was taken and formed into a tablet using an Autograph AG5000A (Shimazu Corporation) to obtain an 8 mm diameter tablet containing 20 mg of donepezil hydrochloride. The results of the solubility test are shown in table 5.

Example 13

300 mg of donepezil hydrochloride (Eisai Co. Ltd), 375 mg of etocel 10FP (ethyl cellulose, Dow Chemical Company), 1500 mg of AQOAT MF (hydroxypropyl methylcellulose acetate succinate, Shin-Etsu Chemical), 795 mg of lactose and 30 mg of magnesium stearate were mixed in a mortar Mallinckrodt Baker, Inc.). 200 mg of this mixture was taken and formed into a tablet using an Autograph AG5000A (Shimazu Corporation) to obtain an 8 mm diameter tablet containing 20 mg of donepezil hydrochloride. The results of the solubility test are shown in table 5.

Example 14

130 g of donepezil hydrochloride (Eisai Co. Ltd), 312 g of etocel 10FP (ethyl cellulose, Dow Chemical Company), 624 g of Eudragit L100-55 (Röhm GmbH & Co. KG) and 1456 g of lactose were mixed in a granulator. Wet granulation was carried out by adding 52 g of an aqueous solution of 52 g of hydroxypropyl cellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water. The resulting granules were heat dried in a centrifugal dryer and sieved to obtain granules of the desired size. After sizing, 1 g of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 99 g of granules and mixed, and a rotary tabletter was used to obtain an 8 mm diameter tablet containing 10 mg of donepezil hydrochloride in 200 mg of tablet. To apply a water-soluble film coating to the resulting tablet containing hydroxypropyl methylcellulose as its main component (coating amount: 8 mg / tablet), Opadry Yellow (Colorcon Japan Limited) was used, resulting in a film-coated tablet. The results of the solubility test are shown in table 4.

Example 15

130 g of donepezil hydrochloride (Eisai Co. Ltd), 624 g of etocel 10FP (ethyl cellulose, Dow Chemical Company), 780 g of Eudragit L100-55 (Röhm GmbH & Co. KG) and 988 g of lactose were mixed in a granulator. Wet granulation was carried out by adding 52 g of an aqueous solution of 52 g of hydroxypropyl cellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water. The resulting granules were heat dried in a centrifugal dryer and sieved to obtain granules of the desired size. After sizing, 1 g of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 99 g of granules and mixed, and a rotary tabletter was used to obtain an 8 mm diameter tablet containing 10 mg of donepezil hydrochloride in 200 mg of tablet. To apply a water-soluble film coating to the resulting tablet containing hydroxypropyl methylcellulose as its main component (coating amount: 8 mg / tablet), Opadry Yellow (Colorcon Japan Limited) was used, resulting in a film-coated tablet. The results of the solubility test are shown in table 4.

Example 16

130 g of donepezil hydrochloride (Eisai Co. Ltd), 780 g of etocel 10FP (ethyl cellulose, Dow Chemical Company), 858 g of Eudragit L100-55 (Röhm GmbH & Co. KG) and 754 g of lactose were mixed in a granulator. Wet granulation was carried out by adding 52 g of an aqueous solution of 52 g of hydroxypropyl cellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water. The resulting granules were heat dried in a centrifugal dryer and sieved to obtain granules of the desired size. After sizing, 1 g of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 99 g of granules and mixed, and a rotary tabletter was used to obtain an 8 mm diameter tablet containing 10 mg of donepezil hydrochloride in 200 mg of tablet. To apply a water-soluble film coating to the resulting tablet containing hydroxypropyl methylcellulose as its main component (coating amount: 8 mg / tablet), Opadry Yellow (Colorcon Japan Limited) was used, resulting in a film-coated tablet. The results of the solubility test are shown in table 4.

Example 17

130 g of donepezil hydrochloride (Eisai Co. Ltd), 832 g of etocell 10FP (ethyl cellulose, Dow Chemical Company), 962 g of Eudragit L100-55 (Röhm GmbH & Co. KG) and 598 g of lactose were mixed in a granulator. By adding to this mixture an aqueous solution of 52 g of hydroxypropyl cellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water, wet granulation was carried out and the resulting granules were heat dried in a centrifugal dryer and sieved to obtain granules desired size. After sizing, 1 g of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 99 g of granules and mixed, and a rotary tabletter was used to obtain an 8 mm diameter tablet containing 10 mg of donepezil hydrochloride in 200 mg of tablet. To apply a water-soluble film coating to the resulting tablet containing hydroxypropyl methylcellulose as its main component (coating amount: 8 mg / tablet), Opadry Yellow (Colorcon Japan Limited) was used, resulting in a film-coated tablet. The results of the solubility test are shown in table 4.

Example 18

12 g of memantine hydrochloride (Lachema s.r.o. Czech Republic), 28.8 g of etocel 10FP (ethyl cellulose, Dow Chemical Company), 36 g of Eudragit L100-55 (Röhm GmbH & Co. KG) and 39.6 g of lactose were mixed in a granulator. By adding to this mixture an aqueous solution of 2.4 g of hydroxypropyl cellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water, wet granulation was carried out and the resulting granules were heat dried in a centrifugal dryer and sieved with obtaining granules of the desired size. After sizing, 1 g of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 99 g of granules and mixed, and a rotary tabletter was used to obtain an 8 mm diameter tablet containing 20 mg memantine hydrochloride in 200 mg tablets.

Example 19

6 g of donepezil hydrochloride (Eisai Co. Ltd), 12 g of memantine hydrochloride (Lachema sro), 28.8 g of etocel 10FP (ethyl cellulose, Dow Chemical Company), 36 g of eudragit L100-55 (Röhm GmbH & Co. KG) were mixed in a granulator. ) and 45.6 g of lactose. By adding to this mixture an aqueous solution of 2.4 g of hydroxypropyl cellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water, wet granulation was carried out and the resulting granules were heat dried in a centrifugal dryer and sieved with obtaining granules of the desired size. After sizing, 1 g of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 109 g of granules and mixed, and a rotary tabletter was used to obtain an 8 mm diameter tablet containing 10 mg of donepezil hydrochloride and 20 mg of memantine hydrochloride in 220 mg of product. Opadry yellow (Colorcon Japan Limited) was used to apply a water-soluble film coating product containing hydroxypropyl methylcellulose (the amount of coating: 8 mg / tablet) to this compression molded product obtained by compression molding to obtain a film-coated tablet.

The following comparative examples 1 and 2 are provided to illustrate the superior effects of the sustained release matrix-type preparation of the present invention.

Comparative Example 1

300 mg of donepezil hydrochloride (Eisai Co. Ltd), 750 mg of etocel 10FP (ethyl cellulose, Dow Chemical Company), 1920 mg of lactose and 30 mg of magnesium stearate (Mallinckrodt Baker, Inc.) were mixed in a mortar. 200 mg of this mixture was taken and formed into a tablet using an Autograph AG5000A (Shimazu Corporation) to obtain an 8 mm diameter tablet containing 20 mg of donepezil hydrochloride. The results of the solubility test are shown in table 1.

Reference Example 2

300 mg of donepezil hydrochloride (Eisai Co. Ltd), 375 mg of etocel 10FP (ethyl cellulose, Dow Chemical Company), 2295 mg of lactose and 30 mg of magnesium stearate (Mallinckrodt Baker, Inc.) were mixed in a mortar. 200 mg of this mixture was taken and formed into a tablet using an Autograph AG5000A (Shimazu Corporation) to obtain an 8 mm diameter tablet containing 20 mg of donepezil hydrochloride. The results of the solubility test are shown in table 5.

Example 20

7 g of donepezil hydrochloride (Eisai Co. Ltd), 37.8 g of etocel 10FP (ethyl cellulose, Dow Chemical Company), 22.4 g of Eudragit L100-55 (Röhm GmbH & Co. KG) and 68.18 g of lactose were mixed in a granulator . By adding to this mixture an aqueous solution of 4.2 g of hydroxypropyl cellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water, wet granulation was carried out and the resulting granules were heat dried in a centrifugal dryer and sieved with obtaining granules of the desired size. After sizing, 0.3 g of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 99.7 g of granules and mixed, and a single die tabletting device was used to obtain an 8 mm diameter tablet containing 10 mg of donepezil hydrochloride in 200 mg of tablet. . The results of the solubility test are shown in table 4.

Examples 21 to 23 and comparative example 3

Each component was mixed in a mortar according to the number of components in table 11. 200 mg of this mixture was selected and formed into a tablet using an Autograph AG5000A (Shimazu Corporation) to obtain a tablet (tablet weight: 200 mg) with a diameter of 8 mm containing 20 mg of hydrochloride donepezil. The results of the solubility test are shown in tables 6 and 7.

Table 11 Component Name Seller example 21 example 22 example 23 will compare. example 3 Donepezil-HCl Eisai 300 300 300 300 It is a 10 FP Dow chemical 750 - - - Eudragit RS PO Rohm - 750 750 750 Eudragit L100-55 Rohm - 1500 - - Eudragit L100 Rohm 1500 - - - AQOAT LF SHIN-ETSU CHEMICAL - - 1500 - Lactose (FlowLac 100) Meggle 420 435 435 1935 Magnesium stearate Mallinckrodt thirty fifteen fifteen fifteen Total (mg) 3000 3000 3000 3000

Example 24

In a granulator, 3.5 g of donepezil hydrochloride (Eisai Co. Ltd), 37.8 g of etocel 10FP (ethyl cellulose, Dow Chemical Company), 22.4 g of Eudragit L100-55 (Röhm GmbH & Co. KG) and 73.5 were mixed g of lactose (Pharmatose 200M manufactured by DMV Corporation). By adding to this mixture an aqueous solution of 2.8 g of hydroxypropyl cellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water, wet granulation was carried out and the resulting granules were heat dried in a centrifugal dryer and sieved with obtaining granules of the desired size by means of an electric crusher. After sizing, 50 mg of calcium stearate (Merck KGaA, Darmstadt, Germany) per 5000 mg of granules was added and mixed, and an Autograph AG5000A (Shimazu Corporation) was used to compress the product with an diameter of 8 mm containing 5 mg of donepezil hydrochloride in 202 mg of the product by compression molding. ), with a pressing pressure of 1200 kgf.

Example 25

700 g of donepezil hydrochloride (Eisai Co. Ltd), 2700 g of etocel 10FP (ethyl cellulose, Dow Chemical Company), 2100 g of Eudragit L100-55 (Röhm GmbH & Co. KG) and 4250 g of lactose were mixed in a granulator. By adding to this mixture an aqueous solution of 220 g of hydroxypropyl cellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water, wet granulation was carried out and the resulting granules were heat dried in a fluidized bed dryer and sieved with obtaining granules of the desired size. After sizing, 0.3 g of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 99.7 g of granules and mixed, and a rotary tabletter was used to obtain an 8 mm diameter tablet containing 14 mg of donepezil hydrochloride in 200 mg of tablet. Opadry magenta (Colorcon Japan Limited) was used to coat the resulting tablet with a water-soluble film coating containing hydroxypropylmethyl cellulose as its main component (coating amount: 8 mg / tablet) to obtain a film-coated tablet.

Example 26

700 g of donepezil hydrochloride (Eisai Co. Ltd), 2700 g of etocel 10FP (ethyl cellulose, Dow Chemical Company), 1900 g of eudragit L100-55 (Röhm GmbH & Co. KG) and 4450 g of lactose were mixed in a granulator. By adding to this mixture an aqueous solution of 220 g of hydroxypropyl cellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water, wet granulation was carried out and the resulting granules were heat dried in a fluidized bed dryer and sieved with obtaining granules of the desired size. After sizing, 0.3 g of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 99.7 g of granules and mixed, and a rotary tabletter was used to obtain an 8 mm diameter tablet containing 14 mg of donepezil hydrochloride in 200 mg of tablet. Opadry magenta (Colorcon Japan Limited) was used to coat the resulting tablet with a water-soluble film coating containing hydroxypropylmethyl cellulose as its main component (coating amount: 8 mg / tablet) to obtain a film-coated tablet.

Example 27

700 g of donepezil hydrochloride (Eisai Co. Ltd), 2700 g of etocel 10FP (ethyl cellulose, Dow Chemical Company), 1900 g of eudragit L100-55 (Röhm GmbH & Co. KG) and 4420 g of lactose were mixed in a granulator. By adding to this mixture an aqueous solution of 250 g of hydroxypropyl cellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water, wet granulation was performed and the resulting granules were heat dried in a fluidized bed dryer and sieved with obtaining granules of the desired size. After sizing, 0.3 g of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 99.7 g of granules and mixed, and a rotary tabletter was used to obtain an 8 mm diameter tablet containing 14 mg of donepezil hydrochloride in 200 mg of tablet. Opadry magenta (Colorcon Japan Limited) was used to coat the resulting tablet with a water-soluble film coating containing hydroxypropylmethyl cellulose as its main component (coating amount: 8 mg / tablet) to obtain a film-coated tablet. The results of the solubility test are shown in table 8 and figure 7.

Example 28

1050 g of donepezil hydrochloride (Eisai Co. Ltd), 3780 g of etocel 10FP (ethyl cellulose, Dow Chemical Company), 2240 g of Eudragit L100-55 (Röhm GmbH & Co. KG) and 6538 g of lactose were mixed in a granulator. By adding to this mixture an aqueous solution of 350 g of hydroxypropyl cellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water, wet granulation was performed and the resulting granules were heat dried in a fluidized bed dryer and sieved with obtaining granules of the desired size. After sizing, 0.3 g of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 99.7 g of granules and mixed, and a rotary tabletter was used to obtain an 8 mm diameter tablet containing 15 mg of donepezil hydrochloride in 200 mg of tablet. Opadry magenta (Colorcon Japan Limited) was used to coat the resulting tablet with a water-soluble film coating containing hydroxypropylmethyl cellulose as its main component (coating amount: 8 mg / tablet) to obtain a film-coated tablet. The results of the solubility test are shown in table 8 and figure 8.

Example 29

1400 g of donepezil hydrochloride (Eisai Co. Ltd), 3500 g of etocel 10FP (ethyl cellulose, Dow Chemical Company), 2520 g of Eudragit L100-55 (Röhm GmbH & Co. KG) and 6118 g of lactose were mixed in a granulator. Wet granulation was carried out by adding 420 g of an aqueous solution of 420 g of hydroxypropyl cellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water to this mixture, and the resulting granules were heat dried in a fluidized bed dryer and sieved with obtaining granules of the desired size. After sizing, 0.3 g of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 99.7 g of granules and mixed, and a rotary tabletter was used to obtain an 8 mm diameter tablet containing 20 mg of donepezil hydrochloride in 200 mg of tablet. Opadry red (Colorcon Japan Limited) was used to coat a resulting tablet with a water-soluble film coating containing hydroxypropyl methylcellulose as its main component (coating amount: 8 mg / tablet), thereby obtaining a film-coated tablet. The results of the solubility test are shown in table 8 and figure 8.

Example 30

1150 g of donepezil hydrochloride (Eisai Co. Ltd), 2500 g of etocel 10FP (ethyl cellulose, Dow Chemical Company), 1800 g of eudragit L100-55 (Röhm GmbH & Co. KG) and 4220 g of lactose were mixed in a granulator. By adding to this mixture an aqueous solution of 300 g of hydroxypropyl cellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water, wet granulation was carried out and the resulting granules were heat dried in a fluidized bed dryer and sieved with obtaining granules of the desired size. After sizing, 0.3 g of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 99.7 g of granules and mixed, and a rotary tabletter was used to obtain an 8 mm diameter tablet containing 23 mg of donepezil hydrochloride in 200 mg of the tablet. Opadry red (Colorcon Japan Limited) was used to coat a resulting tablet with a water-soluble film coating containing hydroxypropyl methylcellulose as its main component (coating amount: 8 mg / tablet), thereby obtaining a film-coated tablet. The results of the solubility test are shown in table 8 and figure 9.

Example 31

1150 g of donepezil hydrochloride (Eisai Co. Ltd), 2200 g of etocel 10FP (ethyl cellulose, Dow Chemical Company), 2100 g of Eudragit L100-55 (Röhm GmbH & Co. KG) and 4220 g of lactose were mixed in a granulator. By adding to this mixture an aqueous solution of 300 g of hydroxypropyl cellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water, wet granulation was performed and the resulting granules were heat dried in a fluidized bed dryer and sieved with obtaining granules of the desired size. After sizing, 0.3 g of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 99.7 g of granules and mixed, and a rotary tabletter was used to obtain an 8 mm diameter tablet containing 23 mg of donepezil hydrochloride in 200 mg of the tablet. Opadry red (Colorcon Japan Limited) was used to coat a resulting tablet with a water-soluble film coating containing hydroxypropyl methylcellulose as its main component (coating amount: 8 mg / tablet), thereby obtaining a film-coated tablet. The results of the solubility test are shown in table 8 and figure 9.

Examples 32-38

The film-coated tablets shown in Table 12 can be prepared by the methods described above. Table 12 shows the amounts (mg) of each component in a film-coated tablet.

Table 12 Component Name Seller example 32 example 33 example 34 example 35 example 36 example 37 example 38 Donepezil-HCl Eisai 12 12 fourteen eighteen eighteen thirty thirty It is a 10 FP Dow chemical 54 54 48 54 44 fifty 44 Eudragit L100-55 Rohm 32 38 44 38 42 36 42 Lactose (Pharmatose 200M) DMV International 97.4 91.4 88.4 84,4 90,4 77.4 77.4 HPC-L Nippon soda four four 5 5 5 6 6 Magnesium stearate Mallinckrodt 0.6 0.6 0.6 0.6 0.6 0.6 0.6 Total in tablet (mg) 200 200 8 8 8 8 8 magenta (mg / tablet) Colorcon japan 8 8 8 8 8 8 8 Total Film Coated (mg) 208 208 208 208 208 208 208

Examples 39-44 and comparative examples 4 and 5

Each component was mixed in a mortar according to the amounts of the components in Table 13. 200 mg of this mixture was taken and formed into a tablet using an Autograph AG5000A (Shimazu Corporation) to obtain a tablet (tablet weight: 200 mg) with a diameter of 8 mm containing 20 mg of hydrochloride memantine.

Table 13 Component Name Seller example 39 example 40 example 41 example 42 example 43 example 44 Compares. example 4 Compares. example 4 Memantine Lachema s.r.o. 300 300 300 300 300 300 300 300 It is a 10 FP Dow chemical - 750 750 750 - - 750 - Eudragit RS PO Rohm - - - - 750 750 - 750 Eudragit L100-55 Rohm 1500 1500 - - 1500 - - - Eudragit L100 Rohm - - 1500 - - - - - AQOAT LF SHIN-ETSU CHEMICAL - - - 1500 - 1500 - Lactose (FlowLec) Meggle 1170 420 420 420 435 435 1920 1935 Magnesium stearate Mallinckrodt thirty thirty thirty thirty fifteen fifteen thirty fifteen Total (mg) 3000 3000 3000 3000 3000 3000 3000 3000

Industrial applicability

According to the present invention, in a sustained-release matrix-type preparation containing the main drug or its salt with a higher solubility of 0.1N. a solution of hydrochloric acid and a neutral aqueous solution, pH 6.0, than in the main aqueous solution, pH 8.0, at an early stage of dissolution, the pH dependence of the dissolution of the drug or its salt is reduced, and the ratio of the dissolution rate of the drug or its salt in acid test solution to the dissolution rate of the drug or its salt in a neutral test solution (dissolution rate in an acidic test solution / dissolution rate in a neutral test solution) when dissolved as it passes The solubility test decreases (in the late stage of the solubility test, the ratio becomes less than in the early stage).

Claims (11)

1. The composition of the matrix type sustained release containing:
(1) donepezil hydrochloride and / or memantine hydrochloride;
(2) an intestinal soluble polymer that is at least one selected from the group consisting of a methacrylic acid-ethyl acrylate copolymer, a methacrylic acid-methyl methacrylate copolymer, hydroxypropyl methyl cellulose phthalate and hydroxypropyl methyl cellulose acetate succinate; and
(3) a water-insoluble polymer, which is at least one selected from the group consisting of ethyl cellulose, an aminoalkyl methacrylate copolymer RS and an ethyl acrylate-methyl methacrylate copolymer. 2. The sustained release matrix type composition according to claim 1, further comprising a water soluble sugar, which is at least one selected from the group consisting of lactose, sucrose, glucose, dextrin and pullulan. 3. The sustained release matrix type composition of claim 1, further comprising a water soluble sugar alcohol, which is at least one selected from the group consisting of mannitol, erythritol, xylitol, and sorbitol. 4. The sustained release matrix type composition according to claim 1, wherein the gut-soluble polymer is a methacrylic acid-ethyl acrylate copolymer and the water-insoluble polymer is ethyl cellulose. 5. The sustained release matrix type composition according to claim 1, wherein the amount of intestinally soluble polymer in the sustained release matrix type composition is from 5 to 90% by weight of 100% by weight of the sustained release matrix type composition. 6. The sustained release matrix type composition according to claim 1, wherein the total amount of water-insoluble polymer and intestinal soluble polymer in the sustained release matrix type composition is from 25 to 95 wt.% From 100 wt.% Of the sustained release matrix type composition. 7. The sustained release matrix type composition of claim 2, wherein the total amount of water soluble sugar is from 3 to 70% by weight of 100% by weight of the slow type matrix type composition. 8. The delayed-release matrix type composition according to claim 3, wherein the total amount of water-soluble sugar alcohol is from 3 to 70% by weight from 100% by weight of the slow-release matrix type composition. 9. The sustained release matrix type composition according to claim 1, wherein the sustained release matrix type composition is a tablet, granule, a finely divided granule or capsule. 10. A method of obtaining a composition of a matrix type with sustained release, comprising the steps of:
mixing (1) donepezil hydrochloride and / or memantine hydrochloride; (2) an intestinal soluble polymer that is at least one selected from the group consisting of a methacrylic acid-ethyl acrylate copolymer, a methacrylic acid-methyl methacrylate copolymer, hydroxypropyl methyl cellulose phthalate and hydroxypropyl methyl cellulose acetate succinate; and (3) a water-insoluble polymer which is at least one selected from the group consisting of ethyl cellulose, an aminoalkyl methacrylate copolymer RS and an ethyl acrylate-methyl methacrylate copolymer;
and compression molding the mixture obtained in the mixing step. 11. The method of obtaining a matrix-type composition with a slow release according to claim 10, further comprising granulating the mixture obtained in the mixing step to the compression molding step.

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