阅读说明：本技术 用于预防或治疗痴呆和认知功能障碍、含有多奈哌齐或其药学上可接受的盐和美金刚或其药学上可接受的盐的药物组合物，及其制备方法 (Pharmaceutical composition for preventing or treating dementia and cognitive dysfunction, containing donepezil or a pharmaceutically acceptable salt thereof and memantine or a pharmaceutically accepta) 是由 具亨谟 高灿永 李磨世 于 2017-09-29 设计创作，主要内容包括：本发明涉及一种用于预防或治疗痴呆和认知功能障碍的药物组合物,及其制备方法,该药物组合物含有多奈哌齐或其药学上可接受的盐和美金刚或其药学上可接受的盐,该方法包括以下步骤：通过湿法过程将多奈哌齐或其药学上可接受的盐颗粒化；并且将其中将美金刚或其药学上可接受的盐添加到该颗粒化的多奈哌齐或其药学上可接受的盐中的混合物直接压制并将该混合物均质化。以便解决如下问题：其中由于当共同给予通常出售的Aricept(多奈哌齐盐酸盐)和Ebixa(美金刚盐酸盐)时的溶解度降低现象可能使活性成分多奈哌齐的功效降低,并且通过选择具有与活性成分的粒径类似的粒径的赋形剂来保证量均匀度。此外,本发明的药物组合物是非常稳定的且具有少的杂质。(The present invention relates to a pharmaceutical composition for preventing or treating dementia and cognitive dysfunction, which contains donepezil or a pharmaceutically acceptable salt thereof and memantine or a pharmaceutically acceptable salt thereof, and a preparation method thereof, the method comprising the steps of: granulating donepezil or a pharmaceutically acceptable salt thereof by a wet process; and directly compressing the mixture in which memantine or a pharmaceutically acceptable salt thereof is added to the granulated donepezil or a pharmaceutically acceptable salt thereof and homogenizing the mixture. In order to solve the following problems: wherein the efficacy of donepezil as an active ingredient may be lowered due to a solubility reduction phenomenon when commonly sold Aricept (donepezil hydrochloride) and Ebixa (memantine hydrochloride) are co-administered, and the amount uniformity is secured by selecting an excipient having a particle size similar to that of the active ingredient. Furthermore, the pharmaceutical composition of the present invention is very stable and has few impurities.)

1. An immediate release pharmaceutical composition for preventing or treating dementia and cognitive dysfunction, comprising memantine or a pharmaceutically acceptable salt thereof; and donepezil or a pharmaceutically acceptable salt thereof granulated by a wet process, and

Are directly compressed into the form of tablets.

2. The immediate release pharmaceutical composition of claim 1, wherein the granulated donepezil or pharmaceutically acceptable salt thereof is included in an amount of 1 wt% to 20 wt%.

3. The immediate release pharmaceutical composition of claim 1, wherein the granulated donepezil or pharmaceutically acceptable salt thereof and the memantine or pharmaceutically acceptable salt thereof are mixed in a weight ratio of 1:0.8 to 5.

4. The immediate release pharmaceutical composition of claim 1, wherein the granulated donepezil or pharmaceutically acceptable salt thereof has a particle size distribution d (0.5) of 120 μm to 200 μm.

5. The immediate release pharmaceutical composition of claim 1, wherein the granulated donepezil or pharmaceutically acceptable salt thereof comprises 15 to 25 wt% of particles having a size of 20 mesh or more to less than 50 mesh, 25 to 35 wt% of particles having a size of 50 mesh or more to less than 80 mesh, 20 to 30 wt% of particles having a size of 80 mesh or more to less than 200 mesh, and 15 to 25 wt% of particles having a size of at least 200 mesh, and

The amount of particles having a size of 20 mesh or larger to less than 50 mesh is less than the amount of particles having a size of at least 200 mesh.

6. The immediate release pharmaceutical composition of claim 1, wherein the granulated donepezil or pharmaceutically acceptable salt thereof is included in an amount of 5 wt% to 15 wt% as particles having a size of 20 mesh.

7. The immediate release pharmaceutical composition of claim 1, further comprising an excipient.

8. the immediate release pharmaceutical composition of claim 7, wherein the excipient is a mixture of lactose and microcrystalline cellulose in a weight ratio of 3 to 20: 1.

9. The immediate release pharmaceutical composition of claim 1, wherein the excipient comprises particles having a size of 80 mesh or larger in an amount of 50 wt% or more.

10. A method for preparing an immediate release pharmaceutical composition for preventing or treating dementia and cognitive dysfunction, the method comprising:

Granulating donepezil or a pharmaceutically acceptable salt thereof by a wet process; and is

Memantine or a pharmaceutically acceptable salt thereof is added to the granulated donepezil or a pharmaceutically acceptable salt thereof, and the resulting mixture is directly compressed and homogenized.

Technical Field

The present invention relates to an immediate release pharmaceutical composition for preventing or treating dementia and cognitive dysfunction, which comprises donepezil or a pharmaceutically acceptable salt thereof and memantine or a pharmaceutically acceptable salt thereof as active ingredients, and a method for preparing the same.

Background

With the development of the medical industry and the rapid economic growth, the quality of life is improved, and various diseases and the elderly population are increasing, and thus, the economic burden is increasing.

Among various diseases, brain function-related diseases have recently become major problems, and functional disorders such as fatigue, depression, insomnia, attention/memory impairment, or oxidative brain damage occur due to causes including uncontrollable or inevitable stress. In addition, the prevalence of neurodegenerative disorders (such as alzheimer's disease dementia, parkinson's disease, huntington's disease and lewy body disease, and consequent irreversible dementia) is increasing.

More than 50% of senile dementia is dementia of the alzheimer type (AD).

In the 90 s of the 20 th century, therapeutic agents for dementia or cognitive dysfunction were introduced in clinical practice, a series of acetylcholinesterase inhibitors (AChEi) such as donepezil, galantamine, rivastigmine, etc. were developed as therapeutic agents for alzheimer's disease dementia, and memantine, which is developed as a therapeutic agent for parkinson's disease and is an N-methyl-D-aspartate (NMDA) receptor antagonist, was approved as a therapeutic agent for alzheimer's disease dementia.

In the acetylcholinesterase inhibitor, donepezil is administered at a dose of 5mg once a day, at an increasing dose of 10mg after 4 to 6 weeks, and in the form of solid preparations for oral administration such as film-coated tablets, capsules, and granules.

Memantine was developed as a therapeutic agent for moderate to severe alzheimer's disease and was administered in the form of a film coating or a liquid formulation, and the drug was administered at a dose of 5mg per day and then at a maximum dose of 20 mg/day (i.e., 10mg each in the morning and evening), with 5mg being increased every week, but many clinical researchers currently administer drugs once per day due to a long half-life of 60 to 80 hours and relatively high side effects.

According to the previous study (Tariot, 2004), in the case where Donepezil and memantine were co-administered to Moderate to Severe Alzheimer dementia Patients, as a result of 24-week follow-up examination, it was reported that this disease case exhibited excellent cognitive function and excellent behavior score as compared with the group treated with Donepezil only (pierce n. Tariot et al, [ management strategy in Patients with both Moderate to sensor Alzheimer disease discovery Receiving Donepezil a random modulated Controlled trial ], ma, volume 291, phase 3, page 317-.

In addition, elderly patients, most of those suffering from dementia suffer from dysphagia, and their cognitive abilities are reduced, resulting in poor compliance with their own drugs and low fidelity to the drugs. Indeed, there are studies showing that patients taking one pill exhibit about 20% higher fidelity than patients taking two pills. Therefore, when a combination drug for treating dementia is developed, the drug dose and the drug fidelity can be increased.

conventionally, korean patent registration No. 1213345 discloses a technique for a combined preparation of donepezil and memantine and a technique for sustained release of one of the two drugs. However, in the case of a sustained-release type combined preparation, which is a preparation designed based on in vitro tests in a elution machine, it is not easy to produce a product having a constant sustained release rate, and when one takes the combined preparation directly, it is also not easy to predict the sustained release time accurately due to the difference in gastrointestinal motility between individuals. Thus, two drugs with long half-lives, which are usually co-administered and are expected to have no interaction, can be used as an immediate release formulation that exhibits efficacy over a short period of time.

Therefore, there is a need for an immediate release pharmaceutical composition which not only enhances the therapeutic effect by the synergistic effect between drugs, but also exhibits an elution rate similar to that of commercially available donepezil and memantine by using donepezil or a pharmaceutically acceptable salt thereof and memantine or a pharmaceutically acceptable salt thereof.

Disclosure of Invention

Accordingly, the present invention has been made in view of the above problems, and it is an object of the present invention to provide an immediate release pharmaceutical composition for preventing or treating dementia and cognitive dysfunction, which comprises donepezil or a pharmaceutically acceptable salt thereof and memantine or a pharmaceutically acceptable salt thereof as active ingredients.

It is another object of the present invention to provide a method for preparing an immediate release pharmaceutical composition for preventing or treating dementia and cognitive dysfunction, which comprises donepezil or a pharmaceutically acceptable salt thereof and memantine or a pharmaceutically acceptable salt thereof as active ingredients.

In accordance with the present invention, the above and other objects can be accomplished by the provision of an immediate release pharmaceutical composition for the prevention or treatment of dementia and cognitive dysfunction, comprising memantine or a pharmaceutically acceptable salt thereof; and donepezil or a pharmaceutically acceptable salt thereof, the memantine or a pharmaceutically acceptable salt thereof and the donepezil or a pharmaceutically acceptable salt thereof being granulated by a wet process and directly compressed into the form of tablets.

Granulated donepezil or a pharmaceutically acceptable salt thereof may be included in an amount of 1 wt% to 20 wt%.

The granulated donepezil or a pharmaceutically acceptable salt thereof and memantine or a pharmaceutically acceptable salt thereof may be mixed in a weight ratio of 1:0.8 to 5.

The granulated donepezil or pharmaceutically acceptable salt thereof may have a particle size distribution d (0.5) of 120 μm to 200 μm.

The granulated donepezil or pharmaceutically acceptable salt thereof may include 15 wt% to 25 wt% of particles having a size of 20 mesh or more to less than 50 mesh, 25 wt% to 35 wt% of particles having a size of 50 mesh or more to less than 80 mesh, 20 wt% to 30 wt% of particles having a size of 80 mesh or more to less than 200 mesh, and 15 wt% to 25 wt% of particles having a size of at least 200 mesh, and the amount of the particles having a size of 20 mesh or more to less than 50 mesh may be less than the amount of the particles having a size of 200 mesh or more.

Granulated donepezil or a pharmaceutically acceptable salt thereof may be included in an amount of 5 wt% to 15 wt% as particles of 20 mesh in size.

The pharmaceutical composition may further comprise an excipient.

The excipient may be a mixture of lactose and microcrystalline cellulose in a weight ratio of 3 to 20: 1.

The excipient may consist of particles having a size of 80 mesh or larger included in an amount of 50 wt% or more.

In accordance with one aspect of the present invention, the above and other objects can be accomplished by the provision of a method for preparing an immediate release pharmaceutical composition for the prevention or treatment of dementia and cognitive dysfunction, which comprises granulating donepezil or a pharmaceutically acceptable salt thereof by a wet process, and adding memantine or a pharmaceutically acceptable salt thereof to the granulated donepezil or a pharmaceutically acceptable salt thereof, and directly compressing and homogenizing the resulting mixture.

[ description of the drawings ]

The above and other objects, features and other advantages of the present invention will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings, in which:

Fig. 1a is a graph showing the measurement results of the elution rate of donepezil hydrochloride of the commercial product of control 1, the mixed tablets of controls 1 and 2, and the combined tablet prepared according to example 1 over time, and fig. 1b is a graph showing the measurement results of the elution rate of memantine hydrochloride of the commercial product of control 2, the mixed tablets of controls 1 and 2, and the combined tablet of example 1 over time;

Fig. 2a is a graph showing the measurement results of the elution rate of donepezil hydrochloride salts of the combination tablets prepared according to examples 1 to 4 over time, and fig. 2b is a graph showing the measurement results of the elution rate of memantine hydrochloride salts of the combination tablets of examples 1 to 4 over time;

Fig. 3a is a graph showing the particle size of donepezil granules of example 1, fig. 3b is a graph showing the particle size of donepezil granules of example 2, fig. 3c is a graph showing the particle size of donepezil granules of example 3, and fig. 3d is a graph showing the particle size of donepezil granules of example 4;

Fig. 4a is a graph showing the measurement results of the elution rate of donepezil hydrochloride over time for the tablets prepared according to comparative examples 2 and 3 and fig. 4b is a graph showing the measurement results of the elution rate of memantine hydrochloride over time for the tablets according to comparative examples 1 and 2 and 3;

Fig. 5a is a graph showing the particle size of SD lactose, fig. 5b is a graph showing the particle size of lactose hydrate, fig. 5c is a graph showing the particle size of microcrystalline cellulose (Vivapur 12), and fig. 5d is a graph showing microcrystalline cellulose (MCC 102); and is

Fig. 6 is a graph showing the sieved particle size of the combined tablet of example 1 using lactose and microcrystalline cellulose having the above particle size.

Detailed Description

Reference will now be made in detail to the preferred embodiments of the present invention, examples of which are illustrated in the accompanying drawings. Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like parts.

The present disclosure relates to immediate release pharmaceutical compositions for the prevention or treatment of dementia and cognitive dysfunction, comprising donepezil or a pharmaceutically acceptable salt thereof and memantine or a pharmaceutically acceptable salt thereof, and a process for preparing the same.

Donepezil hydrochloride salt is formulated and is currently under the trade name donepezil hydrochloride(containing 5mg or 10mg of donepezil hydrochloride salt), and memantine hydrochloride salt is formulated and currently available under the trade name(containing 10mg of memantine hydrochloride) was sold. As commercially availableAndin vitro (elution test) test of (1), which found, albeit atIn the case of (2), single elution rate and combined elution rateThe same result is obtained, but inIn the case of (2), single elution rate and combined elution rateIs significantly reduced. This is because the elution is carried out at the time of elutionAndThe combined elution rate of Aricept is 20% or more lower than the single elution rate in 15 minutes. Such an elution deterioration phenomenon significantly affects the drug absorption rate and bioavailability of donepezil, thereby failing to exhibit desired efficacy.

The initial 5-minute elution rate of donepezil or a pharmaceutically acceptable salt thereof can be suppressed to 35% or less due to the characteristics of the active ingredient, such as digestive system side effects (e.g., nausea, vomiting, and diarrhea), and psychonervous system side effects (e.g., muscle spasm, fatigue, and dizziness).

In the tablet form in which donepezil or a pharmaceutically acceptable salt thereof and memantine or a pharmaceutically acceptable salt thereof are uniformly mixed without being separated as in a bilayer tablet, a multilayer tablet, etc., it is difficult to achieve elution rates of donepezil and memantine, which belong to the Biopharmaceutical Classification System (BCS) class I having high solubility, for 35% or less and 60% or more, respectively, over the initial 5 minutes as those of commercially available formulations, by using a general method, not by a special method.

Therefore, in the present invention, in order to suppress the initial elution rate of donepezil, wet granulation is performed, and in order to improve the combined preparation(wherein the elution rate of donepezil is 20% or less within 15 minutes), the particle size of donepezil or a pharmaceutically acceptable salt thereof is set.

Conventionally, korean patent publication No. 2009-0016611 discloses that when memantine is produced by a direct compression method, content uniformity is lowered, and problems of adhesiveness and capping occur, and thus it is necessary to granulate the memantine by a wet process. However, in the present invention, memantine is produced using a direct compression method capable of reducing cost and time while maintaining the advantages (tabletability, mixing uniformity, and capping) obtained by performing a wet process.

In addition, when a combined preparation is prepared by mixing donepezil or a pharmaceutically acceptable salt thereof and memantine or a pharmaceutically acceptable salt thereof and directly compressing the resulting mixture, costs and time may be reduced by simplifying the manufacturing process, but it may be difficult to reduce the initial 5-minute elution rate of donepezil. In addition, when a combined preparation is prepared by mixing donepezil or a pharmaceutically acceptable salt thereof and memantine or a pharmaceutically acceptable salt thereof and wet granulating the resulting mixture, or by wet granulating donepezil or a pharmaceutically acceptable salt thereof and memantine or a pharmaceutically acceptable salt thereof, respectively, a memantine-related substance occurs due to interaction with donepezil.

For example, as a result of confirming the relevant substance by performing a stability test on a combined preparation prepared by the following method: (a) wet granulating donepezil or a pharmaceutically acceptable salt thereof, and wet granulating memantine or a pharmaceutically acceptable salt thereof; (b) wet granulating donepezil or its pharmaceutically acceptable salt, and directly compressing memantine or its pharmaceutically acceptable salt; (c) mixing donepezil or a pharmaceutically acceptable salt thereof and memantine or a pharmaceutically acceptable salt thereof, and directly compressing the resulting mixture; (d) directly compressing donepezil or a pharmaceutically acceptable salt thereof, and carrying out wet granulation on memantine or a pharmaceutically acceptable salt thereof; and (e) mixing donepezil or a pharmaceutically acceptable salt thereof and memantine or a pharmaceutically acceptable salt thereof, and subjecting the resulting mixture to wet granulation, a larger amount of the relevant substance is produced in the production processes (a), (d), and (e) than in the production processes (b) and (c).

Accordingly, the inventors of the present invention confirmed that a combined preparation comprising donepezil or a pharmaceutically acceptable salt thereof and memantine or a pharmaceutically acceptable salt thereof (which have different mechanisms of action) has an improved therapeutic effect due to a synergistic effect between the two drugs, has an elution rate similar to that of commercially available donepezil and commercially available memantine, ensures compressibility, and hardly causes the generation of degradation products (related substances), and is very stably stored, and thus completed the present invention.

Hereinafter, the present invention will be described in detail.

The immediate release pharmaceutical composition of the present invention for preventing or treating dementia and cognitive dysfunction includes memantine or a pharmaceutically acceptable salt thereof and wet granulated donepezil or a pharmaceutically acceptable salt thereof, and is directly compressed (hereinafter referred to as a combined preparation), and may be in the form of tablets in various forms such as tablets, capsules, injections, etc.

In particular, the method for preparing an immediate release pharmaceutical composition for preventing or treating dementia and cognitive dysfunction includes: granulating donepezil or a pharmaceutically acceptable salt thereof by a wet process, and adding memantine or a pharmaceutically acceptable salt thereof to the granulated donepezil or a pharmaceutically acceptable salt thereof, and directly compressing and homogenizing the resulting mixture.

When two drugs having different mechanisms of action are mixed, the mixture is unstable in the presence of moisture, and thus the amount of the relevant substance may rapidly increase due to its physical and chemical properties. Therefore, in order to overcome this, in the present invention, donepezil or a pharmaceutically acceptable salt thereof is first granulated by a wet process, and memantine or a pharmaceutically acceptable salt thereof and additives are then added thereto, and the resulting mixture is directly compressed.

First, in the present invention, donepezil or a pharmaceutically acceptable salt thereof is granulated by a wet process to adjust its initial elution rate. That is, donepezil or a pharmaceutically acceptable salt thereof may be granulated by a wet process and then mixed with memantine or a pharmaceutically acceptable salt thereof, followed by direct compression, thereby inhibiting elution of donepezil or a pharmaceutically acceptable salt thereof over an initial 5 minutes. Preferably, the initial 5 minute elution can be suppressed to 35% or less.

Donepezil is a compound having the chemical name of 1-benzyl-4- [ (5, 6-dimethoxy-1-indanon-2-yl) methyl ] piperidine, and donepezil or a pharmaceutically acceptable salt thereof is known as a useful drug for the prevention of senile dementia, particularly, for the prevention and treatment of dementia with alzheimer's disease.

The pharmaceutically acceptable salt of donepezil is not particularly limited, but may be any salt that increases the solubility of donepezil, preferably an acid addition salt.

Pharmaceutically acceptable salts must have low human toxicity and must not adversely affect the biological activity and physicochemical properties of the parent compound. In addition, free acids that can be used to prepare pharmaceutically acceptable salts can be divided into inorganic and organic acids. As the inorganic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, or the like can be used. As the organic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, gluconic acid, tartaric acid, benzoic acid, pamoic acid (pamoic acid), aspartic acid, glutamic acid, and the like can be used. Organic bases that may be used to prepare organic base addition salts include tris (hydroxymethyl) methylamine, dicyclohexylamine, and the like. Amino acids that can be used to prepare the amino acid addition bases include natural amino acids such as alanine, glycine, and the like. Furthermore, donepezil according to the present invention may include any hydrate or solvate of donepezil, in addition to its pharmaceutically acceptable salt. The hydrate or solvate of donepezil can be prepared by: donepezil is dissolved in a water-miscible solvent such as methanol, ethanol, acetone or 1, 4-dioxane, to which a free acid or a free base is added, and the resulting solution is crystallized or recrystallized. In this case, solvates (especially hydrates) may be formed. Thus, in addition to various amounts of aqueous compounds that may be prepared using methods such as lyophilization, the compounds of the present invention may also include stoichiometric solvates (including hydrates).

The pharmaceutically acceptable salt of donepezil is preferably the hydrochloride salt.

The amount of donepezil or pharmaceutically acceptable salt thereof in the pharmaceutical composition of the present invention ranges from 1 wt% to 20 wt%, preferably from 2 wt% to 10 wt%. When the amount of donepezil or a pharmaceutically acceptable salt thereof is less than the above lower limit, the mass of the combination tablet is 521.5mg or more, and thus the convenience of administration may deteriorate. When the amount of donepezil or a pharmaceutically acceptable salt thereof is greater than the above upper limit, the mass of the combination tablet is less than 104.3mg and it may not be easy to combine with memantine or a pharmaceutically acceptable salt thereof to prepare a combination preparation.

in addition, donepezil or a pharmaceutically acceptable salt thereof is granulated by a wet process, since the active ingredient has a high frequency of characteristics of digestive system side effects (such as nausea, vomiting and diarrhea) and psychonervous system side effects (such as muscle spasm, fatigue and dizziness), thereby suppressing the initial 5-minute elution to 35% or less, so that the initial 5-minute elution is set to be in contact with the commercial donepezil drug substanceThe same level.

Further, when donepezil or a pharmaceutically acceptable salt thereof is subjected to a direct compression process rather than a wet process, it is not possible to secure a suitable initial elution rate (35% or less in 5 minutes), and when donepezil or a pharmaceutically acceptable salt thereof is mixed with memantine or a pharmaceutically acceptable salt thereof in a subsequent process, it is possible to prepare a composition exhibiting digestive system side effects such as nausea, vomiting, and diarrhea, and psychonervous system side effects such as muscle spasm, fatigue, and dizziness.

The wet granulation method includes granulating donepezil or a pharmaceutically acceptable salt thereof and a first pharmaceutically acceptable additive (preferably one or more selected from excipients, binders, diluents and disintegrants) in a liquid to form granules, and drying and shaking the granules. The scope of the present invention is not limited to the use of the first additive, and in addition to the above-mentioned additives, common additives selected by those of ordinary skill in the art within a range not adversely affecting the present invention may be used.

Excipients may include, but are not limited to, at least one selected from the following: lactose, microcrystalline cellulose, mannitol, starch, and corn starch; the binder may include, but is not limited to, at least one selected from the group consisting of: polyvinyl pyrrolidone, polyvinyl alcohol, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, and methyl cellulose; diluents may include, but are not limited to, calcium phosphate (dibasic and/or tribasic), calcium sulfate, powdered cellulose, dextrates (dextrates), dextrin, fructose, kaolin, lactitol, lactose, maltose, mannitol, microcrystalline cellulose, sorbitol, starch, and sucrose; and the disintegrant may include, but is not limited to, at least one selected from the group consisting of: croscarmellose sodium, crospovidone, microcrystalline cellulose, polyacrolein potassium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and starch.

Next, in the present invention, memantine or a pharmaceutically acceptable salt thereof and a second additive are added to and mixed with granulated donepezil or a pharmaceutically acceptable salt thereof, and the resulting mixture is directly compressed and homogenized, so that the active ingredient is uniformly distributed.

Memantine is a compound having the chemical name of 3, 5-dimethyladamantan-1-amine and has been reported as an orally active NMDA receptor antagonist, and memantine or a pharmaceutically acceptable salt thereof is considered as a useful drug for the prevention and treatment of alzheimer's disease.

The pharmaceutically acceptable salt of memantine is not particularly limited, but may be any salt that increases the solubility of donepezil, preferably an acid addition salt, and more preferably a hydrochloride salt.

Donepezil or a pharmaceutically acceptable salt thereof and memantine or a pharmaceutically acceptable salt thereof are mixed in a weight ratio of 1:0.8 to 5 (preferably in a weight ratio of 1:1 to 3). When the amount of memantine or a pharmaceutically acceptable salt thereof relative to the amount of donepezil or a pharmaceutically acceptable salt thereof exceeds the above range, digestive system side effects (such as nausea, vomiting and diarrhea) and psychonervous system side effects (such as muscle spasm, fatigue and dizziness) may occur.

Further, a mixture of memantine or a pharmaceutically acceptable salt thereof, an additive and granulated donepezil or a pharmaceutically acceptable salt thereof is homogenized by a direct compression process, and a large amount of related substances appears when a wet process or a direct compression process subsequent to the wet process is performed instead of the direct compression process.

The homogenization method by the direct compression process is a method of directly compressing the above ingredients without physically changing the combined preparation, and compression by a rotary tablet press includes homogenizing powder by up-down pressing, reducing the homogenized material to a granule size, and then compressing the resultant material.

The second additive may be one or more selected from: excipients, binders, lubricants, and coating agents, which are pharmaceutically acceptable. The scope of the present invention is not limited to the use of the second additive, and in addition to the above-mentioned additives, common additives selected by those of ordinary skill in the art within a range not adversely affecting the present invention may be used.

The types of excipients and binders are the same as those described in the first additive. Lubricants may include, but are not limited to, one or more selected from the following: colloidal silicon dioxide, hydrated silicon dioxide, magnesium stearate and sodium stearyl fumarate, and coating agents may include, but are not limited to, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, copovidone (copovidone),Series ofAnd (4) series.

In the above process, in order to uniformly mix memantine or a pharmaceutically acceptable salt thereof in the form of fine particles with donepezil or a pharmaceutically acceptable salt thereof having a relatively large particle diameter, it is necessary to perform grinding mixing by adding an excipient mixture of a fine particle excipient and an excipient having a relatively large particle diameter.

The particulate excipient included in the excipient mixture must have a particle size similar to that of memantine or a pharmaceutically acceptable salt thereof in a particulate form, and the excipient having a relatively larger particle size included in the excipient mixture must have a particle size similar to that of donepezil or a pharmaceutically acceptable salt thereof having a relatively larger particle size. When the particle size of each excipient included in the excipient mixture is not similar to the particle size of memantine or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt thereof, a combined formulation comprising memantine or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt thereof may not satisfy the acceptable range in terms of content uniformity.

for example, the particle size distribution d (0.5) of the excipient relative to d (0.5) (donepezil d (0.5) μm) of donepezil or a pharmaceutically acceptable salt thereof granulated by a wet process is donepezil d (0.5) μm ± 55 to 60 μm, the particle size distribution d (0.9) of the excipient relative to d (0.9) (donepezil d (0.9) μm) is donepezil d (0.9) μm ± 380 to 400 μm, the particle size distribution d (0.5) of the excipient relative to d (0.5) (memantine d (0.5) μm) of memantine or a pharmaceutically acceptable salt thereof is memantine d (0.5) μm ± 55 to 60 μm, and the particle size distribution d (0.9) of the excipient relative to d (0.9) (memantine d (0.9) μm) is memantine d (0.9) μm ± 90 to 95 μm. In addition, assuming that the difference between the d (0.5) values of memantine or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt thereof is 100, the difference between the d (0.5) values of the particle size distribution of the excipients included in the excipient mixture ranges from 93 to 105, and assuming that the difference between the d (0.9) values of memantine or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt thereof is 100, the difference between the d (0.9) values of the particle size distribution of the excipients included in the excipient mixture may range from 30 to 50. d (0.5) and d (0.9) represent sizes corresponding to 50% and 90% of the maximum value in the cumulative distribution measured by the particle size analyzer.

As the powders become finer, the specific surface area increases and the adhesive cohesion between the powders increases. For example, when an excipient having a particle diameter much larger than that of an active ingredient having a small particle diameter is used, the active ingredient having a small particle diameter cannot be sufficiently and uniformly mixed with the excipient and partially coagulated or concentrated, resulting in non-uniform mixing, and the opposite case also causes the same phenomenon to occur.

Thus, in order to adjust the initial 5-minute elution rate of donepezil or a pharmaceutically acceptable salt thereof to 35% or less, the wet granulated particles may have a particle size distribution d (0.5) of 120 μm to 200 μm. When d (0.5) is less than the above lower limit, an elution rate of more than 35% is obtained at the time of elution for the initial 5 minutes, and when d (0.5) is greater than the above upper limit, an elution rate of not more than 35% at the time of elution for the initial 5 minutes, but 70% in 15 minutes, which is comparable to that of the controlThe elution rate (85%) was much lower.

further, donepezil or a pharmaceutically acceptable salt thereof comprising 15 to 25 wt% of particles having a size of 20 mesh or more to less than 50 mesh, 25 to 35 wt% of particles having a size of 50 mesh or more to less than 80 mesh, 20 to 30 wt% of particles having a size of 80 mesh or more to less than 200 mesh, and 15 to 25 wt% of particles having a size of at least 200 mesh exhibits an elution rate of not more than 35% upon elution over the initial 5 minutes. More preferably, the case where the amount of particles having a size of 20 mesh to less than 50 mesh is less than the amount of particles having a size of 200 mesh or more exhibits an elution rate of not more than 35% at the time of elution over an initial 5 minutes, and exhibits an elution rate of 15 minutes compared to that of the control(85%) higher elution rate.

In addition, in order to achieve mixing uniformity after directly compressing the wet granulated donepezil or a pharmaceutically acceptable salt thereof, and memantine or a pharmaceutically acceptable salt thereof added later, in one embodiment, content uniformity is ensured by adjusting the ratio of lactose (spray-dried lactose) (d (0.1)23.1 μm, d (0.5)69.2 μm, d (0.9)164.9 μm) and microcrystalline cellulose (Vivapur 12; d (0.1)153.5 μm, d (0.5)193.0 μm, d (0.9)386.7 μm).

More preferably, when lactose having a particle size of 80 mesh or more and microcrystalline cellulose are included in an amount of 50 wt% or more, excellent content uniformity can be secured.

The weight ratio of lactose to microcrystalline cellulose is in the range of 3 to 20:1 (preferably 5 to 15: 1). When the amount of lactose exceeds the above range with respect to the amount of microcrystalline cellulose, it may be difficult to suppress the initial 5-minute elution rate of donepezil or a pharmaceutically acceptable salt thereof to 35% or less.

In the pharmaceutical composition of the present invention, the initial 5-minute elution rate of donepezil or a pharmaceutically acceptable salt thereof is suppressed to 35% or less and the initial 5-minute elution rate of memantine or a pharmaceutically acceptable salt thereof is 60% or more under the condition of pH 1.2 eluent. Further, in the pharmaceutical composition of the present invention, given a pH 1.2 eluent, donepezil or a pharmaceutically acceptable salt thereof is eluted in an amount of 75% or more (preferably 80% or more) relative to the total weight of the active ingredient in 15 minutes, and memantine or a pharmaceutically acceptable salt thereof is eluted in an amount of 85% or more (preferably 85% to 95%) relative to the total weight of the active ingredient in 15 minutes, and is eluted in an amount of 90% or more relative to the total weight of the active ingredient in 30 minutes.

The selected dosage level of the composition may vary depending on the activity of the compound used, the route of administration, the severity of the condition being treated, the condition of the patient being treated, and the prior medical history. However, it is within the knowledge of the skilled person to start with a dose of the compound at a level lower than that required to achieve the desired therapeutic effect, gradually increasing the dose of the compound until the desired effect is achieved, and suitable doses may be determined by age, sex, body shape and body weight. The composition may be further processed before being formulated into a pharmaceutically acceptable pharmaceutical formulation, and preferably comminuted or ground into smaller particles. In addition, the composition may vary depending on the condition of the patient being treated, but may be determined non-inventively.

Hereinafter, exemplary embodiments will be described to assist understanding of the present invention, and it will be apparent to those of ordinary skill in the art that the following examples are provided for illustrative purposes only, and that various changes and modifications may be made within the spirit and scope of the present invention, and such changes and modifications should be within the scope of the appended claims.

Control 1: commercial formulations10mg

10mg of donepezil hydrochloride containing 10mg are used(available from Eisai Korea).

Control 2: commercial formulations10mg X 2

20mg (10mg X2) containing 10mg of memantine hydrochloride was used(available from Lundbeck Korea co., Ltd).