WO2024072049A1 - Pharmaceutical combination containing donepezil and rivastigmine for preventing, alleviating or treating dementia or cognitive impairment, and preparation method therefor - Google Patents

Abstract

Provided are a: pharmaceutical combination, composition or kit for preventing, alleviating or treating dementia or cognitive impairment, containing donepezil or a pharmaceutically acceptable salt thereof, and rivastigmine or a pharmaceutically acceptable salt thereof, and having high drug compliance and an excellent treatment effect; and a preparation method therefor.

Description

Pharmaceutical combination containing donepezil and rivastigmine for preventing, improving or treating dementia or cognitive dysfunction and method for manufacturing the same

The present invention relates to a pharmaceutical combination containing donepezil and rivastigmine for preventing, improving or treating dementia or cognitive dysfunction, and a method for producing the same.

Due to the rapid increase in the number of patients with dementia or cognitive dysfunction due to the increase in the elderly population due to the extension of lifespan, management of these patients is emerging as a serious social problem, increasing the economic burden on individuals and society.

In particular, more than 50% of geriatric dementia is a disease called Alzheimer's disease or Alzheimer type dementia (AD).

However, to date, there is no treatment that can fundamentally treat Alzheimer's dementia. However, drugs that help relieve symptoms include donepezil (brand name: Aricept), rivastigmine (brand name: Exelon), galantamine, and glutamic acid, which are inhibitors of acetylcholine esterase that prevent the breakdown of the neurotransmitter acetylcholine. Memantine, an NMDA receptor antagonist that binds to the receptor and prevents excessive activation, is approved and prescribed in many countries, including the United States.

In addition, elderly patients, who make up the majority of dementia patients, have difficulty swallowing and have reduced cognitive ability, which results in poor adherence to medication. In fact, research results show that patients who took one pill had about 20% higher fidelity than patients who took two pills. In this way, if a combination drug for dementia treatment is developed, drug dosage and fidelity to the drug can be improved.

According to a previous study, when a combination of donepezil and memantine was prescribed to patients with moderate to severe Alzheimer's dementia, follow-up test results, cognitive function, and behavioral measures at 24 weeks were improved compared to the group treated with donepezil alone. It has been reported to be superior in all aspects of the score, and the combination therapy of memantine and donepezil has been approved by the FDA for the treatment of moderate to severe Alzheimer's.

According to the 2010 Dementia Disease Treatment Guidelines, acetylcholine esterase inhibitors, including donepezil, can be administered in combination with memantine, an NMDA receptor antagonist, and the efficacy of donepezil does not appear or is not sufficient in monotherapy. If not, it is recommended to switch to another acetylcholine esterase inhibitor and prescribe it. Additionally, combination therapy with two or more types of acetylcholine esterase inhibitors should be avoided as it may increase the side effects of drugs in the same class.

Meanwhile, among acetylcholine esterase inhibitors, donepezil is oral (tablet) once a day, patch once or twice a week, and rivastigmine is oral (capsule) twice a day, patch. Products that are administered once a day are prescribed, but it is known that compliance is low due to gastrointestinal side effects, side effects due to skin irritation, and technical problems, resulting in insufficient therapeutic effect.

Donepezil once-daily oral medication has been commercialized under the product name Aricept®. The daily dosages are 5 mg, 10 mg, and 23 mg, with the most commonly prescribed doses being 5 mg and 10 mg. Rivastigmine oral medication twice a day is commercialized under the product name Exelon®, and is prescribed in daily doses of 3 mg, 6 mg, 9 mg, and 12 mg. Based on the daily dose of the oral agent, when the donepezil dose is 23 mg, the rivastigmine dose is 0.13 to 0.52 times, and when the donepezil dose is 5 mg, the rivastigmine dose is 0.6 to 2.4 times.

In order to solve the above problems with commercialized products of donepezil or rivastigmine, a study was proposed to develop a combination treatment with the optimal weight ratio of donepezil, an acetylcholine esterase inhibitor with high medication compliance and excellent therapeutic effect, and rivastigmine. It has been done.

The purpose of the present invention is to provide a pharmaceutical combination for preventing, improving or treating dementia or cognitive dysfunction, which has high medication compliance and excellent therapeutic effect when administered in combination with donepezil and rivastigmine, and a method for producing the same.

As an aspect for achieving the above object, the present invention provides the prevention and improvement of dementia or cognitive dysfunction comprising donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof. or to a pharmaceutical combination for treatment.

In another aspect, the present invention provides a pharmaceutical composition for preventing, improving or treating dementia or cognitive dysfunction, comprising an effective amount of donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof. It's about.

In another aspect, the present invention provides a pharmaceutical composition for preventing, improving or treating dementia or cognitive dysfunction, comprising an effective amount of donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof. or to a kit containing the combination.

In one embodiment, the pharmaceutical combination, composition or kit includes separate individual preparations each containing effective amounts of donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof. It may be that each individual agent is administered simultaneously or sequentially. When prepared as the individual preparation, various administration routes and/or administration formulations can be selected. For example, a combination of one or more preparations selected from the group consisting of oral preparations, patch preparations, and injection preparations of donepezil and one or more preparations selected from the group consisting of oral preparations, patch preparations, and injection preparations of rivastigmine. You can. Preferably, separate individual preparations each containing effective amounts of donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof may be provided to the subject in the same dosage form and through the same route of administration. there is.

In one embodiment, the pharmaceutical combination, composition or kit may include a single agent comprising an effective amount of a mixture of donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof. there is. In one embodiment, the pharmaceutical combination according to the present invention may be prepared in the form of the same preparation comprising donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof as a mixture, It may be manufactured and contained as separate individual preparations containing each of the above two active ingredients.

In one embodiment, the pharmaceutical combination according to the present invention may be prepared by preparing the two active ingredients into tablets, patches, or injection preparations.

In one embodiment, the pharmaceutical combination according to the present invention is in the form of a mixture of two active ingredients contained in one microsphere, or in the form containing a combination of microspheres containing each individual active ingredient, or in the form of a mixture of two active ingredients contained in one microsphere. is provided in the form of a preparation containing microspheres, and other active ingredients may be provided in the form of a preparation different from the microspheres.

In one embodiment, the total content of donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof contained in the pharmaceutical combination, composition or kit is the pharmaceutical combination according to the present invention. It may be 0.1 to 99% by weight based on the total weight of water, composition or kit.

In addition, when donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof are included as individual preparations in the pharmaceutical combination according to the present invention, 100 parts by weight of each individual preparation. It may be included in an amount of 0.1 to 65 parts by weight (based on donepezil) and 0.1 to 50 parts by weight (based on rivastigmine).

In addition, the weight ratio of donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof may be 1:0.003 to 1:1.3 based on the daily dose of donepezil and rivastigmine, respectively. there is. Preferably, the weight ratio of donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof may be 1:0.003 to 1:0.66, more preferably 1:0.003 to 1:0.16. there is.

In one embodiment, the pharmaceutical combination, composition, or kit of the present invention may have an administration cycle at intervals of 1 day to 3 months, for example, once a day, once a week, or once a month. , may be for administration once every two months, or once every three months.

In one embodiment, the pharmaceutical combination for preventing, improving or treating dementia or cognitive dysfunction comprising donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof of the present invention is, The AUC _0-∞ /C _max of donepezil and rivastigmine when administered to an individual is more than 5 hr (hours).

In another aspect, the present invention comprises the step of administering a pharmaceutical combination, composition or kit containing an effective amount of donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof. , relates to methods of preventing, improving or treating dementia or cognitive dysfunction.

The pharmaceutical combination according to the present invention is a formulation that combines a formulation containing donepezil or a pharmaceutically acceptable salt thereof, which continuously releases the drug for more than 1 day, and rivastigmine or a pharmaceutically acceptable salt thereof. By allowing concurrent medication, side effects caused by rapid changes in drug concentration in the blood can be minimized and medication compliance can be improved. Additionally, improved medication compliance can significantly improve the treatment effect for patients with dementia or cognitive impairment.

Figure 1 is a graph showing the results of a pharmacokinetic test measuring drug concentration after administering the microspheres of Examples 1 to 3 to rats. Examples 1 and 2 show the PK results when administered with single microspheres of donepezil and rivastigmine, respectively, and Example 3 shows changes in blood concentration after administration of combined microspheres mixed with donepezil and rivastigmine microspheres. This is the result of checking.

Figure 2 is a graph confirming the change in AChE mRNA expression level when treated with donepezil or rivastigmine alone in SH-SY5Y cell line. In Figure 2, when the p-value (probability of significance) value compared to the control is less than 0.001, it is indicated as ****.

Figures 3 and 4 show the results of an experiment confirming the effect of combined administration of donepezil and rivastigmine on AChE mRNA expression in SH-SY5Y cell line according to Example 4. In Figure 3, the p-value (probability of significance) compared to the control group (donepezil treatment group) is indicated as * if it is less than 0.05, *** if it is less than 0.005, and **** if it is less than 0.001. In Figure 4, the p-value (probability of significance) compared to the control group (donepezil treatment group) is indicated as ** if it is less than 0.01, *** if it is less than 0.005, and **** if it is less than 0.001.

Figure 5 shows the results of an experiment confirming the effect of rivastigmine administration alone on AChE mRNA expression in the APP-H4 cell line.

Figure 6 shows the results of an experiment confirming the effect of combined administration of donepezil and rivastigmine on AChE mRNA expression in APP-H4 cell line.

Hereinafter, the present invention will be described in detail.

The dementia is a neurodegenerative disease characterized by learning and cognitive deficits, and is usually accompanied by behavioral symptoms, mental symptoms, and motor symptoms. Dementia includes dementia-related diseases such as Alzheimer's disease, Vascular dementia, Parkinson's disease, Lewy body dementia, Huntington's disease, frontotemporal dementia, It may be caused by Creutzfeldt-Jacob disease or Pick's disease, or may accompany the above diseases. Therefore, the dementia of the present invention includes Alzheimer's disease type dementia, Vascular dementia, Parkinson's disease type dementia, Lewy body dementia, Huntington's disease type dementia, and Creutzfeldt dementia. -It may be Creutzfeldt-Jacob disease type dementia or Pick's disease type dementia.

The cognitive dysfunction refers to cognitive function or cognitive areas such as working memory, attention and vigilance, verbal learning and memory, visual learning and memory, reasoning and problem solving such as executive function, processing speed or social cognition. Includes degradation. In particular, cognitive deficits or cognitive dysfunction include attention deficit, disorganized thinking, slow thinking, difficulty understanding, poor concentration, difficulty solving problems, poor memory, difficulty expressing thoughts, and/or difficulty in thinking, feeling, and acting. It may refer to difficulties in integration or in the disappearance of unrelated ideas. The terms “cognitive deficit” and “cognitive dysfunction” are used interchangeably to refer to the same thing. Examples of such cognitive dysfunction may include, but are not limited to, Alzheimer's disease, schizophrenia, Parkinson's disease, Down syndrome, Tourette's syndrome, etc.

Donepezil or a pharmaceutically acceptable salt thereof included in the pharmaceutical combination according to the present invention is known as a drug useful for the prevention of senile dementia, especially for the prevention, improvement and treatment of Alzheimer's disease. This drug is approved for the treatment of mild, moderate, and severe dementia. Donepezil is a reversible inhibitor of the enzyme acetylcholine esterase and is also sold as the hydrochloride salt under the brand name Aricept ®.

Rivastigmine, another active ingredient included in the pharmaceutical combination according to the present invention, is a drug approved for the treatment of mild, moderate, and severe dementia in Alzheimer's disease. Rivastigmine is a reversible cholinesterase inhibitor and is also sold under the trade names Exelon ® as its tartrate salt and under the trade names Exelon Patch ® as rivastigmine base.

There is no particular limitation as to the pharmaceutically acceptable salt of donepezil or rivastigmine, but it is preferably an acid addition salt. The pharmaceutically acceptable salt should have low toxicity to the human body and not adversely affect the biological activity and physicochemical properties of the parent compound. Additionally, free acids that can be used in the preparation of the pharmaceutically acceptable salts can be divided into inorganic acids and organic acids. Inorganic acids may include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, etc. Organic acids include acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, pamoic acid, palmitic acid, stearic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, and gluconic acid. , tartaric acid, salicylic acid, malic acid, oxalic acid, benzoic acid, aspartic acid, glutamic acid, etc. can be used. Organic bases that can be used to prepare organic base addition salts include tris(hydroxymethyl)methylamine and dicyclohexylamine. Amino acids that can be used to produce amino acid addition bases are natural amino acids such as alanine and glycine.

Additionally, donepezil or rivastigmine according to the present invention may include not only pharmaceutically acceptable salts but also all hydrates and solvates. The hydrate or solvate is obtained by dissolving the donepezil or rivastigmine in a water-miscible solvent such as methanol, ethanol, acetone, or 1,4-dioxane, and then crystallizing or recrystallizing after adding a free acid or free base. It can get angry. In such cases, solvates (especially hydrates) may be formed. Accordingly, the compounds of the present invention may include stoichiometric solvates, including hydrates, in addition to compounds containing various amounts of water that can be prepared by methods such as freeze-drying. The pharmaceutically acceptable salt of donepezil may preferably be hydrochloride salt, and the pharmaceutically acceptable salt of rivastigmine may be hydrochloride salt of rivastigmine.

In one embodiment, the pharmaceutical combination may be for combined administration.

In one embodiment, the pharmaceutical combination may be a composition or mixture containing an effective amount of donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof, and the mixture may include two effective amounts. The ingredients may be administered together.

Alternatively, the pharmaceutical combination may be in the form of effective amounts of donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof contained in separate individual preparations, each of the active ingredients The individual preparations comprising may be in a form for simultaneous or sequential administration.

Additionally, the pharmaceutical combination may be in kit form.

In a specific embodiment, the total content of donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof is 0.1 to 99% by weight, 1 to 90% by weight, based on the total weight of the pharmaceutical combination according to the present invention. Weight percent, 1 to 85% by weight, 1 to 75% by weight, 1 to 50% by weight, 5 to 85% by weight, 10 to 80% by weight, 20 to 70% by weight, 30 to 60% by weight, or 40 to 50% by weight. It may be included, but is not limited thereto.

When donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof are included as individual preparations in the pharmaceutical combination according to the present invention, donepezil is used in 100 weight of the individual preparation for donepezil. It may be included in an amount of 0.1 to 65 parts by weight, and rivastigmine may be included in an amount of 0.1 to 50 parts by weight based on 100 parts by weight of the individual preparation for rivastigmine.

The pharmaceutical combination of the present invention can be administered orally or parenterally (e.g., intravenously, subcutaneously, intramuscularly, intraperitoneally, transdermally, transnasally) through various administration routes depending on the desired method. Through these administration routes, it can be administered systemically or locally. In the present invention, when the pharmaceutical combination includes two separate preparations, the preparations containing each active ingredient are administered through the same or different routes, for example, the donepezil or its pharmaceutically acceptable The salt may be administered parenterally or orally, preferably orally. Additionally, the rivastigmine or a pharmaceutically acceptable salt thereof can be administered parenterally.

In the pharmaceutical combination of the present invention, the appropriate dosage of donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof depends on the patient's weight, age, gender, health condition, diet, The range varies depending on the administration time, administration method, excretion rate, and severity of the disease. As a specific example, the daily dosage of donepezil or a pharmaceutically acceptable salt thereof of the present invention is about 1 to 60 mg, preferably 1 to 50 mg, 2 to 40 mg, or 2 to 30 mg, based on donepezil. , 2 to 25 mg, 5 to 40 mg, 5 to 30 mg, 10 to 40 mg, 10 to 30 mg, or 25 to 50 mg. Additionally, the daily dosage of rivastigmine or a pharmaceutically acceptable salt thereof of the present invention may be about 0.003 to 15 mg, preferably 0.015 to 3 mg, based on rivastigmine. However, the dosage of each ingredient may vary greatly depending on the above conditions, and is not limited by the above examples.

In the pharmaceutical combination of the present invention, the appropriate administration cycle of donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof may be determined according to the dosage. For example, to prevent, improve or treat diseases related to dementia or cognitive impairment according to the present invention, they can be administered simultaneously, sequentially (in any order), or in combination. For example, donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof of the present invention may be administered once a day to once every three months, preferably 1 time. It can be administered once a day, twice a week, once a week, once every two weeks, once a month, once every two months, or once every three months.

In one embodiment, the pharmaceutical combination for preventing, improving or treating dementia or cognitive dysfunction comprising donepezil or a pharmaceutically acceptable salt and rivastigmine or a pharmaceutically acceptable salt of the present invention is donepezil and Based on the daily dose of rivastigmine, the weight ratio is 1:0.003 to 1:1.3, 1:0.003 to 1:1, 1:0.03 to 1:0.66, 1:0.003 to 1:0.5, 1:0.003 to 1: 0.3, 1:0.003 to 1:0.16, 1:0.003 to 1:0.1, 1:0.003 to 1:0.05, 1:0.003 to 1:0.025, 1:0.003 to 1:0.02, 1:0.003 to 1:0.01, 1:0.01 to 1:0.025, 1:0.01 to 1:1, 1:0.01 to 1:0.66, 1:0.01 to 1:0.5, 1:0.01 to 1:0.3, 1:0.01 to 1:0.16, 1: 0.01 to 1:0.1, 1:0.01 to 1:0.05, 1:0.01 to 1:0.025, 1:0.01 to 1:0.0.02, 1:0.01 to 1:0.015, 1:0.03 to 1:1, 1: 0.03 to 1:0.66, 1:0.03 to 1:0.5, 1:0.03 to 1:0.3, 1:0.03 to 1:0.16, 1:0.03 to 1:0.1, 1:0.03 to 1:0.08, 1:0.03 to 1:0.05, 1:0.03 to 1:0.0.04, 1:0.05 to 1:1, 1:0.05 to 1:0.66, 1:0.05 to 1:0.5, 1:0.05 to 1:0.3, 1:0.05 to 1:0.2, 1:0.05 to 1:0.16, 1:0.05 to 1:0.15, 1:0.05 to 1:0.12, 1:0.05 to 1:0.1, 1:0.05 to 1:0.08, 1:0.05 to 1: 0.075, 1: 0.1 to 1:1, 1: 0.1 to 1:0.66, 1:0.1 to 1:0.6, 1:0.1 to 1:0.5, 1:0.1 to 1:0.4, 1:0.1 to 1:0.3, 1:0.1 to 1:0.25, 1:0.1 to 1:0.2, 1:0.1 to 1:0.16, 1:0.1 to 1:0.15, 1:0.1 to 1:0.13, 1:0.1 to 1:0.12, 1: 0.15 to 1:1, 1:0.15 to 1:0.66, 1:0.15 to 1:0.5, 1:0.15 to 1:0.4, 1:0.15 to 1:0.3, 1:0.15 to 1:0.25, 1:0.15 to It may be 1:0.2, 1:0.15 to 1:0.0.16.

For example, when the pharmaceutical combination is the same oral formulation or patch formulation, the weight ratio of donepezil and rivastigmine is 1:0.01 to 1:1, 1:0.01 to 1:0.66, 1 based on the daily dose. :0.01 to 1:0.5, 1:0.01 to 1:0.3, 1:0.01 to 1:0.16, 1:0.01 to 0.1, 1:0.01 to 1:0.03, 1:0.02 to 1:0.025, 1:0.03 to 1 :1, 1:0.03 to 1:0.66, 1:0.03 to 1:0.5, 1:0.03 to 1:0.3, 1:0.03 to 1:0.16, 1:0.05 to 1:1, 1:0.05 to 1:0.66 , 1:0.05 to 1:0.5, 1:0.05 to 1:0.3, 1:0.05 to 1:0.16, 1:0.07 to 1:1, 1:0.07 to 1:0.66, 1:0.07 to 1:0.5, 1 :0.07 to 1:0.3, 1:0.07 to 1:0.16, 1:0.1 to 1:1, 1:0.1 to 1:0.66, 1:0.1 to 1:0.5, 1:0.1 to 1:0.3, 1:0.1 to 1:0.16, 1:0.15 to 1:1, 1:0.15 to 1:0.66, 1:0.15 to 1:0.5, 1:0.15 to 1:0.3, or 1:0.15 to 1:0.2. The drug in the formulation may be included in the free base form of the drug or in the form of various salts. In this case, the content of the drug contained in the formulation may be stated based on the free base form of the drug.

In another example, when the pharmaceutical combination is in the same microsphere injection formulation, it is preferable that the content of rivastigmine is lower than that of donepezil, for example, the weight ratio of donepezil and rivastigmine based on the daily dose is 1:0.003 to 1:0.66, 1:0.003 to 1:0.16, 1:0.003 to 1:0.13, 1:0.03 to 0.1, 1:0.03 to 1:0.03, 1:0.01 to 1:0.015, 1:0.02 to 1:0.3, 1:0.02 to 1:0.2, 1:0.02 to 1:0.1, 1:0.03 to 1:0.2, 1:0.03 to 1:0.2, 1:0.03 to 1:0.1, 1:0.04 to 1: 0.3, 1:0.04 to 1:0.2, 1:0.04 to 1:0.1, 1:0.1 to 1:0.66, 1:0.1 to 1:0.2, 1:0.1 to 1:0.16, 1:0.15 to 1:0.3, It may be 1:0.15 to 1:0.66, or 1:0.15 to 1:0.2. The drug in the microspheres may be contained in the free base form of the drug or in the form of various salts. In this case, the content of the drug contained in the microspheres may be stated based on the free base form of the drug.

The pharmaceutical combination according to the present invention was confirmed to have a synergistic and complementary effect of the acetylcholine esterase inhibitor donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof, and as a result, excellent dementia and It shows efficacy in improving, preventing or treating diseases related to cognitive impairment. Therefore, the combination of the present invention for preventing, improving or treating diseases related to dementia or cognitive impairment can be usefully used as a treatment strategy, and is particularly preferably used for the treatment of Alzheimer's disease.

In addition, donepezil or a pharmaceutically acceptable salt thereof contained in the pharmaceutical combination according to the present invention has the effect of inhibiting the accumulation of amyloid precursor protein, but due to an increase in the threshold with long-term use. There is a problem in that the efficacy of inhibiting the accumulation of amyloid precursor protein is also reduced and the efficacy gradually decreases. In this case, the efficacy of the acetylcholine esterase inhibitor decreases due to an increase in the threshold of donepezil by using rivastigmine or a pharmaceutically acceptable salt thereof together with donepezil or a pharmaceutically acceptable salt thereof, and the resulting amyloid By compensating for the decrease in the ability to inhibit the accumulation of precursor proteins, it can provide excellent improvement, prevention, or treatment efficacy for diseases related to dementia and cognitive impairment. In particular, the pharmaceutical combination according to the present invention is combined with donepezil at a dose that is much lower than the effective dose for the treatment of rivastigmine, but due to their combined use, when donepezil and rivastigmine are administered alone, the It exhibits an irreversible acetylcholine esterase inhibitory effect.

In particular, the pharmaceutical combination according to the present invention uses a dose similar to the commonly used effective dose for donepezil treatment, but due to the combination of a lower dose of rivastigmine compared to the conventional effective dose of rivastigmine, donepezil or Riva When stigmine is administered alone, it has an unpredictable acetylcholine esterase inhibitory effect.

In the present invention, donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof included in the pharmaceutical combination of the present invention are each contained in separate preparations or mixed to form the same preparation. The preparation may be prepared in unit dosage form by using a pharmaceutically acceptable carrier according to a method that can be easily performed by a person skilled in the art to which the invention pertains. It can be manufactured by placing it in a capacity container. The pharmaceutically acceptable carriers are commonly used in formulations and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, Includes, but is not limited to, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition to the above components, the pharmaceutical combination of the present invention may further include lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc.

Additionally, the preparation may be of various types known in the art for oral administration or parenteral administration. Examples of such preparations include, but are not limited to, powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosol external preparations, suppositories, transdermal preparations, or injection preparations. The pharmaceutical combination according to the present invention can be prepared as a composition or mixture containing an effective amount of donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof in the same preparation form. Alternatively, the pharmaceutical combination may be prepared by using the two active ingredients as separate preparations, and when prepared as separate preparations, it may be manufactured in the same or different preparation form. Specifically, an example of providing different preparations containing two active ingredients as single ingredients may be a combination of oral preparations or a combination of oral and parenteral preparations, for example, a combination of tablets and patches.

As an example, the preparation may be an injection preparation containing microspheres containing a drug. The microspheres are active ingredients in which donepezil or a pharmaceutically acceptable salt thereof and/or rivastigmine or a pharmaceutically acceptable salt thereof are evenly distributed or surrounded by a biodegradable polymer, and the active ingredients are continuously released. You can. The two active ingredients may be mixed and included in one microsphere, or individual microspheres containing individual active ingredients may be prepared and provided as a combination of these microspheres, or one active ingredient may be provided in the form of a preparation containing microspheres. And other active ingredients may be provided in formulations different from microspheres.

In one example of the present invention, when donepezil or a pharmaceutically acceptable salt thereof and/or rivastigmine or a pharmaceutically acceptable salt thereof are prepared as individual microsphere preparations, the content of the drug in the microspheres is the content of donepezil. may be 20-65 wt% of the total microspheres, and the content of rivastigmine may be 3 to 30 wt% of the total microspheres. The drug in the microspheres may be contained in the free base form of the drug or in the form of various salts. In this case, the content of the drug contained in the microspheres may be stated based on the free base form of the drug.

Despite the small dosage compared to oral administration, the microspheres are excellent in preventing or treating diseases related to dementia or cognitive impairment due to their high bioavailability. The microspheres may have an average particle diameter of 10 μm to 150 μm.

These microspheres may be manufactured using methods for producing microspheres well known in the art, such as solvent extraction and evaporation, but are not limited thereto.

As a specific example, the pharmaceutical combination according to the present invention includes separately prepared microspheres containing donepezil or a pharmaceutically acceptable salt thereof and microspheres containing rivastigmine or a pharmaceutically acceptable salt thereof. may be included. Alternatively, microspheres containing a mixture of donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof may be included in the pharmaceutical combination. Alternatively, the pharmaceutical combination according to the present invention is an agent in which only one of donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof is contained in the microspheres together with an agent that is not contained in the microspheres. Other active ingredients may be included in other types of preparations (for example, transdermal absorbents).

The term "solvent extraction and evaporation method" used in the present invention refers to adding a biodegradable polymer or a biodegradable polymer solution prepared by dissolving a biodegradable polymer and a drug in an organic solvent to a continuous phase in the form of an aqueous solution containing a surfactant. This refers to a method of producing biodegradable polymer microspheres by creating an emulsion, extracting and evaporating the organic solvent from the dispersed phase in the emulsion into a continuous phase to form microspheres, and recovering the microspheres from the continuous phase.

The weight average molecular weight of the biodegradable polymer is not particularly limited, but its lower limit may be 5,000 or more, preferably 10,000 or more, and its upper limit may be 500,000 or less, preferably 200,000 or less.

The type of the biodegradable polymer is not particularly limited, but includes polyethylene glycol-poly(lactide-co-glycolide) block-copolymer, polyethylene glycol-polylactide block-copolymer, and polyethylene glycol-polycaprolactone block-copolymer. There is one or more selected from the group consisting of polymer, polylactide, polyglycolide, poly(lactide-co-glycolide), poly(lactide-co-glycolide)glucose, polycaprolactone, and mixtures thereof. , more preferably polylactide, poly(lactide-co-glycolide) and polycaprolactone.

When poly(lactide-co-glycolide) is used as the biodegradable polymer, the molar ratio of lactic acid to glycolic acid in the copolymer may be 99:1 to 50:50, preferably 50:50, 75:50. :25, or 85:15.

When two or more types of biocompatible polymers are included, the types of polymers exemplified above may be a combination or blend of different polymers, but polymers of the same type may have different intrinsic viscosity, molecular weight, and/or monomer ratio. A combination of polymers (e.g. a combination or blend of two or more poly(lactide-co-glycolides) with different intrinsic viscosity), or the same type of polymer with different end groups (e.g. an ester end group or an acid end group) It may be.

Examples of commercial biodegradable polymer, which can be used in the present invention, are the Evonica's resomer series RG502H, RG503H, RG504H, RG502, RG503, RG504, RG653H, RG752H, RG752S, RG753H, RG753S, RG755S, RG756S , Rg858s, R202H, R203H, R205H, R202S, R203S, R205S, Cobion's PDL 02A, PDL 02, PDL 04, PDL 05, PDLG 7502A, PDLG 7502, PDLG 7504A, PDLG 7504, PDLG 7507, PDLG 5002A, PDLG 5002, PDLG 5004A , PDLG 5004, PDLG 5010, PL 10, PL 18, PL 24, PL 32, PL 38, PDL 20, PDL 45, PC 02, PC 04, PC 12, PC 17, PC 24, etc., alone, in combination or in blends, etc. Includes, but is not limited to. The appropriate molecular weight or blending ratio of the biocompatible polymer applicable to the present invention can be appropriately selected by a person skilled in the art in consideration of the decomposition rate of the biocompatible polymer and the resulting drug release rate.

In a specific embodiment, in order to manufacture micro particles according to the present invention, the biocompatible polymers used to prepare the dispersed phase are PLA and PLGA polymers, such as Purasorb PDL02A ((IV=0.16-0.24 dL/g; Manufacturer: Corbion, Germany), Purasorb PDL04A ((IV=0.35-0.45 dL/g; Manufacturer: Corbion, Germany), Purasorb PDLG7504A (IV=0.35-0.45 dL/g; Manufacturer: Corbion, Germany), Resomer R205S (IV=0.55-0.75 dL/g; Manufacturer: Evonik, Germany), Resomer R206S (IV=0.8-1.2 dL/g; Manufacturer: Evonik, Germany), Resomer R203H (IV=0.25-0.35 dL/g; Manufacturer: Evonik, Germany), Resomer RG 653H (IV=0.32-0.44 dL/g; Manufacturer: Evonik, Germany), Resomer RG 753H (IV=0.32-0.44 dL/g; Manufacturer: Evonik, Germany), Resomer RG755S (IV= 0.50-0.70 dL/g ; Manufacturer: Evonik, Germany), Resomer RG 756S (IV=0.71-1.0 dL/g; Manufacturer: Evonik, Germany), Resomer RG 858S (IV = 1.3-1.7 dL/g; Manufacturer: Evonik, Germany) and Resomer RG One or two or more types selected from the group consisting of 503H (IV = 0.32-0.44 dL/g; Manufacturer: Evonik, Germany) can be used.

As an example, the preparation may be a transdermal absorbent in the form of a reservoir or matrix containing donepezil or a pharmaceutically acceptable salt thereof and/or rivastigmine or a pharmaceutically acceptable salt thereof as active ingredients. These transdermal absorbents are safe and relatively easy to store and handle during commercial production, are inexpensive, have excellent storage stability, allow the drug to be administered in appropriate doses over a long period of time, and can be quickly removed from the skin, eliminating the risk that may occur in some cases. It has the advantage of being able to avoid problems such as side effects relatively quickly. The transdermal absorbent can be manufactured using various ingredients such as adhesive polymers, administration accelerators, and plasticizers by methods well known in the art.

In the present invention, the term "individual" includes mammals, especially humans, and the administration plan, administration interval, dosage, etc. can be easily set, changed, and adjusted by a person skilled in the art based on the above-mentioned factors.

The pharmaceutical combination for the prevention or treatment of dementia or cognitive dysfunction containing donepezil and rivastigmine of the present invention allows each drug to be administered for at least 1 day, at least 1 week, at least 2 weeks, at least 1 month, or at least 3 months. It is characterized by continuous release.

In one embodiment, the pharmaceutical combination for preventing, improving or treating dementia or cognitive dysfunction comprising donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof of the present invention is, It is characterized in that the AUC _0-∞ /C _max of donepezil and rivastigmine that appear when administered to an individual is each 5 hr (hours) or more.

In the present invention, AUC refers to the area under the plasma concentration-time curve, which is a measure of total bioavailability, AUC _0-∞ refers to the area under the plasma concentration-time curve until infinite time, and C _max (maximum blood concentration) refers to the area under the plasma concentration-time curve, which is a measure of total bioavailability. It refers to the highest blood concentration of the administered drug when administered. Additionally, these values are all pharmacokinetic parameters in single administration.

The pharmaceutical combination according to the present invention exhibits the AUC _0-∞ /C _max value as described above, and when the drug is administered, the blood concentration of the drug does not change excessively and is therapeutically effective while maintaining a constant level. Common side effects caused by acetylcholine esterase inhibitors such as pezil and rivastigmine, such as nausea, vomiting, abdominal pain, gastrointestinal side effects such as duodenal ulcer, anorexia, confusion, insomnia, muscle cramps, weight loss, It has the advantage of significantly reducing side effects such as elevated liver levels, bradycardia, heart block, or syncope.

As another embodiment, the pharmaceutical combination of the present invention is characterized in that the area under the blood concentration curve (AUC) of donepezil is not smaller than the AUC of rivastigmine. Specifically, when the pharmaceutical combination according to the present invention is administered to an individual, based on the AUC value of donepezil as 100%, the AUC of rivastigmine is 100% or less, for example, 80%, 70%, 60%. Or, it is characterized in that it is 50% or less.

Hereinafter, preferred embodiments are presented to aid understanding of the present invention. However, the following examples are merely illustrative of the present invention, and it is clear to those skilled in the art that various changes and modifications are possible within the scope and spirit of the present invention. It is natural that such variations and modifications fall within the scope of the attached patent claims.

Example 1. Preparation of donepezil microspheres

Donepezil microspheres were prepared to confirm the effect of combined administration of donepezil and rivastigmine according to the present invention.

The dispersed phase was prepared by mixing 6.5 g of the biocompatible polymer Resomer R203H (IV = 0.32-0.44 dL/g; manufacturer: Evonik, Germany) and 3.5 g of donepezil with 17.11 g of dichloromethane (manufacturer: J.T. Baker, USA). The dispersed phase was sufficiently dissolved by stirring for more than 2 hours. A 0.5% (w/v) polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s) aqueous solution was used as the continuous phase, and an emulsion was prepared by supplying 3,400 ml of the continuous phase to the membrane emulsifier and simultaneously injecting the prepared dispersed phase. The emulsion was stirred at 200 rpm.

The temperature of the membrane emulsifier and emulsion was maintained at 25°C. After the injection of the dispersed phase was completed, the emulsion was stirred for 30 minutes and then heated to 45°C and maintained for 3 hours to remove the organic solvent to prepare microspheres. After removal of the organic solvent, the temperature of the microparticle suspension was lowered to 25°C. The microsphere suspension was washed several times with distilled water, recovered, and dried to prepare biodegradable polymer microspheres containing donepezil.

Example 2: Preparation of rivastigmine microspheres

The dispersed phase was 6.45 g of the biocompatible polymer Resomer RG653H (IV = 0.32-0.44 dL/g; manufacturer: Evonik, Germany) and 2.00 g of rivastigmine, a pharmaceutically acceptable salt of rivastigmine, in dichloromethane ( Manufacturer: J.T.Baker, USA) It was prepared by mixing with 32.29g. The dispersed phase was sufficiently dissolved by stirring for more than 2 hours. A 1.0% (w/v) polyvinyl alcohol (viscosity: 4.8-5.8 mPa·s) aqueous solution was used as the continuous phase, and an emulsion was prepared by supplying 4,836 ml of the continuous phase to the membrane emulsifier and simultaneously injecting the prepared dispersed phase. The emulsion was stirred at 200 rpm.

The temperature of the membrane emulsifier and emulsion was maintained at 25 °C. After the injection of the dispersed phase was completed, the emulsion was stirred for 30 minutes and then heated to 45 °C and maintained for 3 hours to remove the organic solvent to prepare microspheres. After removal of the organic solvent, the temperature of the microparticle suspension was lowered to 25 °C. The microsphere suspension was washed several times with distilled water, recovered, and dried to prepare biodegradable polymer microspheres containing rivastigmine.

Example 3: Preparation of combination microspheres containing donepezil and rivastigmine

Microspheres for combined use were prepared by mixing the microspheres containing donepezil and rivastigmine prepared in Examples 1 and 2 at a weight ratio of 1.59:1.

Experimental Example 1: Drug content test of donepezil microspheres

To measure the content of donepezil in the biodegradable polymer microspheres prepared in Examples 1 and 3, 10 mg of the microspheres were completely dissolved in DMSO and then diluted with a mobile phase. 20 μl of the diluted solution was injected into HPLC and measured at a detection wavelength of 271 nm. The column used in this experiment was Inertsil ODS-3, 5 μm, 4.6 x 150 mm, and the mobile phase was a mixture of phosphate buffer (pH 5.0) and acetonitrile in a 6:4 ratio (v/v).

Experimental Example 2: Drug content test of rivastigmine microspheres

To measure the content of rivastigmine in the biodegradable polymer microspheres prepared in Examples 2 and 3, 10 mg of the microspheres were completely dissolved in DMSO and then diluted with a mobile phase. 20 μl of the diluted solution was injected into HPLC and measured at a detection wavelength of 210 nm. The column used in this experiment was Inertsil ODS-3, 5μm, 4.6

The drug content in the biodegradable polymer microspheres performed in Experimental Examples 1 and 2 is shown in Table 1 below.

division	Drug content (%, w/w)
	donepezil	Rivastigmine
Example 1	30.40	-
Example 2	-	16.07
Example 3	18.64	6.21

Experimental Example 3: Pharmacokinetics (PK) test of combined microspheres containing donepezil and rivastigmine

To confirm changes in the pharmacokinetics of drug-containing microspheres, the drug-containing microspheres prepared in Examples 1 to 3 were administered to rats, and then the blood concentrations of donepezil and rivastigmine were measured. The conditions for administering microspheres to rats are shown in Table 2 below.

division	Dosage of drug-containing microspheres (mg/head)	Drug dosage (mg/head)
Example 1	42.83	13.02 (donepezil)
Example 2	27.01	4.34 (rivastigmine)
Example 3	69.84	17.36 (donepezil 13.02, rivastigmine 4.34)

Figure 1 shows the results of measuring blood drug concentration after administering microspheres containing the drug according to Examples 1 to 3 to rats according to the administration conditions in Table 2 above. In Figure 1, Example 1 and Example 2 are the results of confirming the drug release pattern in experimental animals of microspheres containing donepezil and rivastigmine, respectively, and Example 3 is the result of combined use containing donepezil and rivastigmine. This is the result of confirming the release pattern of each drug in experimental animals after administration of microspheres.

Example 4. AChE mRNA expression pattern 1 according to combined administration of donepezil and rivastigmine

In order to establish the susceptibility of cells to donepezil and rivastigmine and the optimal concentration range of each drug, the AChE mRNA expression level analysis test according to treatment of each drug alone has been used for a long time as a research model for human neuron phenotype and Alzheimer's disease. The study was performed on SH-SY5Y cell line, a human neuroblastoma.

Specifically, the SH-SY5Y cell line was cultured in a 6-well plate (6 × 10 ⁵ /well) using high-glucose Dulbecco's modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum and penicillin-streptomycin. SH-SY5Y cells were treated with donepezil at a final concentration of 10, 20, 30, 40 (15.2 μg/ml) μM , or rivastigmine at a final concentration of 0.01, 0.1, 0.5, 1, 5 (1.25 μg/ml) μM. After culturing for 24 hours, total RNA was extracted from each cell using TRIzol, and cDNA was synthesized using the SuperScript III cDNA synthesis kit. Real-time polymerase chain reaction (Quantitative Real-time PCR, qRT-PCR) was performed using QuantStudio 3 using the synthesized cDNA, the primers shown in Table 3 below, and SYBR Green. To confirm the amplification and accumulation of the target gene in real time, qRT-PCR was performed using an initial denaturation reaction of 2 minutes at 50°C and 10 minutes at 95°C, followed by 40 cycles of 15 seconds at 95°C and 1 minute at 60°C. proceeded.

denomination	order	sequence number
Human AchE (forward)	5’-AGAGCTGGTAGCCTGCCTT-3’	One
Human AchE (reverse)	5’-CCGGAAGAGCTTTCTTGAGG-3’	2
Human GAPDH (forward)	5’-GGAGCGAGATCCCTCCAAAAT-3’	3
Human GAPDH (reverse)	5’-GGCTGTTGTCATACTTCTCATGG-3’	4

The amplified gene expression level was calculated using the Comparative Ct Method, one of the methods for quantifying the expression level of a specific gene, and the analysis results are shown in Figures 2 to 4.

[AChE mRNA expression level analysis relationship for each sample]

ΔCt value = Ct value of AChE in each sample - Ct value of reference gene (GAPDH) in the sample.

(Here, Ct refers to the cycle value at which amplification begins to increase significantly during the PCR process.)

As shown in Figure 2, AChE mRNA expression was increased dependently up to 20 μM donepezil concentration, but there was no difference beyond that, and no statistically significant change was observed by treatment with 0.01 to 5 μM rivastigmine. Through this, it was determined that a donepezil concentration of 20 μM or less, which clearly shows the increase in AChE activity and quantity due to taking donepezil as seen in clinical trials, would be suitable for drug combination testing.

Based on the above experimental results, in order to confirm the effect of combined administration of donepezil and rivastigmine on AChE gene expression, donepezil and rivastigmine were treated alone or in combination, and the level of AChE mRNA expression was analyzed.

Specifically, the SH-SY5Y cell line was cultured in a 6-well plate (6×10 ⁵ /well) using DMEM supplemented with 10% fetal bovine serum and penicillin-streptomycin. SH-SY5Y cells were treated with donepezil alone or donepezil and rivastigmine in combination, and comparative analysis of gene expression was performed by qRT-PCR in the same manner as the existing experimental method.

As shown in Figure 3, the increased AChE mRNA expression following treatment with 5 μM (1.9 μg/ml) donepezil alone was suppressed by combined treatment with 1, 5, and 10 (2.5 μg/ml) μM rivastigmine. , when used in combination with 1 μM rivastigmine (weight ratio 1:0.13), the inhibitory effect on AChE gene expression was highest. However, as the rivastigmine drug concentration increased, the combined effect of the two drugs was canceled out, showing low physiological/statistical significance at the donepezil:rivastigmine ratio of 1:1.32 (molar ratio 1:2).

According to the above test results, the mRNA expression of AChE was compared and analyzed when donepezil 20 μM was used in combination with low concentration rivastigmine. Specifically, we sought to confirm the effect in a ratio range lower than the weight ratio of 1:0.13, which was confirmed as the most effective combination ratio in [Figure 3].

Specifically, SH-SY5Y cells were treated with donepezil alone at a final concentration of 20 μM, or donepezil 20 μM in combination with rivastigmine 0.1, 0.5, 1, and 5 μM, and qRT-PCR was performed in the same manner as the existing experimental method. Then, gene expression was compared and analyzed.

As shown in FIG. 4, as a result of combined treatment with donepezil and rivastigmine at various concentrations, the weight ratio was 1:0.003 and 1:0.016. The ability to suppress AChE expression was confirmed at ratios of 1:0.03 and 1:0.16. In particular, the 1:0.016 ratio specifically shows the greatest inhibitory power, and the optimal mixing ratio for manufacturing a pharmaceutical combination containing donepezil and rivastigmine for preventing, improving, or treating dementia or cognitive dysfunction is based on the dosage. It was confirmed that it was 1:0.016.

Example 5. AChE mRNA expression pattern 2 according to combined administration of donepezil and rivastigmine

The APP-H4 cell line introduces the Swedish mutation of Amyloid Precursor Protein (APP) into human neuroglioblastoma H4 cells, increasing abnormal segments of APP by beta-secretase, leading to Alzheimer's disease. It is known as a dementia model cell line in which hyperphosphorylation of the and Tau proteins is induced. In order to re-verify the effect of combined administration of donepezil and rivastigmine on AChE mRNA expression and the combination ratio of drugs confirmed through previous studies, donepezil and rivastigmine were used alone or in combination as active ingredients in APP-H4 cells. and analyzed for AChE gene expression.

Specifically, the APP-H4 cell line was cultured in DMEM containing 10% fetal bovine serum and gentamycine. Cells were treated with donepezil 50 (19 μg/ml) μM alone or in combination with donepezil 50 μM and rivastigmine 1 or 5 (1.25 μg/ml) μM at a final concentration, and qRT-PCR was performed in the same manner as the existing experimental method. (see Table 4 below for primers) to compare gene expression.

denomination	order	sequence number
Human AchE (forward)	5’-GGGGCTCAGCAGTACGTTAG-3’	5
Human AchE (reverse)	5’-CGGTGGCGCTGAGCAATTT-3’	6
Human GAPDH (forward)	5’-TGGGCTACACTGAGGACCACT-3’	7
Human GAPDH (reverse)	5’-GGGAGTGTCTGTTGAAGTCG-3’	8

APP-H4 cells were treated with donepezil and rivastigmine alone or in combination, and cultured for 24 hours. The results of measuring AChE mRNA expression by qRT-PCR are shown in Figures 5 and 6.

As shown in Figure 5, rivastigmine did not appear to affect AChE mRNA expression in the concentration range of 0.5, 1, or 10 μM.

As shown in Figure 6, the AChE expression increased by 50 μM donepezil was reduced by combined treatment with 1 and 5 μM (1:0.13 and 1:0.66 by weight ratio) rivastigmine, which was reduced by prior treatment using SH-SY5Y. It was confirmed that it was within the range of donepezil:rivastigmine combination ratio confirmed through experiments.

Summarizing the above experimental results, it can be seen that induction of AChE mRNA expression by donepezil and administration of rivastigmine alone in human neuroblastoma cells do not affect AChE mRNA expression. However, when low-concentration rivastigmine, which does not affect AChE mRNA expression, was combined with donepezil, it was confirmed that it had the effect of significantly suppressing the AChE mRNA expression increased by donepezil.

Donepezil and rivastigmine are both inhibitors of acetylcholinesterase (AChE), with donepezil acting only on AChE and rivastigmine acting on AChE and butyryl-cholinesterase (BuChE). It shows the mechanism of action that inhibits the breakdown of acetylcholine. Therefore, it should be understood that donepezil and rivastigmine theoretically do not affect the expression of the gene that creates AChE, but in clinical research results, there are many reports of actual increases in AChE activity and quantity in patients taking donepezil for a long period of time. It is true that it has existed. Regarding this phenomenon, taking donepezil inhibits the breakdown of acetylcholine by AChE and maintains the amount of acetylcholine in the brain, increasing AChE gene expression to decompose acetylcholine as a regulatory mechanism in vivo. I'm guessing he ordered it.

However, when rivastigmine is administered together with donepezil at a certain ratio as in the present invention, the amount of AChE mRNA expression increased by donepezil is effectively suppressed, and the expression of the AChE gene, which is increased by the regulatory mechanism, is excellently suppressed. It was confirmed that it was possible. In particular, in the case of rivastigmine, this effect is difficult to predict in that it effectively suppresses the expression of AChE mRNA when combined with donepezil in the ratio according to the present invention, even though it is administered alone in an amount that does not affect AChE. It is judged. Moreover, the results of the present invention are the first to show that the combined use ratio of donepezil and rivastigmine by weight is much lower than the ratio based on commercialized dosage, thereby suppressing the expression level of AChE mRNA more effectively.

Claims (15)

1. A pharmaceutical combination for preventing, improving or treating dementia or cognitive dysfunction containing donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof.
2. The method of claim 1, wherein the combination includes an individual agent comprising donepezil or a pharmaceutically acceptable salt thereof and an individual agent comprising rivastigmine or a pharmaceutically acceptable salt thereof, wherein the individual agents are A pharmaceutical combination that is administered to a patient simultaneously or sequentially.
3. The method of claim 2, wherein the individual preparations containing donepezil or a pharmaceutically acceptable salt thereof and the individual preparations containing rivastigmine or a pharmaceutically acceptable salt thereof have the same dosage form or different dosage forms. , pharmaceutical combination.
4. The pharmaceutical combination according to claim 2, wherein the individual agents in the pharmaceutical combination are oral formulation, patch formulation, or injection formulation.
5. The pharmaceutical composition according to claim 1, wherein the weight ratio of the daily dose of donepezil and the daily dose of rivastigmine contained in the pharmaceutical combination is 1:0.0031 to 1:1 as donepezil:rivastigmine. Combination.
6. The method of claim 4, wherein when all of the individual agents in the pharmaceutical combination are oral formulations or patch formulations, the weight ratio for the daily dose of donepezil and the daily dose of rivastigmine is as donepezil:rivastigmine. Pharmaceutical combinations from 1:0.01 to 1:1.
7. The method of claim 4, wherein when all of the individual agents in the pharmaceutical combination are injectable formulations, the weight ratio for the daily dose of donepezil and the daily dose of rivastigmine is 1:0.003 as donepezil:rivastigmine. to 1:0.66.
8. The pharmaceutical composition according to claim 1, wherein the total content of donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof is 0.1 to 99% by weight based on the total weight of the pharmaceutical combination. Combination.
9. The method of claim 1, wherein when the donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof are each included as separate preparations, for 100 parts by weight of each individual preparation, donepezil Or a pharmaceutically acceptable salt thereof, as donepezil, contained in an amount of 0.1 to 65 parts by weight, and rivastigmine or a pharmaceutically acceptable salt thereof, as rivastigmine, contained in an amount of 0.1 to 50 parts by weight. Combination.
10. The method of claim 1, wherein the daily dose of donepezil or a pharmaceutically acceptable salt thereof is 1 to 60 mg as donepezil, or the daily dose of the rivastigmine or a pharmaceutically acceptable salt thereof is Rivasti A pharmaceutical combination of 0.003 to 15 mg as a drug.
11. The pharmaceutical combination according to claim 1, wherein the rivastigmine compensates for the decrease in the ability of donepezil or a pharmaceutically acceptable salt thereof to inhibit the accumulation of amyloid precursor protein.
12. The pharmaceutical combination according to claim 1, wherein the AUC _0-∞ /C _max of donepezil and rivastigmine that appears upon administration to a subject is 5 hours (hr) or more.
13. The pharmaceutical combination according to claim 1, wherein at least one of the donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof is a preparation encapsulated in microspheres.
14. The method of claim 13, wherein the donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof are a preparation in the form of encapsulated microspheres, or

    A pharmaceutical combination, which is a mixed preparation comprising a preparation in the form of individual microspheres encapsulated with the donepezil or a pharmaceutically acceptable salt thereof and a preparation in the form of individual microspheres encapsulated with the rivastigmine or a pharmaceutically acceptable salt thereof. water.
15. Comprising the step of administering a pharmaceutical combination comprising donepezil or a pharmaceutically acceptable salt thereof and rivastigmine or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutical combination is administered A method for preventing, improving or treating dementia or cognitive dysfunction, wherein the weight ratio of the daily dose of donepezil and the daily dose of rivastigmine is 1:0.0031 to 1:1 as donepezil:rivastigmine.

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