WO2024072049A1 - Association pharmaceutique contenant du donépézil et de la rivastigmine pour prévenir, soulager ou traiter la démence ou la déficience cognitive et procédé de préparation s'y rapportant - Google Patents

Association pharmaceutique contenant du donépézil et de la rivastigmine pour prévenir, soulager ou traiter la démence ou la déficience cognitive et procédé de préparation s'y rapportant Download PDF

Info

Publication number
WO2024072049A1
WO2024072049A1 PCT/KR2023/014929 KR2023014929W WO2024072049A1 WO 2024072049 A1 WO2024072049 A1 WO 2024072049A1 KR 2023014929 W KR2023014929 W KR 2023014929W WO 2024072049 A1 WO2024072049 A1 WO 2024072049A1
Authority
WO
WIPO (PCT)
Prior art keywords
donepezil
rivastigmine
pharmaceutically acceptable
acceptable salt
pharmaceutical combination
Prior art date
Application number
PCT/KR2023/014929
Other languages
English (en)
Korean (ko)
Inventor
이희용
설은영
이주한
정혜정
김인규
Original Assignee
주식회사 지투지바이오
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 주식회사 지투지바이오 filed Critical 주식회사 지투지바이오
Publication of WO2024072049A1 publication Critical patent/WO2024072049A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • 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.
  • geriatric dementia is a disease called Alzheimer's disease or Alzheimer type dementia (AD).
  • AD Alzheimer type dementia
  • 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.
  • 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.
  • acetylcholine esterase inhibitors including donepezil
  • memantine an NMDA receptor antagonist
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical combination according to the present invention may be prepared by preparing the two active ingredients into tablets, patches, or injection preparations.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • p-value probability of significance
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the pharmaceutically acceptable salt of donepezil or rivastigmine 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.
  • 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.
  • 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.
  • 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
  • the pharmaceutically acceptable salt of rivastigmine may be hydrochloride salt of rivastigmine.
  • the pharmaceutical combination may be for combined administration.
  • 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.
  • 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.
  • the pharmaceutical combination may be in kit form.
  • 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.
  • donepezil 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.
  • parenterally e.g., intravenously, subcutaneously, intramuscularly, intraperitoneally, transdermally, transnasally
  • parenterally e.g., intravenously, subcutaneously, intramuscularly, intraperitoneally, transdermally, transnasally
  • parenterally e.g., intravenously, subcutaneously, intramuscularly, intraperitoneally, transdermally, transnasally
  • administration routes e.g., intravenously, subcutaneously, intramuscularly, intraperitoneally, transdermally, transnasally
  • the preparations containing each active ingredient are administered through the same or different routes, for example, the donepezil or its
  • 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.
  • 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.
  • 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.
  • the dosage of each ingredient may vary greatly depending on the above conditions, and is not limited by the above examples.
  • 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.
  • they can be administered simultaneously, sequentially (in any order), or in combination.
  • 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.
  • 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
  • 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.
  • 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:
  • 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.
  • 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.
  • 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
  • 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
  • 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.
  • 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.
  • 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.
  • the pharmaceutical combination of the present invention may further include lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ m to 150 ⁇ m.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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
  • the same type of polymer with different end groups e.g. an ester end group or an acid end group
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • AUC area under the blood concentration curve
  • 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.
  • Donepezil microspheres were prepared to confirm the effect of combined administration of donepezil and rivastigmine according to the present invention.
  • 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.
  • 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.
  • the drug content in the biodegradable polymer microspheres performed in Experimental Examples 1 and 2 is shown in Table 1 below.
  • 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.
  • 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.
  • Example 1 and Example 2 are the results of confirming the drug release pattern in experimental animals of microspheres containing donepezil and rivastigmine, respectively
  • 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
  • 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.
  • 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 ⁇ g/ml) ⁇ M , or rivastigmine at a final concentration of 0.01, 0.1, 0.5, 1, 5 (1.25 ⁇ g/ml) ⁇ M. 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.
  • 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.
  • ⁇ Ct value Ct value of AChE in each sample - Ct value of reference gene (GAPDH) in the sample.
  • Ct refers to the cycle value at which amplification begins to increase significantly during the PCR process.
  • AChE mRNA expression was increased dependently up to 20 ⁇ M donepezil concentration, but there was no difference beyond that, and no statistically significant change was observed by treatment with 0.01 to 5 ⁇ M rivastigmine.
  • a donepezil concentration of 20 ⁇ M 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.
  • donepezil and rivastigmine were treated alone or in combination, and the level of AChE mRNA expression was analyzed.
  • 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.
  • SH-SY5Y cells were treated with donepezil alone at a final concentration of 20 ⁇ M, or donepezil 20 ⁇ M in combination with rivastigmine 0.1, 0.5, 1, and 5 ⁇ M, and qRT-PCR was performed in the same manner as the existing experimental method. Then, gene expression was compared and analyzed.
  • 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.
  • 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.
  • APP Amyloid Precursor Protein
  • the APP-H4 cell line was cultured in DMEM containing 10% fetal bovine serum and gentamycine.
  • Cells were treated with donepezil 50 (19 ⁇ g/ml) ⁇ M alone or in combination with donepezil 50 ⁇ M and rivastigmine 1 or 5 (1.25 ⁇ g/ml) ⁇ M 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.
  • 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.
  • rivastigmine did not appear to affect AChE mRNA expression in the concentration range of 0.5, 1, or 10 ⁇ M.
  • 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.
  • AChE acetylcholinesterase
  • BuChE butyryl-cholinesterase
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une association pharmaceutique, une composition ou un kit pour prévenir, soulager ou traiter la démence ou la déficience cognitive, contenant du donépézil ou un sel pharmaceutiquement acceptable de celui-ci, ainsi que de la rivastigmine ou un sel pharmaceutiquement acceptable de celle-ci, et ayant une observance médicamenteuse élevée et un excellent effet de traitement. L'invention concerne également un procédé de préparation s'y rapportant.
PCT/KR2023/014929 2022-09-26 2023-09-26 Association pharmaceutique contenant du donépézil et de la rivastigmine pour prévenir, soulager ou traiter la démence ou la déficience cognitive et procédé de préparation s'y rapportant WO2024072049A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2022-0121865 2022-09-26
KR20220121865 2022-09-26

Publications (1)

Publication Number Publication Date
WO2024072049A1 true WO2024072049A1 (fr) 2024-04-04

Family

ID=90478648

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2023/014929 WO2024072049A1 (fr) 2022-09-26 2023-09-26 Association pharmaceutique contenant du donépézil et de la rivastigmine pour prévenir, soulager ou traiter la démence ou la déficience cognitive et procédé de préparation s'y rapportant

Country Status (2)

Country Link
KR (1) KR20240043716A (fr)
WO (1) WO2024072049A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20180094518A (ko) * 2017-01-17 2018-08-24 한국화학연구원 미립구형 서방출 주사제 및 그의 제조방법
KR20190110457A (ko) * 2018-03-20 2019-09-30 (주)인벤티지랩 도네페질 및 메만틴을 포함하는 인지 장애 관련 질병의 예방 또는 치료용 약학적 복합 조성물 및 이의 제조 방법
WO2020236159A1 (fr) * 2019-05-21 2020-11-26 La Pharma Tech Inc. Nouvelles compositions pharmaceutiques et méthodes de traitement de troubles mentaux, comportementaux et cognitifs
KR102271305B1 (ko) * 2020-05-21 2021-06-30 주식회사 아리바이오 치매 예방 및 치료용 조성물

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20180094518A (ko) * 2017-01-17 2018-08-24 한국화학연구원 미립구형 서방출 주사제 및 그의 제조방법
KR20190110457A (ko) * 2018-03-20 2019-09-30 (주)인벤티지랩 도네페질 및 메만틴을 포함하는 인지 장애 관련 질병의 예방 또는 치료용 약학적 복합 조성물 및 이의 제조 방법
WO2020236159A1 (fr) * 2019-05-21 2020-11-26 La Pharma Tech Inc. Nouvelles compositions pharmaceutiques et méthodes de traitement de troubles mentaux, comportementaux et cognitifs
KR102271305B1 (ko) * 2020-05-21 2021-06-30 주식회사 아리바이오 치매 예방 및 치료용 조성물

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
XIAOHONG ZHANG: "Effects of rivastigmine hydrogen tartrate and donepezil hydrochloride on the cognitive function and mental behavior of patients with Alzheimer's disease", EXPERIMENTAL AND THERAPEUTIC MEDICINE, SPANDIDOS PUBLICATIONS, GR, vol. 20, no. 2, 1 January 2020 (2020-01-01), GR , pages 1789 - 1795, XP093154879, ISSN: 1792-0981, DOI: 10.3892/etm.2020.8872 *

Also Published As

Publication number Publication date
KR20240043716A (ko) 2024-04-03

Similar Documents

Publication Publication Date Title
KR101811797B1 (ko) 도네페질을 포함하는 비경구투여용 약제학적 조성물
US5962535A (en) Composition for alzheimer's disease
US6376517B1 (en) Pipecolic acid derivatives for vision and memory disorders
JP3984787B2 (ja) 機能性及び／又は器質性痛み症候群の治療のための製薬組成物の調製のためのアセチルコリンエステラーゼ阻害剤の使用
WO2011120281A1 (fr) Utilisation de l-oxiracétam dans la préparation de médicaments en vue de prévenir ou de traiter un dysfonctionnement cognitif
KR20120022721A (ko) ＪＮＫ(ｃ-Ｊｕｎ 아미노 말단 키나제) 저해 펩티드를 이용한 망막 질환의 예방 또는 치료제, 망막 질환의 예방 또는 치료 방법, 및 이 펩티드의 용도
WO2001066096A2 (fr) Compositions destinees a la prevention et au traitement de la demence
JP2007509055A (ja) ［２−（８，９−ジオキソ−２，６−ジアザビシクロ［５．２．０］ノナ−１（７）−エン−２−イル）アルキル］ホスホン酸および誘導体の経口投与
CA3025268A1 (fr) Promedicaments a base d'agonistes de trpv1 phenoliques en association avec des anesthesiques locaux et des vasoconstricteurs pour ameliorer une anesthesie locale
WO1998030243A1 (fr) Inhibiteurs d'acetylcholinesterase en combinaison avec des agonistes muscariniques utilises dans le traitement de la maladie d'alzheimer
WO2021010719A1 (fr) Formulation à longue durée d'action contenant de la rivastigmine et son procédé de préparation
JPH0812575A (ja) 口腔乾燥症治療剤
WO2024072049A1 (fr) Association pharmaceutique contenant du donépézil et de la rivastigmine pour prévenir, soulager ou traiter la démence ou la déficience cognitive et procédé de préparation s'y rapportant
WO2012077968A2 (fr) Formulation complexe contenant de l'hydrochlorure de lercanidipine et du valsartan et son procédé de préparation
KR20010102219A (ko) 알쯔하이머성 치매를 치료하기 위한 데스옥시페가닌의 용도
JPH0782146A (ja) 抗痴呆薬
EP0952826B1 (fr) Agent combine contenant de l'idebenone pour le traitement de la maladie d'alzheimer
CZ244497A3 (cs) Kombinace protivirových látek a farmaceutický prostředek
JP2005501108A (ja) 神経変性治療におけるネフィラセタムの使用
US6395758B1 (en) Small molecule carbamates or ureas for vision and memory disorders
WO2023085503A1 (fr) Microsphères comprenant de la varénicline à dose élevée, leur procédé de préparation et composition pharmaceutique les comprenant
US6333340B1 (en) Small molecule sulfonamides for vision and memory disorders
EP1552834A1 (fr) Promoteur de production du facteur neurotrophique
WO2020159044A1 (fr) Composition pour la prévention ou le traitement de déficience cognitive contenant de la dapsone en tant que principe actif
WO2015083996A1 (fr) Forme posologique pharmaceutique destinée au traitement d'une leucémie myéloïde chronique, contenant un extrait d'écorce de liriodendron tulipifera l. comme principe actif

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23873160

Country of ref document: EP

Kind code of ref document: A1