WO2018062941A1 - Composition pharmaceutique pour la prévention ou le traitement d'une démence et d'un dysfonctionnement cognitif, contenant du donépézil ou un sel de qualité pharmaceutique de celui-ci et de la mémantine ou un sel de qualité pharmaceutique de celle-ci, et son procédé de préparation - Google Patents

Composition pharmaceutique pour la prévention ou le traitement d'une démence et d'un dysfonctionnement cognitif, contenant du donépézil ou un sel de qualité pharmaceutique de celui-ci et de la mémantine ou un sel de qualité pharmaceutique de celle-ci, et son procédé de préparation Download PDF

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WO2018062941A1
WO2018062941A1 PCT/KR2017/010953 KR2017010953W WO2018062941A1 WO 2018062941 A1 WO2018062941 A1 WO 2018062941A1 KR 2017010953 W KR2017010953 W KR 2017010953W WO 2018062941 A1 WO2018062941 A1 WO 2018062941A1
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Prior art keywords
pharmaceutically acceptable
donepezil
acceptable salt
memantine
mesh
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PCT/KR2017/010953
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English (en)
Korean (ko)
Inventor
구형모
고찬영
이마세
Original Assignee
주식회사 바이오파마티스
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Priority claimed from KR1020170125220A external-priority patent/KR101938872B1/ko
Application filed by 주식회사 바이오파마티스 filed Critical 주식회사 바이오파마티스
Priority to EP17856827.5A priority Critical patent/EP3520792A4/fr
Priority to CN201780069152.9A priority patent/CN110573156B/zh
Priority to JP2019539722A priority patent/JP6887506B2/ja
Publication of WO2018062941A1 publication Critical patent/WO2018062941A1/fr

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    • 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
    • A61K31/13—Amines
    • 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

Definitions

  • the present invention relates to a rapid-release pharmaceutical composition for the prevention or treatment of dementia and cognitive dysfunction, which contains donepezil or a pharmaceutically acceptable salt thereof and memantine or a pharmaceutically acceptable salt thereof as an active ingredient, and a method for preparing the same. .
  • brain function-related diseases have become a major issue, and dysfunctions such as fatigue, depression, insomnia, concentration / memory disorder or oxidative brain damage are caused by causes including stress that cannot be controlled or avoided.
  • degenerative brain disorders such as Alzheimer's dementia, Parkinson's disease, Huntington's disease or Lewy body disease and its irreversible dementia are increasing.
  • AD dementia More than 50% of senile dementia is Alzheimer's (AD) dementia.
  • acetylcholinesterase inhibitors such as donepezil, galantamine, and rivastigmin Memantine, an NMDA-D-asfartate (NMDA) receptor antagonist, has been approved for the treatment of Alzheimer's dementia.
  • donepezil is administered once daily, starting at 5 mg, increasing to 10 mg after 4-6 weeks, and oral solid dosage forms such as film coated tablets, capsules and granules. Are administered in the form of.
  • the memantine is developed as a moderate to high Alzheimer's dementia treatment, and is administered in the form of a film coating or liquid.
  • the drug is administered 5 mg per day and then increased by 5 mg per week, and the maximum dose is morning and evening. Although 10 mg is administered 20 mg per day, many clinical researchers now take it once a day because of its long half-life of 60 to 80 hours and relatively high side effects.
  • Conventional Korean Patent No. 1213345 relates to a combination preparation of Donepezil and Memantine, and relates to a technique for delayed release of one of the two drugs, Donepezil and Memantine.
  • the delayed release combination preparation it is not easy to manufacture a product having a constant release delay as an agent designed for in vitro testing such as an eluent, and it is not easy to manufacture a gastrointestinal exercise for each person if taken directly by a person. Because of this difference, it is not easy to accurately predict the emission delay time.
  • a rapid-release preparation that exhibits efficacy in a short time is preferable.
  • another object of the present invention is to prepare a rapid-release pharmaceutical composition for the prevention or treatment of dementia and cognitive impairment containing Donepezil or a pharmaceutically acceptable salt thereof and memantine or a pharmaceutically acceptable salt thereof as an active ingredient. To provide a method.
  • Immediate-release pharmaceutical compositions for the prevention or treatment of dementia and cognitive impairment of the present invention for achieving the above object is donepezil or pharmaceutically acceptable granulated by memantine or a pharmaceutically acceptable salt thereof and a wet process. It may be in the form of a tablet directly compressed, including the salt.
  • the granulated donepezil or a pharmaceutically acceptable salt thereof may be contained in an amount of 1 to 20% by weight.
  • the granulated donepezil or a pharmaceutically acceptable salt thereof and memantine or a pharmaceutically acceptable salt thereof may be mixed in a weight ratio of 1: 0.8-5.
  • Particle distribution of the granulated donepezil or a pharmaceutically acceptable salt thereof may have a d (0.5) of 120 ⁇ 200 ⁇ m.
  • the particle size of the granulated donepezil or a pharmaceutically acceptable salt thereof is 15 to 25% by weight of 20 mesh or more and less than 50 mesh, 25 to 35% by weight of 50 mesh or more and less than 80 mesh, and 80 to 200 20-30 wt% less than mesh and 15-25 wt% of 200 mesh or more,
  • the content of particles of 20 mesh or more to less than 50 mesh may be less than the content of particles of 200 mesh or more.
  • the particle size of the granulated donepezil or a pharmaceutically acceptable salt thereof may be 5 to 15% by weight of 20 mesh.
  • the pharmaceutical composition may further include an excipient.
  • the excipient may be a mixture of lactose and microcrystalline cellulose in a weight ratio of 3-20: 1.
  • the excipient may be one containing at least 50% by weight of particles of 80 mesh or more.
  • the method for producing a rapid-release pharmaceutical composition for the prevention or treatment of dementia and cognitive impairment of the present invention for achieving the above another object comprises the steps of granulating donepezil or a pharmaceutically acceptable salt thereof in a wet process;
  • the pharmaceutical composition for preventing or treating dementia and cognitive impairment of the present invention is prepared by directly compressing a mixture of donepezil or a pharmaceutically acceptable salt thereof and memantine or a pharmaceutically acceptable salt thereof granulated by a wet process.
  • aricept donepezil hydrochloride
  • ebixa memantine hydrochloride
  • the pharmaceutical composition of the present invention by selecting an excipient having a particle size similar to the particles of the active ingredient to ensure the uniformity of content, to suppress the generation of the flexible material to increase the stability, and to improve the drug compliance more.
  • Figure 1a is a graph measuring the dissolution rate of donepezil hydrochloride of the commercial tablet of the control group 1, the mixed control tablets 1 and 2 and the composite tablet prepared in Example 1 over time
  • Figure 1b is a control 2 over time It is a graph measuring the dissolution rate of memantine hydrochloride of the mixed tablet prepared in the commercially available, control 1 and 2 and the composite tablet prepared in Example 1.
  • Figure 2a is a graph measuring the dissolution rate of donepezil hydrochloride of the composite tablet prepared in Examples 1 to 4 over time
  • Figure 2b is the dissolution rate of memantine hydrochloride of the composite tablet prepared in Examples 1 to 4 over time Is a graph measured.
  • Figure 3a is a graph showing the particle size of the donepezil granules of Example 1
  • Figure 3b is a graph showing the particle size of the donepezil granules of Example 2
  • Figure 3c is a particle size of the donepezil granules of Example 3
  • Figure 3d is a graph showing the particle size of the donepezil granules of Example 4.
  • Figure 4a is a graph measuring the dissolution rate of donepezil hydrochloride of the tablets prepared in Control 1, Comparative Examples 2 and 3 over time
  • Figure 4b is a Meman of the tablets prepared in Control 1, Comparative Examples 2 and 3 over time It is a graph which measured the dissolution rate of chitin hydrochloride.
  • Figure 5a is a graph showing the particle size of the SD lactose
  • Figure 5b is a graph showing the particle size of the lactose hydrate
  • Figure 5c is a graph showing the particle size of vivapur 12 is a microcrystalline cellulose
  • Figure 5d is a microcrystalline cellulose MCC 102 This graph shows the particle size of.
  • Figure 6 is a graph showing the fractionation of the fractionated particle size of the composite tablet prepared according to Example 1 using the lactose and microcrystalline cellulose having a particle size of the above.
  • the present invention relates to a rapid-release pharmaceutical composition for the prevention or treatment of dementia and cognitive impairment, including donepezil or a pharmaceutically acceptable salt thereof and memantine or a pharmaceutically acceptable salt thereof, and a method for preparing the same.
  • Donepezil hydrochloride is formulated and currently marketed under the trade name 'Aricept' (containing 5 mg and 10 mg of Donepezil hydrochloride), and memantine hydrochloride is formulated and now sold under the trade name 'Ebixa' (including 10 mg of memantine hydrochloride). It is sold.
  • In vitro (elution test) test results of commercially available acept and Ebik, Ebik obtained the same result with a single dissolution rate and a compound dissolution rate (Aricept + Ebik), but in the case of Aricept, a single dissolution rate and a compound dissolution rate (Aricept + Ebik) ) Is found to drop significantly.
  • Donepezil or its pharmaceutically acceptable salts inhibit the initial 5-minute dissolution rate to less than 35% due to the characteristics of active ingredients with high frequency of side effects such as nausea, vomiting and diarrhea of the digestive system and muscle cramps, fatigue and dizziness It is preferable to make it.
  • the high solubility of BCS in tablets in the form of a homogeneous mixture without splitting such as donepezil or a pharmaceutically acceptable salt thereof and memantine or a pharmaceutically acceptable salt thereof, such as bilayer or multilayer tablets Biopharmaceutics Classification System
  • wet granulation was performed in order to suppress the initial dissolution rate of donepezil, and in order to improve the composite preparation (aricept + Evica) in which the dissolution rate of donepezil was lowered by more than 20% in 15 minutes, donepezil Or particle size of pharmaceutically acceptable salts thereof.
  • Korean Patent Laid-Open Publication No. 2009-0016611 discloses that when the memantine is manufactured by a direct compression method, the content uniformity is lowered, and the tableting and capping problems occur, resulting in granulation of the memantine by a wet process.
  • the present invention while maintaining the benefits (tableting, mixing uniformity, capping) obtained by performing the memantine wet process was prepared by a direct compression method that can reduce the cost and time.
  • the preparation of a composite formulation by mixing the donepezil or its pharmaceutically acceptable salts and memantine or its pharmaceutically acceptable salts directly and compressing can simplify the manufacturing process to reduce costs and time, However, it may be difficult to reduce the dissolution rate during the initial 5 minutes of donepezil.
  • the present inventors have improved the therapeutic effect by synergistic interaction between co-drugs including Donepezil or its pharmaceutically acceptable salts and memantine or its pharmaceutically acceptable salts with different mechanisms of action.
  • the dissolution rate of was similar to the commercially available Donepezil and memantine commercially secured, the tableting properties and the generation of decomposition products (flexible material) with very little storage of the present invention was completed.
  • the immediate release pharmaceutical composition for preventing or treating dementia and cognitive impairment of the present invention is directly compressed by including memantine or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt thereof granulated by a wet process.
  • memantine or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt thereof granulated by a wet process.
  • the method for producing a rapid-release pharmaceutical composition for preventing or treating dementia and cognitive impairment of the present invention comprises the steps of granulating donepezil or a pharmaceutically acceptable salt thereof by a wet process; And directly compressing and homogenizing the mixture of memantine or a pharmaceutically acceptable salt thereof added to the granulated donepezil or a pharmaceutically acceptable salt thereof.
  • the flexible substance may increase rapidly due to physicochemical properties, and thus, the present invention is directed to donepezil or a pharmaceutically acceptable salt thereof.
  • Granulation is carried out in a wet process, followed by direct compression by adding memantine or a pharmaceutically acceptable salt and additives thereof.
  • the present invention controls the initial dissolution rate of donepezil or its pharmaceutically acceptable salts by granulating the donepezil or its pharmaceutically acceptable salts in a wet process. That is, donepezil or its pharmaceutically acceptable salts are granulated by the wet process and then mixed directly with memantine or its pharmaceutically acceptable salts to be compressed directly for the first 5 minutes. This elution can be suppressed. Preferably, the initial 5-minute elution can be suppressed to 35% or less.
  • the donepezil is a compound having the chemical name '1-benzyl-4-[(5,6-dimethoxy-1-indanon) -2-ylmethyl] piperidine', and donepezil or a pharmaceutical thereof.
  • the acceptable salts are known to be useful drugs for the prevention of senile dementia, in particular for the prevention and treatment of Alzheimer's disease.
  • the pharmaceutically acceptable salt of donepezil is not particularly limited, but any of them may be used to increase the solubility of donepezil, and may preferably be an acid addition salt.
  • the pharmaceutically acceptable salts should be low toxic to the human body and not adversely affect the biological activity and physicochemical properties of the parent compound.
  • the free acid that can be used to prepare the pharmaceutically acceptable salt can be divided into inorganic and organic acids.
  • the inorganic acid may be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, or the like.
  • Organic acids include acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, Benzoic acid, embonic acid, aspartic acid, glutamic acid and the like can be used.
  • Organic bases that can be used for the preparation of organic base addition salts are tris (hydroxymethyl) methylamine, dicyclohexylamine and the like.
  • Amino acids that can be used to prepare amino acid addition bases are natural amino acids such as alanine, glycine and the like.
  • Donepezil according to the present invention may also include all hydrates and solvates as well as pharmaceutically acceptable salts.
  • the hydrate or solvate may be crystallized or recrystallized after dissolving the donepezil in a solvent which may be mixed with water such as methanol, ethanol, acetone, 1,4-dioxane and then adding a free acid or free base. .
  • solvates particularly hydrates
  • the compounds of the present invention may also include stoichiometric solvates, including hydrates, in addition to various amounts of water-containing compounds that may be prepared by methods such as lyophilization.
  • the pharmaceutically acceptable salt of the donepezil may be preferably a hydrochloride salt.
  • the donepezil or a pharmaceutically acceptable salt thereof is contained in the pharmaceutical composition of the present invention in an amount of 1 to 20% by weight, preferably 2 to 10% by weight. If the content of donepezil or a pharmaceutically acceptable salt thereof is less than the lower limit, the combined tablet may have a mass of 521.5 mg or more, which may cause a problem in inability to take the drug. If the upper limit exceeds the upper limit, the combined tablet may have a mass of 104.3. It may not be easy to prepare a co-formulation with memantine or a pharmaceutically acceptable salt thereof by less than mg.
  • the donepezil or a pharmaceutically acceptable salt thereof is granulated by a wet process, characterized by the active ingredient with high frequency of side effects of the nervous system such as nausea, vomiting, diarrhea and muscle nervous system side effects, fatigue, dizziness, Initial 5-minute elution was suppressed to 35% or less, to be on par with the commercially available donepezil drug (Aricept).
  • a composition may be prepared in which the digestive system side effects such as nausea, vomiting and diarrhea and mental nervous system side effects such as muscle spasms, fatigue, and dizziness appear.
  • the method of granulating with the wet process comprises granulating in done liquid one or more selected from donepezil or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable first additive, preferably an excipient, a binder, a diluent and a disintegrant. Forming granules and drying and oscillating the granules.
  • a pharmaceutically acceptable first additive preferably an excipient, a binder, a diluent and a disintegrant.
  • the excipient may include, but is not limited to, one or more selected from the group consisting of lactose, microcrystalline cellulose, mannitol, starch and corn starch;
  • the binder may include, but is not limited to, one or more selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl methyl cellulose, hydroxy propyl cellulose, ethyl cellulose and methyl cellulose;
  • the diluents include calcium phosphate (dibasic and / or tribasic), calcium sulfate, powdered cellulose, dexrate, dextrin, fructose, kaolin, lactitol, lactose, maltose, mannitol, microcrystalline cellulose, sorbitol, May include, but is not limited to, one or more of starch and sucrose;
  • the disintegrant may include, but is not limited to, croscarmellose sodium, crospovid
  • the present invention adds memantine or a pharmaceutically acceptable salt thereof and a second additive to the granulated donepezil or a pharmaceutically acceptable salt thereof to directly compress and homogenize the mixed mixture, whereby Make it evenly distributed.
  • Memantine is a compound with the chemical name '3,5-dimethyladamantane-1-amine' and is reported as an orally active NMDA receptor antagonist, and memantine or a pharmaceutically acceptable salt thereof is Alzheimer's. It is known to be a useful drug for the prevention and treatment of dementia diseases.
  • the pharmaceutically acceptable salt of memantine is not particularly limited, but may be any one for increasing solubility of donepezil, preferably acid addition salt, and more preferably hydrochloride salt. have.
  • the donepezil or a pharmaceutically acceptable salt thereof and the memantine or a pharmaceutically acceptable salt thereof are mixed in a weight ratio of 1: 0.8 to 5, preferably in a weight ratio of 1: 1 to 3. If the content of memantine or its pharmaceutically acceptable salts, based on donepezil or its pharmaceutically acceptable salts, is outside of the above ranges, then you may experience side effects such as nausea, vomiting, diarrhea and gastrointestinal side effects such as muscle spasms, fatigue, and dizziness. Nervous system side effects may occur.
  • the mixture of the memantine or a pharmaceutically acceptable salt, additive and granulated Donepezil or a pharmaceutically acceptable salt thereof is homogenized by a direct compression process, instead of a direct compression process, a wet process or a direct In the case of performing the direct pressing process after the wet process instead of the pressing process, a large amount of the flexible material is generated.
  • the method of homogenizing by the direct compression process is to directly compress the components without physical change of the composite, and the compression by the rotary tablet press homogenizes the powder by the upper and lower punches, and then reduces the homogenized material to granule size and compresses it. It includes a step.
  • the second additive may be at least one selected from pharmaceutically acceptable excipients, binders, lubricants and coating bases.
  • the scope of the present invention is not limited to the use of the second additive, and in addition to the additives described above, additives commonly used by a person skilled in the art may be used within the scope of not impairing the effects of the present invention.
  • the kind of the excipient and the binder is the same as the kind described in the first additive;
  • the lubricant may include, but is not limited to, one or more of colloidal silicon dioxide, hydrous silicon dioxide, magnesium stearate, and sodium stearyl fumarate;
  • the coating base may include, but is not limited to, one or more of hydroxypropylmethyl cellulose, polyvinylpyrrolidone, copovidone, Opadry series and Eudragit series.
  • Memantine or pharmaceutically acceptable salts thereof present in particulate form in this step are mixed with relatively large particles of donepezil or pharmaceutically acceptable salts thereof in order to be homogeneously mixed with the excipients of the particulates and the relatively large particle excipients. Dispersion mixing should be performed by adding mixed excipient.
  • the excipient of the microparticles contained in the mixed excipient should have a particle size similar to memantine or a pharmaceutically acceptable salt thereof present in the particulate form, and the relatively large excipient contained in the mixed excipient may be relatively Particle sizes should be similar to those of large donepezil or pharmaceutically acceptable salts thereof, each particle size of excipients contained in the mixed excipient is memantine or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt thereof. If not similar to a possible salt, the complex saccharide comprising memantine or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt thereof may not satisfy the tolerance in terms of content uniformity.
  • the particle distribution d (0.5) value of the excipient is donepezil d (0.5).
  • the particle distribution d (0.5) value of the excipient relative to the d (0.5) value (memantine d (0.5) ⁇ m) of the tin or its pharmaceutically acceptable salt is memantine d (0.5) ⁇ m ⁇ 55 to 60 ⁇ m, d
  • the particle distribution d (0.9) value of the excipient relative to the (0.9) value (memantine d (0.9) ⁇ m) is memantine d (0.9) ⁇ m ⁇ 90 to 95 ⁇ m, while at the same time memantine or a pharmaceutically acceptable salt thereof.
  • the difference in d (0.5) and donepezil or a pharmaceutically acceptable salt thereof is 100, the difference in d (0.5) of each particle distribution of the excipients contained in the mixed excipient is within 93. 105 and the difference in d (0.9) between memantine or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable salt is 100, the difference in d (0.9) of each particle distribution of excipients in the mixed excipient It is preferable that the value is 30-50.
  • the d (0.5) and d (0.9) means a size value corresponding to 50%, 90% of the highest value in the cumulative distribution measured by the particle size analyzer.
  • the specific surface area increases and adhesion cohesion between the powders increases.
  • the active ingredient of the small particles may not be mixed evenly with the excipient but may be partially agglomerated or scattered on a part, resulting in uneven mixing. This is caused, and the same phenomenon occurs in the reverse case.
  • the distribution of the wet granulated particles in order to make the 5-minute dissolution rate of Donepezil or its pharmaceutically acceptable salt 35% or less is preferably d (0.5) of 120 to 200 ⁇ m. If d (0.5) is less than the lower limit, the dissolution rate is over 35% at the initial dissolution time of 5 minutes. If the upper limit is exceeded, the dissolution rate at the initial dissolution time of 5 minutes does not exceed 35%. It shows a 70% dissolution rate that is significantly lower than the Aricept dissolution rate (85%).
  • the particle size of the donepezil or a pharmaceutically acceptable salt thereof is 15 to 25% by weight of at least 20 mesh and less than 50 mesh, 25 to 35% by weight of at least 50 mesh and less than 80 mesh, and 80 to 200 mesh. Less than 20 to 30% by weight and more than 200 mesh to 15 to 25% by weight indicates an dissolution rate of not more than 35% at the time of the initial dissolution 5 minutes. More preferably, the content of the particles of 20 mesh or more and less than 50 mesh is less than the content of the particles of 200 mesh or more, and the dissolution rate of the 15-minute dissolution rate is 85% while the dissolution rate is less than 35% at the initial 5 minutes. Higher than).
  • a spray-dried lactose (d (0.1) 23.1 ⁇ m, d (0.5) 69.2 um, d (0.9) 164.9 ⁇ m), Microcrystalline Cellulose, Vivapur 12; d (0.1) 153.5 ⁇ m, d (0.5) 193.0 ⁇ m, d (0.9) 386.7 ⁇ m
  • the content uniformity was secured by adjusting the ratio of h).
  • the weight ratio of the lactose and microcrystalline cellulose is 3-20: 1, preferably 5-15: 1. If the content of lactose based on the microcrystalline cellulose is outside the above range, it may be difficult to suppress the 5-minute dissolution rate of donepezil or a pharmaceutically acceptable salt thereof to 35% or less.
  • the pharmaceutical composition of the present invention inhibits the dissolution of donepezil or its pharmaceutically acceptable salts to 35% or less for the first 5 minutes in an eluate condition of pH 1.2, and the first 5 minutes of memantine or its pharmaceutically acceptable salts. Allow at least 60% to dissolve.
  • the pharmaceutical composition of the present invention is donepezil or a pharmaceutically acceptable salt thereof is eluted at least 75%, preferably at least 80% of the total weight of the active ingredient after 15 minutes, memantine or All of the pharmaceutically acceptable salts thereof are at least 85%, preferably 85 to 95% of the total weight of the active ingredient after 15 minutes; After 30 minutes more than 90% of the total weight of the active ingredient is eluted.
  • the chosen level of administration of the composition will depend on the activity of the compound, the route of administration, the severity of the condition being treated and the condition and previous history of the patient being treated. However, it is within the knowledge of the art to start with a dose of the compound at a lower level than required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved, with the preferred dosage being age, sex , Body shape and weight.
  • the composition may be further processed before being formulated into a pharmaceutically acceptable pharmaceutical formulation, and may preferably be ground or ground into smaller particles.
  • the composition will also vary depending on the condition and the patient being treated, but this can be determined non-originally.
  • Control group 2 Commercially available Ebiksa 10 mg X 2
  • Example 1 was prepared to satisfy 10 mg of donepezil hydrochloride, 20 mg of memantine hydrochloride.
  • Example 2 The same procedure as in Example 1 was carried out, but the mixture was filtered through an oscillator 16 mesh to obtain a donepezil formulation.
  • Example 2 The same procedure as in Example 1 was carried out, except that the mixture was filtered through an oscillator 25 mesh to obtain a donepezil formulation.
  • Example 2 The same procedure as in Example 1 was carried out, but the mixture was filtered through an oscillator 30 mesh to obtain a donepezil formulation.
  • Example 2 was also prepared to satisfy 10 mg of donepezil hydrochloride, 20 mg of memantine hydrochloride.
  • the donepezil hydrochloride mixture and the memantine hydrochloride mixture were dried at 60 ° C. for 2 hours, sieved by an oscillator, filtered through 20 mesh, mixed by adding 48 g of Vivapur 12 filtered through 20 mesh, and 16 g of magnesium stearate was added. Was added and mixed. Thereafter, the mixture of donepezil and memantine was compressed by a rotary tablet press, and then compressed into a film using Opadry 40 g coating base.
  • Donepezil hydrochloride monohydrate 41.72 g, mannitol 480 g, hypromellose 20 g, memantine 80 g, hydroxypropyl cellulose 20 g, SD lactose 492 g, Vivapur 12 48 g were mixed with 20 mesh, followed by stearic acid 16 g additional magnesium was added and mixed. Thereafter, the mixture of donepezil and memantine was compressed by a rotary tablet press, and then compressed into a film using Opadry 40 g coating base.
  • the dissolution test was performed on the composite tablets prepared in Controls 1 and 2 and Example 1 under the following conditions.
  • Control 1 Control 1 (Aricept 10 mg) single elution
  • Control Group 2 Control Group 2 (Evica 10 mg X 2 tablets) Single Elution
  • Control 1, 2 Control 1 (Aricept 10 mg) and Control 2 (Ebixa 10 mg X 2 tablets) by simple mixing simultaneously simultaneous elution
  • Figure 1a is a graph measuring the dissolution rate of donepezil hydrochloride of the commercial tablet of the control group 1, the mixed control tablets 1 and 2 and the composite tablet prepared in Example 1 over time
  • Figure 1b is a control 2 over time It is a graph measuring the dissolution rate of memantine hydrochloride of the mixed tablet prepared in the commercially available, control 1 and 2 and the composite tablet prepared in Example 1.
  • Control 1 elutes less than 35% for the first 5 minutes and at least 80% for 15 minutes. However, when simultaneous simultaneous dissolution of the control groups 1 and 2 was eluted at less than 35% for the first 5 minutes, the dissolution rate was lowered due to physical interference of the control group 2 due to eluting at less than 60% for 15 minutes. It was.
  • Example 1 shows that when eluting undivided and homogeneously mixed Donepezil hydrochloride and memantine hydrochloride simultaneously, less than 35% of Donepezil is eluted for 5 minutes, 80% or more for 15 minutes, and memantine is dissolved for 5 minutes. It was confirmed that more than 60%, eluted at least 90% for 15 minutes.
  • the composite tablet prepared according to Example 1 of the present invention similar to the commercially available control 1 inhibits the donepezil hydrochloride to be eluted to less than 35% for the first 5 minutes, Similar to 2, memantine hydrochloride was prepared to elute at least 60% in the first 5 minutes.
  • the composite tablet prepared according to Example 1 was confirmed that 87% of the donepezil hydrochloride eluted at 15 minutes, 97% at 30 minutes, memantine hydrochloride was eluted at 90% at 15 minutes, at 30 minutes It was confirmed that 95% eluted.
  • the composite tablet prepared according to Example 1 of the present invention improved the dissolution rate of donepezil, which may occur when co-administration of commercially available acept (Control 1) and Ebik (Control 2), and donepezil hydrochloride. And memantine hydrochloride were both eluted with a similar dissolution pattern as the tablets of each control group commercially available.
  • Figure 2a is a graph measuring the dissolution rate of donepezil hydrochloride of the composite tablet prepared in Examples 1 to 4 over time
  • Figure 2b is a memantine hydrochloride of the composite tablet prepared in Examples 1 to 4 over time It is a graph measuring the dissolution rate of.
  • Table 2 shows the dissolution rate of donepezil hydrochloride numerically
  • Table 3 shows the dissolution rate of memantine hydrochloride numerically.
  • Example 2 the co-formulation of Example 2 was confirmed that the dissolution rate of the donepezil is less than 35% for 5 minutes, but eluted after 15 minutes because 71% eluted for 15 minutes; Memantine was eluted at 60% or less for 5 minutes and 90% or more for 15 minutes, so the initial dissolution rate was confirmed to be low.
  • Examples 3 and 4 confirmed that the initial dissolution rate was high because Donepezil eluted at least 35% for 5 minutes, 90% or more for 15 minutes; It was confirmed that memantine eluted at least 60% for 5 minutes and at least 90% for 15 minutes.
  • the co-formulation of Examples 2 to 4 inhibits the dissolution of donepezil hydrochloride in less than 35% for the first 5 minutes, similar to the control 1 commercially available, and similar to the control 2 memantine hydrochloride It was not prepared to elute more than 60% in this initial 5 minutes.
  • Figure 3a is a graph showing the particle size of the donepezil granules of Example 1
  • Figure 3b is a graph showing the particle size of the donepezil granules of Example 2
  • Figure 3c is a particle of the donepezil granules of Example 3 It is a graph showing the size
  • Figure 3d is a graph showing the particle size of the donepezil granules of Example 4.
  • Figure 4a is a graph measuring the dissolution rate of donepezil hydrochloride of the tablet prepared in Control 1, Comparative Examples 2 and 3 over time
  • Figure 4b is a tablet prepared in Control 1, Comparative Examples 2 and 3 over time It is the graph which measured the dissolution rate of memantine hydrochloride of.
  • Table 4 shows the dissolution rate of donepezil hydrochloride numerically
  • Table 5 shows the dissolution rate of memantine hydrochloride numerically.
  • the composite tablets prepared in Examples and Comparative Examples were subjected to accelerated stability tests by applying aluminum (Alu-Alu) packaging under 40 and 75% relative humidity, and the total amount of the flexible substance with time by gas chromatography every two weeks. (%) was analyzed.
  • the composite tablet prepared according to Example 1 was confirmed to have a similar substance content as the commercial controls 1 and 2.
  • Formulation uniformity test is a test method to show the uniform degree of the main component content between individual formulations.
  • the main component content of each formulation was measured by an appropriate method to calculate a judgment value (based on the judgment value: judged that the content uniformity was secured when it was 15 or less).
  • the determination value is calculated according to the following [Equation 1] of the formulation uniformity test method of the Korean Pharmacopoeia general test method.
  • M 98.5% when average content is less than 98.5%
  • Table 8 is a table showing the content uniformity of donepezil
  • Table 9 is a table showing the memantine content uniformity.
  • Example 1 using excipients having similar particle distributions as donepezil hydrochloride and memantine hydrochloride compared to excipients with donepezil hydrochloride granules and excipients having particle distributions not similar to memantine hydrochloride.
  • Figure 5a is a graph showing the particle size of the SD lactose
  • Figure 5b is a graph showing the particle size of the lactose hydrate
  • Figure 5c is a graph showing the particle size of vivapur 12 is a microcrystalline cellulose
  • Figure 5d is a microcrystalline cellulose MCC 102 This graph shows the particle size of.
  • Figure 6 is a graph showing the fractionation classification size of the composite tablet prepared according to Example 1 using the lactose and microcrystalline cellulose having the above particle size.
  • the pharmaceutical composition for preventing or treating dementia and cognitive dysfunction of the present invention has a reduced efficacy due to the dissolution of the donepezil active ingredient when co-administration of aricept (donepezil hydrochloride) and ebixa (memantine hydrochloride) commercially available.
  • aricept donepezil hydrochloride
  • ebixa memantine hydrochloride

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Abstract

La présente invention concerne une composition pharmaceutique pour la prévention ou le traitement d'une démence et d'un dysfonctionnement cognitif, contenant du donépézil ou un sel de qualité pharmaceutique de celui-ci et de la mémantine ou un sel de qualité pharmaceutique de celle-ci, et son procédé de préparation, le procédé comprenant les étapes suivantes : granulation du donépézil ou d'un sel de qualité pharmaceutique de celui-ci par un procédé par voie humide ; et compression directe d'un mélange dans lequel de la mémantine ou un sel de qualité pharmaceutique de celle-ci est ajouté au donépézil ou au sel de qualité pharmaceutique de celui-ci granulé, cela étant suivi d'une homogénéisation du mélange, de manière à résoudre le problème qui fait que l'efficacité du principe actif, le donépézil, peut être réduite en raison d'un phénomène de dégradation de la dissolution lorsque de l'Aricept (chlorhydrate de donépézil) et de l'Ebixa (chlorhydrate de mémantine), qui sont classiquement disponibles sur le marché, sont co-administrés, et à assurer une uniformisation des quantités en choisissant un excipient ayant une taille de particule similaire à celle des particules de principe actif. De plus, la présente composition pharmaceutique de la présente invention est très stable et présente une faible teneur en impuretés.
PCT/KR2017/010953 2016-09-30 2017-09-29 Composition pharmaceutique pour la prévention ou le traitement d'une démence et d'un dysfonctionnement cognitif, contenant du donépézil ou un sel de qualité pharmaceutique de celui-ci et de la mémantine ou un sel de qualité pharmaceutique de celle-ci, et son procédé de préparation WO2018062941A1 (fr)

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EP17856827.5A EP3520792A4 (fr) 2016-09-30 2017-09-29 Composition pharmaceutique pour la prévention ou le traitement d'une démence et d'un dysfonctionnement cognitif, contenant du donépézil ou un sel de qualité pharmaceutique de celui-ci et de la mémantine ou un sel de qualité pharmaceutique de celle-ci, et son procédé de préparation
CN201780069152.9A CN110573156B (zh) 2016-09-30 2017-09-29 用于预防或治疗痴呆和认知功能障碍、含有多奈哌齐或其药学上可接受的盐和美金刚或其药学上可接受的盐的药物组合物，及其制备方法
JP2019539722A JP6887506B2 (ja) 2016-09-30 2017-09-29 ドネペジル又はその薬学的に許容可能な塩及びメマンチン又はその薬学的に許容可能な塩を含む認知症（ｄｅｍｅｎｔｉａ）及び認知機能障害の予防又は治療用薬学組成物及びその製造方法

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KR10-2016-0126230 2016-09-30
KR20160126230 2016-09-30
KR1020170125220A KR101938872B1 (ko) 2016-09-30 2017-09-27 도네페질 또는 그의 약학적으로 허용 가능한 염 및 메만틴 또는 그의 약학적으로 허용 가능한 염을 함유하는 치매 및 인지기능 장애 예방 또는 치료용 약학 조성물 및 이의 제조방법
KR10-2017-0125220 2017-09-27

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KR20050024296A (ko) * 2002-05-31 2005-03-10 하. 룬트벡 아크티에 셀스카브 알츠하이머 질환의 치료용 ｎｍｄａ 길항제 및 아세틸콜린에스테라제 억제제의 조합물
US20060160852A1 (en) * 2004-12-27 2006-07-20 Eisai Co. Ltd. Composition containing anti-dementia drug
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KR101406456B1 (ko) * 2005-04-06 2014-06-20 아다마스 파마슈티칼스, 인코포레이티드 Ｃｎｓ 장애의 치료를 위한 방법 및 조성물

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US20060160852A1 (en) * 2004-12-27 2006-07-20 Eisai Co. Ltd. Composition containing anti-dementia drug
KR101406456B1 (ko) * 2005-04-06 2014-06-20 아다마스 파마슈티칼스, 인코포레이티드 Ｃｎｓ 장애의 치료를 위한 방법 및 조성물
KR101213345B1 (ko) * 2005-04-28 2012-12-17 에자이 알앤드디 매니지먼트 가부시키가이샤 항치매약을 함유하는 조성물
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Publication number Priority date Publication date Assignee Title
WO2020240505A1 (fr) * 2019-05-31 2020-12-03 TECNIMEDE - Sociedade Técnico-medicinal, SA Combinaison à dose fixe et à libération immédiate de mémantine et de donépézil
EP4238555A3 (fr) * 2019-05-31 2023-09-20 Tecnimede, Sociedade Técnico-Medicinal, SA Combinaison à dose fixe et à libération immédiate de mémantine et de donépézil

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