A composition of donepezil, microtablets and a preparation method and application thereof

Abstract

The application provides a donepezil composition, microtablet and preparation method and application thereof, and belongs to the technical field of medicines.The composition comprises donepezil or a pharmaceutically acceptable salt thereof and a crystal form stabilizer, and the crystal form stabilizer comprises povidone and propylene glycol.The microtablet comprises a sustained-release layer and an immediate-release layer, the sustained-release layer contains memantine or a pharmaceutically acceptable salt thereof, and the immediate-release layer comprises donepezil or a pharmaceutically acceptable salt thereof and a crystal form stabilizer, and the crystal form stabilizer comprises povidone and propylene glycol.The crystal form of donepezil or the pharmaceutically acceptable salt thereof in the composition and the microtablet is stable;the microtablet has small tablet weight, small volume, good uniformity, convenient use and good use compliance.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a donepezil composition, microplates, preparation method and application thereof. Background Technology

[0002] Alzheimer's disease (AD), also known as Alzheimer's disease, senile dementia, or brain degeneration, is a persistent neurological disorder characterized by progressively worsening cognitive impairment (memory impairment, learning disabilities, attention deficit, spatial cognitive function, and problem-solving abilities), leading to a gradual inability to adapt to society and eventually making it impossible to perform simple daily tasks independently. Symptoms may include rigidity or flexion paralysis of the limbs, sphincter dysfunction, and often systemic complications such as lung infections, urinary tract infections, pressure sores, and systemic failure symptoms, ultimately resulting in death from these complications.

[0003] The "Guidelines for the Diagnosis and Treatment of Alzheimer's Disease and Dementia in China (2020 Edition)" published by the Alzheimer's Disease Branch (ADC) Guidelines Group of the Chinese Association for Geriatric Health Care states that for patients with moderate to severe Alzheimer's disease, the combination of a cholinesterase inhibitor and mimantine can lead to better cognition, daily living abilities, and social functioning, and improve psychosocial symptoms. Multiple studies have also shown that the combination of mimantine and a cholinesterase inhibitor can significantly delay hospitalization for Alzheimer's patients. Furthermore, it has been proven that patients with moderate to severe AD experience better treatment outcomes when treated with mimantine hydrochloride in combination with donepezil hydrochloride.

[0004] Existing compound sustained-release formulations for Alzheimer's disease primarily employ technologies including microcapsule membrane control and microcapsule / granule co-filling. Existing microcapsule membrane control technology suffers from several problems. It cannot precisely control the particle size of each microcapsule, typically allowing for a wide range. Experiments have shown that within a batch of 710-850 micrometer membrane-controlled microcapsules, the release difference between 710-micrometer and 850-micrometer membrane-controlled microcapsules is significant (similarity factor f² < 50), indicating poor uniformity and a substantial potential risk to safety and efficacy. Existing microcapsule / granule co-filling technology requires modification to specialized capsule filling equipment, with one hopper for microcapsules and another for granules. This technology results in large variations in filling volume, difficulty in monitoring the production process, low yield, and slow production speed. Furthermore, for patients with swallowing difficulties, the significant difference in properties between microcapsules and granules makes them difficult to dissolve after opening the capsule, leading to potential loss.

[0005] Therefore, there is still an urgent need for a drug for treating Alzheimer's disease that is easy to use, has good patient compliance, and releases uniformly. Summary of the Invention

[0006] To address the aforementioned technical problems, the inventors unexpectedly discovered that using microtablets (1-2 mm in diameter and 1-2 mm in height) allows for sustained-release effects with only a small amount of sustained-release matrix material, reducing the dosage weight. Furthermore, the microtablets are pressed using a special die, resulting in uniform external dimensions and minimal release variation per tablet (similarity factor f² greater than 80). This also offers advantages in terms of compliance when using only one microtablet form for capsule filling and clinical use. Additionally, the inventors creatively discovered that coating donepezil hydrochloride onto the surface of the microtablets, using a combination of povidone and propylene glycol, improves the stability of the donepezil hydrochloride coating crystal form during production and storage. Therefore, to achieve the above technical objectives, this invention provides a composition, microtablets, a method for their preparation, and their applications.

[0007] In a first aspect, the present invention provides a composition.

[0008] A composition comprising donepezil or a pharmaceutically acceptable salt thereof and a crystal form stabilizer, said crystal form stabilizer comprising povidone and propylene glycol. The use of povidone and propylene glycol as crystal form stabilizers is beneficial for improving the crystal form stability of donepezil hydrochloride.

[0009] In some embodiments, the povidone is povidone K30.

[0010] In some embodiments, the composition further includes ammonium manganese or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the pharmaceutically acceptable salt of donepezil is donepezil hydrochloride (2-[(1-benzyl-4-piperidinyl)methyl]-5,6-dimethoxy-2,3-dihydro-1-indanone hydrochloride; CAS No.: 120011-70-3).

[0012] In some embodiments, the pharmaceutically acceptable salt of the memantine is memantine hydrochloride (English name: Memantine hydrochloride; chemical name: 1,3-dimethyl-5-aminoadamantane hydrochloride; CAS number: 41100-52-1).

[0013] In some embodiments, the memantine hydrochloride is in crystalline solid form. In some embodiments, the powder X-ray diffraction pattern of the memantine hydrochloride has characteristic peaks at at least four of the following diffraction angles 2θ: 13.1°, 13.6°, 13.9°, 14.9°, 15.3°, 16.1°, 17.6°, 22.0°, and 22.5°. In some embodiments, the powder X-ray diffraction pattern of the memantine hydrochloride has characteristic peaks at the following diffraction angles 2θ: 13.1°, 13.6°, 13.9°, and 14.9°. In some embodiments, the powder X-ray diffraction pattern of the memantine hydrochloride has characteristic peaks at the following diffraction angles 2θ: 13.1°, 13.6°, 13.9°, 14.9°, 15.3°, 16.1°, 17.6°, 22.0°, and 22.5°.

[0014] In some embodiments, the mass ratio of povidone to propylene glycol is 0.5:2.0 to 2.0:0.5; this range of mass ratios is more conducive to improving the crystal stability of donepezil or its pharmaceutically acceptable salts. In some embodiments, the mass ratio of povidone to propylene glycol is 1.0:1.0.

[0015] In some embodiments, the mass ratio of donepezil or its pharmaceutically acceptable salt to the crystal stabilizer is (5.0–15.0):(2.5–3.6); this range of mass ratios is more conducive to improving the crystal stability of donepezil or its pharmaceutically acceptable salt. In some embodiments, the mass ratio of donepezil or its pharmaceutically acceptable salt to the crystal stabilizer is 8.9:3.6, 5.0:2.5, or 15.0:2.5.

[0016] Secondly, the present invention provides a microchip.

[0017] A microplate comprising a sustained-release layer and an immediate-release layer, the sustained-release layer comprising memantine or a pharmaceutically acceptable salt thereof, the immediate-release layer comprising donepezil or a pharmaceutically acceptable salt thereof, and a crystal form stabilizer comprising povidone and propylene glycol.

[0018] In some embodiments, the sustained-release layer further includes a sustained-release matrix material.

[0019] In some embodiments, the sustained-release layer further includes one or more of fillers, adhesives, lubricants, and flow aids.

[0020] In some embodiments, the sustained-release matrix material comprises behenate glycerol.

[0021] In some embodiments, the filler includes one or more of microcrystalline cellulose, lactose, mannitol, sucrose, and starch.

[0022] In some embodiments, the adhesive includes one or more of hydroxypropyl methylcellulose, ethylcellulose, and starch paste.

[0023] In some embodiments, the lubricant includes one or more of magnesium stearate, stearic acid, hydrogenated castor oil, and polyethylene glycol.

[0024] In some embodiments, the flow aid includes one or more of silica and talc.

[0025] In some embodiments, the immediate-release layer further includes a film-forming material.

[0026] In some embodiments, the film-forming material includes one or more of hydroxypropyl cellulose, polyvinyl alcohol, and ethyl cellulose.

[0027] In some embodiments, the pharmaceutically acceptable salt of the memantine is memantine hydrochloride.

[0028] In some embodiments, the pharmaceutically acceptable salt of donepezil is donepezil hydrochloride.

[0029] In some embodiments, the behenicol glyceride is composed of monoglycerides, diglycerides, and triglycerides.

[0030] In some embodiments, the behenicol glyceride is Compritol 888ATO.

[0031] In some embodiments, the behenate glycerides, calculated by total mass, consist of 8.0 wt%-22.0 wt% monoglycerides, 40.0 wt%-60.0 wt% diglycerides, and 25.0 wt%-35.0 wt% triglycerides; or, calculated by total mass, the behenate glycerides consist of 18.0 wt% ± 1.0 wt% monoglycerides, 52.0 wt% ± 0.6 wt% diglycerides, and the balance being triglycerides.

[0032] In some embodiments, the K value of the povidone is 27.0 to 32.0.

[0033] In some embodiments, the specific rotation of the propylene glycol is [α]D20-15.0°.

[0034] In some embodiments, the microplates are cylindrical with a diameter of 1-2 mm and a height of 1-2 mm; this allows for the use of only a small amount of sustained-release matrix material to achieve a longer sustained-release effect, reducing the weight of the drug and providing unexpected technical benefits. In addition, the microplates are uniform in size, and the release differences between each microplate are minimal (similarity factor f2 is greater than 80).

[0035] In some embodiments, the upper and lower surfaces of the microplate are either planar or convex.

[0036] In some embodiments, the content of behenicol glyceride is 15.0 wt%-35.0 wt% based on the total mass of the microplates. In some embodiments, the content of behenicol glyceride is 26.8 wt%-35.0 wt% based on the total mass of the microplates.

[0037] In some embodiments, the content of the amantadine or its pharmaceutically acceptable salt is 20.0 wt%-30.0 wt% or 25.0 wt% based on the total mass of the microflakes.

[0038] In some embodiments, the content of donepezil or a pharmaceutically acceptable salt thereof is 5.0 wt% to 15.0 wt% or 8.9 wt% based on the total mass of the microplates.

[0039] In some embodiments, the content of povidone is 0.5 wt% to 2.0 wt% or 1.8 wt% based on the total mass of the microsheets.

[0040] In some embodiments, the propylene glycol content is 0.5 wt% to 2.0 wt% or 1.8 wt% based on the total mass of the microsheets.

[0041] In some embodiments, the filler content is 15.0 wt% to 35.0 wt% based on the total mass of the microsheets.

[0042] In some embodiments, the adhesive content is 1.0 wt% to 2.0 wt% or 1.8 wt% based on the total mass of the microsheets.

[0043] In some embodiments, the lubricant content is 0.5 wt% to 1.0 wt% or 0.9 wt%, calculated based on the total mass of the microplates.

[0044] In some embodiments, the content of the flow aid is 0.5 wt% to 1.0 wt% or 0.9 wt% based on the total mass of the microplates.

[0045] In some embodiments, the content of the film-forming material is 5.0 wt% to 15.0 wt% or 8.9 wt% to 10.7 wt% based on the total mass of the microsheets.

[0046] In some embodiments, the mass ratio of the povidone to the propylene glycol is 0.5:2.0 to 2.0:0.5. In some embodiments, the mass ratio of the povidone to the propylene glycol is 1.0:1.0.

[0047] In some embodiments, the mass ratio of donepezil or its pharmaceutically acceptable form to the crystal stabilizer is (5.0–15.0):(2.5–3.6). In some embodiments, the mass ratio of donepezil or its pharmaceutically acceptable form to the crystal stabilizer is 8.9:3.6, 5.0:2.5, or 15.0:2.5.

[0048] In some embodiments, the sustained-release layer comprises memantine hydrochloride, a sustained-release matrix material, a filler, a binder, a lubricant, and a flow aid; the immediate-release layer comprises donepezil hydrochloride, a crystal stabilizer, and a film-forming material; the crystal stabilizer comprises povidone K30 and propylene glycol; the sustained-release matrix material is glyceryl behenate Compritol 888ATO; the filler is microcrystalline cellulose; the binder is hydroxypropyl methylcellulose E5; the lubricant comprises one or more of magnesium stearate, stearic acid, hydrogenated castor oil, and polyethylene glycol; the flow aid comprises one or more of silica and talc; and the film-forming material is hydroxypropyl cellulose.

[0049] In some embodiments, the sustained-release layer comprises memantine hydrochloride, a sustained-release matrix material, a filler, a binder, a lubricant, and a flow aid; the immediate-release layer comprises donepezil hydrochloride, a crystal stabilizer, and a film-forming material; the crystal stabilizer comprises povidone K30 and propylene glycol; the sustained-release matrix material is glyceryl behenate Compritol 888ATO; the filler is microcrystalline cellulose; the binder is hydroxypropyl methylcellulose E5; the lubricant comprises one or more of magnesium stearate, stearic acid, hydrogenated castor oil, and polyethylene glycol; the flow aid comprises one or more of silica and talc; the film-forming material is hydroxypropyl cellulose; based on the total mass of the microsheets, the content of glyceryl behenate is 15.0 wt%-35.0 wt% or 26.8 wt%-35.0 wt%, the content of memantine hydrochloride is 20.0 wt%-30.0 wt%, and the content of donepezil hydrochloride is 5%. The content of the polyvinylpyrrolidone is 0.5wt% to 2.0wt%, the content of the propylene glycol is 0.5wt% to 2.0wt%, the content of the filler is 15.0wt% to 35.0wt%, the content of the adhesive is 1.0wt% to 2.0wt% or 1.8wt%, the content of the lubricant is 0.5wt% to 1.0wt% or 0.9wt%, the content of the flow aid is 0.5wt% to 1.0wt% or 0.9wt%, and the content of the film-forming material is 5.0wt% to 15.0wt%.

[0050] In some embodiments, the sustained-release layer comprises memantine hydrochloride, a sustained-release matrix material, a filler, a binder, a lubricant, and a flow aid; the immediate-release layer comprises donepezil hydrochloride, a crystal stabilizer, and a film-forming material; the crystal stabilizer comprises povidone K30 and propylene glycol; and the sustained-release matrix material is glyceryl behenate (Compritol). 888ATO; the filler is microcrystalline cellulose, the binder is hydroxypropyl methylcellulose E5, the lubricant includes one or more of magnesium stearate, stearic acid, hydrogenated castor oil, and polyethylene glycol; the flow aid includes one or more of silica and talc; the film-forming material is hydroxypropyl cellulose; based on the total mass of the microsheets, the content of glyceryl behenate is 26.8wt%-35.0wt%, the content of memantine hydrochloride is 25.0wt%, the content of donepezil hydrochloride is 8.9wt%, the content of povidone is 1.8wt%, the content of propylene glycol is 1.8wt%, the content of the filler is 15.0wt%-35.0wt%, the content of the binder is 1.8wt%, the content of the lubricant is 0.9wt%, the content of the flow aid is 0.9wt%, and the content of the film-forming material is 8.9wt%-10.7wt%.

[0051] In some embodiments, the sustained-release layer comprises memantine hydrochloride, a sustained-release matrix material, a filler, a binder, a lubricant, and a flow aid; the immediate-release layer comprises donepezil hydrochloride, a crystal stabilizer, and a film-forming material; the crystal stabilizer comprises povidone K30 and propylene glycol; and the sustained-release matrix material is glyceryl behenate (Compritol). 888ATO; the filler is microcrystalline cellulose, the binder is hydroxypropyl methylcellulose E5, the lubricant includes one or more of magnesium stearate, stearic acid, hydrogenated castor oil, and polyethylene glycol; the flow aid includes one or more of silica and talc; the film-forming material is hydroxypropyl cellulose; based on the total mass of the microsheets, the content of glyceryl behenate is 26.8 wt%, the content of memantine hydrochloride is 20.0 wt%-30.0 wt%, the content of donepezil hydrochloride is 5.0 wt%-15.0 wt% or 8.9 wt%, the content of povidone is 0.5 wt%-2.0 wt% or 1.8 wt%, and the content of propylene glycol... The alcohol content is 0.5wt%-2.0wt% or 1.8wt%, and the mass ratio of the polyvinylpyrrolidone to the propylene glycol is 0.5:2.0 to 2.0:0.5 or 1.0:1.0; the mass ratio of donepezil hydrochloride to the crystal stabilizer is (5.0-15.0):(2.5-3.6), 8.9:3.6, 5.0:2.5 or 15.0:2.5; the filler content is 15.0wt%-35.0wt%; the binder content is 1.8wt%; the lubricant content is 0.9wt%; the flow aid content is 0.9wt%; and the film-forming material content is 8.9wt%-10.7wt%.

[0052] In some embodiments, the sustained-release layer comprises memantine hydrochloride, a sustained-release matrix material, a filler, a binder, a lubricant, and a flow aid; the immediate-release layer comprises donepezil hydrochloride, a crystal stabilizer, and a film-forming material; the crystal stabilizer comprises povidone K30 and propylene glycol; and the sustained-release matrix material is glyceryl behenate (Compritol). 888ATO; the filler is microcrystalline cellulose, the binder is hydroxypropyl methylcellulose E5, the lubricant includes one or more of magnesium stearate, stearic acid, hydrogenated castor oil, and polyethylene glycol; the flow aid includes one or more of silica and talc; the film-forming material is hydroxypropyl cellulose; based on the total mass of the microsheets, the content of glyceryl behenate is 26.8 wt%, the content of memantine hydrochloride is 25.0 wt%, the content of donepezil hydrochloride is 8.9 wt%, the content of povidone is 1.8 wt%, the content of propylene glycol is 1.8 wt%, the content of filler is 23.2 wt%, the content of binder is 1.8 wt%, the content of lubricant is 0.9 wt%, the content of flow aid is 0.9 wt%, and the content of film-forming material is 8.9 wt%.

[0053] In some embodiments, the sustained-release layer comprises memantine hydrochloride, a sustained-release matrix material, a filler, a binder, a lubricant, and a flow aid; the immediate-release layer comprises donepezil hydrochloride, a crystal stabilizer, and a film-forming material; the crystal stabilizer comprises povidone K30 and propylene glycol; and the sustained-release matrix material is glyceryl behenate (Compritol). 888ATO; the filler is microcrystalline cellulose, the binder is hydroxypropyl methylcellulose E5, the lubricant includes one or more of magnesium stearate, stearic acid, hydrogenated castor oil, and polyethylene glycol; the flow aid includes one or more of silica and talc; the film-forming material is hydroxypropyl cellulose; based on the total mass of the microsheets, the content of glyceryl behenate is 26.8 wt%, the content of memantine hydrochloride is 20.0 wt%, the content of donepezil hydrochloride is 15.0 wt%, the content of povidone is 0.5 wt%, the content of propylene glycol is 2.0 wt%, the content of filler is 23.2 wt%, the content of binder is 1.8 wt%, the content of lubricant is 0.9 wt%, the content of flow aid is 0.9 wt%, and the content of film-forming material is 8.9 wt%.

[0054] In some embodiments, the sustained-release layer comprises memantine hydrochloride, a sustained-release matrix material, a filler, a binder, a lubricant, and a flow aid; the immediate-release layer comprises donepezil hydrochloride, a crystal stabilizer, and a film-forming material; the crystal stabilizer comprises povidone K30 and propylene glycol; and the sustained-release matrix material is glyceryl behenate (Compritol). 888ATO; the filler is microcrystalline cellulose, the binder is hydroxypropyl methylcellulose E5, the lubricant includes one or more of magnesium stearate, stearic acid, hydrogenated castor oil, and polyethylene glycol; the flow aid includes one or more of silica and talc; the film-forming material is hydroxypropyl cellulose; based on the total mass of the microsheets, the content of glyceryl behenate is 26.8 wt%, the content of memantine hydrochloride is 30.0 wt%, the content of donepezil hydrochloride is 5.0 wt%, the content of povidone is 2.0 wt%, the content of propylene glycol is 0.5 wt%, the content of filler is 23.2 wt%, the content of binder is 1.8 wt%, the content of lubricant is 0.9 wt%, the content of flow aid is 0.9 wt%, and the content of film-forming material is 8.9 wt%.

[0055] In some embodiments, the memantine hydrochloride is in crystalline solid form. In some embodiments, the powder X-ray diffraction pattern of the memantine hydrochloride has characteristic peaks at at least four of the following diffraction angles 2θ: 13.1°, 13.6°, 13.9°, 14.9°, 15.3°, 16.1°, 17.6°, 22.0°, and 22.5°. In some embodiments, the powder X-ray diffraction pattern of the memantine hydrochloride has characteristic peaks at the following diffraction angles 2θ: 13.1°, 13.6°, 13.9°, and 14.9°. In some embodiments, the powder X-ray diffraction pattern of the memantine hydrochloride has characteristic peaks at the following diffraction angles 2θ: 13.1°, 13.6°, 13.9°, 14.9°, 15.3°, 16.1°, 17.6°, 22.0°, and 22.5°.

[0056] In some embodiments, the release characteristics of the microplates in the in vitro release test are as follows: in pH 1.2 sodium chloride / hydrochloric acid buffer, the release of memantine hydrochloride is ≤10% at 1h, 30%–50% at 6h, 55%–75% at 12h, and ≥80% at 24h; the release of donepezil hydrochloride is ≥85% at 10min.

[0057] Thirdly, the present invention provides a method for preparing the aforementioned microplates.

[0058] In some embodiments, a method for preparing the microplates according to the second aspect includes: mixing memantine or a pharmaceutically acceptable salt thereof with a sustained-release matrix material and pressing it into microplates, and then coating the surface of the microplates with donepezil hydrochloride coating film containing a crystal form stabilizer.

[0059] In some embodiments, a method for preparing the microplate described in the second aspect includes:

[0060] Step S1: Mix memantine or its pharmaceutically acceptable salt, sustained-release matrix material and filler, then add an aqueous solution of binder, granulate to obtain wet granules;

[0061] Step S2: Dry the wet granules and granulate them;

[0062] Step S3: Mix the sized wet granules with lubricant and flow aid to obtain mixed granules;

[0063] Step S4: Press the mixed particles using a micro-blade punch to obtain a sustained-release layer;

[0064] Step S5: Mix donepezil or its pharmaceutically acceptable salt, film-forming material and crystal stabilizer with an aqueous ethanol solution to obtain a mixed solution, and coat the surface of the sustained-release layer obtained in step S4 with the mixed solution to obtain the microplate.

[0065] In some embodiments, the aqueous ethanol solution is a 75% vol aqueous ethanol solution.

[0066] Fourthly, the present invention provides an application of the aforementioned composition, the aforementioned microsheets, or the microsheets obtained by the aforementioned preparation method.

[0067] The use of a composition described in the first aspect, a microsheet described in the second aspect, or a microsheet obtained by the preparation method described in the third aspect in the preparation of capsules.

[0068] In some embodiments, the application includes filling the composition of the first aspect, the microplates of the second aspect, or the microplates obtained by the preparation method of the third aspect into a capsule shell to obtain a capsule.

[0069] Beneficial effects

[0070] Compared with the prior art, a certain embodiment of the present invention includes at least one of the following beneficial effects:

[0071] (1) The micro-flakes of the present invention slowly release memantine hydrochloride for 24 hours and completely release donepezil hydrochloride within 10 minutes.

[0072] (2) The microchips of the present invention have precise size control, stable release curve, and similarity factor f2 > 50 between each chip.

[0073] (3) This invention has only one compound micro-tablet form, with high yield and fast production speed. When patients open the capsules to take the medicine, it is not easy to lose the medicine.

[0074] (4) The microplates of the present invention have a high drug loading ratio, which can significantly reduce tablet weight, and are small in size, making them easier to swallow and greatly improving patient compliance. (5) The crystal form of the donepezil hydrochloride coating membrane of the present invention does not change during production and storage, and its quality is stable.

[0075] (6) The present invention uses both povidone and propylene glycol as crystal stabilizers for donepezil or its pharmaceutically acceptable salts, which is more conducive to improving the crystal stability of donepezil or its pharmaceutically acceptable salts.

[0076] (7) The mass ratio of polyvinylpyrrolidone to propylene glycol provided by the present invention (the mass ratio of polyvinylpyrrolidone to propylene glycol is 0.5:2.0 to 2.0:0.5) is more conducive to improving the crystal stability of donepezil or its pharmaceutically acceptable salt.

[0077] (8) The mass ratio of donepezil or its pharmaceutically acceptable salt to the crystal stabilizer provided by the present invention (the mass ratio of donepezil or its pharmaceutically acceptable salt to the crystal stabilizer is (5.0-15.0): (2.5-3.6)) is more conducive to improving the crystal stability of donepezil or its pharmaceutically acceptable salt.

[0078] (9) Compared with other sustained-release matrix materials, the behenicol glyceride used in this invention is more conducive to the sustained-release effect of memantine hydrochloride. It is beneficial to allow memantine hydrochloride to be slowly released for 24 hours with the addition of a small amount of behenicol glyceride, which has unexpected technical effects. Attached Figure Description

[0079] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation of the scope. For those skilled in the art, other related drawings can be obtained from these drawings without creative effort.

[0080] Figure 1 This is a schematic diagram of the structure of the memantine donepezil hydrochloride sustained-release microplates provided in Example 1.

[0081] Figure 2 This is the release curve of the memantine donepezil hydrochloride sustained-release microtablet F1 provided in Example 1.

[0082] Figure 3 The pharmacokinetic-dopezil sustained-release microtablets F1 and Ebix provided in Example 1 are the pharmacokinetic-dopezil-methylenediamine hydrochloride ...

[0083] Figure 4 The pharmacokinetic and donepezil hydrochloride sustained-release microtablets F1 and Aricept provided in Example 1 are the pharmacokinetic and donepezil hydrochloride pharmacokinetic ...

[0084] Terminology Explanation

[0085] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings:

[0086] The term "multiple" means two or more, such as two, three, four or five.

[0087] "%vol" indicates a volume percentage.

[0088] “wt%” indicates a percentage by mass.

[0089] The term “and / or” should be understood to mean any one of the options or any combination of two or more of the options.

[0090] The terms "optional" or "optionally" refer to an event or situation that may, but is not necessarily, occur, as described below, and the description includes both the possibility that the event or situation occurs and the possibility that it does not occur. For example, "optionally condensing agent" means that a condensing agent may or may not be present.

[0091] In the foregoing description of this invention, all figures disclosed herein, whether or not the words “approximately” or “about” are used, are approximate values. Based on the disclosed figures, the value of each figure may vary by less than ±10% or by a difference that is considered reasonable by those skilled in the art, such as ±1%, ±2%, ±3%, ±4%, or ±5%.

[0092] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples. Detailed Implementation

[0093] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to provide a more detailed description of the present invention.

[0094] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0095] Example 1: Memantine Hydrochloride Sustained-Release-Donepezil Immediate-Release Microtablets

[0096] To investigate the effects of the content of the formulation components on the sustained-release effect and crystal stability, a series of screening experiments were conducted. The formulation of this embodiment is shown in Table 1. The preparation method was carried out according to the process description above. The release rate (cumulative release rate) of each formulation microplate was tested using the Chinese Pharmacopoeia Method II, paddle method, pH 1.2 / sodium chloride medium, rotation speed 50 rpm, release volume 1000 ml, and release rate sampling times at 10 min, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 10 h, 16 h, and 24 h (only donepezil hydrochloride release was measured at 10 min, and memantine hydrochloride release was measured at other time points). The test data of release rate are shown in Tables 2 and 3.

[0097] Table 1: Formulation Analysis of Memantine Hydrochloride Sustained-Release-Donepezil Immediate-Release Microtablets

[0098]

[0099]

[0100] " / " indicates that the ingredient is not present.

[0101] Preparation method:

[0102] Step S1: Mix memantine hydrochloride, slow-release matrix material and filler, then add an aqueous solution of binder, granulate to obtain wet granules;

[0103] Step S2: Dry the wet granules and granulate them;

[0104] Step S3: Mix the sized wet granules with lubricant and flow aid to obtain mixed granules;

[0105] Step S4: Press the mixed particles using a micro-blade punch to obtain a sustained-release layer;

[0106] Step S5: Mix donepezil hydrochloride, film-forming material and crystal stabilizer with 75% vol ethanol aqueous solution to obtain a mixed solution, and coat the surface of the sustained-release layer obtained in step S4 with the mixed solution to obtain the microplate.

[0107] Table 2: Memantine Hydrochloride Release Rate in Memantine Hydrochloride Sustained-Release-Donepezil Immediate-Release Microtablets with Different Formulations

[0108]

[0109] Table 3: Donepezil hydrochloride release rates in memantine hydrochloride sustained-release-donepezil immediate-release microtablets with different formulation compositions

[0110]

[0111] Conclusion: As shown in Table 2, the sustained-release capacity of the microplates of memantine hydrochloride gradually increases with the increase of the content of the sustained-release matrix material, glyceryl behenate (Compritol 888ATO). A plateau is reached when the content reaches 30%, and the release curve no longer changes significantly. The microplates prepared in this embodiment, such as F1, can achieve 24-hour sustained release of memantine hydrochloride with only 26.8% glyceryl behenate added. Its in vitro active ingredient release rates are 3.2% at 1 hour, 44.5% at 6 hours, 69.3% at 12 hours, and 95.3% at 24 hours. The sustained-release capacity of glyceryl behenate in the formulation is significantly better than other sustained-release matrix materials such as hydroxypropyl methylcellulose K100M and ethyl cellulose 40cps, exhibiting unexpected technical effects. As shown in Table 3, all formulations of donepezil hydrochloride can achieve a cumulative release rate of over 85% within 10 minutes.

[0112] Example 2: Comparison of release rates between memantine hydrochloride sustained-release-donepezil immediate-release microtablets and sustained-release microgranules

[0113] Prescription for sustained-release microcapsules: see Table 4.

[0114] Table 4: Prescription for sustained-release microcapsules

[0115]

[0116] Preparation of sustained-release microcapsules: Select sucrose pellet cores with a size of 710-850 micrometers (Sulex Core, PF010, 20 / 25 mesh, Shanghai Carrefour). First, coat the surface of the sucrose pellet cores with memantine hydrochloride and talc using a fluidized bed to obtain particle 1. Then, coat the surface of particle 1 with a sustained-release coating ethyl cellulose aqueous dispersion (Type B, Sulis, E-7-19040, Shanghai Carrefour) using a fluidized bed to obtain particle 2. Finally, coat the surface of particle 2 with donepezil hydrochloride, hydroxypropyl cellulose, povidone, propylene glycol, and a film coating premix to obtain sustained-release microcapsules.

[0117] Three samples of microplate F1 were randomly selected, namely F1-1, F1-2, F1-1, and F1-3; then prescriptions F13, F14, and F15 were selected, and the release curves of memantine hydrochloride of the above six samples were detected. The results are shown in Table 5.

[0118] Table 5: Comparison of release rates between memantine hydrochloride sustained-release and donepezil immediate-release microtablets and sustained-release microcapsules

[0119]

[0120] Table 5 shows that even within the same batch of sustained-release microcapsules, the release rates of microcapsules with different particle sizes varied significantly. The release similarity factor f2 between the largest and smallest coated microcapsules was only 46, below 50, indicating dissimilarity. However, among the microflakes from the same batch, three randomly selected samples showed identical release rates, with a release similarity factor exceeding 89, indicating similarity. These results suggest that the release rate of microflakes is more stable.

[0121] Formula for calculating f2:

[0122]

[0123] Where n is the number of sampling time points, Rt is the release rate of the reference sample (or the sample before the change) at time t, and Tt is the release rate of the test batch (the sample after the change) at time t. f2 is considered similar if it is greater than or equal to 50. Only one time point is taken where the release rate is greater than 85%.

[0124] Example 3: Comparison of donepezil hydrochloride crystal forms

[0125] Samples of formulations F1 (polyvinyl chloride K30: propylene glycol = 1:1 (mass ratio) as crystal stabilizer), F6 (polyvinyl chloride K30 as crystal stabilizer), F7 (propylene glycol as crystal stabilizer), F8 (polyvinyl chloride K30: propylene glycol = 0.5:2.0 (mass ratio) as crystal stabilizer), F9 (polyvinyl chloride K30: propylene glycol = 2.0:0.5 (mass ratio) as crystal stabilizer), F10 (sodium carboxymethyl cellulose: polyvinyl alcohol = 1.8:1.8 (mass ratio) as crystal stabilizer), F11 (polyvinyl chloride: polyvinyl alcohol = 1:1 (mass ratio) as crystal stabilizer), and F12 (propylene glycol: sodium carboxymethyl cellulose = 1:1 (mass ratio) as crystal stabilizer) were subjected to XRD analysis at 0 days and 3 months under accelerated testing (40℃ / 65%RH). The analysis equipment was a D2 X-ray powder diffractometer. PHASER, Instrument Parameters: X-rays: Cu, kα 1.54060;

[0126] 1.54439; Kα2 / Kα1 intensity ratio: 0.50; X-ray tube settings: 30kV, 10mA; Scan mode: reflection mode; Sample holder: single crystal silicon. Scan mode: continuous. Scan range (°2TH): 3°~40°. The superimposed XRD patterns are shown in Table 6.

[0127] Table 6: Results of the crystal form stability study of donepezil hydrochloride in different formulations

[0128]

[0129]

[0130] in conclusion:

[0131] The XRD patterns of formulations F1, F8, and F9, after subtracting the blank excipient from the 2θ of the accelerated test samples at 0 days and 3 months, showed characteristic peaks at 13.1°, 13.6°, 13.9°, 14.9°, 15.3°, 16.1°, 17.6°, 22.0°, and 22.5°. These peaks are characteristic of crystal form I, indicating that formulation F1 retains crystal form I. In contrast, formulations F6, F7, F10, F11, and F12, under accelerated conditions (40℃ / 65% RH), showed characteristic peaks at 2θ of 13.1°, 13.6°, 13.9°, 14.9°, 15.3°, 16.1°, 17.6°, 22.0°, and 22.5°. The XRD patterns after 3 months showed characteristic peaks at 6.5°, 13.0°, 15.0°, 15.2°, 18.5°, 21.6°, 22.0°, and 22.5° after subtracting the blank excipient from the 2θ value. Among these, 6.5°, 13.0°, 15.0°, 15.2°, 18.5°, and 21.6° were characteristic peaks of crystal form III, while 22.0° and 22.5° were characteristic peaks of crystal form I. This indicates that all five formulations contain both crystal form I and crystal form III.

[0132] Experimental results show that, compared with other crystal form stabilizers or combinations of other crystal form stabilizers, using povidone K30 and propylene glycol as crystal form stabilizers, donepezil hydrochloride can maintain its I crystal form during stable storage, thus avoiding crystal transformation.

[0133] Example 5: Animal Experiment

[0134] The main pharmacokinetic parameters of the memantine hydrochloride sustained-release-donepezil immediate-release microtablets F1 prepared in Example 1 were tested, and the results are shown in Tables 7 and 8. Figure 3 , Figure 4 As shown. Eight beagle dogs were randomly divided into one experimental group and one control group, with four dogs in each group. All beagle dogs were fasted overnight. The experimental group received one tablet of prescription F1 (28mg / 10mg), while the control group received one tablet each of Ebix (memantine hydrochloride tablet, 10mg) and Aricept (donepezil hydrochloride tablet, 10mg). At 14 blood collection time points, 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24h, and 48h, approximately 2ml of blood was collected from the femoral vein of each beagle dog and placed into tubes containing EDTA-K2. The blood samples were centrifuged at 3000±100 rpm for 5 minutes below 10°C. The blood samples were kept in an ice-water bath before centrifugation and during aliquoting.

[0135] The concentration of memantine in the plasma samples of the subjects was determined by LC-MS / MS. Memantine-d6 was used as an internal standard, and memantine and memantine-d6 were extracted from the plasma by liquid-liquid extraction. Isocratic elution was performed using 70% mobile phase A (methanol) and 30% mobile phase B (0.1% formic acid solution) at a total flow rate of 1.00 mL / min. Chromatographic separation was performed using an Eclipse XDB C8150 X4.6 mm, 5 μm column. Memantine and memantine-d6 were monitored in positive ion mode using MRM ion pairing in ESI mode. Quantitative analysis was performed at m / z 180.06→163.03 (memantine) and m / z 186.13→169.12 (memantine-d6).

[0136] The concentration of donepezil in plasma samples from subjects was determined by LC-MS / MS. Donepezil and donepezil-d7 were extracted from plasma using liquid-liquid extraction with donepezil-d7 as an internal standard. Isocratic elution was performed using 90% mobile phase A (acetonitrile) and 10% mobile phase B (5 mM ammonium formate buffer) at a total flow rate of 1.00 mL / min. Chromatographic separation was performed using an ACE 5C18100 X4.6 mm column. Donepezil and donepezil-d7 were monitored in positive ion mode using MRM ion pairs in ESI mode. Quantitative analysis was performed at m / z 380.00→91.00 (donepezil) and m / z 387.20→98.10 (donepezil-d7).

[0137] Statistical analysis of the PK parameters AUC0–t, AUC0–inf, and Cmax for the natural logarithm (ln) transformation was performed using analysis of variance (ANOVA).

[0138] Table 7: Key Pharmacokinetic Parameters of Memantine Hydrochloride Extended-Release - Donepezil Immediate-Release Microtablets F1 and Ibuprofen - Memantine Hydrochloride

[0139]

[0140] Among them, C max C represents the peak concentration (mg / L) of the drug during the curve. min The trough concentration (mg / L) of the drug on the curve, AUC 0-t The area under the curve during drug administration (mg*h / L) refers to the drug's effect, and t refers to the experimental time (h).

[0141] From Table 7 and Figure 3 It can be seen that, compared with Ebexol, the memantine hydrochloride sustained-release-donepezil immediate-release microtablets (F1) provided by this invention show a significant sustained-release effect. max (h) was significantly prolonged, and the drug-time curve was stable.

[0142] Table 8: Key Pharmacokinetic Parameters of Memantine Hydrochloride Extended-Release-Donepezil Immediate-Release Microtablets F1 and Aricept - Donepezil Hydrochloride

[0143]

[0144] From Table 8 and Figure 4 It can be seen that, compared with Aricept, the memantine hydrochloride sustained-release-donepezil immediate-release microtablets (F1) provided by the present invention also have a significant immediate-release effect.

[0145] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. A microchip, characterized in that, The microplate comprises a sustained-release layer and an immediate-release layer. The sustained-release layer contains memantine or a pharmaceutically acceptable salt thereof and a sustained-release matrix material. The immediate-release layer contains donepezil or a pharmaceutically acceptable salt thereof and a crystal form stabilizer. The preparation method of the microplate comprises: mixing memantine or a pharmaceutically acceptable salt thereof and a sustained-release matrix material and pressing them to obtain a sustained-release layer, and then coating the surface of the sustained-release layer with a coating film containing donepezil or a pharmaceutically acceptable salt thereof containing a crystal form stabilizer. The crystal form stabilizer includes polyvinylpyrrolidone and propylene glycol; The sustained-release matrix material includes glyceryl behenate; the glyceryl behenate is Compritol 888 ATO; the content of the glyceryl behenate is 26.8 wt%-35.0 wt% based on the total mass of the microplates. The mass ratio of the polyvinylpyrrolidone to the propylene glycol is 0.5:2.0 to 2.0:0.

5.

2. The microplate according to claim 1, The sustained-release layer further includes one or more of fillers, adhesives, lubricants, and flow aids; and / or The filler includes one or more of microcrystalline cellulose, lactose, mannitol, sucrose, and starch; and / or The adhesive comprises one or more of hydroxypropyl methylcellulose, ethylcellulose, and starch paste; and / or The lubricant comprises one or more of magnesium stearate, stearic acid, hydrogenated castor oil, and polyethylene glycol; and / or The flow aid includes one or more of silica and talc; and / or The immediate-release layer further includes a film-forming material; and / or The pharmaceutically acceptable salt of the memantine is memantine hydrochloride; and / or The pharmaceutically acceptable salt of donepezil is donepezil hydrochloride.

3. The microsheet according to claim 2, wherein the film-forming material comprises one or more of hydroxypropyl cellulose, polyvinyl alcohol, and ethyl cellulose.

4. The microsheets according to any one of claims 1-3, wherein the K value of the povidone is 27.0 to 32.0; and / or The specific rotation of the propylene glycol is [α]D20-15.0°; and / or The microplates are cylindrical, with a diameter of 1-2 mm and a height of 1-2 mm; and / or The micro-chip has two surfaces, the top and bottom, that are either planar or convex.

5. The microplate according to claim 1, Based on the total mass of the microflakes, the content of the amantadine or its pharmaceutically acceptable salt is 20.0 wt%-30.0 wt%; and / or Based on the total mass of the microplates, the content of donepezil or its pharmaceutically acceptable salt is 5.0 wt% to 15.0 wt%.

6. The microplate according to claim 1, wherein the content of the amantadine or a pharmaceutically acceptable salt thereof is 25.0 wt% based on the total mass of the microplate; and / or Based on the total mass of the microplates, the content of donepezil or its pharmaceutically acceptable salt is 8.9 wt%.

7. The microsheets according to claim 2, wherein the content of the povidone, calculated based on the total mass of the microsheets, is 0.5 wt% to 2.0 wt%; and / or Based on the total mass of the microplates, the propylene glycol content is 0.5 wt% to 2.0 wt%; and / or Based on the total mass of the microflakes, the filler content is 15.0 wt% to 35.0 wt%; and / or Based on the total mass of the microplates, the adhesive content is 1.0 wt% to 2.0 wt%; and / or Based on the total mass of the microplates, the lubricant content is 0.5wt%~1.0wt%; and / or Based on the total mass of the microplates, the content of the gliding agent is 0.5 wt% to 1.0 wt%; and / or Based on the total mass of the microplates, the content of the film-forming material is 5.0 wt% to 15.0 wt%; and / or The mass ratio of the polyvinylpyrrolidone to the propylene glycol is 1.0:1.

0.

8. The microsheets according to claim 2, wherein the content of the povidone is 1.8 wt% based on the total mass of the microsheets; and / or Based on the total mass of the microplates, the content of propylene glycol is 1.8 wt%; and / or Based on the total mass of the microplates, the adhesive content is 1.8 wt%; and / or Based on the total mass of the microplates, the lubricant content is 0.9 wt%; and / or Based on the total mass of the microplates, the content of the gliding agent is 0.9 wt%; and / or Based on the total mass of the microplates, the content of the film-forming material is 8.9 wt% to 10.7 wt%; and / or The mass ratio of the polyvinylpyrrolidone to the propylene glycol is 1.0:1.

0.

9. The microplate according to any one of claims 1 to 3, The mass ratio of donepezil or its pharmaceutically acceptable form to the crystal stabilizer is (5.0~15.0):(2.5~3.6).

10. The microplate according to any one of claims 1 to 3, The donepezil or its pharmaceutically acceptable mass ratio to the crystal stabilizer is 8.9:3.6, 5.0:2.5 or 15.0:2.

5.

11. The microsheet according to any one of claims 1-3, wherein the sustained-release layer comprises memantine hydrochloride, a sustained-release matrix material, a filler, a binder, a lubricant, and a flow aid; the immediate-release layer comprises donepezil hydrochloride, a crystal stabilizer, and a film-forming material; the crystal stabilizer comprises povidone K30 and propylene glycol; the filler is microcrystalline cellulose; the binder is hydroxypropyl methylcellulose E5; the lubricant comprises one or more of magnesium stearate, stearic acid, hydrogenated castor oil, and polyethylene glycol; the flow aid comprises one or more of silica and talc; and the film-forming material is hydroxypropyl cellulose.

12. The microsheet according to claim 11, wherein, based on the total mass of the microsheet, the content of memantine hydrochloride is 20.0wt%-30.0wt%, the content of donepezil hydrochloride is 5.0wt%-15.0wt%, the content of povidone K30 is 0.5wt%-2.0wt%, the content of propylene glycol is 0.5wt%-2.0wt%, the content of filler is 15.0wt%-35.0wt%, the content of adhesive is 1.0wt%-2.0wt%, the content of lubricant is 0.5wt%-1.0wt% or 0.9wt%, the content of flow aid is 0.5wt%-1.0wt% or 0.9wt%, and the content of film-forming material is 5.0wt%-15.0wt%.

13. The microplate according to claim 11, Based on the total mass of the microfilms, the content of memantine hydrochloride is 25.0 wt%, the content of donepezil hydrochloride is 8.9 wt%, the content of povidone K30 is 1.8 wt%, the content of propylene glycol is 1.8 wt%, the content of filler is 15.0 wt% to 35.0 wt%, the content of binder is 1.8 wt%, the content of lubricant is 0.9 wt%, the content of flow aid is 0.9 wt%, and the content of film-forming material is 8.9 wt% to 10.7 wt%.

14. The microplate according to claim 11, Based on the total mass of the microfilms, the content of glyceryl behenate is 26.8 wt%, the content of memantine hydrochloride is 20.0 wt%-30.0 wt%, the content of donepezil hydrochloride is 5.0 wt%-15.0 wt%, the content of povidone K30 is 0.5 wt%-2.0 wt%, and the content of propylene glycol is 0.5 wt%-2.0 wt%. The mass ratio of donepezil hydrochloride to crystal stabilizer is (5.0~15.0):(2.5~3.6). The content of filler is 15.0 wt%-35.0 wt%, the content of binder is 1.8 wt%, the content of lubricant is 0.9 wt%, the content of flow aid is 0.9 wt%, and the content of film-forming material is 8.9 wt%-10.7 wt%.

15. A method for preparing the microplate according to claim 1, characterized in that, include: The sustained-release matrix material is mixed with memantine or a pharmaceutically acceptable salt thereof and pressed to obtain a sustained-release layer. Then, a coating film containing donepezil or a pharmaceutically acceptable salt thereof containing a crystal stabilizer is coated on the surface of the sustained-release layer.

16. A method for preparing the microplate according to claim 1, characterized in that, include: Step S1: Mix memantine or its pharmaceutically acceptable salt, sustained-release matrix material and filler, then add an aqueous solution of binder, granulate to obtain wet granules; Step S2: Dry the wet granules and granulate them; Step S3: Mix the sized wet granules with lubricant and flow aid to obtain mixed granules; Step S4: Press the mixed particles using a micro-blade punch to obtain a sustained-release layer; Step S5: Mix donepezil or a pharmaceutically acceptable salt thereof, a film-forming material, and a crystal stabilizer with an aqueous ethanol solution to obtain a mixed solution. Coat the surface of the sustained-release layer obtained in step S4 with the mixed solution to obtain the microplates; and / or The ethanol-water solution is a 75% vol ethanol-water solution.

17. The use of a microplate according to any one of claims 1-14 or a microplate obtained by the preparation method according to any one of claims 15-16 in the preparation of capsules.

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