CN113209037B - Oxiracetam osmotic pump controlled release tablet and application thereof - Google Patents

Oxiracetam osmotic pump controlled release tablet and application thereof Download PDF

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CN113209037B
CN113209037B CN202110509449.0A CN202110509449A CN113209037B CN 113209037 B CN113209037 B CN 113209037B CN 202110509449 A CN202110509449 A CN 202110509449A CN 113209037 B CN113209037 B CN 113209037B
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oxiracetam
mass concentration
weight
parts
coating
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CN113209037A (en
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叶衍涓
徐卫娟
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Southern Medical University Zhujiang Hospital
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Southern Medical University Zhujiang Hospital
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Abstract

Aiming at the problems that the oral administration of oxiracetam in the prior art needs to be carried out 2-3 times per day and the administration of patients is inconvenient, the invention provides an oxiracetam osmotic pump controlled release tablet which can realize zero-order release and has the 12-hour cumulative release degree of more than 90 percent on one hand. The invention also provides application of the oxiracetam osmotic pump controlled release tablet.

Description

Oxiracetam osmotic pump controlled release tablet and application thereof
Technical Field
The invention belongs to the field of sustained-release preparations of medicaments, and particularly relates to an oxiracetam osmotic pump controlled-release tablet and application thereof.
Background
The western medicines belong to pyrrolidone nootropic drugs, and selectively act on cerebral cortex and hippocampus by assimilating biological energy metabolism in brain cells, so as to protect, activate or promote recovery of nerve cell function and improve brain integration mechanism related to mental behavior. The medicaments mainly comprise oxiracetam, piracetam, aniracetam, pramipexole, levetiracetam and the like. With the coming of the aging society of China, the demand of the medicines of the Western class is increasing.
Oxiracetam was first chemically named 4-hydroxy-2-oxo-1-pyrrolidineacetamide and was first synthesized in 1974 by the company starchy, italy. The indication approved in China by oxiracetam is applicable to memory and intelligence disorders caused by mild and moderate vascular dementia, senile dementia, cerebral trauma and the like. The formulation which is approved to be on the market in China comprises injection and conventional capsules.
The usage amount of the oxiracetam capsule on the market at home is 2 oral administration, each 400mg, 2-3 times a day, and T ismaxThe half-life is 3.34 plus or minus 1.59-4.74 plus or minus 1.41 h. For patients with mild and moderate vascular dementia, senile dementia and brain trauma, the medicine is taken 2-3 times per day, and for patients with mild and moderate vascular dementia, senile dementia and brain trauma, the medicine is very sleepyIt is difficult to ensure the treatment effect, so the development of an oxiracetam sustained-release preparation is urgently needed. The oxiracetam sustained-release preparation has clinical application value only when the accumulative release degree and the bioavailability of the oxiracetam sustained-release preparation meet the requirements at the same time, and the oxiracetam sustained-release preparation on the market is not available in China due to difficulties.
Disclosure of Invention
1. Problems to be solved
The invention provides an oxiracetam osmotic pump controlled release tablet, which can realize zero-order release, and the cumulative release degree of 12h is more than 90%. The invention also provides application of the oxiracetam osmotic pump controlled release tablet.
2. Technical scheme
In order to solve the above problems, the present invention adopts the following technical solutions.
Defining:
polyethylene oxide: the product is called Polyethylene Oxide, which is a nonionic homopolymer prepared by polymerizing ethylene Oxide (or called ethylene Oxide) at high temperature and high pressure in the presence of an initiator and a catalyst.
8％PVPk30Ethanol solution: refers to PVPk30The mass concentration of (2) is 8%. For example: with PVPk30200mg of ethanol solution indicates that 16mg of PVP is containedk30。
4% cellulose acetate: the mass concentration of the acetate fiber in the coating solution is 4 percent. For example: the total weight of the coating solution is 100mg, and the content of the cellulose acetate is 4 mg.
0.6% polyethylene glycol 1500: the mass concentration of the polyethylene glycol 1500 in the coating solution is 0.6%. For example: when the total weight of the coating solution is 100mg, the polyethylene glycol 1500 is 0.6 mg.
Coating weight gain is 6%: means a 6% weight gain relative to the core. For example: the tablet core weighs 1000mg, and the dosage of the coating liquid is 60 mg.
In some embodiments of the present invention, the osmotic pump controlled release preparation comprises a tablet core, a retardant, a semi-permeable membrane and a drug release hole, wherein the tablet core comprises a therapeutically effective amount of a western medicine, and the retardant is polyethylene oxide.
In some embodiments of the present invention, the therapeutically effective amount of the drug from the group of western medicines may be 50mg to 1200mg per dose. In some embodiments of the invention, the therapeutically effective amount of the drug from the group of western medicines may be 50mg to 1100mg per dose. In some embodiments of the present invention, the therapeutically effective amount of the drug from the group of western medicines may be 50mg to 1000mg per dose. In some embodiments of the present invention, the therapeutically effective amount of the drug from the group of western medicines may be 50mg to 1000mg per dose. In some embodiments of the present invention, the therapeutically effective amount of the drug from the group of western medicines may be 50mg to 950mg per dose. In some embodiments of the present invention, the therapeutically effective amount of the drug from the group of western medicines may be 50mg to 900mg per dose. In some embodiments of the present invention, the therapeutically effective amount of the drug from the group of western medicines may be 50mg to 850mg per dose. In some embodiments of the present invention, the therapeutically effective amount of the drug from the group of western medicines may be 50mg to 800mg per dose. In some embodiments of the present invention, the therapeutically effective amount of the drug from the group of western medicines may be 50mg to 750mg per dose. In some embodiments of the present invention, the therapeutically effective amount of the drug from the group of western medicines may be 50mg to 700mg per dose. In some embodiments of the present invention, the therapeutically effective amount of the drug from the group of western medicines may be 50mg to 650mg per dose. In some embodiments of the present invention, the therapeutically effective amount of the drug from the group of western medicines may be 50mg to 600mg per dose. In some embodiments of the present invention, the therapeutically effective amount of the racetam may be between 50mg and 550mg per dose. In some embodiments of the present invention, the therapeutically effective amount of the drug from the group of western medicines may be 50mg to 500mg per dose. In some embodiments of the present invention, the therapeutically effective amount of the drug from the group of western medicines may be 50mg to 450mg per dose. In some embodiments of the present invention, the therapeutically effective amount of the drug from the group of western medicines may be 50mg to 400mg per dose. In some embodiments of the present invention, the therapeutically effective amount of the drug from the group of western medicines may be 50mg to 350mg per dose. In some embodiments of the present invention, the therapeutically effective amount of the drug from the group of western medicines may be 50mg to 300mg per dose. In some embodiments of the present invention, the therapeutically effective amount of the drug from the group of western medicines may be 50mg to 250mg per dose. In some embodiments of the present invention, the therapeutically effective amount of the racetam may be between 100mg and 250mg per dose. In some embodiments of the present invention, the therapeutically effective amount of the drug from the group of western medicines may be 100mg to 200mg per dose.
In some embodiments of the invention, the drug of the racetam class is oxiracetam, piracetam, aniracetam, pramiperacetam or levetiracetam.
In some embodiments of the invention, the drug of the western family is oxiracetam.
In some embodiments of the invention, the oxiracetam is levo-oxiracetam, dextro-oxiracetam, or oxiracetam racemate.
In some embodiments of the invention, the therapeutically effective amount of oxiracetam may be between 50mg and 1200mg per dose. In some embodiments of the invention, the therapeutically effective amount of oxiracetam may be between 50mg and 1100mg per dose. In some embodiments of the invention, the therapeutically effective amount of oxiracetam may be between 50mg and 1000mg per dose. In some embodiments of the invention, the therapeutically effective amount of oxiracetam may be between 50mg and 1000mg per dose. In some embodiments of the invention, the therapeutically effective amount of oxiracetam may be between 50mg and 950mg per dose. In some embodiments of the invention, the therapeutically effective amount of oxiracetam may be between 50mg and 900mg per dose. In some embodiments of the invention, the therapeutically effective amount of oxiracetam may be between 50mg and 850mg per dose. In some embodiments of the invention, the therapeutically effective amount of oxiracetam may be between 50mg and 800mg per dose. In some embodiments of the invention, the therapeutically effective amount of oxiracetam may be between 50mg and 750mg per dose. In some embodiments of the invention, the therapeutically effective amount of oxiracetam may be between 50mg and 700mg per dose. In some embodiments of the invention, the therapeutically effective amount of oxiracetam may be between 50mg and 650mg per dose. In some embodiments of the invention, the therapeutically effective amount of oxiracetam may be between 50mg and 600mg per dose. In some embodiments of the invention, the therapeutically effective amount of oxiracetam may be between 50mg and 550mg per dose. In some embodiments of the invention, the therapeutically effective amount of oxiracetam may be between 50mg and 500mg per dose. In some embodiments of the invention, the therapeutically effective amount of oxiracetam may be between 50mg and 450mg per dose. In some embodiments of the invention, the therapeutically effective amount of oxiracetam may be between 50mg and 400mg per dose. In some embodiments of the invention, the therapeutically effective amount of oxiracetam may be between 50mg and 350mg per dose. In some embodiments of the invention, the therapeutically effective amount of oxiracetam may be between 50mg and 300mg per dose. In some embodiments of the invention, the therapeutically effective amount of oxiracetam may be between 50mg and 250mg per dose. In some embodiments of the invention, the therapeutically effective amount of oxiracetam may be between 100mg and 250mg per dose. In some embodiments of the invention, the therapeutically effective amount of oxiracetam may be between 100mg and 200mg per dose.
In some embodiments of the invention, the retarder is composed of two polyethylene oxides of different molecular weights.
In some embodiments of the present invention, the molecular weight of the polyethylene oxide and the ratio of the two can be adjusted by one skilled in the art according to different drugs in the western family.
In some embodiments of the invention, the polyethylene oxide may have a molecular weight in the range of 5 to 700 million. In some embodiments of the invention, the polyethylene oxide may have a molecular weight in the range of 5 to 600 million. In some embodiments of the invention, the polyethylene oxide may have a molecular weight in the range of 5 to 500 million. In some embodiments of the invention, the polyethylene oxide may have a molecular weight in the range of 5 to 400 million. In some embodiments of the invention, the polyethylene oxide may have a molecular weight in the range of 10 to 300 million. In some embodiments of the invention, the polyethylene oxide may have a molecular weight in the range of 15 to 250 ten thousand.
In some embodiments of the present invention, the weight ratio of 10 million molecular weight polyethylene oxide to 500 million molecular weight polyethylene oxide is 4 (0.5-20). In some embodiments of the present invention, the weight ratio of 10 million molecular weight polyethylene oxide to 500 million molecular weight polyethylene oxide is 4 (0.5-15). In some embodiments of the present invention, the weight ratio of 10 million molecular weight polyethylene oxide to 500 million molecular weight polyethylene oxide is 4 (0.5-10). In some embodiments of the invention, the weight ratio of 10 million molecular weight polyethylene oxide to 500 million molecular weight polyethylene oxide is 4 (0.5-8). In some embodiments of the present invention, the weight ratio of 10 million molecular weight polyethylene oxide to 500 million molecular weight polyethylene oxide is 4 (1-8). In some embodiments of the present invention, the weight ratio of 10 million molecular weight polyethylene oxide to 500 million molecular weight polyethylene oxide is 4 (1-6). In some embodiments of the present invention, the weight ratio of 10 million molecular weight polyethylene oxide to 500 million molecular weight polyethylene oxide is 4 (1-5).
In some embodiments of the invention, the retarder comprises:
4 parts by weight of polyethylene oxide with the molecular weight of 10 ten thousand;
1-3 parts of polyethylene oxide with the molecular weight of 500 ten thousand.
In some embodiments of the invention, the semipermeable membrane material is cellulose acetate, ethyl cellulose, cellulose propionate, polyvinyl alcohol, polyethylene, or polyvinyl chloride.
In some embodiments of the present invention, the mass concentration of the semipermeable membrane material can be adjusted according to different drugs. In some embodiments of the present invention, the semipermeable membrane material has a mass concentration of 0.5% to 10%. In some embodiments of the invention, the semipermeable membrane material has a mass concentration of 0.5% -8%. In some embodiments of the invention, the semipermeable membrane material has a mass concentration of 0.5% -6%. In some embodiments of the present invention, the semipermeable membrane material has a mass concentration of 0.5% to 5%. In some embodiments of the invention, the semipermeable membrane material has a mass concentration of 1% to 5%. In some embodiments of the invention, the semipermeable membrane material has a mass concentration of 1% to 4%. In some embodiments of the invention, the semipermeable membrane material has a mass concentration of 2% to 4%. In some embodiments of the invention, the semipermeable membrane material is cellulose acetate with a mass concentration of 4% to 9%. In some embodiments of the invention, the semipermeable membrane material is cellulose acetate with a mass concentration of 4% or 9%.
In some embodiments of the present invention, the osmotic pump controlled release formulation further comprises a binder, which is an aqueous solution of water, ethanol, gelatin, sucrose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, or an alcoholic solution of polyvinylpyrrolidone.
In some embodiments of the present invention, the mass concentration of the binder may be adjusted according to the drug. In some embodiments of the invention, the binder is at a mass concentration of 1% to 10%. In some embodiments of the invention, the binder is present at a mass concentration of 2% to 10%. In some embodiments of the invention, the binder is present at a mass concentration of 3% to 8%. In some embodiments of the invention, the binder is at a mass concentration of 3% to 5%. In some embodiments of the invention, the binder is PVP at a mass concentration of 5% to 8%k30Ethanol solution. In some embodiments of the invention, the binder is PVP at a concentration of 5% or 8% by massk30Ethanol solution.
In some embodiments of the present invention, the osmotic pump controlled release formulation further comprises a lubricant, wherein the lubricant is aerosil, talc, magnesium lauryl sulfate, polyethylene glycol, sodium dodecyl sulfate, hydrogenated vegetable oil, stearic acid, magnesium stearate, calcium stearate or talc.
In some embodiments of the present invention, the osmotic pump controlled release formulation further comprises a plasticizer. In some embodiments of the invention, the plasticizer is propylene glycol, castor oil, polyethylene glycol, silicone oil, glycerol, or diethyl phthalate.
In some embodiments of the present invention, the osmotic pump controlled release formulation further comprises a push layer.
In some embodiments of the invention, the mass concentration of cellulose acetate is 1% to 10%. In some embodiments of the invention, the mass concentration of cellulose acetate is 1% to 8%. In some embodiments of the invention, the mass concentration of cellulose acetate is 1% to 7%. In some embodiments of the invention, the mass concentration of cellulose acetate is between 2% and 6%. In some embodiments of the invention, the mass concentration of cellulose acetate is between 2% and 5%.
In some embodiments of the invention, the mass concentration of polyethylene glycol 1500 is 0.1% to 5%. In some embodiments of the invention, the mass concentration of polyethylene glycol 1500 is 0.1% to 4%. In some embodiments of the invention, the mass concentration of polyethylene glycol 1500 is 0.1% to 3%. In some embodiments of the invention, the mass concentration of polyethylene glycol 1500 is 0.1% to 2%. In some embodiments of the invention, the mass concentration of polyethylene glycol 1500 is 0.3% to 2%.
In some embodiments of the invention, the osmotic pump controlled release formulation comprises:
Figure BDA0003059723990000051
and coating liquid, the coating liquid includes acetone, cellulose acetate and polyethylene glycol 1500, wherein the mass concentration of the cellulose acetate is 4% -9%, the mass concentration of the polyethylene glycol 1500 is 0.6% -1.0%, and the weight of the coating is increased by 6% -10%;
and a medicine releasing hole with the diameter of 254-500 μm.
In some embodiments of the invention, the osmotic pump controlled release formulation comprises:
Figure BDA0003059723990000052
and coating liquid, the coating liquid comprises acetone, cellulose acetate and polyethylene glycol 1500, wherein the mass concentration of the cellulose acetate is 4%, the mass concentration of the polyethylene glycol 1500 is 0.6%, and the weight of the coating is increased by 6%;
and drug release holes, the diameter of the drug release holes is 254 μm;
or
Figure BDA0003059723990000053
Figure BDA0003059723990000061
And coating liquid, the coating liquid comprises acetone, cellulose acetate and polyethylene glycol 1500, wherein the mass concentration of the cellulose acetate is 4%, the mass concentration of the polyethylene glycol 1500 is 0.6%, and the weight of the coating is increased by 6%;
and drug release holes, the diameter of the drug release holes is 254 μm;
or
Figure BDA0003059723990000062
And coating liquid, the coating liquid comprises acetone, cellulose acetate and polyethylene glycol 1500, wherein the mass concentration of the cellulose acetate is 4%, the mass concentration of the polyethylene glycol 1500 is 0.6%, and the weight of the coating is increased by 6%;
and drug release holes, the diameter of the drug release holes is 254 μm;
or
Figure BDA0003059723990000063
And a coating solution, wherein the coating solution comprises acetone, cellulose acetate and polyethylene glycol 1500, wherein the mass concentration of the cellulose acetate is 9%, the mass concentration of the polyethylene glycol 1500 is 1.0%, and the weight of the coating is increased by 6%;
and drug release holes with the diameter of 500 mu m.
In some embodiments of the invention, the osmotic pump controlled release formulation comprises:
Figure BDA0003059723990000064
and coating liquid, the coating liquid comprises acetone, cellulose acetate and polyethylene glycol 1500, wherein the mass concentration of the cellulose acetate is 4%, the mass concentration of the polyethylene glycol 1500 is 0.6%, and the weight of the coating is increased by 6%;
and drug release holes, the diameter of the drug release holes is 254 μm;
or
Figure BDA0003059723990000071
And coating liquid, the coating liquid comprises acetone, cellulose acetate and polyethylene glycol 1500, wherein the mass concentration of the cellulose acetate is 4%, the mass concentration of the polyethylene glycol 1500 is 0.6%, and the weight of the coating is increased by 6%;
and drug release holes, the diameter of the drug release holes is 254 μm;
or
Figure BDA0003059723990000072
And coating liquid, the coating liquid comprises acetone, cellulose acetate and polyethylene glycol 1500, wherein the mass concentration of the cellulose acetate is 4%, the mass concentration of the polyethylene glycol 1500 is 0.6%, and the weight of the coating is increased by 6%;
and drug release holes, the diameter of the drug release holes is 254 μm;
or
Figure BDA0003059723990000073
The coating solution comprises acetone, cellulose acetate and polyethylene glycol 1500, wherein the mass concentration of the cellulose acetate is 9%, the mass concentration of the polyethylene glycol 1500 is 1.0%, and the coating weight is increased by 10%;
and drug release holes with the diameter of 500 mu m.
Because the dosage of the oxiracetam is larger and reaches 800mg after the oxiracetam is prepared into a controlled release preparation, the invention greatly reduces the dosage of auxiliary materials by skillfully selecting the polyethylene oxides with different molecular weights, thereby ensuring that the weight of the whole controlled release tablet is about 1 g/dosage and simultaneously realizing zero-order release. If the dosage of the auxiliary materials is too large, the controlled release tablet is large and is inconvenient for patients to use.
In some embodiments of the invention, the osmotic pump controlled release formulation is a tablet or capsule. In some embodiments of the invention, the osmotic pump controlled release formulation is a gel matrix tablet, an erodible matrix tablet, an insoluble matrix tablet, a sustained release granule, a sustained release capsule, a sustained release implant, or a delayed release formulation.
In some embodiments of the present invention, the osmotic pump controlled release preparation has 1, 2 or 3 drug release pores with a diameter of 50 μm to 500 μm. In some specific embodiments of the invention, the pores have a diameter of 50 μm to 450 μm. In some specific embodiments of the invention, the pores have a diameter of 50 μm to 400 μm. In some specific embodiments of the invention, the pores have a diameter of 50 μm to 350 μm. In some specific embodiments of the invention, the pores have a diameter of 50 μm to 300. mu.m. In some specific embodiments of the invention, the pores have a diameter of 50 μm to 300. mu.m. In some specific embodiments of the invention, the pores have a diameter of 50 μm to 250 μm. In some specific embodiments of the invention, the pores have a diameter of 50 μm to 100 μm. In some specific embodiments of the invention, the pores have a diameter of 150 μm to 300. mu.m. In some embodiments of the present invention, the osmotic pump controlled release preparation has 1 release hole and a hole diameter of 254 μm or 500 μm.
In some embodiments of the invention, the osmotic pump controlled release preparation is applied to preparing drugs for treating memory and intelligence disorders caused by mild and moderate vascular dementia, senile dementia or cerebral trauma.
In some embodiments of the present invention, the preparation method of the osmotic pump controlled release preparation comprises the steps of sieving and uniformly mixing oxiracetam, polyethylene oxide (molecular weight is 10 ten thousand) and polyethylene oxide (molecular weight is 500 ten thousand), and using PVP (polyvinyl pyrrolidone)k30Ethanol (the mass concentration of PVPk30 is 8%) is used as an adhesive to prepare a soft material, the soft material is granulated by a 20-mesh sieve, the soft material is dried for 8 to 10 hours in a 45-DEG C oven, the granulated material is sieved by the 20-mesh sieve to obtain dry granules, and the dry granules are added with talcum powder to be pressed into a tablet core.
Coating film
Dissolving cellulose acetate and polyethylene glycol 1500 by using acetone, wherein the mass concentration of the cellulose acetate is 4%, the mass concentration of the polyethylene glycol 1500 is 0.6%, preparing to obtain a coating solution, coating the tablet core by using a coating pan, the flow rate of the coating solution is 0.5ml/min, the coating temperature is 35-40 ℃, the coating weight is increased by 6%, and then, drilling a drug release pore with the diameter of 254 mu m on the coating tablet by using laser to obtain the oxiracetam osmotic pump controlled release tablet.
In some embodiments of the present invention, the coating process for the osmotic pump controlled release formulation is fluidized bed coating. In some embodiments of the present invention, parameters of the coating process, such as flow rate, coating temperature, coating weight, may be adjusted for different drugs.
3. Advantageous effects
Compared with the prior art, the invention has the beneficial effects that:
(1) the oxiracetam osmotic pump controlled release tablet can realize controlled release administration.
Drawings
FIG. 1 is the release profile of the Oxiracetam osmotic pump controlled release tablet of example 1;
FIG. 2 is the release profile of the Oxiracetam osmotic pump controlled release tablet of example 2;
FIG. 3 is the release profile of the Oxiracetam osmotic pump controlled release tablet of example 3;
FIG. 4 is the release profile of the Oxiracetam osmotic pump controlled release tablet of example 4;
FIG. 5 is the release profile of the Oxiracetam osmotic pump controlled release tablet of example 5;
FIG. 6 is the release profile of the Oxiracetam osmotic pump controlled release tablet of example 6;
FIG. 7 is the release curve of the Oxiracetam osmotic pump controlled release tablet in examples 1-6.
Detailed Description
The present invention will be described in detail below with reference to the accompanying drawings.
Example 1
Preparation of oxiracetam osmotic pump controlled release tablet
Polyethylene oxide alone (molecular weight 10 ten thousand)
Prescription
Figure BDA0003059723990000091
Preparation method
Sieving oxiracetam and polyethylene oxide (molecular weight 10 ten thousand) with 20 mesh sieve, mixing, and adding PVPk30Ethanol (PV)Pk30Mass concentration of 8%) as adhesive, granulating with 20 mesh sieve, oven drying at 45 deg.C for 8-10 hr, sieving with 20 mesh sieve to obtain dry granule, adding pulvis Talci, and pressing into tablet core.
Coating film
Dissolving cellulose acetate and polyethylene glycol 1500 by using acetone, wherein the mass concentration of the cellulose acetate is 4%, the mass concentration of the polyethylene glycol 1500 is 0.6%, preparing to obtain a coating solution, coating the tablet core by using a coating pan, the flow rate of the coating solution is 0.5ml/min, the coating temperature is 35-40 ℃, the coating weight is increased by 6%, and then, drilling a drug release pore with the diameter of 254 mu m on the coating tablet by using laser to obtain the oxiracetam osmotic pump controlled release tablet.
Measurement of Release degree
According to the first method (rotating basket method) in the determination method of dissolution and release in Chinese pharmacopoeia, taking water as medium, respectively sampling at 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 10h and 12h, filtering, and taking as test solution. And accurately weighing oxiracetam reference substances, dissolving the oxiracetam reference substances to obtain reference substance solution, performing high performance liquid chromatography determination, and calculating the cumulative release degree.
High performance liquid chromatography conditions:
mobile phase: methanol/water (V/V) ═ 5: 95;
wavelength: 214 nm;
a chromatographic column: 150mm × 4.6mm, 5 μm, C18；
Flow rate: 0.8 ml/min;
column temperature: 25 ℃;
sample introduction amount: 20 μ L.
Results
The release profile is shown in figure 1, and the release profile does not conform to zero-order release, and basically does not release after 6h, and the cumulative release degree is 91% after 12 h.
Example 2
Preparation of oxiracetam osmotic pump controlled release tablet
Polyethylene oxide alone (molecular weight 500 ten thousand)
Prescription
Figure BDA0003059723990000101
Preparation method
Sieving oxiracetam and polyethylene oxide (molecular weight 500 ten thousand) with 20 mesh sieve, mixing, and adding PVPk30Ethanol (PVP)k30Mass concentration of 8%) as adhesive, granulating with 20 mesh sieve, oven drying at 45 deg.C for 8-10 hr, sieving with 20 mesh sieve to obtain dry granule, adding pulvis Talci, and pressing into tablet core.
Coating film
Dissolving cellulose acetate and polyethylene glycol 1500 by using acetone, wherein the mass concentration of the cellulose acetate is 4%, the mass concentration of the polyethylene glycol 1500 is 0.6%, preparing to obtain a coating solution, coating the tablet core by using a coating pan, the flow rate of the coating solution is 0.5ml/min, the coating temperature is 35-40 ℃, the coating weight is increased by 6%, and then, drilling a drug release pore with the diameter of 254 mu m on the coating tablet by using laser to obtain the oxiracetam osmotic pump controlled release tablet.
Measurement of Release degree
According to the first method (rotating basket method) in the determination method of dissolution and release in Chinese pharmacopoeia, taking water as medium, respectively sampling at 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 10h and 12h, filtering, and taking as test solution. And accurately weighing oxiracetam reference substances, dissolving the oxiracetam reference substances to obtain reference substance solution, performing high performance liquid chromatography determination, and calculating the cumulative release degree.
High performance liquid chromatography conditions:
mobile phase: methanol/water (V/V) ═ 5: 95;
wavelength: 214 nm;
a chromatographic column: 150mm × 4.6mm, 5 μm, C18；
Flow rate: 0.8 ml/min;
column temperature: 25 ℃;
sample introduction amount: 20 μ L.
Results
The release profile is shown in figure 2, and the release profile does not conform to zero-order release, and basically does not release after 8h, and the cumulative release degree is 86% after 12 h.
Example 3
Preparation of oxiracetam osmotic pump controlled release tablet
Polyethylene oxide combinations of different molecular weights
Prescription
Figure BDA0003059723990000111
Preparation method
Sieving oxiracetam, polyethylene oxide (molecular weight 10 ten thousand) and polyethylene oxide (molecular weight 500 ten thousand) with 20 mesh sieve, mixing, and adding PVPk30Ethanol (PVP)k30Mass concentration of 8%) as adhesive, granulating with 20 mesh sieve, oven drying at 45 deg.C for 8-10 hr, sieving with 20 mesh sieve to obtain dry granule, adding pulvis Talci, and pressing into tablet core.
Coating film
Dissolving cellulose acetate and polyethylene glycol 1500 by using acetone, wherein the mass concentration of the cellulose acetate is 4%, the mass concentration of the polyethylene glycol 1500 is 0.6%, preparing to obtain a coating solution, coating the tablet core by using a coating pan, the flow rate of the coating solution is 0.5ml/min, the coating temperature is 35-40 ℃, the coating weight is increased by 6%, and then, drilling a drug release pore with the diameter of 254 mu m on the coating tablet by using laser to obtain the oxiracetam osmotic pump controlled release tablet.
Measurement of Release degree
According to the first method (rotating basket method) in the determination method of dissolution and release in Chinese pharmacopoeia, taking water as medium, respectively sampling at 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 10h and 12h, filtering, and taking as test solution. And accurately weighing oxiracetam reference substances, dissolving the oxiracetam reference substances to obtain reference substance solution, performing high performance liquid chromatography determination, and calculating the cumulative release degree.
High performance liquid chromatography conditions:
mobile phase: methanol/water (V/V) ═ 5: 95;
wavelength: 214 nm;
a chromatographic column: 150mm × 4.6mm, 5 μm, C18；
Flow rate: 0.8 ml/min;
column temperature: 25 ℃;
sample introduction amount: 20 μ L.
Results
The release profile is shown in figure 3, and the release profile conforms to zero-order release, and the cumulative release degree in 12h is 99.8%.
Absolute bioavailability assay
Figure BDA0003059723990000121
The 6 beagle dogs are randomly divided into 2 groups, and the cross double-cycle design is adopted, wherein the elution cycle is 5-7 days. Before the experiment, the patient fasts for more than 12 hours in the night, and one tablet of oxiracetam osmotic pump controlled release tablet of the embodiment is orally taken in the morning of the experiment or 6g of oxiracetam injection which is sold on the market is injected. The administration was 4h followed by food intake. 2ml of blood was collected from femoral veins before and after administration at 0.25h, 0.5h, 0.75h, 1h, 2h, 3h, 4h, 6h, 8h, 12h, and 24h, and plasma was separated and stored under refrigeration for measurement. And (3) centrifuging the plasma, adding an internal standard solution by taking piracetam as an internal standard, drying by using nitrogen, adding acetonitrile to precipitate protein, centrifuging, filtering, taking 20 mu L of supernatant, injecting, and calculating the concentration of the oxiracetam in the plasma according to a standard curve by an internal standard method.
Chromatographic conditions are as follows:
a chromatographic column: c18；
Mobile phase: acetonitrile/water (V/V with 0.1% acetic acid) 80: 20;
flow rate: 1.0 ml/min;
wavelength: 210 nm;
sample introduction amount: 20 mu L of the solution;
column temperature: 40 ℃;
the absolute bioavailability of the oxiracetam osmotic pump controlled release tablet of the embodiment is measured to be 87.1%.
Example 4
Preparation of oxiracetam osmotic pump controlled release tablet
Polyethylene oxide combinations of different molecular weights
Prescription
Figure BDA0003059723990000131
Preparation method
Oxiracetam and polyepoxySieving ethane (molecular weight 10 ten thousand) and polyethylene oxide (molecular weight 500 ten thousand) with 20 mesh sieve, mixing, and adding PVPk30Ethanol (PVP)k30Mass concentration of 8%) as adhesive, granulating with 20 mesh sieve, oven drying at 45 deg.C for 8-10 hr, sieving with 20 mesh sieve to obtain dry granule, adding pulvis Talci, and pressing into tablet core.
Coating film
Dissolving cellulose acetate and polyethylene glycol 1500 by using acetone, wherein the mass concentration of the cellulose acetate is 4%, the mass concentration of the polyethylene glycol 1500 is 0.6%, preparing to obtain a coating solution, coating the tablet core by using a coating pan, the flow rate of the coating solution is 0.5ml/min, the coating temperature is 35-40 ℃, the coating weight is increased by 6%, and then, drilling a drug release pore with the diameter of 254 mu m on the coating tablet by using laser to obtain the oxiracetam osmotic pump controlled release tablet.
Measurement of Release degree
According to the first method (rotating basket method) in the determination method of dissolution and release in Chinese pharmacopoeia, taking water as medium, respectively sampling at 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 10h and 12h, filtering, and taking as test solution. And accurately weighing oxiracetam reference substances, dissolving the oxiracetam reference substances to obtain reference substance solution, performing high performance liquid chromatography determination, and calculating the cumulative release degree.
High performance liquid chromatography conditions:
mobile phase: methanol/water (V/V) ═ 5: 95;
wavelength: 214 nm;
a chromatographic column: 150mm × 4.6mm, 5 μm, C18；
Flow rate: 0.8 ml/min;
column temperature: 25 ℃;
sample introduction amount: 20 μ L.
Results
The release profile is shown in figure 4, and the release profile conforms to zero-order release, and the cumulative release degree in 12h is 90%.
Absolute bioavailability assay
Figure BDA0003059723990000141
The 6 beagle dogs are randomly divided into 2 groups, and the cross double-cycle design is adopted, wherein the elution cycle is 5-7 days. Before the experiment, the patient fasts for more than 12 hours in the night, and one tablet of oxiracetam osmotic pump controlled release tablet of the embodiment is orally taken in the morning of the experiment or 6g of oxiracetam injection which is sold on the market is injected. The administration was 4h followed by food intake. 2ml of blood was collected from femoral veins before and after administration at 0.25h, 0.5h, 0.75h, 1h, 2h, 3h, 4h, 6h, 8h, 12h, and 24h, and plasma was separated and stored under refrigeration for measurement. And (3) centrifuging the plasma, adding an internal standard solution by taking piracetam as an internal standard, drying by using nitrogen, adding acetonitrile to precipitate protein, centrifuging, filtering, taking 20 mu L of supernatant, injecting, and calculating the concentration of the oxiracetam in the plasma according to a standard curve by an internal standard method.
Chromatographic conditions are as follows:
a chromatographic column: c18；
Mobile phase: acetonitrile/water (V/V with 0.1% acetic acid) 80: 20;
flow rate: 1.0 ml/min;
wavelength: 210 nm;
sample introduction amount: 20 mu L of the solution;
column temperature: 40 ℃;
the absolute bioavailability of the oxiracetam osmotic pump controlled release tablet of the embodiment is determined to be 72.5%.
Example 5
Preparation of oxiracetam osmotic pump controlled release tablet
Polyethylene oxide combinations of different molecular weights
Prescription
Figure BDA0003059723990000151
Preparation method
Sieving oxiracetam, polyethylene oxide (molecular weight 10 ten thousand) and polyethylene oxide (molecular weight 500 ten thousand) with 20 mesh sieve, mixing, and adding PVPk30Ethanol (PVP)k30Mass concentration of 8%) as adhesive, granulating with 20 mesh sieve, oven drying at 45 deg.C for 8-10 hr, sieving with 20 mesh sieve to obtain dry granule, adding pulvis Talci, and pressing into tablet core.
Coating film
Dissolving cellulose acetate and polyethylene glycol 1500 by using acetone, wherein the mass concentration of the cellulose acetate is 4%, the mass concentration of the polyethylene glycol 1500 is 0.6%, preparing to obtain a coating solution, coating the tablet core by using a coating pan, the flow rate of the coating solution is 0.5ml/min, the coating temperature is 35-40 ℃, the coating weight is increased by 6%, and then, drilling a drug release pore with the diameter of 254 mu m on the coating tablet by using laser to obtain the oxiracetam osmotic pump controlled release tablet.
Measurement of Release degree
According to the first method (rotating basket method) in the determination method of dissolution and release in Chinese pharmacopoeia, taking water as medium, respectively sampling at 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 10h and 12h, filtering, and taking as test solution. And accurately weighing oxiracetam reference substances, dissolving the oxiracetam reference substances to obtain reference substance solution, performing high performance liquid chromatography determination, and calculating the cumulative release degree.
High performance liquid chromatography conditions:
mobile phase: methanol/water (V/V) ═ 5: 95;
wavelength: 214 nm;
a chromatographic column: 150mm × 4.6mm, 5 μm, C18；
Flow rate: 0.8 ml/min;
column temperature: 25 ℃;
sample introduction amount: 20 μ L.
Results
The release profile is shown in figure 5, and the release profile conforms to zero-order release, and the cumulative release degree in 12h is 93%.
Absolute bioavailability assay
Figure BDA0003059723990000161
The 6 beagle dogs are randomly divided into 2 groups, and the cross double-cycle design is adopted, wherein the elution cycle is 5-7 days. Before the experiment, the patient fasts for more than 12 hours in the night, and one tablet of oxiracetam osmotic pump controlled release tablet of the embodiment is orally taken in the morning of the experiment or 6g of oxiracetam injection which is sold on the market is injected. The administration was 4h followed by food intake. 2ml of blood was collected from femoral veins before and after administration at 0.25h, 0.5h, 0.75h, 1h, 2h, 3h, 4h, 6h, 8h, 12h, and 24h, and plasma was separated and stored under refrigeration for measurement. And (3) centrifuging the plasma, adding an internal standard solution by taking piracetam as an internal standard, drying by using nitrogen, adding acetonitrile to precipitate protein, centrifuging, filtering, taking 20 mu L of supernatant, injecting, and calculating the concentration of the oxiracetam in the plasma according to a standard curve by an internal standard method.
Chromatographic conditions are as follows:
a chromatographic column: c18；
Mobile phase: acetonitrile/water (V/V with 0.1% acetic acid) 80: 20;
flow rate: 1.0 ml/min;
wavelength: 210 nm;
sample introduction amount: 20 mu L of the solution;
column temperature: 40 ℃;
the absolute bioavailability of the oxiracetam osmotic pump controlled release tablet of the embodiment is determined to be 71.2%.
Example 6
Preparation of oxiracetam osmotic pump controlled release tablet
Polyethylene oxide combinations of different molecular weights
Prescription
Figure BDA0003059723990000162
Figure BDA0003059723990000171
Preparation method
Sieving oxiracetam, polyethylene oxide (molecular weight 10 ten thousand) and polyethylene oxide (molecular weight 500 ten thousand) with 20 mesh sieve, mixing, and adding PVPk30Ethanol (PVP)k30Mass concentration of 8%) as adhesive, granulating with 20 mesh sieve, oven drying at 45 deg.C for 8-10 hr, sieving with 20 mesh sieve to obtain dry granule, adding pulvis Talci, and pressing into tablet core.
Coating film
Dissolving cellulose acetate and polyethylene glycol 1500 by using acetone, wherein the mass concentration of the cellulose acetate is 4%, the mass concentration of the polyethylene glycol 1500 is 0.6%, preparing to obtain a coating solution, coating the tablet core by using a coating pan, the flow rate of the coating solution is 0.5ml/min, the coating temperature is 35-40 ℃, the coating weight is increased by 10%, and then, drilling a medicine release pore with the diameter of 500 mu m on the coating tablet by using laser to obtain the oxiracetam osmotic pump controlled release tablet.
Measurement of Release degree
According to the first method (rotating basket method) in the determination method of dissolution and release in Chinese pharmacopoeia, taking water as medium, respectively sampling at 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 10h and 12h, filtering, and taking as test solution. And accurately weighing oxiracetam reference substances, dissolving the oxiracetam reference substances to obtain reference substance solution, performing high performance liquid chromatography determination, and calculating the cumulative release degree.
High performance liquid chromatography conditions:
mobile phase: methanol/water (V/V) ═ 5: 95;
wavelength: 214 nm;
a chromatographic column: 150mm × 4.6mm, 5 μm, C18；
Flow rate: 0.8 ml/min;
column temperature: 25 ℃;
sample introduction amount: 20 μ L.
Results
The release profile is shown in figure 6, and the release profile conforms to zero-order release, and the cumulative release degree in 12h is 90%.
Absolute bioavailability assay
Figure BDA0003059723990000172
The 6 beagle dogs are randomly divided into 2 groups, and the cross double-cycle design is adopted, wherein the elution cycle is 5-7 days. Before the experiment, the patient fasts for more than 12 hours in the night, and one tablet of oxiracetam osmotic pump controlled release tablet of the embodiment is orally taken in the morning of the experiment or 6g of oxiracetam injection which is sold on the market is injected. The administration was 4h followed by food intake. 2ml of blood was collected from femoral veins before and after administration at 0.25h, 0.5h, 0.75h, 1h, 2h, 3h, 4h, 6h, 8h, 12h, and 24h, and plasma was separated and stored under refrigeration for measurement. And (3) centrifuging the plasma, adding an internal standard solution by taking piracetam as an internal standard, drying by using nitrogen, adding acetonitrile to precipitate protein, centrifuging, filtering, taking 20 mu L of supernatant, injecting, and calculating the concentration of the oxiracetam in the plasma according to a standard curve by an internal standard method.
Chromatographic conditions are as follows:
a chromatographic column: c18；
Mobile phase: acetonitrile/water (V/V with 0.1% acetic acid) 80: 20;
flow rate: 1.0 ml/min;
wavelength: 210 nm;
sample introduction amount: 20 mu L of the solution;
column temperature: 40 ℃;
the absolute bioavailability of the oxiracetam osmotic pump controlled release tablet of the embodiment is determined to be 75.7%.
Cumulative release data for examples 1-6 are shown in Table 1 below
TABLE 1,
Figure BDA0003059723990000181
As can be seen from fig. 1 to 6, when polyethylene oxide is used alone as a retarder, the oxiracetam osmotic pump controlled release tablet does not conform to zero-order release, and the controlled release effect cannot be achieved. The polyethylene oxide with the molecular weight of 500 ten thousand is used as the retarder alone, and compared with the polyethylene oxide with the molecular weight of 10 ten thousand which is used as the retarder alone, the controlled release tablet with the polyethylene oxide with the molecular weight of 500 ten thousand is released faster at the early stage and is released slowly at the later stage. The release of the controlled release tablet which singly uses polyethylene oxide with the molecular weight of 10 ten thousand is slow in the early stage and fast in the later stage.
When two polyethylene oxides with different molecular weights are used as retarders, the oxiracetam osmotic pump controlled release tablet conforms to zero-order release, and the cumulative release degree is 90% -99.8% within 12 h. Therefore, the two polyethylene oxides with different molecular weights play a synergistic role as the retarder, zero-order release is realized, and unexpected effects are achieved. The osmotic pump controlled release tablet can greatly reduce the medication frequency of patients, only 1 tablet is needed in one day, and for senile dementia patients, because the patients frequently forget to take the tablet, the osmotic pump controlled release tablet realizes the once-a-day medication, improves the compliance, and has the advantages of simple preparation, less used auxiliary materials, low cost and clinical use value.

Claims (5)

1. The osmotic pump controlled release preparation is characterized by comprising a tablet core, a retardant, a semi-permeable membrane and a drug release hole, wherein the tablet core comprises a therapeutically effective amount of a western medicine, the retardant is polyethylene oxide, and the osmotic pump controlled release preparation comprises:
800 parts of oxiracetam;
40 parts by weight of polyethylene oxide having a molecular weight of 10 ten thousand;
10-30 parts by weight of polyethylene oxide with a molecular weight of 500 ten thousand;
40-90 parts of talcum powder;
5%~8%PVPk30120-200 parts by weight of an ethanol solution;
the coating liquid comprises acetone, cellulose acetate and polyethylene glycol 1500, wherein the mass concentration of the cellulose acetate is 4-9%, the mass concentration of the polyethylene glycol 1500 is 0.6-1.0%, and the weight of the coating is increased by 6-10%;
and drug release holes with the diameter of 254 μm to 500 μm.
2. The osmotic pump controlled release formulation of claim 1, comprising:
800 parts of oxiracetam;
40 parts by weight of polyethylene oxide having a molecular weight of 10 ten thousand;
10 parts by weight of polyethylene oxide having a molecular weight of 500 ten thousand;
40 parts of talcum powder;
8%PVPk30200 parts of ethanol solution;
and coating liquid, the coating liquid comprises acetone, cellulose acetate and polyethylene glycol 1500, wherein the mass concentration of the cellulose acetate is 4%, the mass concentration of the polyethylene glycol 1500 is 0.6%, and the weight of the coating is increased by 6%;
and drug release holes, the diameter of the drug release holes is 254 μm;
or
800 parts of oxiracetam;
40 parts by weight of polyethylene oxide having a molecular weight of 10 ten thousand;
20 parts by weight of polyethylene oxide having a molecular weight of 500 ten thousand;
40 parts of talcum powder;
8%PVPk30200 parts of ethanol solution;
and coating liquid, the coating liquid comprises acetone, cellulose acetate and polyethylene glycol 1500, wherein the mass concentration of the cellulose acetate is 4%, the mass concentration of the polyethylene glycol 1500 is 0.6%, and the weight of the coating is increased by 6%;
and drug release holes, the diameter of the drug release holes is 254 μm;
or
800 parts of oxiracetam;
40 parts by weight of polyethylene oxide having a molecular weight of 10 ten thousand;
30 parts by weight of polyethylene oxide having a molecular weight of 500 ten thousand;
40 parts of talcum powder;
8%PVPk30200 parts of ethanol solution;
and coating liquid, the coating liquid comprises acetone, cellulose acetate and polyethylene glycol 1500, wherein the mass concentration of the cellulose acetate is 4%, the mass concentration of the polyethylene glycol 1500 is 0.6%, and the weight of the coating is increased by 6%;
and drug release holes, the diameter of the drug release holes is 254 μm;
or
800 parts of oxiracetam;
40 parts by weight of polyethylene oxide having a molecular weight of 10 ten thousand;
30 parts by weight of polyethylene oxide having a molecular weight of 500 ten thousand;
90 parts of talcum powder;
5%PVPk30120 parts of ethanol solution;
the coating solution comprises acetone, cellulose acetate and polyethylene glycol 1500, wherein the mass concentration of the cellulose acetate is 9%, the mass concentration of the polyethylene glycol 1500 is 1.0%, and the coating weight is increased by 10%;
and drug release holes with the diameter of 500 mu m.
3. The osmotic pump controlled release formulation of claim 1, comprising:
800mg of oxiracetam;
40mg of polyethylene oxide having a molecular weight of 10 ten thousand;
10mg of polyethylene oxide having a molecular weight of 500 ten thousand;
40mg of talcum powder;
8%PVPk30200mg of ethanol solution;
and coating liquid, the coating liquid comprises acetone, cellulose acetate and polyethylene glycol 1500, wherein the mass concentration of the cellulose acetate is 4%, the mass concentration of the polyethylene glycol 1500 is 0.6%, and the weight of the coating is increased by 6%;
and drug release holes, the diameter of the drug release holes is 254 μm;
or
800mg of oxiracetam;
40mg of polyethylene oxide having a molecular weight of 10 ten thousand;
20 mg of polyethylene oxide having a molecular weight of 500 ten thousand;
40mg of talcum powder;
8%PVPk30200mg of ethanol solution;
and coating liquid, the coating liquid comprises acetone, cellulose acetate and polyethylene glycol 1500, wherein the mass concentration of the cellulose acetate is 4%, the mass concentration of the polyethylene glycol 1500 is 0.6%, and the weight of the coating is increased by 6%;
and drug release holes, the diameter of the drug release holes is 254 μm;
or
800mg of oxiracetam;
40mg of polyethylene oxide having a molecular weight of 10 ten thousand;
30 mg of polyethylene oxide having a molecular weight of 500 ten thousand;
40mg of talcum powder;
8%PVPk30200mg of ethanol solution;
and coating liquid, the coating liquid comprises acetone, cellulose acetate and polyethylene glycol 1500, wherein the mass concentration of the cellulose acetate is 4%, the mass concentration of the polyethylene glycol 1500 is 0.6%, and the weight of the coating is increased by 6%;
and drug release holes, the diameter of the drug release holes is 254 μm;
or
800mg of oxiracetam;
40mg of polyethylene oxide having a molecular weight of 10 ten thousand;
30 mg of polyethylene oxide having a molecular weight of 500 ten thousand;
90 mg of talcum powder;
5%PVPk30120 mg of ethanol solution;
the coating solution comprises acetone, cellulose acetate and polyethylene glycol 1500, wherein the mass concentration of the cellulose acetate is 9%, the mass concentration of the polyethylene glycol 1500 is 1.0%, and the coating weight is increased by 10%;
and drug release holes with the diameter of 500 mu m.
4. The osmotic pump controlled release formulation of any of claims 1-3, wherein the osmotic pump controlled release formulation is a tablet or capsule.
5. The use of the osmotic pump controlled release formulation according to any of claims 1-3 in the preparation of a medicament for treating memory and intellectual impairment due to mild-moderate vascular dementia, senile dementia or brain trauma.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101422442A (en) * 2008-12-09 2009-05-06 沈阳药科大学 Levetiracetam osmotic pump controlled release tablet and preparation method thereof
WO2009084017A2 (en) * 2007-10-10 2009-07-09 Rubicon Research Private Limited Taste-masked orally disintegrating tablets of memantine hydrochloride
CN102871982A (en) * 2012-10-16 2013-01-16 中国科学院上海药物研究所 Medicine osmotic pump preparation
CN109718222A (en) * 2017-10-27 2019-05-07 重庆润泽医药有限公司 Oxiracetam enteric coated preparations and preparation method thereof
CN111407738A (en) * 2020-04-03 2020-07-14 江苏艾立康药业股份有限公司 Brivaracetam controlled-release preparation and preparation method thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009084017A2 (en) * 2007-10-10 2009-07-09 Rubicon Research Private Limited Taste-masked orally disintegrating tablets of memantine hydrochloride
CN101422442A (en) * 2008-12-09 2009-05-06 沈阳药科大学 Levetiracetam osmotic pump controlled release tablet and preparation method thereof
CN102871982A (en) * 2012-10-16 2013-01-16 中国科学院上海药物研究所 Medicine osmotic pump preparation
CN109718222A (en) * 2017-10-27 2019-05-07 重庆润泽医药有限公司 Oxiracetam enteric coated preparations and preparation method thereof
CN111407738A (en) * 2020-04-03 2020-07-14 江苏艾立康药业股份有限公司 Brivaracetam controlled-release preparation and preparation method thereof

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