CN116059159A - Levetiracetam oral solution - Google Patents

Levetiracetam oral solution Download PDF

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Publication number
CN116059159A
CN116059159A CN202211482960.7A CN202211482960A CN116059159A CN 116059159 A CN116059159 A CN 116059159A CN 202211482960 A CN202211482960 A CN 202211482960A CN 116059159 A CN116059159 A CN 116059159A
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weight
parts
levetiracetam
oral solution
lactose
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程浩文
孙先法
钱祥祥
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Jiangsu Guangcheng Pharmaceutical Co ltd
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Jiangsu Guangcheng Pharmaceutical Co ltd
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    • 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
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    • A61P25/10—Antiepileptics; Anticonvulsants for petit-mal

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Abstract

The invention relates to a levetiracetam oral solution. Specifically, the invention provides a levetiracetam oral solution, which comprises levetiracetam, sucralose, polyethylene glycol 400, glycerol, lactose, mannitol, sorbitol, hydroxyethyl cellulose, citric acid, disodium hydrogen phosphate, sodium bisulphite and water. The levetiracetam oral solution disclosed by the invention can effectively mask the bitter taste and the residue of levetiracetam, so that the levetiracetam oral solution has excellent oral compliance, has excellent illumination, high temperature and high humidity stability, can be packaged in a transparent container, is convenient to store and transport, ensures the quality safety and ensures the medication safety.

Description

Levetiracetam oral solution
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to levetiracetam oral solution.
Background
Levetiracetam (CAS number: 102767-28-2) is an antiepileptic drug, and is mainly used for the additive treatment of partial seizures of adult and children older than 4 years old, and the structural formula of levetiracetam is as follows:
Figure BDA0003962480430000011
the clinically commonly used preparation of levetiracetam comprises a tablet, an injection and an oral solution, wherein the oral solution of levetiracetam can rapidly exert curative effect after oral administration due to convenient oral administration, and has strong patient compliance, however, the existing oral solution of levetiracetam has the defects of bitter taste and bitter residual after oral administration, and the oral solution of levetiracetam needs to be administered for a long time, thus leading to poor oral administration compliance of patients, especially children. In addition, levetiracetam has the defect of poor stability under the conditions of illumination and high temperature and high humidity, so that levetiracetam is often required to be stored in a brown bottle which shields light, and the brown bottle is packaged with levetiracetam, so that when a patient purchases or uses the levetiracetam oral solution, the characteristics of the oral solution such as clarity, whether precipitate particles exist, mildewing, foreign matters and other deterioration phenomena are difficult to simply, quickly and effectively observe through the brown bottle, the problem of medication safety is easily caused, and the production cost is increased due to the fact that the brown bottle is packaged with levetiracetam.
Therefore, there is a need in the art to develop a levetiracetam oral solution, which improves the taste and stability of the levetiracetam oral solution, thereby improving the application value of the levetiracetam oral solution.
Disclosure of Invention
The invention aims to provide a levetiracetam oral solution, which has excellent taste, improves oral compliance of patients and has excellent stability.
In a first aspect of the present invention, there is provided an oral levetiracetam solution comprising levetiracetam, sucralose, polyethylene glycol 400, glycerol, lactose, mannitol, sorbitol, hydroxyethylcellulose, citric acid, disodium hydrogen phosphate, sodium hydrogen sulfite, and water.
Preferably, the levetiracetam is 5-15 parts by weight, preferably 8-12 parts by weight, more preferably 10 parts by weight.
Preferably, the levetiracetam is present in an amount of 5-15g/100ml, preferably 8-12g/100ml, more preferably 10g/100ml.
Preferably, the sucralose is 0.05 to 0.15 parts by weight, preferably 0.06 to 0.10 parts by weight, more preferably 0.08 parts by weight.
Preferably, the sucralose content is 0.05-0.15g/100ml, preferably 0.06-0.10g/100ml, more preferably 0.08g/100ml.
Preferably, the polyethylene glycol 400 is 0.5 to 1.5 parts by weight, preferably 0.8 to 1.2 parts by weight, more preferably 1.0 part by weight.
Preferably, the polyethylene glycol 400 is contained in an amount of 0.5 to 1.5g/100ml, preferably 0.8-1.2g/100ml, more preferably 1.0g/100ml.
Preferably, the glycerol is 2.0 to 3.0 parts by weight, preferably 2.3 to 2.7 parts by weight, more preferably 2.5 parts by weight.
Preferably, the glycerol content is 2.0-3.0g/100ml, preferably 2.3-2.7g/100ml, more preferably 2.5g/100ml.
Preferably, the lactose is 0.2-0.8 parts by weight, preferably 0.4-0.6 parts by weight, more preferably 0.5 parts by weight.
Preferably, the lactose content is 0.2-0.8g/100ml, preferably 0.4-0.6g/100ml, more preferably 0.5g/100ml.
Preferably, the mannitol is 1.0 to 2.0 parts by weight, preferably 1.3 to 1.7 parts by weight, more preferably 1.5 parts by weight.
Preferably, the mannitol is present in an amount of 1.0-2.0g/100ml, preferably 1.3-1.7g/100ml, more preferably 1.5g/100ml.
Preferably, the sorbitol is 1.5-2.5 parts by weight, preferably 1.8-2.2 parts by weight, more preferably 2.0 parts by weight.
Preferably, the sorbitol is present in an amount of 1.5-2.5g/100ml, preferably 1.8-2.2g/100ml, more preferably 2.0g/100ml.
Preferably, the hydroxyethyl cellulose is 0.2 to 1.0 parts by weight, preferably 0.4 to 0.8 parts by weight, more preferably 0.6 parts by weight.
Preferably, the content of the hydroxyethyl cellulose is 0.2-1.0g/100ml, preferably 0.4-0.8g/100ml, more preferably 0.6g/100ml.
Preferably, the citric acid is 0.02-0.08 parts by weight, preferably 0.03-0.07 parts by weight, more preferably 0.05 parts by weight.
Preferably, the citric acid content is 0.02-0.08g/100ml, preferably 0.03-0.07g/100ml, more preferably 0.05g/100ml.
Preferably, the disodium hydrogen phosphate is 0.1 to 0.5 parts by weight, preferably 0.2 to 0.4 parts by weight, more preferably 0.3 parts by weight.
Preferably, the disodium hydrogen phosphate is present in an amount of 0.1 to 0.5g/100ml, preferably 0.2 to 0.4g/100ml, more preferably 0.3g/100ml.
Preferably, the sodium bisulfite is in the range of 0.02 to 0.06 parts by weight, preferably 0.03 to 0.05 parts by weight, more preferably 0.04 parts by weight.
Preferably, the sodium bisulphite is present in an amount of 0.02-0.06g/100ml, preferably 0.03-0.05g/100ml, more preferably 0.04g/100ml.
Preferably, the water is 90-110 parts by weight, preferably 95-105 parts by weight, more preferably 100 parts by weight.
Preferably, the water is purified water.
Preferably, the levetiracetam oral solution comprises:
component (A) Dosage of
Levetiracetam 5-15 parts by weight
Sucralose 0.05 to 0.15 part by weight
Polyethylene glycol 400 0.5 to 1.5 parts by weight
Glycerol 2.0 to 3.0 parts by weight
Lactose and lactose 0.2 to 0.8 part by weight
Mannitol (mannitol) 1.0 to 2.0 parts by weight
Sorbitol 1.5 to 2.5 parts by weight
Hydroxyethyl cellulose 0.3 to 1.0 part by weight
Citric acid 0.02-0.08 part by weight
Disodium hydrogen phosphate 0.1 to 0.5 part by weight
Sodium bisulfite 0.02-0.06 parts by weight; and
water and its preparation method 90-110 parts by weight.
Preferably, the levetiracetam oral solution comprises:
component (A) Dosage of
Levetiracetam 8-12 parts by weight
Sucralose 0.06-0.10 part by weight
Polyethylene glycol 400 0.8-1.2 parts by weight
Glycerol 2.3 to 2.7 parts by weight
Lactose and lactose 0.4 to 0.6 part by weight
Mannitol (mannitol) 1.3 to 1.7 parts by weight
Sorbitol 1.8 to 2.2 parts by weight
Hydroxyethyl cellulose 0.5 to 0.7 part by weight
Citric acid 0.04 to 0.06 part by weight
Disodium hydrogen phosphate 0.2 to 0.4 part by weight
Sodium bisulfite 0.03-0.05 parts by weight; and
water and its preparation method 95-105 parts by weight.
Preferably, the levetiracetam oral solution comprises:
Figure BDA0003962480430000031
Figure BDA0003962480430000041
/>
preferably, the levetiracetam oral solution comprises:
component (A) Dosage of
Levetiracetam 10g
Sucralose 0.08g
Polyethylene glycol 400 1.0g
Glycerol 2.5g
Lactose and lactose 0.5g
Mannitol (mannitol) 1.5g
Sorbitol 2.0g
Hydroxyethyl cellulose 0.6g
Citric acid 0.05g
Disodium hydrogen phosphate 0.3g
Sodium bisulfite 0.04g; and
adding water To 100ml.
In a second aspect of the present invention, there is provided a process for preparing an oral solution of levetiracetam as defined in the first aspect of the invention, said process comprising the steps of:
mixing levetiracetam, sucralose, polyethylene glycol 400, glycerol, lactose, mannitol, sorbitol, hydroxyethyl cellulose, citric acid, disodium hydrogen phosphate, sodium bisulfate and water to obtain the levetiracetam oral solution.
Preferably, the levetiracetam oral solution is prepared by the following method:
(1) Taking 75-85% of the prescription amount of water after boiling and cooling, adding the prescription amount of hydroxyethyl cellulose, stirring and mixing at 35-45 ℃, adding the prescription amount of polyethylene glycol 400 and the prescription amount of glycerin, stirring and mixing at 35-45 ℃, adding the prescription amount of levetiracetam, and stirring and mixing at 35-45 ℃ to obtain the liquid medicine.
(2) Adding the prescription amount of sucralose, the prescription amount of lactose, the prescription amount of mannitol, the prescription amount of sorbitol, the prescription amount of citric acid, the prescription amount of disodium hydrogen phosphate and the prescription amount of sodium bisulphate into the liquid medicine obtained in the step (1), stirring and mixing at 35-45 ℃, adding boiled and cooled water to a fixed volume, stirring and mixing, and filtering by a microporous filter membrane with the size of 0.45 mu m and a microporous filter membrane with the size of 0.22 mu m in sequence to obtain the levetiracetam oral solution.
In a third aspect of the present invention, there is provided a kit comprising a transparent container and an oral levetiracetam solution as described in the first aspect of the present invention;
the levetiracetam oral solution is packaged in the transparent container.
Preferably, the transparent container comprises a transparent plastic container (such as a transparent PET bottle) or a transparent glass container.
In a fourth aspect of the present invention, there is provided the use of levetiracetam oral solution as described in the first aspect of the present invention for the preparation of an antiepileptic drug.
Preferably, the epilepsy comprises partial seizure epilepsy.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions.
Detailed Description
The levetiracetam oral solution disclosed by the invention can be used for effectively covering the bitter taste and the residue of levetiracetam, so that the levetiracetam oral solution has excellent oral compliance, has excellent illumination, high-temperature and high-humidity stability, can be packaged in a transparent container, is convenient to store and transport, ensures quality safety and ensures medication safety.
Terminology
As used herein, the terms "comprising," "including," and "containing" are used interchangeably, and include not only closed-form definitions, but also semi-closed-form and open-form definitions. In other words, the term includes "consisting of … …", "consisting essentially of … …".
As used herein, the term "PET" refers to polyethylene terephthalate, english name Poly (ethylene Terephthalate).
As used herein, the term "parts by weight" may be any fixed weight in milligrams, grams, or kilograms (e.g., 1mg, 1g, or 1kg, etc.). For example, a composition comprising 1 part by weight of component a and 9 parts by weight of component b may be a composition comprising 1 gram of component a+9 gram of component b, or 10 grams of component a+90 gram of component b, etc. In the pharmaceutical composition, the percentage content of a certain component= (the parts by weight of the component/the sum of the parts by weight of all components) ×100%, and therefore, in the composition composed of 1 part by weight of component a and 9 parts by weight of component b, the content of component a is 10%, and the content of component b is 90%.
Levetiracetam oral solution and preparation method thereof
The invention provides a levetiracetam oral solution, which comprises levetiracetam, sucralose, polyethylene glycol 400, glycerol, lactose, mannitol, sorbitol, hydroxyethyl cellulose, citric acid, disodium hydrogen phosphate, sodium bisulfate and water.
In a preferred embodiment of the present invention, the levetiracetam is 5 to 15 parts by weight, preferably 8 to 12 parts by weight, more preferably 10 parts by weight.
Preferably, the levetiracetam is present in an amount of 5-15g/100ml, preferably 8-12g/100ml, more preferably 10g/100ml.
In a preferred embodiment of the present invention, the sucralose is 0.05 to 0.15 parts by weight, preferably 0.06 to 0.10 parts by weight, more preferably 0.08 parts by weight.
Preferably, the sucralose content is 0.05-0.15g/100ml, preferably 0.06-0.10g/100ml, more preferably 0.08g/100ml.
In a preferred embodiment of the present invention, the polyethylene glycol 400 is 0.5 to 1.5 parts by weight, preferably 0.8 to 1.2 parts by weight, more preferably 1.0 part by weight.
Preferably, the polyethylene glycol 400 is present in an amount of 0.5-1.5g/100ml, preferably 0.8-1.2g/100ml, more preferably 1.0g/100ml.
In a preferred embodiment of the invention, the glycerol is 2.0 to 3.0 parts by weight, preferably 2.3 to 2.7 parts by weight, more preferably 2.5 parts by weight.
Preferably, the glycerol content is 2.0-3.0g/100ml, preferably 2.3-2.7g/100ml, more preferably 2.5g/100ml.
In a preferred embodiment of the invention, the lactose is 0.2-0.8 parts by weight, preferably 0.4-0.6 parts by weight, more preferably 0.5 parts by weight.
Preferably, the lactose content is 0.2-0.8g/100ml, preferably 0.4-0.6g/100ml, more preferably 0.5g/100ml.
In a preferred embodiment of the present invention, the mannitol is 1.0 to 2.0 parts by weight, preferably 1.3 to 1.7 parts by weight, more preferably 1.5 parts by weight.
Preferably, the mannitol is present in an amount of 1.0-2.0g/100ml, preferably 1.3-1.7g/100ml, more preferably 1.5g/100ml.
In a preferred embodiment of the invention, the sorbitol is 1.5-2.5 parts by weight, preferably 1.8-2.2 parts by weight, more preferably 2.0 parts by weight.
Preferably, the sorbitol is present in an amount of 1.5-2.5g/100ml, preferably 1.8-2.2g/100ml, more preferably 2.0g/100ml.
In a preferred embodiment of the present invention, the hydroxyethyl cellulose is 0.2 to 1.0 parts by weight, preferably 0.4 to 0.8 parts by weight, more preferably 0.6 parts by weight.
Preferably, the content of the hydroxyethyl cellulose is 0.2-1.0g/100ml, preferably 0.4-0.8g/100ml, more preferably 0.6g/100ml.
In a preferred embodiment of the invention, the citric acid is 0.02-0.08 parts by weight, preferably 0.03-0.07 parts by weight, more preferably 0.05 parts by weight.
Preferably, the citric acid content is 0.02-0.08g/100ml, preferably 0.03-0.07g/100ml, more preferably 0.05g/100ml.
In a preferred embodiment of the present invention, the disodium hydrogen phosphate is 0.1 to 0.5 parts by weight, preferably 0.2 to 0.4 parts by weight, more preferably 0.3 parts by weight.
Preferably, the disodium hydrogen phosphate is present in an amount of 0.1 to 0.5g/100ml, preferably 0.2 to 0.4g/100ml, more preferably 0.3g/100ml.
In a preferred embodiment of the present invention, the sodium bisulfite is in the range of 0.02 to 0.06 parts by weight, preferably 0.03 to 0.05 parts by weight, more preferably 0.04 parts by weight.
Preferably, the sodium bisulphite is present in an amount of 0.02-0.06g/100ml, preferably 0.03-0.05g/100ml, more preferably 0.04g/100ml.
In a preferred embodiment of the invention, the water is 90-110 parts by weight, preferably 95-105 parts by weight, more preferably 100 parts by weight.
Representatively, the levetiracetam oral solution comprises:
Figure BDA0003962480430000061
Figure BDA0003962480430000071
/>
representatively, the levetiracetam oral solution comprises:
component (A) Dosage of
Levetiracetam 8-12 parts by weight
Sucralose 0.06-0.10 part by weight
Polyethylene glycol 400 0.8-1.2 parts by weight
Glycerol 2.3 to 2.7 parts by weight
Lactose and lactose 0.4 to 0.6 part by weight
Mannitol (mannitol) 1.3 to 1.7 parts by weight
Sorbitol 1.8 to 2.2 parts by weight
Hydroxyethyl cellulose 0.5 to 0.7 part by weight
Citric acid 0.04 to 0.06 part by weight
Disodium hydrogen phosphate 0.2 to 0.4 part by weight
Sodium bisulfite 0.03-0.05 parts by weight; and
water and its preparation method 95-105 parts by weight.
Typically, the levetiracetam oral solution comprises:
component (A) Dosage of
Levetiracetam 10 parts by weight
Sucralose 0.08 part by weight
Polyethylene glycol 400 1.0 part by weight
Glycerol 2.5 parts by weight
Lactose and lactose 0.5 part by weight
Mannitol (mannitol) 1.5 parts by weight
Sorbitol 2.0 parts by weight
Hydroxyethyl cellulose 0.6 part by weight
Citric acid 0.05 part by weight
Disodium hydrogen phosphate 0.3 part by weight
Sodium bisulfite 0.04 parts by weight; and
water and its preparation method 95-105 parts by weight.
Typically, the levetiracetam oral solution comprises:
Figure BDA0003962480430000072
/>
Figure BDA0003962480430000081
the invention provides a method for preparing levetiracetam oral solution, which comprises the following steps:
mixing levetiracetam, sucralose, polyethylene glycol 400, glycerol, lactose, mannitol, sorbitol, hydroxyethyl cellulose, citric acid, disodium hydrogen phosphate, sodium bisulfate and water to obtain the levetiracetam oral solution.
Typically, the levetiracetam oral solution is prepared by the following method:
(1) Taking 75-85% of the prescription amount of water after boiling and cooling, adding the prescription amount of hydroxyethyl cellulose, stirring and mixing at 35-45 ℃, adding the prescription amount of polyethylene glycol 400 and the prescription amount of glycerin, stirring and mixing at 35-45 ℃, adding the prescription amount of levetiracetam, and stirring and mixing at 35-45 ℃ to obtain the liquid medicine.
(2) Adding the prescription amount of sucralose, the prescription amount of lactose, the prescription amount of mannitol, the prescription amount of sorbitol, the prescription amount of citric acid, the prescription amount of disodium hydrogen phosphate and the prescription amount of sodium bisulphate into the liquid medicine obtained in the step (1), stirring and mixing at 35-45 ℃, adding boiled and cooled water to a fixed volume, stirring and mixing, and filtering by a microporous filter membrane with the size of 0.45 mu m and a microporous filter membrane with the size of 0.22 mu m in sequence to obtain the levetiracetam oral solution.
Use of the same
The invention also provides application of the levetiracetam oral solution in preparing antiepileptic drugs.
Preferably, the epilepsy comprises partial seizure epilepsy.
The main excellent technical effects of the invention include:
the levetiracetam oral solution can effectively mask the bitter taste and the residual of levetiracetam, has excellent oral compliance, and is suitable for oral administration of patients, particularly children. The levetiracetam oral solution provided by the invention has excellent illumination, high temperature and high humidity stability, can be packaged in a transparent container for storage and transportation, and can be simply, quickly and effectively observed through the transparent container when a patient purchases or uses the levetiracetam oral solution, such as clarity, whether precipitate particles, mildews, foreign matters and other deterioration phenomena exist in the levetiracetam oral solution, so that the medication safety is ensured, and in addition, the high temperature and high humidity stability can effectively ensure the stability of the levetiracetam oral solution in the transportation and storage process, thereby being convenient for storage and transportation and ensuring the quality safety.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedure, in which specific conditions are not noted in the examples below, is generally followed by conventional conditions.
EXAMPLE 1 levetiracetam oral solution
This example 1 prepared an oral solution of levetiracetam whose prescription composition is shown in table 1:
TABLE 1 prescription composition of levetiracetam oral solution (levetiracetam specification 0.1 g/ml)
Component (A) Dosage of
Levetiracetam 10g
Sucralose 0.08g
Polyethylene glycol 400 1.0g
Glycerol 2.5g
Lactose and lactose 0.5g
Mannitol (mannitol) 1.5g
Sorbitol 2.0g
Hydroxyethyl cellulose 0.6g
Citric acid 0.05g
Hydrogen phosphate disodium salt 0.3g
Sodium bisulfite 0.04g
Adding purified water To 100ml.
The preparation method of levetiracetam oral solution of this example 1 is as follows:
(1) Taking 80% of the purified water with the prescription amount after boiling and cooling, adding the hydroxyethyl cellulose with the prescription amount, stirring and mixing at 40 ℃, adding the polyethylene glycol 400 with the prescription amount and the glycerin with the prescription amount, stirring and mixing at 40 ℃, adding the levetiracetam with the prescription amount, and stirring and mixing at 40 ℃ to obtain the liquid medicine.
(2) Adding the prescription amount of sucralose, the prescription amount of lactose, the prescription amount of mannitol, the prescription amount of sorbitol, the prescription amount of citric acid, the prescription amount of disodium hydrogen phosphate and the prescription amount of sodium bisulphate into the liquid medicine obtained in the step (1), stirring and mixing at 40 ℃, adding the boiled and cooled purified water to a fixed volume to a dosage volume, stirring and mixing, filtering by a microporous filter membrane with the size of 0.45 mu m and a microporous filter membrane with the size of 0.22 mu m in sequence, obtaining levetiracetam oral solution, and subpackaging in transparent PET bottles.
EXAMPLE 2 levetiracetam oral solution
This example 2 a levetiracetam oral solution was prepared with the prescription composition shown in table 2:
TABLE 2 prescription composition of levetiracetam oral solution (levetiracetam specification 0.1 g/ml)
Figure BDA0003962480430000091
Figure BDA0003962480430000101
The preparation method of levetiracetam oral solution of this example 2 is as follows:
(1) Taking 80% of the purified water with the prescription amount after boiling and cooling, adding the hydroxyethyl cellulose with the prescription amount, stirring and mixing at 40 ℃, adding the polyethylene glycol 400 with the prescription amount and the glycerin with the prescription amount, stirring and mixing at 40 ℃, adding the levetiracetam with the prescription amount, and stirring and mixing at 40 ℃ to obtain the liquid medicine.
(2) Adding the prescription amount of sucralose, the prescription amount of lactose, the prescription amount of mannitol, the prescription amount of sorbitol, the prescription amount of tartaric acid, the prescription amount of disodium hydrogen phosphate and the prescription amount of sodium bisulphate into the liquid medicine obtained in the step (1), stirring and mixing at 40 ℃, adding the boiled and cooled purified water to a fixed volume to a dosage volume, stirring and mixing, filtering by a microporous filter membrane with the size of 0.45 mu m and a microporous filter membrane with the size of 0.22 mu m in sequence, obtaining levetiracetam oral solution, and subpackaging in transparent PET bottles.
EXAMPLE 3 levetiracetam oral solution
This example 3 an oral levetiracetam solution was prepared with the prescription composition shown in table 3:
TABLE 3 prescription composition of levetiracetam oral solution (levetiracetam specification 0.1 g/ml)
Component (A) Dosage of
Levetiracetam 10g
Sucralose 0.08g
Polyethylene glycol 400 1.0g
Glycerol 2.5g
Lactose and lactose 0.5g
Sorbitol 2.0g
Hydroxyethyl cellulose 0.6g
Citric acid 0.05g
Disodium hydrogen phosphate 0.3g
Sodium bisulfite 0.04g
Adding purified water To 100ml.
The preparation method of levetiracetam oral solution of this example 3 is as follows:
(1) Taking 80% of the purified water with the prescription amount after boiling and cooling, adding the hydroxyethyl cellulose with the prescription amount, stirring and mixing at 40 ℃, adding the polyethylene glycol 400 with the prescription amount and the glycerin with the prescription amount, stirring and mixing at 40 ℃, adding the levetiracetam with the prescription amount, and stirring and mixing at 40 ℃ to obtain the liquid medicine.
(2) Adding the prescription amount of sucralose, the prescription amount of lactose, the prescription amount of sorbitol, the prescription amount of citric acid, the prescription amount of disodium hydrogen phosphate and the prescription amount of sodium bisulphate into the liquid medicine obtained in the step (1), stirring and mixing at 40 ℃, adding the boiled and cooled purified water to fix the volume to the dosage volume, stirring and mixing, filtering by a microporous filter membrane with the size of 0.45 mu m and a microporous filter membrane with the size of 0.22 mu m in sequence to obtain levetiracetam oral solution, and subpackaging in transparent PET bottles.
EXAMPLE 4 levetiracetam oral solution
This example 4 an oral levetiracetam solution was prepared with the prescription composition shown in table 4:
TABLE 4 prescription composition of levetiracetam oral solution (levetiracetam specification 0.1 g/ml)
Component (A) Dosage of
Levetiracetam 10g
Sucralose 0.08g
Polyethylene glycol 400 1.0g
Glycerol 0.6g
Lactose and lactose 0.5g
Mannitol (mannitol) 1.5g
Sorbitol 2.0g
Hydroxyethyl cellulose 1.0g
Citric acid 0.05g
Disodium hydrogen phosphate 0.3g
Sodium bisulfite 0.04g
Adding purified water To 100ml.
The preparation method of levetiracetam oral solution of this example 4 is as follows:
(1) Taking 80% of the purified water with the prescription amount after boiling and cooling, adding the hydroxyethyl cellulose with the prescription amount, stirring and mixing at 40 ℃, adding the polyethylene glycol 400 with the prescription amount and the glycerin with the prescription amount, stirring and mixing at 40 ℃, adding the levetiracetam with the prescription amount, and stirring and mixing at 40 ℃ to obtain the liquid medicine.
(2) Adding the prescription amount of sucralose, the prescription amount of lactose, the prescription amount of mannitol, the prescription amount of sorbitol, the prescription amount of citric acid, the prescription amount of disodium hydrogen phosphate and the prescription amount of sodium bisulphate into the liquid medicine obtained in the step (1), stirring and mixing at 40 ℃, adding the boiled and cooled purified water to a fixed volume to a dosage volume, stirring and mixing, filtering by a microporous filter membrane with the size of 0.45 mu m and a microporous filter membrane with the size of 0.22 mu m in sequence, obtaining levetiracetam oral solution, and subpackaging in transparent PET bottles.
EXAMPLE 5 levetiracetam oral solution
This example 5 a levetiracetam oral solution was prepared with the prescription composition shown in table 5:
TABLE 5 prescription composition of levetiracetam oral solution (levetiracetam specification 0.1 g/ml)
Figure BDA0003962480430000111
Figure BDA0003962480430000121
The preparation method of levetiracetam oral solution of this example 5 is as follows:
(1) Taking 80% of the purified water with the prescription amount after boiling and cooling, adding the hydroxyethyl cellulose with the prescription amount, stirring and mixing at 40 ℃, adding the glycerin with the prescription amount, stirring and mixing at 40 ℃, adding the levetiracetam with the prescription amount, and stirring and mixing at 40 ℃ to obtain the liquid medicine.
(2) Adding the prescription amount of sucralose, the prescription amount of lactose, the prescription amount of mannitol, the prescription amount of sorbitol, the prescription amount of citric acid, the prescription amount of disodium hydrogen phosphate and the prescription amount of sodium bisulphate into the liquid medicine obtained in the step (1), stirring and mixing at 40 ℃, adding the boiled and cooled purified water to a fixed volume to a dosage volume, stirring and mixing, filtering by a microporous filter membrane with the size of 0.45 mu m and a microporous filter membrane with the size of 0.22 mu m in sequence, obtaining levetiracetam oral solution, and subpackaging in transparent PET bottles.
Taste and stability investigation of levetiracetam oral solution
1. Taste investigation
Taking 20 subjects to orally examine the mouthfeel of levetiracetam oral solutions prepared in the examples 1-5, wherein the mouthfeel evaluation indexes are the taste and bitter taste residues, and the scoring standards of the taste and bitter taste residues are as follows: 0 minutes (none, pleasant mouthfeel); score 1 (slight, no impact on mouthfeel); 2 minutes (have, influence on mouthfeel); score 3 (more severe, acceptable); score 4 (severe, unacceptable).
In the taste evaluation test, the subject cannot make a possible taste judgment on the levetiracetam oral solution to be tasted in advance from the levetiracetam oral solution label by adopting a single-blind method, and the examination result is shown in table 6:
table 6 taste evaluation of levetiracetam oral solutions prepared in examples 1-5
Experimental group Degree of bitter taste in mouth Residual bitter taste
Example 1 0.2 0.1
Example 2 0.8 0.5
Implementation of the embodimentsExample 3 2.8 2.1
Example 4 1.9 1.4
Example 5 2.4 1.8
As can be seen from table 6, the levetiracetam oral solution prepared in this example can improve the bitter taste of levetiracetam, and in particular, the levetiracetam oral solution prepared in example 1 has an excellent taste, and can effectively mask the bitter taste and the residue thereof, thereby having an excellent oral compliance, and being suitable for oral administration to patients, particularly children.
2. Stability investigation of illumination factor
The levetiracetam oral solution prepared in examples 1 to 5 and sub-packaged in transparent PET bottles was placed under light conditions (4500 lx,25 ℃) for 0 days, 5 days and 10 days, and the levetiracetam content, the levetiracetam impurity content and the total impurity content at different investigation time points were measured by high performance liquid chromatography according to the principle of stability test of chinese pharmacopoeia preparations, so that the light stability of the levetiracetam oral solution prepared in examples 1 to 5 was examined, and the results are shown in table 7.
TABLE 7 stability examination of levetiracetam oral solution prepared in examples 1-5 under illumination conditions (4500 lx,25 ℃ C.)
Figure BDA0003962480430000131
As can be seen from table 7, the levetiracetam oral solution prepared in example 1 has strong light stability and excellent light stability, and can be stored and transported in transparent containers in a split-charging manner, so that not only can the production and storage costs be reduced, but also the characteristics of the levetiracetam oral solution, such as clarity, whether there are precipitated particles, mold, foreign matters and other deterioration phenomena, can be simply, rapidly and effectively observed by the transparent containers when a patient purchases or uses the levetiracetam oral solution, and the medication safety is ensured.
3. High temperature and high humidity acceleration stability investigation
The levetiracetam oral solution prepared in example 1 and packaged in transparent PET bottles was placed at a temperature of 40±2 ℃ and a relative humidity RH of 75±5% for 0 days, 1, 3 and 6 months, and the levetiracetam content, the impurity content of levetiracetam acid and the total impurity content at different investigation time points were measured by high performance liquid chromatography according to the principle of stability test guidance of the chinese pharmacopoeia formulation, so that the high temperature and high humidity acceleration stability of the levetiracetam oral solution prepared in example 1 was investigated, and the results are shown in table 8.
Table 8 accelerated stability examination of levetiracetam oral solution prepared in example 1 at a temperature of 40±2 ℃ and a relative humidity RH of 75±5%
Figure BDA0003962480430000141
As can be seen from table 8, the levetiracetam oral solution prepared in example 1 has excellent high-temperature and high-humidity stability, can reduce the storage and transportation costs of levetiracetam oral solution, and can ensure the quality requirements of levetiracetam oral solution during transportation and storage, and ensure the quality safety.
While the invention has been described in terms of one embodiment, it should be noted that modifications could be made without departing from the principles of the invention, which would be apparent to those skilled in the art, would also be considered to be within the scope of the invention.

Claims (10)

1. The levetiracetam oral solution is characterized by comprising levetiracetam, sucralose, polyethylene glycol 400, glycerol, lactose, mannitol, sorbitol, hydroxyethyl cellulose, citric acid, disodium hydrogen phosphate, sodium bisulfate and water.
2. Levetiracetam oral solution as claimed in claim 1, characterized in that the levetiracetam is 5-15 parts by weight, preferably 8-12 parts by weight, more preferably 10 parts by weight;
the sucralose is 0.05 to 0.15 parts by weight, preferably 0.06 to 0.10 parts by weight, more preferably 0.08 parts by weight;
the polyethylene glycol 400 is 0.5 to 1.5 parts by weight, preferably 0.8 to 1.2 parts by weight, more preferably 1.0 part by weight;
the glycerin is 2.0 to 3.0 parts by weight, preferably 2.3 to 2.7 parts by weight, more preferably 2.5 parts by weight;
the lactose is 0.2-0.8 parts by weight, preferably 0.4-0.6 parts by weight, more preferably 0.5 parts by weight;
the mannitol is 1.0 to 2.0 parts by weight, preferably 1.3 to 1.7 parts by weight, more preferably 1.5 parts by weight;
the sorbitol is 1.5-2.5 parts by weight, preferably 1.8-2.2 parts by weight, more preferably 2.0 parts by weight;
the hydroxyethyl cellulose is 0.2 to 1.0 parts by weight, preferably 0.4 to 0.8 parts by weight, more preferably 0.6 parts by weight;
the citric acid is 0.02-0.08 weight parts, preferably 0.03-0.07 weight parts, more preferably 0.05 weight parts;
the disodium hydrogen phosphate is 0.1 to 0.5 parts by weight, preferably 0.2 to 0.4 parts by weight, more preferably 0.3 parts by weight;
the sodium bisulphite is 0.02-0.06 parts by weight, preferably 0.03-0.05 parts by weight, more preferably 0.04 parts by weight; and
the water is 90-110 parts by weight, preferably 95-105 parts by weight, more preferably 100 parts by weight.
3. The levetiracetam oral solution of claim 1, wherein the levetiracetam oral solution comprises:
component (A) Dosage of Levetiracetam 5-15 parts by weight Sucralose 0.05 to 0.15 part by weight Polyethylene glycol 400 0.5 to 1.5 parts by weight Glycerol 2.0 to 3.0 parts by weight Lactose and lactose 0.2 to 0.8 part by weight Mannitol (mannitol) 1.0 to 2.0 parts by weight Sorbitol 1.5 to 2.5 parts by weight Hydroxyethyl cellulose 0.3 to 1.0 part by weight Citric acid 0.02-0.08 part by weight Disodium hydrogen phosphate 0.1 to 0.5 part by weight Sodium bisulfite 0.02-0.06 parts by weight; and water and its preparation method 90-110 parts by weight.
4. The levetiracetam oral solution of claim 1, wherein the levetiracetam oral solution comprises:
component (A) Dosage of Levetiracetam 8-12 parts by weight Sucralose 0.06-0.10 part by weight Polyethylene glycol 400 0.8-1.2 parts by weight Glycerol 2.3 to 2.7 parts by weight Lactose and lactose 0.4 to 0.6 part by weight Mannitol (mannitol) 1.3 to 1.7 parts by weight Sorbitol 1.8 to 2.2 parts by weight Hydroxyethyl cellulose 0.5 to 0.7 part by weight Citric acid 0.04 to 0.06 part by weight Disodium hydrogen phosphate 0.2 to 0.4 part by weight Sodium bisulfite 0.03-0.05 parts by weight; and water and its preparation method 95-105 parts by weight.
5. The levetiracetam oral solution of claim 1, wherein the levetiracetam oral solution comprises:
component (A) Dosage of Levetiracetam 10 parts by weight Sucralose 0.08 part by weight Polyethylene glycol 400 1.0 part by weight Glycerol 2.5 parts by weight Lactose and lactose 0.5 part by weight Mannitol (mannitol) 1.5 parts by weight Sorbitol 2.0 parts by weight Hydroxyethyl cellulose 0.6 part by weight Citric acid 0.05 part by weight Disodium hydrogen phosphate 0.3 part by weight Sodium bisulfite 0.04 part by weightThe method comprises the steps of carrying out a first treatment on the surface of the And water and its preparation method 95-105 parts by weight.
6. The levetiracetam oral solution of claim 1, wherein the levetiracetam oral solution comprises:
Figure FDA0003962480420000021
Figure FDA0003962480420000031
7. the levetiracetam oral solution of claim 1, characterized in that a process for preparing the levetiracetam oral solution of the first aspect of the invention is provided, the process comprising the steps of:
mixing levetiracetam, sucralose, polyethylene glycol 400, glycerol, lactose, mannitol, sorbitol, hydroxyethyl cellulose, citric acid, disodium hydrogen phosphate, sodium bisulfate and water to obtain the levetiracetam oral solution.
8. A kit comprising a transparent container and the levetiracetam oral solution of claim 1;
the levetiracetam oral solution is packaged in the transparent container.
9. Use of levetiracetam oral solution as defined in claim 1 for the preparation of an antiepileptic drug.
10. The use according to claim 9, wherein the epilepsy comprises partial seizure epilepsy.
CN202211482960.7A 2022-11-24 2022-11-24 Levetiracetam oral solution Pending CN116059159A (en)

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