CN114699368B - Lacosamide oral solution and preparation method thereof - Google Patents
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Abstract
The invention relates to a lacosamide oral solution and a preparation method thereof, wherein sodium carboxymethyl cellulose, povidone and polyethylene glycol are used as taste masking combined matrixes, so that the viscosity of the oral solution is increased, the contact time between a medicine and taste buds is reduced, the strong bitter taste of the lacosamide oral solution can be effectively masked under the condition that a sweetener is not added, the attention of a patient to the bitter taste is transferred through the cooling effect of menthol, the medication compliance of the patient is improved, the stability of the oral solution is improved, and the effective period of the medicine is prolonged. In the lacosamide oral solution provided by the invention, the auxiliary materials are few in variety, the preparation method is simple, and the lacosamide oral solution has good taste masking effect and stability.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and in particular relates to a lacosamide oral solution and a preparation method thereof.
Background
Lacosamide is a novel antiepileptic drug, a novel N-methyl-D-aspartate (NMDA) receptor glycine site binding antagonist developed by Schwarz Biosciences, germany, belgium, pharma. The glycine site binding antagonist of the NMDA receptor belongs to a new class of functional amino acids, and is an anticonvulsant with brand-new double mechanism action. It can selectively promote slow inactivation of sodium channels and regulate collapse response mediated protein 22 (CRMP 22), while CRMP22 may slow or even stop seizures and alleviate neuropathic pain in diabetes.
At present, the lacosamide on the market is mainly an oral solid preparation, the administration is inflexible, the dosage is not easy to accurately control, and the lacosamide is difficult to take for patients and children with dysphagia. The oral liquid preparation can effectively solve the problems, but the strong bitter taste brought by the raw materials can influence the taste of a patient, and a large amount of sweetener is needed to be added for flavoring.
For example, chinese patent 112022804a discloses an oral solution of lacosamide comprising lacosamide, a solubilizer, a thickener, a flavoring agent, an acidity regulator and a preservative; the mass concentration of the flavoring agent is 180-300mg/mL, the addition of a large amount of sweetener can cause the defects of stability and taste, for example, when natural sweetener such as sucrose and the like is added, the heat quantity is high, the natural sweetener is easy to spoil, the stability of the solution is poor, the solution is not suitable for storage, the taste is not friendly to special people, the added artificial synthetic sweetener is not pure enough, metal taste exists, the sensitivity of taste buds can be influenced when the higher sweetness is excessively eaten, and the safety of most synthetic sweeteners remains to be purchased.
Therefore, the bitterness of the solution is reduced without using a sweetener by a preparation method, and the stability of the solution is enhanced while the oral compliance is improved.
Disclosure of Invention
The invention aims to provide a lacosamide oral solution based on the prior art, which takes sodium carboxymethyl cellulose, povidone and polyethylene glycol as taste masking combined matrixes, so that the viscosity of the oral solution is increased, the contact time between a drug and taste buds is reduced, the strong bitter taste of the lacosamide oral solution can be effectively masked under the condition of not adding a sweetener, the compliance of a patient in drug administration is improved, the stability of the oral solution is improved, and the effective period of the drug is prolonged.
The invention also aims to provide a preparation method of the lacosamide oral solution.
The technical scheme of the invention is as follows:
an oral solution of lacosamide comprises active components of lacosamide, sodium carboxymethyl cellulose, povidone, polyethylene glycol, a bacteriostatic agent, a pH regulator and a cooling agent; wherein, the mass concentration of the lacosamide is 10mg/ml, the mass concentration of the carboxymethylcellulose sodium is 10-20 mg/ml, the mass concentration of the povidone is 60-80 mg/ml, the mass concentration of the polyethylene glycol is 20-30 mg/ml, the mass concentration of the bacteriostat is 2-3 mg/ml, the mass concentration of the cooling agent is 0.1-0.3 mg/ml, and the pH value of the oral solution is adjusted to 4.0-5.0 by adopting a pH regulator.
The invention takes lacosamide as an active component, adopts sodium carboxymethyl cellulose, povidone and polyethylene glycol as a taste masking combined matrix, and strictly controls the addition amount of each component, so that the prepared lacosamide oral solution has a dense taste and is not bitter and sweet under the condition of not adding a sweetener, thereby not only reducing the bitter taste and improving the patient compliance, but also enhancing the solution stability. In the experimental process, it is found that even though the addition amount of each component is strictly controlled, single sodium carboxymethylcellulose, povidone, polyethylene glycol or any two of the components are adopted and replaced by other similar components, the prepared lacosamide oral solution cannot solve the problem of bitter taste, the compliance of patients in administration is poor, and the stability of the oral solution is poor. For the invention, when the dosage and the proportion of each component in sodium carboxymethyl cellulose, povidone and polyethylene glycol are higher or lower, a good taste masking effect cannot be obtained, and the stability of the oral solution is also reduced.
The lacosamide oral solution provided by the invention has low energy and low sugar content because no sweetener (such as sucrose) is added, and is particularly suitable for special drug administration people needing careful intake of sugar, such as diabetics. The invention considers the different reactions of the drug population to the sweet taste and the worry of partial population to the safety of the chemical synthesis sweetener, improves the existing formula when preparing the lacosamide oral solution, does not add artificial synthesis sweetener, has a dense taste, can well inhibit the bitter taste, improves the stability of the oral solution and prolongs the effective period of the drug.
For the purposes of the present invention, the bacteriostatic agent selected is sodium methylparaben. The pH regulator is citric acid, and the pH value of the oral solution is regulated to 4.0-5.0 in the process of preparing the oral solution.
Further, the povidone is preferably povidone K90. The polyethylene glycol is polyethylene glycol 2000, polyethylene glycol 4000 or polyethylene glycol 6000, preferably polyethylene glycol 4000.
In a preferred scheme, the lacosamide oral solution has the mass concentration of 10mg/ml, the mass concentration of sodium carboxymethylcellulose is 10-20 mg/ml, the mass concentration of povidone K90 is 70mg/ml, the mass concentration of polyethylene glycol 4000 is 25mg/ml, the mass concentration of sodium hydroxybenzoate is 2.6mg/ml, the mass concentration of menthol is 0.12mg/ml, and the pH value of the oral solution is adjusted to 4.5 by adopting citric acid.
In a preferred scheme, the lacosamide oral solution has the mass concentration of 10mg/ml, the mass concentration of sodium carboxymethylcellulose is 15mg/ml, the mass concentration of povidone K90 is 60-80 mg/ml, the mass concentration of polyethylene glycol 4000 is 25mg/ml, the mass concentration of sodium hydroxybenzoate is 2.6mg/ml, the mass concentration of menthol is 0.12mg/ml, and the pH value of the oral solution is adjusted to 4.5 by adopting citric acid.
In a preferred scheme, the lacosamide oral solution has the mass concentration of 10mg/ml, the mass concentration of sodium carboxymethylcellulose is 15mg/ml, the mass concentration of povidone K90 is 70mg/ml, the mass concentration of polyethylene glycol 4000 is 20-30 mg/ml, the mass concentration of sodium hydroxybenzoate is 2.6mg/ml, the mass concentration of menthol is 0.12mg/ml, and the pH value of the oral solution is adjusted to 4.5 by adopting citric acid.
In a more preferred embodiment, the concentration of lacosamide in the lacosamide oral solution is 10mg/ml, the concentration of sodium carboxymethylcellulose is 15mg/ml, the concentration of povidone K90 is 70mg/ml, the concentration of polyethylene glycol 4000 is 25mg/ml, the concentration of sodium hydroxybenzoate is 2.6mg/ml, the concentration of menthol is 0.12mg/ml, and the pH value of the oral solution is adjusted to 4.5 by citric acid.
In a more preferred embodiment, the concentration of lacosamide in the lacosamide oral solution is 10mg/ml, the concentration of sodium carboxymethylcellulose is 15mg/ml, the concentration of povidone K90 is 60mg/ml, the concentration of polyethylene glycol 4000 is 25mg/ml, the concentration of sodium hydroxybenzoate is 2.6mg/ml, the concentration of menthol is 0.12mg/ml, and the pH value of the oral solution is adjusted to 4.5 by citric acid.
In a more preferred embodiment, the concentration of lacosamide in the lacosamide oral solution is 10mg/ml, the concentration of sodium carboxymethylcellulose is 15mg/ml, the concentration of povidone K90 is 80mg/ml, the concentration of polyethylene glycol 4000 is 25mg/ml, the concentration of sodium hydroxybenzoate is 2.6mg/ml, the concentration of menthol is 0.12mg/ml, and the pH value of the oral solution is adjusted to 4.5 by citric acid.
In a more preferred embodiment, the concentration of lacosamide in the lacosamide oral solution is 10mg/ml, the concentration of sodium carboxymethylcellulose is 10mg/ml, the concentration of povidone K90 is 70mg/ml, the concentration of polyethylene glycol 4000 is 25mg/ml, the concentration of sodium hydroxybenzoate is 2.6mg/ml, the concentration of menthol is 0.12mg/ml, and the pH value of the oral solution is adjusted to 4.5 by citric acid.
In a more preferred embodiment, the concentration of lacosamide in the lacosamide oral solution is 10mg/ml, the concentration of sodium carboxymethylcellulose is 20mg/ml, the concentration of povidone K90 is 70mg/ml, the concentration of polyethylene glycol 4000 is 25mg/ml, the concentration of sodium hydroxybenzoate is 2.6mg/ml, the concentration of menthol is 0.12mg/ml, and the pH value of the oral solution is adjusted to 4.5 by citric acid.
In a more preferred embodiment, the concentration of lacosamide in the lacosamide oral solution is 10mg/ml, the concentration of sodium carboxymethylcellulose is 15mg/ml, the concentration of povidone K90 is 70mg/ml, the concentration of polyethylene glycol 4000 is 20mg/ml, the concentration of sodium hydroxybenzoate is 2.6mg/ml, the concentration of menthol is 0.12mg/ml, and the pH value of the oral solution is adjusted to 4.5 by citric acid.
In a more preferred embodiment, the concentration of lacosamide in the lacosamide oral solution is 10mg/ml, the concentration of sodium carboxymethylcellulose is 15mg/ml, the concentration of povidone K90 is 70mg/ml, the concentration of polyethylene glycol 4000 is 30mg/ml, the concentration of sodium hydroxybenzoate is 2.6mg/ml, the concentration of menthol is 0.12mg/ml, and the pH value of the oral solution is adjusted to 4.5 by citric acid.
The invention also provides a preparation method of the lacosamide oral solution, which comprises the following steps:
(1) Adding a bacteriostatic agent and a pH regulator into purified water with the total amount of 50-70%, and stirring until the water is dissolved;
(2) Heating the mixed solution obtained in the step (1) to 50-70 ℃, adding the active component lacosamide into the mixed solution, and stirring the mixed solution until the solution is clear;
(3) Slowly adding sodium carboxymethyl cellulose, povidone and polyethylene glycol, and stirring until the sodium carboxymethyl cellulose, povidone and polyethylene glycol are dissolved;
(4) Adding cooling agent, stirring to dissolve, adding the rest purified water to desired volume, filtering, and packaging.
For the purposes of the present invention, the bacteriostatic agent selected is sodium methylparaben. The pH regulator is citric acid, and the pH value of the oral solution is regulated to 4.0-5.0 in the process of preparing the oral solution.
Further, the povidone is preferably povidone K90. The polyethylene glycol is polyethylene glycol 2000, polyethylene glycol 4000 or polyethylene glycol 6000, preferably polyethylene glycol 4000.
In the step (1), the amount of purified water added is 50 to 70% of the total amount, and may be, but not limited to, 50%, 55%, 60%, 65% or 70%, and the amount of purified water added is 60% of the total amount for obtaining a better effect.
In the step (2), the mixed solution obtained in the step (1) is heated to 50 to 70℃and may be, but not limited to, 50℃55℃60℃65℃or 70℃and, for obtaining a better effect, the mixed solution obtained in the step (1) is heated to 60 ℃.
By adopting the technical scheme of the invention, the advantages are as follows:
according to the invention, sodium carboxymethyl cellulose, povidone and polyethylene glycol are used as taste masking combined matrixes, so that the viscosity of an oral solution is increased, the contact time between a medicine and taste buds is reduced, the strong bitter taste of the lacosamide oral solution can be effectively masked under the condition of not adding a sweetener, the attention of a patient to the bitter taste is transferred through the cooling effect of menthol, the medication compliance of the patient is improved, the stability of the oral solution is improved, and the effective period of the medicine is prolonged. In the lacosamide oral solution provided by the invention, the auxiliary materials are few in variety, the preparation method is simple, and the lacosamide oral solution has good taste masking effect and stability.
Detailed Description
The lacosamide oral solution of the present invention is further illustrated by the following examples, which are not meant to limit the present invention in any way.
Examples:
the formula of the lacosamide oral solution provided by the invention is shown in table 1.
Table 1 formulation of the lacosamide oral solution in the examples
The preparation method of the oral solution in examples 1 to 7 is as follows:
(1) Adding 60% of purified water into a liquid preparation tank, adding a bacteriostatic agent and a pH regulator, and stirring until the water is dissolved;
(2) Heating the mixed solution obtained in the step (1) to 60 ℃, adding the active component lacosamide into the mixed solution, and stirring the mixture until the mixture is dissolved;
(3) Slowly adding sodium carboxymethylcellulose, povidone K90 and polyethylene glycol 4000, and stirring until the materials are dissolved;
(4) Adding cooling agent, stirring to dissolve, adding the rest purified water to 1000ml, filtering, and packaging.
Comparative example
To examine the effect of each component on oral solutions, a relevant comparative example was set, and the formulation thereof is shown in table 2.
Table 2 formulation of the lacosamide oral solution in comparative example
The preparation method of the oral solution in comparative examples 1 to 13 is as follows:
(1) Adding 60% of purified water into a liquid preparation tank, adding a bacteriostatic agent and a pH regulator, and stirring until the water is dissolved;
(2) Heating the mixed solution obtained in the step (1) to 60 ℃, adding the active component lacosamide into the mixed solution, and stirring the mixture until the mixture is dissolved;
(3) Slowly adding sodium carboxymethylcellulose, povidone K90 and polyethylene glycol 4000, and stirring until the materials are dissolved; if the formula has glycerol, propylene glycol or hydroxyethyl cellulose and other alternative matrixes, adding the matrix in the step (3);
(4) Adding correctant and/or cooling agent, stirring to dissolve, adding the rest purified water to 1000ml, filtering, and packaging.
Taste evaluation
Samples prepared in each example and comparative example of the invention were taken to be disordered in order, twenty tasters were found and the bitter tastes of each sample were compared and scored, the sample with the best taste (if no distinction was possible, two were chosen at most) was selected, the scoring range was 0-10 points, the lower the score was the stronger the bitter taste and the worse the taste, wherein twenty had chosen 36 preferred sample numbers altogether, the results are shown in table 3 below.
TABLE 3 evaluation results of bitterness
From the above scoring results, the taste masking combination matrix species selected in the invention has the best effect of masking the bitter taste, can mask the bitter taste even if the sweetener is not added in the formula, increases the compliance of the sweetener to different people, is not more acceptable by sweet taste, and is not more acceptable by people with stronger sweet taste. Especially, the addition of the cooling agent can greatly improve the compliance of people.
Stability investigation
The stability of the lacosamide oral solution was examined and the results are shown in tables 4-6 below.
Table 4 example stability results
TABLE 5 stability results for comparative examples 1-7
TABLE 6 stability results for comparative examples 8-13
As can be seen from tables 4 to 6, the oral solution prepared in the examples of the present invention is optimal for example 1, and the strong bitter taste of the lacosamide oral solution can be effectively masked without adding a sweetener by strictly controlling the amounts and proportions of sodium carboxymethylcellulose, povidone and polyethylene glycol in the taste masking combined matrix, so that the compliance of patients in drug administration is improved, the content of related substances is low, the stability of the oral solution is improved, and the effective period of the drug is prolonged. The oral solution prepared in part of the comparative examples can not achieve the taste masking effect of the invention by changing the dosage and proportion of each component in the taste masking combined matrix or replacing the components with other components, and has high content of related substances and poor stability. Even though the addition of the sweetener improves the taste masking effect in some of the comparative examples, the content of the related substances increases and the stability of the oral solution is greatly reduced.
The above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments may be modified or some technical features may be replaced equivalently; such modifications and substitutions do not depart from the spirit of the invention.
Claims (12)
1. The lacosamide oral solution is characterized by comprising active components of lacosamide, sodium carboxymethyl cellulose, povidone, polyethylene glycol, a bacteriostatic agent, a pH regulator and menthol as a cooling agent; the mass concentration of the lacosamide is 10mg/ml, the mass concentration of the carboxymethylcellulose sodium is 10-20 mg/ml, the mass concentration of the povidone is 60-80 mg/ml, the mass concentration of the polyethylene glycol is 20-30 mg/ml, the mass concentration of the bacteriostat is 2-3 mg/ml, the mass concentration of the cooling agent is 0.1-0.3 mg/ml, and the pH value of the oral solution is adjusted to 4.0-5.0 by adopting a pH regulator.
2. The lacosamide oral solution according to claim 1, wherein the bacteriostatic agent is sodium methylparaben; the pH regulator is citric acid.
3. The lacosamide oral solution according to claim 2, wherein the povidone is povidone K90; the polyethylene glycol is polyethylene glycol 2000, polyethylene glycol 4000 or polyethylene glycol 6000.
4. A lacosamide oral solution according to claim 3, characterized in that the povidone is povidone K90; the polyethylene glycol is polyethylene glycol 4000.
5. The lacosamide oral solution according to claim 4, wherein the mass concentration of lacosamide in the oral solution is 10mg/ml, the mass concentration of carboxymethylcellulose sodium is 10-20 mg/ml, the mass concentration of povidone K90 is 70mg/ml, the mass concentration of polyethylene glycol 4000 is 25mg/ml, the mass concentration of sodium oxybenzoate is 2.6mg/ml, the mass concentration of menthol is 0.12mg/ml, and the pH value of the oral solution is adjusted to 4.5 by citric acid.
6. The lacosamide oral solution according to claim 4, wherein the mass concentration of lacosamide in the oral solution is 10mg/ml, the mass concentration of carboxymethylcellulose sodium is 15mg/ml, the mass concentration of povidone K90 is 60-80 mg/ml, the mass concentration of polyethylene glycol 4000 is 25mg/ml, the mass concentration of sodium oxybenzoate is 2.6mg/ml, the mass concentration of menthol is 0.12mg/ml, and the pH value of the oral solution is adjusted to 4.5 by citric acid.
7. The lacosamide oral solution according to claim 4, wherein the mass concentration of lacosamide in the oral solution is 10mg/ml, the mass concentration of carboxymethylcellulose sodium is 15mg/ml, the mass concentration of povidone K90 is 70mg/ml, the mass concentration of polyethylene glycol 4000 is 20-30 mg/ml, the mass concentration of sodium oxybenzoate is 2.6mg/ml, the mass concentration of menthol is 0.12mg/ml, and the pH value of the oral solution is adjusted to 4.5 by citric acid.
8. The method for preparing the lacosamide oral solution according to claim 1, which is characterized in that the method comprises the following steps:
(1) Adding a bacteriostatic agent and a pH regulator into purified water with the total amount of 50-70%, and stirring until the water is dissolved;
(2) Heating the mixed solution obtained in the step (1) to 50-70 ℃, adding the active component lacosamide into the mixed solution, and stirring the mixed solution until the solution is clear;
(3) Slowly adding sodium carboxymethyl cellulose, povidone and polyethylene glycol, and stirring until the sodium carboxymethyl cellulose, povidone and polyethylene glycol are dissolved;
(4) Adding Mentholum as cooling agent, stirring to dissolve, adding the rest purified water to desired volume, filtering, and packaging.
9. The method for preparing an oral solution of lacosamide according to claim 8, wherein the bacteriostatic agent is sodium methylparaben; the pH regulator is citric acid.
10. The method for preparing an oral solution of lacosamide according to claim 8, wherein the povidone is povidone K90; the polyethylene glycol is polyethylene glycol 2000, polyethylene glycol 4000 or polyethylene glycol 6000.
11. The method for preparing an oral solution of lacosamide according to claim 10, wherein the polyethylene glycol is polyethylene glycol 4000.
12. The method for preparing an oral solution of lacosamide according to claim 8, wherein in the step (1), the purified water is added in an amount of 60% of the total amount; in step (2), the temperature of heating was 60 ℃.
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