CN112494425B - Oral solution of oxarogridia sodium and preparation method thereof - Google Patents

Oral solution of oxarogridia sodium and preparation method thereof Download PDF

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CN112494425B
CN112494425B CN202011462907.1A CN202011462907A CN112494425B CN 112494425 B CN112494425 B CN 112494425B CN 202011462907 A CN202011462907 A CN 202011462907A CN 112494425 B CN112494425 B CN 112494425B
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oral solution
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bacteriostat
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李新明
左斌海
张勇
柯兴斌
黄丽萍
张君兰
邓敏仪
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Zhuhai Yourun Co ltd
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Abstract

The invention discloses an oxarogridone oral solution and a preparation method thereof, and belongs to the technical field of medicines. The oral solution comprises the following components in percentage by concentration: 10-30 mg/ml of oxarogalide, 10-20 mg/ml of antioxidant, 10-20 mg/ml of bacteriostat and 62-250 mg/ml of flavoring agent; and the pH value of the oral solution is adjusted to 7.5-8.0 by using buffer salt and pH regulator. Adding a prescribed amount of buffer salt into purified water to prepare a buffer salt solution, adding an antioxidant and oxarogoli sodium, and uniformly stirring; adding cosolvent and bacteriostat and stirring uniformly; adding a flavoring agent and uniformly stirring; after regulating the pH value, adding purified water, and regulating the concentration of the oxaragril sodium; filtering and filling to obtain clear and transparent oral solution of the oxaagoli sodium. The oral solution is clear and transparent, has high quality uniformity and good stability, has proper taste, and effectively improves the medicine taking compliance of patients.

Description

Oral solution of oxarogridia sodium and preparation method thereof
Technical Field
The invention relates to the technical field of medicines, in particular to an oral solution of oxaagoli sodium and a preparation method thereof.
Background
Endometriosis refers to a disease that endometriosis or endometrium-like tissue is not on the inner surface of uterine cavity at the normal part of the endometriosis or the endometriosis hyperplasia at other parts outside uterus, is one of the most common diseases of women of childbearing age, and has the main clinical manifestations that: pelvic pain, menstrual disorder, infertility, chocolates, etc. Endometriosis is a hormone-dependent disease, the main treatment methods at present are surgery and sex hormone treatment, and the treatment of endometriosis still becomes a hot spot for many doctors due to the high postoperative recurrence rate and the large side effects of hormone treatment.
The oxaragroli is an oral GnRH antagonist which can treat pain caused by endometriosis by inhibiting the pituitary gonadotrophin releasing hormone receptor and ultimately reducing the level of gonadotrophin in the blood circulation. The chemical name of the oxaragrolide is R-4- ((2- (5- (2-fluoro-3-methoxyphenyl) -3- ((2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2, 6-dioxo-2) and the molecular formula is C 32 H 30 F 5 N 3 O 5 The chemical formula is:
Figure BDA0002833232800000011
CN111246850a discloses an oral dosage form containing oxaragroli, which is a solid preparation with low absorption rate and low bioavailability. As the oxaragroli is easy to chemically degrade in water, the curative effect is reduced and the toxic and side effects are increased. The oxaagole has poor water solubility, and needs to be prepared into sodium salt to increase the solubility, but after the oxaagole is salified, the oxaagole is hydrolyzed to generate the oxaagole under the condition that the pH is less than 7.5, so that the solution is turbid. In addition, the oxaagole has strong bitter taste, and the solution preparation has poor taste and is difficult to accept by patients.
Therefore, it is very necessary to develop an oral solution of oxaagoli sodium with stable quality, good uniformity and good taste.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide the oxaagole oral solution which is clear and transparent, high in quality uniformity, good in stability and proper in taste, and the medicine taking compliance of patients is effectively improved.
In order to solve the problems, the technical scheme adopted by the invention is as follows:
an oral solution of oxaroggolide comprises the following components in percentage by concentration: 10-30 mg/ml of oxarogalide, 10-20 mg/ml of antioxidant, 10-20 mg/ml of bacteriostat and 62-250 mg/ml of flavoring agent; and the pH value of the oral solution is adjusted to 7.5-8.0 by using buffer salt and pH regulator. At this pH, the oxaagole sodium is stable and does not degrade to form byproducts.
As a preferred embodiment of the present invention, the buffer salt is sodium bicarbonate; the pH regulator is hydrochloric acid with the concentration of 10% or phosphoric acid with the concentration of 10%. Through the buffer salt, the oxaroggolide can be ensured to exist in a solution system in the form of sodium salt, and meanwhile, the nipagin ester bacteriostatic agent can exert the maximum bacteriostatic effect, and the nipagin ester bacteriostatic agent can be prevented from being decomposed, so that the nipagin ester bacteriostatic agent exists in the solution system stably.
As a preferred embodiment of the invention, the antioxidant is sodium thiosulfate, can effectively prevent the degradation of the oxaagole in the solution system, and reduces the generation of related substances, thereby reducing the toxic and side effects of the medicine and ensuring that the medicine has better safety.
In a preferred embodiment of the present invention, the bacteriostatic agent is a mixture of methyl paraben and propyl paraben.
As a preferred embodiment of the invention, the invention also comprises a cosolvent for improving the solubility of the nipagin ester bacteriostat; the cosolvent is propylene glycol or ethanol. Wherein propylene glycol can increase the solubility of the propyl p-hydroxybenzoate, so that the propyl p-hydroxybenzoate is completely dissolved in the solution system and remains stable in the solution system. In addition, 10 to 15 percent of propylene glycol can also enhance the antibacterial effect of the nipagin esters.
In a preferred embodiment of the present invention, the flavoring agent is one selected from the group consisting of raspberry essence, orange essence, strawberry essence, and vanilla essence, and the sweetener is one or a mixture of two or more selected from the group consisting of sorbitol, xylitol, sucralose, and saccharin sodium. The taste modifier can cover the bitter taste of the oxadixyl, greatly improve the taste of the oxadixyl and increase the oral compliance of patients.
The invention also provides a preparation method of the oxarogeli oral solution, which comprises the following steps:
s1, adding a prescribed amount of buffer salt into purified water to prepare a buffer salt solution, adding a prescribed amount of antioxidant and oxarogoli sodium, and uniformly stirring; adding cosolvent and bacteriostat and stirring uniformly; adding a prescription amount of flavoring agent and uniformly stirring;
s2, regulating the pH value of the mixed solution prepared in the step S1 to 7.5-8.0; adding purified water to make the concentration of the oxaagoli sodium be 15-30 mg/mL;
and S3, filtering the mixed solution prepared in the step S2 by adopting a 0.45 mu m filter, and filling to obtain a clear and transparent oxarogalli oral solution.
Compared with the prior art, the invention has the beneficial effects that:
the oxarogeli oral solution provided by the invention is clear and transparent, high in quality uniformity, good in stability, suitable in taste, easy to be taken, and convenient to be taken, and effectively increases the medicine taking compliance of patients. The preparation method has simple and feasible process, energy conservation and easy control, and the produced product has high stability.
Detailed Description
The present invention will be described in further detail with reference to the following embodiments.
An oral solution of oxaroggolide comprises the following components in percentage by concentration: 10-30 mg/ml of oxarogalide, 10-20 mg/ml of antioxidant, 10-20 mg/ml of bacteriostat and 62-250 mg/ml of flavoring agent; and the pH value of the oral solution is adjusted to 7.5-8.0 by using buffer salt and pH regulator. The oral solution is stable and will not degrade at this pH, avoiding the production of by-products.
The buffer salt is preferably sodium bicarbonate; the pH regulator is hydrochloric acid with concentration of 10% or phosphoric acid with concentration of 10%. The buffer salt can also be other buffer salt systems which can control the pH value of the system to 7.5-8.0. Through the buffer salt system, the oxaroggolide can be ensured to exist in the solution system in the form of sodium salt, and meanwhile, the nipagin ester bacteriostatic agent can exert the maximum bacteriostatic effect, and the nipagin ester bacteriostatic agent can be prevented from being decomposed, so that the nipagin ester bacteriostatic agent exists in the solution system stably.
The antioxidant is sodium thiosulfate, can effectively prevent the degradation of the oxaagole in the solution system, and reduces the generation of related substances, thereby reducing the toxic and side effects of the medicine and ensuring that the medicine has better safety.
The antibacterial agent is a mixture of methyl benzoate and propyl benzoate. The compound also comprises a cosolvent for improving the nipagin ester bacteriostat; the cosolvent is propylene glycol or ethanol. Wherein propylene glycol can increase the solubility of the propyl p-hydroxybenzoate, so that the propyl p-hydroxybenzoate is completely dissolved in the solution system and remains stable in the solution system. In addition, 10 to 15 percent of propylene glycol can also enhance the antibacterial effect of the nipagin esters.
Flavoring agents include fragrances and sweeteners; wherein the flavoring agent is selected from one of Rubi fructus essence, fructus Citri sinensis essence, strawberry essence, and vanilla essence, and the sweetener is selected from one or more of sorbitol, xylitol, sucralose, and saccharin sodium. The invention screens the variety and the dosage of the flavoring agent, so that the flavoring agent can cover the bitter taste of the oxaragroline, greatly improve the taste of the oxaragroline and increase the oral compliance of patients.
The preparation method of the oxarogeli oral solution comprises the following steps:
s1, adding a prescribed amount of buffer salt into purified water to prepare a buffer salt solution, adding a prescribed amount of antioxidant and oxarogoli sodium, and uniformly stirring; adding cosolvent and bacteriostat and stirring uniformly; adding a prescription amount of flavoring agent and uniformly stirring;
s2, regulating the pH value of the mixed solution prepared in the step S1 to 7.5-8.0; adding purified water to make the concentration of the oxaagoli sodium be 10-30 mg/mL;
and S3, filtering the mixed solution prepared in the step S2 by adopting a 0.45 mu m filter, and filling to obtain a clear and transparent oxarogalli oral solution.
1. Forced damage experiment
An aqueous solution of 15mg/ml of oxaagole was prepared, and forced destruction experiments were performed under the conditions shown in Table 1, and the results are shown in Table 2.
TABLE 1 forced destruction test conditions
Figure BDA0002833232800000051
Note that: after two hours of treatment with strong acid and strong base, the neutralization solution was added immediately to conduct neutralization. The strong acid treated sample was neutralized with 1.0mol/L NaOH solution and the strong base treated sample was neutralized with 1.0mol/LHCl solution.
TABLE 2 forced failure test results
Damage condition Degree of degradation of oxaragrolide
Conditions of strong acid 8.59％
Strong alkaline conditions 7.23％
Strong oxidation conditions 10.77％
Note that: samples under each condition were diluted by the same factor and injected into HPLC, and the content of oxaragril was calculated from the peak area.
Watch with a watch2, it can be seen that the treatment with 1.0mol/L NaOH solution and 1.0mol/L HCl solution for 2H,3% H 2 O 2 After 1h of solution treatment, the oxaagole sodium is degraded to different degrees, and the oxaagole Li Na is presumed to have a tendency to degrade under acid, alkali and oxidation conditions after being prepared into a preparation. It is therefore necessary to strictly control the pH range of the oral solution and add necessary antioxidants.
2. Screening test of bacteriostat
The specific steps of the bacteriostat screening test are as follows:
s1, preparing the oxaagole sodium and other auxiliary materials according to the proportion shown in the table 3.
Table 3 formulation 1-6 raw and auxiliary materials ingredients composition
Figure BDA0002833232800000061
Note that: sodium bicarbonate-hydrochloric acid buffer (sodium bicarbonate g, water ml, pH adjusted to 7.5-7.8 with hydrochloric acid)
S2, adding the prescribed amount of buffer salt into purified water, stirring to dissolve, adding the prescribed amount of antioxidant and oxaroggolide sodium, and stirring uniformly; adding propylene glycol and a bacteriostat and uniformly stirring; adding a prescription amount of flavoring agent and uniformly stirring;
s3, regulating the pH value of the mixed solution prepared in the step S2 to 7.5-8.0; purified water was added to a total of 1000mL so that the concentration of the oxaragrolidine was 15mg/mL;
and S4, filtering the mixed solution prepared in the step S3 by adopting a 0.45 mu m filter, and filling to obtain a clear and transparent oxarogalli oral solution.
The evaluation results of each prescription sample are shown in table 4.
Table 4 results of evaluation of samples 1 to 6 prescriptions
Figure BDA0002833232800000071
Bacteriostats commonly used in the alkaline environment are quaternary ammonium salts and parabens. Benzalkonium bromide and benzalkonium chloride are common quaternary ammonium salt bacteriostats, and as can be seen from the data in table 4, the benzalkonium bromide and benzalkonium chloride solution is clear and has good solubility, but the taste is extremely bitter, the dosage of the sweetener is doubled, and the bitter taste of the benzalkonium bromide and benzalkonium chloride cannot be completely covered; methyl benzoate and propyl benzoate are commonly used basic environmental bacteriostats, and the combination can enhance the bacteriostats, and the data in table 4 shows that the methyl benzoate has good solubility, the propyl benzoate has poor solubility, and the solution is clarified after propylene glycol is added for dissolution assistance. Therefore, the methyl benzoate and the propyl benzoate are used together as the bacteriostat, and a proper amount of propylene glycol is added for dissolution assistance.
3. Antioxidant screening experiment
The specific steps of the bacteriostat screening test are as follows:
s1, preparing the oxaagole sodium and other auxiliary materials according to the proportion shown in the table 5.
Table 5 prescription composition table
Figure BDA0002833232800000072
Figure BDA0002833232800000081
Note that: buffer solution (buffer salt is taken, water is added to dissolve, and the pH is adjusted to 7.5 to 7.8 by corresponding acid)
S2, adding the prescribed amount of buffer salt into purified water, stirring to dissolve, adding the prescribed amount of antioxidant and oxaroggolide sodium, and stirring uniformly; adding propylene glycol and a bacteriostat and uniformly stirring; adding a prescription amount of flavoring agent and uniformly stirring;
s3, regulating the pH value of the mixed solution prepared in the step S2 to 7.5-8.0; purified water was added to a total of 1000ml so that the concentration of the oxaragroli sodium was 15mg/ml;
and S4, filtering the mixed solution prepared in the step S3 by adopting a 0.45 mu m filter, and filling to obtain a clear and transparent oxarogalli oral solution.
The sensory evaluation results of each prescription are shown in table 6.
TABLE 6 antioxidant screening test results
Figure BDA0002833232800000082
As is clear from the results of table 6, the addition of sodium sulfite and sodium metabisulfite as antioxidants affected the taste and smell of the oral solution, and the sweetener and essence could not effectively cover such adverse changes. And no peculiar smell is generated when the sodium thiosulfate is added.
4. pH screening experiments
The specific steps of the pH screening test are as follows:
s1, preparing the oxaagole sodium and other auxiliary materials according to the prescription shown in the table 7.
Table 7 oral solution pH screening protocol
Figure BDA0002833232800000091
S2, adding the prescribed amount of buffer salt into purified water, stirring to dissolve, adding the prescribed amount of oxarogridin, stirring uniformly, adding a proper amount of hydrochloric acid or sodium hydroxide, and regulating the pH value of the solution to a corresponding value;
s3, adding purified water to the total volume of 100ml so as to ensure that the concentration of the oxaagole sodium is 15mg/ml.
The results of evaluating the properties of each prescription are shown in table 8.
Table 8 pH screening test results
Prescription of prescription Prescription 17 Prescription 18 Prescription 19 Prescription 20 Prescription 21 Prescription 22 Prescription 23
Traits (3) Cloudiness Cloudiness Cloudiness is relatively turbid Clarifying Clarifying Clarifying Clarifying
As is clear from the results shown in Table 8, the oxaagole sodium precipitates insoluble substances at a pH of less than 7.5, and clouds the solution, and the oxaagole sodium completely dissolves at a pH of not less than 7.5, thereby keeping the solution clear. Because the bacteriostat methyl paraben and propyl paraben are sensitive to pH value, the bacteriostat methyl paraben and propyl paraben can be decomposed in an environment with the pH higher than 8.0, and the bacteriostasis effect is reduced or even lost. Thus, the pH of the oral solution was determined to be 7.5 to 8.0.
5. Buffer salt screening experiments
The prescription of the buffer salt screening assay is shown in table 9:
table 9 buffer salt screening test prescriptions
Figure BDA0002833232800000092
Figure BDA0002833232800000101
The method comprises the following steps: adding the prescribed amount of oxaagole sodium into purified water, stirring to dissolve, adding the prescribed amount of buffer salt, stirring uniformly, and adjusting the pH value of the solution to 7.5 by using corresponding acid. If turbidity is generated in the solution, 4% sodium hydroxide solution is added dropwise until the turbidity just disappears, the solution is recovered to be clear, and the pH value of the solution at the moment is recorded.
The results of the buffer salt screening experiments are shown in table 10.
Table 10 buffer salt screening test results
Figure BDA0002833232800000102
As is clear from the results shown in Table 10, the sodium bicarbonate-hydrochloric acid system can keep the sodium oxaragril in a dissolved state in the range of pH7.5 to 8.0, while the disodium hydrogen phosphate-citric acid system and the potassium dihydrogen phosphate-sodium hydroxide system can cause turbidity of the solution. Sodium bicarbonate was chosen as buffer salt and hydrochloric acid as pH regulator.
Example 1:
an oral solution of oxaragrolidine, comprising the following components:
Figure BDA0002833232800000103
Figure BDA0002833232800000111
the components are prepared according to the following steps:
s1, adding sodium bicarbonate into 65ml of distilled water, stirring to prepare a buffer salt solution, adding sodium thiosulfate and oxarogoli sodium, and stirring uniformly; adding propylene glycol, stirring, adding methyl benzoate and propyl benzoate, and stirring; adding sorbitol, xylitol and sucralose and uniformly stirring;
s2, detecting the pH value of the mixed solution prepared in the step S1 and adjusting the pH value to 7.5-8.0 by using hydrochloric acid; adding purified water to make the concentration of the oxaagoli sodium be 15mg/mL;
and S3, filtering the mixed solution prepared in the step S2 by adopting a 0.45 mu m filter, filling, plugging, sterilizing and packaging to obtain the clear and transparent oxarogalli oral solution.
Example 2:
an oral solution of oxaragrolidine, comprising the following components:
Figure BDA0002833232800000112
Figure BDA0002833232800000121
the components are prepared according to the following steps:
s1, adding sodium bicarbonate into 65ml of distilled water, stirring to prepare a buffer salt solution, adding sodium thiosulfate and oxarogoli sodium, and stirring uniformly; adding propylene glycol, stirring, adding methyl benzoate and propyl benzoate, and stirring; adding sorbitol, xylitol and sucralose and uniformly stirring;
s2, detecting the pH value of the mixed solution prepared in the step S1 and adjusting the pH value to 7.5-8.0 by using hydrochloric acid; adding purified water to make the concentration of the oxaagoli sodium be 15mg/mL;
and S3, filtering the mixed solution prepared in the step S2 by adopting a 0.45 mu m filter, filling, plugging, sterilizing and packaging to obtain the clear and transparent oxarogalli oral solution.
Example 3:
an oral solution of oxaragrolidine, comprising the following components:
Figure BDA0002833232800000122
the components are prepared according to the following steps:
s1, adding sodium bicarbonate into 65ml of distilled water, stirring to prepare a buffer salt solution, adding sodium thiosulfate and oxarogoli sodium, and stirring uniformly; adding propylene glycol, stirring, adding methyl benzoate and propyl benzoate, and stirring; adding sorbitol, xylitol and sucralose and uniformly stirring;
s2, detecting the pH value of the mixed solution prepared in the step S1 and adjusting the pH value to 7.5-8.0 by using hydrochloric acid; adding purified water to make the concentration of the oxaagoli sodium be 15mg/mL;
and S3, filtering the mixed solution prepared in the step S2 by adopting a 0.45 mu m filter, filling, plugging, sterilizing and packaging to obtain the clear and transparent oxarogalli oral solution.
Example 4:
an oral solution of oxaragrolidine, comprising the following components:
Figure BDA0002833232800000131
the components are prepared according to the following steps:
s1, adding sodium bicarbonate into 65ml of distilled water, stirring to prepare a buffer salt solution, adding sodium thiosulfate and oxarogoli sodium, and stirring uniformly; adding propylene glycol, stirring, adding methyl benzoate and propyl benzoate, and stirring; adding sorbitol, xylitol and sucralose and uniformly stirring;
s2, detecting the pH value of the mixed solution prepared in the step S1 and adjusting the pH value to 7.5-8.0 by using hydrochloric acid; adding purified water to make the concentration of the oxaagoli sodium be 15mg/mL;
and S3, filtering the mixed solution prepared in the step S2 by adopting a 0.45 mu m filter, filling, plugging, sterilizing and packaging to obtain the clear and transparent oxarogalli oral solution.
Example 5:
an oral solution of oxaragrolidine, comprising the following components:
Figure BDA0002833232800000141
the components are prepared according to the following steps:
s1, adding disodium hydrogen phosphate and sodium hydroxide into 65ml of distilled water, stirring to prepare a buffer salt solution, adding sodium thiosulfate and oxarogoli sodium, and stirring uniformly; adding propylene glycol, stirring, adding methyl benzoate and propyl benzoate, and stirring; adding sorbitol, xylitol and sucralose and uniformly stirring;
s2, detecting the pH value of the mixed solution prepared in the step S1 and adjusting the pH value to 7.5-8.0 by using hydrochloric acid; adding purified water to make the concentration of the oxaagoli sodium be 15mg/mL;
and S3, filtering the mixed solution prepared in the step S2 by adopting a 0.45 mu m filter, filling, plugging, sterilizing and packaging to obtain the clear and transparent oxarogalli oral solution.
Example 6:
an oral solution of oxaragrolidine, comprising the following components:
Figure BDA0002833232800000151
the components are prepared according to the following steps:
s1, adding sodium bicarbonate into 65ml of distilled water, stirring to prepare a buffer salt solution, adding sodium thiosulfate and oxarogoli sodium, and stirring uniformly; adding propylene glycol, stirring, adding methyl benzoate and propyl benzoate, and stirring; adding sorbitol, xylitol and sucralose and uniformly stirring;
s2, detecting the pH value of the mixed solution prepared in the step S1 and adjusting the pH value to 7.5-8.0 by using hydrochloric acid; adding purified water to make the concentration of the oxaagoli sodium be 15mg/mL;
and S3, filtering the mixed solution prepared in the step S2 by adopting a 0.45 mu m filter, filling, plugging, sterilizing and packaging to obtain the clear and transparent oxarogalli oral solution.
Example 7:
an oral solution of oxaragrolidine, comprising the following components:
Figure BDA0002833232800000161
the components are prepared according to the following steps:
s1, adding disodium hydrogen phosphate and sodium hydroxide into 65ml of distilled water, stirring to prepare a buffer salt solution, adding sodium thiosulfate and oxarogoli sodium, and stirring uniformly; adding propylene glycol, stirring, adding methyl benzoate and propyl benzoate, and stirring; adding sorbitol, xylitol and sucralose and uniformly stirring;
s2, detecting the pH value of the mixed solution prepared in the step S1 and adjusting the pH value to 7.5-8.0; adding purified water to make the concentration of the oxaagoli sodium be 15mg/mL;
and S3, filtering the mixed solution prepared in the step S2 by adopting a 0.45 mu m filter, filling, plugging, sterilizing and packaging to obtain the clear and transparent oxarogalli oral solution.
6. Comparative experiments
Comparative experiments were performed according to the recipe shown in table 11, with the following steps:
s1, preparing the oxaagole sodium and other auxiliary materials according to the proportion shown in the table 11.
Table 11 Table of the prescription composition
Figure BDA0002833232800000171
S2, adding the prescribed amount of buffer salt into purified water, stirring to dissolve, adding the prescribed amount of antioxidant and oxaroggolide sodium, and stirring uniformly; adding propylene glycol and a bacteriostat and uniformly stirring; adding a prescription amount of flavoring agent and uniformly stirring;
s3, regulating the pH value of the mixed solution prepared in the step S2 to the corresponding value in the table; purified water is added to the total volume of 1000ml;
and S4, filtering the mixed solution prepared in the step S3 by adopting a 0.45 mu m filter, and filling to obtain a clear and transparent oxarogalli oral solution.
The solutions of the prescriptions 27-33 in the above table are respectively subjected to high temperature (50+ -2deg.C), strong light (illuminance 4500 lx+ -500 lx, total illuminance not less than 1.2X10) 6 lux hr), protected from light (the samples were wrapped with black opaque plastic and placed with the glare control samples) for 30 days. The clarity, content, related substances and pH of the solution were examined. The results are shown in Table 12.
TABLE 12 influence factor experiment results
Figure BDA0002833232800000181
Note that: "related substances" refer primarily to the raw materials, intermediates, degradation products, isomers, polymers, side reaction products, etc. that are carried over during the production process.
As shown in the experimental results of Table 12, the comparative prescriptions 27-28 have obviously increased related substances and correspondingly reduced contents under the conditions of high temperature, strong light and light shielding. The invention (prescriptions 29-31) uses the optimized buffer salt and antioxidant, and is placed for 30 days under the conditions of high temperature, strong light and light shielding, the content is stable, the related substances are slowly grown, and the properties and the pH are all in accordance with the requirements. Therefore, the oral solution of the oxaagole sodium has excellent stability.
The above embodiments are only preferred embodiments of the present invention, and the scope of the present invention is not limited thereto, but any insubstantial changes and substitutions made by those skilled in the art on the basis of the present invention are intended to be within the scope of the present invention as claimed.

Claims (4)

1. An oral solution of oxaragrolidine sodium, which is characterized in that: comprises the following components in percentage by concentration: oxagolide sodium 10 mg/ml, antioxidant 1.0 mg/ml, bacteriostat 1.6 mg/ml, corrigent 96.5 mg/ml, cosolvent 80 mg/ml; and adjusting the pH of the oral solution to 7.7 using a buffer salt and a pH adjuster; wherein the buffer salt is sodium bicarbonate; the pH regulator is hydrochloric acid with the concentration of 10%; the antioxidant is sodium thiosulfate; the bacteriostat is methyl benzoate and propyl benzoate; the cosolvent is propylene glycol; the flavoring agent comprises a flavoring agent and a sweetening agent; the aromatic is raspberry essence, and the sweetener consists of 70% sorbitol solution (w/w), xylitol and sucralose.
2. An oral solution of oxaragrolidine sodium, which is characterized in that: comprises the following components in percentage by concentration: oxagolide 15mg/ml, antioxidant 2 mg/ml, bacteriostat 2 mg/ml, flavoring agent 123 mg/ml and cosolvent 100 mg/ml; and adjusting the pH of the oral solution to 7.8 using a buffer salt and a pH adjuster; wherein the buffer salt is sodium bicarbonate; the pH regulator is hydrochloric acid with the concentration of 10%; the antioxidant is sodium thiosulfate; the bacteriostat is methyl benzoate and propyl benzoate; the cosolvent is propylene glycol; the flavoring agent comprises a flavoring agent and a sweetening agent; the aromatic is raspberry essence, and the sweetener consists of 70% sorbitol solution (w/w), xylitol and sucralose.
3. An oral solution of oxaragrolidine sodium, which is characterized in that: comprises the following components in percentage by concentration: 20. 20mg/ml of oxagolide sodium, 2.5 mg/ml of antioxidant, 2.4 mg/ml of bacteriostat, 150 mg/ml of flavoring agent and 120 mg/ml of cosolvent; and adjusting the pH of the oral solution to 7.7 using a buffer salt and a pH adjuster; wherein the buffer salt is sodium bicarbonate; the pH regulator is hydrochloric acid with the concentration of 10%; the antioxidant is sodium thiosulfate; the bacteriostat is methyl benzoate and propyl benzoate; the cosolvent is propylene glycol; the flavoring agent comprises a flavoring agent and a sweetening agent; the aromatic is raspberry essence, and the sweetener consists of 70% sorbitol solution (w/w), xylitol and sucralose.
4. A process for the preparation of an oral solution of oxaragrolidine as claimed in any one of claims 1 to 3, characterized in that: the method comprises the following steps:
s1, adding a prescribed amount of buffer salt into purified water to prepare a buffer salt solution, adding a prescribed amount of antioxidant and oxarogoli sodium, and uniformly stirring; adding cosolvent and bacteriostat and stirring uniformly; adding a prescription amount of flavoring agent and uniformly stirring;
s2, adjusting the pH value of the mixed solution prepared in the step S1 to 7.7 or 7.8; purified water was added to give a concentration of oxaagole of 10 mg/mL or 15mg/mL or 20 mg/mL;
and S3, filtering the mixed solution prepared in the step S2 by adopting a 0.45 mu m filter, and filling to obtain a clear and transparent oral solution of the oxarogridin.
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