Stable oxymetazoline hydrochloride preparation and preparation method thereof

Abstract

The invention belongs to the technical field of sympathetic nerve mimetic pharmaceutical preparations, and particularly relates to a stable oxymetazoline hydrochloride preparation and a preparation method thereof. The oxymetazoline hydrochloride preparation is prepared from oxymetazoline hydrochloride, rutin, a pH regulator, a preservative, an isotonic agent and water. According to the invention, the intermolecular interaction of oxymetazoline hydrochloride and rutin is utilized to form a compound system, and the preparation method of the oxymetazoline hydrochloride preparation is optimized, so that the stability of the oxymetazoline hydrochloride preparation is effectively improved.

Description

Technical Field

[0001] The invention belongs to the technical field of sympathomimetic drug preparations, and particularly relates to a stable oxymetazoline hydrochloride preparation and a preparation method thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Oxymetazoline hydrochloride is an α-adrenaline receptor agonist widely used in clinical practice. 11 H 15 ClN2O is usually a white or off-white crystalline powder. It stimulates the α-1 receptors in the nasal cavity, causing vasoconstriction, thereby reducing nasal blood flow, reducing swelling and congestion, and relieving nasal congestion. It is mainly used clinically to relieve nasal congestion, eye congestion and other symptoms related to vasodilation, for example, it can relieve nasal congestion caused by colds, allergic rhinitis or sinusitis, and is used to relieve eye congestion.

[0004] Studies have found that the poor photostability of oxymetazoline hydrochloride is mainly related to its chemical structure and the photochemical reactions that may occur under light. Oxymetazoline hydrochloride is an organic compound containing aromatic rings and amino groups. Many compounds containing aromatic rings are prone to photodegradation reactions under light. Under light conditions, oxymetazoline hydrochloride may react with oxygen to produce oxidation products. This photooxidation reaction usually leads to the breakage of the molecular structure or other chemical changes, thereby reducing the stability and effectiveness of the drug. In addition, light can excite compounds to produce free radicals, which are very reactive substances that can further trigger chain reactions and lead to drug degradation.

[0005] Chinese patent publication number CN101951886A discloses a method for enhancing the photostability of oxymetazoline, wherein the photostability of oxymetazoline in a topical decongestant composition is enhanced by lowering the pH of the composition to 3-6 using a buffer solution.

[0006] The Chinese patent with publication number CN105997856A discloses an oxymetazoline hydrochloride eye drop, which improves the stability of the preparation by improving the preparation method, specifically, oxymetazoline hydrochloride, an osmotic pressure regulator, an antibacterial agent, and water for injection are heated and boiled for 15 to 30 minutes, cooled, and a cooling agent-ethanol solution is added, and a viscosity enhancer is added, and the pH value is adjusted to 4.0 to 5.0 to obtain the eye drop. However, it is well known that oxymetazoline hydrochloride has poor tolerance to high temperatures and may accelerate degradation under high temperature conditions.

[0007] Currently, the existing technology has not solved the problem of poor stability of oxymetazoline hydrochloride, especially photostability. Summary of the invention

[0008] In order to overcome the deficiencies of the prior art, the present invention provides a stable oxymetazoline hydrochloride preparation, which comprises, by mass fraction, 0.01% to 0.05% of oxymetazoline hydrochloride, 0.05% to 0.15% of rutin (CAS: 153-18-4, content 99%), 0.002% to 0.01% of a preservative, 0.01% to 0.1% of an isotonic agent, an appropriate amount of a pH regulator, and an appropriate amount of water.

[0009] Among them, the preservative is selected from at least one of benzalkonium bromide, benzalkonium chloride, and chlorobutanol; the pH adjuster is selected from at least one of borax-boric acid buffer solution, citric acid-sodium citrate buffer solution-disodium hydrogen phosphate-sodium dihydrogen phosphate buffer solution; and the isotonic agent is selected from at least one of glucose, sodium chloride, and glycerol.

[0010] The present invention also provides a method for preparing the above-mentioned stable oxymetazoline hydrochloride preparation, the preparation method comprising:

[0011] (1) dissolving oxymetazoline hydrochloride in water and performing sonication to obtain solution A;

[0012] (2) dissolving rutin in a weakly alkaline ethanol solution and sonicating to obtain solution B;

[0013] (3) Slowly drip solution A into solution B, let stand for 2 to 4 hours, remove the solvent by vacuum rotary evaporation at 30°C to 50°C in a water bath, and cool to obtain solution C;

[0014] (4) Solution C is adjusted to pH 4.5-6.0 with a pH adjuster, a preservative and an isotonic agent are added, water is added to the total amount, microfiltered, nitrogen bubbled, and sterilized to obtain the solution.

[0015] Oxymetazoline hydrochloride and rutin are combined through molecular interactions (physical and chemical forces such as hydrogen bonding, π-π stacking, and electrostatic interactions) to form an oxymetazoline hydrochloride-rutin complex (it should be noted that the complex has been verified by infrared spectroscopy, and the oxymetazoline hydrochloride-rutin complex and the mixed solution of oxymetazoline hydrochloride and rutin were subjected to infrared measurement, and the absorption peak positions were different). Rutin has multiple hydroxyl (-OH) and sugar (-OCH2) structures. These functional groups can form hydrogen bonds with nitrogen atoms or other hydrogen-containing groups in oxymetazoline hydrochloride. Hydrogen bonds are very important interaction forces between molecules and can stabilize the formation of the complex.

[0016] Furthermore, since rutin has poor water solubility, it is necessary to find a solvent that can dissolve rutin. After trying methanol, ethanol, sodium hydroxide, hydrochloric acid, phosphate solution, carbonate solution, tartrate solution and mixed solutions thereof, it was found that carbonate-ethanol solution had the best effect in dissolving rutin. Therefore, screening experiments were conducted on the type and concentration of carbonate and the concentration of ethanol. It was found that a weakly alkaline ethanol solution of 3.5% to 9.5% carbonate-85% to 95% ethanol by mass fraction completely dissolved rutin, wherein the carbonate was sodium carbonate and / or sodium bicarbonate.

[0017] It should be noted that if the mixing speed of the oxymetazoline hydrochloride solution and the rutin solution is too fast, it will cause an over-rapid reaction and the appearance of tiny crystals or flocs. Therefore, controlling the mixing speed of solutions A and B is a key factor in the formation of the oxymetazoline hydrochloride-rutin complex. Experiments have shown that the speed at which solution A is dripped into solution B is 0.05-0.15 ml / min, which neither causes an over-rapid reaction nor saves time costs.

[0018] Compared with the prior art, the technical effects of the present invention are:

[0019] (1) The present invention utilizes the molecular interaction between oxymetazoline hydrochloride and rutin to form a complex system, thereby avoiding the aromatic ring structure in oxymetazoline hydrochloride from easily undergoing photodegradation reaction under light, thereby affecting the effective content and impurity content.

[0020] (2) The present invention explores a preparation method suitable for oxymetazoline hydrochloride preparations, especially explores a solvent system for dissolving rutin and the interaction rate between the rutin solution and the dissolution of oxymetazoline hydrochloride, more efficiently promotes the formation of an oxymetazoline hydrochloride-rutin complex, thereby effectively improving the stability of the oxymetazoline hydrochloride preparation. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 : The content of oxymetazoline hydrochloride in each group of oxymetazoline hydrochloride preparations prepared using different solvents in the illumination test.

[0022] Figure 2 : Changes in oxymetazoline hydrochloride content in the illumination tests of the oxymetazoline hydrochloride preparations of Examples 1 to 5 and the oxymetazoline hydrochloride preparations of Comparative Examples 1 to 3.

[0023] Figure 3 : Structural formula of related substances.

[0024] Figure 4 : Changes in the contents of related substances in the illumination tests of the oxymetazoline hydrochloride preparations of Examples 1 to 5 and the oxymetazoline hydrochloride preparations of Comparative Examples 1 to 3. DETAILED DESCRIPTION

[0025] In order to make the purpose and technical solution of the present invention clearer, the present invention is further described below in conjunction with embodiments, but the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. It should be understood by those skilled in the art that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0026] Screening of Rutin Solvents

[0027] In order to explore the solubility of rutin, various solvents were tried for dissolution.

[0028] Table 1 Solubility of rutin in different solvents

[0029] Group Solvents Solubility 1 water 1:8450 2 95% ethanol 1:350 3 Hot 95% ethanol 1:145 4 Hot water 1:120 5 5.5% sodium bicarbonate solution 1:450 6 5.5% sodium carbonate solution 1:350 7 6.5% Sodium Bicarbonate-95% Ethanol 1:30 8 4.5% Sodium Carbonate-90% Ethanol 1:20 9 95% Methanol 1:105 10 95% hot methanol 1:82 11 5.5% Sodium Bicarbonate-95% Methanol 1:175 12 3.5% Sodium Bicarbonate-95% Methanol 1:220

[0030] Table 1 shows the solubility of rutin in different solvents, which shows that the dissolution effect of hot solvents is better than that of cold solvents, and the dissolution effect of methanol is worse than that of ethanol. However, the dissolution effect of a mixed solvent of methanol and a weak alkaline solution is far inferior to the solubility of a mixed solvent of ethanol and a weak alkaline solution.

[0031] The rutin was dissolved by using the solvents in groups 1 to 12, and the preparation was carried out according to the formula and preparation method of Example 1, and then the content of oxymetazoline hydrochloride at 30 days was verified by a light test.

[0032] Figure 1 The content of oxymetazoline hydrochloride in the illumination test of each group of oxymetazoline hydrochloride preparations prepared using different solvents. The solubility of rutin directly affects its concentration in the system, which in turn affects the degree of interaction between rutin and oxymetazoline hydrochloride. If the degree of interaction between the two is weak, oxymetazoline hydrochloride will be directly exposed to the solution, and the degradation of oxymetazoline hydrochloride by light cannot be avoided.

[0033] Example 1 Oxymetazoline hydrochloride preparation

[0034] formula:

[0035]

[0036] Preparation method:

[0037] (1) dissolving oxymetazoline hydrochloride in water and performing sonication to obtain solution A;

[0038] (2) rutin was dissolved in 6.5% sodium bicarbonate-90% ethanol solution and sonicated to obtain solution B;

[0039] (3) Solution A was added dropwise to solution B at a rate of 0.01 ml / min, and the mixture was allowed to stand for 3 h. The solvent was removed by rotary evaporation under reduced pressure in a water bath at 35°C to 40°C, and the mixture was cooled to obtain solution C.

[0040] (4) Solution C is adjusted to pH = 5.0 with a pH adjuster, a preservative and an isotonic agent are added, water is added to the total amount, microfiltered, nitrogen bubbled, and sterilized to obtain the solution.

[0041] Example 2 Oxymetazoline hydrochloride preparation

[0042] formula:

[0043]

[0044] Preparation method:

[0045] (1) dissolving oxymetazoline hydrochloride in water and performing sonication to obtain solution A;

[0046] (2) rutin was dissolved in 3.5% sodium bicarbonate-95% ethanol solution and sonicated to obtain solution B;

[0047] (3) adding solution A to solution B at a rate of 0.15 ml / min, allowing to stand for 2 to 4 h, removing the solvent by vacuum rotary evaporation at 30°C to 40°C in a water bath, and cooling to obtain solution C;

[0048] (4) Solution C is adjusted to pH 4.5 with a pH adjuster, a preservative and an isotonic agent are added, water is added to the total amount, microfiltered, nitrogen bubbled, and sterilized to obtain the solution.

[0049] Example 3 Oxymetazoline hydrochloride preparation

[0050] formula:

[0051]

[0052] Preparation method:

[0053] (1) dissolving oxymetazoline hydrochloride in water and performing sonication to obtain solution A;

[0054] (2) rutin was dissolved in 9.5% sodium bicarbonate-85% ethanol solution and sonicated to obtain solution B;

[0055] (3) adding solution A to solution B at a rate of 0.05 ml / min, allowing to stand for 2 to 4 h, removing the solvent by vacuum rotary evaporation in a water bath at 40°C to 50°C, and cooling to obtain solution C;

[0056] (4) Solution C is adjusted to pH=6.0 with a pH adjuster, a preservative and an isotonic agent are added, water is added to the total amount, microfiltered, nitrogen bubbled, and sterilized to obtain the solution.

[0057] Example 4 Oxymetazoline Hydrochloride Preparation

[0058] formula:

[0059]

[0060] Preparation method:

[0061] (1) dissolving oxymetazoline hydrochloride in water and performing sonication to obtain solution A;

[0062] (2) rutin was dissolved in 3.5% sodium carbonate-85% ethanol solution and sonicated to obtain solution B;

[0063] (3) Solution A was added dropwise to solution B at a rate of 0.15 ml / min, and the mixture was allowed to stand for 3 h. The solvent was removed by rotary evaporation under reduced pressure at 30°C to 40°C in a water bath, and the mixture was cooled to obtain solution C.

[0064] (4) Solution C is adjusted to pH 4.5 with a pH adjuster, a preservative and an isotonic agent are added, water is added to the total amount, microfiltered, nitrogen bubbled, and sterilized to obtain the solution.

[0065] Example 5 Oxymetazoline Hydrochloride Preparation

[0066] formula:

[0067]

[0068] Preparation method:

[0069] (1) dissolving oxymetazoline hydrochloride in water and performing sonication to obtain solution A;

[0070] (2) rutin was dissolved in 9.5% sodium carbonate-95% ethanol solution and sonicated to obtain solution B;

[0071] (3) adding solution A to solution B at a rate of 0.05 ml / min, allowing to stand for 2 to 4 h, removing the solvent by vacuum rotary evaporation in a water bath at 40°C to 50°C, and cooling to obtain solution C;

[0072] (4) Solution C is adjusted to pH=6.0 with a pH adjuster, a preservative and an isotonic agent are added, water is added to the total amount, microfiltered, nitrogen bubbled, and sterilized to obtain the solution.

[0073] Comparative Example 1 Oxymetazoline Hydrochloride Preparation

[0074] formula:

[0075]

[0076]

[0077] Preparation method:

[0078] (1) dissolving oxymetazoline hydrochloride and rutin in hot water at 40°C ± 2°C, and performing ultrasound to obtain a mixed solution; (2) adjusting the pH of the mixed solution to 5.0 with a pH adjuster, adding a preservative and an isotonic agent, adding water to the full amount, microfiltering, bubbling with nitrogen, and sterilizing to obtain the product.

[0079] Comparative Example 2 Oxymetazoline Hydrochloride Preparation

[0080] formula:

[0081]

[0082] Preparation method:

[0083] Dissolve oxymetazoline hydrochloride in water, adjust the pH to 5.0 with a pH adjuster, add a preservative and an isotonic agent, add water to the full amount, microfilter, bubble with nitrogen, and sterilize to obtain the product.

[0084] Comparative Example 3 Oxymetazoline Hydrochloride Preparation

[0085] formula:

[0086]

[0087] Preparation method:

[0088] (1) dissolving oxymetazoline hydrochloride in water and performing sonication to obtain solution A;

[0089] (2) rutin was dissolved in 6.5% sodium bicarbonate-90% ethanol solution and sonicated to obtain solution B;

[0090] (3) Solution A was added dropwise to solution B at a rate of 5 ml / min, and the mixture was allowed to stand for 3 h. The solvent was removed by vacuum rotary evaporation in a water bath at 35°C to 40°C, and the mixture was cooled to obtain solution C.

[0091] (4) Solution C is adjusted to pH = 5.0 with a pH adjuster, a preservative and an isotonic agent are added, water is added to the total amount, microfiltered, nitrogen bubbled, and sterilized to obtain the solution.

[0092] Study on the stability of oxymetazoline hydrochloride preparations by light exposure test

[0093] The oxymetazoline hydrochloride preparations of Examples 1 to 5 and the oxymetazoline hydrochloride preparations of Comparative Examples 1 to 3 were packaged and placed under conditions of 4500lx±500lx, and illuminated for 0 days, 5 days, 10 days, and 30 days, and samples were taken to detect the content of oxymetazoline hydrochloride and the content of related substances (determined according to the method under the item of oxymetazoline hydrochloride in the first part of the main text of Part II of the 2020 edition of the Chinese Pharmacopoeia).

[0094] Figure 2 The changes in the oxymetazoline hydrochloride content of the oxymetazoline hydrochloride preparations of Examples 1 to 5 and the oxymetazoline hydrochloride preparations of Comparative Examples 1 to 3 in the light irradiation test show that the degradation degree of the active ingredient oxymetazoline hydrochloride in the oxymetazoline hydrochloride preparations of Examples 1 to 5 of the present invention is low in the light irradiation test, and the content can basically be kept stable.

[0095] Figure 4The relevant substances ( Figure 3 The oxymetazoline hydrochloride preparations of Examples 1 to 5 are more stable in the light irradiation test, while the oxymetazoline hydrochloride preparations of Comparative Examples 1 to 3 produce more impurities under the action of light.

Claims

1. A stable oxymetazoline hydrochloride preparation, characterized in that: The stable oxymetazoline hydrochloride preparation comprises, by mass fraction, 0.01% to 0.05% of oxymetazoline hydrochloride, 0.05% to 0.15% of rutin, an appropriate amount of a pH regulator, 0.002% to 0.01% of a preservative, 0.01% to 0.1% of an isotonic agent, and water.

2. The stable oxymetazoline hydrochloride preparation according to claim 1, characterized in that The preservative is selected from at least one of benzalkonium bromide, benzalkonium chloride and chlorobutanol; preferably, the preservative is benzalkonium bromide.

3. The stable oxymetazoline hydrochloride preparation according to claim 1, characterized in that The pH regulator is selected from at least one of borax-boric acid buffer solution, citric acid-sodium citrate buffer solution-disodium hydrogen phosphate-sodium dihydrogen phosphate buffer solution; preferably, the pH regulator is borax-boric acid buffer solution.

4. The stable oxymetazoline hydrochloride preparation according to claim 1, characterized in that The isotonic agent is selected from at least one of glucose, sodium chloride and glycerol; preferably, the isotonic agent is sodium chloride.

5. The stable oxymetazoline hydrochloride preparation according to claim 1, characterized in that The stable oxymetazoline hydrochloride preparation comprises, by mass fraction, 0.03% of oxymetazoline hydrochloride, 0.10% of rutin complex, an appropriate amount of pH regulator, 0.005% of preservative, 0.05% of isotonic agent and water.

6. A method for preparing the stable oxymetazoline hydrochloride preparation according to claim 1, characterized in that: The preparation method is: (1) dissolving oxymetazoline hydrochloride in water and performing sonication to obtain solution A; (2) dissolving rutin in a weakly alkaline ethanol solution and sonicating to obtain solution B; (3) Slowly drip solution A into solution B, let stand for 2 to 4 hours, remove the solvent by vacuum rotary evaporation at 30°C to 50°C in a water bath, and cool to obtain solution C; (4) Solution C is adjusted to pH 4.5-6.0 with a pH adjuster, a preservative and an isotonic agent are added, water is added to the total amount, microfiltered, nitrogen bubbled, and sterilized to obtain the solution.

7. The preparation method according to claim 6, characterized in that: The weak alkaline ethanol solution is a 3.5% to 9.5% carbonate-85% to 95% ethanol solution by mass fraction.

8. The preparation method according to claim 7, characterized in that: The carbonate is sodium carbonate or sodium bicarbonate.

9. The preparation method according to claim 6, characterized in that: The speed at which solution A is dripped into solution B is 0.05-0.15 ml / min.

10. The preparation method according to claim 6, characterized in that: The water bath temperature of the reduced pressure rotary evaporation is 35°C to 40°C.

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