A stable oxymetazoline hydrochloride preparation and its preparation method

Abstract

The present invention belongs to the technical field of sympathomimetic drug preparations, and particularly relates to a stable oxymetazoline hydrochloride preparation and a preparation method thereof. The oxymetazoline hydrochloride preparation of the present invention is composed of oxymetazoline hydrochloride, rutin, a pH regulator, a preservative, an isotonic agent, and water. The present invention utilizes the intermolecular interaction between oxymetazoline hydrochloride and rutin to form a complex system, and optimizes the preparation method of the oxymetazoline hydrochloride preparation, effectively improving the stability of the oxymetazoline hydrochloride preparation.

Description

Technical Field

[0001] The present 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] Disclosing the information of this background art section is only intended to enhance the understanding of the overall background of the present invention, and is not necessarily to be regarded as an admission or any form of implication that this information constitutes the prior art already known to those of ordinary skill in the art.

[0003] Oxymetazoline hydrochloride is an α-adrenergic receptor agonist widely used in clinical practice, with the molecular formula C 11 H 15 ClN 2 O, 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, alleviating swelling and congestion, and achieving the effect of relieving nasal congestion. Clinically, it is mainly used 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 reduce eye congestion.

[0004] Studies have found that the poor photostability of oxymetazoline hydrochloride is mainly related to its chemical structure and the possible photochemical reactions under light. Oxymetazoline hydrochloride is an organic compound containing an aromatic ring and an amino group. 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 cleavage of the molecular structure or other chemical changes, thereby reducing the stability and effectiveness of the drug. In addition, light can excite compounds to generate free radicals, which are highly reactive substances and can further initiate chain reactions, leading to the degradation of the drug.

[0005] Chinese Patent No. CN101951886A discloses a method for enhancing the photostability of oxymetazoline by using a buffer solution to reduce the pH of the composition to 3-6 to enhance the photostability of oxymetazoline in a topical decongestant composition.

[0006] Chinese Patent No. 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 to boiling for 15-30 minutes, cooled, a cooling agent - ethanol solution is added, a thickening agent is added, and the pH value is adjusted to 4.0-5.0. However, it is well known that oxymetazoline hydrochloride has poor tolerance to high temperatures and may degrade more rapidly under high temperature conditions.

[0007] At present, the existing technology has not yet solved the problem of poor stability of oxymetazoline hydrochloride, especially its photo-stability. Summary of the Invention

[0008] To overcome the deficiencies of the existing technology, the present invention provides a stable oxymetazoline hydrochloride preparation, which contains, by mass fraction, 0.01% - 0.05% of oxymetazoline hydrochloride, 0.05% - 0.15% of rutin (CAS: 153-18-4, content 99%), 0.002% - 0.01% of preservative, 0.01% - 0.1% of isotonic agent, an appropriate amount of 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 regulator is selected from at least one of borax-boric acid buffer solution, citric acid-sodium citrate buffer solution, and disodium hydrogen phosphate-sodium dihydrogen phosphate buffer solution; 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, and the preparation method is as follows:

[0011] (1) Dissolve oxymetazoline hydrochloride in water and ultrasonicate to obtain solution A;

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

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

[0014] (4) Adjust the pH of solution C to pH = 4.5 - 6.0 with a pH regulator, add a preservative and an isotonic agent, add water to the full volume, microfilter, bubble with nitrogen, and sterilize to obtain the product.

[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 this complex has been verified by infrared spectroscopy. Infrared measurements were carried out on the oxymetazoline hydrochloride-rutin complex and a mixed solution of oxymetazoline hydrochloride and rutin, and there are differences in the absorption peak positions). Rutin has multiple hydroxyl (-OH) and glycosyl (-OCH 2 ) structures, and these functional groups can form hydrogen bonds with nitrogen atoms or other hydrogen-containing groups in oxymetazoline hydrochloride. Hydrogen bonding is a very important intermolecular force that can stabilize the formation of the complex.

[0016] Further, due to the poor water solubility of rutin, 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 their mixed solutions, it is found that the carbonate-ethanol solution has the best effect on dissolving rutin. Therefore, screening experiments are carried out on the types and concentrations of carbonates and the concentration of ethanol. It is found that a weakly alkaline ethanol solution of 3.5% - 9.5% carbonate - 85% - 95% ethanol by mass fraction can completely dissolve rutin, and the carbonate is 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 the reaction to be too fast and tiny crystals or flocs will appear. Therefore, controlling the mixing speed of solution A and B is the key factor in the formation of the oxymetazoline hydrochloride-rutin complex. Through experiments, it is found that when the dropping speed of solution A into solution B is 0.05 - 0.15 ml / min, there will be no situation of too fast reaction, and the time cost can be relatively saved on this basis.

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

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

[0020] (2) The present invention explores a preparation method suitable for oxymetazoline hydrochloride preparations, especially explores the solvent system for dissolving rutin and the interaction speed between the rutin solution and the dissolution of oxymetazoline hydrochloride, more efficiently promoting the formation of the oxymetazoline hydrochloride-rutin complex, thereby effectively improving the stability of the oxymetazoline hydrochloride preparation. Description of the Drawings

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

[0022] Figure 2 : Changes in the content of oxymetazoline hydrochloride in the light exposure test of the oxymetazoline hydrochloride preparations of Examples 1 - 5 and Comparative Examples 1 - 3.

[0023] Figure 3 : Structural formula of related substances

[0024] Figure 4 : Changes in the content of related substances in the light exposure test of the oxymetazoline hydrochloride preparations of Examples 1 - 5 and Comparative Examples 1 - 3. Detailed Embodiments

[0025] In order to make the objectives and technical solutions of the present invention clearer and more understandable, the following further describes the present invention in conjunction with embodiments. However, the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. Those skilled in the art should understand 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] To explore the dissolution of rutin, various solvents were tried for dissolution.

[0028] Table 1 Solubility of rutin in different solvents

[0029] Group Solvent 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 Hot 95% 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, indicating that the dissolution effect of hot solvents is better than that of cold solvents, and the dissolution effect of methanol is better than that of ethanol. However, the dissolution effect of the mixed solvent of methanol and weak alkaline solution is much lower than that of the mixed solvent of ethanol and weak alkaline solution.

[0031] Dissolve rutin with the solvents in groups 1 to 12 above, prepare the preparation according to the formula and preparation method of Example 1, and then verify the content of oxymetazoline hydrochloride at 30 days by light exposure test.

[0032] Figure 1 It is the content of oxymetazoline hydrochloride in the light exposure test of each group of oxymetazoline hydrochloride preparations prepared with different solvents. The solubility of rutin directly affects its concentration in the system, and then 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 in the solution, and it is impossible to avoid the degradation effect of light on oxymetazoline hydrochloride.

[0033] Example 1 Oxymetazoline hydrochloride preparation

[0034] Formula:

[0035]

[0036] Preparation method:

[0037] (1) Dissolve oxymetazoline hydrochloride in water and sonicate to obtain solution A;

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

[0039] (3) Drop solution A into solution B at a speed of 0.01 ml / min, let it stand for 3 h, evaporate the solvent under reduced pressure in a water bath at 35°C - 40°C, cool, and obtain solution C;

[0040] (4) Solution C is adjusted to pH = 5.0 with a pH regulator, preservatives and isotonic agents are added, water is added to the full volume, microfiltered, bubbled with nitrogen, and sterilized to obtain the product.

[0041] Example 2 Oxymetazoline Hydrochloride Preparation

[0042] Formulation:

[0043]

[0044] Preparation method:

[0045] (1) Dissolve oxymetazoline hydrochloride in water and sonicate to obtain Solution A;

[0046] (2) Dissolve rutin in 3.5% sodium bicarbonate - 95% ethanol solution and sonicate to obtain Solution B;

[0047] (3) Slowly drip Solution A into Solution B at a rate of 0.15 ml / min, let it stand for 2 - 4 h, remove the solvent by rotary evaporation under reduced pressure in a water bath at 30°C - 40°C, cool to obtain Solution C;

[0048] (4) Solution C is adjusted to pH = 4.5 with a pH regulator, preservatives and isotonic agents are added, water is added to the full volume, microfiltered, bubbled with nitrogen, and sterilized to obtain the product.

[0049] Example 3 Oxymetazoline Hydrochloride Preparation

[0050] Formulation:

[0051]

[0052] Preparation method:

[0053] (1) Dissolve oxymetazoline hydrochloride in water and sonicate to obtain Solution A;

[0054] (2) Dissolve rutin in 9.5% sodium bicarbonate - 85% ethanol solution and sonicate to obtain Solution B;

[0055] (3) Slowly drip Solution A into Solution B at a rate of 0.05 ml / min, let it stand for 2 - 4 h, remove the solvent by rotary evaporation under reduced pressure in a water bath at 40°C - 50°C, cool to obtain Solution C;

[0056] (4) Solution C is adjusted to pH = 6.0 with a pH regulator, preservatives and isotonic agents are added, water is added to the full volume, microfiltered, bubbled with nitrogen, and sterilized to obtain the product.

[0057] Example 4 Oxymetazoline Hydrochloride Preparation

[0058] Formulation:

[0059]

[0060] Preparation method:

[0061] (1) Dissolve oxymetazoline hydrochloride in water and sonicate to obtain solution A;

[0062] (2) Dissolve rutin in a 3.5% sodium carbonate - 85% ethanol solution and sonicate to obtain solution B;

[0063] (3) Drop solution A into solution B at a rate of 0.15 ml / min, let it stand for 3 h, rotary evaporate under reduced pressure to remove the solvent in a water bath at 30°C - 40°C, cool to obtain solution C;

[0064] (4) Adjust solution C to pH = 4.5 with a pH regulator, add preservatives and isotonic agents, add water to the full volume, microfilter, bubble with nitrogen, and sterilize to obtain the product.

[0065] Example 5 Oxymetazoline Hydrochloride Preparation

[0066] Formulation:

[0067]

[0068] Preparation method:

[0069] (1) Dissolve oxymetazoline hydrochloride in water and sonicate to obtain solution A;

[0070] (2) Dissolve rutin in a 9.5% sodium carbonate - 95% ethanol solution and sonicate to obtain solution B;

[0071] (3) Drop solution A into solution B at a rate of 0.05 ml / min, let it stand for 2 - 4 h, rotary evaporate under reduced pressure to remove the solvent in a water bath at 40°C - 50°C, cool to obtain solution C;

[0072] (4) Adjust solution C to pH = 6.0 with a pH regulator, add preservatives and isotonic agents, add water to the full volume, microfilter, bubble with nitrogen, and sterilize to obtain the product.

[0073] Comparative Example 1 Oxymetazoline Hydrochloride Preparation

[0074] Formulation:

[0075]

[0076]

[0077] Preparation method:

[0078] (1) Dissolve oxymetazoline hydrochloride and rutin in hot water at 40°C ± 2°C and sonicate to obtain a mixed solution; (2) Adjust the pH of the mixed solution to pH = 5.0 with a pH regulator, add preservatives and isotonic agents, add water to the full volume, microfilter, bubble with nitrogen, and sterilize to obtain the product.

[0079] Comparative Example 2 Oxymetazoline Hydrochloride Preparation

[0080] Formulation:

[0081]

[0082] Preparation method:

[0083] Dissolve oxymetazoline hydrochloride in water, adjust the pH to 5.0 with a pH regulator, add preservatives and isotonic agents, add water to the full volume, microfilter, bubble with nitrogen, and sterilize to obtain the product.

[0084] Comparative Example 3 Oxymetazoline Hydrochloride Preparation

[0085] Formulation:

[0086]

[0087] Preparation method:

[0088] (1) Dissolve oxymetazoline hydrochloride in water and sonicate to obtain Solution A;

[0089] (2) Dissolve rutin in a 6.5% sodium bicarbonate - 90% ethanol solution and sonicate to obtain Solution B;

[0090] (3) Drop Solution A into Solution B at a rate of 5 ml / min, let it stand for 3 h, remove the solvent by rotary evaporation under reduced pressure at 35°C - 40°C in a water bath, and cool to obtain Solution C;

[0091] (4) Adjust the pH of Solution C to 5.0 with a pH regulator, add preservatives and isotonic agents, add water to the full volume, microfilter, bubble with nitrogen, and sterilize to obtain the product.

[0092] The stability of oxymetazoline hydrochloride preparations was investigated by light exposure test

[0093] Pack the oxymetazoline hydrochloride preparations of Examples 1 - 5 and Comparative Examples 1 - 3, place them under the condition of 4500 lx ± 500 lx, expose them to light for 0 days, 5 days, 10 days, and 30 days, and sample to detect the content of oxymetazoline and the content of related substances (determined according to the method under the item of oxymetazoline hydrochloride in the first part of the second volume of the Chinese Pharmacopoeia 2020 edition).

[0094] Figure 2 Shows the change in the content of oxymetazoline in the light exposure test of the oxymetazoline hydrochloride preparations of Examples 1 - 5 and Comparative Examples 1 - 3. It shows that the effective ingredient oxymetazoline in the oxymetazoline hydrochloride preparations of Examples 1 - 5 of the present invention has a low degradation degree in the light exposure test and can basically maintain a stable content.

[0095] Figure 4The changes in the content of related substances ( Figure 3 ) in the oxymetazoline hydrochloride preparations of Examples 1-5 and the oxymetazoline hydrochloride preparations of Comparative Examples 1-3 during the light exposure test. The oxymetazoline hydrochloride preparations of Examples 1-5 have higher stability during the light exposure test, while the oxymetazoline hydrochloride preparations of Comparative Examples 1-3 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 adjuster, 0.002% to 0.01% of a preservative, 0.01% to 0.1% of an isotonic agent, and water; The preparation method of the stable oxymetazoline hydrochloride preparation is: (1) dissolving oxymetazoline hydrochloride in water and sonicating to obtain solution A; (2) rutin was dissolved in a 3.5% to 9.5% carbonate-85% to 95% ethanol solution by mass fraction and ultrasonicated to obtain solution B; (3) Add solution A to solution B at a rate of 0.05-0.15 ml / min, let stand for 2-4 h, remove the solvent by vacuum rotary evaporation at 30-50 °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, and a preservative and an isotonic agent are added. Water is added to the total amount, and the solution is microfiltered, nitrogen bubbled, and sterilized. The carbonate is sodium carbonate or sodium bicarbonate.

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.

3. The stable oxymetazoline hydrochloride preparation according to claim 2, characterized in that: The preservative is benzalkonium bromide.

4. 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, and disodium hydrogen phosphate-sodium dihydrogen phosphate buffer solution.

5. The stable oxymetazoline hydrochloride preparation according to claim 4, characterized in that The pH regulator is a borax-boric acid buffer solution.

6. 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.

7. The stable oxymetazoline hydrochloride preparation according to claim 6, characterized in that: The isotonic agent is sodium chloride.

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

9. The stable oxymetazoline hydrochloride preparation according to claim 1, characterized in that The water bath temperature of the vacuum rotary evaporation is 35°C-40°C.

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