A sprayable carrageenan liquid formulation and its preparation method

Abstract

This application relates to a sprayable carrageenan liquid formulation and its preparation method, belonging to the field of pharmaceutical technology. The sprayable carrageenan liquid formulation comprises 0.12%-0.2% by weight of 1-carrageenan, 0.5%-1.5% by weight of carboxymethyl chitosan, 0.5%-2.5% by weight of sodium chloride, a pH adjuster, and water, and can be applied to the nasal cavity or oral cavity in the form of a spray to provide good coverage.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical technology, specifically to sprayable liquid preparations, and particularly to a sprayable carrageenan liquid preparation and its preparation method. Background Technology

[0002] Respiratory transmission is one of the main routes of viral transmission. Breathed air primarily enters the body through the nose, and the nasal cavity also plays a role in clearing foreign particles, including dust, airborne droplets, and pathogens. Anatomically speaking, the total surface area of ​​the nasal cavity is approximately 150 cm². 2 At the cellular level, the nasal cavity is largely composed of typical airway epithelial cells, whose cilia and microvilli greatly increase the effective surface area (approximately 9.6 m²). 2 While the large surface area of ​​the nasal cavity provides an efficient platform for filtration, it also presents greater exposure for viruses upon entry. Therefore, the coverage of the nasal spray within the nasal cavity significantly impacts its effectiveness.

[0003] Carrageenan possesses antiviral, antibacterial, and anti-allergic properties, and its commonly used concentration in clinical applications is 0.12% (1.2 mg / mL) to 0.16% (1.6 mg / mL). The core mechanism by which carrageenan exerts its antiviral, antibacterial, and anti-allergic effects lies in its ability to form a temporary protective barrier on the surface of the respiratory tract and nasal mucosa, inhibiting the invasion of viruses, bacteria, and allergens.

[0004] Carrageenan, an anionic linear sulfated polysaccharide, exhibits shear-thinning properties in its aqueous solution; that is, the higher the carrageenan concentration, the more pronounced the decrease in solution viscosity with increasing shear rate. Low-concentration carrageenan solutions, under the high shear rates of commercially available spray bottles, do not show sufficient viscosity reduction, meaning the shear-thinning effect is inadequate. This results in excessively strong cohesion when the low-concentration carrageenan solution is ejected from the nozzle, making it difficult to fully break down into fine droplets. Consequently, it produces an undesirable "spray" or "water column" pattern, affecting the distribution, coverage, and bioavailability of the active ingredient in the nasal cavity. Furthermore, it can cause irritation upon contact with the nasal surface, negatively impacting patient compliance.

[0005] Carboxymethyl chitosan is an amphoteric polyelectrolyte whose molecular chains simultaneously carry a positive charge (-NH3). + ) and negative charge (-COO) - Carboxymethyl chitosan also possesses excellent antiviral, antibacterial, and anti-allergic properties. Similar to the mechanism of carrageenan, carboxymethyl chitosan can form a gel on the mucosal surface, blocking viruses, bacteria, and allergens in the air.

[0006] Publication No. CN116887814A discloses a sprayable antiviral preparation, which addresses the issue of sprayability. The preparation includes an antiviral agent and a carrier polymer. The antiviral agent includes sulfated polysaccharides (such as carrageenan), and the carrier polymer includes non-sulfated polysaccharides (such as extracellular polysaccharides, dextran, alginate, pectin, and xanthan gum). The preparation addresses the sprayability of carrageenan in aqueous solution by using carrageenan and non-sulfated polysaccharides in a certain proportion.

[0007] Publication No. WO2023281272A1 discloses an aqueous composition for nasal sprays, which mainly consists of carrageenan, sodium chloride, a buffer, and water. The aqueous composition in this patent contains 0.1-1.0% w / w carrageenan and 0.1-0.9% w / w NaCl, with NaCl preferably at about 0.5% w / w. The patent describes a problem with the aqueous composition itself, which is addressed by applying shear force through a spray pump. Furthermore, the carrageenan aqueous solution prepared according to the patent's formulation still exhibits a jetting pattern when sprayed through a conventional nozzle, failing to reproduce the spray plume described in the patent.

[0008] For example, patented products with publication numbers CN104042640A, EP4079289A1, TR202507844U5, CN107847430B, and US20240299293A1 all contain carrageenan and sodium chloride. However, sodium chloride is used as an osmotic pressure regulator in the above-mentioned carrageenan sprays, and there is no record of sodium chloride affecting the sprayability of the carrageenan spray.

[0009] US20160220584A1 discloses an aqueous nasal spray composition containing chitosan, which is formulated as a low-viscosity preform and becomes adhesive upon contact with a desired surface. It also uses sodium chloride as an osmotic pressure regulator. The patent does not specifically address the issue of sprayability, nor does it record that sodium chloride affects the sprayability of the chitosan solution. Summary of the Invention

[0010] Therefore, the purpose of this invention is to provide a carrageenan liquid formulation that can solve the above-mentioned spraying problems, so as to obtain good spraying characteristics (such as forming uniform and fine droplets) while maintaining the biological activity of carrageenan.

[0011] In a first aspect, this application provides a sprayable carrageenan liquid formulation, which comprises:

[0012] The ingredients are ι-carrageenan, carboxymethyl chitosan, sodium chloride, pH adjuster, and water, with ι-carrageenan comprising 0.12%-0.2% by weight, carboxymethyl chitosan comprising 0.5%-1.5% by weight, and sodium chloride comprising 0.5%-2.5% by weight.

[0013] Preferably, the weight percentage of ι-carrageenan is 0.12%.

[0014] Preferably, the weight percentage of carboxymethyl chitosan is 1%-1.5%.

[0015] More preferably, the weight percentage of carboxymethyl chitosan is 1%.

[0016] Preferably, the sodium chloride content is 2%-2.5% by weight.

[0017] More preferably, the sodium chloride content is 2.5% by weight.

[0018] Optionally, carrageenan liquid formulations are used as nasal sprays and / or oral sprays.

[0019] Alternatively, carrageenan liquid formulations can be used as multi-surface sprays.

[0020] Preferably, the pH adjuster is sodium dihydrogen phosphate.

[0021] The beneficial effects of the sprayable carrageenan liquid formulation of this application are as follows: Firstly, the carrageenan liquid formulation of this application contains ι-carrageenan, carboxymethyl chitosan, and sodium chloride. By combining ι-carrageenan, carboxymethyl chitosan, and sodium chloride at appropriate concentrations, the three components work synergistically to adjust the viscosity of the carrageenan liquid formulation to an ideal state, exhibiting excellent shear-thinning characteristics, easy atomization, and can be applied to the nasal cavity or oral cavity in the form of spraying through commercially available ordinary spray bottles, thereby providing good coverage. Secondly, the carrageenan liquid formulation of this application contains both ι-carrageenan and carboxymethyl chitosan. Both components have the effect of adsorbing viruses, bacteria, and allergens. The dual action of the two components effectively improves the antiviral, antibacterial, and anti-allergic effects of the carrageenan liquid formulation.

[0022] Secondly, this application provides a method for preparing a sprayable carrageenan liquid formulation, the method comprising the following steps:

[0023] (1) Dissolve carboxymethyl chitosan uniformly in part of the prescribed water to obtain the first solution;

[0024] (2) Disperse ι-carrageenan in the first solution under stirring to obtain a homogeneous colloid;

[0025] (3) Dissolve sodium chloride evenly in part of the prescription water to obtain a second solution;

[0026] (4) Add the second solution to the colloid while stirring, mix well to obtain a mixed solution;

[0027] (5) Adjust the pH of the mixed solution to 5.5-7.0, add the remaining prescription water, mix well to obtain carrageenan liquid preparation, and fill.

[0028] Optionally, in step (2), the dispersion is carried out at 60℃-80℃ and a rotation speed of not less than 1000 rpm for 20 minutes by high-speed shear dispersion.

[0029] Optionally, in step (4), the second solution is added in a thin stream, and the system temperature is maintained at 20℃-45℃ during the addition process.

[0030] The beneficial effects of the method for preparing the sprayable carrageenan liquid formulation of this application are that the method first forms a basic colloid containing ι-carrageenan and carboxymethyl chitosan, and then adds an electrolyte solution containing sodium chloride, which can prevent local aggregation or phase separation. At the same time, placing the pH adjustment step last can avoid early interference of pH fluctuations on the charge state and interaction of ι-carrageenan and carboxymethyl chitosan, thus avoiding affecting the uniformity of the formed weak gel network structure. Attached Figure Description

[0031] Figure 1 This is a sprayability test diagram for Comparative Example 1 of this application;

[0032] Figure 2 This is a sprayability test diagram of Example 2 of this application;

[0033] Figure 3 This is a sprayability test diagram of Example 6 of this application;

[0034] Figure 4 This is a test spraying effect diagram of Comparative Example 1 of this application;

[0035] Figure 5 This is a test spraying effect diagram of Embodiment 6 of this application. Detailed Implementation

[0036] To make the technical problems, technical solutions, and beneficial effects to be solved by this application clearer, the following detailed description is provided in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of this application and are not intended to limit the scope of this application.

[0037] Unless otherwise specified, all materials and reagents used in the embodiments of this application are commercially available.

[0038] The sprayable carrageenan liquid formulation of this application can be applied to the surface of human mucous membranes, for example, as a nasal spray and / or oral spray. After use, the liquid formulation can be removed by the body's natural mucus clearance process or manually by the user. For example, when used as a nasal spray, the user can remove the nasal spray by blowing their nose; when used as an oral spray, the user can rinse the oral spray into the esophagus by drinking a liquid (such as water).

[0039] The sprayable carrageenan liquid formulation of this application can also be used as a multi-surface spray. In use, the multi-surface spray can be sprayed onto any surface, such as a countertop, the outer surface of personal protective equipment or items, or the inner surface of a ventilator tubing. After use, the multi-surface spray can be safely wiped off or washed away.

[0040] Preparation of test samples of sprayable carrageenan liquid formulation: Test samples of sprayable carrageenan liquid formulations Comparative Examples 1-2 and Examples 1-7 were prepared according to Table 1.

[0041] Table 1: Formulations of Comparative Examples 1-2 and Examples 1-7

[0042]

[0043] The preparation method of Comparative Example 1 is as follows:

[0044] (1) Dissolve 0.12 g of ι-carrageenan and 0.5 g of sodium chloride evenly in 90 g of the prescribed water;

[0045] (2) Add sodium dihydrogen phosphate until the pH of the mixed solution is adjusted to 5.5-7.0, add the prescription water to 100g, mix well to obtain carrageenan solution, and fill.

[0046] The preparation method of Comparative Example 2 is the same as that of Comparative Example 1, and the amount of ι-carrageenan added is adjusted according to Table 1.

[0047] The preparation method of the test sample in Example 1 is as follows:

[0048] (1) Dissolve 0.5g of carboxymethyl chitosan evenly in 30g of the prescribed water to obtain the first solution;

[0049] (2) 0.12 g of ι-carrageenan was dispersed in the first solution under stirring to obtain a uniform colloid. The dispersion was carried out at 60℃-80℃ and at a speed of not less than 1000 rpm for 20 minutes.

[0050] (3) Dissolve 0.5g of sodium chloride evenly in 60g of the prescribed water to obtain the second solution;

[0051] (4) Under stirring, the second solution is added to the colloid in a thin stream, and the system temperature is maintained at 20℃-45℃ during the addition process. The mixture is homogeneous to obtain a mixed solution.

[0052] (5) Add sodium dihydrogen phosphate until the pH of the mixed solution is adjusted to 5.5-7.0, add water to 100g, mix well to obtain carrageenan liquid preparation, and fill.

[0053] The preparation methods of Examples 2-7 are the same as those of Example 1, except that the amounts of 1-carrageenan, carboxymethyl chitosan and sodium chloride are adjusted according to Table 1.

[0054] Rheological testing: Three samples of each of Comparative Examples 1-2 and Examples 1-7 were prepared using the above method, and the rheological parameters of the above samples were tested using the following method.

[0055] The viscosity of the sample was measured at 25°C using a rotational rheometer.

[0056] Table 2: Viscosities of the samples from Comparative Examples 1-2 and Examples 1-7

[0057]

[0058] Referring to Table 2, Comparative Examples 1 and 2 show that the carrageenan liquid formulation without carboxymethyl chitosan has a higher viscosity.

[0059] Comparative Example 1 and Examples 1-3 show that, while keeping the concentrations of 1-carrageenan and sodium chloride constant, increasing the concentration of carboxymethyl chitosan reduces the viscosity of the carrageenan liquid formulation. Specifically, the carrageenan liquid formulation with a concentration of 1%-1.5% carboxymethyl chitosan exhibits a relatively low viscosity.

[0060] Examples 2 and 4-6 show that, keeping the concentrations of ι-carrageenan and carboxymethyl chitosan constant, the viscosity of the carrageenan liquid formulation gradually decreases with increasing sodium chloride concentration, and the viscosity remains stable after the sodium chloride concentration increases to a certain level. Specifically, the carrageenan liquid formulation with 0.12% ι-carrageenan and 1% carboxymethyl chitosan, combined with 2%-2.5% sodium chloride, exhibits significant shear-thinning behavior and has a lower viscosity compared to the comparative example.

[0061] In Examples 3 and 7, keeping the concentrations of 0.12% ι-carrageenan and 1.5% carboxymethyl chitosan constant, the concentration of sodium chloride was increased from 0.5% to 2.5%, resulting in a decrease in the viscosity of the carrageenan liquid formulation. In Examples 6 and 7, keeping the concentrations of 0.12% ι-carrageenan and 2.5% sodium chloride constant, the concentration of carboxymethyl chitosan was increased from 1% to 1.5%, resulting in minimal change in the viscosity of the carrageenan liquid formulation.

[0062] Through in-depth research, the inventors discovered that ι-carrageenan, as an anionic linear sulfated polysaccharide, possesses unique rheological properties in its aqueous solution. When sprayed using commercially available ordinary spray bottles, it was found that the shear-thinning effect of a single carrageenan solution is insufficient at high shear rates, resulting in inadequate viscosity reduction. This leads to excessively strong cohesion when the liquid exits the nozzle, making it difficult to fully break down into fine droplets, thus producing an undesirable "spray" or "water column" state.

[0063] Carboxymethyl chitosan, as an amphoteric polyelectrolyte, carries a positive charge (-NH3) on its molecular chain. + ) and negative charge (-COO) - The inventors have discovered that when carboxymethyl chitosan is introduced into a system containing ι-carrageenan (strongly negatively charged), the two may form a dynamic and reversible weak gel network structure through electrostatic interactions, molecular chain entanglement, etc. This structure can maintain appropriate viscosity and suspension stability under static or low shear conditions.

[0064] The inventors further discovered that when the sodium chloride concentration is within the specific range described in this invention (e.g., 2% to 2.5%), it may be able to shield the excessively strong electrostatic interaction between ι-carrageenan and carboxymethyl chitosan, adjusting the weak gel network formed above to a suitable strength. This allows the weak gel network structure of the carrageenan liquid formulation of this application to be rapidly and completely temporarily destroyed when subjected to the high shear generated by the spray bottle, exhibiting excellent shear-thinning properties and a sharp decrease in viscosity, thus making the carrageenan liquid formulation easy to atomize; and once it leaves the shear field (after spraying), the viscosity can partially recover, which helps the droplets to remain on the nasal mucosa.

[0065] The synergistic use of carboxymethyl chitosan with a specific concentration of sodium chloride essentially constitutes a rheological modification scheme that endows the carrageenan system with an ideal shear-thinning response behavior, thereby achieving a transformation from poor spraying to ideal spraying (atomization) under conventional spray bottle conditions. This effect was unexpected and could not be achieved by using carboxymethyl chitosan or sodium chloride alone.

[0066] The above mechanism analysis is a reasonable scientific inference based on the experimental phenomena and rheological test data of the present invention (see Comparative Examples 1-2 and Examples 1-7 above), and is used to help understand the technical contribution of the present invention. The scope of protection of the present invention is not limited by this specific theoretical explanation.

[0067] Sprayability test: The sprayability of the test samples of Comparative Examples 1-2 and Examples 1-7 were tested by the following methods.

[0068] (1) Take 10 ml of the test sample, add 10 mg of methylene blue, mix thoroughly to obtain a blue test sample;

[0069] (2) Place the blue test sample into a commercially available ordinary spray bottle (nozzle pointing vertically upward);

[0070] (3) Test spray the blue sample until it sprays smoothly;

[0071] (4) Spray the blue test sample vertically upward once onto a horizontal piece of paper suspended 10cm away from the nozzle of a commercially available ordinary spray bottle;

[0072] (5) Dry the paper and analyze the percentage of coverage of the blue sample spray on the paper using image analysis software (e.g., ImageJ);

[0073] (6) Repeat the above steps multiple times to calculate the average coverage percentage.

[0074] Generally speaking, the higher the percentage of coverage after spraying, the better the spray's sprayability.

[0075] Table 3: Sprayability test results of Comparative Examples 1-2 and Examples 1-7

[0076]

[0077] Please refer to Tables 1 and 3 together. Figure 1 and Figure 4 Comparative Examples 1 and 2 show that the carrageenan liquid formulation without carboxymethyl chitosan has a relatively low coverage percentage after being sprayed from a commercially available ordinary spray bottle, exhibiting the following characteristics: Figure 1 The coverage distribution shown is concentrated.

[0078] Please refer to Tables 1 and 3 together. Figure 1 and Figure 2Comparative Example 1 and Examples 1-3 show that, keeping the concentrations of ι-carrageenan and sodium chloride constant, the coverage percentage of the carrageenan liquid formulation after being sprayed from a commercially available ordinary spray bottle increases after the addition of carboxymethyl chitosan. In particular, a larger coverage percentage is observed for carrageenan liquid formulations with a ratio of 0.12% ι-carrageenan, 0.5% sodium chloride, and 1%-1.5% carboxymethyl chitosan.

[0079] Please refer to Tables 1 and 3 together. Figure 3 and Figure 5 Examples 2 and 4-6 show that, keeping the concentrations of 1-carrageenan and carboxymethyl chitosan constant, the coverage percentage of the spray after being sprayed from a commercially available ordinary spray bottle gradually increases with increasing sodium chloride concentration. For a carrageenan liquid formulation with a ratio of 0.12% 1-carrageenan, 1% carboxymethyl chitosan, and 2.5% sodium chloride, a large coverage percentage is observed, as shown in the example. Figure 3 The coverage and dispersion effect shown.

[0080] To more clearly demonstrate the actual spraying effect of the sprayable carrageenan liquid formulation as a nasal spray, the liquid formulations of Comparative Example 1 and Example 6 were placed in a commercially available ordinary spray bottle (slanted nozzle) for spraying effect demonstration. Comparative Example 1 showed the effect as follows: Figure 4 The spraying state shown in Example 6 is as follows. Figure 5 The spraying status is shown.

[0081] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0082] The embodiments described above are merely illustrative of several implementation methods of this application, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the protection scope of this application. Therefore, the protection scope of this patent application should be determined by the appended claims.

Claims

1. A sprayable karaya gum liquid formulation, characterized in that, Include: The mixture comprises 1-carrageenan, carboxymethyl chitosan, sodium chloride, a pH adjuster, and water, wherein the 1-carrageenan comprises 0.12%-0.2% by weight, the carboxymethyl chitosan comprises 0.5%-1.5% by weight, and the sodium chloride comprises 0.5%-2.5% by weight. The preparation method of the sprayable carrageenan liquid formulation includes the following steps: (1) Dissolve the carboxymethyl chitosan uniformly in a portion of the prescribed water to obtain a first solution; (2) The ι-carrageenan is dispersed in the first solution under stirring to obtain a homogeneous colloid; (3) Dissolve the sodium chloride uniformly in a portion of the prescription water to obtain a second solution; (4) Add the second solution to the colloid while stirring, mix well to obtain a mixed solution; (5) Adjust the pH of the mixed solution to 5.5-7.0, add the remaining prescription water, mix well to obtain carrageenan liquid preparation, and fill.

2. The sprayable carrageenan gum liquid formulation according to claim 1, characterized in that, The ι-carrageenan has a weight percentage of 0.12%.

3. The sprayable carrageenan gum liquid formulation according to claim 2, characterized in that, The carboxymethyl chitosan has a weight percentage of 1%.

4. The sprayable carrageenan gum liquid formulation according to claim 3, characterized in that, The sodium chloride content is 2.5% by weight.

5. The sprayable carrageenan gum liquid formulation according to any one of claims 1-4, wherein, The carrageenan liquid formulation is used as a nasal spray and / or oral spray.

6. The sprayable carrageenan gum liquid formulation according to any one of claims 1-4, wherein, In step (2) of the method for preparing the sprayable carrageenan liquid formulation, the dispersion is carried out at 60℃-80℃ with a rotation speed of not less than 1000 rpm for 20 minutes.

7. The sprayable carrageenan gum liquid formulation according to any one of claims 1 to 4, wherein, In step (4) of the method for preparing the sprayable carrageenan liquid formulation, the second solution is added in a thin stream, and the system temperature is maintained at 20℃-45℃ during the addition process.

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