Stable cetirizine hydrochloride ophthalmic pharmaceutical composition

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a cetirizine hydrochloride-sodium alginate aqueous solution pharmaceutical composition and an ophthalmic preparation thereof, and sodium alginate is a stabilizer. According to the composition, the speed of generating oxidative degradation impurities by reacting a cetirizine hydrochloride aqueous solution with auxiliary materials under high-temperature and illumination conditions is remarkably inhibited, meanwhile, the problem that the viscosity of a cetirizine hydrochloride solution type ophthalmic preparation is reduced under the illumination condition is solved, and the problem that the optical and thermal stability of the cetirizine hydrochloride ophthalmic preparation is poor is solved; and the storage stability of the preparation is greatly improved.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to a cetirizine hydrochloride-sodium alginate aqueous solution pharmaceutical composition and an ophthalmic preparation thereof. Background Art

[0002] Cetirizine hydrochloride, with cetirizine hydrochloride as the main active ingredient, is a selective histamine H1 receptor antagonist, mainly used to relieve allergic symptoms of allergic diseases and treat ocular itching associated with allergic conjunctivitis.

[0003] Cetirizine hydrochloride liquid preparations are widely used in clinical practice, but their stability issues are gradually becoming prominent. ([1] Zhang Ziran, Jiang Lingtao. Interaction between cetirizine hydrochloride and excipients Research[J]. West China Journal of Pharmaceutical Sciences, 2002, 17(5):2.) According to the report, due to the high chemical activity of cetirizine, many excipients cannot tolerate its chemical activity under high temperature, light, acceleration or long-term storage, resulting in an increase in drug-related substances. The inventors found through experiments that the stability problem of cetirizine hydrochloride liquid preparations is more prominent, especially with many commonly used excipients for ophthalmic preparations. The current solution to the problem of cetirizine quality stability in the field is mainly to avoid the use of excipients that interact greatly with it, use some excipients that interact less or do not interact with it, which is limited in the selection of excipients, or to increase the requirements for product packaging, or to lower the storage temperature.

[0004] Patent CN101491524A solves the problem of poor quality stability of cetirizine oral preparations due to the limitation of excipients by adding at least one group of alkaline compounds such as carbonates, bicarbonates, and hydroxides as stabilizers in the formula. The invention mainly lists the improvement of the stability of cetirizine hydrochloride solid preparations by adding alkaline compounds, but does not explain the effect of cetirizine hydrochloride liquid preparations. The inventors found through experiments that this method cannot improve the stability of ophthalmic preparations, because thickeners, tackifiers, surfactants and other polymer excipients with complex structures are generally added to ophthalmic preparations, and at the same time cannot replace the role of thickeners, tackifiers, and surfactants in ophthalmic preparations.

[0005] The original formulation of cetirizine hydrochloride eye drops is marketed under the trade name Zerviate TM, its patent US9993471B2 proposes a topical ophthalmic preparation containing 0.1% to 0.25% (w / v) cetirizine hydrochloride or dihydrochloride, wherein cetirizine is the only active ingredient in the preparation, and the preparation is formulated in a mixture containing polyethylene glycol 400, anhydrous disodium hydrogen phosphate, hydroxypropyl methylcellulose, polysorbate 80, glycerol, disodium edetate, benzalkonium chloride and purified water. The public data in the literature of the invention show that after being placed under accelerated conditions for one month, the total impurities are about 0.5-1.0%, mainly degradation impurities that gradually increase with the placement time. The product is packaged in aluminum foil bags, and judging from its use, it is mainly to improve light and oxidation stability. However, in daily use, once the outer aluminum foil packaging is opened, the product in the package is inevitably exposed to light and oxygen conditions, and the stability cannot be guaranteed.

[0006] Patent CN113876702A improves the currently available cetirizine hydrochloride eye drops in the United States into levocetirizine hydrochloride eye drops containing only a single chiral enantiomer with pharmacological activity, and removes the inactive right cetirizine enantiomer to reduce the occurrence of drug side effects and the possibility of drug resistance. The use of thickeners in the invention can significantly prolong the residence time of levocetirizine in the eye, increase the bioadhesion of eye drops, and reduce the fluidity of the drug; the levocetirizine hydrochloride eye drops proposed in the invention include levocetirizine hydrochloride, thickeners, buffers, wetting agents, metal chelators, pH regulators and water for injection. The invention is characterized by reducing the amount of raw material input and reducing the occurrence of drug side effects. However, the excipients used in the invention are similar to those in the Zerviate patent, and the invention does not mention the preparation stability data. Moreover, the invention mainly improves the preparation stability by optimizing the raw material structure, and is not generally applicable to finished raw materials that can be purchased on the market.

[0007] Patent CN113712908A replaces the preservative benzalkonium chloride in the formula with polyhexamethylene biguanide, the osmotic pressure regulator is sodium chloride, the pH regulator is edetate disodium, and the thickener is hydroxypropyl methylcellulose. The invention points out that the relevant substances are significantly superior to the original cetirizine hydrochloride eye drops and have better long-term stability. However, the invention does not contain specific data to illustrate the results of the stability study.

[0008] Regarding the stability problem of cetirizine hydrochloride reported in the above documents and patents, the inventors found in experiments that the piperazine group in cetirizine hydrochloride is easy to combine with free oxygen to form oxidative degradation impurities, which can be produced at room temperature and under daily lighting conditions. The increase of impurities under high temperature and strong lighting conditions is more significant. In addition, the lighting conditions will also produce photodegradation impurities. And under 4000~5000lux lighting conditions, the viscosity of cetirizine hydrochloride eye drops has a significant downward trend. The viscosity of 10 days of illumination is detected by the Pin capillary viscometer method. Compared with 0 days, the viscosity decreases by about 15%, and the viscosity decreases by about 35% after 30 days of illumination. On the one hand, the appropriate viscosity can ensure that there is no discomfort in clinical use. On the other hand, the viscosity will also affect the retention time of the liquid in the eye, thereby affecting the absorption rate. Regarding the stability of cetirizine hydrochloride ophthalmic preparations, the inventors tested the compatibility of cetirizine hydrochloride with several commonly used excipients for eye drops. The results showed that cetirizine hydrochloride was not compatible with polymer excipients such as hydroxypropyl methylcellulose, polyethylene glycol, and Tween, which are used to adjust the viscosity of the solution, prolong the residence time of cetirizine in the eye, and increase the bioadhesion of eye drops. However, as an ophthalmic preparation, it is inevitable to add similar polymer excipients used to increase bioadhesion to achieve clinical efficacy. However, there are no literature reports on improving the poor stability of the combination of cetirizine hydrochloride and commonly used excipients for ophthalmic preparations in the prior art. In order to extend the shelf life of the product, the commercially available products only improve the product quality by adding outer packaging and recommending a suitable storage temperature (15~25°C).

[0009] Sodium alginate was included in the United States Pharmacopoeia as early as 1938. The 2020 edition of the Chinese Pharmacopoeia Pharmaceutical Excipients mentions that sodium alginate (SA) is extracted and refined from brown seaweed plants with dilute alkali, and its main component is the sodium salt of alginate. Sodium alginate is a bioadhesive polysaccharide with good biocompatibility and degradability. Traditionally, sodium alginate is used as a binder for tablets. Sodium alginate is also used in ophthalmic preparations as a viscosity enhancer to reduce surface tension and increase the residence time of the drug in the conjunctival sac, which has good eye tolerance, or use its gelling properties produced by shrinkage under acidic conditions to prepare hydrogels. According to literature data, the viscosity of 2.5 mg / mL sodium alginate solution is 12.63 mm 2 / s, the common dosage of sodium alginate in eye drops is 1.0mg / mL. At this dosage, the main function of sodium alginate in the prescription is a thickener, and an acidic pH environment is required. In a near-neutral pH environment, the viscosity of sodium alginate cannot achieve the effect of thickening. Therefore, when sodium alginate is used in eye drops, it generally requires a dosage of at least 1mg / ml and a suitable pH environment.

[0010] The problem to be solved in the art is to develop a cetirizine hydrochloride ophthalmic preparation that can protect the piperazine group of cetirizine hydrochloride from being easily oxidized, thereby improving the stability of cetirizine and its preparations and the viscosity stability under light conditions. Summary of the invention

[0011] The purpose of the present invention is to solve the problems of easy oxidation of cetirizine and unstable viscosity under light conditions in the prior art cetirizine aqueous solution pharmaceutical composition, and to provide a cetirizine hydrochloride aqueous solution pharmaceutical composition with simple and easy-to-obtain raw and auxiliary materials, simple preparation and high stability.

[0012] To achieve the above object, the technical solution of the present invention is: The invention provides a cetirizine hydrochloride-sodium alginate aqueous solution pharmaceutical composition. The pharmaceutical composition mainly consists of cetirizine hydrochloride and sodium alginate and is used for preparing an aqueous pharmaceutical solution ophthalmic preparation.

[0013] In certain embodiments, the inventors surprisingly found that when sodium alginate is used in a much smaller amount than conventionally used in the art, although it cannot function as a thickener, due to the large amount of -COO in sodium alginate, － , it can show polyanion behavior in aqueous solution. The aqueous solution of cetirizine hydrochloride is acidic. Sodium alginate is in acidic conditions. -COO － It is converted into -COOH, the degree of ionization is reduced, the hydrophilicity of sodium alginate is reduced, the molecular chain shrinks, and a gel state is formed to wrap cetirizine hydrochloride to form a composition, and the cetirizine hydrochloride ophthalmic preparation is finally neutral. As the pH value is adjusted to increase, the -COOH group is continuously dissociated, the hydrophilicity of sodium alginate is increased, the molecular chain stretches, and finally a dynamic equilibrium is reached in a neutral environment. Sodium alginate, as a stabilizer, can protect the piperazine group in cetirizine hydrochloride so that it is not easily oxidized, so that the stability of cetirizine hydrochloride is significantly improved when it is matched with other commonly used excipients for eye drops, especially the stability under high temperature and light conditions is more significantly improved. At the same time, such a composition presents a suitable viscosity in the solution, which can enhance the viscosity and thickening effect of hydroxypropyl methylcellulose, polyethylene glycol 400, and Tween 80, improve bioadhesion, and the solution viscosity is close to that of commercially available Zerviate within a suitable dosage range. TM The viscosity of the prescription solution has no significant downward trend under light conditions, which is better than Zerviate. TM The molar mass ratio of cetirizine hydrochloride to sodium alginate is selected from 4.5:1 to 5.5:1, and the content of sodium alginate is ≤0.1% in terms of w / v.

[0014] Preferably, the molar mass ratio of cetirizine hydrochloride to sodium alginate is 5:1.

[0015] In certain embodiments, the content of cetirizine hydrochloride is 0.1-1%, and the content of sodium alginate is 0.01-0.1% on a w / v basis.

[0016] In certain preferred embodiments, the content of cetirizine hydrochloride is 0.1-0.5%, and the content of sodium alginate is 0.01-0.05%, calculated on a w / v basis.

[0017] In certain more preferred embodiments, the content of cetirizine hydrochloride is 0.25-0.30% and the amount of sodium alginate is 0.025-0.03% by w / v. Further, the cetirizine hydrochloride-sodium alginate aqueous solution pharmaceutical composition can be prepared by adding any of a thickener, a viscosity enhancer, an osmotic pressure regulator, a metal chelator, an antibacterial agent, a buffer regulator, a pH regulator and water for injection to prepare a cetirizine hydrochloride-sodium alginate ophthalmic preparation.

[0018] In certain preferred embodiments, the thickener is selected from polyols such as dextran 40 / 70; glycerol, polyethylene glycol 300, polyethylene glycol 400, polysorbate 80, propylene glycol, etc., and the content is 0.1-3.0% by w / v; The viscosity enhancer is selected from carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hypromellose, methyl cellulose; gelatin; polyvinyl alcohol, povidone, and the content is 0.1-3.0% by w / v; The osmotic pressure regulator is selected from one or more of glycerol, sodium chloride, propylene glycol, polyethylene glycol 400, and Tween 80, and the content is 0.5-3.0% by w / v; The metal chelating agent is selected from edetate disodium and edetate calcium sodium, and the content is 0.01-0.1% by w / v; The antibacterial agent is selected from benzalkonium chloride, sorbic acid, polyquaternium salts, hypochlorite, perchlorate or chlorite compounds, alkyl esters of p-hydroxybenzoic acid and mixtures thereof; The buffer regulator is selected from boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, various phosphate buffers and mixtures thereof; The pH adjuster is selected from hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, boric acid and formic acid.

[0019] In certain embodiments, in the aqueous pharmaceutical solution composition of cetirizine disclosed in the present invention, the osmotic pressure molar concentration is selected from 280 to 320 mOsm / kg, the viscosity is selected from 4 to 8 mPa·s, and the pH value is selected from 6.0 to 8.0.

[0020] The inventor prepared Zerviate using the patent US9993471 technology TMThe commercially available eye drop preparation was used as a reference. Based on the prescription process technology reported in the patent technology, the stability of the aqueous drug solution prepared under different prescription conditions and the viscosity stability under light conditions were investigated by taking 0.285% cetirizine hydrochloride pharmaceutical composition ophthalmic preparation as an example. The detailed prescriptions are shown in Examples 2 to 13. At the same time, compared with the comparison patent CN101491524 adding alkaline compounds (Example 14), the patent CN113712908 replacing the preservative benzalkonium chloride in the formula with polyhexamethylene biguanide (Example 15), and the commercially available Zerviate TM The stability of the eye drop preparation product (Example 16) was compared, and the evaluation results are shown in Tables 1 and 2. The results show that the existing technology in the field has no significant effect on improving the stability of ophthalmic preparations under light or high temperature conditions without changing the structural characteristics of the raw materials. The stability of the water-soluble ophthalmic preparation of cetirizine hydrochloride is significantly improved by adding an appropriate amount of sodium alginate. Moreover, it can be seen from the results of the prescriptions of different ratios of cetirizine hydrochloride to sodium alginate in Examples 7 to 11 that the amount of sodium alginate added as a conventional thickener not only does not improve the stability, but promotes the generation of degradation impurities and affects the stability of the preparation. It is precisely at the amount and ratio that are generally not considered in the field that sodium alginate plays an unexpected role as a stabilizer for cetirizine hydrochloride, which has a surprising effect on the stability of the preparation.

[0021] The inventors investigated the stability of different prescription products by combining cetirizine hydrochloride with sodium alginate in an appropriate amount and ratio (see Examples 2, 3, 4, 5, 6, 7, 9), combining cetirizine hydrochloride with sodium alginate in an inappropriate amount and ratio (see Examples 8, 10, 12, 13), and not adding sodium alginate (see Examples 14 to 16). The results are shown in Tables 1 and 2. The experimental data obtained fully show that the cetirizine hydrochloride-sodium alginate pharmaceutical composition can effectively inhibit the generation of oxidative degradation impurities, the product viscosity is within a suitable range, and there is no downward trend, which significantly improves the storage stability of the preparation, while the inappropriate amount or the prescription without sodium alginate is more significantly oxidatively degraded during the test, especially under light and high temperature conditions. The stability difference is more obvious, and the viscosity is significantly reduced under light conditions. The composition of the present invention prolongs the storage time of the product, so that the cetirizine hydrochloride ophthalmic preparation does not need to pay special attention to light shielding and oxygen isolation in daily use, which greatly reduces the requirements for product storage conditions.

[0022] Table 1 Comparison of the stability of cetirizine hydrochloride ophthalmic preparations prepared by different processes

[0023] Table 2 Comparison of viscosity of cetirizine hydrochloride ophthalmic preparations prepared by different processes

[0024] The beneficial effects of the present invention are as follows: the cetirizine hydrochloride-sodium alginate aqueous solution pharmaceutical composition disclosed in the present invention significantly inhibits the speed at which the cetirizine hydrochloride aqueous solution reacts with the auxiliary materials under high temperature and light conditions to produce oxidative degradation impurities, while solving the problem of viscosity decrease of the cetirizine hydrochloride solution-type ophthalmic preparation under light conditions, improving the problem of poor light and heat stability of the cetirizine hydrochloride ophthalmic preparation, and greatly improving the storage stability of the preparation.

[0025] In the present invention, "stability" and "stable" refer to the resistance of the cetirizine hydrochloride-sodium alginate pharmaceutical composition and other optional active agents to chemical degradation under given manufacturing, preparation, transportation and storage conditions. The "stable" formulation of the present invention also preferably has an increase in oxidative degradation impurities of no more than 0.20% under given manufacturing, preparation, transportation and / or storage conditions, and more preferably, the oxidative degradation impurities do not exceed 0.10%.

[0026] In the present invention, "no decreasing trend in viscosity" means that the viscosity decreases by no more than 10% of the viscosity on day 0.

[0027] In certain embodiments, the cetirizine hydrochloride-sodium alginate pharmaceutical composition formulation is stable for at least 3 months when directly exposed to a daily light intensity range of 100-1000 lux; and there is no decreasing trend in viscosity after 30 days of exposure to 4000-5000 lux light.

[0028] In certain embodiments, the cetirizine hydrochloride-sodium alginate pharmaceutical composition formulation is stable within a temperature range of about 50 to -60°C for at least 1 month; and there is no decreasing trend in viscosity after irradiation with 4000-5000 lux for 30 days.

[0029] In certain embodiments, the cetirizine hydrochloride-sodium alginate pharmaceutical composition formulation is stable within a temperature range of about 30 to 40° C. for at least 6 months; and there is no decreasing trend in viscosity under 4000-5000 lux light conditions for 30 days.

[0030] In other embodiments, the cetirizine hydrochloride-sodium alginate pharmaceutical composition formulation is stable for at least 36 months within a temperature range of about 20 to 30° C.; and there is no decreasing trend in viscosity under 4000-5000 lux light conditions for 30 days.

[0031] The preparation of the present invention may be packaged as a single-dose product or a multi-dose product.

[0032] Although the formulations of the present invention are preferably formulated as "ready-to-use" aqueous solutions, alternative formulations are contemplated within the scope of the present invention, so that, for example, the active ingredients, surfactants, salts, chelating agents or other components of the ophthalmic solution, or mixtures thereof, may be lyophilized or otherwise provided as dry powders or tablets ready for dissolution. DETAILED DESCRIPTION

[0033] The present invention is further described below in conjunction with examples, but the following examples are not intended to limit the present invention. Example 1

[0034] Prescription of cetirizine hydrochloride-sodium alginate ophthalmic drug composition

[0035] The preparation process is as follows: Dissolve the prescribed amount of sodium alginate in 90g of water, add cetirizine hydrochloride and stir to completely dissolve, and add water to make the volume to 100ml.

[0036] Example 2 Ophthalmic preparation prescription of cetirizine hydrochloride-sodium alginate combination

[0037] The preparation process is as follows: Dissolve edetate disodium and 0.7g disodium hydrogen phosphate in 70g water, add the prescribed amount of hydroxypropyl methylcellulose and sodium alginate to make it completely swell, add cetirizine hydrochloride and stir to make it completely dissolved, adjust the pH to 6-8 with disodium hydrogen phosphate aqueous solution, add glycerol, polyethylene glycol 400 and Tween 80, and add water to make up to 100ml.

[0038] Example 3 Ophthalmic preparation prescription of cetirizine hydrochloride-sodium alginate combination

[0039] The preparation process is as follows: Dissolve edetate disodium and 2.0g disodium hydrogen phosphate in 70g water, add the prescribed amount of hydroxypropyl methylcellulose and sodium alginate to make it completely swell, add cetirizine hydrochloride and stir to make it completely dissolved, adjust the pH to 6-8 with disodium hydrogen phosphate aqueous solution, add glycerol, polyethylene glycol 400 and Tween 80, and add water to make up to 100ml.

[0040] Example 4 Ophthalmic preparation prescription of cetirizine hydrochloride-sodium alginate combination

[0041] The preparation process is as follows: Dissolve edetate disodium and 2.2g disodium hydrogen phosphate in 70g water, add the prescribed amount of hydroxypropyl methylcellulose and sodium alginate to make them completely swell, add cetirizine hydrochloride and stir to make them completely dissolved, adjust the pH to 6-8 with sodium hydroxide aqueous solution, add glycerol, polyethylene glycol 400 and Tween 80, and add water to make up to 100ml. Example 5

[0042] Ophthalmic preparation prescription of cetirizine hydrochloride-sodium alginate combination

[0043] The preparation process is as follows: Dissolve disodium edetate and disodium hydrogen phosphate in 70g of water, add the prescribed amount of hydroxypropyl methylcellulose and sodium alginate to make them completely swell, add cetirizine hydrochloride and stir to make them completely dissolved, adjust the pH to 6-8 with sodium hydroxide aqueous solution, add glycerol, polyethylene glycol 400 and Tween 80, and add water to make up to 100ml. Example 6

[0044] Ophthalmic preparation prescription of cetirizine hydrochloride-sodium alginate combination

[0045] The preparation process is as follows: Dissolve disodium edetate and disodium hydrogen phosphate in 70g of water, add the prescribed amount of hydroxypropyl methylcellulose and sodium alginate to make them completely swell, add cetirizine hydrochloride and stir to make them completely dissolved, adjust the pH to 6-8 with sodium hydroxide aqueous solution, add glycerol, polyethylene glycol 400 and Tween 80, and add water to make up to 100ml. Example 7

[0046] Ophthalmic preparation prescription of cetirizine hydrochloride-sodium alginate combination

[0047] The preparation process is as follows: Dissolve disodium edetate and disodium hydrogen phosphate in 70g of water, add the prescribed amount of hydroxypropyl methylcellulose and sodium alginate to make them completely swell, add cetirizine hydrochloride and stir to make them completely dissolved, adjust the pH to 6-8 with sodium hydroxide and hydrochloric acid aqueous solution, add glycerol, polyethylene glycol 400 and Tween 80, and add water to make up to 100ml. Example 8

[0048] Ophthalmic preparation prescription of cetirizine hydrochloride-sodium alginate combination

[0049] The preparation process is as follows: Dissolve disodium edetate and disodium hydrogen phosphate in 70g of water, add the prescribed amount of hydroxypropyl methylcellulose and sodium alginate to make them completely swell, add cetirizine hydrochloride and stir to make them completely dissolved, adjust the pH to 6-8 with sodium hydroxide and hydrochloric acid aqueous solution, add glycerol, polyethylene glycol 400 and Tween 80, and add water to make up to 100ml.

[0050] Example 9 Ophthalmic preparation prescription of cetirizine hydrochloride-sodium alginate combination

[0051] The preparation process is as follows: Dissolve disodium edetate and disodium hydrogen phosphate in 70g of water, add the prescribed amount of hydroxypropyl methylcellulose and sodium alginate to make them completely swell, add cetirizine hydrochloride and stir to make them completely dissolved, adjust the pH to 6-8 with sodium hydroxide and hydrochloric acid aqueous solution, add glycerol, polyethylene glycol 400 and Tween 80, and add water to make up to 100ml.

[0052] Example 10 A cetirizine hydrochloride-sodium alginate combination ophthalmic preparation, 100 ml of which comprises the following components: cetirizine hydrochloride-0.285% (w / v), sodium alginate-0.030%, hydroxypropyl methylcellulose-0.24%, polyethylene glycol 400-1%, glycerol-1.8%, Tween 80-0.1%, edetate disodium 0.025%, appropriate amounts of disodium hydrogen phosphate, hydrochloric acid, sodium hydroxide and water for injection.

[0053] Ophthalmic preparation prescription of cetirizine hydrochloride-sodium alginate combination

[0054] The preparation process is as follows: Dissolve disodium edetate and disodium hydrogen phosphate in 70g of water, add the prescribed amount of hydroxypropyl methylcellulose and sodium alginate to make them completely swell, add cetirizine hydrochloride and stir to make them completely dissolved, adjust the pH to 6-8 with sodium hydroxide and hydrochloric acid aqueous solution, add glycerol, polyethylene glycol 400 and Tween 80, and add water to make up to 100ml. Embodiment 11

[0055] Ophthalmic preparation prescription of cetirizine hydrochloride-sodium alginate combination

[0056] The preparation process is as follows: Dissolve disodium edetate and disodium hydrogen phosphate in 70g of water, add the prescribed amount of hydroxypropyl methylcellulose and sodium alginate to make them completely swell, add cetirizine hydrochloride and stir to make them completely dissolved, adjust the pH to 6-8 with sodium hydroxide and hydrochloric acid aqueous solution, add glycerol, polyethylene glycol 400 and Tween 80, and add water to make up to 100ml.

[0057] Example 12 Ophthalmic preparation prescription of cetirizine hydrochloride-sodium alginate combination

[0058] The preparation process is as follows: Dissolve disodium edetate and disodium hydrogen phosphate in 70g of water, add the prescribed amount of hydroxypropyl methylcellulose and sodium alginate to make them completely swell, add cetirizine hydrochloride and stir to make them completely dissolved, adjust the pH to 6-8 with sodium hydroxide and hydrochloric acid aqueous solution, add glycerol, polyethylene glycol 400 and Tween 80, and add water to make up to 100ml. Embodiment 13

[0059] Ophthalmic preparation prescription of cetirizine hydrochloride-sodium alginate combination

[0060] The preparation process is as follows: Dissolve disodium edetate and disodium hydrogen phosphate in 70g of water, add the prescribed amount of sodium alginate to make it completely swell, add cetirizine hydrochloride and stir to make it completely dissolved, adjust the pH to 6-8 with sodium hydroxide and hydrochloric acid aqueous solution, add glycerol, polyethylene glycol 400 and Tween 80, and add water to make up to 100ml.

[0061] Example 14 Control group 1 According to CN101491524 Ophthalmic preparation prescription of cetirizine hydrochloride-sodium alginate combination

[0062] The preparation process is as follows: Dissolve disodium edetate and disodium hydrogen phosphate in 70g of water, add the prescribed amount of hydroxypropyl methylcellulose and sodium alginate to make them completely swell, add cetirizine hydrochloride and stir to make them completely dissolved, adjust the pH to 6-8 with sodium hydroxide aqueous solution, add glycerol, polyethylene glycol 400 and Tween 80, and add water to make up to 100ml.

[0063] Example 15 Control group 2 Based on patent CN113712908 Ophthalmic preparation prescription of cetirizine hydrochloride-sodium alginate combination

[0064] The preparation process is as follows: Add edetate disodium, cetirizine hydrochloride in appropriate amount of water in turn, and continue stirring until dissolved; add hydroxypropyl methylcellulose to appropriate amount of water, continue stirring until evenly dispersed, then add polyhexamethylene biguanide; mix the above two solutions and continue stirring; add sodium hydroxide dropwise to adjust the pH of the above solution to 7.45, and then add enough water for injection.

[0065] Example 16 Control group 3: Commercially available Zerviate TM , specification 0.24%, 3 batches in total, source: Eyevance Pharmaceuticals Llc.

Claims

1. A cetirizine hydrochloride-sodium alginate aqueous solution pharmaceutical composition, characterized in that: The pharmaceutical composition is mainly composed of cetirizine hydrochloride and sodium alginate, wherein the molar mass ratio of cetirizine hydrochloride to sodium alginate is selected from 5.5:1 to 4.5:1, and the amount of sodium alginate is ≤0.1% in terms of w / v.

2. A cetirizine hydrochloride-sodium alginate aqueous solution pharmaceutical composition according to claim 1, characterized in that: The molar mass ratio of cetirizine hydrochloride to sodium alginate is selected from 5:

1.

3. A cetirizine hydrochloride-sodium alginate aqueous solution pharmaceutical composition according to claim 1, characterized in that: In terms of w / v, the content of cetirizine hydrochloride is selected from 0.1-1%, and the content of sodium alginate is selected from 0.01-0.1%.

4. A cetirizine hydrochloride-sodium alginate aqueous solution pharmaceutical composition according to claim 3, characterized in that: In terms of w / v, the content of cetirizine hydrochloride is selected from 0.1-0.5%, and the content of sodium alginate is selected from 0.01-0.05%.

5. A cetirizine hydrochloride-sodium alginate aqueous solution pharmaceutical composition according to claim 4, characterized in that: In terms of w / v, the content of cetirizine hydrochloride is selected from 0.25-0.30%, and the amount of sodium alginate is selected from 0.025-0.030%.

6. A cetirizine hydrochloride-sodium alginate aqueous solution pharmaceutical composition according to claim 1, characterized in that: The pharmaceutical composition contains two or more of a thickener, a viscosity enhancer, an osmotic pressure regulator, a metal chelating agent, an antibacterial agent, a buffer regulator, a pH regulator and injection water to prepare a cetirizine hydrochloride-sodium alginate eye preparation.

7. The cetirizine hydrochloride-sodium alginate aqueous solution pharmaceutical composition according to claim 1, characterized in that: The osmotic pressure molar concentration of the pharmaceutical composition is selected from 280 to 320 mOsm / kg, the viscosity is selected from 4 to 8 mPa·s, and the pH value is selected from 6.0 to 8.0.

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