CN114668722A - Cetirizine hydrochloride spray and preparation method thereof - Google Patents

Abstract

The invention relates to a cetirizine hydrochloride spray and a preparation method thereof, belonging to the field of pharmaceutical preparations. The spray comprises cetirizine hydrochloride, an absorption enhancer, a pH regulator, a dispersant and purified water, and the prepared cetirizine hydrochloride spray avoids blood absorption and metabolism, has small influence on the body, can directly act on a focus and takes effect quickly; the invention well improves the problem of impurities generated by the degradation of the preparation by optimizing the prescription, solves the problem that the spraying agent is difficult to store, greatly improves the stability, has simple preparation process, is suitable for industrial production and is convenient for market popularization.

Description

Cetirizine hydrochloride spray and preparation method thereof

Technical Field

The invention relates to a cetirizine hydrochloride spray and a preparation method thereof, belonging to the field of pharmaceutical preparations.

Technical Field

Cetirizine hydrochloride is a second generation H1 antihistamine, and is a long-acting and selective oral potent antiallergic agent. Is suitable for allergic diseases of respiratory system, skin and eye, including perennial allergic diseases such as allergic dermatoses, urticaria, allergic rhinitis, ocular pruritus, conjunctivitis and asthma. The product can also be used for treating various skin allergic diseases. For example, it can be used for treating chronic, artificial, cold, delayed stress, solar urticaria, atopic dermatitis, etc. It is also an effective medicine for treating rapid onset of wind mass, rapid onset of cumulus mass and pruritus caused by mosquito bite.

The cetirizine hydrochloride has good anti-allergic effect, less side reaction and tolerance, and has good clinical application prospect. The cetirizine hydrochloride preparation existing in China at present is mainly a tablet, and the invention aims at providing a spray which can improve the adaptability of patients and meets the requirements of the majority of patients.

Chinese patents CN 1634063a and CN 100589805a disclose levocetirizine hydrochloride external preparations, but do not disclose specific formulations of aerosols.

Chinese patent CN 102028658A discloses a cetirizine hydrochloride spray, which contains cetirizine hydrochloride, a solvent, a latent solvent, a preservative, urea and sodium chloride, wherein the latent solvent is propylene glycol or glycerol, and the pH value of the cetirizine hydrochloride spray is 5.0-7.0. However, it has been found that cetirizine hydrochloride is not in the most stable state in the pH range of 5.0-7.0, and is easily degraded, resulting in increased impurities, especially in the moist environment of a spray, which is not favorable for storage.

Therefore, based on the problems, the invention aims to provide a cetirizine hydrochloride spray with good transdermal property and high stability so as to meet the requirements of a large number of patients.

Disclosure of Invention

The invention overcomes the defects of the prior art, well improves the problem of impurities generated by the degradation of the preparation by optimizing the prescription, solves the problem that the spray is difficult to store, and greatly improves the stability.

The invention aims to provide a prescription of a cetirizine hydrochloride spray, which comprises an absorption enhancer, a pH regulator, a dispersant and purified water.

Further, the composition comprises the following components in percentage by weight:

wherein the absorption enhancer is one or more selected from polysorbate 20, polysorbate 80, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, sodium lauryl sulfate, azone, poloxamer 188, oleic acid and/or its salt, chitosan, ethanol, and propylene glycol.

In order to achieve the effects of improving the in vitro permeability and promoting the absorption of the drugs, the inventor further prefers an absorption enhancer, and researches show that the mixture of propylene glycol and chitosan can be used as the absorption enhancer to obviously improve the in vitro permeability.

Further, the inventors also prefer the weight ratio of propylene glycol and chitosan to be the best in vitro permeation effect at a weight ratio of 9: 1.

In addition, the inventor also unexpectedly finds that the addition of the propylene glycol and the chitosan can play a role in maintaining the stable pH value, however, the pH value of the cetirizine hydrochloride spray plays a crucial role in the stability of the preparation, and the cetirizine hydrochloride spray can be prevented from degrading within a certain pH range, so that the content of related substances in the preparation is reduced, and the stability of the preparation is improved.

Further, the content of the absorption enhancer is 1mg/mL, 4mg/mL, 8mg/mL, 12mg/mL, 15 mg/mL.

Furthermore, the inventor finds that one or more of hydrochloric acid, sodium bicarbonate, sodium hydroxide, citric acid and phosphoric acid has a good effect as a pH regulator through a large amount of experiments, and preferably sodium hydroxide is used.

Further, the dispersing agent is one of povidone K30, magnesium stearate, calcium stearate and polyethylene glycol, and is preferably povidone K30.

The second purpose of the invention is to provide a preparation method of a cetirizine hydrochloride spray, which comprises the following steps:

(1) stirring and dissolving a dispersing agent by using purified water to obtain a solution I;

(2) dissolving cetirizine hydrochloride in purified water by stirring, and then adding the absorption enhancer into the solution and uniformly stirring to obtain a solution II;

(3) adding the solution I into the solution II, uniformly stirring and mixing, adding purified water to a full volume, adding a pH regulator to regulate the pH value to 7-9, filtering, and filling into a quantitative spraying device to obtain the cetirizine hydrochloride spraying agent.

Further, the pH value is adjusted to 7.5-8.5, and the preferable pH value is 8.1; the quantitative spraying device in the step (3) is a single-dose, double-dose or multi-dose device.

Compared with the prior art, the technical scheme of the invention has the beneficial effects that:

(1) the spraying agent disclosed by the invention has the advantages that through the preferable combination of auxiliary materials, the propylene glycol and the chitosan are particularly used as the absorption promoters, so that the cetirizine hydrochloride has a better absorption effect, and the transdermal absorption effect can be obviously improved.

(2) The invention also unexpectedly discovers that the addition of the propylene glycol and the chitosan can play a role in maintaining the stability of the pH value of the preparation, the pH value of the cetirizine hydrochloride spray plays a crucial role in the stability of the preparation, and the cetirizine hydrochloride spray can be prevented from being degraded within the pH value range of 7-9, so that the content of related substances in the preparation is reduced, the stability of the preparation is improved, and the shelf life of the cetirizine hydrochloride spray is prolonged.

(3) The cetirizine hydrochloride spray prepared by the invention has the advantages of no need of taking the spray, prevention of blood absorption and metabolism, reduction of adverse effects on bodies, direct action on focuses, quick response, simple preparation process, suitability for industrial production and convenience for market popularization.

Detailed Description

In order to make the purpose and technical solution of the present invention more clear, the present invention is further described with reference to the following examples, but the scope of the present invention is not limited to these examples, and the examples are only used for explaining the present invention. It will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true scope of the invention.

Preparation of cetirizine hydrochloride spray with different absorption promoting agents

Weighing povidone K30, propylene glycol, chitosan, NaOH and cetirizine hydrochloride according to the prescription amount. Dissolving polyvidone K30 in purified water under stirring to obtain solution I; dissolving cetirizine hydrochloride by using about 100ml of purified water through stirring, and then adding propylene glycol into the solution through stirring uniformly to obtain a solution II for later use; adding the solution I into the solution II, stirring and mixing uniformly, adding water for injection to a full volume, adding a pH regulator NaOH, regulating the pH value to 8.1, filtering, and filling into a quantitative spraying device to obtain the cetirizine hydrochloride spraying agent.

Repeating 3 groups of experiments in each example to obtain a cetirizine hydrochloride spray, wherein the content of cetirizine hydrochloride is 1 mg/mL; quantitatively filling the prepared cetirizine hydrochloride spraying agent into a spraying device, and respectively filling the cetirizine hydrochloride spraying agents prepared by 3 groups of experiments into the quantitative spraying device: (1) an APF multi-dosage device manufactured by Aptar company has the loading capacity of 10mL, and the spraying amount per time is 0.1 mL; (2) the loading capacity of the UDS single-dose device is 0.1mL, and the spraying amount of each time is 0.1 mL; (3) the BDS double-dosage device has the loading amount of 0.2mL and the spraying amount of 0.1 mL.

The specific implementation formula is as follows, wherein comparative examples 1-3 adjust the preparation method according to the absorption enhancer.

Table 1 preparation of cetirizine hydrochloride sprays with different absorption enhancers

Preparation of cetirizine hydrochloride spray with different pH values

Weighing povidone K30, propylene glycol, chitosan, NaOH and cetirizine hydrochloride according to the prescription amount. Dissolving polyvidone K30 in purified water under stirring to obtain solution I; dissolving cetirizine hydrochloride by using about 100ml of purified water through stirring, and then adding propylene glycol into the solution through stirring uniformly to obtain a solution II for later use; and adding the solution I into the solution II, uniformly stirring and mixing, adding water for injection to a full volume, adding a pH regulator NaOH, regulating the pH value to 7-9, filtering, and filling into a quantitative spraying device to obtain the cetirizine hydrochloride spraying agent.

Repeating 3 groups of experiments in each example to obtain a cetirizine hydrochloride spray, wherein the content of cetirizine hydrochloride is 1 mg/mL; quantitatively filling the prepared cetirizine hydrochloride spraying agent into a spraying device, and respectively filling the cetirizine hydrochloride spraying agents prepared by 3 groups of experiments into the quantitative spraying device: (1) an APF multi-dosage device manufactured by Aptar company has the loading capacity of 10mL, and the spraying amount per time is 0.1 mL; (2) the loading capacity of the UDS single-dose device is 0.1mL, and the spraying amount of each time is 0.1 mL; (3) the BDS double-dosage device has the loading amount of 0.2mL and the spraying amount of 0.1 mL.

The specific implementation formula is as follows:

TABLE 2 preparation of cetirizine hydrochloride sprays with different pH values

In-vitro permeability research of cetirizine hydrochloride spray

Selecting pig skin as an experimental model, respectively using the sprays prepared in examples 1-3 and comparative examples 1-3, selecting a Franz diffusion cell to perform an in vitro permeation experiment, sampling at 0, 5, 10, 15, 20, 30, 40, 60, 90, 120 and 180min after administration, detecting the cetirizine hydrochloride content by adopting high performance liquid chromatography, comparing with a control group, and evaluating the in vitro skin permeation of the cetirizine hydrochloride sprays prepared by different formulas. The results are shown in the following table.

Table 3 skin penetration parameters of cetirizine hydrochloride spray within 30min (mean ± SEM, n ═ 3) at different propylene glycol doses

According to the in vitro permeation data, the selection of the absorption enhancer has an important influence on the permeability, and the cetirizine hydrochloride spray prepared by the embodiment of the invention has an excellent permeation effect after the absorption enhancer and the proportional dosage thereof are optimized, thereby being beneficial to the absorption of the medicine and improving the medicine effect.

Stability study of cetirizine hydrochloride spray

1. Accelerated test

The stability of the sprays prepared in examples 1 to 3 of the present invention and comparative examples 1 to 3 was measured, and the sprays were tested in an accelerated test for 6 months under conditions of 40 ℃ ± 2 ℃ and 75% ± 5% relative humidity, and were sampled and analyzed at 0, 3, and 6 months, respectively, to observe the contents of the relevant substances, and the like, and the results are as follows.

TABLE 4 evaluation of the stability of the sprays of the examples (accelerated test)

The absorption enhancer can promote the penetration and absorption of the drug to increase the drug effect and can also play a role in stabilizing the pH of the preparation to a certain extent, after the variety and the dosage of the absorber are preferably promoted, the accelerated test shows that the pH of the preparation can be basically maintained at about 8.1 of the initial preparation after 6 months, while the comparative example does not well maintain the pH in the accelerated test, so that the content of the related substances and the content of cetirizine hydrochloride are further determined, and the pH plays a vital role in the content of the related substances. Therefore, the effect of pH on cetirizine hydrochloride spray stability was next further explored.

2. Long term test

The cetirizine hydrochloride spray prepared in the examples 4-8 and the comparative example 4 is packaged on the market, placed under the conditions that the temperature is 25 +/-2 ℃ and the relative humidity is 60% +/-10%, and sampled at the 0 th month, the 3 th month, the 6 th month, the 9 th month, the 12 th month, the 24 th month and the 36 th month of the test period respectively, the content of related substances and the content of cetirizine hydrochloride are detected, and the physical properties of the spray are observed.

Table 5 evaluation of stability of spray of examples (long-term test)

The table shows that when the pH of the preparation is in a range of 7.0-8.5, the content of related substances of the cetirizine hydrochloride spray is low, the content of the related substances is only slightly increased even if the preparation is placed for 36 months under the conditions that the temperature is 25 +/-2 ℃ and the relative humidity is 60% +/-10%, and particularly under the environment that the pH is 7.5-8.5, the cetirizine hydrochloride is more stable and the content is basically kept unchanged.

Fifth, some examples of the cetirizine hydrochloride spray of the present invention

Example 9:

the preparation method comprises the following steps:

(1) stirring and dissolving a dispersing agent by using purified water to obtain a solution I;

(2) dissolving cetirizine hydrochloride in purified water by stirring, and then adding the absorption enhancer into the solution and uniformly stirring to obtain a solution II;

(3) adding the solution I into the solution II, stirring and mixing uniformly, adding purified water to a full volume, adding a pH regulator to regulate the pH value to 8.1, filtering, and filling into a quantitative spraying device to obtain the cetirizine hydrochloride spraying agent.

Example 10:

the preparation method comprises the following steps:

(1) stirring and dissolving a dispersing agent by using purified water to obtain a solution I;

(2) dissolving cetirizine hydrochloride in purified water by stirring, and then adding the absorption enhancer into the solution and uniformly stirring to obtain a solution II;

(3) adding the solution I into the solution II, stirring and mixing uniformly, adding purified water to full volume, adding a pH regulator to regulate the pH value to 8.1, filtering, and filling into a quantitative spraying device to obtain the cetirizine hydrochloride spray.

Example 11:

the preparation method comprises the following steps:

(1) stirring and dissolving a dispersing agent by using purified water to obtain a solution I;

(2) dissolving cetirizine hydrochloride in purified water by stirring, and then adding the absorption enhancer into the solution and uniformly stirring to obtain a solution II;

(3) adding the solution I into the solution II, stirring and mixing uniformly, adding purified water to a full volume, adding a pH regulator to regulate the pH value to 8.1, filtering, and filling into a quantitative spraying device to obtain the cetirizine hydrochloride spraying agent.

Example 12:

the preparation method comprises the following steps:

(1) stirring and dissolving a dispersing agent by using purified water to obtain a solution I;

(2) dissolving cetirizine hydrochloride in purified water by stirring, and then adding the absorption enhancer into the solution and uniformly stirring to obtain a solution II;

(3) adding the solution I into the solution II, stirring and mixing uniformly, adding purified water to a full volume, adding a pH regulator to regulate the pH value to 8.1, filtering, and filling into a quantitative spraying device to obtain the cetirizine hydrochloride spraying agent.

Example 13:

the preparation method comprises the following steps:

(1) stirring and dissolving a dispersing agent by using purified water to obtain a solution I;

(2) dissolving cetirizine hydrochloride in purified water by stirring, and then adding the absorption enhancer into the solution and uniformly stirring to obtain a solution II;

(3) adding the solution I into the solution II, stirring and mixing uniformly, adding purified water to a full volume, adding a pH regulator to regulate the pH value to 8.1, filtering, and filling into a quantitative spraying device to obtain the cetirizine hydrochloride spraying agent.

Example 14:

the preparation method comprises the following steps:

(1) stirring and dissolving a dispersing agent by using purified water to obtain a solution I;

(2) dissolving cetirizine hydrochloride in purified water by stirring, and then adding the absorption enhancer into the solution and uniformly stirring to obtain a solution II;

(3) adding the solution I into the solution II, stirring and mixing uniformly, adding purified water to a full volume, adding a pH regulator to regulate the pH value to 8.1, filtering, and filling into a quantitative spraying device to obtain the cetirizine hydrochloride spraying agent.

The above are some examples of the cetirizine hydrochloride spray of the invention, and the investigation of the items such as physical properties, in vitro permeation experiments, content, preparation stability and the like of the cetirizine hydrochloride spray prepared in the above examples can reach the pharmacopoeia standard, and the effect is good.

Claims (10)

1. The cetirizine hydrochloride spray is characterized by comprising an absorption enhancer, a pH regulator, a dispersant and purified water.

2. The cetirizine hydrochloride spray of claim 1, wherein the cetirizine hydrochloride spray comprises, by weight:

3. the cetirizine hydrochloride spray according to claim 1, wherein the absorption enhancer is selected from one or more of polysorbate 20, polysorbate 80, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, sodium lauryl sulfate, azone, poloxamer 188, oleic acid and/or its salts, chitosan, ethanol, propylene glycol.

4. The cetirizine hydrochloride spray of claim 1, wherein the absorption enhancer is a mixture of propylene glycol and chitosan.

5. The cetirizine hydrochloride spray according to claim 4, wherein the propylene glycol and chitosan are in a weight ratio of 9: 1.

6. The cetirizine hydrochloride spray according to claim 1, wherein the pH regulator is selected from one or more of hydrochloric acid, sodium bicarbonate, sodium hydroxide, citric acid, phosphoric acid, preferably sodium hydroxide.

7. The cetirizine hydrochloride spray according to claim 1, characterized in that the dispersant is one of povidone K30, magnesium stearate, calcium stearate, polyethylene glycol, preferably povidone K30.

8. A process for the preparation of cetirizine hydrochloride spray according to claim 1, characterized by the steps of:

(1) stirring and dissolving a dispersing agent by using purified water to obtain a solution I;

(2) dissolving cetirizine hydrochloride in purified water by stirring, and then adding the absorption enhancer into the solution and uniformly stirring to obtain a solution II;

(3) adding the solution I into the solution II, uniformly stirring and mixing, adding purified water to a full volume, adding a pH regulator to regulate the pH value to 7-9, filtering, and filling into a quantitative spraying device to obtain the cetirizine hydrochloride spraying agent.

9. The method according to claim 8, wherein the pH value is adjusted to 7.5-8.5, preferably 8.1.

10. The method of claim 8, wherein the metered dose spray device of step (3) is a single dose, double dose, multi-dose device.