A cetirizine hydrochloride formulation containing menthol and a method of preparing the same

Abstract

The present application relates to a kind of preparation method of menthol-containing cetirizine hydrochloride preparation, and the form of existence of menthol in preparation.Menthol is crystalline solid, not easy to crush, has strong irritating smell, not easy to implement in mass production process, and seriously pollutes production environment, is not conducive to environmental protection and is not conducive to the health of production personnel, since menthol is directly exposed, it is extremely easy to sublimate, and it is easy to cause the cooling degree to drop during the storage of buccal tablets, affect the taste.The present application is that β-cyclodextrin and menthol form menthol inclusion compound under the best process condition, the menthol prepared by this method is good in stability, good in taste, easy to mass production, and can be widely applied in various preparations containing menthol.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, and in particular to a method for preparing a cetirizine hydrochloride preparation containing menthol. Background Technology

[0002] Menthol, also known as menthol, has the chemical name 1-1-methyl-4-isopropylcyclohexane-3-ol. It is obtained from the fresh stems and leaves of the plant *Mentha haplocalyx* Briq. (Lamiaceae family) through steam distillation, freezing, and recrystallization. Menthol has a wide range of applications in the pharmaceutical, hygiene, food, and cosmetic industries, such as as a flavoring agent in the production of beverages, candies, toothpaste, perfumes, and other food and light industrial products.

[0003] In medicine, menthol can be used for cooling, antipruritic, and analgesic effects on the skin or mucous membranes, or for treating inflammation of the nose, pharynx, and throat, as well as headaches and neuralgia. It can also be taken internally as a carminative. Menthol has the effects of dispelling wind, clearing heat, and detoxifying. It can be used to treat headaches, red eyes, external wind-heat, sore throat, headaches, mouth ulcers, urticaria, measles, chest and abdominal distension, and has anti-pregnancy effects, with anti-inflammatory and analgesic properties. In addition, menthol has an anti-irritant effect, can stimulate the production of new secretions in the trachea, and facilitate the discharge of thick mucus, thus having an expectorant effect and a good antitussive effect. Furthermore, when applied to the skin or mucous membranes, it can produce a cooling sensation to relieve discomfort and pain. It can be used for surgical anesthesia, postoperative analgesia, nerve blocks, and intractable pruritic skin diseases. When applied topically, it can promote blood circulation and has anti-inflammatory and antipruritic effects, and can be used for anti-inflammatory, antipruritic, analgesic, and edema-reducing effects.

[0004] Menthol can also be used as a stimulant, acting on the skin or mucous membranes to have a cooling and antipruritic effect. It is often used in the production of mentholatum, analgesics, toothpaste, etc.

[0005] In many pharmaceutical formulations, menthol is used as a cooling agent. However, menthol is a crystalline solid, difficult to pulverize, and has a strong, pungent odor, making it difficult to implement in large-scale production processes. Furthermore, it causes significant environmental pollution, harming both the environment and the health of production workers. Because menthol is directly exposed, it is highly susceptible to sublimation, which can lead to a decrease in cooling effect during storage of lozenges, affecting their taste. In this invention, menthol is pre-prepared as a menthol inclusion complex, and cyclodextrin is used to encapsulate the menthol, resulting in a more stable exertion of its effects. Summary of the Invention

[0006] The purpose of this invention is to overcome the problems of menthol's poor storage and unstable performance in existing menthol-containing preparations. It relates to a method for preparing a menthol inclusion complex, which involves dissolving β-cyclodextrin in an aqueous solution or dilute ethanol solution to prepare a β-cyclodextrin aqueous solution or a β-cyclodextrin dilute ethanol solution. Menthol is then added to the cyclodextrin solution for inclusion, and the reaction is carried out for 2-4 hours. After cooling to below room temperature, the mixture is filtered, washed with water, and dried at 60-70°C to obtain the menthol inclusion complex. When menthol is added to the menthol-containing preparation in the form of the menthol inclusion complex, the resulting preparation exhibits a reduced and more persistent pungent odor. This indicates that the menthol inclusion complex prepared by this method, after being encapsulated by cyclodextrin, is more stable, less prone to sublimation, has less impact on taste, and can exert its effects more effectively.

[0007] This invention discloses a cetirizine hydrochloride formulation containing menthol, comprising cetirizine hydrochloride raw material, filler, binder, disintegrant, flavoring agent, and lubricant. The filler is composed of one or more of microcrystalline cellulose, lactose, starch, and sucrose; the binder is composed of one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, and povidone; the disintegrant is composed of one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and crospovidone; the flavoring agent is composed of one or more of sucrose, mannitol, menthol, glycerin, sorbitol, and β-cyclodextrin; and the lubricant is magnesium stearate.

[0008] More preferably, the formulation of the raw materials and excipients is as follows, based on parts by weight:

[0009]

[0010] The present invention discloses a method for preparing a cetirizine hydrochloride formulation containing menthol, comprising the following steps:

[0011] (1) Inclusion process of menthol inclusion complex: β-cyclodextrin is added to an aqueous solution or a dilute ethanol solution to prepare an inclusion solution; menthol is added to the inclusion solution to perform menthol inclusion; the inclusion complex is filtered, washed and dried to obtain menthol inclusion complex.

[0012] (2) Slurry preparation process: Add hydroxypropyl cellulose to an aqueous solution or a dilute ethanol solution to prepare the slurry;

[0013] (3) Granulation process: Cetirizine hydrochloride is mixed evenly with the slurry obtained in (2), and granulation is performed using a wet granulator.

[0014] (4) Drying process: Dry the particles obtained in (3) to meet the requirements;

[0015] (5) Mixing and sieving process: The cetirizine hydrochloride granules obtained in (4) are mixed with the menthol inclusion complex, lactose, low-substituted hydroxypropyl cellulose and mannitol obtained in (1), and the mixture is sieved and then mixed again.

[0016] Mix the powder obtained in (4) with magnesium stearate;

[0017] (6) Tableting process: Tableting is performed using a tablet press.

[0018] in:

[0019] Step (1) is as follows: Menthol inclusion complex inclusion process: Menthol is included in β-cyclodextrin solution for 2-4 hours, allowed to stand until precipitation is complete, filtered, rinsed clean and then dried.

[0020] Step (2) is as follows: slurry preparation process: add hydroxypropyl cellulose to dilute ethanol solution, stir for 20-40 minutes, and let stand.

[0021] Step (3) is as follows: Granulation process: Cetirizine hydrochloride is mixed evenly with the slurry obtained in (2), the slurry addition time is 3-5 minutes, and wet granulation is performed using a wet granulation machine for 5-10 minutes.

[0022] Step (4) is: Drying process: The particles obtained in (3) are dried using a fluidized bed for 2-4 hours to achieve a moisture content of 1.0%-5.0%.

[0023] Step (5) is as follows: mixing and sieving process: cetirizine hydrochloride granules obtained in (4) and menthol inclusion complex, lactose, low-substituted hydroxypropyl cellulose and mannitol are added to a three-dimensional mixer in sequence and mixed for 15-30 minutes; the mesh size of the sieve used for sieving the powder is 1.0-2.4 mm; then mix for another 5-15 minutes; add magnesium stearate and mix for 5-8 minutes.

[0024] Step (6) is as follows: tableting process: a PG65 high-speed rotary tablet press is used, and the mold specification is Φ8.0mm circular shallow concave; the theoretical tablet weight is calculated according to the cetirizine hydrochloride content in the mixed powder, the tableting speed is 100,000 to 200,000 tablets / hour, the average tableting main pressure is 6.0KN, the tablet weight range is: theoretical tablet weight ±7%, the average hardness is 40-80N, and the tablet weight difference, brittleness and disintegration time of the whole tablet meet the requirements.

[0025] As a more preferred technical solution, the preparation method of a cetirizine hydrochloride formulation containing menthol according to the present invention includes the following steps:

[0026] Inclusion process of menthol complex: β-cyclodextrin is added to 70% ethanol solution to prepare inclusion solution; menthol is added to inclusion solution and inclusion is carried out for 3 hours to obtain menthol inclusion complex.

[0027] Slurry preparation process: Add hydroxypropyl cellulose to a 70% ethanol solution, prepare the slurry, stir evenly, and let stand until all bubbles disappear.

[0028] Granulation process: Cetirizine hydrochloride is mixed evenly with the slurry obtained in (2), the slurry addition time is 3 minutes, and wet granulation is performed for 10 minutes.

[0029] Drying process: The particles obtained in (3) are dried using a fluidized bed for 2 hours to keep the moisture content below 3%.

[0030] Mixing and sieving process: The cetirizine hydrochloride granules obtained in (4) and menthol inclusion complex, lactose, low-substituted hydroxypropyl cellulose and mannitol are added to the three-dimensional mixer in sequence and mixed for 20 minutes. After passing through a 2.0 mm sieve, the powder is mixed again for 10 minutes.

[0031] Mix the above powder with magnesium stearate for 5 minutes.

[0032] Tableting process: A PG65 high-speed rotary tablet press is used, with a Φ8.0mm circular shallow concave mold. The theoretical tablet weight is calculated based on the cetirizine hydrochloride content in the mixed powder. The tableting speed is 100,000 to 200,000 tablets / hour, with an average main tableting pressure of 6.0KN. The tablet weight range is: theoretical tablet weight ±7%. The average hardness is 40-80N. The content uniformity A+2.2S≤15.0, the friability is ≤1%, and the disintegration time meets the requirements.

[0033] Experimental studies have shown that the menthol-containing preparations obtained by this invention have the following advantages:

[0034] 1) This menthol-containing preparation has a good taste, is non-irritating, has no odor, and is readily accepted by patients.

[0035] 2) This menthol-containing preparation has good stability, is easy to mass-produce, and is easy to store. It can be widely used in various preparations containing menthol.

[0036] 3) In this menthol-containing preparation, the menthol is more evenly distributed, less volatile, easier to store, and better exerts the effect of menthol in the preparation. Detailed Implementation

[0037] The present invention will be further described in detail below with reference to specific embodiments. However, the embodiments of the present invention are not limited to the following embodiments. Any further changes, modifications, substitutions, combinations and simplifications made on the basis of the essence of the present invention should be regarded as equivalent substitutions and included within the scope of protection of the present invention.

[0038] Example 1: This menthol-containing preparation

[0039] The prescription consists of 1000 tablets.

[0040]

[0041]

[0042] Preparation process:

[0043] Add the prescribed amount of β-cyclodextrin to a dilute ethanol solution to prepare an inclusion solution; add menthol to the inclusion solution to encapsulate the menthol. Add hydroxypropyl cellulose to a dilute ethanol solution to prepare a slurry; mix cetirizine hydrochloride evenly with the slurry and granulate using a wet granulator; dry the resulting granules to meet the requirements; mixing and sieving process: mix cetirizine hydrochloride granules with menthol inclusion complex, lactose, low-substituted hydroxypropyl cellulose, and mannitol, sieve, and then mix the powder again; mix the resulting powder with magnesium stearate; compress into tablets using a tableting machine.

[0044] Example 2: This menthol-containing preparation

[0045] The prescription consists of 1000 tablets.

[0046] Element weight Cetirizine Hydrochloride 18g β-Cyclodextrin 23g Hydroxypropyl cellulose 8g lactose 20g Low-substituted hydroxypropyl cellulose 8g Mannitol 25g magnesium stearate 3g

[0047] Preparation process: The preparation method of Example 1 was adopted.

[0048] Example 3: This menthol-containing preparation

[0049] The prescription consists of 1000 tablets.

[0050]

[0051]

[0052] Preparation process: Hydroxypropyl cellulose is added to a dilute ethanol solution to form a slurry; cetirizine hydrochloride is mixed evenly with the slurry and granulated using a wet granulator; the resulting granules are dried to meet the requirements; mixing and sieving process: cetirizine hydrochloride granules are mixed with menthol, lactose, low-substituted hydroxypropyl cellulose, and mannitol, sieved, and the mixture is then mixed again; the resulting mixture is mixed with magnesium stearate; tablets are then compressed using a tableting machine.

[0053] Comparison of experimental results:

[0054] The tablets obtained in the examples were placed in a constant temperature and humidity chamber with high temperature (40°C) and high humidity (70-80% relative humidity) for 6 months for accelerated testing, and the menthol content was detected at 0 days and 6 months.

[0055] The table below shows a comparison of the stability of the examples after 6 months of acceleration.

[0056]

[0057] As can be seen from the data in the table, the accelerated test results show that the formulation prepared by the present invention has a much higher stability of menthol than that in Examples 2 and 3 after accelerated testing. The resulting product has better stability, significantly improves the stability of menthol in the menthol-containing formulation, increases the shelf life of the menthol-containing formulation, and effectively extends the product's shelf life.

Claims

1. A cetirizine hydrochloride preparation containing menthol, characterized in that, The formulation of the cetirizine hydrochloride preparation containing menthol, by weight, is as follows: 10-20 parts cetirizine hydrochloride, 20-30 parts β-cyclodextrin, 15-20 parts menthol, 5-10 parts hydroxypropyl cellulose, 15-30 parts lactose, 5-10 parts low-substituted hydroxypropyl cellulose, 20-30 parts mannitol, and 1-5 parts magnesium stearate; The method for preparing the cetirizine hydrochloride formulation containing menthol includes the following steps: (1) Inclusion process of menthol inclusion complex: β-cyclodextrin is added to an aqueous solution or a dilute ethanol solution to prepare an inclusion solution; menthol is added to the inclusion solution to perform menthol inclusion; the inclusion complex is filtered, washed and dried to obtain menthol inclusion complex. (2) Slurry preparation process: Add hydroxypropyl cellulose to an aqueous solution or a dilute ethanol solution to prepare the slurry; (3) Granulation process: Cetirizine hydrochloride is mixed evenly with the slurry obtained in (2), and granulation is performed using a wet granulation machine; (4) Drying process: Dry the particles obtained in (3) to meet the requirements; (5) Mixing and sieving process: The cetirizine hydrochloride granules obtained in (4) are mixed with the menthol inclusion complex, lactose, low-substituted hydroxypropyl cellulose and mannitol obtained in (1), sieved and then mixed again; then mixed with magnesium stearate; (6) Tableting process: Tableting is performed using a tablet press.

2. The cetirizine hydrochloride preparation containing menthol according to claim 1, characterized in that, In step (1) of the menthol inclusion complex process, menthol is included in β-cyclodextrin solution for 2-4 hours, allowed to stand until precipitation is complete, filtered, rinsed clean and then dried.

3. The cetirizine hydrochloride preparation containing menthol according to claim 1, characterized in that, The step (2) slurry preparation process is as follows: add hydroxypropyl cellulose to a dilute ethanol solution, stir for 20-40 minutes, and let stand.

4. The cetirizine hydrochloride preparation containing menthol according to claim 1, characterized in that, The granulation process in step (3) is as follows: Cetirizine hydrochloride is mixed evenly with the slurry obtained in (2), the slurry addition time is 3-5 minutes, and wet granulation is performed using a wet granulator for 5-10 minutes.

5. The cetirizine hydrochloride preparation containing menthol according to claim 1, characterized in that, The drying process in step (4) uses a fluidized bed to dry the particles obtained in (3) for 2-4 hours, so that the moisture content reaches 1.0%-5.0%.

6. The cetirizine hydrochloride preparation containing menthol according to claim 1, characterized in that, The mixing and sieving process in step (5) is as follows: cetirizine hydrochloride granules obtained in (4) and menthol inclusion complex, lactose, low-substituted hydroxypropyl cellulose and mannitol obtained in (1) are added to a three-dimensional mixer in sequence and mixed for 15-30 minutes; the mesh size of the sieve used for sieving the powder is 1.0-2.4 mm; then mixed for another 5-15 minutes; magnesium stearate is added and mixed for 5-8 minutes.

7. The cetirizine hydrochloride preparation containing menthol according to claim 1, characterized in that, The tableting process in step (6) uses a PG65 high-speed rotary tablet press with a Φ8.0mm circular shallow concave mold. The theoretical tablet weight is calculated based on the cetirizine hydrochloride content in the mixed powder. The tableting speed is 100,000 to 200,000 tablets / hour, the average tableting main pressure is 6.0KN, the tablet weight range is: theoretical tablet weight ±7%, the average hardness is 40-80N, and the tablet weight difference, brittleness, and disintegration time of the whole tablet all meet the requirements.

8. The cetirizine hydrochloride preparation containing menthol according to any one of claims 2-7, characterized in that, The preparation method of the cetirizine hydrochloride formulation containing menthol includes the following steps: (1) Inclusion process of menthol inclusion complex: β-cyclodextrin was added to 70% ethanol solution to prepare inclusion solution; menthol was added to inclusion solution and inclusion was carried out for 3 hours. After filtration, rinsing and drying, menthol inclusion complex was obtained. (2) Slurry preparation process: Add hydroxypropyl cellulose to 70% ethanol solution, prepare slurry, stir evenly, and let stand until all bubbles disappear; (3) Granulation process: Cetirizine hydrochloride is mixed evenly with the slurry obtained in (2), the slurry addition time is 3 minutes, and wet granulation is performed for 10 minutes. (4) Drying process: The particles obtained in (3) are dried using a fluidized bed for 2 hours to keep the moisture content below 3%. (5) Mixing and sieving process: The cetirizine hydrochloride granules obtained in (4) and menthol inclusion complex, lactose, low-substituted hydroxypropyl cellulose and mannitol are added to a three-dimensional mixer in sequence and mixed for 20 minutes. After passing through a 2.0 mm sieve, the powder is mixed again for 10 minutes. The powder is then mixed with magnesium stearate for 5 minutes. (6) Tableting process: Use PG65 high-speed rotary tablet press with a Φ8.0mm circular shallow concave mold; calculate the theoretical tablet weight based on the cetirizine hydrochloride content in the mixed powder, the tableting speed is 100,000 to 200,000 tablets / hour, the average tableting main pressure is 6.0KN, the tablet weight range is: theoretical tablet weight ±7%, the average hardness is 40-80N, the content uniformity is A+2.2S≤15.0, the brittleness is ≤1%, and the disintegration time meets the requirements.

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