A combination suppository of varenicline tartrate and houttuynia cordata and a preparation method thereof

Abstract

The application belongs to the technical field of medicine, and particularly relates to a combination suppository of varenicline tartrate and houttuynia cordata and a preparation method thereof. Varenicline tartrate is a nicotinic acetylcholine receptor agonist, houttuynia cordata can relieve the uncomfortable symptoms such as anxiety, headache and excessive sputum in the process of quitting smoking, can clear lung heat, discharge smoke toxin, and promote the discharge of nicotine in the body. The suppository is selected in the application, and rectal administration can reduce the irritability of the drug itself and the irritability of the drug to the gastrointestinal mucosa, and reduce the generation of adverse reactions such as nausea and vomiting. The suppository has the advantages of simple preparation, convenient use, small side effects and the like.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a combination suppository of varenicline tartrate and houttuynia cordata and its preparation method. Background Technology

[0002] Smoking damages various organs: it increases platelet stickiness, making blood more prone to clotting, harming the heart and blood vessels; the adverse effects of smoking on the lungs are undeniable, and the damage is often irreversible: smoking leads to lung cancer and emphysema, and people who smoke 10 cigarettes a day are 10 times more likely to develop these diseases than non-smokers. Therefore, quitting smoking has many benefits: reducing the risk of disease, improving blood circulation, slowing aging, and extending lifespan, among others. Surveys show that over 70% of smokers have considered quitting, but less than 3% actually succeed.

[0003] China is the world's largest producer and consumer of tobacco, with a smoking rate of 63% for adult men and 4% for adult women, totaling 350 million people, nearly one-third of the world's total smoking population. If 17% of Chinese smokers wanted to quit, 60 million smokers would need to undergo cessation treatment. Assuming each person needs to spend 500 yuan to quit, the Chinese smoking cessation market would be nearly 300 billion yuan, representing enormous market potential. Varenicline, a non-nicotine drug, is a first-line treatment for smoking cessation.

[0004] Varenicline selectively binds to the α4β2 nicotinic acetylcholine receptor, exhibiting a high affinity for it. Varenicline exerts an agonistic effect by binding to the α4β2 nicotinic acetylcholine receptor subtype, while simultaneously blocking nicotine from binding to this receptor. This is the mechanism by which varenicline exerts its smoking cessation effect, alleviating nicotine cravings and withdrawal symptoms, reducing the pleasure derived from smoking, and thus helping smokers quit successfully.

[0005] The benefits of houttuynia cordata in smoking cessation primarily lie in helping to alleviate discomfort such as anxiety, headaches, and excessive phlegm that may occur during the quitting process. It not only clears lung heat and detoxifies from tobacco, but also promotes the excretion of nicotine from the body. Furthermore, houttuynia cordata has antibacterial, antiviral, and diuretic effects, which can help enhance the body's immunity and improve resistance.

[0006] Currently available varenicline tartrate tablets have the following drawbacks: First, they easily cause gastrointestinal adverse reactions such as nausea, gastroesophageal reflux disease, vomiting, constipation, diarrhea, bloating, abdominal pain, toothache, indigestion, flatulence, and dry mouth. Second, they easily cause negative emotions in smokers trying to quit, such as restlessness, depression, insomnia, irritability, frustration, anger, anxiety, difficulty concentrating, and fidgeting. Third, the tablets are quite bitter. Therefore, they suffer from poor adherence, low success rates, and high relapse rates.

[0007] In the prior art, CN107753449A discloses a varenicline tablet composition, but this application requires controlling the particle size of varenicline tartrate to a certain size, the process is complicated and costly, and sodium lauryl sulfate needs to be added. Sodium lauryl sulfate is toxic to the human body, has great side effects, and is not suitable for long-term use.

[0008] CN116392593A discloses a varenicline tablet composition, which reduces the irritation of the drug itself by adding menthol. CN116370439A discloses a transdermal formulation of varenicline, which reduces the irritation of the drug through in vitro transdermal release and absorption. CN110381919A reduces the irritation of the drug by adding inclusion complexes such as cyclodextrin.

[0009] As can be seen from the above patent applications, various attempts have been made in the prior art to reduce the irritation of the drug itself, but the results are not ideal. Therefore, it is necessary to develop a drug formulation that is less irritating and more effective. Summary of the Invention

[0010] The purpose of this invention is to provide a combination suppository of varenicline tartrate and houttuynia cordata, which, through the combination of a nicotinic acetylcholine receptor agonist and a traditional Chinese medicine that alleviates smoking cessation symptoms, helps to quit smoking while relieving many symptoms of smoking cessation syndrome and promoting successful smoking cessation.

[0011] Another objective of this invention is to provide a method for preparing the aforementioned combined suppository, which is low in cost, simple in process, and conducive to industrial production.

[0012] To achieve the above objectives, the present invention adopts the following technical solution:

[0013] A combination suppository of varenicline tartrate and houttuynia cordata, comprising the following components by weight: 0.5-2 parts varenicline tartrate, 50-200 parts houttuynia cordata, 800-1000 parts semi-synthetic fatty acid glycerides, and 1 part Tween.

[0014] Semi-synthetic fatty acid glycerides can be selected from semi-synthetic fatty acid glycerides commonly used in suppositories, such as coconut oil ester, palm oil ester, Litsea cubeba oil ester, or propylene glycol stearate.

[0015] The preparation method of the combined suppository of varenicline tartrate and houttuynia cordata includes the following steps:

[0016] (1) Wash and dry the houttuynia cordata (preferably at 40°C until the moisture content is below 3%), pulverize it and pass it through a 100-mesh sieve, then put it into a cell wall breaker to break it down to a particle size of 100 nm, and obtain houttuynia cordata dry powder.

[0017] (2) Crush varenicline tartrate and pass it through a 200-mesh sieve for later use;

[0018] (3) Mix the varenicline tartrate from step (2), the dried Houttuynia cordata powder from step (1), the semi-synthetic fatty acid glycerides, and Tween according to the formula ratio.

[0019] (4) Heat the mixture obtained in step (3) (preferably 45°C) to a molten state and stir to make it evenly mixed (preferably 30 min).

[0020] (5) Inject the molten mixture from step (4) into a suppository mold coated with water-based lubricant;

[0021] (6) After cooling and molding, cut off the overflow part (preferably at 25°C), open the mold, take out the suppository, and package it.

[0022] Furthermore, the aqueous lubricant in step (5) is a mixed solution with a mass ratio of soft soap: water: 95% ethanol = 1:1:5.

[0023] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0024] This invention uses suppositories for rectal administration, avoiding the oral and gastrointestinal irritation caused by oral administration of varenicline tartrate, thus increasing patient compliance. The addition of houttuynia cordata can alleviate discomfort symptoms such as anxiety, headache, and excessive phlegm during the smoking cessation process, clear lung heat, eliminate tobacco toxins, and promote the excretion of nicotine from the body, which is beneficial for successful smoking cessation. The suppositories of this invention have significant smoking cessation effects and good appearance and storage stability. Detailed Implementation

[0025] The present invention will be further explained and illustrated below through specific embodiments and comparative examples, but this is not intended to limit the scope of protection of the claims of the present invention. Any modifications, equivalent substitutions, or improvements made by those skilled in the art based on the fundamental ideas of the present invention should be included within the scope of protection of the present invention.

[0026] Examples 1-3 and Comparative Examples 1-3:

[0027] Table 1: Prescription information for examples and comparative cases (single dose / mg)

[0028] Varenicline tartrate 1 0.5 2 1 0 0 Houttuynia cordata 100 50 200 0 100 0 Semi-synthetic fatty acid glycerides 900 950 800 1000 900 1000 Twain 80 1 1 1 1 1 1

[0029] The preparation method of the combined suppository of varenicline tartrate and houttuynia cordata includes the following steps:

[0030] (1) After washing the houttuynia cordata, dry it at 40°C until the moisture content is below 3%, crush it and pass it through a 100-mesh sieve, and then put it into a cell wall breaker to break it down to a particle size of 100nm to obtain houttuynia cordata powder.

[0031] (2) Crush varenicline tartrate and pass it through a 200-mesh sieve for later use;

[0032] (3) Mix the varenicline tartrate from step (2), the dried Houttuynia cordata powder from step (1), the semi-synthetic fatty acid glycerides, and Tween 80 according to the formula ratio.

[0033] (4) Heat the mixture from step (3) to 45°C until it becomes molten, and stir for 30 minutes to make it evenly mixed;

[0034] (5) Inject the molten mixture from step (4) into a suppository mold coated with an aqueous lubricant (a mixture of soft soap, water, and 95% ethanol in a mass ratio of 1:1:5). The parameters of the suppository mold are: SJM1-10 bullet-shaped suppository mold, 10 holes, and a suppository weight of approximately 1g.

[0035] (6) After cooling and molding at 25℃, cut off the overflowing part, open the mold, take out the suppository, and package it.

[0036] Example 4: Stability Study

[0037] Take three suppositories from Examples 1-3 and Comparative Examples 1-3 respectively. Refer to the melting time test method in General Chapter 0922 of the 2020 edition of the Chinese Pharmacopoeia, Part IV, and measure the time it takes for the three suppositories to reach "complete melting, softening, or no hard core upon touch." Calculate the average time, which is called the melting time. The melting time measured at time 0 is marked as T0. Next, place the suppositories from each example and comparative example at 5±2℃ for 2 weeks, then at 35±2℃ for 2 weeks. Repeat this low-temperature-high-low-temperature treatment three times for a total of 6 weeks. Measure the melting time of the suppositories, marking it as T6. Calculate the percentage change in melting time (%) after 6 weeks: Percentage change in melting time (%) = (|T6-T0|÷T0)×100%.

[0038] The closer the percentage change in melting time is to 0, the less the melting time changes after 6 weeks of low-temperature-high-low temperature treatment, indicating good physical stability of the suppository. The greater the percentage change in melting time, the greater the change in melting time after 6 weeks of low-temperature-high-low temperature treatment, indicating poor physical stability of the suppository.

[0039] Samples stored at room temperature for 0 months, 3 months, 6 months, 9 months, 12 months, 18 months, and 24 months were used to measure the percentage change in melting time.

[0040] Table 2: Percentage Change in Melting Time (%)

[0041] Example 1 9 9 9 9 10 10 10 Example 2 8 8 9 9 9 8 9 Example 3 9 9 8 9 9 10 9 Comparative Example 1 10 9 9 9 9 10 9 Comparative Example 2 9 9 8 8 9 9 9 Comparative Example 3 9 9 9 10 10 9 10

[0042] As shown in Table 2 above, the percentage change in melting time (%) of the suppositories prepared in Examples 1-3 and Comparative Examples 1-3 of the present invention is within the range of 8-10%, with a small change range and relatively stable melting time. This indicates that the suppositories prepared by the present invention have good physical stability and stable properties during storage within the shelf life, and can meet the requirements of quality standards.

[0043] Example 5: Acute toxicity test

[0044] (1) Sixty SD rats (180-220g), 6-8 weeks old, half male and half female, were selected for acute toxicity testing. The rats were randomly divided into two groups: the experimental group and the control group, with 30 rats in each group. The rats were fasted but allowed to drink water the night before the test to empty their feces. When administering the drug, the rats were fixed in place, and one sample was gently inserted into the rectum of each rat through the anus. A rectal thermometer was gently inserted into the anus. After 5 minutes, the rectal thermometer was removed, the rats were released from their cages, and their normal diet was resumed.

[0045] (2) The combination suppository of Example 1 was administered rectally to 30 rats in the experimental group, one suppository at a time, once a day for 14 consecutive days, and the toxic reactions and number of deaths of the rats were observed and recorded.

[0046] (3) The suppository of Comparative Example 3 was used as the control group and administered to 30 rats rectally. One suppository was administered once a day for 14 consecutive days, and the toxic reactions and number of deaths of the rats were observed and recorded.

[0047] Experimental results: No significant differences were observed between the control group and the experimental group after drug administration. The rats were observed continuously for 14 days, and their overall condition, diet, water intake, and weight gain were all normal.

[0048] Example 6: Efficacy Test

[0049] Eighty SD rats (180-220g), 6-8 weeks old, half male and half female, were randomly selected. They were housed in a clean-grade animal room with alternating 12h light / 12h dark cycles, a temperature of 22-25℃, and a humidity of 40%-70%. The rats were acclimatized to the environment for approximately one week prior to the experiment, with free access to food and water. Animal experiments were conducted in accordance with the requirements of the "Guidelines for Ethical Review of Laboratory Animal Welfare" (GB / T35892-2018) in my country, ensuring strict adherence to laboratory animal welfare and ethical standards.

[0050] The rats were trained using a two-lever control device, with food serving as a reward. First, SD rats with restricted food intake were taught that pressing a specific lever 30 times would earn them one food item.

[0051] Next, nicotine was injected into the rats as a training stimulus, teaching them to eat by pressing a designated lever. In other words, the psychoactive effect of this "training" drug became a signal within the organism, enabling it to learn to eat (positive response) through the correct lever.

[0052] 0.4 mg / kg of nicotine was injected subcutaneously twice a day for seven consecutive days, and the training was repeated until the rats achieved a high positive feedback rate.

[0053] On the day of the experiment, rats were divided into 8 groups, with 9 trained rats in each group: Group 1 received a subcutaneous injection of 1 mg / ml nicotine at a dose of 0.4 mg / kg; Group 2 received varenicline tartrate tablets (1 mg, Chanpec, Pfizer) by gavage at a dose of 0.09 mg / kg (calculated as varenicline); Group 3 received suppositories of Example 1 rectally at a dose of 0.09 mg / kg (calculated as varenicline); Group 4 received suppositories of Example 2 rectally at a dose of 0.045 mg / kg (calculated as varenicline); Group 5 received suppositories of Example 3 rectally at a dose of 0.18 mg / kg (calculated as varenicline); Group 6 received suppositories of Comparative Example 1 rectally at a dose of 0.09 mg / kg (calculated as varenicline); Group 7 received suppositories of Comparative Example 2 rectally at the same dose as Group 3; and Group 8 received suppositories of Comparative Example 3 rectally at the same dose as Group 6. Record the number of times SD rats ate within 24 hours.

[0054] Table 3: Comparison of efficacy data for subcutaneous nicotine replacement therapy

[0055]

[0056] The data in the table above shows that the average number of times the third group consumed the suppository was higher than that of the second group. This indicates that, under the same specifications, the combination suppository of varenicline tartrate and houttuynia cordata (1 mg / suppository) is more effective at replacing nicotine than varenicline tartrate tablets (1 mg / tablet). This demonstrates that, under the same specifications, the combination suppository of varenicline tartrate and houttuynia cordata is more effective for smoking cessation than varenicline tartrate tablets.

[0057] After completing the efficacy evaluation experiment of subcutaneous nicotine replacement, blood was drawn from the hearts of rats in each group using a heparinized syringe, and blood oxygen saturation was measured. The results are shown in Table 4 below:

[0058] Table 4: Comparison of Blood Oxygen Saturation Data

[0059]

[0060]

[0061] The data in the table above shows that the blood oxygen saturation of the third group was higher than that of the second group. This indicates that, under the same specifications, the combination suppository of varenicline tartrate and houttuynia cordata (1 mg / suppository) is more effective at replacing nicotine than varenicline tartrate tablets (1 mg / tablet). This demonstrates that, under the same specifications, the combination suppository of varenicline tartrate and houttuynia cordata is more effective for smoking cessation than varenicline tartrate tablets.

[0062] Example 7: Clinical Efficacy Observation

[0063] Seventy subjects were selected, all of whom were males with a history of smoking. They were randomly divided into an observation group and a control group using a random number table. The observation group consisted of 35 subjects, with an age of (34.6±11.8) years, a smoking history of (13.3±5.3) years, and a daily cigarette consumption of (21.5±5.1). The control group consisted of 35 subjects, with an age of (34.8±12.3) years, a smoking history of (13.1±4.6) years, and a daily cigarette consumption of (21.7±5.6). There were no significant differences in age, smoking history, daily cigarette consumption, or other general characteristics between the two groups, making them comparable.

[0064] Experimental group: Rectal administration of varenicline tartrate and houttuynia cordata combination suppositories (1 mg / suppository), twice daily, one suppository each time; Control group: Oral administration of varenicline tartrate tablets (1 mg / tablet), one tablet each time, twice daily. Both groups underwent a 3-month treatment course.

[0065] 1. Efficacy Evaluation Criteria: ① Complete Smoking Cessation: After 3 months of medication, the patient has no desire to smoke, feels nauseous from the smell of cigarettes, experiences significant improvement in mental state compared to when smoking, and respiratory problems are alleviated; ② Effective Smoking Cessation: After 3 months of medication, the patient's smoking amount is reduced by 80%, with slight withdrawal symptoms, and respiratory problems are slightly alleviated; ③ Ineffective Smoking Cessation: After 3 months of medication, the patient's smoking amount remains unchanged or even increases, withdrawal symptoms are obvious, and respiratory problems worsen. Overall Effective Smoking Cessation Rate = [(Number of Complete Smoking Cessation + Number of Effective Smoking Cessation) / Total Number of Cases] × 100%.

[0066] 2. Evaluation of gastrointestinal irritation: ① No irritation at all: No gastrointestinal irritation was felt during medication administration; ② Some irritation: Some gastrointestinal irritation was felt during medication administration, but not to the point of nausea and vomiting; ③ Significant irritation: Nausea and vomiting occurred during medication administration. Total irritation = Some irritation + Significant irritation.

[0067] Table 5: Comparison of clinical efficacy between the two groups of subjects

[0068]

[0069] The data in the table above shows that the overall effective rate of smoking cessation in the experimental group was greater than that in the control group. That is, the combination suppository of varenicline tartrate and houttuynia cordata (specification: 1mg / suppository) was more effective than oral varenicline tartrate tablets (specification: 1mg / tablet).

[0070] Table 6: Comparison of gastrointestinal irritation between the two groups of subjects

[0071]

[0072] The data in the table above shows that the gastrointestinal irritation in the experimental group was generally lower than that in the control group. Specifically, the gastrointestinal irritation of the combination suppository of varenicline tartrate and houttuynia cordata (specification: 1mg / suppository) was lower than that of the oral varenicline tartrate tablets (specification: 1mg / tablet).

[0073] The above description of specific embodiments of the present invention does not limit the present invention. Those skilled in the art can make various changes or modifications based on the present invention, and as long as they do not depart from the spirit of the present invention, they should all fall within the scope of protection of the claims of the present invention.

Claims

1. A combination suppository of varenicline tartrate and houttuynia cordata for smoking cessation, characterized in that, It is made from the following components by weight: 1 part vareniclan tartrate, 100 parts houttuynia cordata, 900 parts semi-synthetic fatty acid glycerides, and 1 part Tween. The preparation method of the combined suppository of varenicline tartrate and houttuynia cordata includes the following steps: (1) Wash, dry, and crush the houttuynia cordata and pass it through a 100-mesh sieve. Then, break the cell wall to a particle size of 100 nm to obtain houttuynia cordata powder. (2) Crush varenicline tartrate and pass it through a 200-mesh sieve for later use; (3) Mix the varenicline tartrate from step (2), the dried Houttuynia cordata powder from step (1), the semi-synthetic fatty acid glycerides, and Tween according to the formula ratio. (4) Heat the mixture obtained in step (3) to a molten state and stir to make it evenly mixed; (5) Inject the molten mixture from step (4) into a suppository mold coated with water-based lubricant; (6) After cooling and molding, cut off the overflowing part, open the mold, take out the suppository, and package it; The drying temperature in step (1) is 40°C, and the moisture content is dried to below 3%. The heating temperature in step (4) is 45°C; The aqueous lubricant in step (5) is a mixed solution with a mass ratio of soft soap: water: 95% ethanol = 1:1:5.

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