A varenicline tartrate oral cavity spray and a preparation method and application thereof

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a varenicline tartrate oral spray, a preparation method thereof and application. The varenicline tartrate oral spray comprises an active ingredient and pharmaceutical excipients, the active ingredient is varenicline tartrate, and the pharmaceutical excipients comprise a solvent, a cosolvent, an absorption promoter, a buffer system, a preservative, a flavoring agent and a viscosity regulator. The oral spray comprises 0.01-0.5% varenicline tartrate in terms of mass / volume percentage. The pH value of the oral spray is 6.0-7.5. Compared with the prior art, the varenicline tartrate oral spray is developed for the first time, the first-pass effect is avoided, direct absorption through the oral mucosa is achieved, the peak time is shortened to 15-30 min, and acute smoking addiction can be quickly relieved. The excipients are screened in multiple dimensions, including the cosolvent, the absorption promoter, the buffer system and the preservative, and the optimization of solubility, stability and mucosal irritation is considered.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a varenicline tartrate oral spray and its preparation method and application. Background Technology

[0002] Varenicline tartrate (CAS: 375815-87-5) is a highly selective partial agonist of the α4β2 nicotinic acetylcholine receptor, exhibiting both agonist and antagonist effects. Its agonist effect alleviates withdrawal symptoms, while its antagonist effect blocks nicotine binding to receptors and reduces the euphoric effects of smoking. It is a first-line smoking cessation drug recommended by the WHO. Varenicline tartrate is a white to off-white powder, readily soluble in water, highly hygroscopic, stable in acidic conditions (pH 4-6), and easily degraded in alkaline conditions (pH > 7.5). Its melting point is 206-208℃.

[0003] Currently, varenicline tartrate is available in oral tablets and nasal sprays. Patent application CN109432022A discloses a pharmaceutical composition containing varenicline tartrate, comprising: varenicline tartrate, a filler, a binder, a disintegrant, a flow aid, and a lubricant, prepared using a tableting method. Oral tablets of varenicline tartrate exhibit a first-pass effect, T... max The effects are slow, taking 3-4 hours to take effect and unable to cope with sudden cravings; gastrointestinal adverse reactions (nausea, vomiting) are frequent, leading to poor patient compliance; nasal sprays cause significant nasal irritation, and long-term use can easily lead to nasopharyngitis. Existing technologies, such as oral mucosal absorption formulations for smoking cessation or rapid relief of cravings, like the orally disintegrating film disclosed in patent application US2011206621A1, primarily focus on nicotine replacement therapy and have not researched or developed for varenicline tartrate.

[0004] Therefore, there is an urgent need to develop an oral spray with varenicline tartrate as the active ingredient, and to optimize its formulation in terms of hygroscopicity, pH sensitivity, atomization performance, mucosal retention, stability and absorption efficiency, so as to meet the needs of patients for rapid relief of acute nicotine cravings. Summary of the Invention

[0005] In view of the above-mentioned defects or improvement needs of the existing technology, the present invention provides an oral spray with varenicline tartrate as the active ingredient, which achieves rapid onset of action, mucosal friendliness, strong stability and uniform atomization, solves the problems of slow onset of action of oral tablets and high irritation of nasal sprays, and meets the clinical need for rapid relief of acute nicotine cravings.

[0006] To achieve the above technical objectives, the specific technical solution is as follows: In a first aspect, the present invention provides a varenicline tartrate oral spray, comprising an active ingredient and pharmaceutical excipients, wherein the active ingredient is varenicline tartrate, and the pharmaceutical excipients include solvents, cosolvents, absorption enhancers, buffer systems, preservatives, flavoring agents, and viscosity modifiers. Furthermore, the oral spray comprises 0.01-0.5% varenicline tartrate by weight-volume percentage; Furthermore, the pH value of the oral spray is 6.0~7.5.

[0007] Further, the oral spray comprises, by weight-volume percentage: Vareniclan tartrate 0.01~0.5%, cosolvent 1~20%, absorption promoter 0.5~10%, buffer system 0.1~5%, preservative 0.01~1%, flavoring agent 0.01~2%, and viscosity modifier 0.1~5%, with the balance being solvent.

[0008] Further, the oral spray comprises, by weight-volume percentage: Vareniclan tartrate 0.1%–0.3%, cosolvent 5%–12%, absorption promoter 1%–5%, buffer system 0.3%–2%, preservative 0.02%–0.2%, flavoring agent 0.05%–1%, and viscosity modifier 0.2%–2%, with the balance being solvent.

[0009] Furthermore, the co-solvent is selected from one or more of ethanol, glycerol, polyethylene glycol 400, and propylene glycol.

[0010] Furthermore, the absorption enhancer is selected from one or two of hydroxypropyl-β-cyclodextrin (HP-β-CD) and laurocapram; Furthermore, the varenicline tartrate forms an inclusion complex with the absorption promoter.

[0011] Furthermore, the buffer system is selected from one or more of the following: citrate-sodium citrate buffer pair, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer pair, and tartaric acid-sodium tartrate buffer pair.

[0012] Furthermore, the preservative is selected from one or more of benzalkonium chloride, chlorhexidine, and ethylparaben.

[0013] Furthermore, the flavoring agent is selected from one or more of menthol, steviol glycosides, sucralose, and aspartame.

[0014] Furthermore, the viscosity modifier is selected from one or more of sodium carboxymethyl cellulose (CMC-Na), xanthan gum, gelatin, and sodium alginate.

[0015] Furthermore, the solvent is purified water.

[0016] Secondly, the present invention provides a method for preparing the above-mentioned varenicline tartrate oral spray, comprising the steps of: Take varenicline tartrate, add solubilizer and part of solvent, and stir until completely dissolved; Add an absorption promoter, stir at room temperature to form an inclusion complex, and filter to remove insoluble matter. Add a buffer system to the filtrate and adjust the pH to 6.0–7.5; Add the preservative, flavoring agent, and viscosity modifier in sequence, and stir until all components are dissolved; Add solvent to the specified total amount, filter, and fill into a metered spray bottle to obtain the varenicline tartrate oral spray.

[0017] Furthermore, the stirring time at room temperature is 1-3 hours, and more specifically, the stirring time at room temperature is 2 hours. Furthermore, the pre-filtration before filling into the metered spray bottle uses a 0.22 μm microporous filter membrane.

[0018] Thirdly, the present invention provides the use of the above-mentioned varenicline tartrate oral spray in the preparation of a medicament for smoking cessation and / or rapid relief of nicotine cravings.

[0019] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) Dosage form innovation: The first development of varenicline tartrate oral spray avoids the first pass effect and is directly absorbed through the oral mucosa, which greatly shortens the time to peak concentration and can quickly relieve acute nicotine cravings; (2) Formulation optimization: Multi-dimensional screening of excipients, including solubilizers, absorption promoters, buffer systems and preservatives, taking into account the optimization of solubility, stability and mucosal irritation; (3) Improved stability: By using solubilizers to solubilize, pH to precisely control, and absorption promoters to encapsulate, the problem of hygroscopic degradation of varenicline tartrate is solved, and the drug's shelf life can reach 24 months; (4) Quality controllable: Establish a comprehensive evaluation system covering physicochemical properties, atomization performance, mucosal penetration, stability and microbial limits to ensure batch consistency. Detailed Implementation

[0020] The present invention will be further described below with reference to embodiments, but the scope of protection of the present invention is not limited thereto. It should be noted that the implementation steps in the embodiments can be further adjusted according to the specific experimental environment, and the implementation steps not specified are usually conditions in conventional experiments. All compounds involved in the following embodiments are commercially available pharmaceutical products.

[0021] Example 1 The formulation of the varenicline tartrate oral spray prepared in this embodiment has the following composition:

[0022] The preparation process includes the following steps: Take varenicline tartrate, add a solubilizer (polyethylene glycol 400) and a portion of the solvent (purified water), and stir until completely dissolved; add an absorption promoter (hydroxypropyl-β-cyclodextrin), stir at room temperature for 2 hours to form an inclusion complex, and filter to remove insoluble matter; add a buffer system (citric acid-sodium citrate) to the filtrate to adjust the pH to 6.0-7.5; add the preservative (benzalkonium chloride), flavoring agent (menthol), and viscosity modifier (sodium carboxymethyl cellulose) in sequence, and stir until all components are dissolved; add solvent to 100 mL, filter, and fill into a metered spray bottle to obtain the varenicline tartrate oral spray.

[0023] Varenicline tartrate oral spray was prepared according to the specified process. It is a colorless, clear liquid, free of sediment and foreign matter, and possesses a characteristic aroma. Testing showed that its properties, pH, atomization performance, stability, microbial limits, and oral mucosal irritation all met the relevant quality requirements. Example 1 was subjected to accelerated stability testing at 40°C and long-term stability testing at 25°C. The results are shown in the table below. The results indicate that the sample tested after 6 months of accelerated testing met the quality standard requirements. After 6 months of accelerated testing at 40°C ± 2°C / 75% RH ± 5% RH, no significant changes were observed in any of the quality indicators, indicating a shelf life of 24 months under conditions of 25°C ± 2°C / 60% RH ± 5% RH. Specific stability test indicators are shown in the table below.

[0024] Example 2 The formulation of the varenicline tartrate oral spray prepared in this embodiment has the following composition:

[0025] The preparation process is the same as in Example 1. The finished product in this example is clear and transparent, exhibits normal atomization, and shows no stratification or precipitation even after long-term storage. Compared to Example 1, the dissolution time of the active pharmaceutical ingredient is comparable, and there are no significant differences in the sample's properties, viscosity, pH value, or related substances.

[0026]

[0027] Example 3 The formulation of the varenicline tartrate oral spray prepared in this embodiment has the following composition:

[0028] The preparation process is the same as in Example 1. In this example, the system dissolves completely, the spray pattern is uniform, and the stability and preservative effect are good. Compared with Example 1, the dissolution time of the active pharmaceutical ingredient is similar, and there are no significant differences in the properties, viscosity, pH value, and related substances of the samples.

[0029]

[0030] Example 4 The formulation of the varenicline tartrate oral spray prepared in this embodiment has the following composition:

[0031] The preparation process is the same as in Example 1. The finished product of this example has stable physicochemical properties and a good user experience. Compared with Example 1, the dissolution time of the active pharmaceutical ingredient is similar, and there are no significant differences in the properties, viscosity, pH value, and related substances of the samples.

[0032]

[0033] Example 5 The formulation of the varenicline tartrate oral spray prepared in this embodiment has the following composition:

[0034] The preparation process is the same as in Example 1. In this example, the drug is completely dissolved, and the atomization and mucosal suitability meet the standards. Compared with Example 1, the dissolution time of the active pharmaceutical ingredient is similar, and there are no significant differences in the properties, viscosity, pH value, and related substances of the samples.

[0035]

[0036] In vitro mucosal permeation tests were conducted using porcine oral mucosa (Franz diffusion cell method), and the results are shown in the table below. The results indicate that the cumulative permeation (Q) of the sample encapsulated and solubilized with hydroxypropyl-β-cyclodextrin (HP-β-CD) was 26% after 2 hours, while the cumulative permeation (Q) of the sample encapsulated and enhanced with laurocapram was 17%. HP-β-CD encapsulation showed better solubilization and permeation-enhancing effects on the active pharmaceutical ingredient.

[0037]

[0038] Example 6 The formulation of the varenicline tartrate oral spray prepared in this embodiment has the following composition:

[0039] Varenicline tartrate oral spray was prepared according to the specified process. Compared with Example 1, the dissolution time of the active pharmaceutical ingredient was similar, and there were no significant differences in the appearance, viscosity, pH value, or related substances of the samples.

[0040]

[0041] Microbial limit and preservative efficacy tests (challenge tests) were conducted on Examples 1 and 6. The bacterial survival rate after 7 days was ≤0.1%, and the mold / yeast survival rate after 14 days was ≤1.0%. Pseudomonas aeruginosa and Staphylococcus aureus were not detectable. The results showed that the microbial limits of both batches of samples met the requirements.

[0042] In Examples 1 and 6, the oral sprays were allowed to stand at room temperature for 24 hours. The droplet size distribution (D50) was measured at 0 h, after shaking for 5 min, and after shaking for 5 min followed by standing for 2 h, 4 h, and 6 h. Each sample was measured in triplicate, and the average value was taken. The results are shown in the table below. The results show that the sample prepared with xanthan gum has a slightly higher viscosity than CMC-Na, and the droplet size is larger. The viscosity of the sample changed significantly after shaking, resulting in a noticeable change in droplet size.

[0043]

[0044] In accordance with the general requirements of the section on sprays in the Chinese Pharmacopoeia, a spray particle size analyzer and a quantitative spray device were used for testing. Six bottles of each sample were tested in parallel, with each bottle sprayed 10 times consecutively. The weight of each spray, droplet diameter D50, spray morphology, and atomization uniformity were measured.

[0045]

[0046] Comparative Example 1

[0047] Samples were prepared without using a buffer salt system. The pH was adjusted using a sodium hydroxide solution / dilute hydrochloric acid solution. The samples were then placed under high temperature and light conditions for influence factor testing. Conclusion: After 10 days of storage, the solution became slightly turbid, the content of drug-related substances increased significantly, and varenicline tartrate underwent significant degradation. Mucosal irritation test: The oral mucosa showed slight redness under alkaline conditions, indicating higher irritation than in Example 1; Conclusion: When the pH exceeds the range defined in this invention, the drug stability decreases significantly, mucosal irritation increases, and the formulation cannot meet the requirements for use.

[0048] Comparative Example 2

[0049] An in vitro porcine oral mucosa permeation experiment was conducted using a Franz diffusion cell. After 120 minutes, the cumulative drug permeation was only 41% of that in Example 1, indicating a significant reduction in drug absorption efficiency through the mucosa, failing to achieve the goal of rapid onset of action. This demonstrates that using an absorption enhancer below the lower limit of this invention severely weakens the transdermal permeation enhancement effect.

[0050] Comparative Example 3

[0051] Long-term stability test (25℃, 6 months): The system pH gradually increased to 7.8, the drug content decreased by 8.7%, and related substances exceeded the standard; while in Example 1, the pH fluctuation was ≤0.2, and the drug content remained basically stable. This confirms that the buffer system is the core component for maintaining the long-term stability of this formulation, and its absence would compromise the product's shelf life.

[0052] Comparative Example 4

[0053] Atomization capability test: The viscosity of the liquid was too high, resulting in a significantly increased D50 of the spray droplets, coarse mist, and rapid settling, making it impossible to adhere evenly to the oral mucosa; the dosage deviation per spray exceeded the standard, leading to a poor user experience. This indicates that exceeding the upper limit of viscosity modifier dosage will directly damage the performance of the spray formulation.

[0054] Experimental Example 1. Comparative study of overall efficacy and pharmacokinetics Example 1 and commercially available varenicline tartrate oral tablets were selected for an in vivo pharmacokinetic and smoking cessation efficacy comparative study in animals.

[0055] Pharmacokinetic results: The oral spray of this invention is absorbed through the oral mucosa and reaches peak concentration in 18-25 minutes; the oral tablets have a significant first-pass effect and reach peak concentration in 3.2-3.8 hours. The onset of action of this formulation is much faster than that of the oral formulation.

[0056] Efficacy results: Animal model experiments on acute nicotine addiction relief showed that this preparation can significantly improve withdrawal reactions in a short time after administration, with rapid onset and stable effect; oral tablets have a delayed onset and cannot cope with sudden acute nicotine addiction.

[0057] 2. Taste Evaluation Taste evaluation was conducted on Examples 1, 2, 3, 4, 5, and 6 using a single-blind method. Ten adult evaluators were selected, and each person received two sprays of the medication. The taste was evaluated without drinking water. The scoring criteria were: 0 points: no bitterness, excellent taste; 1 point: slight bitterness, good taste; 2 points: noticeable bitterness, average taste; 3 points: strong bitterness, poor taste. The results are shown in the table below. The results indicate that all examples had a moderate taste and no strong bitterness.

[0058]

[0059] 3. Evaluation of mucosal retention time Mucosal retention time was evaluated for Examples 1, 2, 3, 4, 5, and 6. The blank control group consisted of commercially available oral tablets, which were ground and dissolved in purified water. A single-blind method was used, selecting 10 healthy adult volunteers (half male and half female) with no oral diseases or drug allergies. Participants were prohibited from eating, drinking, or rinsing their mouths for 30 minutes prior to the experiment. Each participant received two sprays of the spray. After spraying, participants kept their mouths closed and moved their oral cavity naturally, without swallowing, rinsing, or drinking water. Subjective evaluations were conducted at 3, 6, 10, and 15 minutes after administration, recording the presence, moisture, and loss of the medication in the oral cavity.

[0060] The scoring criteria are as follows: 0 points: The medication has completely disappeared without any residue; 1 point: The medication has basically disappeared, with only a brief trace remaining; 2 points: Most of the medication has been lost, with only a small amount remaining in some areas; 3 points: The feeling of moisture has decreased, with some medication lost locally, but no obvious dripping; 4 points: There is a noticeable feeling of moisture, and the oral mucosa is slightly thinned, with no medication dripping; 5 points: The presence of the medication on the oral mucosa is obvious, the moisture is even, there is no obvious flow, and the residue is long-lasting.

[0061] Acceptance criteria: Average score ≥ 3 points at 10 minutes. Results are shown in the table below. All examples achieved an average score ≥ 3 points at 10 minutes after administration, meeting the acceptance criteria and demonstrating good retention of the medication in the oral cavity. The blank control group showed rapid dissipation of the medication and poor sensory retention. All examples exhibited a mild taste, no significant irritation, and excellent user experience.

[0062]

Claims

1. A varenicline tartrate oral spray, characterized in that, It includes an active ingredient and pharmaceutical excipients, wherein the active ingredient is varenicline tartrate, and the pharmaceutical excipients include solvents, cosolvents, absorption enhancers, buffer systems, preservatives, flavoring agents, and viscosity modifiers; The oral spray comprises 0.01-0.5% varenicline tartrate by weight-volume percentage; The pH value of the oral spray is 6.0~7.

5.

2. The varenicline tartrate oral spray according to claim 1, characterized in that, The oral spray comprises, by weight-volume percentage: Vareniclan tartrate 0.01~0.5%, cosolvent 1~20%, absorption promoter 0.5~10%, buffer system 0.1~5%, preservative 0.01~1%, flavoring agent 0.01~2%, and viscosity modifier 0.1~5%, with the balance being solvent.

3. The varenicline tartrate oral spray according to claim 2, characterized in that, The oral spray comprises, by weight-volume percentage: Vareniclan tartrate 0.1%–0.3%, cosolvent 5%–12%, absorption promoter 1%–5%, buffer system 0.3%–2%, preservative 0.02%–0.2%, flavoring agent 0.05%–1%, and viscosity modifier 0.2%–2%, with the balance being solvent.

4. The varenicline tartrate oral spray according to any one of claims 1 to 3, characterized in that, The co-solvent is selected from one or more of ethanol, glycerol, polyethylene glycol 400, and propylene glycol.

5. The varenicline tartrate oral spray according to any one of claims 1 to 3, characterized in that, The absorption enhancer is selected from one or two of hydroxypropyl-β-cyclodextrin and laurocapram.

6. The varenicline tartrate oral spray according to any one of claims 1 to 3, characterized in that, The buffer system is selected from one or more of the following: citrate-sodium citrate buffer pair, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer pair, and tartaric acid-sodium tartrate buffer pair.

7. The varenicline tartrate oral spray according to any one of claims 1 to 3, characterized in that, The preservative is selected from one or more of benzalkonium chloride, chlorhexidine, and ethylparaben.

8. The varenicline tartrate oral spray according to any one of claims 1 to 3, characterized in that, The flavoring agent is selected from one or more of menthol, steviol glycosides, sucralose, and aspartame.

9. The varenicline tartrate oral spray according to any one of claims 1 to 3, characterized in that, The viscosity modifier is selected from one or more of sodium carboxymethyl cellulose, xanthan gum, gelatin, and sodium alginate.

10. The varenicline tartrate oral spray according to claim 1 or 2, characterized in that, The solvent is purified water.

11. A method for preparing varenicline tartrate oral spray as described in claims 1-10, characterized in that, Including the following steps: Take varenicline tartrate, add solubilizer and part of solvent, and stir until completely dissolved; Add an absorption promoter, stir at room temperature to form an inclusion complex, and filter to remove insoluble matter. Add a buffer system to the filtrate and adjust the pH to 6.0–7.5; Add the preservative, flavoring agent, and viscosity modifier in sequence, and stir until all components are dissolved; Add solvent to the specified total amount, filter, and fill into a metered spray bottle to obtain the varenicline tartrate oral spray.

12. The use of the varenicline tartrate oral spray as described in claims 1-10 in the preparation of a medicament for smoking cessation and / or rapid relief of nicotine cravings.

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