Nicotine release system and preparation method thereof

Abstract

The invention discloses a nicotine release system and a preparation method thereof. The nicotine release system comprises nicotine salt, a nicotine controlled-release component and a penetration enhancer, the penetration enhancer comprises a menthol derivative and cineole, and the ratio of the parts of the menthol derivative to the parts of the cineole is 1: (0.5-2). The penetration enhancer of the nicotine release system can enhance the mucous membrane penetration function and improve the mucous membrane penetration efficiency of nicotine.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of nicotine product production, in particular to a nicotine release system and a preparation method thereof. BACKGROUND

[0002] A nicotine oral product is a product capable of releasing nicotine in the oral cavity. Generally, the nicotine oral product includes a nicotine release system capable of releasing nicotine, and the nicotine release system further includes a penetration enhancer. In the existing nicotine release system, the formula of the penetration enhancer is not ideal, resulting in poor permeability of the mucosa, low efficiency of nicotine permeating through the mucosa, and thus reducing the use experience. SUMMARY

[0003] The main purpose of the present application is to provide a nicotine release system and a preparation method thereof, which solves the technical problem of low efficiency of nicotine permeating through the mucosa.

[0004] To achieve the above-mentioned purpose, the first aspect of the present application provides a nicotine release system, which comprises:

[0005] a nicotine salt;

[0006] a nicotine controlled-release component; and

[0007] a penetration enhancer, which includes a menthol derivative and eucalyptol, and the ratio of the parts of the menthol derivative and the eucalyptol is 1:(0.5-2).

[0008] Optionally, the ratio of the parts of the menthol derivative and the eucalyptol is 1:1.

[0009] Optionally, the menthol derivative is modified by at least one of quaternary ammonium salt, sodium dihydrogen phosphate, polyphosphate, sodium dodecyl benzene sulfonate, naphthalene sulfonate and succinic acid monoester.

[0010] Optionally, the menthol derivative is modified by trimethylamine, and the degree of substitution is 0.8-1.2.

[0011] Optionally, the drug release rate of the nicotine controlled-release component is 0.6-0.8 mg / min, and the nicotine controlled-release component includes at least one of nicotine sustained-release gel, microsphere embedding controlled-release component, nanofiber membrane controlled-release component and porous ceramic carrier controlled-release component.

[0012] The second aspect of the present application provides a preparation method of a nicotine release system, which includes a preparation method of a penetration enhancer, and the preparation method of the penetration enhancer includes the following steps:

[0013] mixing and emulsifying a menthol derivative and eucalyptol;

[0014] The emulsified material is sterilized through a 0.22 μm micropore filter membrane;

[0015] The ratio of the menthol derivative and the eucalyptol is 1:(0.5-2).

[0016] Optionally, the step of mixing and emulsifying the menthol derivative and the eucalyptol comprises:

[0017] The menthol derivative is purified;

[0018] The eucalyptol is purified;

[0019] The purified menthol derivative and the eucalyptol are mixed and emulsified.

[0020] Optionally, the purification of the menthol derivative adopts a recrystallization purification method, and 75% ethanol is used for purification.

[0021] Optionally, the purification of the eucalyptol adopts a molecular distillation purification method, the distillation pressure is 0.1±0.01 kPa, and the distillation temperature is 120±15℃.

[0022] Optionally, in the step of mixing and emulsifying the purified menthol derivative and the eucalyptol, a high-shear homogenizer is used, the rotation speed is 10,000-40,000 rpm, the temperature is 30-60℃, and the time is 30±5 minutes.

[0023] In the nicotine release system of the present application, the nicotine release system comprises a penetration enhancer, the penetration enhancer comprises a menthol derivative and eucalyptol, the menthol derivative and the eucalyptol can synergistically activate the TRPV1 channel and improve the efficiency of nicotine permeation through the mucosa; in the penetration enhancer of the present application, the ratio of the menthol derivative to the eucalyptol is 1:(0.5-2), so that the synergistic effect of the two is good, and the penetration effect is good.

[0024] In the nicotine release system of the present application, the nicotine release system comprises a nicotine controlled-release component, the drug release rate of the nicotine controlled-release component is 0.6-0.8 mg / min, and through the cooperation of the nicotine controlled-release component and the penetration enhancer, the nicotine has a relatively ideal sustained-release effect. DETAILED DESCRIPTION

[0025] The technical solutions in the embodiments of the present application are described below in a clear and complete manner. Obviously, the described embodiments are only some of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0026] In addition, the descriptions involving "first", "second", etc. in the present application are only for the purpose of description, and cannot be understood as indicating or implying the relative importance of the indicated technical features or implicitly indicating the number of the indicated technical features. Therefore, the features defined with "first", "second" can explicitly or implicitly include at least one of the features. In addition, "and / or" throughout the text includes three schemes, taking A and / or B as an example, including A technical solution, B technical solution, and A and B simultaneously meet the technical solution; in addition, the technical solutions of various embodiments can be combined with each other, but it must be based on the realization of ordinary skilled in the art, when the combination of technical solutions appears contradictory or cannot be realized, it should be considered that the combination of such technical solutions does not exist, nor within the protection scope required by the present application.

[0027] The present application proposes a nicotine release system, which comprises a nicotine salt, a nicotine controlled-release component and a penetration enhancer. The nicotine salt is used to provide nicotine, the nicotine controlled-release component is used to control the release of nicotine, and the penetration enhancer is used to enhance the mucosal penetration function and improve the efficiency of nicotine penetrating the mucosa.

[0028] The present application introduces the penetration enhancer in detail. The penetration enhancer of the present application is a dual penetration enhancer combination, which comprises a menthol derivative and eucalyptol, and the ratio of the parts of the menthol derivative and eucalyptol is 1:(0.5-2). The penetration enhancer of the present application can meet the safety (irritation index ISI <1.5) and chemical stability (degradation rate <5% / 24h under the environment of pH=5.5-7.0) of the oral mucosa.

[0029] As shown in the data in Tables 1 and 2 below, the theoretical limit ratio range of the menthol derivative:eucalyptol is 1:(0.5-2) through orthogonal test verification. When the ratio of the menthol derivative and eucalyptol is 1:(0.5-2), the penetration efficiency of the penetration enhancer of the present application can be improved by 35-40% compared with the blank control and single penetration enhancer control, so that the penetration enhancer of the present application can have a relatively ideal penetration effect.

[0030] Most preferably, when the parts of the menthol derivative:eucalyptol = 1:1, the synergistic effect of the menthol derivative and eucalyptol on the activation of the TRPV1 channel is optimal, the penetration effect is the best, and the penetration efficiency can be improved by 40%, which is significantly higher than the penetration efficiency of the blank control and single penetration enhancer control.

[0031] Table 1 Detection results of different components

[0032] Group Penetration efficiency improvement TRPV1 channel opening rate Blank 0 100％ Menthol derivative 25％ 180％ Eucalyptol 20％ 150％ Menthol derivative : eucalyptol = 1 : 0.5 35％ 200％ Menthol derivative : eucalyptol = 1 : 1 40％ 220％ Menthol derivative : eucalyptol = 1 : 2 36％ 210％

[0033] Table 2 Theoretical limit ratio range of menthol derivative:eucalyptol

[0034]

[0035] In the penetration enhancer of the present application, menthol derivatives can be modified by the following salts to achieve the functions of mucosal adhesion and penetration enhancement.

[0036] (1) Quaternary ammonium salt

[0037] Trimethylamine: acid-base neutralization reaction with groups with acidity in menthol derivatives (such as carboxyl, phenolic hydroxyl, etc.), forming ionic pairs or salt compounds, degree of substitution 0.8-1.2. Dissolve menthol carboxyl derivative in an appropriate amount of dichloromethane, add an appropriate amount of trimethylamine aqueous solution or trimethylamine organic solution. Under stirring, let the reaction mixture react at room temperature for several hours. After the reaction is completed, remove the organic solvent by distillation, then wash the reaction product with dilute acid solution to remove unreacted trimethylamine and other impurities, and finally purify the product by recrystallization or column chromatography, etc. to obtain the trimethylamine modified menthol derivative.

[0038] (1) Phosphate salt

[0039] Sodium dihydrogen phosphate: form phosphate monoester (esterification degree 1.0-1.5) at menthol hydroxyl site, water solubility from 2.3 g / L to 5.8 g / L, suitable for pH = 6.0-7.0 environment, mucosal adhesion time extended to 35 minutes (quaternary ammonium salt modification for 40 minutes).

[0040] Polyphosphate modification: reaction with sodium hexametaphosphate to form branched phosphate ester (polymerization degree n = 3-5), critical micelle concentration (CMC) reduced to 0.12 mmol / L (quaternary ammonium salt concentration is 0.15 mmol / L), penetration efficiency is equivalent.

[0041] (2) Sulfonate salt

[0042] Sodium dodecylbenzenesulfonate: grafting by sulfonyl chloride reaction (grafting rate 5-8%), surface tension from 72 mN / m to 38 mN / m, form nanoemulsion droplets (particle size = 150-200 nm) when mixed with eucalyptol, penetration efficiency reaches 85% of quaternary ammonium salt modification.

[0043] Naphthalenesulfonate: β-naphthalenesulfonic acid sodium condenses with menthol (condensation degree 1.2-1.8), forming an anionic surfactant, negatively charged in a pH = 5.5-6.0 environment, forming an ionic pair with nicotine cations, promoting transmembrane transport.

[0044] (3) Carboxylate salt

[0045] Succinic acid monoester: menthol reacts with succinic anhydride (esterification degree 1.0-1.3), introducing carboxylic acid groups, which ionize as anions at pH > 6, binding to cationic sites of mucosal glycoproteins, adhesion force reaching 75% of quaternary ammonium salt modification, suitable for alkaline oral environment.

[0046] The release rate of the nicotine controlled release component is 0.6-0.8 mg / min, so that the nicotine has a relatively ideal slow-release effect through the cooperation of the nicotine controlled release component and the penetration enhancer. The nicotine controlled release component can include at least one of a nicotine slow-release gel, a microsphere embedding controlled release component, a nanofiber membrane controlled release component, and a porous ceramic carrier controlled release component.

[0047] In a more preferred embodiment, the nicotine controlled release component is a nicotine slow-release gel, and the nicotine slow-release gel includes HydroxyPropyl Methyl Cellulose (HPMCE3), Polyvinylpyrrolidone (PVP-K15), and chitosan particles. The proportion of HydroxyPropyl Methyl Cellulose is 4-6, the proportion of Polyvinylpyrrolidone is 2-4, and the proportion of chitosan particles is 0.5-1.5. The particle size of the chitosan particles is 50-120 nm. More preferably, the ratio of the proportions of HydroxyPropyl Methyl Cellulose, Polyvinylpyrrolidone, and chitosan particles can be 5:3:1. The chitosan particles are nanoscale chitosan particles. The particle size of the chitosan particles can be 50-120 nm, and preferably, the particle size of the chitosan particles can be 50-100 nm or 80-120 nm. The cross-linking degree of the nicotine slow-release gel can be 8-20%. Further, the cross-linking degree of the nicotine slow-release gel is preferably 12-15%, 18-20%, 8-10%, or 14-16%. The nicotine slow-release gel includes glutaraldehyde, and the mass of the glutaraldehyde is 0.4-0.6% of the total mass of the nicotine slow-release gel. The glutaraldehyde is used to adjust the cross-linking degree of the nicotine slow-release gel.

[0048] The nicotine release performance of the nicotine release system was tested, and the proportion of the nicotine controlled release component was 13-20, the proportion of the nicotine salt was 18-35, and the proportion of the penetration enhancer was 2.4-7. The formula of the nicotine controlled release component was HydroxyPropyl Methyl Cellulose: Polyvinylpyrrolidone: Chitosan particles = 5:3:1, the particle size of the chitosan was 75 nm, and the cross-linking degree was 13.5%. The formula of the nicotine salt was Citrate: Malate: Lactate = 3:2:1, and the particle size was 350 nm. The formula of the penetration enhancer was Menthol derivative: Eucalyptol = 1:1, and the purity was 99.5%. As can be seen from the data in Table 3, the nicotine release system of the present application has a relatively ideal dissolution rate, penetration efficiency, release rate, and relatively low mucous membrane irritation, thereby having a relatively good use experience.

[0049] Table 3. Test parameters for nicotine release performance

[0050]

[0051] The application also provides a preparation method of the nicotine release system, the preparation method comprising a preparation method of the penetration enhancer, the preparation method of the penetration enhancer comprising steps of: S100, mixing and emulsifying the menthol derivative and eucalyptol; and S200, sterilizing the emulsified material through a 0.22 μm micropore filter. Through the preparation method of the nicotine release system, the penetration enhancer with relatively high mucosal permeation efficiency can be prepared.

[0052] The step S100 of mixing and emulsifying the menthol derivative and eucalyptol comprises: S110, purifying the menthol derivative. The purification of the menthol derivative in S110 adopts a recrystallization purification method, and 75% ethanol is used for purification.

[0053] The step S100 of mixing and emulsifying the menthol derivative and eucalyptol comprises: S120, purifying the eucalyptol. The purification of the eucalyptol in S120 adopts a molecular distillation purification method, the distillation pressure is 0.1±0.01 kPa, and the distillation temperature is 120±15℃.

[0054] The step S100 of mixing and emulsifying the menthol derivative and eucalyptol comprises: S130, mixing and emulsifying the purified menthol derivative and eucalyptol. In the step S130 of mixing and emulsifying the purified menthol derivative and eucalyptol, a high-shear homogenizer is used, the temperature of the emulsification kettle is 45±15℃, the stirring speed is 25,000±15,000 rpm, and the emulsification time is 30±5 minutes.

[0055] Specifically, in the emulsification process, the theoretical limit range of the homogenization emulsification speed is 10,000-40,000 rpm (based on the threshold value of the cavitation effect of fluid mechanics). When the speed is <10,000 rpm, the emulsification shear force is insufficient, the droplet particle size is >500 nm (laser particle size instrument detects D90=520 nm), and phase separation (delamination height >10%) occurs after standing for 24 h. When the speed is >40,000 rpm, severe cavitation effect occurs, the temperature rises sharply (temperature rise of 5℃ per minute), and the oxidation degradation rate of eucalyptol is 18% (HPLC detects that the eucalyptol content decreases from 99% to 81%). The optimal value of the speed is 25,000 rpm, at which the particle size distribution is D50=180 nm, PDI=0.18 (ideal range <0.2), and the emulsion stability index under unit energy consumption (kWh / kg) is 0.92 (maximum value is 1).

[0056] The theoretical limit of emulsification temperature is 30-60℃ (based on the thermal stability of ingredients). When the emulsification temperature is <30℃, the solubility of menthol derivative quaternary ammonium salt decreases (from 25 g / L to 12 g / L), and the system becomes turbid (turbidity >10 NTU). When the emulsification temperature is >60℃, eucalyptol undergoes epoxidation reaction (GC-MS detects epoxide content = 9.5%), aroma loss rate = 15%, and quaternary ammonium salt thermal decomposition rate = 5% (TGA weight loss analysis shows). The optimal value of emulsification temperature is 45℃, at which the retention rate of menthol derivative = 98.7%, the retention rate of eucalyptol = 99.2%, a liquid crystal phase structure is formed, and the viscosity = 250 cP (the optimal tabletting flowability range is 200-300 cP).

[0057] The core control step of the emulsification process includes a high-shear homogenization stage (25,000 rpm / 30 minutes), which directly affects the droplet size and distribution (determining the contact area of penetration enhancers and mucosa). For every 5-minute reduction in homogenization time, the particle size D50 increases from 180 nm to 220 nm, and the penetration efficiency decreases from 40% to 32%. When the homogenization time exceeds 30 minutes, the particle size no longer decreases, but the energy consumption increases by 20%. The core control step of the emulsification process also includes temperature synchronous control (45℃±2℃). A jacketed emulsification kettle is used, and the temperature is controlled by circulating heat transfer oil. When the temperature fluctuation exceeds ±2℃, the co-crystal structure destruction rate of quaternary ammonium salt and eucalyptol = 12%, and the penetration efficiency fluctuation ±5%.

[0058] In the emulsification process, a high-speed homogenizer can be used to directly feed the materials to save the pre-mixing and stirring step. The mixing is completed in 1 minute at 25000 rpm, the mixing uniformity RSD = 1.3% (equivalent to pre-mixing), and 90% of time is saved. Micro-jet homogenization can be used instead of traditional mechanical stirring emulsification. The micro-jet pressure is 100-150 MPa, and the cycle number is 3 times. The particle size distribution PDI decreases from 0.18 to 0.12, and the penetration efficiency increases by 10% (up to 44%), which is suitable for large-scale production. Ultrasonic-assisted homogenization can be used instead of single homogenization. The ultrasonic power is 300 W, the homogenization time is 20 minutes, and nano-emulsion droplets (particle size 100-150 nm) are formed, with improved stability (particle size increase <5% after 6 months of storage).

Claims

1. A nicotine release system, characterized in that, The nicotine release system includes: Nicotine salts; Nicotine controlled-release components; and The penetration enhancer includes a menthol derivative and eucalyptol, wherein the ratio of the menthol derivative to the eucalyptol is 1:(0.5-2).

2. The nicotine release system according to claim 1, characterized in that, The ratio of the menthol derivative to the eucalyptol is 1:

1.

3. The nicotine release system according to claim 1, characterized in that, The menthol derivative is modified by at least one of quaternary ammonium salt, sodium dihydrogen phosphate, polyphosphate, sodium dodecylbenzenesulfonate, naphthalene sulfonate, and succinate monoester.

4. The nicotine release system according to claim 3, characterized in that, The menthol derivative is modified with trimethylamine and has a degree of substitution of 0.8 to 1.

2.

5. The nicotine release system according to any one of claims 1 to 4, characterized in that, The nicotine controlled-release component has a drug release rate of 0.6–0.8 mg / min, and the nicotine controlled-release component includes at least one of nicotine sustained-release gel, microsphere-encapsulated controlled-release component, nanofiber membrane controlled-release component, and porous ceramic carrier controlled-release component.

6. A method for preparing a nicotine release system, characterized in that, The preparation method of the nicotine release system includes a method for preparing a penetration enhancer, the method for preparing the penetration enhancer comprising the following steps: Mix and emulsify menthol derivatives and eucalyptol; The emulsified material is sterilized by passing it through a 0.22μm microporous membrane. The ratio of the menthol derivative to the eucalyptol is 1:(0.5-2).

7. The method for preparing the nicotine release system according to claim 6, characterized in that, The step of mixing and emulsifying the menthol derivative and eucalyptol includes: The menthol derivative was purified; The eucalyptol was purified. The purified menthol derivative and the eucalyptol were mixed and emulsified.

8. The method for preparing the nicotine release system according to claim 7, characterized in that, The menthol derivative is purified by recrystallization using 75% ethanol.

9. The method for preparing the nicotine release system according to claim 7, characterized in that, The eucalyptol was purified by molecular distillation at a pressure of 0.1 ± 0.01 kPa and a temperature of 120 ± 15 °C.

10. The method for preparing the nicotine release system according to claim 7, characterized in that, In the step of mixing and emulsifying the purified menthol derivative and the eucalyptol, a high-shear homogenizer was used at a speed of 10,000 to 40,000 rpm, a temperature of 30 to 60°C, and a time of 30 ± 5 minutes.

Images