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 a nicotine controlled-release component, a penetration enhancer and a nicotine slow-release salt, the nicotine slow-release salt is an ultramicro nano composite nicotine slow-release salt, the nicotine slow-release salt comprises at least one of citrate, malate and lactate, and the penetration enhancer is an ultramicro nano composite nicotine slow-release salt. The particle size of the nicotine sustained-release salt is 200-500nm, and the specific surface area of the nicotine sustained-release salt is 150 + / -50m < 2 > / g. According to the nicotine slow-release salt, the dissolving effect of nicotine in the oral cavity is relatively good.

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 nicotine salt. In the existing nicotine release system, the formula of the nicotine salt is not ideal, which leads to poor dissolution rate of nicotine in the oral cavity, and further leads to poor release effect of nicotine, thereby reducing the user 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 poor release effect of nicotine caused by the non-ideal formula of nicotine salt.

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

[0005] a nicotine controlled-release component;

[0006] a penetration enhancer; and

[0007] a nicotine sustained-release salt, the nicotine sustained-release salt being a super-micro-nano composite nicotine sustained-release salt, the nicotine sustained-release salt including at least one of citrate, malate and lactate, the particle size of the nicotine sustained-release salt being 200-500 nm, and the specific surface area of the nicotine sustained-release salt being 150±50 m 2 / g.

[0008] Optionally, the nicotine sustained-release salt includes the citrate, the malate and the lactate, and the ratio of the parts of the citrate, the malate and the lactate is 3:2:1.

[0009] Optionally, the nicotine controlled-release component includes at least one of a nicotine sustained-release gel, a microsphere-embedded controlled-release component, a nanofiber membrane controlled-release component and a porous ceramic carrier controlled-release component.

[0010] Optionally, the nicotine controlled-release component is the nicotine sustained-release gel, the nicotine sustained-release gel including hydroxypropyl methyl cellulose, polyvinyl pyrrolidone and chitosan particles, the part of the hydroxypropyl methyl cellulose being 4-6, the part of the polyvinyl pyrrolidone being 2-4, the part of the chitosan particles being 0.5-1.5, the particle size of the chitosan particles being 50-120 nm, and the cross-linking degree of the nicotine sustained-release gel being 8-20%.

[0011] Optionally, the release rate of the nicotine controlled release component is 0.6-0.8 mg / min, the nicotine controlled release component is the nicotine sustained release gel, the nicotine sustained release gel comprises hydroxypropyl methyl cellulose, polyvinyl pyrrolidone and gelatin, the proportion of the hydroxypropyl methyl cellulose is 4-6, the proportion of the polyvinyl pyrrolidone is 2-4, the proportion of the gelatin is 1.5-2.5, and the cross-linking degree of the nicotine sustained release gel is 8-20%.

[0012] Optionally, in the nicotine release system, the proportion of the nicotine controlled release component is 13-20, the proportion of the nicotine sustained release salt is 18-35, and the proportion of the penetration enhancer is 2.4-7.

[0013] The second aspect of the present application provides a preparation method of a nicotine release system, the preparation method of the nicotine release system comprising a preparation method of a nicotine sustained release salt, the preparation method of the nicotine sustained release salt comprising the steps of:

[0014] removing the crystallization water of nicotine citrate, nicotine malate and nicotine lactate and mixing;

[0015] dissolving the mixed salt with ethanol;

[0016] atomizing the mixed salt solution, collecting and screening the dried powder, and completing the preparation;

[0017] wherein the ratio of the proportions of the citrate, the malate and the lactate is 3:2:1, the particle size of the nicotine release system is 200-500 nm, and the specific surface area of the nicotine release system is 150±50 m 2 / g.

[0018] Optionally, in the step of removing the crystallization water of nicotine citrate, nicotine malate and nicotine lactate and mixing, the nicotine citrate, the nicotine malate and the nicotine lactate are subjected to vacuum drying treatment, the drying temperature is 60±5℃, the drying air pressure is -0.09±0.01 Mpa, and the drying time is 4±0.5 hours.

[0019] Optionally, in the step of dissolving the mixed salt with ethanol, the concentration of ethanol is 70%, the addition ratio of ethanol is 10 mL per gram of total salt, and the preheating temperature of ethanol is 40±5℃.

[0020] Optionally, in the step of atomizing the mixed salt solution and collecting the dried powder, the drying is performed by a centrifugal spray dryer, the inlet air temperature is 200±20℃, the outlet air temperature is 80±5℃, the atomization pressure is 3.5±0.5MPa, the feeding rate is 5±0.5mL / min, the negative pressure in the drying tower is kept at -100Pa±10, and the dried powder is collected by a cyclone separator and screened by a 200-mesh sieve with a pore size of 75μm.

[0021] In the nicotine release system of the present application, the nicotine release system comprises a nicotine sustained-release salt, the nicotine sustained-release salt is a super-micro-nano composite nicotine sustained-release salt, the nicotine sustained-release salt comprises at least one of citrate, malate and lactate, the particle size of the nicotine sustained-release salt is 200-500nm, and the specific surface area of the nicotine sustained-release salt is 150±50m 2 / g. The nicotine sustained-release salt of the present application makes the dissolution rate of nicotine in the oral cavity more appropriate.

[0022] In the nicotine release system of the present application, the nicotine release system comprises a nicotine sustained-release salt, the nicotine sustained-release salt is a super-micro-nano composite nicotine sustained-release salt, the nicotine sustained-release salt comprises at least one of citrate, malate and lactate, the particle size of the nicotine sustained-release salt is 200-500nm, and the specific surface area of the nicotine sustained-release salt is 150±50m DETAILED DESCRIPTION

[0023] The technical solutions in the embodiments of the present application are described below clearly and completely. Obviously, the described embodiments are only some of the embodiments of the present application, but not all the embodiments. Based on the embodiments in the present application, all the other embodiments obtained by those skilled in the art without creative work fall within the scope of protection of the present application.

[0024] In addition, the description of "first", "second" and the like in the present application is 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 as "first", "second" can explicitly or implicitly include at least one of the features. In addition, "and / or" throughout the text includes three solutions, for example, A and / or B includes 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 those skilled in the art, when the combination of technical solutions appears contradictory or unachievable, it should be considered that the combination of technical solutions does not exist, and is not within the scope of protection claimed by the present application.

[0025] The present application provides a nicotine release system, which comprises a nicotine controlled release component, a penetration enhancer and a nicotine sustained release salt. In the nicotine release system of the present application, the proportion of the nicotine controlled release component is 13-20, the proportion of the nicotine sustained release salt is 18-35, and the proportion of the penetration enhancer is 2.4-7. The nicotine controlled release component is used to control the release of nicotine in the nicotine sustained release salt. The penetration enhancer is used to enhance the mucosal permeability. The nicotine sustained release salt can be used to control the release rate of nicotine, avoid throat irritation, nausea and other discomfort caused by high nicotine concentration in a short time, prolong the release period, reduce the blood drug concentration fluctuation, prolong the satisfaction, and reduce the frequent smoking demand.

[0026] The nicotine sustained release salt of the present application is a super-micro-nano composite nicotine sustained release salt, which comprises citrate, malate and lactate, at least one of the citrate, the particle size of the nicotine sustained release salt is 200-500 nm, and the specific surface area of the nicotine sustained release salt is 150±50 m 2 / g, so that the dissolution rate of nicotine in the oral cavity is appropriate. Preferably, the particle size of the nicotine sustained release salt is about 350 nm, and the specific surface area of the nicotine sustained release salt is about 150 m 2 / g.

[0027] In a preferred embodiment, the nicotine sustained release salt comprises citrate, malate and lactate, and the ratio of the proportions of the citrate, the malate and the lactate is 3:2:1.

[0028] The release rate of the nicotine controlled release component of the present application is 0.6-0.8 mg / min, so that the nicotine can have a relatively ideal sustained release effect through the cooperation of the nicotine controlled release component and the nicotine sustained release salt. The nicotine controlled release component can comprise at least one of a nicotine sustained release gel, a microsphere embedding controlled release component, a nanofiber membrane controlled release component and a porous ceramic carrier controlled release component.

[0029] In an embodiment, the nicotine controlled release component is a nicotine sustained release gel, which comprises Hydroxy Propyl Methyl Cellulose (HPMCE3), Polyvinylpyrrolidone (PVP-K15) and chitosan particles. HPMCE3 can form a 0.1 mm thin film within 15 s, thereby directly blocking the diffusion of nicotine. PVP-K15 controls the gel porosity at 30-40%, forming a nanoscale release channel (pore size 200-500 nm). The chitosan particles form an electrostatic complex (binding constant K=1.8×10 3The adsorption-desorption equilibrium directly determines the release amount of the 4-8 hour sustained release section. Specifically, the proportion of hydroxypropyl methyl cellulose is 4-6, the proportion of polyvinyl pyrrolidone 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. Preferably, the ratio of the proportions of hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, 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.

[0030] The above-mentioned nicotine sustained release gel further comprises glutaraldehyde, and the mass of the glutaraldehyde is 0.4-0.6% of the total mass of the nicotine sustained release gel. Glutaraldehyde is used to adjust the cross-linking degree of the nicotine sustained release gel.

[0031] In another embodiment, the nicotine sustained release gel comprises hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, and gelatin, the proportion of hydroxypropyl methyl cellulose is 4-6, and the proportion of polyvinyl pyrrolidone is 2-4. Preferably, the ratio of hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, and gelatin can be 5:3:2. The use of gelatin can achieve no chemical cross-linking agent residue and improve biological compatibility.

[0032] The cross-linking degree of the above-mentioned two nicotine sustained release gels can be 8-20%. Further, the cross-linking degree of the nicotine sustained release gel is preferably 12-15%, 18-20%, 8-10%, or 14-16%.

[0033] The application determines the sustained release effect of nicotine salts with different formulations, and the nicotine controlled release component uses a nicotine sustained release gel comprising HPMC E3, PVP-K15, and chitosan particles (determined below, this combination has the best sustained release effect on nicotine sustained release salts). In order to adapt to the dissolution rate of salts with different formulations, the formulation of the above-mentioned nicotine sustained release gel is also adjusted accordingly.

[0034] The determination results are shown in Table 1 below. The determination results show that the nicotine sustained release effect of the lactic acid salt+maleic acid salt combination, the malic acid salt+ fumaric acid salt combination, and the citric acid salt+malic acid salt+lactic acid salt combination is good, and the dissolution rates of the three combinations are close. However, the lactic acid salt+maleic acid salt combination needs to be additionally treated with 0.5% Tween 80, and the malic acid salt+ fumaric acid salt combination needs to be additionally grafted with carboxymethyl chitosan, which is more complicated than the citric acid salt+malic acid salt+lactic acid salt combination. Therefore, the nicotine sustained release salt uses the citric acid salt+malic acid salt+lactic acid salt combination, which is the best.

[0035] Table 1 Release results of nicotine salts with different formulations

[0036]

[0037]

[0038] The application determines different proportions of HPMCE3, PVP-K15 and chitosan, and it is verified that the optimal proportion is HPMCE3:PVP-K15:chitosan=5:3:1. As shown in Table 2 below, if the above proportion is adjusted to 4:4:2, the mechanical strength of the gel decreases by 50%, and the tablet is easy to break during pressing; if the above proportion is adjusted to 6:2:2, the blockage rate of the release channel increases by 30%.

[0039] Table 2 Determination results of different proportions of HPMCE3, PVP-K15 and chitosan

[0040]

[0041] The application determines the nicotine release effect of the nicotine sustained-release salt by using different nicotine controlled-release components. As shown in Table 3 below, compared with the microsphere embedding controlled-release component, the nanofiber membrane controlled-release component and the porous ceramic carrier controlled-release component, the combination of hydroxypropyl methylcellulose: polyvinylpyrrolidone: chitosan particles = 5:3:1 has the best nicotine sustained-release effect on the nicotine sustained-release salt. The microsphere embedding controlled-release component, the nanofiber membrane controlled-release component and the porous ceramic carrier controlled-release component used for testing are existing products on the market.

[0042] Table 3 Comparison of in vitro release experiments of different nicotine controlled-release components

[0043]

[0044] The application also provides a preparation method of a nicotine release system, which comprises a preparation method of a nicotine sustained-release salt. The preparation method of the nicotine sustained-release salt comprises the following steps: S100, removing the crystal water of nicotine citrate, nicotine malate and nicotine lactate and mixing; S200, dissolving the mixed salt in ethanol; S300, atomizing the mixed salt solution, collecting and screening the dried powder, and completing the preparation.

[0045] In the step S100 of removing the crystal water of nicotine citrate, nicotine malate and nicotine lactate and mixing, the nicotine citrate, the nicotine malate and the nicotine lactate are subjected to vacuum drying treatment, the drying temperature is 60±5℃, the drying air pressure is-0.09±0.01 Mpa, and the drying time is 4±0.5 hours.

[0046] In the step S200 of dissolving the mixed salt in ethanol, the concentration of the ethanol is 70%, the addition ratio of the ethanol is 10 mL per gram of total salt, and the preheating temperature of the ethanol is 40±5℃.

[0047] In S300, the mixed salt solution is atomized and the dried powder is collected, in the step of completing the preparation, the centrifugal spray dryer is used for drying, the inlet air temperature is 200±20℃, the outlet air temperature is 80±5℃, the atomization pressure is 3.5±0.5MPa, the feeding rate is 5±0.5mL / min, the drying tower is kept at-100Pa±10 negative pressure, the dried powder is collected by the cyclone separator, and the 200 mesh sieve with a pore size of 75μm is used for screening.

[0048] By the preparation method of the nicotine release system, the nanoscale nicotine sustained-release composite salt with a particle size of 200-500nm can be prepared, the specific surface area of the nicotine sustained-release salt is 150±50m 2 / g, which is much higher than the specific surface area of 50m 2 / g of the conventional micron-sized particles. The average particle size of the nicotine sustained-release salt is 350nm and the particle size distribution PDI is <0.25, which are measured by the laser particle size analyzer (such as Malvern Zetasizer). In the phosphate buffer with pH=6.8, under the condition of 37℃ and 50rpm, the dissolution rate of the nicotine sustained-release salt is 1.2mg / min, which is 2.8 times higher than that of the single nicotine citrate (0.43mg / min). Therefore, by the preparation method of the nicotine release system, the nicotine sustained-release salt with good nicotine dissolution effect can be prepared.

Claims

1. A nicotine release system characterized in that, The nicotine release system comprises: a nicotine controlled release component; a penetration enhancer; and A nicotine sustained-release salt is an ultra-micro-nano composite nicotine sustained-release salt, the nicotine sustained-release salt includes at least one of citrate, malate and lactate, the particle size of the nicotine sustained-release salt is 200-500 nm, the specific surface area of the nicotine sustained-release salt is 150±50 m 2 / g.

2. The nicotine-releasing system according to claim 1, characterized in that, The nicotine sustained release salt comprises the citrate salt, the malate salt and the lactate salt, and the ratio of the parts of the citrate salt, the malate salt and the lactate salt is 3:2:

1.

3. The nicotine-releasing system according to claim 1, characterized in that, The drug release rate of the nicotine controlled release component is 0.6-0.8 mg / min, and the nicotine controlled release component comprises at least one of a nicotine sustained release gel, a microsphere embedding controlled release component, a nanofiber membrane controlled release component and a porous ceramic carrier controlled release component.

4. The nicotine-releasing system according to claim 3, characterized in that The nicotine controlled release component is the nicotine sustained release gel, and the nicotine sustained release gel comprises hydroxypropyl methyl cellulose, polyvinyl pyrrolidone and chitosan particles, the part of the hydroxypropyl methyl cellulose is 4-6, the part of the polyvinyl pyrrolidone is 2-4, the part of the chitosan particles is 0.5-1.5, the particle size of the chitosan particles is 50-120 nm, and the cross-linking degree of the nicotine sustained release gel is 8-20%.

5. The nicotine-releasing system according to claim 3, characterized in that, The nicotine controlled release component is the nicotine sustained release gel, and the nicotine sustained release gel comprises hydroxypropyl methyl cellulose, polyvinyl pyrrolidone and gelatin, the part of the hydroxypropyl methyl cellulose is 4-6, the part of the polyvinyl pyrrolidone is 2-4, the part of the gelatin is 1.5-2.5, and the cross-linking degree of the nicotine sustained release gel is 8-20%.

6. The nicotine-releasing system according to any one of claims 1 to 5, characterized in that, In the nicotine release system, the part of the nicotine controlled release component is 13-20, the part of the nicotine sustained release salt is 18-35, and the part of the penetration enhancer is 2.4-7.

7. A method of making a nicotine release system, characterized in that, The preparation method of the nicotine release system comprises a preparation method of a nicotine sustained release salt, and the preparation method of the nicotine sustained release salt comprises the steps of: removing the crystal water of nicotine citrate, nicotine malate and nicotine lactate and mixing; dissolving the mixed salt in ethanol; atomizing the mixed salt solution, collecting and screening the dried powder, and completing the preparation; The ratio of the parts of the citrate, the malate and the lactate is 3:2:1, the particle size of the nicotine release system is 200-500 nm, and the specific surface area of the nicotine release system is 150±50 m 2 / g.

8. The method of claim 7, wherein the nicotine-releasing system is prepared by, In the step of removing the crystal water of nicotine citrate, nicotine malate and nicotine lactate and mixing, the nicotine citrate, the nicotine malate and the nicotine lactate are subjected to vacuum drying treatment, the drying temperature is 60±5℃, the drying air pressure is-0.09±0.01 Mpa, and the drying time is 4±0.5 hours.

9. The method of claim 7, wherein the nicotine-releasing system is prepared by a process comprising: In the step of dissolving the mixed salt in ethanol, the concentration of ethanol is 70%, the addition ratio of ethanol is 10 mL per gram of total salt, and the preheating temperature of ethanol is 40±5℃.

10. The method of claim 7, wherein the nicotine-releasing system is prepared by a process comprising: In the step of atomizing the mixed salt solution and collecting the dried powder, and completing the preparation, centrifugal spray drying machine is used for drying, the inlet air temperature is 200±20℃, the outlet air temperature is 80±5℃, the atomization pressure is 3.5±0.5 MPa, the feeding rate is 5±0.5 mL / min, the negative pressure in the drying tower is maintained at-100 Pa±10, the dried powder is collected by a cyclone separator, and a 200-mesh sieve with a pore size of 75 μm is used for screening.

Images