Method for manufacturing dried nicotine powder for inhalation

Abstract

The present invention provides a method for producing inhalable nicotine dry powder, comprising the steps of: (S1) producing nicotine powder containing nicotine or a nicotine salt, amino acids, and excipients; (S2) producing flavor powder containing flavoring agents and excipients; and (S3) mixing the nicotine powder and the flavor powder in a weight ratio of 9:1 to 6:4, wherein the nicotine content is 0.5% by weight or more and 1.7% by weight or less based on the total weight of the inhalable nicotine dry powder.

Description

Technical Field

[0001] The present invention relates to a method for producing dry powder of nicotine for inhalation.

Background Art

[0002] Nicotine is transmitted into the body in various ways, such as by inhaling combustion-type tobacco such as cigarettes, cigars, and pipe tobacco, by using a method in which an aerosol is generated by heating an aerosol product substance in a cigarette, or by directly inhaling nicotine powder or the like.

[0003] Among them, the method of directly inhaling nicotine powder is to directly deliver it to the user's airway by inhaling dry powder using a dry powder inhaler (DPI). The dry powder contains various active ingredients (drugs) for the purpose of improving diseases in addition to nicotine.

[0004] On the other hand, conventional dry powder of nicotine for inhalation is generally produced by mixing all substances for dry powdering during production and performing spray drying. However, such a method has the disadvantage that the transfer characteristics of the produced dry powder of nicotine are not easy, and there are some problems in ensuring the ease of production because the characteristics of each substance are different from each other for all substances to be mixed.

Summary of the Invention

Problems to be Solved by the Invention

[0005] One object of the present invention is to provide a method for producing dry powder of nicotine for inhalation, which can obtain all appropriate transfer characteristics of nicotine and fragrance in dry powder of nicotine containing nicotine powder and fragrance powder, by superatomizing nicotine powder through spray drying and subjecting fragrance powder to a milling process.

[0006] However, the problems that this invention aims to solve are not limited to those mentioned above, and other problems not mentioned can be clearly understood by those with ordinary skill in the art from the following description. [Means for solving the problem]

[0007] According to one embodiment of the present invention, a method for producing dried nicotine powder for inhalation, Step (S1) of producing nicotine powder containing nicotine or nicotine salt, amino acids, and excipients; Step (S2) to produce a flavor powder containing flavoring agents and excipients; and Step (S3): Mix the nicotine powder and the fragrance powder in a weight ratio of 9:1 to 6:4. Includes, The present invention provides a method for producing inhalable nicotine powder, characterized in that the nicotine content is 0.5% by weight or more and 1.7% by weight or less based on the total weight of the inhalable nicotine powder. [Effects of the Invention]

[0008] One aspect of the present invention provides a method for producing inhalable nicotine dry powder that ensures ease of production compared to existing methods for producing nicotine dry powder. The nicotine dry powder produced by this method has the advantage of not only having excellent nicotine-to-flavor transfer characteristics, but also a good yield of nicotine content. [Brief explanation of the drawing]

[0009] [Figure 1] This figure shows the manufacturing conditions for nicotine powder produced via a spray drying process, as part of a manufacturing method according to one embodiment of the present invention. [Figure 2] This figure shows the manufacturing conditions for a fragrance powder produced via jet milling, which is part of a manufacturing method according to one embodiment of the present invention. [Figure 3] This figure shows the results of measuring the amount of nicotine transferred from each puff of a nicotine dry powder composition according to one embodiment of the present invention. [Modes for carrying out the invention]

[0010] The embodiments will be described in detail below with reference to the attached drawings. However, various modifications may be made to the embodiments, and the scope of the patent application will not be limited or restricted by such embodiments. All modifications, equivalents, or substitutes to the embodiments should be understood to be included within the scope of the patent.

[0011] The terms used in the embodiments are for illustrative purposes only and should not be construed as intended to limit them. Singular expressions include plural expressions unless the context clearly indicates otherwise. In this specification, terms such as “includes” or “having” indicate the presence of features, figures, steps, actions, components, parts, or combinations thereof described in the specification, and should not be understood as preemptively excluding the possibility of the presence or addition of one or more other features, figures, steps, actions, components, parts, or combinations thereof.

[0012] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as those generally understood by a person of ordinary skill in the art to which this embodiment belongs. Commonly used, predefined terms should be interpreted as having the meaning consistent with their meaning in the context of the relevant art, and not as ideal or overly formal unless expressly defined herein.

[0013] Furthermore, when explaining with reference to the attached drawings, the same components will be assigned the same reference numerals regardless of the reference numerals used in the drawings, and redundant explanations will be omitted. In the description of embodiments, if a specific explanation of related prior art is deemed to unnecessarily obscure the gist of the embodiment, such detailed explanation will be omitted.

[0014] In addition, when describing the components of the embodiments, terms such as first, second, A, B, (a), (b), etc. can be used. These terms are for distinguishing the components from other components, and the essence, order, or sequence of the components are not limited by these terms.

[0015] Components that include functions common to the components included in any of the embodiments will be described using the same names in other embodiments. Unless otherwise stated, the descriptions given in any of the embodiments apply to other embodiments as well, and specific descriptions within the overlapping scope will be omitted.

[0016] As used herein, the term "dry powder inhaler" refers to a device that transmits substances such as those generated by the reaction of nicotine-related substances and organic acid substances into the user's lungs through the user's mouth.

[0017] According to an embodiment of the present invention, in a method for producing an inhalable nicotine dry powder, Step (S1) of producing a nicotine powder containing nicotine or a nicotine salt, an amino acid, and an excipient; Step (S2) of producing a fragrance powder containing a flavoring agent and an excipient; and Step (S3) of mixing the nicotine powder and the fragrance powder at a weight ratio of 9:1 to 6:4; are included, The content of the nicotine is 0.5% by weight or more and 1.7% by weight or less based on the total weight of the inhalable nicotine dry powder, and a method for producing an inhalable nicotine dry powder is provided.

[0018] Specific descriptions of each step of the production method are as follows.

[0019] Step S1 is a step of producing a nicotine powder containing nicotine or a nicotine salt. The nicotine salt exists in the form of a salt of nicotine and an organic acid. The organic acid corresponds to, but is not limited to, lactic acid, tartaric acid, pyruvic acid, benzoic acid, citric acid, and / or salicylic acid.

[0020] When forming an organic acid and nicotine salt as described above, for example, it may have the form of nicotine lactate, nicotine tartrate, nicotine pyruvate, or nicotine salicylate. Among them, considering comprehensively stability and harmfulness to the human body in terms of the use of the nicotine powder as a dry powder for human inhalation, the organic acid is preferably lactic acid, and thus the nicotine salt is preferably nicotine lactate.

[0021] On the other hand, when the nicotine salt is nicotine lactate, in the manufacturing process of the nicotine powder, a specific molar ratio of nicotine to lactic acid plays an important role in determining the nicotine yield. Here, from the perspective of forming a stable nicotine salt and achieving a higher nicotine yield, the molar ratio of nicotine to lactic acid in the S1 step is preferably 1:4 or more (for example, 1:5, 1:6, etc.). In particular, although the S1 step is implemented in a high-temperature spray drying process described in detail below, it can be said that the above-mentioned molar ratio of nicotine and lactic acid is more suitable for forming a stable salt without volatilization even at high temperatures.

[0022] Furthermore, when the molar ratio of lactic acid provided to the nicotine salt is extremely large (for example, 1:10), the yield in the nicotine powder relative to the nicotine input is good, but it is not appropriate in terms of the inhalation stability of the user, and preferably, it is preferably 1:9 or less (for example, 1:7, 1:8, etc.).

[0023] The nicotine powder may contain an amino acid and an excipient in addition to the nicotine or nicotine salt.

[0024] The type of amino acid is not greatly restricted, but it corresponds to one or more of leucine, lysine, valine, arginine, threonine, phenylalanine, glycine, and / or methionine, and preferably, the amino acid may contain leucine.

[0025] Thus, when leucine is included as an amino acid, unlike with other amino acids, the fluidity and transfer rate of the final formed nicotine dry powder can be improved.

[0026] Furthermore, it is preferable that the amino acid content at this stage be 5% by weight or less based on the total amount of the dry powder. By adjusting the amino acid content to 5% by weight or less as described above, the particle size and particle size distribution of the final nicotine dry powder can be improved.

[0027] The excipients contained in the nicotine powder may include sugars and / or sugar alcohols, and the types of sugars may include sucrose, trehalose, dextrose, glucose, maltose, etc. Furthermore, the types of sugar alcohols may include mannitol, sorbitol, galactitol, maltitol, xylitol, lactitol, etc.

[0028] Of these, the excipient preferably contains mannitol, which has advantages when formulated by spray drying. Specifically, mannitol is water-soluble, stable in water before and after formulation, has no particularly negative sensory characteristics other than a slight sweetness, and has no special side effects, making it particularly advantageous to use as a carrier substance for delivering nicotine. Furthermore, mannitol has the advantage of binding to sputum and other substances in the bronchi when absorbed into the bronchi, thereby facilitating their excretion.

[0029] Nicotine powder is specifically manufactured using nicotine or nicotine salts, amino acids, and excipients, as detailed above, through a spray drying process. When nicotine powder is manufactured using a spray drying process, better results are obtained in terms of yield compared to when jet milling is used. This is understood to be because when jet milling is used, development occurs in which nicotine is volatilized into the air due to the properties of nicotine powder.

[0030] On the other hand, when performing spray drying, as shown in Figure 1 below, the solvent, nicotine or nicotine salt, amino acids, and excipients can be stirred first via a magnetic stirrer before spray drying is carried out.

[0031] Here, water is used as the solvent, and nicotine powder is formed by spray drying at an inlet temperature of approximately 100°C with specific spray flow rates and ambient flow rates. The spray flow rate is considered appropriate at 2-7 mL / min as a factor determining the final yield, total spray time, and properties of the nicotine powder, and the ambient flow rate is considered appropriate at 0.3-0.4 m / min, taking into account the final yield and particle size of the nicotine powder. 3 / min appears to be appropriate. Furthermore, the aspirator flow rate is determined by pressure or flow rate depending on the equipment characteristics, and around 250 kPa or 1200 L / hr appears to be appropriate.

[0032] Subsequently, step S2 is a step of producing a flavor powder containing a flavoring agent and an excipient, wherein the flavoring agent means a fragrance commonly used in smoking articles and the like, and includes, but is not limited to, rosemary, eucalyptus, licorice, sucrose, fructose syrup, isosweetener, cocoa, lavender, cinnamon, cardamom, celery, fenugreek, cascarilla, sandalwood, bergamot, geranium, honey essence, rose oil, vanilla, lemon oil, orange oil, mint oil, mandarin oil, catechin, grapefruit, caraway, cognac, jasmine, cacao, menthol, cinnamon, ylang-ylang, salvia, spearmint, ginger, coriander, coffee, etc.

[0033] Furthermore, by including a flavoring agent in the aforementioned fragrance powder, it is possible not only to provide users with a sense of flavor, but also, selectively depending on the type of flavoring agent, to exert not only a role as a fragrance but also cough suppression functions such as dilating the bronchi. From this perspective, it is preferable that the flavoring agent includes menthol.

[0034] Furthermore, as with the nicotine powder described earlier, the flavor powder may also contain excipients. As for the types of excipients, as mentioned above, they may include sugars such as sucrose, trehalose, dextrose, glucose, and maltose, and / or sugar alcohols such as mannitol, sorbitol, galactitol, maltitol, xylitol, and lactitol. Of these, mannitol is preferred as the excipient.

[0035] The inhalable nicotine dry powder according to one embodiment of the present invention may contain nicotine powder and flavor powder in a weight ratio of 9:1 to 5:5, preferably in a weight ratio of 8:2 to 6:4.

[0036] By adjusting the nicotine powder and flavor powder within the above-mentioned range, the particle size, particle distribution, and transfer characteristics of the powder are good, and the user can fully satisfy the functions of nicotine and flavor.

[0037] Step S2 is carried out by a jet milling process using the flavoring agents and excipients described in detail above. During jet milling, it is preferable to lower the temperature to prevent it from rising, as high temperatures cause flavoring agents such as menthol to volatilize easily, resulting in a decrease in their content in the powder or adversely affecting the transfer rate. Therefore, unlike nicotine powder, which is spray-dried at high temperatures, it is preferable to manufacture the flavor powder in a separate step through low-temperature jet milling.

[0038] On the other hand, in addition to the jet milling described above, low-temperature milling and pestle milling may also be used. In particular, low-temperature milling is used as a method to prevent the aggregation of powders by raising the ambient temperature in order to prevent the temperature rise caused by strong contact between powders during general milling, and the temperature at this time may be in the range of -20°C to 5°C.

[0039] Subsequently, the nicotine powder and flavor powder produced in step S3 are mixed (post-mixing) in a weight ratio of 8:2 to 6:4. This ensures that the nicotine and other components contained in the nicotine powder and the flavor powder are evenly mixed without any loss of components, resulting in good transfer characteristics when the user inhales.

[0040] On the other hand, after step S3, the method includes a step (S4) of further mixing in a cough suppressant component, depending on additional selections.

[0041] In this case, the final inhalable nicotine dry powder will contain cough suppressant components in addition to nicotine powder and flavor powder. While there are no significant limitations on the types of cough suppressant components, examples include menthol, mint, saccharin, and benzocaine.

[0042] Thus, even when the inhaled nicotine dry powder contains a cough-suppressing component separately, in order to exhibit the effect according to one embodiment of the present invention, the nicotine content, or the amino acid content, the weight ratio of nicotine powder and fragrance powder, etc., must satisfy the preferred range described above.

[0043] The configuration of the present invention and its effects will be described in detail below through embodiments and comparative examples. However, these embodiments are intended to illustrate the present invention more specifically, and the scope of the present invention is not limited to these embodiments.

[0044] <Embodiment>

[0045] 1. Manufacturing example: Manufacturing of dried nicotine powder for inhalation

[0046] 1. Embodiment 1

[0047] 1) Nicotine powder manufacturing - spray drying

[0048] After weighing the components according to the composition ratios shown in Table 1 below, they were placed in DI water and stirred for about 10 minutes. At this point, the mass ratio of water to solid components was 98:2. Nicotine powder was produced using the spray drying process and process conditions shown in Figure 1 below. [Table 1]

[0049] 2) Manufacturing of fragrance powder - Jet milling

[0050] To produce the fragrance powder with the composition shown in Table 2 below, mannitol and menthol were sieved to remove larger particles, and the smaller particle-sized powders were mixed in and placed in a milling machine for milling. The milling process was repeated while measuring the particles with a mastersizer until the desired particle size was reached. [Table 2]

[0051] 3) Preparation of the final dried powder composition

[0052] The manufactured nicotine powder and flavor powder were mixed in a 5:1 weight ratio to produce the final dried nicotine powder composition.

[0053] (2) Embodiments 2-4 and Comparative Example 1

[0054] Embodiments 2 to 4 were manufactured in the same manner as Embodiment 1, except that the nicotine salts were different as shown in Table 3 below. Comparative Example 1 was manufactured in the same manner as Embodiment 1, except that the fragrance powder was not manufactured differently. [Table 3]

[0055] 2. Test Example 1: Measurement of Particle Size and Particle Size Distribution

[0056] The fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD), which are indicators of inhalation efficiency, were measured for the nicotine dry powder produced by the method for producing nicotine dry powder for inhalation described in the previous embodiment, and the results are shown in Table 4 below. The above results are values ​​obtained using NGI (Next Generation Impactor) in accordance with the Guidelines for Particle Size Evaluation of Pharmaceutical Inhalants. [Table 4]

[0057] As shown in Table 4 above, the FPF of the inhalable nicotine dry powder produced by one embodiment of the present invention is close to 50%, and the MMAD is 5.5 μm or less, indicating excellent inhalation efficiency.

[0058] 3. Test Example 2: Evaluation of Transition Characteristics

[0059] The amount of nicotine dry powder composition of Embodiment 1, manufactured above, transferred to a tube filter during 14 puffs is shown (Figure 3).

[0060] Since a total filling amount of 25 mg or more is considered good based on a standard filling amount of 30 mg, it can be seen that the nicotine dry powder composition according to one embodiment of the present invention has good transfer characteristics.

[0061] 4. Test Example 3: Analysis of Nicotine Content by Nicotine and Lactate Molar Ratio

[0062] In the manufacturing method of Embodiment 1 described above, the molar ratios of nicotine and lactic acid were set to 1:1, 1:2, 1:5, and 1:10, respectively, and nicotine powder was produced by spray drying. The nicotine content of the nicotine powder relative to the initial nicotine input was then measured. [Table 5]

[0063] As shown in Table 5 above, a nicotine content efficiency of 80% or more was observed when the molar ratio of nicotine to lactic acid was 1:5. When the molar ratio of nicotine to lactic acid was lower than this (e.g., 1:1, 1:2, etc.), the nicotine content efficiency was not good in terms of the yield relative to the nicotine input. It was found that there is an advantage in the manufacturing process of nicotine powder (yield of approximately 80% or more) when the molar ratio of nicotine to lactic acid is 1:4 or higher.

[0064] Furthermore, it was found that when the lactic acid content is 1:10, the pH value also drops significantly, indicating that too much lactic acid is undesirable from the perspective of inhalation safety.

[0065] Although embodiments of the present invention have been described in detail above with reference to the drawings, a person with ordinary skill in the art can apply various technical modifications and variations based on the above. For example, the described techniques may be performed in a different order than described, and / or the components of the described systems, structures, devices, circuits, etc. may be combined or assembled in a different manner than described, and substituted or replaced by other components or equivalents, while still achieving the desired results.

[0066] Therefore, other embodiments, other examples, and those equivalent to the claims described below also fall within the scope of the claims.

Claims

1. A method for producing dried nicotine powder for inhalation, A step (S1) of producing nicotine powder containing nicotine or nicotine salt, amino acids, and excipients, Step (S2) for producing a flavor powder containing flavoring agents and excipients, The steps include mixing the nicotine powder and the fragrance powder in a weight ratio of 9:1 to 6:4 (S3), Includes, A method for producing inhalable nicotine powder, characterized in that the nicotine content is 0.5% by weight or more and 1.7% by weight or less based on the total weight of the inhalable nicotine powder.

2. The nicotine powder contains nicotine salts, The aforementioned nicotine salt contains nicotine, A method for producing inhalable nicotine dry powder according to claim 1, comprising a salt containing one or more selected from the group consisting of lactic acid, tartaric acid, pyruvic acid, benzoic acid, citric acid, and salicylic acid.

3. The method for producing inhalable nicotine dry powder according to claim 1, wherein the nicotine salt contains nicotine and lactic acid.

4. The method for producing inhalable nicotine dry powder according to claim 3, wherein the molar ratio of nicotine to lactic acid is 1:4 to 1:

9.

5. The method for producing dried nicotine powder for inhalation according to claim 1, wherein step S1 is performed in a spray drying step.

6. The method for producing inhalable nicotine dry powder according to claim 1, wherein step S2 is performed by jet milling.

7. The method for producing inhalable nicotine dry powder according to claim 1, wherein the amino acid comprises one or more selected from the group consisting of leucine, lysine, valine, arginine, threonine, phenylalanine, chrysin, and methionine.

8. The aforementioned amino acids include leucine, The method for producing inhalable nicotine powder according to claim 1, wherein the leucine content is 5% by weight or less of the total weight of the inhalable nicotine powder.

9. The excipient comprises one or more of sugars and sugar alcohols. The aforementioned sugar comprises one or more selected from the group consisting of lactose, sucrose, trehalose, dextrose, glucose, and maltose. The method for producing inhalable nicotine dry powder according to claim 1, wherein the sugar alcohol comprises one or more selected from the group consisting of mannitol, sorbitol, galactitol, maltitol, xylitol, and lactitol.

10. The method for producing inhalable nicotine dry powder according to claim 1, wherein the excipient comprises mannitol.

11. The method for producing inhalable nicotine dry powder according to claim 1, wherein the flavoring agent comprises one or more selected from the group consisting of rosemary, eucalyptus, licorice, sucrose, fructose syrup, isosweet, cocoa, lavender, cinnamon, cardamom, celery, fenugreek, cascarilla, sandalwood, bergamot, geranium, honey essence, rose oil, vanilla, lemon oil, orange oil, mint oil, mandarin oil, catechin, grapefruit, caraway, cognac, jasmine, cacao, menthol, cinnamon, ylang-ylang, salvia, spearmint, ginger, coriander, and coffee.

12. A method for producing inhalable nicotine dry powder according to claim 1, further comprising the step (S4) of further mixing a cough suppressant component.

13. The method for producing inhalable nicotine dry powder according to claim 12, wherein the cough-suppressing component comprises one or more of menthol, mint, saccharin, and benzocaine.

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