Aerosolizable nicotine-containing preparations

Abstract

Novel nicotine-containing formulations for electronic cigarettes and other electric / electronic nicotine delivery systems (ENDS) are disclosed. The disclosed formulations contain much higher concentrations of nicotine than typical conventional nicotine-containing formulations, which contain only about 2-4% (w / w), typically at least 25% (w / w) and often 40-50% (w / w) of the total weight of the formulation. In addition, the formulations of the present invention also contain relatively high concentrations (w / w) of biologically and medicamentously acceptable organic mono- or dicarboxylic acids, such as benzoic acid, salicylic acid, and most preferably lactic acid. By including an acid in the formulation, one or more nicotine salts can be generated and present in the formulations of the present invention, which not only mitigates the loss of nicotine to the atmosphere through natural volatility and evaporation, but also significantly increases the surface energy of the formulation thus generated, i.e., significantly increases the cohesiveness of the globules of the formulation deposited on a heated substrate, greatly reducing the possibility of migration due to wetting the substrate.

Description

[Technical Field]

[0001] The present invention relates, in a broad sense, to a variety of different nicotine-containing formulations suitable for use with certain types of electronic cigarettes or similar aerosolizing or vaporizing electrical appliances, hereinafter referred to as "vaping" devices. More specifically, the present invention relates to a variety of nicotine-containing formulations that can achieve significantly higher concentrations of nicotine compared to the very wide range of nicotine-containing formulations currently available, and are suitable for use with conventional vaping devices, which also come in a wide variety. [Background technology]

[0002] Nicotine-containing formulations for use with reservoir-based vaping devices are already widely available. In fact, the popularity of all types of vaping devices has surged in recent years, and consequently, the availability and variety of nicotine-containing liquid formulations for use with these devices have also increased, with thousands of different formulations now available. Despite this widespread use, the composition and chemical properties of the underlying nicotine-containing formulations are relatively simple. This is because, fundamentally, any liquid formulation, at least those intended for use with conventional wick-and-coil devices, must (1) be easily aerosolized, and (2) contain sufficient nicotine so that every aerosol produced by the device contains enough nicotine to deliver a hit when inhaled. More specifically, recent formulations typically contain the following: 1. Aerosolizable components or "excipients" that are permitted as pharmaceuticals, 2. Nicotine itself and / or any complex, derivative or inclusion complex thereof (for example, various salts of nicotine have recently become popular), or any other chemical component, complex, derivative or system that can release nicotine itself and / or any complex or inclusion complex thereof by being heated or otherwise excited. That is the case.

[0003] Furthermore, many modern formulations contain a low proportion of water, and often one or more flavoring agents, typically at relatively low concentrations relative to the overall composition of the formulation. Naturally, there is a vast variety of flavoring agents, but some of the commonly used flavoring compounds include safrole, ethyl vanillin, camphor, α-thujone, menthol, and coumarin.

[0004] Regarding (1) above, examples of suitable excipients already in use include glycerol, vegetable glycerin (VG), propylene glycol (PG), polyethylene glycol (PEG), trimethylene glycol (TMG), or any combination of two or more of these. One particularly commonly used excipient is any combination of PG and VG, for example, a combination of 10-90% PG and 90-10% VG, although formulations based on pure VG and pure PG are also known.

[0005] Regarding (2) above, the majority of current formulations simply contain very pure nicotine (e.g., less than 1% impurities) produced by synthesis or directly extracted from tobacco itself. Typical nicotine concentrations in most common formulations range from 2-4 mg / ml to 60 mg / ml, but local and national governments are increasingly imposing regulations on the maximum nicotine concentration levels that can be legally sold in the administrative districts under their jurisdiction. For example, the European Tobacco Products Directive (EUTPD) (2014 / 40 / EU), which came into widespread use across Europe in 2015 / 2016, essentially limits the capacity of e-cigarette refill tanks to 2 ml or less and the maximum capacity of a single refill container of nicotine-containing e-liquid (for retail) to 10 ml. Furthermore, this directive regulates the nicotine concentration of formulations (also widely known as "e-liquid," "vape juice," or simply "juice") to 20 mg / ml or less, and also requires that nicotine-containing products and their packaging in general be protected against tampering, particularly by children.

[0006] More recently, it has been proposed to create formulations containing one or more nicotine salts in place of the free base or pure nicotine (see, in particular, U.S. Patent No. 9,215,895 in the name of Juul Labs Inc.). In fact, in recent years (the last two to three years), formulations containing nicotine salts (also called "Nic salts") have become almost as widespread as the pure nicotine-containing formulations mentioned above. To elaborate further, manufacturers of tobacco and other conventional tobacco products (CTPs), widely known in the industry as "Big Tobacco," have long known not only that nicotine salts are already present in tobacco leaves, but also that certain nicotine salts can be usefully used as additives to improve the user experience of conventional tobacco (i.e., nicotine salts generally lower the pH of the smoke / vapor produced from a lit tobacco, effectively reducing the "throat irritation" felt by smokers when inhaling the smoke). (See, in particular, U.S. Patent No. 4830028, granted to RJ Reynolds Tobacco Company, with Thomas Perfetti, who first conducted research on nicotine salts at Reynolds Tobacco in 1978, as the inventor.)

[0007] According to the aforementioned U.S. patent granted to Juul Labs INC., ideally, nicotine salt formulations are manufactured relatively simply by adding pure nicotine, which is a base in chemical terms, to a suitable organic carboxylic acid or dicarboxylic acid, such as benzoic acid, in an appropriate ratio, to obtain a (liquid) formulation containing the nicotine salt (produced by reacting the acid with the nicotine base) and, together with some residual free nicotine base, at a desired concentration level. This formulation is then mixed with a suitable excipient, typically a PG-VG mixture, with a PG:VG weight ratio of 3:7, so that the resulting formulation has a nicotine concentration of 0.5-20% (w / w), ideally about 4% (w / w), of the final formulation. U.S. Patent No. 9,215,895 suggests that inhaling an aerosol produced from such a formulation increases the efficiency of nicotine transfer to the lungs (compared to conventional nicotine-containing formulations that do not contain nicotine salts), and consequently, a rapid increase in plasma nicotine absorption. In short, the presence of nicotine salts in a formulation appears to increase the palatability of the aerosol it produces when inhaled, while simultaneously shortening the time it takes for nicotine in the plasma to reach a certain concentration. As a result, the time it takes for the brain to receive the desired "impact" from the drug after the user first inhales is reduced. This is slightly more difficult to understand, but Juul's U.S. patent suggests that, as a possibility, using nicotine salts in a nicotine-containing form can increase the amount of nicotine in the formulation, thereby potentially leading to a mechanism where the drug is more potent, at least in terms of the amount of drug delivered to the user, compared to conventional formulations without nicotine salts, without significantly affecting the palatability.

[0008] As stated above, it is important to note in relation to the present invention that liquid formulations described in the past are only suitable for conventional wick / coil vaping devices (including cartridge-type devices called "pod mods" or simply "pods"). This is because these types of devices are designed to resemble conventional cigarette smoking as closely as possible as an overall experience by generating a large amount of bulky, visible aerosol with a relatively low nicotine concentration (approximately 0.1 mg or less per aerosol).

[0009] In contrast, the present invention relates to nicotine-containing formulations in which the nicotine concentration significantly exceeds even the highest nicotine-containing formulations currently available, and therefore these are completely unsuitable for most current devices, whether cartridge or tank type, and may even pose a risk. For example, even the strongest formulations currently available (which would be outside of Europe, given the widespread use of TPD) have a nicotine concentration of only 7.5% (w / w), whereas the present invention relates only to formulations with a nicotine content of at least 20% (w / w), and in most cases even exceeding that.

[0010] Those skilled in the art will naturally wonder why such high-nicotine formulations are appropriate or useful. Importantly, even though it is widely accepted that vaping poses far less harm to human health than smoking conventional tobacco products like cigarettes, significant health concerns surrounding vaping as a whole remain. The applicant's fundamental argument is that if some foreign substance must be inhaled, that foreign substance should be minimized as much as possible. Therefore, the applicant has designed a novel, somewhat innovative cartridge-type vaping device in which each cartridge is initially provided in sealed packaging, which is opened and the packaging removed before insertion into the device, and each cartridge is equivalent to a cigarette in terms of its usage profile within the device, the amount of formulation it contains, and consequently, the amount of nicotine present. In contrast, when most conventional tank-type devices are filled with conventional nicotine-containing formulations, the usage profile is roughly equivalent to, or in some cases significantly exceeding, that of a pack of 20 cigarettes.

[0011] Therefore, each cartridge of the applicant's device is precisely and accurately pre-dosed with only a relatively small amount (less than 3 mg) of potent nicotine-containing preparation, which typically originates from 1 to 4 tiny spheres (possibly 1 to 4 mm in diameter or smaller) that directly adhere to one or more surfaces of the cartridge or its internal substrate. Thus, by pre-dosing the cartridge with a suitable high-concentration nicotine-containing preparation so that the amount of aerosol generated during a single operation of the device is precisely controlled each time, and by appropriately designing the heating method of the device (by directly attaching the heating device to the substrate inside the cartridge), the applicant's device can be approved for use as a medical device by medical and clinical regulatory bodies (e.g., the UK's MHRA). This is because it is possible to deliver the drug accurately and repeatedly at the desired target dose, and there is virtually no possibility of the end user tampering with the device, thus eliminating any risk. Those skilled in the art will understand that medically approved devices can be prescribed by physicians for the treatment of nicotine addiction, at least in the UK and many European countries. Furthermore, those skilled in the art will understand that, because the nicotine concentration in the applicant's desired formulation is relatively high, the actual volume of nicotine-containing aerosol produced will inevitably be considerably smaller, possibly even by an order of magnitude, than that typically produced by any conventional vaping device using more conventional formulations with lower nicotine concentrations. For the reasons stated above, this is naturally very advantageous and, at least in terms of the potential health risks associated with inhaling foreign substances, it is a far more medically appealing proposal.

[0012] For reference, those skilled in the art should look to the applicant's own prior published patent applications, particularly International Publication Nos. 2019 / 137994, 2018 / 167166, 2019 / 141577, 2019 / 068780, and 2019 / 137982, which cover various aspects of the applicant's apparatus and cartridges adapted for use therein.

[0013] Despite the advantages of using formulations containing high concentrations of nicotine, the applicant has faced various difficulties, particularly with formulations containing more than 20% (w / w) nicotine. First and foremost, the most widespread problem is chemical stability. Nicotine itself is a volatile liquid, and at concentrations in the aerosolizable formulations to which the present invention relates, the loss of nicotine into the surrounding atmosphere through natural evaporation from the surface can become significant. Furthermore, this loss increases exponentially with concentration, so the higher the proportion of nicotine present in the formulation, the greater the likelihood of loss due to evaporation. Additionally, nicotine is somewhat chemically aggressive, and while the base substrate to which the formulation spheres adhere in the applicant's cartridges is typically glass or other inert ceramic, and would normally resist absorbing, impregnating, or otherwise chemically interacting with the nicotine present in the formulation, in many cases the base substrate is surrounded or partially contained in a plastic material, which together with the substrate constitutes the cartridge as a whole. The applicant has found that, at least when certain plastic materials are used, nicotine leaches from the formulation into the material, thereby not only damaging the material but also reducing the amount of the substance, and consequently lowering the nicotine concentration in the formulation. Those skilled in the art will understand that, in the case of high-precision drug delivery devices that are to be subjected to rigorous testing during the medical device approval process, this type of problem is clearly fatal to ensuring consistent operation of the device.

[0014] During its development, particularly in the development of the cartridge and the base substrate supporting the formulation spheres within it, as well as the formulation itself containing high concentrations of nicotine, the applicant encountered further difficulties regarding the degree to which the formulation tends to spread on the surface of the substrate, i.e., the wettability of the formulation on glass and other inert material substrates. More specifically, the applicant found that simply mixing nicotine at relatively high concentrations with any or a combination thereof of standard excipients produces a solution with relatively high surface and interfacial energies, such that when droplets or spheres come into contact with a glass or ceramic substrate, the droplets or spheres spread immediately and noticeably over a wide area of ​​the substrate surface. Considering that droplets or spheres of the formulation are directly applied only to discontinuous regions of the substrate where electrical resistance heating elements are attached, if the droplets or spheres of the formulation tend to move away from these regions and cross the boundaries of the regions, not only will the proportion of the formulation directly heated decrease, but the (reduced) amount of formulation will receive an amount of heat exceeding expectations, impairing the aerosolization characteristics of any individual heating element, and also reducing the amount of formulation placed on it. [Overview of the project] [Problems that the invention aims to solve]

[0015] Therefore, the main objective of the present invention is to significantly mitigate, if not completely eliminate, these drawbacks. [Means for solving the problem]

[0016] According to a first aspect of the present invention, an aerosolizable formulation, - Free base nicotine, 25-50% (w / w), - One or more combinations of organic mono- or dicarboxylic acids that are safe as pharmaceuticals and biologically, in a concentration of 25-40% (w / w), - One or more combinations of 20-20% (w / w) of liquid excipients that are safe as pharmaceuticals and biologically, - Water, 0-5% (w / w), A preparation comprising the same is provided.

[0017] Preferably, the one or more organic acids are selected from one of the following groups of acids, - an acid containing an aromatic group, - α-(alpha), β-(beta) or ω-(omega) form or any other form of hydroxycarboxylic acid, - a heterocyclic carboxylic acid, - an aromatic carboxylic acid, - a terpenoid acid, - a sugar acid, - pectic acid, - an amino acid, - an alicyclic acid, - an aliphatic carboxylic acid and - a ketocarboxylic acid.

[0018] Preferably, the one or more organic acids present in the preparation are one or more of those shown below (referred to as "List A" elsewhere in the present specification), 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, L-ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, maleic acid, L(-)-malic acid, malonic acid, DL-mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, L-(-)-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, L-(+)-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid.

[0019] Most preferably, the one or more acids selected are one of alpha-keto acids (2-oxo acids), beta-keto acids (3-oxo acids) and gamma-keto acids (4-oxo acids). Alpha-keto acids such as pyruvic acid have a keto group adjacent to the carboxylic acid. Beta-keto acids such as acetoacetic acid have a ketone group on the second carbon of the carboxylic acid. Gamma-keto acids such as levulinic acid have a ketone group on the third carbon of the carboxylic acid.

[0020] Most preferably, the formulation is - only one of lactic acid and benzoic acid, - only lactic acid, - a binary system of two organic acids, wherein one is lactic acid and the other is one of benzoic acid and salicylic acid, and - a binary system of two organic acids, wherein one is lactic acid and the other is selected from the above List A (excluding lactic acid), It includes one of the following.

[0021] When the formulation contains a two-component system of two organic acids, one of them is lactic acid, and the w / w ratio of these two acids is most preferably 1:1.

[0022] If the formulation contains a two-component system of two organic acids, one of which is lactic acid, the second acid is most preferably one of benzoic acid or salicylic acid.

[0023] Most preferably, the formulation contains only one acid, which is lactic acid.

[0024] Preferably, one or more excipients present in the formulation are selected from the following: Glycerol, vegetable glycerin (VG), propylene glycol (PG), polyethylene glycol (PEG), and trimethylene glycol (TMG).

[0025] Most preferably, the formulation contains only one excipient, which is most preferably glycerol.

[0026] In one preferred embodiment, the present invention is a nicotine-containing formulation, - Free base nicotine, 25% (w / w), - Benzoic acid, salicylic acid, one of the two, 25% (w / w), - Glycerol, 50%, The present invention provides a formulation containing the above.

[0027] In another preferred embodiment, the present invention is a nicotine-containing formulation, - Free base nicotine, 25% (w / w), - A lactic acid solution, wherein the solution consists of 12% (w / w) water and 88% lactic acid, a lactic acid solution of 16.2% (w / w), - Water, 1.8%, - Glycerol, 58% (w / w), The present invention provides a formulation containing the above.

[0028] In yet another preferred embodiment, the present invention relates to a nicotine-containing formulation, - Free base nicotine, 25% (w / w), - Lactic acid, 24.3% (w / w), - Water, 2.7% (w / w), - Glycerol, 48% (w / w), The present invention provides a formulation containing the above.

[0029] In yet another preferred embodiment, the present invention relates to a nicotine-containing formulation, - Free base nicotine, 25% (w / w), - Lactic acid, 13.5% (w / w), - Benzoic acid, salicylic acid, one of the two, 6% (w / w), - Water, 1.5% (w / w), - Glycerol, 54% (w / w), The present invention provides a formulation containing the above.

[0030] In yet another preferred embodiment, the present invention relates to a nicotine-containing formulation, - Free base nicotine, 25% (w / w), - Lactic acid, 13.5% (w / w), - Benzoic acid, salicylic acid, one of the two, 5% (w / w), - Water, 1.5% (w / w), - Glycerol, 55% (w / w), The present invention provides a formulation containing the above.

[0031] In yet another preferred embodiment, the present invention relates to a nicotine-containing formulation, - Free base nicotine, 34% (w / w), - A mixture of lactic acid and benzoic acid in a molar ratio of 1:1, 16% (w / w), - Glycerol, 50% (w / w), The present invention provides a formulation containing the above.

[0032] In yet another preferred embodiment, the present invention relates to a nicotine-containing formulation, - Free base nicotine, 46.5% (w / w), - Lactic acid, 31.5% (w / w), - Polyethylene glycol (PEG), 22% (w / w), The present invention provides a formulation containing the above.

[0033] In a further preferred embodiment, the present invention relates to a nicotine-containing formulation, - Free base nicotine, 45% (w / w), - Lactic acid, 32.4% (w / w), - Polyethylene glycol (PEG), 22.6% (w / w), The present invention provides a formulation containing the above.

[0034] These last two embodiments of the present invention are particularly useful because these formulations have such high viscosity at room temperature that they can be handled in a state closer to a solid than a liquid, and in fact, these formulations can satisfy the chemical definition of a solid at room temperature. Thus, such formulations can be applied to a base substrate very easily, repeatedly, in the correct position and in the correct volume, and furthermore, since the wettability of such formulations once placed on the substrate surface is negligible, the formulation does not spread substantially after being applied to the substrate surface.

[0035] According to a further aspect of the present invention, an aerosolizable formulation, - Free base nicotine, 26-40% (w / w), - One or more combinations of pharmaceutically and biologically acceptable organic mono- or dicarboxylic acids, in a concentration of 24-40% (w / w), - One or more combinations of 20-20% (w / w) of pharmaceutically and biocompatible liquid excipients, and optionally, - Water, 0-5% (w / w), The present invention provides a formulation containing the above.

[0036] According to a further aspect of the present invention, an aerosolizable formulation, - Free base nicotine, 25-55% (w / w), - One or more combinations of pharmaceutically and biologically acceptable organic mono- or dicarboxylic acids, in a concentration of 15-35% (w / w), - One or more combinations of pharmaceutically and bioacceptably approved liquid excipients, 60-10% (w / w), and optionally, - Water, 0-5% (w / w), The present invention provides a formulation containing the above.

[0037] To avoid misunderstanding, all preferred embodiments and dependent features of the first aspect of the present invention, as described in detail earlier, should be considered equally applicable to the second and any other aspects of the present invention, which, in some cases, are adjusted to increase the concentration of free base nicotine (in aspects of the present invention following the first aspect). Such preferred embodiments and dependent features are not repeated herein for the sake of brevity.

[0038] The applicant has found that all of the formulations specified above, in particular formulations comprising pure lactic acid, an aqueous solution thereof, or a mixture thereof with benzoic acid (also in pure form or an aqueous solution), exhibit superior chemical stability compared to the corresponding formulations of high concentrations of nicotine alone, as will become apparent from the following specific description, which has been advantageous.

[0039] Furthermore, the applicant has found that aerosols produced from the above-mentioned formulations using the applicant's device, with a relatively much lower volume and more precisely controlled, can be inhaled without significantly increasing irritation to the end user's mouth, throat (buccal cavity), and / or lungs. In fact, the sensations in the mouth, throat, and lungs are very similar, if not identical, to those experienced when inhaling a much larger volume of aerosol containing a significantly lower concentration of nicotine from a conventional wick / coil vaping device, both in terms of physical experience and drug delivery. In other words, even if the effective concentration of nicotine in the novel formulations, and especially in the aerosols produced therefrom, is significantly higher than previously proposed (at least 25%, and potentially higher than 50% after the decomposition of easily destabilized nicotine salts in the resulting aerosol), the presence of nicotine salts and / or organic acids allows the inhaled aerosol to maintain its palatability (also referred to as "tolerability").

[0040] It is worth noting that prior art formulations, which have significantly lower nicotine concentrations than the formulations of the present invention, and yet (in some cases) slightly higher concentrations than more standard, widely available nicotine-only e-liquids or vape juices, also contain both nicotine and one or more salts of nicotine, similar to the present invention. However, this concentration in the prior art is a relative "equivalent" or "effective" nicotine concentration, which is the actual concentration of nicotine present in the resulting aerosol, and this is significantly lower compared to the present invention.

[0041] To elaborate further, it is widely assumed, and indeed widely accepted, that when a nicotine salt present in a formulation is aerosolized at room temperature or slightly below, it decomposes, if not completely, substantially into a precursor acid and free base nicotine (the initial salt being produced by the reaction of these together). Therefore, when any nicotine salt-based formulation is heated, preferably above 100°C, more preferably above 130°C, and even more preferably between 150 and 180°C, most of the salt has already decomposed, and in that case, it is the precursor acid that formed the salt that contributes to the palatability / acceptability of the inhaled aerosol. Furthermore, as a result of the decomposition of the salt, the concentration of free base nicotine present in the inhaled aerosol increases, but those skilled in the art will understand from what has been said above that it is this particular "effective" or "equivalent" concentration that is mentioned in much of the prior art and used to define a particular formulation. Therefore, interpreting the prior art from the above perspective, the resulting "equivalent," "effective" nicotine concentration, or the concentration of nicotine carried by the resulting aerosol, would be in the range of 1-20% (w / w), most commonly between 4-6% (w / w). However, the present invention is clearly distinguished from the prior art because it provides a formulation in which the effective nicotine concentration level in the generated aerosol is much higher, in some cases at least 40%, in most cases 50%, and in some cases even exceeding 50%. Thus, by simply heating and then aerosolizing the formulation of the present invention, the concentration of free base nicotine is effectively doubled compared to the formulation at room temperature.

[0042] There is one more point regarding the chemical properties that those skilled in the art should be aware of. As with many reactions, the reaction of nicotine with most organic acids that are pharmaceutically acceptable in the class described herein and in the prior art does not complete, but rather equilibrates. Therefore, with increasing temperature, the equilibrium shifts to the (free base nicotine + acid) side of the reaction, whereas at room temperature (at least for a mixing ratio of 1:1 mole acid:nicotine), the nicotine salt compound side is far more dominant, and the amount of free base nicotine present is relatively very small. The relative concentrations of nicotine and acid (or salt) present in any formulation must also be carefully considered in light of this fact, along with the temperature.

[0043] Even more surprisingly, an unexpected advantage of the formulation of the present invention is the specific surface energy and interfacial energy (typically mJ / m) of the formulation itself. 2 The effective surface energy of the formulation (also typically in mJ / m²) is related to both of the units. 2 This relates to the unit of surface energy, which is an indicator of the relative surface energy between the formulation itself and the specific substrate on which the formulation is attached and supported. Surface and interfacial energy are, in short, direct indicators of the degree to which a liquid "wets" the surface of the substrate, that is, the degree to which it tends to spread on the surface, and those skilled in the art will understand that this is an important consideration with respect to the applicant's apparatus.

[0044] To elaborate further, while many of the most common substrate materials, such as glass and other similar silicates, the most common ceramics, soda-lime glass and similar materials, can be considered to have roughly equivalent specific surface energies within the relevant range, the applicant has found, advantageously and surprisingly, that adding an organic acid to the formulation, and consequently containing one or more nicotine salts by partially or substantially reacting this acid with free base nicotine, has a dramatic effect on the overall surface energy of the formulation. This effect has shown that this type of high-concentration nicotine / nicotine salt formulation, particularly those containing glycerol or polyethylene glycol as pharmaceutically and biologically acceptable excipients, does not tend to spread or "wet" the substrate beneath it as much as similar nicotine-only formulations. In fact, the reduced wetting effect of the novel formulations is so pronounced that even when the formulation is heated toward the aerosolization temperature, there is almost no spreading or wetting on the substrate, and even after repeated aerosolization, the spheres of the formulation remaining on a suitable substrate appear to remain completely stationary since their initial application. This is particularly advantageous considering that the applicant's device utilizes a cartridge substantially containing a substantially planar glass substrate, to which (a) a planar resistance heating element is used, and (b) subsequently, one or more spheres of a precise amount of the formulation adhere over, above, and onto the area of ​​the substrate where the resistance heating element is provided. Those skilled in the art will readily understand the advantage of significantly reducing the tendency of the formulation to spread on the substrate at the time of adhesion and thereafter. This is because, at that point, the novel formulation, if not completely stationary, largely remains in place directly above and above the resistance heating element that aerosolizes the spheres of formulation by conductively supplying heat to them. As a result, the accuracy of aerosolization, and consequently both the volume of the aerosol produced and the concentration of nicotine contained therein, can be controlled with much greater precision.

[0045] It should also be noted that cohesiveness (i.e., the opposite of "wetting," the tendency for the formulation to remain in place on the substrate) can be further improved by either selecting a substrate with lower surface energy or coating the substrate with a suitable (chemically inert) coating composition, thereby lowering the surface energy of the substrate. Parylene, a known coating composition, has been found to be particularly effective in this regard.

[0046] Herein, specific embodiments of the present invention will be described by reference to examples and the accompanying drawings. [Brief explanation of the drawing]

[0047] [Figure 1A] Figure 1A (prior art) shows a perspective view of a substrate, on which a resistance heating element is attached to one side, and later, small spheres of the formulation are attached to it. [Figure 1B] Figure 1B (prior art) shows a side view of the substrate, on which a resistance heating element is attached to one side, and later, small spheres of the formulation are attached to it. [Figure 1C] Figure 1C (prior art) shows an end view of a substrate, on which a resistance heating element is attached to one side, and later, small spheres of the formulation are attached to it. [Figure 2] This graph shows the difference in stability over a 6-month period between two different nicotine-containing preparations, one prepared by four different individuals A, B, C, and D, one containing only 5% (w / w) benzoic acid and the other containing 25% (w / w) benzoic acid. [Figure 3] Similar to Figure 2, this shows the relative stability of formulations containing different concentrations of lactic acid (not benzoic acid) over a similar 6-month period. [Modes for carrying out the invention]

[0048] To aid in understanding the present invention, particularly regarding its specific surface energy / wetting advantages, those skilled in the art should first look to Figures 1A, 1B, and 1C. These show a prism comprising a rectangular substrate 102 of a substantially chemically inert material, such as silicate glass, lime glass, soda glass, or borosilicate glass, represented as 100 overall. Of course, other similar chemically inert materials, such as ceramics, can also be considered. Ideally, the substrate material is also physically inert, with relatively low thermal conductivity, expansion coefficient, emissivity, and diffusivity properties, most glasses adequately meet this requirement. To provide some conceptual ideas regarding the dimensions required for the prism, dimensions a, b, and c are shown, ideally a and b being approximately 5–50 mm, while the thickness dimension c is considerably smaller, for example, approximately 0.5–5 mm. The substrate 102 has an upper surface 104 and a lower surface 106, and a conductor, collectively denoted as 108, is attached to the upper surface 104. This conductor comprises two separate, isolated parts, namely terminal portions 110A, 110B, and 110C, and resistive elements 112A and 112B. The conductor as a whole is curved but follows a substantially uniform pattern (in the sense that the lengths of the conductors within the pattern are approximately equal) similar to a known square wave. In the illustrated embodiment, the excitation device comprises only two resistive elements 112A and 112B that are adjacent to each other and spaced apart from the terminal portions toward the edges of the substrate, but of course, it is easy to have more than that.

[0049] Important to the extent relevant to the present invention is that a suitable amount of the formulation adheres to, directly above, and above each of the resistive elements 112A and 112B. As can be seen from the figures, each resistive element is covered at least partially, preferably substantially, with the respective spheres 114A and 114B of the formulation, and therefore they can subsequently be aerosolized when a voltage is applied to the element below them. In Figures 1B and 1C, the spheres 114A and 114B are more clearly visible, and it should be noted that in these figures, the spheres of the formulation maintain sufficient cohesion when in contact with the substrate surface, regardless of whether the substrate is coated, and therefore have sufficient surface energy to maintain their spherical shape on the substrate. Also from these figures, it should be noted that the spheres 114A and 114B are completely separated from each other, so that the excitation elements substantially covered with the spheres are suitable for independent control. Those skilled in the art will understand that the tendency for the formulation to "wet" the substrate in an uncontrollable manner as a whole, i.e., to spread across its surface, occurs in many, if not all, formulations containing only nicotine, and that in such a situation, the formulation is most unfavorable because it moves away from the area to which the resistive element is attached and intended to provide its heating effect, and eventually moves outside of it. Needless to say, all of the amount of formulation that moves away from the location of the resistive element will subsequently not be heated at all or only slightly, so the amount of aerosolization is unlikely to be achieved, and these amounts are essentially "losses." If those skilled in the art understand that the total amount of formulation adhering is already very small, any such "loss" inevitably represents a reduction in the amount of nicotine that can be delivered to the user, and therefore such a loss must be considered unacceptable for a device adapted to deliver a precisely measured single dose of nicotine.

[0050] While this invention should not be considered defined in relation to a type of vaping device intended for use with the formulation of the present invention, those skilled in the art should still understand that the formulation is specifically adapted for use only with a particular type of “cartridge-type” vaping device into which the substrates shown in Figures 1A–1C are ultimately inserted. As the name suggests, this type of device is adapted to accommodate a replaceable cartridge, either inserted into or otherwise connected to the device, from the time the device is first used, or after the cartridge that was inside the device has been used up and removed for disposal or reuse. There are already many cartridge-type vaping devices, sometimes referred to as “pod mods,” but those skilled in the art will recognize that what they all have in common is that the “pod” or cartridge they contain is essentially a tank of a certain amount (usually about 0.5–2 ml) of nicotine-containing formulation. Most modern cartridge-type devices are "closed" systems, not intended or configured for user refilling of cartridges or pods; however, some larger "pod mod" devices certainly accommodate removable cartridges that can be manually refilled. Those skilled in the art will understand that this type of device is essentially no different from the more common conventional "tank-type" devices, which include a manually refillable tank component (with a slightly larger volumetric capacity, e.g., 1-5 ml) to which the user can refill any (but usually) flavored or other nicotine-containing liquid formulation as needed. Typically, as the device is used, whatever formulation it contains will gradually evaporate depending on the frequency of use, and refilling will be performed when the tank is empty or nearly empty. This may be done daily for a heavy smoker, or weekly for someone who smokes lightly, irregularly, or otherwise socially.

[0051] The important distinction to be made herein is that tank-type and refillable cartridge-type devices offer virtually no control over the formulation used within them, and therefore the amount of nicotine ultimately delivered to the user, whereas closed-system cartridge-type devices, such as those developed by the applicant, offer a much greater degree of control. Essentially, this is because each cartridge is precisely and precisely pre-filled with a specific formulation containing the desired concentration of nicotine (and a suitable acid), and the cartridges themselves are specifically designed and therefore suitable for use only with vaping devices designed to correspond to them, thus allowing for much more careful control over the delivery of nicotine, whatever its concentration in the formulation may be.

[0052] Considering the present invention itself and formulations containing nicotine and nicotine salts (produced by the reaction of nicotine, a weak base, with an acid), the applicant has tested various formulations and found that at least nicotine itself and pharmaceutically / biologically acceptable glycerol, etc. (or any other such composition or mixture thereof as described above) and one or more of the following: - Pure lactic acid or an aqueous solution thereof, - A two-component system of lactic acid and benzoic acid, either in their pure form or in a suitable aqueous solution, and - We found that formulations containing a two-component system of lactic acid and salicylic acid, either in their pure forms or in suitable aqueous solutions, are the most useful in terms of chemical stability.

[0053] The specific stability tests conducted by the applicant are described and summarized in detail below. [Examples]

[0054] Stability test (benzoic acid) The primary objective of this study was to evaluate the stabilizing effect of benzoic acid when added to nicotine preparations that also contain glycerol. The secondary objective of this study was to investigate the daily and inter-analyst accuracy of the production and analysis of two preparations containing different concentrations of benzoic acid (5% and 25% (w / w), see below). Both of these preparations have already been shown to have good chemical stability data after 8 weeks of storage. In this study, two batches of the two preparations, one containing 5% (w / w) benzoic acid and the other containing 25% (w / w) benzoic acid, were prepared by four individuals (hereinafter, as referred to in Figure 2 of this document, simply A5 or A5). 25 , B5 or B 25 , C5 or C 25 and D5 or D 25 This involved manufacturing the product over two different days (with appropriate anonymization). Therefore, a total of eight batches of the formulation were manufactured.

[0055] To ensure that the manufactured formulations contained the correct amount of nicotine, in-process checks (IPCs) were performed at various stages using high-pressure liquid chromatography (HPLC). For this test, a single "dose" was considered to be the volume of one 0.5 mg nicotine-containing formulation sphere attached to the test substrate. In this case, the amount of formulation used on each test substrate (or per inhalation cartridge) would be greater for lower concentration nicotine formulations (see formulations specified below).

[0056] Overview of the formulation Formulations for 50g batch sizes were manufactured according to the table below. [Table 1] Table 1 - Overview of the formulation

[0057] result [Table 2] Table 2: Tabular summary of stability test data for formulations containing benzoic acid at only 5% (w / w) and formulations containing 25% (w / w) benzoic acid

[0058] Figure 2 of the present document presents the above data in a useful graphical form, from which it can be seen that the formulations containing 25% (w / w) benzoic acid individually prepared by four persons (specifically, the lines in the graph referred to as A 25 , B 25 , C 25 , D 25 ) are all, in terms of chemical stability, immediately seen to be far superior to formulations containing only 5% (w / w) benzoic acid (specifically, the lines in the graph referred to as A5, B5, C5, D5). In fact, even after 6 months, the 25% (w / w) benzoic acid formulations had substantially no nicotine loss, and all of them still retained nicotine at a level exceeding 98% compared to the concentration of the initial formulation.

[0059] Conclusions of Stability Tests Data obtained from the stability tests clearly show that the benzoic acid-containing formulation (25% (w / w) benzoic acid) is stable up to 6 months, and no significant change in nicotine recovery was observed. With respect to the data obtained for the stability test of formulations containing only 5% benzoic acid, the average nicotine loss per month is 3.2%, indicating that stability was not achieved.

[0060] Stability Tests (Lactic Acid) The Applicant conducted generally similar stability tests on formulations containing lactic acid. Details of the various formulations tested are shown in the table below.

[0061] Summary of Formulations

Table 3

[0062] The stability test data, derived using approximately the same method as the stability test for benzoic acid, was plotted in the graph shown in Figure 3 of this document, clearly identifying the data for each of the formulations described above. From this graph, it can be seen that three of the six different formulations described above showed significant improvement in stability over approximately 5-6 months, and these are "Group 1," "Group 3" (the most preferred of all formulations), and "Control." In particular, "Group 3" is considered the most useful due to its intrinsic viscosity and low wettability.

[0063] Therefore, the applicant has experimentally confirmed that, as defined by the present invention, a useful and advantageous formulation can be produced if the relative concentration of the acid (or a two-component acid) is at least about 15% (w / w), preferably at least about 20%, and more preferably at least about 25% (w / w) overall, while at the same time maintaining a high nicotine concentration of at least about 25% (w / w), more than about 30% (w / w) in the most preferred embodiment, about 40-50% (w / w) in a further preferred embodiment, and about 55-60% in some embodiments.

[0064] In this specification, the applicant has conducted important tests on formulations containing benzoic acid alone, and it should be noted that there are some minor concerns that benzoic acid in inhalable aerosols may raise certain toxicological concerns, particularly in terms of specific target organ toxicity (STOT) and irritation. Therefore, it is highly preferable to use lactic acid alone in place of benzoic acid in the formulation, or to use a two-component system in which one component is lactic acid and the other is an acid other than benzoic acid selected from the list above (ideally salicylic acid).

[0065] Based on the applicant's detailed research, the most preferred formulation is, specifically, - Free base nicotine, approximately 45-46% (w / w), - Lactic acid, approximately 31-33% (w / w), - Polyethylene glycol (PEG) as an excipient, specifically high molecular weight PEG compounds such as PEG 3000, at approximately 24-21% (w / w), It was found to contain [something].

[0066] Those skilled in the art will understand that in the formulations described above (and others) that fall within the scope of this specification, the excipients used in the formulations may be any one or any combination of the various excipients disclosed and described herein. Therefore, for example, in the most preferred formulation described above, the excipients may be changed to glycerol, glycerin, or other glycols or any combination thereof.

[0067] Specifically, the formulation referred to as "Group 3" above and in Figure 3 is the applicant's most preferred formulation at present.

[0068] In light of the foregoing, particularly where the term “approximately” is used in the foregoing and elsewhere in this specification, a person skilled in the art should understand that the applicant does not intend any degree of strictness or precision in the percentage values ​​following the term “approximately” to such an extent that any percentage value higher or lower than that number, or any percentage value outside the range limited by the term, would be considered outside the scope of this specification. Rather, a person skilled in the art should understand that the term “approximately” approximates the number or range in question to approximately 1% to 2% of the number immediately following, and thus limited by, the term “approximately.”

Claims

1. A formulation that can be aerosolized, Free base nicotine, approximately 25-55% (w / w), Lactic acid, or a combination of lactic acid and one or more pharmaceutically and biologically acceptable organic mono- or dicarboxylic acids, in an amount of approximately 15-35% (w / w), One or more combinations of pharmaceutically and biologically acceptable liquid excipients, in an amount of approximately 60-10% (w / w), and optionally, A formulation that can be aerosolized, containing approximately 0-5% (w / w) water.

2. The aerosolizable formulation comprises lactic acid and one or more combinations of pharmaceutically and biologically acceptable organic mono- or dicarboxylic acids, comprising about 15-35% (w / w), wherein the organic carboxylic acid is from the group of acids listed below. Acids containing aromatic groups, Hydroxycarboxylic acid, Heterocyclic carboxylic acid, Aromatic carboxylic acids, Terpenoid acids, sugar acid, pectin acid, amino acid, Alicyclic acids, Aliphatic carboxylic acids and Ketocarboxylic acid, An aerosolizable formulation according to claim 1, selected from one of the following.

3. The aerosolizable formulation comprises lactic acid and one or more combinations of pharmaceutically and biologically acceptable organic mono- or dicarboxylic acids, comprising about 15-35% (w / w), wherein the organic carboxylic acid is 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, L-ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-disulfonic acid, ethane An aerosolizable formulation according to claim 1, wherein one or more of the following are present: glyconic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, maleic acid, L(-)-malic acid, malonic acid, DL-mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, L-(-)-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, L-(+)-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, and undecylenic acid.

4. The aerosolizable formulation according to claim 1, wherein the aerosolizable formulation comprises lactic acid and one or more combinations of pharmaceutically and biologically acceptable organic mono- or dicarboxylic acids in about 15 to 35% (w / w), the organic carboxylic acid being any of alpha-keto acid (2-oxo acid), beta-keto acid (3-oxo acid), and gamma-keto acid (4-oxo acid).

5. The aerosolizable formulation according to claim 1, wherein the aerosolizable formulation comprises a two-component system of two organic acids, one of which is lactic acid and the other is one of benzoic acid and salicylic acid.

6. The aerosolizable formulation according to claim 5, wherein the molar ratio of the two organic acids is approximately 1:1, and the total percentage (w / w) of all acids in the formulation is at least approximately 25% (w / w).

7. The aerosolizable formulation according to claim 1, wherein the one or more excipients present in the formulation are selected from glycerol, vegetable glycerin (VG), propylene glycol (PG), polyethylene glycol (PEG), and trimethylene glycol (TMG) as shown below.

8. The aerosolizable formulation according to claim 1, comprising only a single excipient component, which is one of glycerol and polyethylene glycol.

9. Free base nicotine, approximately 25% (w / w), Lactic acid, approximately 24.3% (w / w), Water, approximately 2.7% (w / w), Glycerol, approximately 48% (w / w), A formulation that can be aerosolized, including the above.

10. Free base nicotine, approximately 34% (w / w), A mixture of lactic acid and benzoic acid in a molar ratio of 1:1, approximately 16% (w / w), Glycerol, approximately 50% (w / w), An aerosolizable formulation according to claim 1, comprising:

11. Free base nicotine, approximately 45-46% (w / w), Lactic acid, approximately 31-33% (w / w), Polyethylene glycol, approximately 24-21% (w / w), An aerosolizable formulation according to claim 1, comprising:

12. The aerosolizable formulation according to claim 11, wherein the polyethylene glycol is a high molecular weight polyethylene glycol compound with a molecular weight of 3000.

13. Free base nicotine, approximately 25-50% (w / w), Lactic acid, or a combination of lactic acid and one or more pharmaceutically and biologically acceptable organic mono- or dicarboxylic acids, in an amount of approximately 25-40% (w / w), One or more combinations of pharmaceutically and biologically acceptable liquid excipients, in an amount of approximately 50-20% (w / w), and optionally, A formulation that can be aerosolized, containing approximately 0-5% (w / w) water.

14. Free base nicotine, approximately 25% (w / w), A lactic acid solution, wherein the solution consists of water, about 12% (w / w) and lactic acid, about 88%, and a lactic acid solution of about 16.2% (w / w), Water, approximately 1.8% (w / w), Glycerol, approximately 58% (w / w), Aerosolizable formulation containing the above.

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