Aerosolizable nicotine-containing formulations

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 broadly to a variety of different nicotine-containing formulations suitable for use with certain types of electronic cigarettes or similar aerosolization or vaporization electrical devices, hereinafter referred to as "vaping" devices. More particularly, the present invention relates to a variety of nicotine-containing formulations capable of providing significantly higher concentrations of nicotine compared to the wide range of nicotine-containing formulations currently available, and suitable for use with conventional vaping devices, of which there is also a wide variety. [Background technology]

[0002] Nicotine-containing formulations for use with reservoir-based vaping devices are already widely available. Indeed, in recent years, as the popularity of vaping devices of all kinds has soared, so has the availability and variety of nicotine-containing liquid formulations for use with those devices, which now number in the thousands. Despite this popularity, the composition and chemistry of the underlying nicotine-containing formulations are relatively simple. This is because, essentially, any liquid formulation, at least those intended for use with traditional "wick-and-coil" devices, must (1) be easily aerosolized, and (2) contain a sufficient amount of nicotine so that every single aerosol generated by the device contains enough nicotine to deliver a hit when inhaled by the user. To elaborate further on the components of modern formulations, liquid formulations will generally contain: 1. A medicamentously acceptable aerosolizable component or "excipient"; 2. Nicotine itself and / or any complex, derivative or clathrate thereof (e.g., various salts of nicotine have recently become popular) or any other chemical moiety, complex, derivative or system that can be heated or otherwise excited to release nicotine itself and / or any complex or clathrate thereof; It is.

[0003] Furthermore, many modern formulations also contain a small proportion of water and often will contain one or more flavoring agents, typically at similarly relatively low concentrations relative to the overall composition of the formulation. Of course, there is a huge variety of different flavoring agents, but a few of the more commonly used flavoring compounds include safrole, ethyl vanillin, camphor, alpha-thujone, menthol, and coumarin.

[0004] With regard to (1) above, examples of suitable excipients that have already been used include glycerol, vegetable glycerin (VG), propylene glycol (PG), polyethylene glycol (PEG), trimethylene glycol (TMG), or a combination of any two or more of these. One particularly commonly used excipient is some combination of PG and VG, for example 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 (e.g., less than 1% contaminants) nicotine itself, either synthetically produced or extracted directly from whole tobacco. Typical nicotine concentrations in most popular formulations range anywhere from 2-4 mg / ml to 60 mg / ml of the formulation, although local and national governments are increasingly imposing restrictions on the maximum nicotine concentration levels that can be legally sold in their jurisdictions. For example, the European Tobacco Products Directive (EUTPD) (2014 / 40 / EU), which came into widespread effect across Europe in 2015 / 2016, essentially limits the capacity of e-cigarette refill tanks to 2 ml or less, and limits the maximum capacity of any single refill container of nicotine-containing e-liquid (for retail use) to 10 ml. The Directive further restricts the nicotine concentration in preparations (also commonly known as "e-liquid" or "vape juice" or simply "juice") to 20 mg / ml and also requires that nicotine-containing products and their packaging in general be tamper-resistant, and in particular child-resistant.

[0006] More recently, it has been proposed to create formulations that contain one or more nicotine salts in place of the free base or pure nicotine (see, inter alia, U.S. Patent No. 9,215,895 in the name of Juul Labs Inc.). Indeed, in recent years (the past few years), formulations containing nicotine salts (also referred to as "Nic salts") have become almost as popular as the pure nicotine-containing formulations described above. To further explain, manufacturers of cigarettes and other conventional tobacco products (CTPs), commonly 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 make conventional cigarettes more palatable to the user (i.e., nicotine salts generally lower the pH of the smoke / vapor generated from a lit cigarette, effectively reducing the "throat hit" experienced by smokers when inhaling smoke). (See especially U.S. Patent No. 4,830,028 issued to RJ Reynolds Tobacco Company and named inventor Thomas Perfetti, who first worked on nicotine salts at Reynolds Tobacco in 1978.)

[0007] According to the above-mentioned US patent granted to Juul Labs INC., ideally, nicotine salt formulations are relatively simply prepared, for example, by adding pure nicotine, which is a base in chemical terms, to a suitable organic carboxylic or dicarboxylic acid, such as benzoic acid, in an appropriate ratio to obtain a (liquid) formulation containing nicotine salt (produced by reacting the acid with the nicotine base) together with some remaining nicotine free base at the desired concentration level. This formulation is then mixed with a suitable excipient, typically a PG-VG mixture, with a weight ratio of PG:VG of 3:7, so that the nicotine concentration in the resulting formulation is 0.5-20% (w / w) of the final formulation, ideally about 4% (w / w). In the specification of US Patent No. 9,215,895, it is suggested that inhalation of an aerosol produced from such a formulation results in a more efficient transfer of nicotine to the lungs (compared to conventional nicotine-containing formulations without nicotine salt), which in turn results in a rapid increase in nicotine absorption in plasma. Thus, in the simplest terms, the presence of nicotine salts in a formulation appears to increase the palatability of the aerosol produced therefrom when inhaled, while at the same time reducing the time it takes for a particular concentration of nicotine in the plasma to be reached, thereby reducing the time it takes for the user to receive the desired opioid "hit" from the time of the first inhale. This is a little more subtle, but Juul's U.S. patent teaches that one mechanism by which the use of nicotine salts in nicotine-containing forms could potentially increase the amount of nicotine contained in the formulation, thereby making it more potent, in terms of the amount of drug delivered to the user, without significantly affecting palatability, at least when compared to conventional formulations that do not contain nicotine salts.

[0008] In view of the above, it is important to note in the context of the present invention that the liquid formulations previously described are only suitable for use in traditional wick / coil vaping devices (including cartridge-based devices also known as "pod mods" or simply "pods"), because such devices are generally designed to resemble traditional cigarette smoking as closely as possible by producing large amounts of bulky, visible aerosols with relatively low nicotine concentrations (approximately 0.1 mg or less in each aerosol).

[0009] In contrast, the present invention relates to nicotine-containing formulations whose nicotine concentration is significantly higher than even the highest nicotine-containing formulations currently available, and which therefore make them completely unsuitable and even potentially dangerous for most current devices, be they cartridge or tank-based: for example, even the strongest formulations currently available (outside Europe, given the widespread adoption of TPDs) only have a nicotine concentration of 7.5% (w / w), whereas the present invention relates only to formulations whose nicotine content is at least 20% (w / w), and in most cases even exceeds this.

[0010] Those skilled in the art will naturally ask why such high nicotine formulations are appropriate or useful at all, but the point is that even though vaping is widely accepted to be much less harmful to human health than smoking traditional tobacco products such as cigarettes, there are still significant health concerns surrounding vaping as a whole. The applicant's basic proposition is that if any foreign matter must be inhaled, it should be inhaled as little as possible. The applicant has therefore designed a new and somewhat innovative cartridge-based vaping device, where each cartridge is initially provided in a sealed package that is opened and the package removed before insertion into the device, and where each cartridge is equivalent to a single cigarette in terms of its usage profile within the device and the amount of formulation contained therein, and thus the amount of nicotine present therein. In contrast, when most conventional tank-based devices are filled with conventional nicotine-containing formulations, the usage profile is roughly equivalent to, and in some cases significantly greater than, a pack of 20 cigarettes.

[0011] Thus, each cartridge of the Applicant's device is accurately and precisely pre-dosed with only a relatively small amount (3 mg or less) of a high-strength nicotine-containing formulation, typically originating from 1-4 tiny (potentially 1-4 mm diameter or smaller) globules that are deposited directly on one or other surface of the cartridge or the substrate therein. Thus, by pre-loading the cartridge in this way with a suitable high-concentration nicotine-containing formulation so that the amount of aerosol generated during each actuation of the device is precisely controlled every time, and by appropriately designing the heating mode of the device (applying a heating device directly to a substrate within the cartridge), the Applicant's device can also be approved for use as a medical device by medical and clinical regulatory bodies (e.g. the MHRA in the UK), because it is possible to accurately and repeatedly deliver the desired target dose of drug, and because there is virtually no possibility of the end user tampering with the device, and therefore no risk is ever created. Those skilled in the art will appreciate that medically approved devices can be prescribed by physicians, at least in the UK and many European countries, for the treatment of nicotine addiction conditions. Those skilled in the art will further appreciate that due to the relatively high nicotine concentration in the applicant's desired formulation, the actual volume of nicotine-containing aerosol produced will necessarily be significantly smaller, and may even be an order of magnitude or more smaller, than that normally produced by any conventional vaping device utilizing a more conventional, lower nicotine concentration formulation. For the reasons set out above, this is of course highly advantageous and represents a much more medically attractive proposition, at least in view of the potential health hazards resulting from inhaling a foreign object.

[0012] For reference, those skilled in the art are directed to the Applicant's own prior published patent applications, in particular WO 2019 / 137994, WO 2018 / 167166, WO 2019 / 141577, WO 2019 / 068780 and WO 2019 / 137982, which cover various aspects of the Applicant's device and cartridges adapted for use therein.

[0013] Despite the advantages of using formulations containing high concentrations of nicotine, the applicant has encountered various difficulties, especially with respect to formulations containing more than 20% (w / w) nicotine. The first and most widespread problem is that of chemical stability. Nicotine itself is a volatile liquid, and at the concentrations in the aerosolizable formulations to which the present invention relates, there can be a significant loss of nicotine into the surrounding atmosphere through natural evaporation from the surface, and furthermore, this loss increases exponentially with the concentration, so that the higher the proportion of nicotine present in the formulation, the greater the likelihood of loss by evaporation. Furthermore, nicotine is somewhat chemically aggressive, and although the base substrate to which the globules of the formulation adhere in the applicant's cartridge is usually glass or other inert ceramic, it will usually 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. Applicant has found that at least certain plastic materials can cause nicotine to leach from the formulation into the material, thereby not only damaging the material but also reducing the amount of material and therefore the nicotine concentration in the formulation. Those skilled in the art will appreciate that for high precision drug delivery devices that are destined to be subjected to rigorous testing during the medical device approval process, problems of this nature are clearly fatal to the consistent operation of the device.

[0014] A further difficulty encountered by the applicant during its development, particularly during the development of the cartridge and the base substrate therein which supports the globules of the formulation, as well as the development of the formulations themselves containing high concentrations of nicotine, is the degree to which the formulations tend to spread over the surface of the substrate, i.e., the wettability of the formulations on glass and other inert material substrates. More specifically, the applicant has found that simply mixing nicotine at relatively high concentrations with any of the standard excipients or combinations thereof produces a solution with relatively high both surface and interfacial energies such that when the droplets or globules come into contact with a glass or ceramic substrate, they immediately and significantly spread over a wide area over the substrate surface. Given that the droplets or globules of formulation are applied directly only to the discrete areas of the substrate where the electrical resistive heating elements are applied, if the droplets or globules of formulation had a tendency to leave these areas and cross the boundaries of the areas, not only would the proportion of formulation that was directly heated be reduced, but the (reduced) amount of formulation would accordingly be subjected to a greater than expected amount of heat, compromising the aerosolization properties of any individual heating element and reducing the amount of formulation that can be carried thereon. Summary of the Invention [Problem to be solved by the invention]

[0015] It is therefore a primary object of the present invention to substantially mitigate, if not completely remedy, these drawbacks. [Means for solving the problem]

[0016] According to a first aspect of the invention, there is provided an aerosolizable formulation comprising: - free base nicotine, 25-50% (w / w); - one or a combination of two or more medicamentously and biologically safe organic mono- or dicarboxylic acids, 25-40% (w / w); - one or a combination of any two or more of the following medicamentously and biologically safe liquid excipients, from 50 to 20% (w / w); and, optionally, - water, 0-5% (w / w); The present invention provides a formulation comprising:

[0017] Preferably, the one or more organic acids are selected from one of the groups of acids shown below: - acids containing aromatic groups, - hydroxycarboxylic acids in their α- (alpha), β- (beta) or ω- (omega) forms or in any other form, heterocyclic carboxylic acids, aromatic carboxylic acids, - terpenoid acids, - sugar acid, - pectic acid, - amino acids, - alicyclic acids, - aliphatic carboxylic acids and - Keto carboxylic acids.

[0018] Preferably, the one or more organic acids present in the formulation are one or more of the following (referred to elsewhere in this specification as "List A"): 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 comprises: - only one of lactic acid and benzoic acid, - Lactic acid only, - binary systems of two organic acids, one of which is lactic acid and the other of which is either benzoic or salicylic acid, - binary systems of two organic acids, one of which is lactic acid and the other of which is selected from list A above (excluding lactic acid); Contains one of the following:

[0021] When the formulation comprises a binary system of two organic acids, one of which is lactic acid, the w / w ratio of the two acids is most preferably 1:1.

[0022] When the formulation comprises a binary system of two organic acids, one of which is lactic acid, the second acid is most preferably one of benzoic acid, salicylic acid.

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

[0024] Preferably, 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).

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

[0026] In one preferred embodiment, the present invention provides a nicotine-containing formulation comprising: - nicotine free base, 25% (w / w); - one of benzoic acid, salicylic acid, 25% (w / w); - glycerol, 50%; The present invention provides a formulation comprising:

[0027] In another preferred embodiment, the present invention provides a nicotine-containing formulation comprising: - nicotine free base, 25% (w / w); a lactic acid solution, 16.2% (w / w), which solution consists of 12% (w / w) water and 88% lactic acid; - Water, 1.8%; glycerol, 58% (w / w); The present invention provides a formulation comprising:

[0028] In yet another preferred embodiment, the present invention provides a nicotine-containing formulation comprising: - nicotine free base, 25% (w / w); Lactic acid, 24.3% (w / w); water, 2.7% (w / w); glycerol, 48% (w / w); The present invention provides a formulation comprising:

[0029] In yet another preferred embodiment, the present invention provides a nicotine-containing formulation comprising: - nicotine free base, 25% (w / w); Lactic acid, 13.5% (w / w); - one of benzoic acid, salicylic acid, 6% (w / w); water, 1.5% (w / w); glycerol, 54% (w / w); The present invention provides a formulation comprising:

[0030] In yet another preferred embodiment, the present invention provides a nicotine-containing formulation comprising: - nicotine free base, 25% (w / w); Lactic acid, 13.5% (w / w); - one of benzoic acid, salicylic acid, 5% (w / w); water, 1.5% (w / w); glycerol, 55% (w / w); The present invention provides a formulation comprising:

[0031] In yet another preferred embodiment, the present invention provides a nicotine-containing formulation comprising: - 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 comprising:

[0032] In yet another preferred embodiment, the present invention provides a nicotine-containing formulation comprising: - 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 comprising:

[0033] In a further preferred embodiment, the present invention provides a nicotine-containing formulation comprising: - nicotine free base, 45% (w / w); lactic acid, 32.4% (w / w); - polyethylene glycol (PEG), 22.6% (w / w); The present invention provides a formulation comprising:

[0034] These last two embodiments of the invention are particularly useful because such formulations are sufficiently viscous at room temperature that they can be handled more like solids than liquids, and in fact, they can meet the chemical definition of a solid at room temperature. Thus, not only can such formulations be applied very easily and repeatedly to a base substrate in the correct location and in the correct volume, but such formulations also have negligible wettability once placed on the substrate surface, so that the formulations do not spread substantially after application to the substrate surface.

[0035] According to a further aspect of the invention there is provided an aerosolizable formulation comprising: - free base nicotine, 26-40% (w / w); - 24-40% (w / w) of one or a combination of any two or more of medicamentously and biologically acceptable organic mono- or dicarboxylic acids, - one or a combination of two or more of the following medicamentously and biologically acceptable liquid excipients, from 50 to 20% (w / w); and, optionally, - water, 0-5% (w / w); The present invention provides a formulation comprising:

[0036] According to a further aspect of the invention there is provided an aerosolizable formulation comprising: - free base nicotine, 25-55% (w / w); - one or a combination of two or more of medicamentously and biologically acceptable organic mono- or dicarboxylic acids, from 15 to 35% (w / w); - one or a combination of two or more of the following medicamentously and biologically acceptable liquid excipients, from 60 to 10% (w / w); and, optionally, - water, 0-5% (w / w); The present invention provides a formulation comprising:

[0037] For the avoidance of doubt, all preferred embodiments and subordinate features of the first aspect of the invention as detailed above should be considered to apply equally to the second and any other aspects of the invention, optionally adjusted to increase the concentration of free base nicotine (in aspects of the invention subsequent to the first aspect). Such preferred embodiments and subordinate features will not be repeated herein merely for the purposes of brevity.

[0038] The Applicant has found, advantageously, that all the above-defined formulations, in particular those comprising pure lactic acid, its aqueous solution or its mixture with benzoic acid (also in pure form or in aqueous solution), exhibit superior chemical stability compared to corresponding formulations with high concentrations of nicotine only, as will become apparent from the specific description below.

[0039] Moreover, the applicant has found that the relatively significantly lower and more precisely controlled aerosol volume produced by the applicant's device from the above-mentioned formulations can be inhaled without a significant increase in irritation to the end user's mouth, throat (buccal cavity) and / or lungs. In fact, the sensation in the mouth, throat and lungs is very similar, if not identical, to the physical experience and drug delivery experienced when inhaling a much larger volume of aerosol containing a significantly lower concentration of nicotine from a conventional wick / coil vaping device. That is, even though the effective concentration of nicotine in the new formulations, and in particular in the aerosols produced therefrom, is significantly higher than previously proposed (at least 25%, and potentially as high as 50% or more after decomposition of the easily destabilizing nicotine salts in the resulting aerosols), the inhaled aerosol continues to maintain its palatability (also referred to as "tolerability") due to the presence of nicotine salts and / or organic acids.

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

[0041] To further explain, it is widely assumed, and indeed widely accepted, that when nicotine salts present in a formulation are aerosolized at room temperature or slightly below, they will substantially, if not completely, decompose into precursor acid and free base nicotine (the salts formed in the first stage by reacting together). Thus, when any nicotine salt-based formulation is heated, preferably above at least 100°C, more preferably above at least 130°C, and even more preferably between 150-180°C, most of the salt will have already decomposed, and it is the precursor acid from which the salt was formed that contributes to the palatability / acceptability of the inhaled aerosol. Furthermore, concomitant with the decomposition of the salt is an increase in the concentration of free base nicotine present in the inhaled aerosol, and those skilled in the art will also understand from the above that it is this particular "effective" or "equivalent" concentration that much of the prior art refers to and uses to define a particular formulation. Thus, while the prior art, when construed in this light, would result in an "equivalent," "effective" nicotine concentration, or the concentration of nicotine delivered by the resulting aerosol, in the range of 1-20% (w / w), and most commonly between 4-6% (w / w), the present invention is highly distinct from the prior art in that it provides formulations which produce aerosols with much higher effective nicotine concentration levels, in some cases at least 40%, in most cases 50%, and in some cases even greater than 50%. Thus, the formulations of the present invention effectively double the concentration of free base nicotine compared to room temperature formulations simply by heating and then aerosolizing.

[0042] There is one more point regarding chemistry that those skilled in the art should be aware of. Like many reactions, the reaction between nicotine and most of the medicamentously acceptable organic acids of the type described herein and in the prior art does not go to completion, but rather to equilibrium. Thus, with increasing temperature, the equilibrium shifts to the (free base nicotine + acid) side of the reaction, whereas at room temperature (at least for a 1:1 molar mixture of acid:nicotine), the nicotine salt compound side is much more likely to predominate, and relatively very little free base nicotine will be present. The relative concentrations of nicotine and acid (or salt) present in any formulation should also be carefully considered in light of this fact, along with temperature.

[0043] Even more surprisingly, an unexpected advantage of the formulations of the present invention is that the specific surface and interfacial energies (typically mJ / m 2 The effective surface energy of the formulation (also usually expressed in mJ / m 2 The surface and interfacial energies relate to surface energies (units) that are a measure of the relative surface energy between the formulation itself and the particular substrate on which the formulation is deposited and supported. Those skilled in the art will appreciate that surface and interfacial energies are, in effect, a direct measure of the degree to which a liquid will "wet" or spread over the surface of a substrate, an important consideration with respect to Applicant's devices.

[0044] To further explain, while many of the most common substrate materials, such as glass and other similar silicates, the most common ceramics, soda-lime glass and the like, can be considered roughly equivalent insofar as their specific surface energies are concerned, the applicant has advantageously and surprisingly found that the inclusion of one or more nicotine salts by the addition of an organic acid to the formulation and the consequent partial or substantial reaction of this acid with the free base nicotine, has a dramatic effect on the overall surface energy of the formulation, such that high concentration nicotine / nicotine salt formulations of this type, particularly those containing glycerol or polyethylene glycol as a medicamentarily and biologically acceptable excipient, are less prone to spreading or "wetting" the underlying substrate than similar nicotine-only formulations. In fact, the reduced wetting effect of the novel formulations is so significant that almost no spreading or wetting of the substrate occurs, even when the formulation is heated towards the aerosolization temperature, and even after repeated aerosolization, the globules of formulation remaining on a suitable substrate appear to remain completely stationary from the time they were first applied to said substrate. This is particularly advantageous considering that the applicant's device utilizes a cartridge substantially containing within it a substantially planar substrate of glass, to which (a) a planar resistive heating element is employed, and (b) one or more globules of a precise amount of formulation are subsequently deposited over, above and onto the area of ​​the substrate where the resistive heating element is located. Those skilled in the art will readily appreciate the advantages of greatly reducing the tendency of the formulation to spread over the substrate when and after it is applied to the substrate, since the novel formulation will then remain, if not completely stationary, for the most part in a fixed position directly over and above the resistive heating element that conductively supplies heat to the globules of formulation, thereby aerosolizing them. As a result, the precision of the aerosolization, and thus both the volume of the aerosol produced and the concentration of nicotine contained therein, can be much more precisely controlled.

[0045] It should also be noted that cohesion (i.e., the opposite of "wetting" and the tendency of the formulation to remain in place on the substrate) can be further improved by either selecting a substrate with a lower surface energy or by 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] Specific embodiments of the invention will now be described, by way of example, and with reference to the accompanying drawings, in which: [Brief description of the drawings]

[0047] [Figure 1A] FIG. 1A (prior art) shows a perspective view of a substrate, one side of which has a resistive heating element attached thereto, onto which globules of a pharmaceutical formulation are later deposited. [Figure 1B] FIG. 1B (prior art) shows a side view of a substrate, one side of which has a resistive heating element attached thereto, onto which globules of a formulation will later be deposited. [Figure 1C] FIG. 1C (prior art) shows an end view of a substrate, one side of which has a resistive heating element attached thereto, onto which small beads of a formulation will later be deposited. [Diagram 2] FIG. 1 is a graph showing the difference in stability over a 6 month period of two different nicotine-containing formulations, one containing only 5% (w / w) benzoic acid and the other containing 25% (w / w) benzoic acid, prepared by four different individuals A, B, C, and D, respectively. [Diagram 3] Similar to FIG. 2, the relative stability of formulations containing different concentrations of lactic acid (rather than benzoic acid) is shown, also over a six month period. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0048] To aid in understanding the present invention, particularly with respect to its specific surface energy / wetting advantages, those skilled in the art are first directed to Figures 1A, 1B and 1C, which show a device comprising a rectangular substrate 102 of a substantially chemically inert material, such as silicate, lime, soda or borosilicate glass material, generally designated 100, although it will be appreciated that other similar chemically inert materials, such as ceramics, for example, are also contemplated. Ideally, the substrate material will be physically inert, with relatively low thermal conductivity, coefficient of expansion, emissivity and diffusivity properties, with most glasses meeting this requirement well. To provide some idea of ​​the dimensions required for the device, dimensions a, b and c are shown, although ideally a and b will be on the order of 5-50 mm, while the thickness dimension c will be significantly smaller, for example on the order of 0.5-5 mm. The substrate 102 has a top surface 104 and a bottom surface 106 on which is mounted a conductor, generally indicated at 108, comprising two separate and isolated portions, namely terminal portions 110A, 110B, 110C and resistive elements 112A, 112B, which generally follow a meandering but generally uniform (in the sense that the lengths of the conductors within the pattern are approximately equal) pattern resembling a well known square wave. In the illustrated embodiment, the excitation fixture comprises only two adjacent resistive elements 112A, 112B spaced away from the terminal portions towards the ends of the substrate, although it will be appreciated that more could easily be provided.

[0049] What is important in the context of the present invention is that a suitable amount of formulation is deposited on, directly above and above each of the resistive elements 112A, 112B. As can be seen, each resistive element is at least partially, and preferably substantially, covered with a respective globule 114A, 114B of said formulation, which can then be aerosolized when a voltage is applied to the element below it. In Figs. 1B, 1C, the globules 114A, 114B can be seen more clearly, and it is noted in this figure that the globules of formulation have sufficient surface energy that, when in contact with a substrate surface, they retain sufficient cohesion and therefore maintain their globule shape on the substrate, regardless of whether the substrate is coated or not. Also from this figure, it is noted that the globules 114A, 114B are completely separate from each other, since the excitation elements that are substantially covered with said globules are suitable for independent control. Now, the skilled person will understand that the tendency of the formulation to "wet" the substrate in an entirely uncontrollable manner, i.e. to spread over its upper surface, occurs in many, if not all, formulations containing only nicotine, and in such circumstances is most disadvantageous, since the formulation will move away from and eventually outside the area where the resistive element is applied and intended to give its heating effect. Needless to say, all the amounts of formulation that are out of the position of the resistive element will then not be heated at all or will be heated only slightly, so that aerosolization of said amounts is unlikely to be achieved, and these amounts are in effect "lost". If the skilled person understands that the total amount of the applied formulation is already very small, any such "loss" necessarily represents a reduction in the amount of nicotine that can be delivered to the user, and must therefore be considered unacceptable for a device adapted to provide a precisely measured dose of nicotine.

[0050] Although the present invention should not be considered as defined with respect to the type of vaping device intended for use with the formulation of the present invention, those skilled in the art should nevertheless understand that the formulation is specifically adapted only for use with the particular type of "cartridge-based" vaping device into which the substrate of Figures 1A-1C is ultimately inserted. As the name suggests, this type of device is adapted to accommodate a replaceable cartridge that is inserted or otherwise connected to the device, either from the time the device is first used, or after the cartridge present in the device has been exhausted and removed for disposal or reuse. There are already a great many cartridge-based vaping devices, sometimes referred to as "pod mods", and indeed what all such devices have in common is that the "pod" or cartridge that it accommodates is essentially a reservoir of a certain amount (usually about 0.5-2 ml) of nicotine-containing formulation, as the skilled artisan will recognize. While most modern cartridge-based devices are "closed" systems that are not intended or configured for the user to refill the cartridge or pod, some of the larger "pod-mod" devices do accommodate removable cartridges that can be manually refilled. Those skilled in the art will appreciate that this type of device is essentially no different from the more conventional "tank-based" devices that include a manually refillable reservoir component (of slightly larger volumetric capacity, e.g., 1-5 ml) into which the user can pour in some (usually, but not necessarily) flavored or other nicotine-containing liquid formulation, as and when needed. Typically, as the device is used, whatever formulation is contained therein is gradually emptied depending on the frequency of use, and refilling is done when the reservoir is empty or near empty. This may be daily for a smoker, or weekly for a light, occasional or otherwise social smoker.

[0051] An important distinction to be made here is that whereas tank-based devices and refillable cartridge-based devices offer virtually no control to the end user with respect to the formulation used therein and therefore the amount of nicotine ultimately delivered to the user, closed system cartridge-based devices such as those developed by the applicant offer a much greater degree of control. Essentially, this is because not only will each cartridge be accurately and precisely pre-filled with a specific formulation containing the desired concentration of nicotine (and a suitable acid), but the cartridge itself is also specifically designed and therefore suitable for use only in vaping devices designed for it, allowing much more careful control over the delivery of whatever concentration of nicotine is present in the formulation.

[0052] Considering now the present invention itself and formulations comprising nicotine and nicotine salts (formed by reacting nicotine, a weak base, with an acid), the Applicant has tested various formulations and found that at least nicotine itself, a medicamentarily / biologically acceptable component such as glycerol (or any other such composition or mixture thereof as previously mentioned) and one or more of the following: - pure lactic acid or its aqueous solution, - the binary system of lactic acid and benzoic acid, either in their pure form or in a suitable aqueous solution; - Formulations containing the binary system of lactic acid and salicylic acid, either in their pure form or in a suitable aqueous solution, have been found to be the most useful in terms of chemical stability.

[0053] Specific stability studies performed by applicants are described in detail and summarized below. EXAMPLES

[0054] Stability test (benzoic acid) The primary objective of the study was to evaluate the stabilizing effect of benzoic acid when added to a nicotine formulation that also contained glycerol. A secondary objective of the study was to investigate the day-to-day and inter-analyst precision for the manufacture and analysis of two formulations containing different concentrations of benzoic acid (5% and 25% (w / w), respectively, see below). Both of these formulations have already been shown to have good chemical stability data after 8 weeks of storage. The study involved the analysis of two batches of two formulations, one containing 5% (w / w) benzoic acid and the other containing 25% (w / w) benzoic acid, by four individuals (hereafter referred to simply as A5 or A6, as referenced in Figure 2 of this document). 25 , B5 or B 25 , C5 or C 25 and D5 or D 25 The study included manufacturing batches of 8 formulations on two different days (each batch will be anonymized as appropriate).

[0055] In process checks (IPC) were carried out at various stages using high pressure liquid chromatography (hplc) to ensure that the manufactured formulations contained the correct amount of nicotine. For the purposes of this test, one "dose" was considered as the volume of one pellet of 0.5 mg nicotine formulation applied to the test substrate. The amount of formulation used on each test substrate (or per inhalation cartridge) would then be higher for the lower strength nicotine formulation (see formulation defined below).

[0056] Overview of the formulation A formulation for a batch size of 50 g was produced according to the table shown below. [Table 1] Table 1 - Overview of formulations

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

[0058] Figure 2 of this document usefully presents the above data in graphical form, from which it can be seen that the results of four independently prepared formulations containing 25% (w / w) benzoic acid (specifically A 25 , B 25 , C 25 , D 25 It can be immediately seen that all of the 25% (w / w) benzoic acid formulations (graph lines referenced with A5, B5, C5 and D5) are far superior, where chemical stability is concerned, to the formulations containing only 5% (w / w) benzoic acid (specifically the graph lines referenced with A5, B5, C5 and D5). In fact, the 25% (w / w) benzoic acid formulations had practically no loss of nicotine even after 6 months, and all still retained nicotine at levels greater than 98% compared to the concentration in the initial formulation.

[0059] Conclusion of stability study The data obtained from the stability studies clearly show that the preparations containing benzoic acid (25% (w / w) benzoic acid) are stable after 6 months with no significant changes in nicotine recovery. The data obtained from the stability studies of the preparations containing only 5% benzoic acid show that no stability was achieved with an average loss of 3.2% nicotine per month.

[0060] Stability test (lactic acid) Applicants have performed broadly similar stability studies on formulations containing lactic acid. Details of the various formulations tested are given in the table below.

[0061] Overview of the formulation [Table 3] Table 3 - Overview of lactic acid preparations

[0062] The stability test data, derived in much the same manner as the benzoic acid stability test, have been plotted in the graph shown in Figure 3 of this document, with clear identification of the data for each of the above mentioned formulations. From this figure, it can be seen that three of the six different formulations mentioned above have significantly improved stability over a period of about five to six months, these being "Group 1", "Group 3" (the most preferred of all formulations) and the "Control". In particular, "Group 3" is considered the most useful due to its inherent viscosity and low wettability.

[0063] Thus, Applicant has experimentally determined that useful and advantageous formulations can be produced when the relative concentration of acid (or binary acid) as defined by the present invention is, overall, in an amount of at least about 15% (w / w), preferably at least about 20%, and more preferably at least about 25% (w / w), while at the same time the nicotine concentration remains high, at least about 25% (w / w), in the most preferred embodiments greater than about 30% (w / w), in further preferred embodiments as high as about 40-50% (w / w), and in some embodiments as high as about 55-60%.

[0064] It should be mentioned here that although the applicant has carried out significant testing on formulations containing only benzoic acid, 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. It is therefore highly preferred to use either only lactic acid instead of benzoic acid in the formulation, or a two-component system, one of which is lactic acid and the other of which is a non-benzoic acid selected from the list given above (ideally salicylic acid).

[0065] After detailed investigation by the applicant, the most preferred formulation is specifically: - free base nicotine, about 45-46% (w / w); - lactic acid, about 31-33% (w / w); - Polyethylene glycol (PEG) as an excipient, specifically a high molecular weight PEG compound such as PEG 3000, approximately 24-21% (w / w); It was found that the compound contains

[0066] In the above (and other) formulations within the scope of this specification, it should be understood by those skilled in the art that the excipient used in the formulation can be any one or any combination of the various excipients disclosed and described herein. Thus, for example, in the most preferred formulations described above, the excipient can be changed to glycerol, glycerin, or other glycols, or any combination of the type.

[0067] Specifically, the formulations referred to above and in Figure 3 as "Group 3" are Applicants' currently most preferred formulations.

[0068] From the above, and in particular, when the term "about" is used both in the above and elsewhere in this specification, those skilled in the art should understand that the applicant does not intend the percentage value following the term "about" to be so precise and accurate that any percentage value higher or lower than that number, or any percentage value outside any range defined by said term, would be considered outside the scope of this specification. Rather, those skilled in the art should understand that the term "about" approximates the relevant numerical value or range to "about" 1% to 2% of the number immediately following, i.e., defined by, the term "about."

Claims

1. 1. An aerosolizable formulation comprising: Free base nicotine, about 25-55% (w / w); about 15-35% (w / w) of one or a combination of any two or more of pharma- ceutically and biologically acceptable organic mono- or dicarboxylic acids; about 60-10% (w / w) of one or a combination of any two or more of medicaments that are soluble in water, and optionally, Water, about 0-5% (w / w).

2. The one or more organic acids may be selected from the group of acids shown below: Acids containing aromatic groups, Hydroxy carboxylic acids, Heterocyclic carboxylic acids, Aromatic carboxylic acids, Terpenoid acids, sugar acid, Pectic acid, amino acid, Alicyclic acids, Aliphatic carboxylic acids and ketocarboxylic acids, The formulation of claim 1, wherein the formulation is selected from one of the following:

3. The one or more organic acids present in the formulation may be 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 2. The formulation of claim 1, wherein the carboxylic acid is one or more of: -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.

4. 2. The formulation of claim 1, wherein the one or more acids are any of alpha-keto acids (2-oxoacids), beta-keto acids (3-oxoacids) and gamma-keto acids (4-oxoacids).

5. The formulation comprises: Only one of lactic acid, benzoic acid and salicylic acid Binary systems of two organic acids, one of which is lactic acid and the other of which is benzoic acid or salicylic acid, and A binary system of two organic acids, one of which is lactic acid and the other of which is selected from the list of acids according to claim 3 excluding lactic acid, The formulation of claim 1, comprising one of:

6. 6. The formulation of claim 5, wherein the formulation comprises a binary system of two organic acids, one of which is lactic acid, the molar ratio of the two acids being about 1:1, and the combined percentage (w / w) of total acids in the formulation is at least about 25% (w / w).

7. 2. The formulation of claim 1, wherein the 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).

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

9. Free base nicotine, about 25% (w / w); Benzoic acid, salicylic acid, about 25% (w / w); Glycerol, about 50%; The formulation of claim 1 , comprising:

10. Free base nicotine, about 25% (w / w); Lactic acid, about 24.3% (w / w); Water, about 2.7% (w / w); Glycerol, about 48% (w / w); The formulation of claim 1 , comprising:

11. Free base nicotine, about 25% (w / w); Lactic acid, about 13.5% (w / w); Benzoic acid, salicylic acid, about 5% (w / w); Water, about 1.5% (w / w); Glycerol, about 55% (w / w); The formulation of claim 1 , comprising:

12. Free base nicotine, about 34% (w / w); A 1:1 molar mixture of lactic acid and benzoic acid, about 16% (w / w); Glycerol, about 50% (w / w); The formulation of claim 1 , comprising:

13. Free base nicotine, about 45-46% (w / w); Lactic acid, about 31-33% (w / w); Polyethylene glycol, about 24-21% (w / w); The formulation of claim 1 , comprising:

14. The formulation of claim 13, wherein the polyethylene glycol is a high molecular weight polyethylene glycol compound having a molecular weight of 3000.

15. A composition comprising: a composition comprising nicotine free base, about 25-50% (w / w); about 25-40% (w / w) of one or a combination of any two or more of pharma- ceutically and biologically acceptable organic mono- or dicarboxylic acids; about 50-20% (w / w) of one or a combination of any two or more of a medicamentarily and biologically acceptable liquid excipient; and, optionally, Water, about 0-5% (w / w).

16. A composition comprising: a composition comprising nicotine free base, about 25% (w / w); a lactic acid solution, the solution being comprised of about 12% (w / w) water and about 88% lactic acid, about 16.2% (w / w); Water, about 1.8% (w / w); Glycerol, about 58% (w / w); 1. An aerosolizable formulation comprising:

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