RU2848269C1 - Aerosolisable nicotine-containing composition (variations) - Google Patents

Abstract

FIELD: tobacco industry.

SUBSTANCE: aerosolizable composition comprising about 25-55 wt.% free base nicotine, about 15-35 wt. % of one or a combination of two or more pharmaceutically and biologically acceptable mono- and/or dicarboxylic organic acids, and about 60-10 wt. % of one or a combination of two or more pharmaceutically and biologically acceptable liquid excipients.

EFFECT: by introducing acid into the composition, one or more nicotine salts can be created that remain within the composition according to the present invention, thereby not only reducing the loss of nicotine to the atmosphere due to natural volatility and evaporation, but also significantly increasing the surface energy of the composition thus formed, allowing the globules of the composition, deposited on a heated substrate to be more cohesive and much less prone to migrate across the surface as a result of wetting.

15 cl, 5 dwg, 3 tbl

Description

Field of technology to which the invention relates

The present invention generally relates to the field of various nicotine-containing compositions intended for use in a specific type of electronic cigarette or similar aerosolizing or vaporizing device, hereinafter referred to as a "vaping" device or devices. More specifically, the present invention relates to the field of various nicotine-containing compositions in which the nicotine concentration can be comparatively significantly higher than in the wide range of nicotine-containing compositions currently available and intended for use with a similar wide range of traditional vaping devices.

State of the art

Nicotine-containing compositions for use with tank-based vaping devices have already become widespread. Indeed, with the explosion in popularity of vaping devices of all types in recent years, the availability and variety of nicotine-containing compositions used in them has been extremely wide, to the point that many thousands of different compositions now exist. Despite this proliferation, the fundamental composition and chemical nature of nicotine-containing compositions are relatively simple, as essentially any and all liquid compositions, at least those intended for use in traditional "wick-and-coil" devices, must be (1) readily aerosolizable and (2) contain sufficient nicotine so that each and every aerosol generated by the device also contains sufficient nicotine to deliver a "load" to the user upon inhalation. To further expand on the components in modern compositions, liquid compositions will typically always contain:

1. A pharmaceutically acceptable aerosolizable component or "excipient", and

2. nicotine itself and/or some complex, derivative or conjugate thereof (for example, various nicotine salts have recently become popular), or some other component, complex, derivative or system from which nicotine itself and/or some complex or conjugate thereof is capable of being released when heated or otherwise excited.

Additionally, many modern formulations may contain a small percentage of water and often contain one or more flavorings, again typically in relatively low concentrations relative to the overall composition. Naturally, a wide range of different flavorings exists, but common flavoring compounds include safrole, ethyl vanillin, camphor, α-thujone, menthol, and coumarin, among many others.

With respect to point (1) above, examples of suitable and already used excipients include: glycerin, vegetable glycerin (VG), propylene glycol (PG), polyethylene glycol (PEG), trimethylene glycol (TMG), or some combination of two or more of these. One particularly common excipient is a combination of PG and VG, for example, 10-90% PG with 90-10% VG, although compositions based on pure VG and pure PG are also known.

With regard to point (2) above, the vast majority of modern formulations simply include nicotine alone, either synthetically produced or extracted directly from the tobacco itself, at very high levels of purity (e.g., <1% contaminants). Typical nicotine concentrations in most common formulations range anywhere from 2-4 mg/ml of formulation to 60 mg/ml, although Regional and National Governments are increasingly restricting the maximum nicotine concentration levels that can be legally marketed in their territories. For example, the European Tobacco Products Directive (EUTPD) (2014/40/EU), widely implemented across Europe in 2015/2016, essentially limits the capacity of e-cigarette refill bottles to no more than 2 ml, and the maximum volume of nicotine-containing e-liquids (for retail sale) in a single refill container to 10 ml. In addition, the Directive limits the nicotine concentration in formulations (also commonly known as "e-liquids" or "vape juices" or simply "juices") to no more than 20 mg/ml and also requires that nicotine-containing products and their packaging be protected in every possible way from unauthorised access, and in particular from access by children.

Recently, it has been proposed (see, for example, patent document US 9215895 on behalf of Juul Labs Inc.) to create compositions that include one or more nicotine salts, instead of nicotine in its freebase or pure state. Indeed, compositions including nicotine salts (so-called "nicotine salts") have recently (in the last 2-3 years) become almost as common as the pure nicotine-containing compositions discussed above. For further clarification, manufacturers of cigarettes and other traditional tobacco products (TTPs), commonly known in the industry as "Big Tobacco," have long known that nicotine salts are not only already present in tobacco leaves, but also that certain nicotine salts could be useful as an additive to traditional tobacco to make it more palatable to users (i.e., nicotine salts tend to provide a lower pH of the smoke/vapor produced in a lit cigarette, effectively reducing the "throat hit" experienced by smokers during inhalation). [Specifically, see patent document US4830028, from R.J. Reynolds Tobacco Company, naming Thomas Perfetti as the inventor, who conducted the original nicotine salts research at Reynolds Tobacco in 1978.]

According to the above-mentioned U.S. Patent from Juul Labs Inc., nicotine salt compositions are ideally suited for simple preparation, for example, by adding pure nicotine, which is chemically a base, to a suitable organic carboxylic or dicarboxylic acid, such as benzoic acid, in the proper proportions to form a (liquid) composition comprising both a nicotine salt (formed by reacting the acid with the nicotine base) and some residual nicotine free base at the desired concentration level. This composition is then mixed with a suitable excipient, typically a PG-VG mixture in which the PG:VG ratio by weight is 3:7, such that the resulting composition has a nicotine concentration of between 0.5-20% by weight of the final composition, and ideally about 4% by weight. Patent document US 9,215,895 demonstrates that inhaling aerosols created from such compositions provides increased efficiency in delivering nicotine to the lungs (compared to standard nicotine-containing compositions without nicotine salts), which in turn leads to a rapid increase in nicotine absorption into the blood plasma. Thus, the use of nicotine salts in the compositions would most easily simultaneously enhance the palatability of the inhaled aerosols formed from them and reduce the time it takes to reach a specific concentration of nicotine in the blood plasma, in turn reducing the time the user spends between the first puff and receiving the desired brain hit from the drug. Slightly more sophisticated, Juul's US Patent also potentially suggests that the use of nicotine salts in nicotine-containing compositions could also be one approach to being able to increase the amount of nicotine contained in a composition, thereby making it more potent in terms of the amount of drug delivered to the user, at least compared to a traditional composition that does not contain nicotine salts, without significantly affecting the taste.

In the context of the present invention, it is important to note from the above that the liquid compositions described so far remain suitable only for traditional wick-coil vaping devices (including cartridge-based "Pod Mod" or simply "pod" devices), since such devices are designed primarily to create significant quantities of voluminous, visible aerosols with relatively low nicotine concentrations (about 0.1 mg in each aerosol or less) in order to simulate smoking a traditional cigarette as much as possible.

In contrast, the present invention relates to nicotine-containing compositions in which nicotine concentrations are significantly higher than even those in many currently available nicotine-infused compositions, and therefore the vast majority of current devices, whether cartridge-based or tank-based, would be completely unsuitable and possibly even dangerous. For example, even the most effective composition currently available (although TPD recognition is widespread only outside Europe) has a nicotine concentration of only 7.5% by weight, whereas the present invention relates only to compositions in which the nicotine content is at least 20% by weight, and in most examples even higher.

While a qualified person might rightly question how compositions with such a high nicotine concentration would be suitable or usable, it is important to note that even if it is widely accepted that vaping is far less harmful to human health than smoking traditional tobacco products like cigarettes, there remain significant health concerns associated with vaping in general. The Applicant's fundamental point is that if someone were to inhale something completely unfamiliar, then it would only be possible to inhale this or these unfamiliar substances. Therefore, the Applicant has developed a new, somewhat revolutionary, cartridge-based vaping device, in which each cartridge is initially designed as a sealed package that must be opened and unfolded before insertion into the device. Each cartridge is equivalent to a single cigarette in terms of its use profile within the device, and contains a quantity of the composition, and, in turn, the amount of nicotine present within it. In contrast, many traditional tank-based devices, when filled with traditional nicotine-containing compositions, have a usage profile roughly equivalent to a pack of twenty cigarettes, and in some cases significantly more.

Thus, each cartridge of the Applicant's device is carefully and accurately pre-dosed with only a relatively tiny (3 mg or less) amount of the potent nicotine-containing composition, and thereby typically manifested in 1-4 very small (1-4 mm in diameter, or possibly less) globules placed directly on one or another surface of the cartridge or a substrate within it. By pre-dispensing the appropriate high-concentration nicotine-containing composition from the cartridge in this manner and by properly adjusting the heating conditions of the device (the heater is applied directly to the substrate inside the cartridge) so as to precisely control the amount of aerosol generated during any single activation of the device, the Applicant's device is capable of being approved under medical and clinical regulatory laws (e.g., the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK) for use as a medical device, since it is capable of delivering the desired predetermined dose of the medicinal product both accurately and repeatedly, and it is practically impossible for the end user to tamper with the device in such a way that it becomes dangerous in any way. As will be clear to the skilled reader, medically approved devices, at least in the UK and in many European countries, can be prescribed by doctors for the treatment of a condition associated with nicotine addiction. Furthermore, as the knowledgeable reader will appreciate, since the nicotine concentration in the compositions desired by the Applicant is relatively high, the actual volume of nicotine-containing aerosol generated must necessarily be significantly small, possibly even one or more orders of magnitude smaller than that typically generated by any traditional vaping device using more traditional compositions with lower nicotine concentrations. For the reasons mentioned above, this is, of course, a highly favorable and much more medically attractive proposition, at least in terms of the potential health risks associated with inhaling unfamiliar substances.

For reference, the reader's attention is drawn to the Applicant's own previous published patent applications covering various aspects of its device and cartridges designed and intended for use therein, in particular patent documents WO 2019/137994, WO 2018/167166, WO 2019/141577, WO 2019/Ob8780, WO 2019/137982.

Despite the advantages of using compositions containing high concentrations of nicotine, the Applicant nevertheless encountered various difficulties, particularly with compositions containing over 20% by weight of nicotine. The first and most serious problem is chemical stability. Nicotine itself is a volatile liquid, and at concentrations within the range of the aerosolizable compositions to which the present invention relates, significant nicotine loss into the surrounding atmosphere due to natural evaporation from the surface can occur. Moreover, this loss increases exponentially with concentration, so that the higher the proportion of nicotine present in the composition, the greater the likelihood of loss due to evaporation. Furthermore, nicotine is somewhat chemically aggressive, and although the base substrates onto which the globules of the composition are deposited in the Applicant's cartridges are typically composed of glass or some other inert ceramic material, which would therefore generally be resistant to absorption, becoming impregnated with it, or otherwise chemically interacting with the nicotine present in the composition, the base substrates are surrounded by, or partially encapsulated within, plastic materials, which, together with the substrate, make up the cartridge as a whole. The Applicants have found that, at least with certain plastic materials, nicotine can leach from the composition into such materials, thereby not only degrading the material but also significantly reducing its quantity, and thereby lowering the nicotine concentration within the composition. As the reader will appreciate, for a high-precision drug delivery device that is expected to undergo rigorous testing during the drug approval process, such problems are clearly detrimental to the stable performance of the device.

Another additional difficulty that Applicants encountered during their development, particularly of their cartridges and the base substrates within them that support the composition globules, and of the compositions themselves with high nicotine concentrations, is the degree to which the compositions tend to spread over the substrate surface—that is, the ability of the compositions to wet glass and other inert substrate materials. More specifically, Applicants found that simply mixing nicotine at a relatively high concentration with any of the standard excipients or combinations thereof results in solutions that have both relatively large surface areas and interfacial energies, such that when a droplet or globule is applied to a glass or ceramic substrate, that droplet or globule immediately and substantially spreads over the entire surface of the substrate. When it is assumed that droplets or globules of the composition are applied directly to substrates only in individual areas thereof, in which electrically resistive heating elements are provided, the tendency of droplets or globules of the composition to spread beyond the boundaries of such areas causes not only a partial loss of the composition that should be directly heated, but also that at the same time a (smaller) amount of the composition will receive a greater amount of heat than is intended, worsening the characteristics of aerosol formation by any individual heating element and the amount of composition remaining on it.

Therefore, the main objectives of the present invention are to mitigate, if not completely eliminate, such disadvantages.

The essence of the invention

According to a first aspect of the present invention, there is provided an aerosolizable composition comprising

- between 25-50% by weight of nicotine as free base,

- between 25-40% by weight of one or some combination of two or more pharmaceutically and biologically safe mono- and/or dicarboxylic organic acids,

- between 50-20% by weight of one or some combination of two or more pharmaceutically and biologically safe liquid excipients, and, optionally,

- between 0-5 wt.% water.

One or more organic acids are preferably selected from one of the following groups of acids:

- acids containing an aromatic group,

- hydroxycarboxylic acids belonging to the α-(alpha), β-(beta) or ω-(omega) variant, or to some other variant,

- heterocyclic carboxylic acids,

- aromatic carboxylic acids,

- terpenoid acids,

- sugar acids,

- pectin acids,

- amino acids,

- cycloaliphatic acids,

- aliphatic carboxylic acids, and

- ketocarboxylic acids.

The one or more organic acids present in the composition are preferably one or more of the following (hereinafter otherwise referred to 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, ascorbic acid (L), aspartic acid (L), 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, mucic acid, gentisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), undecylenic acid.

Most preferably, one or more of the selected acids are one of: an alpha-keto acid (2-oxoacid), a beta-keto acid (3-oxoacid), and a gamma-keto acid (4-oxoacid). Alpha-keto acids, such as pyruvic acid, have a keto group adjacent to the carboxyl group of the acid. Beta-keto acids, such as acetoacetic acid, have a keto group at the second carbon atom from the carboxyl group of the acid. Gamma-keto acids, such as levulinic acid, have a keto group at the third carbon atom from the carboxyl group of the acid.

The composition most preferably includes one of:

- only one of: lactic acid and benzoic acid,

- only lactic acid,

- a binary system of two organic acids, one of which is lactic acid, and the other one of benzoic acid, salicylic acid, and

- a binary system of two organic acids, one of which is lactic acid and the other is selected from List A above, excluding lactic acid.

In the case where the composition comprises a binary system of two organic acids, one of which is lactic acid, the weight ratio between the two acids is most preferably 1:1.

In the case where the composition includes 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.

Most preferably, the composition comprises only one acid, namely, lactic acid.

One or more excipients present in the composition are preferably selected from the following:

glycerin, vegetable glycerin (VG), propylene glycol (PG), polyethylene glycol (PEG), and trimethylene glycol (TMG).

The composition most preferably includes only one excipient, most preferably glycerin.

In one preferred embodiment, the invention provides a nicotine-containing composition comprising

- 25 wt.% free-base nicotine

- 25% by weight of one of: benzoic acid, salicylic acid

- 50% glycerin.

In another preferred embodiment, the invention provides a nicotine-containing composition comprising

- 25 wt.% free-base nicotine

16.2% by weight of a lactic acid solution, said solution consisting of 12% by weight of water and 88% of lactic acid,

- 1.8 wt.% water, and

- 58 wt.% glycerol.

In yet another further preferred embodiment, the invention provides a nicotine-containing composition comprising

- 25 wt.% free-base nicotine

- 24.3 wt.% lactic acid,

- 2.7 wt.% water, and

- 48 wt.% glycerol.

In yet another further preferred embodiment, the invention provides a nicotine-containing composition comprising

- 25 wt.% free-base nicotine

- 13.5 wt.% lactic acid,

- 6 wt.% of one of: benzoic acid, salicylic acid

- 1.5 wt.% water, and

- 54 wt.% glycerol.

In yet another further preferred embodiment, the invention provides a nicotine-containing composition comprising

- 25 wt.% free-base nicotine

- 13.5 wt.% lactic acid,

- 5 wt.% of one of: benzoic acid, salicylic acid

- 1.5 wt.% water, and

- 55 wt.% glycerol.

In yet another further preferred embodiment, the invention provides a nicotine-containing composition comprising

- 34 wt.% free-base nicotine

- 16 wt.% of a mixture in a 1:1 molar ratio of lactic acid and benzoic acid, and,

- 50 wt.% glycerin.

In yet another further preferred embodiment, the invention provides a nicotine-containing composition comprising

- 46.5 wt.% free-base nicotine

- 31.5 wt.% lactic acid, and,

- 22 wt.% polyethylene glycol (PEG).

In yet another further preferred embodiment, the invention provides a nicotine-containing composition comprising

- 45 wt.% free-base nicotine

- 32.4 wt.% lactic acid, and,

- 22.6 wt.% polyethylene glycol (PEG).

These last two embodiments of the invention are particularly useful because such compositions are so viscous at room temperature that they must be handled as solids rather than liquids, and indeed, these compositions can meet the chemical definition of a solid at room temperature. Thus, not only can such compositions be applied to a base substrate very simply, repeatedly, positionally, and volumetrically precisely, but such compositions also have negligible wetting properties, remaining adherent to the substrate surface in such a way that the compositions virtually do not spread over the substrate surface once applied to it.

According to a further aspect of the present invention, there is provided an aerosolizable composition comprising

- between 26-40 wt.% nicotine in the form of free base,

- between 24-40 wt.% of one or some combination of two or more pharmaceutically and biologically safe mono- and/or dicarboxylic organic acids,

- between 50-20% by weight of one or some combination of two or more pharmaceutically and biologically safe liquid excipients, and, optionally,

- between 0-5 wt.% water.

According to yet another aspect of the present invention, there is provided an aerosolizable composition comprising

- between 25-55% by weight of nicotine in the form of free base,

- between 15-35% by weight of one or some combination of two or more pharmaceutically and biologically safe mono- and/or dicarboxylic organic acids,

- between 60-10% by weight of one or some combination of two or more pharmaceutically and biologically safe liquid excipients, and, optionally,

- between 0-5 wt.% water.

For the avoidance of doubt, all preferred embodiments and dependent features of the first aspect of the present invention, detailed above, should be considered as equally applicable to the second and any additional aspects of the present invention intended to increase (in aspects subsequent to the first aspect of the invention) the concentration of free-base nicotine, as the case may be. Such preferred embodiments and dependent features have not been repeated here simply for reasons of brevity.

The applicant has advantageously found that all of the above compositions, and in particular those containing only lactic acid, its aqueous solution, or a mixture thereof with benzoic acid, again either in pure form or in an aqueous solution, exhibit superior chemical stability, compared to corresponding compositions containing only nicotine at a high concentration, as will become apparent from the following specific description.

Furthermore, the Applicant also discovered that relatively much smaller, more precisely controlled volumetric quantities of aerosols generated from the above-mentioned compositions by the Applicant's device can also be inhaled by end users without significant irritation of the mouth, throat (oral cavity), and/or lungs. Indeed, the sensations in the mouth, throat, and lungs are very similar, if not identical, in both physical experience and drug delivery, to those experienced when inhaling much larger volumes of aerosols containing significantly lower concentrations of nicotine from traditional wick-and-coil vaping devices. Thus, even if the effective concentration of nicotine in the new compositions, and in particular in the aerosols formed from them, is significantly higher than has ever been previously proposed (at least 25%, and in the aerosol formed, as a result of the decomposition of the easily destabilized nicotine salt, possibly at least 50% or more), the presence of the nicotine salt and/or organic acid continues to maintain the taste qualities (also referred to as “tolerability”) of the inhaled aerosol.

It's also worth noting here that, while the prior art compositions, all of which contain significantly lower nicotine concentrations than the compositions of the present invention, but nonetheless (in some cases) slightly higher concentrations than many standard, widely available, nicotine-only e-liquids or vape juices, still contain both nicotine and one or more nicotine salts, as in the present invention. However, in the prior art, these relatively "equivalent" or "effective" nicotine concentrations, being the actual concentrations of nicotine present in the generated aerosols, are significantly lower than in the present invention.

For further clarification, it is a widely held, indeed generally accepted, belief that aerosolization of a nicotine salt present in a composition at room temperature or slightly below substantially, if not completely, decomposes it into the precursor acid and free-base nicotine, the reaction of which primarily results in the said salt or salts. Therefore, when any nicotine salt-based composition is heated to a temperature above, preferably at least 100°C, more preferably at least 130°C, and further preferably to a level between 150-180°C, most of the salt(s) will have already decomposed, and then more of the precursor acid from which the salt was formed becomes available, which contributes to the taste/tolerability of the inhaled aerosol. Furthermore, it will also be clear to the skilled reader from the foregoing that the decomposition of the salt simultaneously increases the concentration of free-base nicotine present in the inhaled aerosol, and it is this "effective" or "equivalent" concentration that is more relevant to the prior art and which is used to define specific compositions. Thus, when the prior art is interpreted in light of the foregoing, resulting in "equivalent," "effective," or achievable aerosol nicotine concentrations in the range of 1-20% by weight, but most often between 4-6% by weight, the present invention is quite clearly distinguished, as it presents compositions with much higher effective levels of nicotine concentration in the formed aerosol, in some cases at least 40%, in many cases 50%, and in some cases even higher than 50%. Thus, simply by heating and then aerosolizing the compositions of the present invention, this effectively doubles the concentration of free-base nicotine, compared to the compositions at room temperature.

There is one additional chemical consideration that the knowledgeable reader should be aware of. Like many reactions, the reaction of nicotine with most organic pharmaceutically acceptable acids, such as those mentioned here and in the prior art, does not proceed completely, but rather proceeds toward equilibrium. Thus, as the temperature is increased, the equilibrium shifts more toward the reaction (nicotine free base + acid), whereas at room temperature (at molar ratios in acid:nicotine mixtures of at least 1:1), the nicotine salt derivative is much more likely to predominate, with relatively little free base nicotine present. So, with this fact in mind, the relative concentrations of nicotine and acid (or salt) present in any composition should be carefully considered in relation to temperature.

Another unexpected benefit of the compositions of the present invention relates to the effective surface energies (typically in mJ/ ^m2 ) of the compositions, both in terms of the specific surface energy of the composition itself and the interfacial energy (again typically in mJ/ ^m2 ), which is a measure of the relative surface energies between the composition itself and the particular substrate onto which the composition is deposited and by which it is supported. As will be appreciated by the skilled reader, surface energy and interfacial energy essentially represent a direct measure of the extent to which a liquid will "wet," that is, spread, over the surface of a substrate, and in the context of Applicant's devices, this is an important consideration.

To further clarify, many of the most common substrate materials, such as glass and other similar silicates, most commonly ceramic materials, soda-lime glass, can be considered to be substantially equivalent as far as their surface energies are concerned, but Applicant has advantageously and unexpectedly discovered that the addition of organic acids to compositions that in turn contain one or more nicotine salts, through a partial or significant reaction of the acid with the nicotine free base, has a dramatic effect on the surface energy of the composition as a whole, with the result that such high nicotine/nicotine salt concentration compositions, particularly those containing glycerol or polyethylene glycol as a pharmaceutically, biologically acceptable excipient, do not tend to spread onto or "wet" the underlying substrate as do many such nicotine-only compositions. Indeed, the reduced wetting ability of the new compositions is so pronounced, even when the composition is heated to the aerosol formation temperature, that very little spreading or wetting of the substrate occurs at all, and even after repeated aerosolizations, the remaining globules of the compositions on suitable substrates appear to remain completely static after the initial application to said substrate. This is particularly advantageous when the Applicant's devices are considered as using cartridges, substantially enclosed in a shell, which, as a rule, are flat glass substrates, to which (a) flat resistive heating elements are attached, and (b) one or more globules in a precise amount of the composition are then deposited on, on, above, or on the areas of the substrate where said resistive heating elements were provided. As will be readily apparent to the experienced reader, the significantly reduced tendency of the composition to spread across the substrate during and after application is advantageous, as the new compositions now remain largely, if not entirely, static, positioned directly on or above the resistive heating elements, which directly conductively transfer heat to the composition globules, ensuring aerosolization. This allows for much more precise control of aerosolization precision, and, in turn, both the volume of aerosol generated and the nicotine concentration within it.

It should also be noted that cohesiveness (i.e., the opposite of "wetting" and the tendency of a composition to remain in place on a substrate) can be further improved either by selecting a substrate with low surface energy or by coating the substrate with a suitable (chemically inert) coating composition, which, in turn, reduces the effective surface energy of the substrate. The well-known coating composition Parylene has been found to be particularly effective in this regard.

A specific embodiment 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

Figures 1A, 1B, 1C (all according to the prototype) respectively show a perspective view, enlarged side views and end views of the substrate up to one surface onto which the resistive heating element was applied, and after that onto which the globules of the composition were deposited.

Figure 2 shows a graph illustrating the difference in stability over a 6 month period of two different nicotine-containing compositions, one containing only 5 wt.% benzoic acid and the other containing 25 wt.% benzoic acid, each of which was formed by 4 different individual members A, B, C, D, and

Figure 3, like Figure 2 above, illustrates the relative stability of formulations including varying concentrations of lactic acid (as opposed to benzoic acid) over a similar 6 month time period.

Detailed description of the invention

To facilitate an understanding of the present invention, particularly with respect to its specific surface energy/wetting advantages, the reader's attention is first directed to Figures 1A, 1B, 1C, which show a device generally designated by the numeral 100 and including a rectangular substrate 102 made of a substantially chemically inert material, such as a silicate, soda-lime, or borosilicate glass material, although other similar chemically inert materials, such as a ceramic material, may of course be envisaged. Ideally, the substrate material is one that is also physically inert, that is, has relatively low thermal conductivity, coefficient of expansion, emissivity, and diffusion properties—many grades of glass readily meet these requirements. To give some idea of the required dimensions of the device, the dimensions a, b and c are shown, and ideally a and b are of the order of 5-50 mm, while the thickness dimension "c" is much smaller, perhaps of the order of 0.5-5 mm. The substrate 102 has an upper and lower surface 104, 106, respectively, and on top of the upper surface 104 there is applied an electrical conductor, generally designated by the number 108, which includes two different and separate regions, namely, contact regions 110A, 110B, 100C, and resistive elements 112A, 112B, in which the conductor as a whole forms a tortuous structure, but generally uniform (with the lengths of the conductor within the pattern being approximately equal) pattern, similar to that which represents the well-known square wave. In the illustrated embodiment, the excitation device includes only two resistive elements 112A, 112B, placed adjacent to the end of the substrate, remote from the contact areas, but, of course, it could easily be different.

As far as the present invention is concerned, it is important that a proper amount of the composition is deposited on, over, and above each of the resistive elements 112A, 112B. As can be seen from the Figure, each resistive element is at least partially, and preferably substantially completely, coated with corresponding globules 114A, 114B of the said composition, which can thereby be subsequently aerosolized by the underlying elements when an electric current is applied to them. The globules 114A, 114B can be seen more clearly in Figures 1B, 1C, and it should be noted that in the Figures the globules are composed of a composition having sufficient surface energy so that when they come into contact with the surface of the substrate, whether coated or otherwise, the said globules sufficiently retain their cohesive capacity and thus their globular shape on the substrate. Furthermore, it should be noted from the Figures that the globules 114A, 114B are completely separated from one another, as is consistent with the independently adjustable stimulating elements that essentially overlap said globules. As will now be clear to the skilled reader, any tendency of the composition to "wet" the substrate, that is, to spread over its upper surface in a substantially uncontrolled manner, as occurs with many, if not all, nicotine-only compositions, is a most unfavorable factor, since under such circumstances the composition could migrate from, and most likely beyond, the areas where the resistive elements were attached and were intended to exert their heating action. Of course, any amounts of composition that leaked from the resistive elements would not be sufficiently heated at all, or would be heated only minimally, so that aerosolization of said amounts would most likely not be achieved, and said amounts would effectively be "lost." When the trained reader understands that the total amounts of composition deposited are already very small, any such "loss" would inevitably result in a reduction in the amount of nicotine capable of being delivered to the user, and for a device which is intended to deliver a precisely measured dose of nicotine, such a loss must therefore be considered unacceptable.

Although the present invention should not be considered as being defined with reference to the type of vaping device with which the compositions according to the present invention are intended to be used, it will nevertheless be clear to the skilled reader that the said compositions were specifically intended for use with a particular type of "cartridge-based" vaping device, into which the substrate according to Figures 1A-1C will ultimately be inserted. As the name suggests, such devices are designed to accommodate a replaceable cartridge, which is inserted into the device or otherwise connected to it, either from the first use of the device or after the cartridge located inside the device, exhausted as a result of use, has been removed for disposal or reuse. As the skilled reader will be aware, there are already quite a number of cartridge-based vaping devices, sometimes described as "pod mods", but that virtually all of these devices typically feature a "pod", or insert a cartridge into them, essentially a reservoir for a quantity (usually about 0.5-2 ml) of nicotine-containing composition. While most modern cartridge-based devices are "closed" systems in which the cartridge or "pod" is not intended or designed to be refilled by the user, some larger "pod mod" devices accept removable cartridges that can be manually refilled. The reader will recognize that such devices are essentially no different from more common and traditional "tank-based" devices, which include a manually fillable reservoir component (with a slightly larger capacity, e.g., 1-5 ml) that can be refilled by the user with any (usually, but not necessarily) nicotine-containing e-liquid composition, flavored or otherwise, as and when required. Typically, the reservoir is refilled when it becomes empty after any composition within it gradually depletes over use of the device—depending on frequency of use, this could be daily for a heavy smoker, or weekly for a light, infrequent, or social smoker.

An important distinguishing feature introduced here is that while tank-based devices and refillable cartridge-based devices leave the end user with virtually no control over the compositions used in them, and thus the amount of nicotine ultimately delivered to the user, devices based on a closed cartridge system, such as those developed by the Applicant, provide a much greater degree of control. Essentially, this is achieved by the fact that each cartridge will not only be accurately and precisely pre-dosed with a specific nicotine-containing composition (and a suitable acid) at the desired concentration, but also the cartridge itself will be specifically designed and thus adapted for use only within a correspondingly configured vaping device, and thus the delivery of the nicotine present in the composition at a certain concentration can be much more precisely regulated.

Turning now to the invention itself, and to compositions containing a nicotine salt (formed by the reaction of nicotine as a weak base with an acid), the Applicant has tested various compositions and found that the most useful, at least in terms of chemical stability, is one containing nicotine itself, a pharmaceutically/biologically acceptable excipient such as glycerol (or any other composition or mixtures thereof, as previously mentioned), and one or more of the following:

- only lactic acid, or its aqueous solution,

- a binary system of lactic acid and benzoic acid, either in their pure form or in suitable aqueous solutions, and

- a binary system of lactic acid and salicylic acid, either in their pure form or in suitable aqueous solutions.

Specific stability studies conducted by the Applicant are described and summarized below:

Stability study (with benzoic acid):

The primary objective of this study was to evaluate the stabilizing effect of benzoic acid when added to nicotine formulations that also contain glycerin. A secondary objective of the study was to examine the inter- and intra-analyst precision in the preparation and analysis of two formulations containing benzoic acid at varying concentrations (see below, 5 wt.%, 25 wt.%, respectively). Both of these formulations have previously demonstrated positive chemical stability characteristics after 8 weeks of storage. This study involved the preparation of two batches of each formulation, i.e., one containing 5 wt.% benzoic acid and one containing 25 wt.% benzoic acid, by four separate representatives (hereinafter anonymized as simply A ₅ or A ₂₅ , B ₅ or B ₂₅ , C ₅ or C ₂₅ , and D ₅ or D ₂₅ , as appropriate and as presented in Figure 2) on two different days. Essentially, a total of 8 batches of formulations were prepared.

In this study, IPC checks were performed on the compositions obtained for testing, which contained the correct amount of nicotine, at various stages using high-pressure liquid chromatography (HPLC). For the purposes of this study, one "dose" is defined as the volumetric amount of a single globule of composition applied to the test pad, containing 0.5 mg of nicotine. Essentially, the amount of composition used on each test pad (or per puff from the cartridge) will be greater than for a composition with a lower nicotine concentration (see composition characteristics below).

SUMMARISATION OF COMPOSITIONS

The compositions were obtained according to the table below for 50 g batches:

RESULTS

The above data are clearly illustrated here in the form of a graph in Figure 2, from which it can be immediately seen that all of the four individually prepared compositions which contained 25% by weight of benzoic acid (graph lines specifically designated as A ₂₅ , B ₂₅ , C ₂₅ , D ₂₅ ) are significantly superior, when considering chemical stability, to the compositions containing only 5% by weight of benzoic acid (graph lines specifically designated as A ₅ , B ₅ , C ₅ , D ₅ ). Indeed, after 6 months, the compositions with 25% by weight of benzoic acid showed virtually no loss of nicotine at all, with all still showing nicotine retention levels in excess of 98%, compared to their concentrations in the original compositions.

CONCLUSION from the stability test:

Data obtained from stability studies clearly demonstrate product stability for benzoic acid-containing formulations (25% benzoic acid by weight) for up to six months, without significant changes in nicotine retention. Data obtained from stability studies indicate that product stability was not achieved for formulations containing only 5% benzoic acid, due to an average nicotine loss of 3.2% per month.

Stability study (with lactic acid):

The applicant conducted extensive stability studies of compositions containing lactic acid. Details for the various compositions tested are provided in the table below:

SUMMARISATION OF COMPOSITIONS

Stability data from an extensive stability study conducted identically to the benzoic acid test are plotted in Figure 3, along with data for each of the clearly defined formulations mentioned above. This figure shows that of the six different formulations mentioned above, three exhibited significantly improved stability over approximately 5-6 months, designated "Arm 1," "Arm 3" (the most preferred of all formulations), and "Control." In particular, formulation "Arm 3" is considered the most suitable given its intrinsic viscosity and low wetting ability.

Thus, the Applicant has experimentally confirmed that useful and advantageous compositions can be created, provided that the relative concentrations of the acid (or acids in binary systems), in general, are in an amount of at least about 15 wt.%, and preferably at least about 20%, and even more preferably at least about 25 wt.%, while the nicotine concentrations remain high at a level of at least about 25 wt.%, and in the most preferred embodiments more than about 30 wt.%, and in still further preferred embodiments at least about 40-50 wt.%, and even, in some embodiments, at least about 55-60%, as prescribed by the present invention.

It should be noted here that, although the Applicant has conducted extensive testing of compositions containing only benzoic acid, some concerning circumstances have been identified, such as the potential for benzoic acid in an inhalable aerosol to pose toxicological concerns in terms of its specific systemic target organ toxicity (STOT) and irritant effects. Therefore, it is much preferable to use lactic acid alone in the compositions instead of benzoic acid, or to use a binary acid system in which one acid is lactic acid and the others are selected from the above list (ideally salicylic acid), but not benzoic acid.

The Applicant's detailed studies have led to the discovery of a most preferred composition, more specifically comprising,

- about 45-46% by weight of free-base nicotine,

- about 31-33 wt.% lactic acid, and

about 24-21% by weight of polyethylene glycol (PEG) as an excipient, more specifically, a high molecular weight PEG compound such as PEG 3000.

In the above (and other) compositions within this field, the skilled reader will appreciate that the excipient used in the compositions may be any one of the various excipients or combinations thereof disclosed and described herein. Thus, for example, in the above-mentioned most preferred composition, the excipient may be replaced by glycerin, vegetable glycerin, or certain other glycols, or any combination thereof.

More specifically, the composition designated as “Arm 3” in the above and in Figure 3 is currently considered by Applicant to be the most preferred composition.

It should be clear to the skilled reader from the foregoing, and in particular with respect to the use of the word "about" both here and elsewhere in this specification, that the Applicant does not intend that the numerical percentage values following the word "about" be strictly defined and precise, such that any percentage values above or below this number, or outside of any range defined by said word, would be considered as outside the scope of the invention. On the contrary, the reader should understand that the word "about" creates an approximation to the relevant number or range, and with "about" 1%-2% of this or those numbers that immediately follow it, and thus being qualified by said word "about."

Claims (50)

1. An aerosolizable composition comprising - in the range between about 25-55% by weight of free-base nicotine, - in the range between about 15-35 wt.% of one or a combination of two or more pharmaceutically and biologically acceptable mono- or dicarboxylic organic acids, - in the range between about 60-10% by weight of one or a combination of two or more pharmaceutically and biologically acceptable liquid excipients. 2. The composition according to claim 1, further comprising water in an amount greater than 0 wt.% and less than or equal to 5 wt.%. 3. The composition according to claim 1, wherein at least one organic acid is selected from one of the following groups of acids: - acids containing an aromatic group, - hydroxycarboxylic acids, - heterocyclic carboxylic acids, - aromatic carboxylic acids, - terpenoid acids, - sugar acids, - pectin acids, - amino acids, - cycloaliphatic acids, - aliphatic carboxylic acids, and - ketocarboxylic acids. 4. A composition according to any one of claims. 1 or 2, wherein the at least one organic acid present in the composition is at least one of the following: 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, ascorbic acid (L), aspartic acid (L), 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, mucic acid, gentisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), undecylenic acid. 5. The composition according to any one of claims 1 or 2, wherein at least one acid is any one of: an alpha-keto acid (2-oxoacid), a beta-keto acid (3-oxoacid), and a gamma-keto acid (4-oxoacid). 6. A composition according to any one of claims 1 or 2, comprising one of: - only one of: lactic acid, benzoic acid and salicylic acid, - a binary system of two organic acids, one of which is lactic acid, and the other one of benzoic acid, salicylic acid, and - a binary system of two organic acids, one of which is lactic acid and the other is selected from the list of acids specified in paragraph 4. 7. The composition of claim 6, comprising a binary system of two organic acids, one of which is lactic acid, wherein the molar ratio between the two acids is about 1:1, and the total combined weight percentage of the acid in the composition is at least about 25 wt.%. 8. The composition according to any one of claims 1 or 2, wherein at least one auxiliary substance present in the composition is selected from the following: glycerin, vegetable glycerin (VG), propylene glycol (PG), polyethylene glycol (PEG) and trimethylene glycol (TMG). 9. A composition according to any one of claims 1 or 2, which comprises only one excipient, namely one of glycerol and polyethylene glycol. 10. The composition according to claim 1, including about 25% by weight of free-base nicotine, about 25% by weight of one of: benzoic acid, salicylic acid, about 50% glycerin. 11. The composition according to claim 2, including about 25% by weight of free-base nicotine, about 24.3 wt.% lactic acid, about 2.7% by weight of water, and about 48% by weight glycerol. 12. The composition according to claim 2, including - about 25% by weight of free-base nicotine, - about 13.5 wt.% lactic acid, - about 5% by weight of one of: benzoic acid, salicylic acid, about 1.5% by weight of water, and about 55% by weight glycerol. 13. The composition according to claim 1, including - about 34% by weight of free-base nicotine, - about 16 wt.% of a mixture in a 1:1 molar ratio of lactic acid and benzoic acid, and - about 50% by weight of glycerin. 14. The composition according to claim 1, including - about 45-46% by weight of free-base nicotine, - about 31-33% by weight of lactic acid, - about 24-21% by weight of polyethylene glycol. 15. The composition of claim 13, wherein the polyethylene glycol is a high molecular weight polyethylene glycol compound having a molecular weight of 3000.