AEROSOLIZABLE NICOTINE-CONTAINING FORMULATIONS

Abstract

Nicotine-containing formulations for electric/electronic nicotine delivery systems are disclosed, containing both nicotine at relatively much higher concentrations, typically at least 25% by weight of total formulation weight, w/w, and in many cases as much as 40-50% w/w, than is typical for conventional nicotine containing formulations, which only contain about 2-4% w/w nicotine. The formulations also include a biologically and pharmaceutically acceptable mono- or di-carboxylic organic acid, such as benzoic acid, salicylic acid and most preferably lactic acid also at relatively high w/w concentrations. One or more nicotine salts may be created and be extant within the formulations, which not only mitigates against the loss of nicotine to the atmosphere through natural volatility and evaporation, but also markedly increases the surface energy of the formulations created, and the globules of formulations deposited on a heating substrate are much more cohesive and much less likely to migrate through wetting over the substrate.

Claims

1. An aerosolisable formulation comprising Between about 25-50%, w/w free-base nicotine, Between about 15-35% w/w of one, or some combination of two or more pharmaceutically and biologically acceptable mono- or di-carboxylic organic acids, Between about 60%-10% w/w of one or some combination of two or more pharmaceutically and biologically acceptable liquid excipients, and optionally Between about 0-5% w/w water.

2. A formulation according to claim 1 wherein the one or more organic acids 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, Pectic acids, Amino acids, Cycloaliphatic acids, Aliphatic carboxylic acids, and Keto carboxylic acids.

3. A formulation according to claim 1 wherein the one or more organic acids present in the formulation is one or more 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, dodecyl sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric 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.

4. A formulation according to claim 1 wherein the one or more acids is any of: an Alpha-keto acid (2-oxoacid), a Beta-keto acid (3-oxoacid), and a Gamma-keto acid (4-oxoacid).

5. A formulation according to claim 1 wherein the formulation includes one of: Only one of: lactic acid, benzoic acid and salicylic acid, A binary system of two organic acids, one being one of lactic acid and the other being one of: benzoic acid, salicylic acid, and A binary system of two organic acids, one being lactic acid and the other being chosen from the above list excepting lactic acid.

6. A formulation according to claim 5 wherein the formulation includes a binary system of two organic acids, one of which is lactic acid, and the molar ratio between the two acids is about 1:1, and the overall combined w/w percentage of acid in the formulation is at least about 25% w/w.

7. A formulation according to claim 1 wherein the one or more excipients present in the formulation is/are selected from the following: Glycerol, Vegetable Glycerin (VG), Propylene Glycol (PG), Polyethylene Glycol (PEG), and trimethylene glycol (TMG).

8. A formulation according to claim 1 which includes only a single excipient component, being one of Glycerol and Polyethylene Glycol.

9. A formulation according to claim 1 comprising about 25% w/w freebase nicotine about 25% w/w of one of: benzoic acid, salicylic acid about 50% glycerol.

10. A formulation according to claim 1 comprising about 25% w/w freebase nicotine about 24.3% w/w lactic acid solution, about 24.3% lactic acid, about 2.7% w/w water, and about 48% w/w glycerol.

11-17. (canceled)

18. A formulation according to claim 1 comprising about 25% w/w freebase nicotine about 13.5% w/w lactic acid, about 5% w/w of one of: benzoic acid, salicylic acid about 1.5% w/w water, and about 55% w/w glycerol.

19. A formulation according to claim 1 comprising about 34% w/w freebase nicotine about 16% w/w of a 1:1 molar ratio mixture of lactic acid and benzoic acid, and about 50% w/w glycerol.

20. A formulation according to claim 1 comprising about 45-46%, w/w free-base nicotine, about 31-33% w/w of lactic acid, about 24-21% w/w polyethylene glycol.

21. A formulation according to claim 20 wherein the polyethylene glycol is a high molecular weight polyethylene glycol compound having a molecular weight of 3000.

22. An aerosolisable formulation comprising Between about 25-50%, w/w free-base nicotine, Between about 25-40% w/w of one, or some combination of two or more pharmaceutically and biologically acceptable mono- or di-carboxylic organic acids, Between about 50-20% w/w of one or some combination of two or more pharmaceutically and biologically acceptable liquid excipients, and optionally Between about 0-5% w/w water.

23. An aerosolisable formulation comprising about 25% w/w freebase nicotine, about 16.2% w/w lactic acid solution, said solution consisting of 12% w/w water and 88% lactic acid, about 1.8% w/w water, and about 58% w/w Glycerol.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0107] FIGS. 1A, 1B 1C (all prior art) respectively show a perspective view, side and end elevations of a substrate to one surface of which a resistive heating element has been applied, and thereafter onto which globules of formulation have been deposited.

[0108] FIG. 2 shows a graph illustrating the difference in stability over a 6 month time period of two different nicotine-containing formulations, one containing only 5% w/w benzoic acid and the other containing 25 w/w % benzoic acid, each being prepared by 4 different individuals A, B, C, D, and

[0109] FIG. 3, similar to FIG. 2 above, illustrates the relative stabilities of formulations including different concentrations of lactic acid (as opposed to benzoic acid) over a similar 6 month time period.

DETAILED DESCRIPTION

[0110] To assist with the understanding of the present invention, particularly as regards the specific surface energy/wetting advantages thereof, the reader's attention is firstly drawn to FIGS. 1A, 1B, 1C, in which there is shown a device indicated generally at 100 and comprising a cuboid substrate 102 of a substantially chemically inert material, such as a silicate, lime, soda or borosilicate glass material though of course other similarly chemically inert materials may be considered, such as for example a ceramic. Ideally, the substrate material is one which is also physically inert that it possesses relatively low thermal conductivity, expansivity, emissivity, and diffusivity characteristicsmost glasses fulfil these requirements adequately. To provide some idea of the required dimensions of the device, dimensions a, b, and c are shown, and ideally a and b are of the order of a 5-50 mm, whereas the thickness dimension c is significantly smaller, perhaps of the order of 0.5-5 mm. Substrate 102 possesses upper and lower surfaces 104, 106 respectively, and over the upper surface 104 is applied an electrical conductor indicated generally at 108 which comprises 2 distinct and separate portions, namely contact portions 110A, 110B, 110C, and resistive elements 112A, 112B in which the conductor follows a generally meandering but generally uniform (in that the conductor lengths within the pattern are roughly equal) pattern similar to that of a well-known square wave. In the embodiment depicted, the excitation device comprises only two resistive elements 112A, 112B arranged adjacently at towards the end of the substrate remote from the contact portions, but of course there could be easily be more.

[0111] Importantly as far as the present invention is concerned, onto, over, and above each of the resistive elements 112A, 112B there is deposited a suitable amount of formulation. As can be seen from the Figure, each resistive element is at least partially, and preferably substantially covered with respective globules 114A, 114B of said formulation, which can thus be subsequently aerosolised by the underlying elements when they become energised. Globules 114A, 114B can be more clearly seen in FIGS. 1B, 1C, and it is to be noted that in the Figures, the globules are of a formulation having sufficient surface energy so that when coming into contact with the substrate surface, whether coated or otherwise, said globules retain sufficient cohesiveness and thus their globular shape upon the substrate. Also to be noted from the Figures is that globules 114A 114B are entirely separate from one another, as befits the independently controllable excitation elements said globules substantially overlie. As the skilled reader will now understand, any tendency of the formulation to wet the substrate, i.e. spread out over the upper surface thereof in generally uncontrollable fashion, as occurred with many if not all nicotine-only containing formulations, is most disadvantageous, because in such circumstances, the formulation would migrate away from and eventually out with the regions where the resistive elements had been applied and were intended to provide their heating effect. Of course, any amounts of formulation which strayed away from the resistive elements would not be subsequently heated at all, or would only be heated very marginally such that aerosolization of said amounts would not likely be achieved, these said amounts being effectively lost. When the skilled reader understands that the total amounts of formulation being deposited is already very small, any such loss would necessarily represent a reduction in the amount of nicotine capable of being delivered to a user, and for a device which is adapted to provide a precise measured dose of nicotine, such a loss must thus be regarded as unacceptable.

[0112] Although the present invention should not be considered as being defined with reference to the type of vaping device with which the formulations of the present invention are intended to be used, it should nevertheless be understood by the skilled reader that the said formulations have been specifically adapted for use only with a specific type of cartridge-based vaping device into which the substrate of FIGS. 1A-1C is ultimately inserted. As the name suggests, such devices are adapted to receive a replaceable cartridge which is inserted into or otherwise connected to the device either from the first use of the device or after a cartridge extant within the device, exhausted through use, has been removed to be discarded or recycled. As the skilled reader will be aware, there are already a great many cartridge based vaping devices in existence, sometimes described as pod mods, but what practically all these devices have in common is that the pod or cartridge they receive is, in essence, a reservoir for an amount (usually about 0.5-2 ml) of a nicotine-containing formulation. Although most modern cartridge-based devices are closed systems wherein the cartridge or pod is not intended or adapted to be refilled by a user, some of the larger pod mod devices do accept removable cartridges which can be manually refilled. The reader will understand that such devices are essentially no different at all to the more common and conventional reservoir-based devices, which include a manually refillable reservoir component (of slightly larger volumetric capacity, e.g. 1-5 ml) which can be topped up by a user with any (usually, but not necessarily) nicotine-containing liquid formulation, flavoured or otherwise, as and when required. Typically, the reservoir is refilled when it is or approaches empty after whatever formulation therein is progressively depleted as the device is useddepending on the frequency of use, this may be daily for a heavy smoker or weekly for a light, infrequent or social smoker.

[0113] The important distinction to be made here is that whereas reservoir-based devices and refillable cartridge-based devices offer practically no end-user control in terms of the formulations used therein and thus the amount of nicotine ultimately delivered to a user, closed system cartridge-based devices such those being developed by Applicant offer a much greater degree of control. Fundamentally, this is because each cartridge will not only be accurately and precisely pre-dosed with a specific formulation containing nicotine (and a suitable acid) at a desired concentration, but also the cartridge itself will be specifically designed and thus suited for use only within a correspondingly designed vaping device, and thus the delivery of whatever concentration of nicotine is present in the formulation can be much more carefully regulated.

[0114] Turning now to the invention itself, and the nicotine and nicotine-salt (arising from the reaction of the weak base nicotine with an acid) containing formulations, Applicant has tested various formulations and found that the most useful, in terms of chemical stability at least, contain nicotine itself, a pharmaceutically/biologically acceptable such as glycerol (or any other such composition or mixtures thereof previously mentioned), and one or more of the following: [0115] Only Lactic acid, or an aqueous solution thereof, [0116] A binary system of lactic and benzoic acid, either in their pure form or in appropriate aqueous solutions, and [0117] A binary system of lactic and salicylic acid, either in their pure form or in appropriate aqueous solutions.

[0118] Specific stability studies conducted by Applicant are set out and summarised below:

Stability Study (Benzoic Acid):

[0119] The primary purpose of this study was to evaluate the stabilising effect of Benzoic Acid when added to nicotine formulations which also contain glycerol. The secondary purpose of the study was to investigate the interday and inter analyst accuracy in the manufacture and analysis of two formulations containing different concentrations of Benzoic acid (see below, 5%, 25% w/w respectively). Both of these formulations have previously demonstrated positive chemical stability data after 8 weeks storage. This study involved the manufacture of two batches of each formulation, i.e. one having 5% w/w Benzoic Acid and the other having 25% w/w Benzoic Acid, by four individuals (hereinafter anonymised as simply A.sub.5 or A.sub.25, B.sub.5 or B.sub.25, C.sub.5 or C.sub.25, and D.sub.5 or D.sub.25 as appropriate, and as referenced in FIG. 2 hereof) over two different days. As such, 8 batches of formulation were manufactured in total.

[0120] In process checks (IPC) were conducted on the formulations manufactured to check they contained the correct amount of nicotine, at various stages, using high pressure liquid chromatography (hplc). For the purpose of this study, one dose is considered to be the volumetric quantity of a single globule of formulation applied to the test substrate and which contains 0.5 mg of nicotine. As such the amount of formulation used on each test substrate (or per inhalation cartridge) will be greater for the lower concentration nicotine formulation (see formulation specifics below).

Formulation Summary

[0121] Formulations were manufactured according to the table below for batch sizes of 50 g:

TABLE-US-00001 TABLE 1 Formulation Summary Mass of the Nicotine Benzoic Glycerol formulation to Formulation (g) Acid (g) (g) dose (0.5 mg) 5% Benzoic Acid 22.50 g 2.50 g 25.00 g 1.12 mg Solution 25% Benzoic Acid 12.50 g 12.50 g 25.00 g 2.0 mg Solution

Results

TABLE-US-00002 TABLE 2 Summary of data from stability study in tabular format, for the formulation containing only 5% w/w Benzoic Acid Concentration, and for that containing 25% w/w Benzoic Acid. Nicotine Recovered (%) Time Point (weeks/ moment) Days (A) 5% (B) 5% (C) 5% (D) 5% (D) 25% (B) 25% (A) 25% (C) 25% T0 W 0 100 100 100 100.00 100 100 100 100 T1 W 7 96.6 91.6 96.8 93.70 96.7 100.1 101.9 101.1 T2 W 14 89.6 87.1 89.3 95.30 101 98.7 99.8 99 T3 W 21 89.9 83.7 90.9 94.30 102.1 101.5 101.3 98.4 T4 W 28 92.2 89.1 92.7 82.30 101.1 101.2 99.5 101 T2 M 56 89.9 83.8 91 86.00 98.8 99.5 98.2 98.2 T3 M 84 92.2 87.7 91.4 93.80 99.8 99.6 99.0 98.2 T6 M 182 83.7 81.2 84.7 74.2 98.4 99.0 99.9 98.3

[0122] The data above is usefully illustrated in Graphical form in FIG. 2 hereof, wherefrom it can be instantly seen that all of the four individually prepared formulations which contained 25% w/w benzoic acid (graph lines specifically referenced at A.sub.25, B.sub.25, C.sub.25, D.sub.25) markedly outperform, as far as chemical stability is concerned, the formulation containing only 5% w/w/ benzoic acid (graph lines specifically referenced at A.sub.5, B.sub.5, C.sub.5, D.sub.5). Indeed, after 6 months, the 25% w/w benzoic acid formulations lost practically no nicotine at all, with all still showing nicotine retention levels at over 98% as compared to the concentrations thereof in the initial formulations.

Conclusion of Stability Test:

[0123] The data generated on the stability study clearly demonstrates product stability for benzoic acid containing formulations (25% w/w Benzoic Acid) for up to six months, with no appreciable change in the recovery of nicotine. The data generated on the stability study demonstrates that product stability for the formulations containing only 5% benzoic acid stability has not been attained with an average loss of nicotine of 3.2% per month.

Stability Study (Lactic Acid).

[0124] Applicants conducted a broadly similar stability study for formulations comprising lactic acid. Details the various formulations tested are provided in the table below:

Formulation Summary

TABLE-US-00003 TABLE 3 Lactic Acid Formulation Summary Lactic Excipient Flavour Formulation Acid Nicotine (Name, (Name, Name/Ref (w/w %) (w/w %) w/w %) w/w %) Arm 1 18 25 Glycerol, 57 NONE, 0 Arm 3 32.4 45 PEG 3000, 22.6 NONE, 0 Arm 4 29 41 PEG 200, 20 Menthol, 10 Arm 6 41.4 58.6 NONE, 0 NONE, 0 Arm 7 37.3 52.7 NONE, 0 Menthol, 10 Control 18 25 Glycerol, 57 NONE, 0

[0125] The Stability test data, derived in a broadly identical manner as that for the Benzoic Acid Stability Study, are plotted in the Graph provided in FIG. 3 hereof, with data for each of the above formulations being clearly identified. From this Figure, it can be seen that of the 6 different formulations above, three had markedly improved stability over approximately 5-6 months, these being Arm 1, Arm 3 (the most preferred of all the formulations), and Control. Arm 3 in particular is considered most useful on account of its inherent viscosity and low wettability.

[0126] Thus, Applicant has experimentally confirmed that useful and advantageous formulations can be created, provided that the relative concentrations of the acid (or acids in binary systems), in toto, amount to at least about 15% w/w, and preferably at least about 20%, and yet further preferably at least about 25% w/w, while nicotine concentrations remain high at at least about 25% w/w, and in most preferred embodiments more than about 30% w/w, and in yet further preferred embodiments as much as about 40-50% w/w, and even, in some embodiments, as much as about 55-60%, as prescribed by the present invention.

[0127] It should be mentioned here that although Applicant has done significant testing of formulations including only benzoic acid, some mild concerns have been raised that benzoic acid in an inhalable aerosol could give rise to some toxicology concerns, particularly in terms of its Specific target organ toxicity (STOT) and irritant qualities. It is therefore much preferred to use either lactic acid alone in place of benzoic acid in the formulations, or to use a binary system of acids, one being lactic acid, and the other selected from the list provided above (ideally salicylic acid), not being benzoic acid.

[0128] Applicant's detailed investigations have found a most preferred formulation to be comprised of, specifically, [0129] About 45-46%, w/w free-base nicotine, [0130] About 31-33% w/w of lactic acid, and [0131] About 24-21% w/w of polyethylene glycol (PEG) as excipient, specifically a high molecular weight PEG compound such as PEG 3000.

[0132] In the above (and other) formulations falling within the scope hereof, the skilled reader should understand that the excipient employed within the formulations may be any one or some combination of the various excipients disclosed and described herein. Thus, for example, in the above most preferred formulation, the excipient may be changed to a Glycerol, a Glycerin, or some other glycol, or any combination of such.

[0133] Specifically, the formulation referenced as Arm 3 in the above and in FIG. 3 is currently Applicant's most preferred formulation.

[0134] The skilled reader should understand from the above, and in particular use of the word about both therein and elsewhere in this specification, that Applicant does not intend the percentage figure following the word about to be precise and exact such that any percentage value above or below the number, or outside any range qualified by said word, would be considered outside the scope hereof. Instead reader should understand that the word about imparts an approximation to the relevant figure or range, of about 1%-2% of that or those numbers immediately following, and thus being qualified by the said word about.