EP4494486A1 - Composition de nicotine à stabilité et toxicologie améliorées - Google Patents

Composition de nicotine à stabilité et toxicologie améliorées Download PDF

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Publication number
EP4494486A1
EP4494486A1 EP23186556.9A EP23186556A EP4494486A1 EP 4494486 A1 EP4494486 A1 EP 4494486A1 EP 23186556 A EP23186556 A EP 23186556A EP 4494486 A1 EP4494486 A1 EP 4494486A1
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EP
European Patent Office
Prior art keywords
nicotine
composition
acid
lactic acid
present
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP23186556.9A
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German (de)
English (en)
Inventor
Martin Steinbauer
Maia Stoicovici
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Individual
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Individual
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Priority to EP23186556.9A priority Critical patent/EP4494486A1/fr
Priority to PCT/EP2024/070544 priority patent/WO2025017181A1/fr
Publication of EP4494486A1 publication Critical patent/EP4494486A1/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
    • A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
    • A24B15/10—Chemical features of tobacco products or tobacco substitutes
    • A24B15/16—Chemical features of tobacco products or tobacco substitutes of tobacco substitutes
    • A24B15/167—Chemical features of tobacco products or tobacco substitutes of tobacco substitutes in liquid or vaporisable form, e.g. liquid compositions for electronic cigarettes
    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
    • A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
    • A24B15/18—Treatment of tobacco products or tobacco substitutes
    • A24B15/28—Treatment of tobacco products or tobacco substitutes by chemical substances
    • A24B15/30—Treatment of tobacco products or tobacco substitutes by chemical substances by organic substances

Definitions

  • the present disclosure relates to a liquid composition comprising nicotine and an organic acid wherein the nicotine is presented in protonated form for improved toxicology from decreased degradants, increased stability of nicotine, an extended shelf-life of the composition, and for an optimized user experience.
  • Nicotine is a well-known and widely used chemical stimulant which is usually consumed from various tobacco products typically by smoking.
  • the biological effects of nicotine include an increase in heart rate and blood pressure when provided to an individual or animal. Nicotine is also addictive and is reported be associated with satisfying physical and emotional sensations.
  • nicotine has not been linked to carcinogenic risk and is used in pharmaceutical nicotine replacement therapy with the aim of smokers quitting cigarettes or switching to a safer consumer product.
  • Chemically nicotine comprises a pyridine and pyrrolidine ring which each contain a nitrogen atom which can be protonated depending on the pH value of the solution. Therefore, nicotine may be present in a solution in different protonation states.
  • the protonation states the free base form of Nicotine (i.e. unprotonated form), a monoprotonated form with a protonation at the N-atom of the pyrrolidine ring and a diprotonated form with an additional protonation at the N-atom of the pyridine ring (see Figure 1 ).
  • Different levels of protonation of nicotine affect both nicotine stability and user experience during consumption.
  • NRT nicotine replacement therapy
  • different formulations of delivering reduced amounts of nicotine are used to alleviate a subject's withdrawal symptoms and improve the subject's mood. These formulations include gums, patches, lozenges, inhalers, (un)metered dose inhalers (MDI), nasal sprays or electronic cigarettes.
  • MDI tered dose inhalers
  • the present application refers to nicotine compositions which may be used in electronic devices such as electronic cigarettes, inhalers, nebulizers, soft mist inhalers, and vaporizers to produce an aerosol comprising nicotine.
  • Nicotine contributes to a number of these factors, and is strongly associated with factors such as impact, irritation and smoothness; these are readily perceived by consumers, and electronic delivery devices may offer too much or too little of these parameters for consumers. Different individual preferences also require certain variations of products to accommodate different consumers' expectations.
  • Nicotine absorption in the mouth is typically obtained from nicotine in the vapor phase.
  • nicotine absorbed from the lungs is typically obtained from the particulate phase of the aerosol which is inhaled.
  • a further challenge of providing a nicotine composition is the instability of nicotine and its volatility. Due to the vapor pressure of nicotine in solution as well as degradation of nicotine by e.g. pyrolysis the nicotine content within the nicotine solution gradually declines over time. Instead various nicotine degradation products accumulate in the solution. Hence, manufacturers are interested in nicotine solutions with improved stability and extended shelf life, i.e., nicotine composition which maintain a stable or nearly stable nicotine concentration over an extended period. Furthermore, the accumulation of nicotine degradation products also affects the safety and consumers' experience as well as the potential regulatory approval of these products, as some nicotine degradation products have undesired effects or toxicity.
  • the present application presents a solution to the above problems by providing a nicotine composition with improved safety through better toxicity levels measured in harmful and potentially harmful chemicals testing, stability and extended shelf-life, as well as an optimized consumer experience during consumption.
  • Patent application CA 2964829 discloses that by protonating at least some of the nicotine present in a solution, the stability of the nicotine solution may be enhanced. By diprotonating at least, a portion of the nicotine, and specifically at least 5 wt.% of the nicotine present, loss of the nicotine during storage is reduced.
  • Protonation of nicotine also strongly affects the consumers' experience.
  • the use of purified, free-base (unprotonated) nicotine is associated with a consumption experience which at least some users consider insufficient and not satisfactory.
  • the experience from using combustion type tobacco products, such as cigarettes is preferred by some tobacco users because they describe a perception of a "throat hit” sensation in their respiratory tract.
  • This "throat hit” experience does not occur when free-base nicotine is provided in the composition.
  • Nicotine in its free-base has high electron density at the N-atoms, this causes a "harsh” sensation, which is off-putting to many users, when introduced to the respiratory tract, or into the oral cavity.
  • this "harshness” can be mitigated and adjusted to a consumers' experience that allows switching from combustion cigarettes to new safer products by protonation of nicotine by a suitable pH of the composition or by salt formation which binds the nicotine molecules.
  • the present invention relates to a composition
  • a composition comprising a solution of nicotine and lactic acid, wherein the solvent comprises non-aqueous solvents or solutions with low water content, wherein the water content is less than 5% (w/w).
  • the present invention relates to process for producing the composition of the invention, wherein the process comprises the following steps:
  • the invention in another aspect relates to a method for delivering the composition of the invention to subject, wherein the administration of the composition of the invention involves inhalation of the vaporized composition of the invention.
  • the invention relates to a process for improving the user's sensation of a vaporized nicotine solution, the process comprises:
  • the invention relates to a composition
  • a composition comprising a solution of nicotine and a weak acid, wherein the solvent comprises non-aqueous solvents or solutions with low water content, wherein the water content is less than 5%w/w, wherein the weak acid is characterized by a pKa-value of less than 4.2.
  • the "bite” or “throat hit” of consumption of the nicotine composition of the invention describes the sensation which is felt by the consumer during consumption of vaporized nicotine compositions.
  • the sensation is dependent on the individual subject and can be recorded using consumer surveys. However, depending on the conditions before and after vaporization in the nicotine composition the sensation can be adjusted, modified, and altered. In particular, the chemistry of the functional groups of nicotine or in nicotine complexes is of relevance for regulating sensation.
  • the consumers' sensation of "bite” or “throat hit” is affected by the protonation state of nicotine. The consumers' sensation may be described as either “harsh” or “smooth”.
  • Harsh and “harshness” of the "throat hit” are used synonymously herein and according to the common understanding describe an unpleasant sensory reaction in the respiratory tract of the consumer, including but not limited to burning or itching sensations and/or other unpleasant or painful sensory reactions in the respiratory tract. Harshness may be quantified, for example, with a visual analogue scale (“VAS”), as well as with other quantification methodologies known in the art such as, for example, where a study participant is asked to rate the level of physical and/or emotional satisfaction he or she felt on a categorical scale, e.g., 0-5, 0-10, strongly like to strongly dislike, etc.
  • VAS visual analogue scale
  • the opposite end of the scale of "harshness”, i.e., a composition which is not considered to be “harsh” is typically described as “smooth”.
  • VAS visual analogue scale
  • VAS can be presented in a number of ways, including, but not limited to, scales with a middle point, graduations or numbers (numerical rating scales), meter-shaped scales (curvilinear analogue scales), "box-scales” consisting of circles equidistant from each other (one of which the subject has to mark), and scales with descriptive terms at intervals along a line (graphic rating scales or Likert scales).
  • Such "VAS" scales are widely used and commonly accepted in the field and the skilled person is aware of use and design of these scales.
  • delivery means delivering delivering administered or “administering”, are used synonymously herein and refer to providing a quantifiable dose of nicotine in form of an inhalable aerosol.
  • aerosol is generated from a liquid nicotine formulation with an electronic cigarette or low temperature vaporizer.
  • the effect includes, but is not limited to, a stimulating effect or a relaxing effect.
  • a stimulating effect may comprise an increased heart rate, an increased blood pressure, or a feeling of satisfaction (e.g., physical satisfaction) of the subject.
  • “Degree of protonation of nicotine” refers within this application to the relative fractions of nicotine protonation states, i.e., the relative ratios between free-base, monoprotonated and diprotonated nicotine.
  • a low degree of protonation refers to a ratio with predominant free-base nicotine, in contrast a high degree of protonation suggests predominance of diprotonated nicotine.
  • Respiratory tract comprises the “upper respiratory tract” and the “lower respiratory tract” of a subject.
  • the “upper respiratory tract” encompasses the nose, nasal cavities, sinuses, pharynx, and the upper portions of the larynx above the vocal folds (e.g., also known as vocal cords or voice reeds.)
  • the “lower respiratory tract” encompasses the lower portion of the larynx below the vocal folds, trachea, bronchi, bronchioles, and alveoli.
  • agitate or “agitation” refer to various mechanical methods of mixing of different substances which may include, but are not limited to, rotating, vibrating, vortexing, swirling, shaking, ultrasonicating, stirring, or any movement that causes mixing.
  • Mechanical movements include movements performed by hand or by a rotator.
  • organic acid refers to an organic compound with acidic properties (e.g., according to Bronsted-Lowry definition, or Lewis definition).
  • a common class of organic acid is group of carboxylic acids, whose acidity is associated with their carboxyl group, i.e., -COOR.
  • a dicarboxylic acid possesses two carboxylic acid groups. The relative acidity of an organic is measured by its pKa value and one of skill in the art knows how to determine the acidity of an organic acid based on its given pKa value.
  • Nicotine degradation products herein refer to any and all nicotine degradation products and byproducts which are derived from degradation of nicotine overtime to various possible processes such as, but not limited to, pyrolysis, hydrolysis or similar processes. This includes “minor tobacco alkaloids” as group of compounds which are formed by nicotine degradation. Hence, “nicotine degradation products” does not include other possible impurities from different sources.
  • shelf life refers to the storage period under recommended storage conditions (stable cool temperature, low humidity, no exposure to UV-light) during which at least 95% of the original nicotine amount is present in unmodified or undegraded form within the storage container for pharmaceutical applications.
  • shelf life refers to the storage period under recommended storage conditions (stable cool temperature, low humidity, no exposure to UV-light) during which at least 80% of the original nicotine amount is present in unmodified or undegraded form within the storage container for consumer applications.
  • electronic cigarette or “e-cigarette” or “low temperature vaporization device” are used herein, refers to an electronic inhaler that vaporizes a liquid solution into an aerosol mist. These devices are used to simulate and replace the act of tobacco smoking.
  • the liquid solution comprises a formulation comprising nicotine.
  • the design of electronic cigarettes is varied and, in some cases, does not resemble conventional cigarettes. In some cases, the consumer may choose and adjust the administered amount of nicotine.
  • Other embodiment electronic cigarettes include a combined atomizer and reservoir, called a "cartomizer” that may or may not be disposable, a mouthpiece that may be integrated with the cartomizer or not, and a battery.
  • the properties of the nicotine composition are relevant for use and administration. This is includes "viscosity" of the composition, i.e., the measure of a fluid's resistance to gradual deformation by shear stress or tensile stress.
  • Water activity is defined herein as the partial vapor pressure of water in a solution divided by the standard state partial vapor pressure of water.
  • the standard state of water is defined as pure water at the same temperature as the solution, i.e., pure distilled water has a water activity of one.
  • liquid composition comprising nicotine which is used for nicotine administration in electronic cigarettes are referred to as "e-liquid" herein.
  • the nicotine solution may also comprise flavoring components.
  • the carrier may preferably be propylene glycol.
  • flavor and “flavorant” refer to compounds and materials which can be used to create a desired taste or aroma in a product for adult consumers. Addition of such compounds may be subject to local regulation and may require regulatory approval. Possible flavorants are selected form the group comprising flavoring ingredients safe for human inhalation, flavor enhancers, bitterness receptor site blockers, sensorial receptor site activators or stimulators, sugars and/or sugar substitutes, and other. They may be synthetic or natural ingredients, or blends thereof.
  • the invention of the present application provides an improved composition comprising nicotine for application in electronic cigarettes for both consumer and nicotine replacement therapies.
  • the composition of the invention shows increased stability of nicotine and thus an extended shelf-life of the composition with optimized properties for consumer satisfaction regarding the sensual experience during consumption, i.e., taste and throat hit are optimized for according to consumer expectations.
  • the present invention relates to a composition
  • a composition comprising a solution of nicotine (see Figure 2 ) and lactic acid (see Figure 3 ), wherein the solvent comprises non-aqueous solvents or solutions with low water content, wherein the water content is at least less than 5% (w/w), preferably less than 4% (w/w), more preferably less than 3% (w/w), more preferably less than 2% (w/w), more preferably less than 1% (w/w), even more preferably less than 0.5% (w/w) and most preferably less than 0.44% (w/w).
  • the water content is defined according to its water activity.
  • the water activity is at least below about 0.85, preferably below about 0.5, more preferably below about 0.4 and most preferably below about 0.35.
  • Nicotine salts in solution often degrade via pyrolysis and oxidation into pyridine and minor tobacco alkaloids. This makes it difficult to quantify the concentration of nicotine and its minor tobacco alkaloids at a given time in vaporizer e-liquid, making consistent repeatable dosing of nicotine delivery almost impossible under normal use conditions.
  • Unwanted nicotine degradation may be addressed by improving device and tank design and minimizing e-liquid exposure to air. Further, appropriate temperature, i.e., cool storage conditions, are also helpful to control and reduce nicotine degradation. Limiting airflow to systems using a blister pack or vacuum packaging may further decrease nicotine degradation. However, these methods may address only part of the problem of degradation, and none of these methods are currently implementable in a low-waste disposable/recyclable device system.
  • Nicotine is prone to oxidation in two locations: the nitrogen-atom within the pyridine ring and the nitrogen-atom within the pyrrolidine ring.
  • the inventors found that nicotine degradation may be reduced by protonation of nicotine due to addition of lactic acid at a 1:2 molar ratio of the nicotine to lactic acid.
  • oxidation becomes unfavorable, as electrons are tightly bonded to protons donated from lactic acid, which is present in solution as lactate.
  • lactic acid is added as a stabilizing agent which is well-known application of lactic acid in drug delivery systems such as metered dose and dry powder inhalers.
  • Lactic acid has both good stability and a favorable toxicity profile, thus it is a well-suited stabilizing agent for administration.
  • lactic acid is a weak acid which can achieve protonation of free-base nicotine (see Figure 1 ).
  • the composition and the pH of the composition are adjusted to achieve protonation of both available protonation sites of the nicotine molecule, i.e., the two N-atoms of both ring structures of nicotine as shown in Figure 1 . Lactic acid is added to the composition in sufficient quantity to achieve significant diprotonation of nicotine.
  • the improved toxicity through reduced degradants and stability of the composition of the invention is highly relevant for product quality assurance and therefore important for regulatory approval.
  • the degradation of nicotine salts over time can compromise the quality of a vaporizer product or an e-liquid batch. Oxidation can induce, but is not limited to, a color change, viscosity change, foul odor, and inhibit the absorption of nicotine into the bloodstream, potentially deterring users from switching to vaporizers from more harmful combustibles such as conventional cigarettes by creating a less than satisfactory user experience.
  • changes in physical and chemical properties of nicotine can cause problems with manufacturing, processing, storing, and using nicotine vaporizers.
  • degradation of nicotine may inhibit the ability for a particular nicotine device to qualify under pharmacopeia standards as a pharmaceutical system.
  • the composition of the invention comprises protonated nicotine wherein the nicotine is present in the composition in at least 5% diprotonated form as determined by a suitable analytical procedure which is selected from, but not limited to, 1 H NMR spectrometry or calculation based on the pH value of the composition according to Henderson-Hasselbalch equation.
  • nicotine is present in the composition of the invention in at least 10% diprotonated form, more preferably in at least 15% diprotonated form, more preferably in at least 20% diprotonated form, more preferably in at least 25% diprotonated form, more preferably in at least 30% diprotonated form, more preferably in at least 35% diprotonated form, more preferably in at least 40% diprotonated form, more preferably in at least 45% diprotonated form, more preferably in at least 50% diprotonated form, more preferably in at least 55% diprotonated form, more preferably in at least 60% diprotonated form, more preferably in at least 65% diprotonated form, more preferably in at least 70% diprotonated form, more preferably in at least 75% diprotonated form, more preferably in at least 80% diprotonated form, more preferably in at least 85% diprotonated form, more preferably in at least 90% diprotonated form, even more preferably in at least 95% diprotonated form and most preferably
  • NMR spectroscopy is carried out using precision coaxial NMR inserts with experimental parameters as described by Duell et al. Nicotine protonation can be calculated based on difference in chemical shifts between aromatic hydrogens and hydrogens of the methyl (-CH3) group which connects to protonable nitrogen (N) atoms of the pyrrolidine ring and pyridine ring. NMR will confirm the proportion of the lactic acid that is present in its ionic form.
  • the relative fraction of different protonation states of nicotine in solution can be calculated by using the Henderson-Hasselbalch equation based on the pH determination of the composition of the invention.
  • Henderson-Hasselbalch equation is based on the following equilibrium between the protonated and unprotonated stats of a general base: B + H + ⁇ BH +
  • [B] is the amount of non-protonated nicotine (i.e. free base)
  • Nicotine is a diprotic base, wherein each of the protonation states: unprotonated, monoprotonated and diprotonated have different bioavailability.
  • the relative fractions of the available nicotine protonation states can be calculated from the pH of the composition. If the relative fraction of protonated nicotine and the total amount of nicotine in the sample are known, the absolute amount of each nicotine protonation state can be calculated.
  • the composition comprising nicotine according to the invention comprises nicotine in a molar ratio to lactic acid is between about 0.5:2 and about 1.5:2, preferably between about 0.8:2 and about 1.2:2, more preferably between about 0.9:2 and about 1.1:2 and most preferably about 1:2. Accordingly, the higher mixing ration may be needed to achieve near total prevalence of the diprotonated form and even future improved toxicity, stability, and end user acceptance. However, excess lactic acid in the solution that does not bind to the nicotine molecule would be superfluously be present in the composition.
  • the composition of the invention may contain different concentrations of nicotine depending on application.
  • the content of nicotine in the composition is between about 1-100 mg/ml, preferably between 10-90 mg/ml, more preferably between 15-90 mg/ml, even more preferably between 30-75 mg/ml, even more preferably between 35-65 mg/ml and most preferably between 40-60 mg/ml.
  • the present nicotine concentration of the composition determines largely the amount of nicotine administered to the subject with each puff of the electronic cigarettes. Thus, the nicotine concentration affects the patient's/end user's experience.
  • the nicotine used in the invention may be obtained as an extract from a natural tobacco product.
  • the nicotine used in the invention is synthetic S-nicotine which is obtained from artificial synthesis.
  • synthetic S-nicotine provides the advantage of higher purity of nicotine than can be obtained from natural sources. Specifically, this reduces the initial amount of impurities in form of the presence of minor tobacco alkaloids.
  • the nicotine solution of the invention has an improved toxicology profile. Any minor tobacco alkaloids present in the solution of the invention are the direct result of nicotine degradation over time. Starting from a reduced initial amount of minor tobacco alkaloids improves the shelf life of the solution of the invention.
  • the purity of the nicotine used in the composition can be determined by HPLC analysis.
  • HPLC analysis on anhydrous basis achieves between 99.0 % and 101.0 % of the nominal nicotine amount. Analysis of impurities show a total amount of less than 1.0 %.
  • the composition of the invention comprises initial amounts of minor tobacco alkaloids impurities of less than 0.1% (w/w), preferably less than 0.05% (w/w), more preferably less than 0.01% (w/w), more preferably less than 0.005% (w/w), more preferably less than 0.001% (w/w), even more preferably less than 0.0005% (w/w) and most preferably less than 0.0001% (w/w). Further, an absence of minor tobacco alkaloids will inevitably improve in vitro mutagenicity, cytotoxicity and genotoxicity testing results.
  • the carrier of the nicotine solution may be any suitable solvent such that the nicotine solution can be aerosolized for use.
  • the solvent is selected from glycerol, propylene glycol and mixtures thereof.
  • the solvent is at least glycerol.
  • the solvent consists essentially of glycerol.
  • the solvent consists of glycerol.
  • the solvent is at least propylene glycol.
  • the solvent consists essentially of propylene glycol.
  • the solvent consists of propylene glycol.
  • the solvent is at least a mixture of propylene glycol and glycerol.
  • the solvent consists essentially of a mixture of propylene glycol and glycerol.
  • the solvent consists of a mixture of propylene glycol and glycerol.
  • the solvent consists of a mixture of propylene glycol and glycerol.
  • composition of the invention comprising nicotine and lactic acid or other organic acid uses organic solvents with suitable volatility as commonly used for e-liquids.
  • the solvents of the invention are selected from the group comprising glycerol and propylene glycol. The skilled person in the field is aware of different available solvents which may be used to substitute the above solvents.
  • the mixing ratio of the solvents of the composition of the invention can be varied and adjusted depending on application.
  • the ratio of glycerol to propylene glycol in the composition of the invention is between about 80:20% (v/v) and about 20:80% (v/v).
  • composition of the invention may not contain any solvents.
  • the composition of the invention may comprise nicotine and lactic in solid form as powders for extended storage and subsequent dissolution by the consumer or patient at a later time.
  • the composition of the invention comprises at least 5% (w/w) of diprotonated nicotine.
  • This increases stability of nicotine and extends the storage time of the composition, i.e., the composition the invention achieves an extended shelf life.
  • the shelf life of the composition of the invention is extended to at least 1 month, at least 1.5 months, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 1 year, at least 1.5 years, at least 2 years, at least 2.5 years, or at least 3 years.
  • Half-life time of nicotine in the composition of the invention or shelf life of the composition of the invention may be determined by measuring the detectable nicotine concentration after predefined time intervals and thus determine the intermediate loss of nicotine due to degradation.
  • the accumulation of nicotine degradation products may be determined. Accumulation of nicotine degradation products can be measured by determining the amount of minor tobacco alkaloids. It is important to note that if the nicotine used for the formulation is laboratory made S-nicotine, no minor tobacco alkaloids are present at the starting point as very high purity can be achieved for synthetic S-nicotine without natural impurities or degradation products which are derived from nicotine extraction form natural sources.
  • Determination of accumulation minor tobacco alkaloids is in particular relevant to establish best before use dates and for regulatory approval as these degradation products may cause harm to the patient or consumer if present in concentrations exceeding the relevant acceptable thresholds.
  • concentration of nicotine and minor tobacco alkaloids and other nicotine degradation products can be determined using HPLC, gas chromatography, mass spectroscopy, spectroscopy methods using fluorescence or absorption properties of nicotine and its degradation product and any other suitable approach as known to the skilled person in the field.
  • the content of minor tobacco alkaloids present is less than 0.01% (w/w) as determined by HPLC, mass spectroscopy or other suitable detection method.
  • the increased stability of the composition of the invention leads to a reduced loss over time of nicotine during storage of the composition of the invention.
  • Loss of nicotine over time is at least less than 8%/month, preferably less than 6%/month, more preferably less than 4%/month, more preferably less than 3%/month, more preferably less than 2%/month, more preferably less than 1.5%/month, more preferably less than 1.0%/month and most preferably less than 0.5%/month.
  • the composition of the invention is for use in nicotine replacement therapy (NRT) wherein the composition is administered by inhalation.
  • NRT nicotine replacement therapy
  • the composition of the invention is administered using an electronic delivery system as such as an electronic cigarette, a MDI or vaporizer.
  • administration of the composition involves vaporization by suitable method as known to the skilled person in the field. Typically, vaporization is achieved by applying an electrical current to a wire within a vaporizable solution. The resulting heat of the wire leads subsequently to vaporization of the nicotine composition.
  • composition of the invention achieves a sensorial experience comprising an improved "bite” or throat hit when inhaled as determined according to a VAS survey.
  • NRTs often lack this key behavioral aspect, and NRTs with this improved experience will increase the quit rate thus making it a more efficacious quit-smoking device.
  • a visual analog scale (VAS) assessment is commonly and widely used to record and report a subject's sensations and provide a quantification for individual experience. For instance, it is possible to record the sensation of smoothness/harshness of the "bite" when administering the composition of the invention. In this case “very harsh” and “very smooth” sensation could be defined as the extreme endpoints of a spectrum of possible sensations. Between the defined endpoints the subjects can quantify their sensation on a scale (e.g., 0-100 mm). In this instance higher scores, e.g., indicate a harsher sensation associated with throat hit.
  • CEQ E-Cigarette Evaluation Questionnaire
  • a VAS E-Cigarette Evaluation Questionnaire may comprise the following domains: smoking satisfaction, psychological rewards, aversion, enjoyment of respiratory tract sensations, and craving reduction among other domains if required.
  • the composition of the invention when used in NRT administers an amount of nicotine between about 0.00325 mg and about 0.325 mg, preferably between about 0.05 mg and about 0.3 mg, more preferably between about 0.1 mg and about 0.2 mg, most preferably between about 0.13 and about 0.14mg per inhalation.
  • the amount of nicotine per inhalation is determined according to Coresta Recommended Method No 81 and ISO 20769:2018. Briefly the conditions of the method are set as follows: 3 second (+/- 0.1 s) duration, 55mL volume (+/- 0.6 mL), and at an interval of 30 seconds (+/- 0.5 s), repeated 20 times.
  • cigarettes have about 1-2 mg of nicotine that is actively absorbed by the user, and average inhalations have been reported to be between 8-12. If assuming the same user behavior, the inhalation of the NRT to have 0.13/0.14mg per 3 second inhalation equals 1.04/1.12mg (8 inhalations) to 1.56/1.68 mg (12 inhalations), roughly at parity with a cigarette and a likely effective substitute tool for smokers.
  • the process of preparing the composition of the invention involves firstly mixing lactic acid and nicotine in a predefined molar ratio according to the above defined ranges (e.g. 2:1) in a dedicated vessel. No additional application of heat or pressure is required for the desired reaction of combining the components and protonation of nicotine to take place. Agitation/Mixing may be required to achieve homogenous mixing and the desired protonation state. Different devices for mixing may be used as required, e.g., contrarotating mixers. Nicotine and lactic acid may be mixed as solid in powder form or as liquids in solution. The result after dissolution of the mixture is a nicotine lactate solution, which is formed via protonation of the nicotine molecule at two sites, the nitrogen molecule of the Pyroline group and the nitrogen molecule of the Pyrrolidine group.
  • ENDS the primary characteristic that would yield an e-liquid which is incompatible with an ENDS (device) is the viscosity of the e-liquid.
  • Propylene glycol and glycerol are the primary compounds responsible for product viscosity; however, an increased water or ethanol content may significantly decrease product viscosity.
  • E-liquids that are highly viscous may fail to wick to the heating coil at an appropriate rate and, without safety protection in the device, may result in the formation of carbonyls or other thermal degradants of the e-liquid.
  • the solvent properties of the e-liquid for both the device and the primary packaging may result in leachables in the e-liquid.
  • the risk of leachables in e-liquid is thought to be less of a risk to the consumer unless those leachables become aerosolized during use.
  • Leachables of large molecular mass are less likely to become volatile or carried in the aerosol formed during product use.
  • the present invention also related to a composition comprising a solution of nicotine and lactic acid, wherein the composition is obtained by the process described above.
  • composition of the invention in a further aspect of the invention, it relates to a method for delivering the composition of the invention to subject, wherein the administration of the composition of the invention involves inhalation of the vaporized composition of the invention.
  • vaporization is achieved within an electrical device by applying heat to the composition of invention and thus the composition is transformed into vapor.
  • the invention relates to a process for improving the user's sensation of a vaporized nicotine solution, the processes comprises:
  • the composition comprises a solution of nicotine and a weak acid, wherein the solvent comprises non-aqueous solvents or solutions with low water content, wherein the water content is less than 5%w/w, preferably less than 4%w/w, more preferably less than 3%w/w, even more preferably less than 2%w/w, even more preferably less than 1°/w/w, even more preferably less than 0.5%w/w and most preferably less than 0.44%w/w, wherein the weak acid is characterized by a pKa-value of less than 4.2, preferably less than 4.1, more preferably less than 4.0, even more preferably less than 3.9, even more preferably less than 3.8, even more preferably less than 3.7, even more preferably less than 3.6, even more preferably less than 3.5, even more preferably less than 3.4, even more preferably less than 3.3 and most preferably less less
  • the water content is defined according to its water activity.
  • the water activity is at least below about 0.85, preferably below about 0.5, more preferably below about 0.4 and most preferably below about 0.35.
  • the weak organic acid is selected from the group comprising 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, glucohepton
  • composition of the invention can be achieved with a different selection of various weak organic acids provided the acid may achieve protonation of both protonation sites of nicotine and is provided in the composition in a sufficient molar ratio to ensure protonation of nicotine according to the invention.
  • Different weak organic acids will further affect users' sensation when consuming the composition of the invention.
  • appropriate VAS questionnaires need to be performed to determine users' sensation and to adjust the compositions accordingly.
  • the increased degree of protonation of nicotine in the nicotine composition of the invention achieves the improved stability and sensory properties for the consumer as described above. Further, the improved stability as well as the use of synthetic S-nicotine with very high purity improves the toxicology of the product as there are less impurities some of which are toxic. However, toxicology is also affected by the means of aerosolization of the nicotine composition of the invention.
  • the key features relevant to generating an aerosol comes from elements of the reservoir, the heating chamber, and the heating element.
  • aerosolization was achieved using a Nichrome coil with organic cotton plant fiber wick and a silicone coil holder.
  • the coil has a resistance of 1.7 ⁇ 0.1 ⁇ .
  • the width of the coil is 3.5 mm and the coil is wound around the wick in 6 wraps.
  • Each warp of the heating coils are arranged with a distance of 1mm between neighboring wraps. This achieves sufficient distance between each wrap to avoid overheating of the nicotine composition during aerosolization.
  • Overheating of the nicotine composition is an important contributor to the formation of toxic compounds during aerosolization.
  • the described heating coil also contributes to the reduction of toxic components in the aerosol and the improved toxicological properties of the nicotine composition of the invention.
  • a polymer lithium-ion battery is used with 3.7 V and 350 mAh. Further, a 2 ml PCTG liquid chamber is used.
  • composition of the invention was tested for two new tobacco products with distinct formulations.
  • the formulations are either RED TOBACCO or SMOOTH TOBACCO, which both have relatively high glycerol content (table 1).
  • Glycerol content is typically referred to as a ratio of propylene glycol to glycerol or VG:PG.
  • Table 1 The glycerol to propylene glycol solvents ratio of the test compositions FLAVOR VG:PG RED TOBACCO 55:45 SMOOTH TOBACCO 55:45
  • Table 2 Composition of Smooth Tobacco E-liquid % w/w CAS FEMA # Ingredient Classification 3.52 54-11-5 Nicotine Active 3.9093 50-21-5 2611 Lactic Acid Stabilizer 0.4344 7732-18-5 Water Excipient 41.4504 57-55-6 2940 1,2-Propylene glycol Excipient 50.3963 56-81-5 2525 Glycerin Excipient 0.2896 Flavorants Flavor Table 3: Composition of Red Tobacco E-liquid % w/w CAS FEMA # Ingredient Classification 3.5200 54-11-5 Nicotine Active 3.9093 50-21-5 2611 Lactic Acid Stabilizer 0.4344 7732-18-5 Water Excipient 39.4235 57-55-6 2940 1,2-Propylene glycol Excipient 50.7900 56-81-5 2525 Glycerin Excipient 1.9228 Flavorants Flavorants Flavorants Flavorants Flavorants Flavors
  • compositions (table 2 and 3) according to the invention were characterized by their physicochemical properties and tested for nicotine stability and shelf life as well as for harmful or potentially harmful components according to FDA requirements.
  • Samples which are subject to stability testing have been stored in long term storage conditions as detailed within ICH Q1A guidance at 25°C ⁇ 2°C/65% RH ⁇ 5% (relative humidity). For each sample conditions different batches were prepared and all measurements were at least performed in triplicates.
  • a harmful or potentially harmful constituents (HPHC) analysis was conducted to identify a potential increase in degradants or leachables of the initially prepared composition and after a 3 month storage period to test shelf-life. Analysis was performed on the test solutions after aerosolization. Aerosolization was achieved using a Nichrome coil with organic cotton plant fiber wick and a silicone coil holder. The coil has a resistance of 1.7 ⁇ 0.1 ⁇ . The width of the coil is 3.5 mm and the coil is wound around the wick in 6 wraps. For aerosolization a polymer lithium-ion battery is used with 3.7 V and 350 mAh. A schematical representation of the heating coil is shown in Fig. 4 .
  • FDAs guidance to industry issued in June 2019 the inventors evaluated the new tobacco products for the risk of harmful or potentially harmful constituents.
  • a number of FDA's indicative list of 31 compounds includes a number of compounds which are added as part of the product formulations including; glycerol, menthol, nicotine, propylene glycol and vanillin.
  • Complete testing on all of FDA's list of HPHCs were measured in the aerosol generated using the applicant's device as disclosed in US provisional application US 63/431,735 filed on September 19, 2022 , and following the below standard regime.
  • US provisional application US 63/431,735 is hereby included by reference into the present application regarding the technical specifications of the applied device for vaporization.
  • the amount of nicotine as well as harmful and potentially harmful constituents per inhalation is determined according to Coresta Recommended Method No 81 and ISO 20769:2018. Briefly the conditions of the method are set as follows: 3 second (+/- 0.1 s) duration, 55mL volume (+/- 0.6 mL), and at an interval of 30 seconds (+/- 0.5 s), repeated 20 times (Puffing regime see table 4).
  • the standard regime represents an airflow of 1.1 l/min air
  • the purpose of the stability study is to establish, based on testing a minimum of three (3) batches of the drug product, a shelf-life and label storage instructions applicable to all future batches of the new tobacco product manufactured and packaged under similar circumstances.
  • the degree of variability of individual batches affects the confidence that a production batch will remain within specification throughout its shelf life.
  • a 3-month shelf-life study was performed to evaluate the quality of the applicant's products over their intended shelf-life. Samples are to be assessed for; pH, appearance, nicotine assay and nicotine-related substances at predefined intervals through shelf-life. Additionally, water activity, total yeast and mold, total aerobic microbial count and confirmation of absence of a number of microorganisms were performed at the start and end of product shelf-life test periods. Due to the anti-microbial properties of glycerol, propylene glycol and nicotine, and the absence of added water to the formulations of the new tobacco products, it was anticipated that the microbial specification of the product will be met without concern.
  • Table 5 Physical properties of sample formulations Mean Nicotine Amount (mg/g) Mean pH-value Mean Water Activity Red Tobacco 31.81 ⁇ 0.7172 4.14 ⁇ 0.0156 0.32 ⁇ 0.0133 Smooth Tobacco 32.15 ⁇ 0.1205 4.11 ⁇ 0.0464 0.34 ⁇ 0.0097
  • Nicotine n oxide, cotinine and myosmine are three nicotine degradants (due to oxidation, biological activity and reaction with water respectively). Nicotine n oxide and cotinine are understood to be the major related substances which are likely to form over the course of the products shelf-life. According to the observed data, the data indicate clearly that there is no concern of safety issues relating to an increase in nicotine related substances. Nicotine impurities were certified as part of quality control and material sourcing/certification.
  • Nicotine complying with compendial specifications is used in the manufacture of the new tobacco products. Additionally, evaluation of N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)1-(3-pyridyl)-1-butanone (NNK) levels in the aerosol were performed as part of the stability testing. NNN and NNK are tobacco-specific nitrosamines (TSNAs) classified as carcinogenic chemicals. The aim of the NNN and NNK assessment is to confirm the product safety.
  • TSNAs tobacco-specific nitrosamines
  • Nicotine degradants (nicotine n oxide, cotinine and myosmine) and TSNAs (NNN and NNK) could not be detected in the samples.
  • the data clearly indicate that the compositions of the invention are at least stable for 3 months without detrimental loss of nicotine or accumulation of toxic degradation products of nicotine.
  • the presented data indicate stable nicotine within the test samples with only minimal loss of nicotine over the observation period.
  • Sample compositions were tested for further possible impurities, harmful or potentially harmful constituents.
  • the further tested constituents are listed below in table 8.
  • the constituents as listed in table 8 were either not detected within the sample compositions or detected at below the relevant threshold level. Thus, the tested sample compositions are acceptable according to the toxicology review.
  • Table 8 List of tested harmful or potentially harmful constituents Acetaldehyde Acetyl propionyl Acrolein Acrylonitrile Benzene Benzaldehyde Benzyl acetate Butyraldehyde Cadmium Chromium Cinnamaldehyde Crotonaldehyde Diacetyl Diethylene glycol Ethyl acetate Ethyl acetoacetate Ethyl vanillin Ethylene glycol Formaldehyde Furfural Glycerol Glycidol Isopentyl acetate Isobutyl acetate Lead Menthol Methyl acetate N-Butanol Nickel Nicotine 4-(methylnitrosamino)1-(3-pyridyl)-1-butanone (NNK) N-nitrosonornicotine (NNN) Propionic acid Propylene glycol Propylene oxide Toluene Vanillin

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060018840A1 (en) * 2004-06-28 2006-01-26 Nektar Therapeutics Aerosolizable formulation comprising nicotine
CA2964829A1 (fr) 2014-11-07 2016-05-12 Nicoventures Holdings Limited Systeme de fourniture de vapeur electronique et cartomiseur pour celui-ci muni d'un recipient contenant une solution a base de nicotine protonee
US11202470B2 (en) * 2013-05-22 2021-12-21 Njoy, Inc. Compositions, devices, and methods for nicotine aerosol delivery
US20220007715A1 (en) * 2018-11-16 2022-01-13 Nicoventures Trading Limited Method
WO2022152529A1 (fr) 2021-01-12 2022-07-21 Ventus Medical Limited Formulations contenant de la nicotine pouvant être pulvérisées

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060018840A1 (en) * 2004-06-28 2006-01-26 Nektar Therapeutics Aerosolizable formulation comprising nicotine
US11202470B2 (en) * 2013-05-22 2021-12-21 Njoy, Inc. Compositions, devices, and methods for nicotine aerosol delivery
CA2964829A1 (fr) 2014-11-07 2016-05-12 Nicoventures Holdings Limited Systeme de fourniture de vapeur electronique et cartomiseur pour celui-ci muni d'un recipient contenant une solution a base de nicotine protonee
US20220007715A1 (en) * 2018-11-16 2022-01-13 Nicoventures Trading Limited Method
WO2022152529A1 (fr) 2021-01-12 2022-07-21 Ventus Medical Limited Formulations contenant de la nicotine pouvant être pulvérisées

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Premarket Tobacco Product Applications for Electronic Nicotine Delivery Systems", FDA, 2019
A.K. DUELLJ.F. PANKOWD.H. PEYTON: "Free-base nicotine determination in electronic cigarette liquids by H NMR spectroscopy", CHEM RES. IN TOX, vol. 31, no. 6, 2018, pages 431 - 434, XP055596457, DOI: 10.1021/acs.chemrestox.8b00097
BELUSHKIN, M ET AL.: "Role of testing standards in smoke-free product assessments", REGULATORY TOXICOLOGY AND PHARMACOLOGY, 2018, pages 98

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