Oral compositions

Abstract

There is disclosed a composition for generating an inhalable product, said composition containing at least one compound selected from salidroside, a source of salidroside, uridine, and uridine monophosphate. The composition may contain salidroside and uridine or uridine monophosphate in a predetermined ratio. The composition may take the form of an e-liquid.

Description

[0001] ORAL COMPOSITIONS

[0002] The present invention relates to compositions for inhalation, in particular, compositions comprising at least one compound selected from salidroside and uridine.

[0003] Background

[0004] Salidroside, (2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-[2-(4-hydroxyphenyl)ethoxy]oxane-3,4,5-triol, is a phenol glycoside compound with the following structure:

[0005]

[0006] Salidroside is a multifunctional biologically active compound found in Rhodiola plants, with a long history of use in Chinese herbal medicine. It is known as an adaptogen and is available as a dietary supplement in capsule form or as a powder, for example for addition to soups or other foods.

[0007] Dietary supplements containing salidroside are generally taken for the reduction of stress and fatigue, as well as for their potential anti-depressant, anti-inflammatory, and antioxidant properties.

[0008] Salidroside has been the subject of numerous studies, many of which have been reviewed and summarised in review articles, including those cited below.

[0009] Zhang et al, in ‘Salidroside: A review of its recent advances in synthetic pathways and pharmacological properties’, Chemico-Biological Interactions, Volume 339, 2021, 109268, ISSN 0009-2797, httDs: / / doi.org / 10.1016 / i.cbi.2020.109268, present a review of publications reporting pharmacological activities of salidroside, including activities on the cardiovascular and central nervous systems, immune stimulation, and antioxidant, antivirus, antidiabetic, anti-osteoporotic, anti-inflammatory, anti-cancer, anti-hypoxia, antifatigue and anti-ageing activities.

[0010] Zhong et al, in ‘Pharmacological activities, mechanism of action, and safety of salidroside in the central nervous system’, Drug Des Deve Ther, 2018 May 24, summarise studies into the neuropharmacological activities of salidroside, citing anti-Alzheimer’s disease,anti-Parkinson’s disease, anti-stroke, cognition enhancement, anti-depressive, anxiolytic, amelioration of traumatic brain injury, anti-Huntington’s disease, anti-addiction and antiepileptic effects.

[0011] In ‘Therapeutic potential and molecular mechanisms of salidroside in ischemic diseases’, Han et al present a summary of literature relating to the molecular mechanisms and therapeutic effects of salidroside in treating ischemic diseases, referring to its anti- oxidative, anti-apoptotic, anti-inflammatory, angiogenic, and cell-protective properties. A review by Jin et al, in ‘Pharmacological effects of salidroside on central nervous system diseases, Biomedicine and Pharmacotherapy, 2022-12-01, Volume 156, Article 113746, reports that a large number of studies have shown that salidroside can directly or indirectly regulate a variety of intracellular molecules and signalling pathways, thereby improving neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, epilepsy, spinal cord injury, ischemic brain injury, and Huntington’s disease.

[0012] Uridine (1-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine- 2,4(1 H,3H)-dione) is a nucleoside with the following structure:

[0013]

[0014] HO OH

[0015] Uridine is known to play a role in a range of biological processes and can be produced in the human body. It is also found in various foodstuffs, such as sugar beet, sugarcane, tomatoes, yeast, organ meats, and broccoli. It is available as a dietary supplement, often as uridine monophosphate, in capsule or powder form.

[0016] Dietary supplements containing uridine are generally taken to improve cognitive function. The role of uridine in metabolic diseases, tumours, and neurodegenerative diseases is discussed by Yang et al in Front Physiol. 2024 Feb 29; 15:1360891. doi:

[0017] 10.3389 / fphys.2024.1360891. PMID: 38487261 ; PMCID: PMC10937367.

[0018] Summary of the InventionThe present inventors have identified salidroside and uridine as beneficial substances that are suitable for delivery by inhalation, e.g. particularly at defined concentrations.

[0019] Thus, in a first aspect, the present invention provides a composition for generating an inhalable product, said composition comprising at least one compound selected from salidroside, a source of salidroside, uridine, and uridine monophosphate.

[0020] Further, the present inventors have found that any of salidroside, a source of salidroside, uridine, and uridine monophosphate can be included in nicotine-containing compositions for inhalation with the effect of complementing the nicotine-related effects experienced by the user.

[0021] Thus, in a second aspect, the present invention provides a composition for generating an inhalable product comprising nicotine, said composition also comprising at least one compound selected from salidroside, a source of salidroside, uridine and uridine monophosphate.

[0022] The nicotine can be in its free base form or in the form of a salt of an organic acid.

[0023] In a third aspect, the present invention provides the use of salidroside or a source of salidroside in a composition for inhalation, which composition may comprise nicotine or be free of nicotine.

[0024] In a fourth aspect, the present invention provides the use of uridine or uridine monophosphate in a composition for inhalation, which composition may comprise nicotine or be free of nicotine.

[0025] In a fifth aspect, the present invention provides a kit comprising a device for generating an inhalable product and a composition according to the first or second aspects of the present invention.

[0026] In any aspect or embodiment, the salidroside component may be provided as a salidroside compound in a form having at least 50% purity by weight of the component / ingredient, e.g. at least 60%, 70%, 80% or 90% purity. The salidroside component may be provided as a substantially pure salidroside compound, e.g. at least 95% or 98% purity.

[0027] The composition may comprise a carrier. The salidroside compound may comprise up to about 20% by weight of the composition, such as up to about 15%, or up to about 10% by weight of the composition, including the carrier, and in an amount by weight of at least 1%, 2%, 3%, 4% or 5%. Excluding the carrier, salidroside or a source of salidroside maycomprise at least 5%, 10%, 20%, 30%, 40% or 50% by weight of the carrier, e.g. in an amount of up to about 60% by weight of the composition.

[0028] Uridine may comprise up to about 5% by weight of the composition, such as from about 0.5% to about 5% by weight of the composition, for example around 1%, around 1.5%, around 2.0%, around 2.5%, around 3.0%, around 3.5%, around 4.0%, around 4.5%, or around 5.0% by weight of the composition.

[0029] The composition may comprise both salidroside and uridine / uridine monophosphate, e.g. in a predetermined ratio by weight. The salidroside content of the composition may be greater than that of uridine / uridine monophosphate or vice versa. Uridine or uridine monophosphate may be included as a potentiator for salidroside, e.g. at lower content by weight than salidroside such as at a ratio of 1 :2, 1 :3, 1 :4 or lower.

[0030] Optional features described hereinbelow in relation to one aspect of he invention may be applied to other aspects, where practicable and / or compliant.

[0031] Detailed Description

[0032] of the Invention

[0033] As noted above, the present inventors have identified salidroside and uridine as beneficial substances that are suitable for delivery by inhalation. As well as salidroside and uridine in pure compound form, sources of salidroside and uridine monophosphate are suitable in the present context.

[0034] Delivery of these substances by inhalation may provide advantages over the oral capsules and powders currently available. Substances administered orally are most usually absorbed through the small intestine and must move through the digestive tract, passing through the intestinal wall and travelling to the liver before being transferred to its target site via the bloodstream. Metabolism in the intestinal wall and liver decrease the amount of the orally administered substance reaching the bloodstream. A substance delivered through inhalation can bypass the digestive system by direct administration to the lungs. Consequently, the inhaled substance can be more directly absorbed into the bloodstream, through the blood-brain barrier, and to the brain. Thus, delivery by inhalation may improve bioavailability and give a faster onset of action.

[0035] The first aspect of the invention relates to an inhalable composition of salidroside and I or uridine.In said first aspect, the present invention provides a composition for generating an inhalable product, said composition comprising at least one compound selected from salidroside, a source of salidroside, uridine, and uridine monophosphate.

[0036] Natural sources of salidroside include Rhodiola extracts, for example, Rhodiola rosea or Rhodiola crenulata.

[0037] Salidroside can also be generated through fermentation using microorganisms such as bacteria (for example , Escheria coli) and yeast.

[0038] Pathways for the synthesis of salidroside are discussed in Liang K, Ma S, Luo K, Wang R, Xiao C, Zhang X, Gao Y, Li M. ‘Salidroside: An Overview of Its Promising Potential and Diverse Applications’ Pharmaceuticals (Basel). 2024 Dec 17;17(12):1703. doi:

[0039] 10.3390 / ph17121703. PMID: 39770545; PMCID: PMC11678419.

[0040] The salidroside content used in aspects of the present invention can be distinguished from the salidroside content of naturally occurring Rhodiola extracts in terms of their purity and / or relative content by weight. Thus in accordance with aspects of the invention, the salidroside content may comprise or consist of purified, refined or synthesized salidroside. In some embodiments of the present invention, salidroside is provided in refined, synthesized or pure compound form (for example, a compound form having at least 50% purity or a pure compound having a purity of >98%). In some embodiments of the present invention, salidroside is provided in compound form having a purity of >60%, >70%, >80%, >90%, >95% or >98%. Salidroside with a purity of at least 98% is commercially available.

[0041] In some embodiments, the composition contains salidroside or a source of salidroside as the sole active ingredient.

[0042] In some embodiments, the composition contains uridine or uridine monophosphate as the sole active ingredient.

[0043] The composition is suitable for delivery by inhalation using a suitable device such as an electronic cigarette (e-cigarette or vape), water pipe (shisha), atomiser or nebuliser device.

[0044] In some embodiments, for example for use in an e-cigarette or atomiser device, the composition is in the form of an e-liquid, preferably comprising a carrier. Suitable carriers may include glycerin (such as vegetable glycerin), propylene glycol, trimethylene glycol, water, ethanol, and combinations thereof. Preferably, the carrier is selected fromvegetable glycerin (VG), propylene glycol (PG) and a combination thereof. When used in combination, any ratio of VG:PG may be used, for example from about 99:1 to about 1 :99 VG:PG by weight; including, for example, from about 90:10 to about 10:90 VG:PG by weight; from about 80:20 to about 20:80 VG:PG by weight; from about 70:30 to about 30:70 VG:PG by weight; and from about 60:40 to about 40:60 VG:PG by weight. In some embodiments, the VG and PG are used in equal amounts, that is, in a ratio of 1 :1 by weight.

[0045] In some embodiments, for example for use in a water-pipe device, the composition is in the form of a heterogeneous mixture of solids and liquids, with the solids either dissolved in the liquids or remaining as solids in the mixture. Cellulose may be used as a solid base material for water-pipe compositions in accordance with the present invention.

[0046] In some embodiments, for example for use in a nebuliser device, the composition is in liquid form, for example in saline solution.

[0047] In some embodiments of the first aspect of the invention, the composition may also include one or more additional active ingredients, as described below.

[0048] Xanthines

[0049] The composition in accordance with the first aspect of the present invention may comprise a xanthine compound; for example, caffeine (1 ,3,7-trimethylxanthine (1 ,3,7- trimethylpurine-2, 6-dione)):

[0050] o

[0051]

[0052] Synergy of caffeine and Rhodiola rosea have been reported, for example by Liu et al, in ‘Synergistic Effect of Rhodiola rosea and Caffeine Supplementation on the Improvement of Muscle Strength and Muscular Endurance: A Pilot Study for Rats, Resistance Exercise- Untrained and -Trained Volunteers’, Nutrients, 2023, Feb; 15(3): 582; doi:

[0053] httosj^doLorg / IO...3J39O%2 Fnu 150.30582, the entire contents of which are incorporated herein by reference.The inclusion of caffeine, a caffeine salt, or a source of caffeine in a composition in accordance with the first aspect of the present invention may give a product with positive effect on physical performance, energy metabolism, and endurance.

[0054] In some embodiments of the first aspect of the present invention, caffeine may be included in pure form, that is, as a single compound. Caffeine is commercially available as a single compound with high purity. In some embodiments of the present invention, caffeine is used in single compound form, with a purity of at least 98.5% and for example up to 99.99%, such as up to 99.9%.

[0055] In other embodiments, caffeine may be included as an extract from green tea and in a range of purity levels, for example from about 5%, such as from about 40% caffeine to about 95% caffeine, for example from about 50% caffeine, from about 60% caffeine, from about 70% caffeine, from about 80% caffeine, or from about 90% caffeine, for example. Caffeine from green tea is commercially available.

[0056] In other embodiments, caffeine may be included as green coffee, guarana seed, cocoa bean or kola nut extract.

[0057] Caffeine may also be included in the composition of the first aspect of the present invention in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts of caffeine include salts derived from inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, phosphoric, and nitric acids, and salts derived from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, tolunesulfonic, naphthalenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic acids.

[0058] When caffeine or a caffeine salt is included in the composition of the first aspect of the present invention, the composition may further comprise taurine.

[0059] Other xanthine compounds may be included in the composition of the first aspect of the present invention as alternatives to, or in addition to, caffeine. Examples of suitable alternative or additional xanthine compounds include, for example, hypoxanthine (1 ,9-dihydro-6H-purin-6-one), paraxanthine (1 ,7-dimethylxanthine), theophylline (1,3-dimethylxanthine), and theobromine (3,7-dimethylxanthine).

[0060] Compounds active at nicotine receptorsThe composition in accordance with the first aspect of the present invention may comprise a compound active at nicotine receptors.

[0061] One suitable compound is cytisine, (1R,5S)- 1,2, 3, 4, 5, 6- hexahydro- 1 ,5-methano-8H- pyrido[1 ,2a][1 ,5] diazocin-8-one:

[0062]

[0063] Also known as bapitoxine, cystinicline, or sophorine, cytisine is a partial agonist of nicotinic acetylcholine receptors and is widely used in eastern Europe as a smoking cessation aid. Cytisine has been found to be superior to nicotine replacement therapy for smoking cessation, as reported for example by Walker et al, in ‘Cytisine versus Nicotine for Smoking Cessation’, New England Journal of Medicine, Volume 371 , Number 25, December 18, 2014, pages: 2353-2362.

[0064] Pharmaceutically acceptable cytisine salts are also suitable for use in the present invention, including for example, the succinate, mesylate, gentisate and maleate salts of cytisine.

[0065] Other compounds that are active at nicotine receptors may be included as alternatives to, or in addition to, cytisine or a cytisine salt. For example, another suitable compound is varenicline, which is also a nicotinic acetylcholine partial agonist used to treat smoking addiction.

[0066] In preferred embodiments of the composition of the first aspect of the present invention, the composition does not include nicotine or nicotine salts.

[0067] Botanical Extracts

[0068] Other additional active ingredients that may be included in the composition of the first aspect of the present invention include botanical extracts.

[0069] Botanicals are widely used in traditional medicines, with many known to have antiinflammatory and antioxidant benefits that may be advantageous in the present composition.Botanical extracts for use in inhalable compositions such as e-liquids are known to the person skilled in the art. The following is a purely illustrative and non-exhaustive list of botanical ingredients contemplated for use in the composition of the first aspect of the present invention:

[0070] • Ginkgo biloba extract.

[0071] • Olive fruit / leaf / water extract (tyrosol or hydroxytyrosol)

[0072] • Flavonoids derived from ginkgo biloba, including for example Daidzein and Ginkgetin.

[0073] • Huperizin A (from the moss huperzia serrata).

[0074] • Panax ginseng (Asian ginseng)

[0075] • Panax quinqufolius (American ginseng).

[0076] • Eleutherococcus senticosus (Siberian ginseng).

[0077] • Maca (Peruvian ginseng).

[0078] • Brassica oleracea (wild cabbage).

[0079] • Scutellaria baicalensis (Chinese skullcap).

[0080] • Lavandula angustifolia (English lavender).

[0081] • Salvia rosmarius (rosemary).

[0082] • Salvia officinalis (common sage).

[0083] • Melissa officinalis (lemon balm).

[0084] • Mucuna pruriens (velvet bean).

[0085] • Piper methysticum (kava kava).

[0086] • Turnera diffusa (damania).

[0087] • Curcuma longa (turmeric).

[0088] • Angleica sinesis (dong quai).

[0089] • Bidens Pilosa (blackjack).

[0090] • Ligusticum porteri (porter lovage).

[0091] • Centella asiatica (Indian pennywort).

[0092] • Trigonella foenum-graecum (fenugreek).

[0093] • Artemisia annua (sweet wormwood).

[0094] • Bacopa monnieri (water hyssop).

[0095] • Passiflora incarnata (purple passion flower).

[0096] • Hyperium perforatum (perforate St John’s wort).

[0097] • Combretum quandrangulare (sakae naa).

[0098] • Humulus lupulus (common hop).In some embodiments of the first aspect of the invention, the composition may further include one or more additional ingredients, as described below.

[0099] Potentiator Compounds

[0100] In some embodiments, the composition of the first aspect of the present invention may include one or more potentiator compounds. Potentiator compounds are generally included in the composition in catalytic quantities and enhance the effects of the active compounds in the formulation. Potentiator compounds are known to the person skilled in the art, and any suitable known potentiator compound may be included in the composition of the first aspect of the present invention. Examples of suitable potentiator compounds include, but are not limited to, D-serine and sodium D-aspartate, and, in salidroside-containing compositions, uridine and uridine monophosphate.

[0101] Solubiliser compounds

[0102] In some embodiments, the composition of the first aspect of the present invention may include a solubilising compound, for example, an organic acid. Examples of organic acids include benzoic acid, lactic acid, malic acid and the like.

[0103] Cyclodextrin

[0104] In some embodiments, the composition of the first aspect of the present invention may include a cyclodextrin or other cage-type molecule. Such molecules may increase bioavailability by forming water soluble and biodegradable inclusion complexes with active ingredients in the present composition.

[0105] Flavourings and sweeteners

[0106] In some embodiments, the composition of the first aspect of the present invention may include one or more flavourings and / or one or more sweeteners. Natural and artificial flavourings and sweeteners are commonly used in products for use in e-cigarettes and water pipes, for example, and are well known to the person skilled in the art.

[0107] - pH modifiers

[0108] In some embodiments, the composition of the first aspect of the present invention may include a pH modifier, to adjust the pH of the composition to either a higher or a lower pH. pH modifiers are well known to the person skilled in the art and include both inorganic andorganic acids and bases, such as benzoic acid, citric acid, sodium bicarbonate, and sodium acetate, for example.

[0109] Cooling agents

[0110] In some embodiments, the composition of the first aspect of the present invention may include one or more cooling agents. Cooling agents are well known to the person skilled in the art, and include menthol, WS-3 (N-ethyl-2-(isopropyl)-5-methylcyclohexanecarboxamide) and WS-23 (2-isopropyl- / V,2,3-trimethylbutyramide), for example.

[0111] When the composition of the first aspect of the present invention is in the form of an e-liquid comprising a carrier, in some embodiments the carrier may make up to about 98% by weight of the composition, for example from about 60% to about 98% by weight of the composition. In some embodiments, no carrier is included. When salidroside or a source of salidroside is included, it may for example be included in an amount of up to about 20% by weight of the composition, such as up to about 15%, or up to about 10% by weight of the composition, and in an amount of at least about 1% by weight of the composition, such as at least about 2%, for example around 2%, around 2.5%, around 3.0%, around 3.5%, around 4.0%, around 4.5%, around 5.0%, around 5.5%, around 6.0%, around 6.5%, around 7.0%, around 8.0%, around 8.5%, around 9.0%, around 9.5% or around about 10.0% by weight of the composition. When no carrier is present, the salidroside or source of salidroside may be included in greater amounts; for example, a source of salidroside may be included in an amount of up to about 60% by weight of the composition.

[0112] Where compositions, excluding the carrier, comprising at least 5%, 10%, 20%, 30%, 40% or 50% by weight of salidroside are used, a distinction can be drawn between such products and naturally occurring Rhodeola substances and extracts, in which the salidroside content may be only around 1% or lower. When it is considered that such naturally occurring sources of salidroside would need to be mixed with other ingredients to achieve a viable composition, it can be appreciated that this would result in salidroside content of below 1%. In contrast, the current disclosure proposes that a salidroside content of at least 3wt%, 4wt% or 5wt% of the composition may be used to realise the effect of the salidroside in a composition for inhalation (excluding the carrier). When a suitable carrier content is included in the definition of the composition this may equate to a salidroside content by weight of at 1%, 2%, 3%, 5%, 7%When uridine is included, it may be included for example in an amount of up to about 5% by weight of the composition, such as from about 0.5% to about 5% by weight of the composition, for example around 1%, around 1.5%, around 2.0%, around 2.5%, around 3.0%, around 3.5%, around 4.0%, around 4.5%, or around 5.0% by weight of the composition.

[0113] When caffeine or another stimulant compound is included, it may be included for example in an amount of up to about 5% by weight of the composition, such as from about 0.5% to about 5% by weight of the composition, for example around 1%, around 1.5%, around 2.0%, around 2.5%, around 3.0%, around 3.5%, around 4.0%, around 4.5%, or around 5.0% by weight of the composition. When a source of caffeine is included, it may be included in higher amounts, such as up to about 25% by weight of the composition, and for example in amount of at least 5% by weight of the composition.

[0114] When cytisine or another compound active at nAChRs is included, it may be included for example in an amount of up to about 5% by weight of the composition, such as from about 0.5% to about 5% by weight of the composition, for example around 1%, around 1.5%, around 2.0%, around 2.5%, around 3.0%, around 3.5%, around 4.0%, around 4.5%, or around 5.0% by weight of the composition.

[0115] When a botanical extract is included, the total amount of botanical extracts is preferably up to about 20% by weight of the composition, and in an amount of at least about 1% by weight of the composition.

[0116] When a potentiator compound is included, the total amount of potentiator compounds is preferably up to about 10% by weight of the composition, and in an amount of at least about 1% by weight of the composition.

[0117] When a solubiliser compound is included, the total amount of solubiliser compounds is preferably up to about 5% by weight of the composition, for example from about 0.1% to about 5% by weight of the composition.

[0118] When a flavouring or sweetener is included, the total amount of flavourings and sweeteners is preferably up to about 20% by weight of the composition, for example from about 5.0% to about 15% by weight of the composition. pH modifiers, when present, are preferably included in an amount of from up to about 1% by weight of the composition, for example from about 0 / 5% to about 1.0% by weight of the composition.

[0119]

[0120] of the InventionAs further noted above, the present inventors have found that the inclusion of any of salidroside, a source of salidroside, uridine, and uridine monophosphate in nicotine-containing compositions for can complement the nicotine-related effects experienced by the user.

[0121] Nicotine, 3-[(2S)-1 -methylpyrrolidin-2-yl]pyridine:

[0122]

[0123] is a naturally occurring substance found at its highest levels in the tobacco plant. It is widely available in tobacco products including cigarettes, hookah tobacco, and e-cigarettes. It is known to increase dopamine levels when inhaled or otherwise consumed. With specific reference to e-liquids, nicotine-containing e-liquids commercially available in the UK generally contain up to 20mg / ml of nicotine - at this level, a 2ml vape will contain 40mg of nicotine. The present inventors have surprisingly found that the inclusion of any of salidroside, a source of salidroside, uridine, and uridine monophosphate in nicotine-containing e-liquids has the effect of substituting nicotine-related effects experienced by consumers. This has the consequence that, for a given content of nicotine, the addition of any of salidroside, a source of salidroside, uridine, and uridine monophosphate will result in an enhanced experience for the user and allows for the use of lower nicotine amounts when any of salidroside, a source of salidroside, uridine, and uridine monophosphate are included, without negative consequences for the user experience.

[0124] Thus, in a second aspect, the present invention provides a composition for generating an inhalable product comprising nicotine, said composition also comprising at least one compound selected from salidroside, a source of salidroside, uridine and uridine monophosphate.

[0125] Nicotine may be included in the composition of the second aspect of the present invention in its free base form, or in salt form. Examples of suitable salts of nicotine include, for example, nicotine benzoate and nicotine citrate. The skilled person will be aware of suitable alternative salts of nicotine.The nicotine may be in racemic, R-enantiomer ((+)-nicotine), or S-enantiomer ((-)-nicotine) form.

[0126] In some embodiments, the composition of the second aspect of the present invention includes salidroside or a source of salidroside (as described in relation to the first aspect of the invention) and does not contain uridine or uridine monophosphate.

[0127] In some embodiments, the composition of the second aspect of the present invention includes uridine or uridine monophosphate and does not contain salidroside or a source of salidroside (as described in relation to the first aspect of the invention).

[0128] The composition of the second aspect of the present invention preferably contains no xanthine compounds (xanthine compounds are set out herein in relation to the first aspect of the invention). The composition of the second aspect of the present invention preferably contains no additional compounds active at nicotine receptors (compounds active at nicotine receptors are set out herein in relation to the first aspect of the invention). Thus, in contrast to the composition according to the first aspect of the invention, the composition according to the second aspect of the invention does not contain caffeine, a caffeine salt, a source of caffeine, any other xanthine, nor does it contain cytisine, a cytisine salt, varenicline or any other compound active at nAchRs.

[0129] Otherwise, the composition of the second aspect of the present invention may include any of the additional ingredients described above in relation to the first aspect of the invention. Likewise, and as described above in relation to the first aspect of the invention, the composition may be in any form suitable for inhalation using a device adapted for delivery of substances by inhalation.

[0130] When the composition of the second aspect of the present invention is in the form of an e- liquid, the nicotine may be included in pure form or, for example, as a 10% solution in propylene glycol. In the latter form, the nicotine solution may be included for example in an amount of from about 5% to about 15% by weight, such as around 5%, around 10% or about 15%, although amounts outside of this range are contemplated.

[0131] Additional ingredients may be included in the amounts described above in relation to the first aspect of the invention.

[0132]

[0133] of the InventionIn a third aspect, the present invention provides the use of salidroside or a source of salidroside in a composition for inhalation in accordance with either of the first and second aspects of the invention.

[0134] The composition may be in any form suitable for inhalation using a device adapted for delivery of substances by inhalation, as described above in relation to the first aspect of the present invention.

[0135] In developments of the concept disclosed herein, it has been determined that salidroside hydrolyzes into tyrosol when heated in the presence of water. This was originally considered to be only a byproduct occurring during use of salidroside in a heated inhalation product. However its function as an active has been assessed.

[0136] Tyrosol / hydroxytyrosol has been found to offer relatively good absorption into the body, potentially better than salidroside. Furthermore tyrosol / hydroxytyrosol has been found render slightly adjusted pharmacology and potentially more noticeable effects, e.g.at an equivalent or lower dosage than salidroside. Therefore it is proposed that tyrosol / hydroxytyrosol could replace at least a portion of the salidroside content in any aspect of the invention.

[0137] In some examples, tyrosol could work in tandem with salidroside and may require a lower dosage. Thus the combination of tyrosol / hydroxytyrosol and salidroside may be within the percentages and weights of salidroside presented herein but may be provided in an amount that is reduced compared with the discussed salidroside content.

[0138] Tyrosol is readily available and may be used in the form of standardized olive fruit, olive leaf or olive water extracts, e.g. standardized at 10% or 25% hydroxytyrosol. Various methods are known for extracting high-purity hydroxytyrosol or synthesis thereof and suitable strengths of hydroxytyrosol are commercially available.

[0139] According to examples of a composition for generation of an inhalable product, a mix of both tyrosol and salidroside is optionally proposed, e.g. using a greater proportion of salidroside by weight. For example, a salidroside to tyrosol / hydroxytyrosol ratio of at least 3:1 , 5:1 , 7:1 or 10:1 could be used. An example comprises in the region of ten times less tyrosol component than salidroside component.

[0140] Fourth Aspect of the Invention

[0141] In a fourth aspect, the present invention provides the use of uridine or uridine monophosphate in a composition for inhalation in accordance with either of the first and second aspects of the invention.The composition may be in any form suitable for inhalation using a device adapted for delivery of substances by inhalation, as described above in relation to the first aspect of the present invention.

[0142] Fifth Aspect of the Invention

[0143] In a fifth aspect, the present invention provides a kit comprising a device for generating an inhalable product and a composition according to the first or second aspects of the present invention.

[0144] The device may be a device suitable for delivery of a substance by inhalation.

[0145] In some embodiments, the device is an electronic cigarette (vape) device.

[0146] In some embodiments, the device is a water pipe (shisha) device.

[0147] In some embodiments, the device is an atomiser device.

[0148] In some embodiments, the device is a nebuliser device.

[0149] The invention will now be illustrated by the following, non-limiting, examples.

[0150] Illustrative Examples

[0151] With reference to the following examples:

[0152] salidroside was used in the form of a powder with a purity > 98%;

[0153] caffeine was used in the form of a powder with purities as specified;

[0154] theophylline, cytisine, uridine, uridine monophosphate, D-serine and sodium D-aspartate were all used in pure (>98%) powder form;

[0155] vegetable glycerin and propylene glycol were used in liquid form or as a 1 :1 solution; benzoic acid was used in pellet form or as crystal rods;

[0156] guarana extract was used in the form of an alcohol and water-free glycerite;

[0157] ginkgo biloba and rhodiola extracts were used in alcohol and water-free glycerite form; stirring was generally carried out at 500rpm on a stirring hotplate with a magnetic stirrer, but alternative stirring conditions could be used - for example stirring at 100rpm to 1500rpm, and stirring using an overhead stirrer;

[0158] filtering is generally optional; andnicotine may alternatively be used in pure or diluted form.

[0159] CAS numbers for the compounds used in the examples are as follows:

[0160] Ingredient CAS Number

[0161] benzoic acid 65-85-0

[0162] caffeine 58-08-2

[0163] cytisine 485-35-8

[0164] D-aspartic acid 1783-96-6

[0165] D-serine 312-84-5

[0166] ginkgo biloba extract 90045-36-6*

[0167] green tea extract 84650-60-2*

[0168] guarana extract 84929-28-2*

[0169] hypoxanthine 68-94-0

[0170] paraxanthine 611-59-6

[0171] propylene glycol 57-55-6

[0172] rhodiola rosea extract 97404-52-9*

[0173] (-)-nicotine 54-11-5

[0174] salidroside 10338-51-9

[0175] sodium acetate 127-09-3

[0176] sodium bicarbonate 144-55-8

[0177] sodium chloride 7647-14-5

[0178] sodium D-aspartate 10329-81-4

[0179] theophylline 58-55-9

[0180] uridine 58-96-8

[0181] uridine

[0182] monophosphate 58-97-9

[0183]

[0184] vegetable glycerin 56-81-5

[0185] *CAS numbers for extracts refer to the neat extract rather than the glycerite.

[0186] Examples 1-38 illustrate the preparation of e-liquids developed to facilitate explanation and understanding the present disclosure. The prepared e-liquids are intended to be dispensed into suitable cartridges or containers for use with e-cigarettes.

[0187] Example 1: Salidroside

[0188] Salidroside (0.313g) was added to a 10 mL beaker. A 1 :1 solution of vegetable glycerin (VG) and propylene glycol (PG) was added (12.188g) and the mixture was heated with stirring (500 rpm) at 60°C on a stirring hotplate with a magnetic stir bar, for a period of 45 minutes. The solution was then removed from the heat and filtered through a 5-micron syringe filter.Example 2: Salidroside with Caffeine (99%)

[0189] Benzoic acid (0.440g) was added to a 20 mL glass vial, followed by a 1 :1 solution of VG and PG (9.110g) and caffeine (99%) (0.200g). The mixture was heated with stirring (500 rpm) at 60°C on a stirring hotplate with a magnetic stir bar, for a period of 1.5 hours before being removed from the heat. Salidroside (0.250g) was added and the mixture was heated with stirring (500 rpm) at 60°C on a stirring hotplate with a magnetic stir bar, for a period of 45 minutes before being removed from the heat and filtered through a 5-micron syringe filter.

[0190] Example 3: Salidroside with Caffeine (90%>)

[0191] Salidroside (0.250g) and caffeine (90%) (0.050g) were added to a 10 mL beaker. A 1 :1 solution of VG and PG was added (9.700g) and the mixture was heated with stirring (500 rpm) at 60°C on a stirring hotplate with a magnetic stir bar, for a period of 45 minutes. The solution was then removed from the heat and filtered through a 5-micron syringe filter. Example 4: Salidroside with Guarana extract (source of caffeine)

[0192] Salidroside (0.250g) was added to 20 mL glass vial, followed by a 1 :1 solution of VG and PG (9.750g). The mixture was heated with stirring (500 rpm) at 60°C on a stirring hotplate with a magnetic stir bar for a period of 45 minutes, and then removed from the heat.

[0193] Guarana extract (2.500g) was added and the mixture was stirred (500 rpm) without heat for 15 minutes. After allowing cool to ambient temperature, the solution was filtered through a 5-micron syringe filter.

[0194] Example 5: Salidroside with Guarana extract (source of caffeine) and potentiators Salidroside (0.250g), D-serine (0.125g), sodium D-aspartate (0.031g) and uridine (0.125g) were added to a 10 mL beaker, followed by a 1 :1 solution of VG and PG (9.469g). The mixture was heated with stirring (500 rpm) at 80°C on a stirring hotplate with a magnetic stir bar for a period of 1.5 hours, and then removed from the heat. Guarana extract (2.500g) was added and the mixture was stirred (500 rpm) without heat for 15 minutes and filtered through a 5-micron syringe filter.

[0195] Example 6: Salidroside with Theophylline, Guarana extract (source of caffeine) and potentiators

[0196] Composition:

[0197] Salidroside powder 0.200g

[0198]

[0199] Theophylline powder 0.050g Guarana extract powder 1.000g

[0200] D-serine powder 0.100g

[0201] Sodium D-aspartate powder 0.050g

[0202] Uridine powder 0.100g

[0203] Glycerin liquid 4.150g

[0204] Propylene Glycol (PG) liquid 4.150g

[0205]

[0206] The powdered ingredients were added to a 10 mL beaker, one-by-one, followed by glycerin, and finally, PG. The mixture was stirred on a stirring hotplate with a magnetic stir bar, at 80°C for 90 minutes, before being removed from the heat. Once at ambient temperature, the mixture was filtered through a 5 micron syringe filter.

[0207] Example 7: Salidroside with potentiators (no caffeine)

[0208] Salidroside (0.200g), D-serine (0.100g), sodium D-aspartate (0.025g) and uridine (0.100g) were added to a 10 mL beaker, followed by a 1 :1 solution of VG and PG (9.575g). The mixture was heated with stirring (500 rpm) at 80°C on a stirring hotplate with a magnetic stir bar for a period of 1.5 hours, and then removed from the heat and filtered through a 5 micron syringe filter.

[0209] Example 8: Salidroside with potentiators and caffeine (90%)

[0210] Composition:

[0211] Salidroside powder 0.500g

[0212] Caffeine (90%) powder 0.100g

[0213] D-serine powder 0.200g

[0214] Sodium D-aspartate powder 0.050g

[0215] Uridine powder 0.200g

[0216]

[0217] VG / PG 1:1 stock solution 18.950g

[0218] Salidroside, caffeine, and the other powdered ingredients were added to a 10 mL beaker, followed by the VG / PG solution. The mixture was stirred (500 rpm) on a stirring hotplate with a magnetic stir bar, at 80°C for 1.5 hours, before being removed from the heat. The mixture was then filtered through a 5 micron syringe filter.

[0219] Example 9: Salidroside with potentiators and caffeine

[0220] Composition:Salidroside powder 0.250g Caffeine powder 0.200g

[0221] D-serine powder 0.100g

[0222] Sodium D-aspartate powder 0.050g

[0223] Uridine powder 0.100g

[0224] Benzoic Acid pellets 0.440g

[0225]

[0226] VG / PG 1:1 stock solution 18.950g

[0227] Benzoic acid was added to a 10 mL glass beaker, followed by VG / PG and then the caffeine powder. The mixture was heated with stirring (500 rpm) at 80°C on a stirring hotplate with a magnetic stir bar for a period of 1.5 hours, and then removed from the heat. Salidroside and the potentiators (D-serine, sodium D-aspartate and uridine) were added and the mixture was heated at 80°C on a stirring hotplate with a magnetic stir bar for a period of 1.5 hours, before being filtered through a 5-micron syringe filter.

[0228] Example 10: Salidroside with caffeine, cytisine, and potentiators

[0229] Composition:

[0230] Salidroside powder 0.300g

[0231] Caffeine powder 0.025g

[0232] Cytisine powder 0.200g

[0233] D-serine powder 0.100g

[0234] Sodium D-aspartate powder 0.050g

[0235] Uridine powder 0.200g

[0236] Glycerin liquid 4.600g

[0237]

[0238] Propylene Glycol (PG) liquid 4.550g

[0239] Glycerin and PG were added to a 10 mL beaker, followed, one-by-one, by the powdered ingredients. The mixture was stirred on a stirring hotplate with a magnetic stir bar, at 80°C for 90 minutes, after which the mixture was filtered through a 5-micron syringe filter. Example 11 : Salidroside with caffeine, theophylline, cytisine, and potentiators Composition

[0240] Salidroside powder 0.200g

[0241] Caffeine powder 0.025g Theophylline powder 0.050g

[0242] D-serine powder 0.200g

[0243]

[0244] Sodium D-aspartate powder 0.050gUridine powder 0.200g Glycerin liquid 4.695g

[0245] Propylene Glycol liquid 4.550g

[0246]

[0247] Cytisine powder 0.050g

[0248] Glycerin and PG were added to a 10 mL beaker, followed, one-by-one, by the powdered ingredients. The mixture was stirred on a stirring hotplate with a magnetic stir bar, at 80°C for 90 minutes, after which the mixture was removed from the heat, allowed to cool to ambient temperature, and filtered through a 5-micron syringe filter.

[0249] Example 12: Rhodiola extract (extract source of Salidroside active), Guarana and Gingko Biloba

[0250] Rhodiola extract (alcohol and water-free glycerite) (0.800g), Guarana extract (alcohol and water-free glycerite) (0.800g) and Gingko Biloba extract (alcohol and water-free glycerite) (0.400g) were added to a 10 mL beaker, followed by a 1 :1 solution of VG and PG (8.000g). The mixture stirred on a stirring hotplate with a magnetic stir bar at ambient temperature, for a period of 30 minutes.

[0251] Example 13: Rhodiola extract (extract source of Salidroside active), Guarana and Gingko Biloba, with potentiators

[0252] D-Serine (0.100g), sodium d-aspartate (0.025g) and uridine (0.100g), all in powdered form, were added to a 10 mL glass beaker, followed by a 1 :1 solution of VG and PG (7.775g). The mixture was stirred on a stirring hotplate with a magnetic stir bar, at 80°C for 90 minutes, and removed from the heat. Rhodiola extract (alcohol and water-free glycerite) (0.800g), Guarana extract (alcohol and water-free glycerite) (0.800g) and Gingko Biloba extract (alcohol and water-free glycerite) (0.400g) were then added.

[0253] Example 14: Salidroside with Caffeine (95%)

[0254] Salidroside (2.500g) and caffeine (0.238g) were added to a glass beaker, followed by a 1 :1 solution of vegetable glycerin and propylene glycol (22.263g), and the mixture was stirred at 60°C for 60 minutes before cooling and filtering.

[0255] Example 15: Salidroside

[0256] Salidroside (2.500g) was added to a glass beaker, followed by a 1 :1 solution of vegetable glycerin and propylene glycol (22.500g) and the mixture was stirred at 60°C for 60 minutes before cooling and filtering.Example 16: Uridine with nicotine

[0257] Composition

[0258] Uridine powder 0.200g

[0259] (-)-Nicotine solution (10% in PG) 3.000g

[0260] Flavouring liquid 2.400g

[0261] Benzoic acid crystal rods 0.225g

[0262] Vegetable glycerin liquid 7.074g

[0263]

[0264] Propylene glycol liquid 7.100g

[0265] Propylene glycol, benzoic acid and uridine were added to a glass beaker, heated and stirred at 50° C for 60 minutes, before being left to cool. Nicotine solution was added and the mixture was stirred for 10 minutes, followed by the addition of vegetable glycerin and flavouring, and stirring for a further 10 minutes.

[0266] Example 17: Uridine, nicotine and salidroside

[0267] Composition

[0268] Uridine powder 0.500g

[0269] (-)-Nicotine solution (10% in PG) 1.000g

[0270] Salidroside Powder 1.500g

[0271] Flavouring liquid 2.400g

[0272] Benzoic acid crystal rods 0.075g

[0273] Vegetable glycerin liquid 6.525g

[0274]

[0275] Propylene glycol liquid 8.000g

[0276] Propylene glycol, benzoic acid, uridine and salidroside were added to a glass beaker, heated and stirred at 50° C for 60 minutes, before being left to cool. Nicotine solution was added and the mixture was stirred for 10 minutes, followed by the addition of vegetable glycerin and flavouring, and stirring for a further 10 minutes.

[0277] Example 18: Uridine, nicotine and salidroside

[0278] Composition

[0279] Uridine powder 0.500g

[0280] (-)-Nicotine solution (10% in PG) 1.000g

[0281] Salidroside Powder 0.500g

[0282] Flavouring liquid 2.400g

[0283]

[0284] Benzoic acid crystal rods 0.075gVegetable glycerin liquid 7.525g

[0285]

[0286] Propylene glycol liquid 8.000g

[0287] Propylene glycol, benzoic acid, uridine and salidroside were added to a glass beaker, heated and stirred at 50° C for 60 minutes, before being left to cool. Nicotine solution was added and the mixture was stirred for 10 minutes, followed by the addition of vegetable glycerin and flavouring, and stirring for a further 10 minutes.

[0288] Example 19: Uridine, nicotine and salidroside

[0289] Composition

[0290] Uridine powder 0.200g

[0291] (-)-Nicotine solution (10% in PG) 1.000g

[0292] Salidroside Powder 1.000g

[0293] Flavouring liquid 2.400g

[0294] Benzoic acid crystal rods 0.075g

[0295] Vegetable glycerin liquid 7.325g

[0296]

[0297] Propylene glycol liquid 8.000g

[0298] Propylene glycol, benzoic acid, uridine and salidroside were added to a glass beaker, heated and stirred at 50° C for 60 minutes, before being left to cool. Nicotine solution was added and the mixture was stirred for 10 minutes, followed by the addition of vegetable glycerin and flavouring, and stirring for a further 10 minutes.

[0299] Example 20: Uridine, nicotine and salidroside

[0300] Composition

[0301] Uridine powder 0.200g

[0302] (-)-Nicotine solution (10% in PG) 3.000g

[0303] Salidroside Powder 0.500g

[0304] Flavouring liquid 2.400g

[0305] Benzoic acid crystal rods 0.225g

[0306] Vegetable glycerin liquid 7.000g

[0307]

[0308] Propylene glycol liquid 6.674g

[0309] Propylene glycol, benzoic acid, uridine and salidroside were added to a glass beaker, heated and stirred at 50° C for 60 minutes, before being left to cool. Nicotine solution wasadded and the mixture was stirred for 10 minutes, followed by the addition of vegetable glycerin and flavouring, and stirring for a further 10 minutes.

[0310] Example 21: Uridine, nicotine and salidroside

[0311] Composition

[0312] Uridine powder 0.200g

[0313] (-)-Nicotine solution (10% in PG) 2.000g

[0314] Salidroside Powder 0.500g

[0315] Flavouring liquid 2.400g

[0316] Benzoic acid crystal rods 0.150g

[0317] Vegetable glycerin liquid 7.350g

[0318]

[0319] Propylene glycol liquid 7.400g

[0320] Propylene glycol, benzoic acid, uridine and salidroside were added to a glass beaker, heated and stirred at 50° C for 60 minutes, before being left to cool. Nicotine solution was added and the mixture was stirred for 10 minutes, followed by the addition of vegetable glycerin and flavouring, and stirring for a further 10 minutes.

[0321] Example 22: Uridine, nicotine and salidroside

[0322] Composition

[0323] Uridine powder 0.500g

[0324] (-)-Nicotine solution (10% in PG) 1.000g

[0325] Salidroside Powder 1.500g

[0326] Flavouring liquid 2.400g

[0327] Benzoic acid crystal rods 0.075g

[0328] Vegetable glycerin liquid 6.525g

[0329]

[0330] Propylene glycol liquid 8.000g

[0331] Propylene glycol, benzoic acid, uridine and salidroside were added to a glass beaker, heated and stirred at 50° C for 60 minutes, before being left to cool. Nicotine solution was added and the mixture was stirred for 10 minutes, followed by the addition of vegetable glycerin and flavouring, and stirring for a further 10 minutes.

[0332] Example 23: Uridine with nicotine

[0333] Composition

[0334] Uridine powder(-)-Nicotine solution (10% in PG) 2.000g

[0335] Flavouring liquid 2.400g

[0336] Benzoic acid crystal rods 0.150g

[0337] Vegetable glycerin liquid 7.600g

[0338]

[0339] Propylene glycol liquid 7.650g

[0340] Propylene glycol and uridine were added to a glass beaker, heated and stirred at 50° C for 60 minutes, before being left to cool. Nicotine solution was added and the mixture was stirred for 10 minutes, followed by the addition of vegetable glycerin and flavouring, and stirring for a further 10 minutes.

[0341] Example 24: Uridine, nicotine and salidroside

[0342] Composition

[0343] Uridine powder 0.200g

[0344] (-)-Nicotine solution (10% in PG) 2.000g

[0345] Salidroside powder 0.500g

[0346] Flavouring liquid 2.400g

[0347] Vegetable glycerin liquid 7.400g

[0348]

[0349] Propylene glycol liquid 7.500g

[0350] Propylene glycol, uridine and salidroside were added to a glass beaker, heated and stirred at 50° C for 60 minutes, before being left to cool. Nicotine solution was added and the mixture was stirred for 10 minutes, followed by the addition of vegetable glycerin and flavouring, and stirring for a further 10 minutes.

[0351] Example 25: Uridine with nicotine

[0352] Composition

[0353] Salidroside powder 0.250g

[0354] (-)-Nicotine liquid (10% in PG) 1.000g

[0355] Flavouring liquid 2.400g

[0356] Vegetable glycerin liquid 3.775g

[0357] Propylene glycol liquid 3.775g

[0358]

[0359] Propylene glycol and salidroside were added to a glass beaker, heated and stirred at 50° C for 60 minutes, before being left to cool. Nicotine solution was added and the mixturewas stirred for 10 minutes, followed by the addition of vegetable glycerin and flavouring, and stirring for a further 10 minutes.

[0360] Example 26: Salidroside with caffeine (>90%)

[0361] Composition

[0362] Salidroside powder 5.000g

[0363] Caffeine (>90%) powder 0.950g

[0364] D-serine powder 1.000g

[0365] Flavouring liquid 2.400g

[0366] Vegetable glycerin liquid 44.025g

[0367]

[0368] Propylene glycol liquid 44.025g

[0369] Vegetable glycerin and propylene glycol were added to a glass beaker, followed by salidroside, caffeine and D-serine, and the mixture was stirred at 80°C for 120 minutes before being left to cool. The flavouring was added and the mixture was stirred for a further 10 minutes before being filtered.

[0370] Example 27: Salidroside with uridine (99%>+)

[0371] Composition

[0372] Salidroside powder 7.500g

[0373] Uridine (99%+) powder 1.000g

[0374] Flavouring liquid 13.500g

[0375] Vegetable glycerin liquid 39.000g

[0376]

[0377] Propylene glycol liquid 39.000g

[0378] Vegetable glycerin and propylene glycol were added to a glass beaker, followed by salidroside and uridine, and the mixture was stirred at 80°C for 60 minutes before being left to cool. The flavouring was added and the mixture was stirred for a further 10 minutes before being filtered.

[0379] Example 28: Salidroside with caffeine (>90%>) and uridine

[0380] Composition

[0381] Salidroside powder 5.000g

[0382] Caffeine (>90%) powder 0.950g

[0383] Uridine powder 1.000g

[0384]

[0385] Flavouring liquid 12.000gVegetable glycerin liquid 40.525g

[0386]

[0387] Propylene glycol liquid 40.525g

[0388] Vegetable glycerin and propylene glycol were added to a glass beaker, followed by salidroside, caffeine and uridine, and the mixture was stirred at 80°C for 60 minutes before being left to cool. The flavouring was added and the mixture was stirred for a further 10 minutes before being filtered.

[0389] Example 29: Salidroside with uridine (99%+)

[0390] Composition

[0391] Salidroside powder 7.500g

[0392] Uridine (99%+) powder 1.000g

[0393] Flavouring liquid 13.500g

[0394] Sodium bicarbonate 1M solution 1.000g

[0395] Vegetable glycerin liquid 38.500g

[0396]

[0397] Propylene glycol liquid 38.500g

[0398] Vegetable glycerin and propylene glycol were added to a glass beaker, followed by salidroside and uridine, and the mixture was stirred at 60°C for 60 minutes before being left to cool. The flavouring and sodium bicarbonate were added and the mixture was stirred for a further 10 minutes before being filtered.

[0399] Example 30: Salidroside with caffeine (>90%>) and uridine

[0400] Composition

[0401] Salidroside powder 5.000g

[0402] Caffeine (>90%) powder 0.950g

[0403] Uridine powder 1.000g

[0404] Flavouring liquid 12.000g

[0405] Sodium bicarbonate 1M solution 0.500g

[0406] Vegetable glycerin liquid 40.275g

[0407]

[0408] Propylene glycol liquid 40.275g

[0409] Vegetable glycerin and propylene glycol were added to a glass beaker, followed by salidroside, caffeine and uridine, and the mixture was stirred at 60°C for 60 minutes before being left to cool. The flavouring and sodium bicarbonate were added and the mixture was stirred for a further 10 minutes before being filtered.Example 31: Salidroside, uridine and nicotine (pure)

[0410] Composition

[0411] Salidroside powder 2.000g

[0412] Uridine powder 1.000g

[0413] Nicotine pure liquid 0.600g

[0414] Flavouring liquid 4.800g

[0415] Benzoic acid crystal rods 0.450g

[0416] Vegetable glycerin liquid 14.050g

[0417]

[0418] Propylene glycol liquid 17.100g

[0419] Benzoic acid and propylene glycol were heated together at 40°C with stirring for a period of 30 minutes, Uridine, salidroside and vegetable glycerin were added and the mixture was heated to 60°C, stirred for a period of 45 minutes and allowed to cool. Nicotine and flavouring were added and the mixture was stirred at room temperature for a period of 10 minutes.

[0420] Example 32: Uridine and nicotine (pure)

[0421] Composition

[0422] Uridine powder 1.400g

[0423] Nicotine pure liquid 0.200g

[0424] Flavouring liquid 5.600g

[0425] Benzoic acid crystal rods 0.150g

[0426] Vegetable glycerin liquid 15.200g

[0427]

[0428] Propylene glycol liquid 17.450g

[0429] Benzoic acid and propylene glycol were heated together at 40°C with stirring for a period of 30 minutes, Uridine and vegetable glycerin were added and the mixture was heated to 60°C, stirred for a period of 45 minutes and allowed to cool. Nicotine and flavouring were added and the mixture was stirred at room temperature for a period of 10 minutes.

[0430] Example 33: Uridine and nicotine (pure)

[0431] Composition

[0432] Uridine powder 1.400g

[0433] Nicotine pure liquid 2.000g

[0434] Flavouring liquid 5.600g

[0435]

[0436] Benzoic acid crystal rods 0.150gVegetable glycerin liquid 15.200g

[0437]

[0438] Propylene glycol liquid 15.650g

[0439] Benzoic acid and propylene glycol were heated together at 40°C with stirring for a period of 30 minutes, Uridine and vegetable glycerin were added and the mixture was heated to 60°C, stirred for a period of 45 minutes and allowed to cool. Nicotine and flavouring were added and the mixture was stirred at room temperature for a period of 10 minutes. Example 34: Uridine and nicotine (pure)

[0440] Composition

[0441] Uridine powder 1.400g

[0442] Nicotine pure liquid 6.000g

[0443] Flavouring liquid 5.600g

[0444] Benzoic acid crystal rods 0.450g

[0445] Vegetable glycerin liquid 13.600g

[0446]

[0447] Propylene glycol liquid 12.950g

[0448] Benzoic acid and propylene glycol were heated together at 40°C with stirring for a period of 30 minutes, Uridine and vegetable glycerin were added and the mixture was heated to 60°C, stirred for a period of 45 minutes and allowed to cool. Nicotine and flavouring were added and the mixture was stirred at room temperature for a period of 10 minutes. Example 35: Salidroside, undine and nicotine

[0449] Composition

[0450] Salidroside powder 1.000g

[0451] Uridine powder 0.500g

[0452] Nicotine Liquid, 10% in PG 1.000g

[0453] Flavouring liquid 3.000g

[0454] Benzoic acid crystal rods 0.075g

[0455] Vegetable glycerin liquid 7.025g

[0456] Propylene glycol liquid 7.400g

[0457]

[0458] Benzoic acid and propylene glycol were heated together at 40°C with stirring for a period of 30 minutes, Uridine, salidroside and vegetable glycerin were added and the mixture was heated to 60°C, stirred for a period of 45 minutes and allowed to cool. Nicotine andflavouring were added and the mixture was stirred at room temperature for a period of 10 minutes.

[0459] Example 36: Salidroside, uridine and nicotine

[0460] Composition

[0461] Salidroside powder 2.000g

[0462] Uridine powder 1.000g

[0463] Nicotine Liquid, 10% in PG 6.000g

[0464] Flavouring liquid 4.800g

[0465] Benzoic acid crystal rods 0.450g

[0466] Vegetable glycerin liquid 14.050g

[0467]

[0468] Propylene glycol liquid 11.700g

[0469] Benzoic acid and propylene glycol were heated together at 40°C with stirring for a period of 30 minutes, Uridine, salidroside and vegetable glycerin were added and the mixture was heated to 60°C, stirred for a period of 45 minutes and allowed to cool. Nicotine and flavouring were added and the mixture was stirred at room temperature for a period of 10 minutes.

[0470] Example 37: Salidroside, undine and caffeine

[0471] Composition

[0472] Salidroside powder 5.000g

[0473] Uridine powder 2.500g

[0474] Caffeine (>90%) powder 0.950g

[0475] Flavouring liquid 10.000g

[0476] Vegetable glycerin liquid 51.550g

[0477]

[0478] Propylene glycol liquid 30.000g

[0479] Vegetable glycerin, propylene glycol and caffeine were heated together to 60°C with stirring for a period of 120 minutes and allowed to cool. Flavouring was added and the mixture was stirred for a period of 10 minutes and filtered.

[0480] Example 38: Salidroside and uridine

[0481] Composition

[0482] Salidroside powder 7.500g

[0483]

[0484] Uridine powder 2.500gFlavouring liquid 13.000g Vegetable glycerin liquid 47.000g

[0485]

[0486] Propylene glycol liquid 30.000g

[0487] Vegetable glycerin, propylene glycol, salidroside and uridine were heated together to 60°C with stirring for a period of 60 minutes and allowed to cool. Flavouring was added and the mixture was stirred for a period of 10 minutes and filtered.

[0488] Example 39: Water-pipe composition: salidroside and uridine

[0489] Composition (1000g batch)

[0490] Salidroside powder 5g

[0491] Uridine powder 1g

[0492] Cellulose fibre 150g

[0493] Fructose liquid 300g

[0494] Flavouring liquid 150g

[0495]

[0496] Vegetable glycerin liquid 544g

[0497] Salidroside and uridine are dissolved in VG with heating at 60°C and stirring for a period of 60 minutes and allowed to cool. Cellulose is added to a separate container and fructose and flavouring added and mixed with cellulose. The salidroside / uridine / VG mixture is added to the cellulose / fructose / flavouring and mixed.

[0498] Example 40: Water-pipe composition: Rhodiola extract and uridine

[0499] Composition (1000g batch)

[0500] Rhodiola extract powder 20g

[0501] Uridine powder 5g

[0502] Guarana extract powder 20g

[0503] Cellulose fibre 150g

[0504] Fructose liquid 300g

[0505] Flavouring liquid 150g

[0506]

[0507] Vegetable glycerin liquid 505g

[0508] Uridine is dissolved in VG with heating at 60°C and stirring for a period of 60 minutes and allowed to cool. Cellulose is added to a separate container and fructose and flavouring added and mixed with cellulose, followed by the Rhodiola extract and Guarana extract. The uridine / VG mixture is then added and mixed.Example 41: Nebuliser composition: salidroside and uridine

[0509] Composition (500g batch)

[0510] Salidroside powder 1.3g

[0511] Uridine powder 0.5g

[0512] Sodium chloride crystals 4.5g

[0513] Sodium bicarbonate powder 0.3g

[0514]

[0515] De-ionised water liquid 493.45g

[0516] Salidroside and uridine are dissolved with stirring in boiling de-ionised water. After allowing to cool to room temperature, sodium chloride is added followed by sodium bicarbonate, with stirring until dissolved.

[0517] Example 42: Nebuliser composition: salidroside, undine and caffeine

[0518] Composition (500g batch)

[0519] Salidroside powder 1.3g

[0520] Uridine powder 0.25g

[0521] Caffeine (99% USE) powder 0.5g

[0522] Sodium chloride crystals 4.5g

[0523] Sodium bicarbonate powder 0.3g

[0524]

[0525] De-ionised water liquid 493.15g

[0526] Salidroside, uridine and caffeine are dissolved with stirring in boiling de-ionised water. After allowing to cool to room temperature, sodium chloride is added followed by sodium bicarbonate, with stirring until dissolved.

[0527] Example 43: Delivery of salidroside and uridine

[0528] E-liquids in accordance with the present invention were prepared and the vapours produced on use of the e-liquids in an e-cigarette were analysed.

[0529] The transfer rate of salidroside was found to be from 27.3% to 41.0%.

[0530] The transfer rate of uridine was found to be from 17.9% to 35.2%.

[0531] Example 44: Complementary effect of salidroside and uridine in nicotine-containing e-liquids: user trial

[0532] Five nicotine-containing e-liquids were prepared and pod samples containing the e-liquids were provided to existing users of nicotine vapes for testing. Each tester was providedwith the test pods at the start of a day and advised not to consume nicotine or caffeine before the trial. The testers were not given information as to the contents of the pods and they were forbidden from discussing their views on the products with the other testers. All of the e-liquids included PG and VG in a 50:50 ratio, and berry flavouring. The nicotine, uridine and salidroside content of the e-liquids were as follows:

[0533] Pod ID Description Remarks

[0534] 1 1.5% Nicotine, Uridine additive

[0535] 2 1.5% Nicotine, Salidroside and Uridine additives

[0536] 3 0.5% Nicotine, Uridine additive

[0537] 4 0.5% Nicotine, Salidroside and Uridine additives

[0538] 5 1.5% Nicotine-only Benchmark

[0539]

[0540] Each tester was asked the following two questions and their responses were collected as free-text:

[0541] 1 ) Did you experience any differences to your existing nicotine vape?;

[0542] 2) What strength nicotine solution do you think the pod is?

[0543] Reponses received from the testers indicated that the perceived strength of the e-liquid was 2% nicotine or higher. Testers reported ‘strong impact’, ‘smoother’, and ‘different effect’ compared with their regular vapes, with pods 3 and 4 being described as having a ‘focussing’ effect.

Claims

CLAIMS1. A composition for generating an inhalable product, said composition comprising at least one compound selected from salidroside, a source of salidroside, uridine, and uridine monophosphate.

2. A composition as claimed in any claim 1 , wherein the composition contains salidroside or a source of salidroside uridine, or uridine monophosphate as the sole active ingredient.

3. A composition as claimed in claim 1 , wherein the composition contains salidroside and uridine or uridine monophosphate in a predetermined ratio.

4. A composition for generating an inhalable product comprising nicotine, said composition also comprising at least one compound selected from salidroside, a source of salidroside, uridine and uridine monophosphate.

5. A composition as claimed in claim 4, where in the nicotine is in free base form or in the form of a salt of an organic acid.

6. A composition as claimed in any preceding claim, wherein the source of salidroside comprises a refined Rhodiola extract having salidroside content of at least 50%, 60% or 70%.

7. A composition as claimed in any preceding claim, wherein the salidroside content by weight of the composition is at least 10%, 20% or 30%.

8. A composition as claimed in claim 7, wherein the composition further comprises a carrier and the salidroside content by weight of the composition including the carrier is at least 1 %, 2% or 3%.

9. A composition as claimed in any one of claims 1-3 and 6-8, further comprising a xanthine compound.

10. A composition as claimed in claim 9, comprising caffeine, a salt of caffeine, or a source of caffeine.

11. A composition as claimed in claim 10, further comprising taurine.

12. A composition as claimed in any one of claims 1 -3 and 6-11, further comprising a compound active at a nicotine receptor.

13. A composition as claimed in claim 12, wherein the compound active at a nicotine receptor is not nicotine, a salt of nicotine, or a source of nicotine.

14. A composition as claimed in claim 12, wherein the compound active at a nicotine receptor is selected from cytisine, a pharmaceutically acceptable salt of cytisine, and varenicline.

15. A composition as claimed in any preceding claim further comprising any of, or any combination of: a botanical extract; a potentiator compound; a solubiliser compound; cyclodextrin; a flavouring; a sweetener; a pH modifier; and a cooling agent.

16. A composition as claimed in any one of the preceding claims, wherein the composition is adapted for use in an electronic cigarette device.

17. A composition as claimed in claim 16, wherein the composition is in the form of an e-liquid.

18. A composition as claimed in claim 17, wherein the composition comprises a carrier forming a majority of the composition by weight.

19. A composition as claimed in claim 18, wherein the carrier is selected from vegetable glycerin, propylene glycol, trimethylene glycol, water, ethanol, and combinations thereof.

20. A composition as claimed in any one of claims 1 -19, wherein the composition is adapted for use in a water pipe (shisha) device, an atomiser device or a nebuliser device.

21. Use of a salidroside compound or a source of salidroside in a composition for inhalation, wherein the salidroside compound or source of salidroside has at last 50% purity.

22. Use as claimed in claim 21 , wherein the composition is as described in any one of claims 1-19.

23. Use of uridine or uridine monophosphate in a composition for inhalation.

24. Use as claimed in claim 23, wherein the composition is as described in any one of claims 1 and 3-19.

25. A kit comprising a device for generating an inhalable product and a composition according to any one of claims 1-19, wherein the device for generating an inhalable product is selected from an electronic cigarette device, a water pipe (shisha) device, an atomiser device and a nebuliser device.

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