CN107072313A - Nicotine dosage - Google Patents

Abstract

A kind of oral suction-type preparation for the method for being used in object alleviate or prevent the craving for tobacco related to tobacco dependence, it includes nicotine or its acceptable salts and propellant, wherein, the daily dose of suction-type preparation is provided in one or more pressurizing vessels, the suction-type preparation is used to utilize simulation cigarette pulmonary administration, the simulation cigarette has housing, be configured to receive and accommodate the suction-type preparation from pressurizing vessel charging reservoir and outlet valve, and the daily dose of the suction-type preparation delivers daily dose comprising the nicotine or its acceptable salts for being less than 60mg.

Description

Nicotine dosage

The present invention relates to a kind of dosage of the suction-type preparation containing nicotine, and for delivering the dosage Device.

Smoking is the Addictive Behaviors related to the pleasant feeling that nicotine is caused, and custom for smoker and ceremony institute are strong Change.These attributes, which are combined, to abandon that smoking is extremely difficult, although the carbon monoxide of tobacco, tar and other combustion products for Health has a large amount of harmful effects.It is not nicotine itself, but the accessory substance insalubrity of tobacco smoke.

There are a large amount of smoking cessation appurtenances used in effective nicotine replacement therapy (NRT), such as cigarette on current market Alkali dermal patch, containing nicotinamide chewing gum, nicotine box and nicotine inhalator.These appurtenances attempt to realize that tobacco smoke is provided Blood nicotine content rise, and in the absence of related dangerous accessory substance.In the NRT of various patterns, nicotine inhalator The ceremony of smoking has most closely been carved again.One class nicotine inhalator is named as " gasifier " or " electronic cigarette ".It is fragrant in electronics " e " In cigarette, as the situation of conventional tobacco cigarette, nicotine must be heated, with oral delivery to user (in cigarettes In the case of cause burning, or cause in the case of e cigarettes gasification).This heating causes to produce such as aldehyde, ketone, nitrosamine With the harmful side product such as heavy metal, by suction, they are then also delivered to user.Therefore, it is used as NRT using e cigarettes In the presence of potential health consequences.

The nicotine inhalator that commercially need not have gasified.These inhalators provide nicotine in polyethylene porous plug Preparation, for exampleInhalator.Porous plug inhalator can be used in 10mg or 15mg magazine, but the delivering of nicotine Dosage is substantially less than the amount provided in the magazine.Because normal in use, many nicotine are still adsorbed in vinyl stopper On.For example, 20 minutes go deep into use after, average 4mg nicotine discharged from 10mg magazines (Hukkanen etc., Pharmacol.Rev.2005,57,79).However, the distribution of the nicotine dosage delivered from porous plug inhalator magazine is height Variable.The dosage of each magazine delivering is 1.3mg~6.2mg.In addition, the nicotine release profiles from vinyl stopper have height The temperature dependency of degree.Temperature often increases by 10 DEG C, the dosage increase by 35% of delivering.

It is such when being delivered to user by porous plug inhalator due to the Pharmacokinetic Characteristics of nicotine Inhalator needs the dosage of up to one day 12 10mg magazines or up to one day 6 15mg magazine, with alleviation and nicotine Rely on related craving for tobacco.Safety problem is added with the nicotine formulation of the so high such high intensity of frequency usage.In view of delivering Nicotine dosage highly variable and its temperature dependency, there is following risk：In hot environment (such as more than 37 DEG C of temperature Degree) under, it may cause total daily delivering more than 60mg using porous plug inhalator in the case where needing to alleviate the dosage of craving for tobacco Dosage.So high-caliber daily nicotine intake, which can emit, the wind for allowing user to be exposed to poisonous or even lethal dose nicotine Danger：The minimal lethal dose of nicotine is it is reported that be as little as 30mg.In the user that nicotine metabolism is damaged, the aggravation of this risk.This Outside, high-nicotine plasma concentration can be caused using the very high and inconsistent nicotine dosage provided by porous plug inhalator, finally led Cause long-term Nicotine Dependence and low successful quitting rate.

There is demand in the dosage for overcoming solid problematic suction-type NRT in the prior art for offer.

The invention provides improved preparation, treatment use and the dosage for NRT.Therefore, the invention provides The dosage of daily dose comprising suction-type nicotine formulation, for alleviating or preventing and tobacco dependence phase in object for (1) The method of the craving for tobacco of pass, or (2) alleviate or prevented the method for the withrawal symptom related to tobacco dependence, or (3) to exist in object The method that the tobacco smoke consumption of suction is reduced or prevented in object, wherein daily dose includes the nicotine less than 60mg or its is medicinal Acceptable salt delivers daily dose.

In one embodiment, it is used to alleviate in object or prevents related to tobacco dependence the invention provides one kind Craving for tobacco method oral suction-type preparation, its include nicotine or its acceptable salts and propellant, wherein at one or The daily dose of suction-type preparation is provided in multiple pressurizing vessels, the suction-type preparation is used to utilize simulation cigarette pulmonary administration, institute The reservoir for the charging for state simulation cigarette there is housing, being configured to receive and accommodating the suction-type preparation from pressurizing vessel with And outlet valve, and the suction-type preparation daily dose include be less than 60mg nicotine or delivering for its acceptable salts Daily dose.

Each side or embodiment as defined herein can be combined with any other aspect or embodiment, unless bright Really indicate opposite situation.Particularly, be indicated as being preferred or favourable any feature can with it is one or more it is any its He is indicated as being preferred or favourable feature and is combined.

It was unexpectedly found that, the nicotine dose height that suction-type nicotine formulation of the invention is delivered user is consistent, When in the manner of the present invention in use, it can use the nicotine than known oral suction-type NRT pattern lower dosages to alleviate Or the prevention craving for tobacco related to tobacco dependence.When being applied according to the dosage of the present invention, the preparation that the present invention is protected can Many ceremonies relevant with smoking are replicated, it provides psychological promote to the physiological effect for applying nicotine.This can be used Than reaching the lesser amount of nicotine needed for the alleviation of phase same level in dosage known to existing oral suction-type nicotine formulation Effectively to alleviate the craving for tobacco relevant with tobacco dependence or withrawal symptom.

In addition, the dosage for each inhalation delivery for passing through this dosage is typically homogeneous, and it is that non-temperature is related. It is, therefore, possible to provide being enough to alleviate or preventing craving for tobacco without making user can dosage delivered exposed to potential more than 60mg/ days Dosage.

In another aspect of the present invention there is provided a kind of for alleviating in object or preventing related to tobacco dependence The oral suction-type preparation of the method for withrawal symptom, it includes nicotine or its acceptable salts and propellant, wherein, at one Or the daily dose of suction-type preparation is provided in multiple pressurizing vessels, the suction-type preparation is used to utilize simulation cigarette pulmonary administration, The reservoir for the charging that the simulation cigarette has housing, is configured to receive and accommodates the suction-type preparation from pressurizing vessel And outlet valve, and the suction-type preparation daily dose include be less than 60mg nicotine or passing for its acceptable salts Send daily dose.

There is provided a kind of tobacco smoke for being used to reducing or preventing suction in object in another aspect of the present invention The oral suction-type preparation of the method for consumption, it includes nicotine or its acceptable salts and propellant, wherein, at one or many The daily dose of suction-type preparation is provided in individual pressurizing vessel, the suction-type preparation is used to utilize simulation cigarette pulmonary administration, described The reservoir for the charging that simulation cigarette has housing, is configured to receive and accommodates the suction-type preparation from pressurizing vessel and Outlet valve, and the daily dose of the suction-type preparation delivers day comprising the nicotine or its acceptable salts for being less than 60mg Dosage.

Another embodiment of the invention is a kind of alleviates in object or the prevention craving for tobacco related to tobacco dependence Method, methods described includes applying the oral suction-type preparation comprising nicotine or its acceptable salts and propellant to object Step, wherein, the daily dose of suction-type preparation is provided in one or more pressurizing vessels, the suction-type preparation is used for using imitative Smell good cigarette pulmonary administration, and the simulation cigarette has housing, is configured to receive and accommodate the suction-type system from pressurizing vessel The reservoir and outlet valve of the charging of agent, and the daily dose of the suction-type preparation includes the nicotine or its medicine for being less than 60mg Daily dose is delivered with acceptable salt.

Another embodiment of the invention is a kind of to alleviate or prevent related to tobacco dependence to give up disease in object The method of shape, methods described includes applying the oral suction-type system comprising nicotine or its acceptable salts and propellant to object The step of agent, wherein, the daily dose of suction-type preparation is provided in one or more pressurizing vessels, the suction-type preparation is used for profit Simulation cigarette pulmonary administration is used, the simulation cigarette has housing, is configured with reception and comprising the suction-type from pressurizing vessel The reservoir and outlet valve of the charging of preparation, and the daily dose of the suction-type preparation includes the nicotine or its for being less than 60mg Acceptable salts deliver daily dose.

Another embodiment of the invention is a kind of consumption for the tobacco smoke that suction is reduced or prevented in object Method, methods described includes applying the oral suction-type preparation comprising nicotine or its acceptable salts and propellant to object Step, wherein, the daily dose of suction-type preparation is provided in one or more pressurizing vessels, wherein, the suction-type preparation is used for Using simulation cigarette pulmonary administration, the simulation cigarette has housing, is configured to receive and accommodates the suction from pressurizing vessel Enter the reservoir and outlet valve of the charging of formula preparation, and the daily dose of the suction-type preparation includes the nicotine for being less than 60mg Or its acceptable salts delivers daily dose.

Term as used herein " diameter " includes the maximum dimension of drop.Liquid-drop diameter specifically described herein can be utilized Malvern Spraytec measurement devices.

Term " Dv10 " used herein refers to following liquid-drop diameters：Drop in preparation no more than 10 volume % has Smaller diameter.Term " Dv50 " used herein refers to following liquid-drop diameters：50 volume % liquid is no more than in preparation Drop has smaller diameter.Term " Dv90 " used herein refers to following liquid-drop diameters：90 bodies are no more than in preparation Product % drop has smaller diameter.Dv10, Dv50 and Dv90 value can use Malvern Spraytec devices to determine.

Term " nicotine free base " used herein refers in high pH levels, i.e., in the pH levels higher than 7, predominantly The form of the nicotine of position.

Term " C used herein_max" refer to that the maximum of the compound (being nicotine in the case of this) in object blood is measured Concentration.

Term " t used herein_max" refer to from being applied compound to reaching C_maxThe consumed time.

Term " patient ", " object " and " user " used herein is used interchangeably, and refers to using the dynamic of NRT Thing, the preferably mankind.

Term " daily dose that can be delivered " refers to the nicotine during more than 24 hours to user's pulmonary administration Cumulant.According to many aspects of the present invention, by the effect of the barometric gradient between two devices, suction-type preparation is from pressurization It is discharged into container in the reservoir of simulation cigarette.In view of the effusion of preparation during supplement, nicotine delivers daily dose It is that the nicotine amount of user can be transferred to from pressurizing vessel by empty the feeding repeatedly for reservoir of simulation cigarette.

When the key element for introducing present disclosure or its preferred embodiment, article " a ", " an ", " the " and " said " meaning Representing there is one (kind) or multiple (kind) key elements.Term "comprising", " comprising " and " having " are intended to pardon, and Expression can also have other key element in addition to listed elements.

Nicotine in the daily dose included according to an embodiment of the invention, in one or more pressurizing vessels or The total content of its acceptable salts be more than 0.2mg and no more than 75mg, 70mg, 65mg, 60mg, 55mg, 50mg, 45mg、40mg、35mg、30mg、25mg、20mg、19mg、18mg、17mg、16mg、15mg、14mg、13mg、12mg、11mg、 10mg、9.5mg、9mg、8.5mg、8mg、7.5mg、7mg、6.5mg、6mg、5.5mg、5mg、4.5mg 4mg、3.5mg、3mg、 2.5mg, 2mg, 1.5mg, 1mg, 0.9mg, 0.8mg, 0.7mg, 0.6mg, 0.5mg, 0.45mg, 0.4mg, 0.35mg, 0.3mg or 0.25mg。

In an embodiment of the invention, the daily dose that delivers of nicotine or its acceptable salts is one or many At least the 60% of the accumulated dose of contained nicotine or its acceptable salts, excellent in the suction-type preparation provided in individual pressurizing vessel Choosing at least 70%, more preferably at least 75%.

In one aspect of the invention, the daily dose of suction-type preparation includes delivering daily dose for more than 0.2mg, and And no more than 60mg, 55mg, 50mg, 45mg, 40mg, 35mg, 30mg, 25mg, 20mg, 19mg, 18mg, 17mg, 16mg, 15mg、14mg、13mg、12mg、11mg、10mg、9.5mg、9mg、8.5mg、8mg、7.5mg、7mg、6.5mg、6mg、5.5mg、 5mg、4.5mg、4mg、3.5mg、3mg、2.5mg、2mg、1.5mg、1mg、0.9mg、0.8mg、0.7mg、0.6mg、0.5mg、 0.45mg, 0.4mg, 0.35mg, 0.3mg, 0.25mg or 0.2mg.In a preferred embodiment, can deliver daily dose for 40mg with Under, preferably below 20mg, more preferably below 18mg.

The preparation of the present invention, device, the special advantage of mode of administration and scheme do not include for it or known to producing in tobacco Harmful chemical present in smog, the harmful chemical is in addition to poisonous to user, also to unborn tire Youngster or the baby of lactation are extremely harmful.Therefore, preparation as described herein, device, mode of administration and scheme are in gestation or nursing period Object in provide pair craving for tobacco related to tobacco dependence effective treatment.Therefore, in an embodiment of the invention, carry The side as described herein for being used to alleviating or preventing the craving for tobacco related to tobacco dependence in pregnant object or nursing period object is supplied Preparation, device, mode of administration and the dosage of method.Used in the alternative embodiment of the present invention there is provided as described herein Preparation, dress in the method for alleviating or preventing the withrawal symptom related to tobacco smoke in pregnant object or nursing period object Put, mode of administration and dosage.It is used in the alternative embodiment of the present invention there is provided as described herein in pregnant object Or preparation, device, mode of administration and the dosage of the method for the consumption of the tobacco smoke of suction are reduced or prevented in nursing period object Scheme.

In an embodiment of the invention, object freely self applies doses, and the dosage is less than to be carried herein The daily dose of confession, and daily dose described herein is maximum daily dose.

In one aspect of the invention, nicotine or its acceptable salts can dosage delivered be substantially temperature not phase Close.In an embodiment of the invention, at about 15 DEG C~about 50 DEG C, preferably from about 20 DEG C~about 30 DEG C of temperature range It is interior, can dosage delivered keep it is constant.Therefore, in an embodiment of the invention, method of the invention and dosage exist Less than 50 DEG C, preferably less than 37 DEG C, more preferably less than 30 DEG C of temperature is administered.

In embodiments of the present invention, pressurizing vessel can comprising about 2mg~about 30mg or about 2mg~about 25mg or About 2mg~about 20mg or about 3mg~about 19mg or about 4mg~about 18mg or about 5mg~about 17mg or about 6mg~about 16mg or about 7mg~about 15mg or about 8mg~about 14mg or about 8mg~about 13mg or about 8mg~about 12mg or about 8mg~ About 11mg or about 9mg~about 10mg nicotine or its acceptable salts.In a preferred embodiment, pressurizing vessel can be wrapped Containing about 15mg~about 20mg, preferably from about 16mg~about 18mg, more preferably from about 17mg~about 18mg nicotine or its is medicinal acceptable Salt.In alternative preferred embodiment, pressurizing vessel can include about 7mg~about 14mg, preferably from about 8mg~about 13mg, more Preferably from about 11mg~about 12mg nicotine or its acceptable salts.In alternative preferred embodiment, pressurizing vessel can be with Include about 2mg~about 7mg, preferably from about 3mg~about 6mg, more preferably from about 4mg~about 5mg nicotine or its acceptable salts.

According to the present invention, the nicotine provided by pressurizing vessel or its acceptable salts can dosage delivered hold for pressurization At least the 60%, preferably at least 70%, more preferably at least 75% of the total amount of contained nicotine or acceptable salts, more excellent in device Choosing at least 78%.

In particularly preferred embodiments, nicotine of the pressurizing vessel comprising about 16mg~about 18mg or its is medicinal acceptable Salt, and provide can dosage delivered be the total amount of nicotine contained in pressurizing vessel or its acceptable salts at least 75%, preferably at least 78%.In alternative preferred embodiment, nicotine of the pressurizing vessel comprising about 11mg~about 12mg or its Acceptable salts, and provide can dosage delivered be nicotine contained in pressurizing vessel or the total amount of its acceptable salts At least 75%, preferably at least 78%.In alternative preferred embodiment, pressurizing vessel includes about 4mg~about 5mg nicotine Or its acceptable salts, and provide can dosage delivered be nicotine or its acceptable salts contained in pressurizing vessel At least the 75% of total amount, preferably at least 78%.

One or more of pressurizing vessels can be as the quantity needed for the delivering daily dose of the suction-type preparation of the present invention Pressurizing vessel constitute.In a preferred embodiment of the invention, total nicotine content is the sheet provided in two pressurizing vessels The daily dose of the delivering of invention.In another preferred embodiment, pressurizing vessel comprising about 2mg~about 7mg nicotine or its Acceptable salts, 5 pressurizing vessels or as an alternative in 4 pressurizing vessels provide suction-type preparation delivering day agent Amount.

In an embodiment of the invention, pressurizing vessel includes~about 40 chargings of about 5 chargings, wherein, charging For a certain amount of suction-type preparation needed for filling simulation cigarette reservoir.In a preferred embodiment, pressurizing vessel includes suction Enter~about 35 chargings of about 10 chargings of formula preparation, or~about 30 chargings of about 15 chargings, or about 17 chargings~about 25 Secondary charging.In a preferred embodiment, about 20 chargings of the pressurizing vessel comprising suction-type preparation.

In an embodiment of the invention, nicotine of each charge packet containing about 0.1mg~1mg or its is medicinal acceptable Salt, or about 0.2mg~0.9mg or about 0.3mg~0.8mg or about 0.3mg~0.7mg or about 0.4mg~0.6mg or about 0.4mg~0.5mg or about 0.4~0.6mg nicotine or its acceptable salts.In a preferred embodiment, each charge packet Nicotine or its acceptable salts containing about 0.66mg~0.69mg, or about 0.43mg~0.45mg nicotine or its medicinal connect By salt, or about 0.21mg~0.23mg nicotine or its acceptable salts.

In an embodiment of the invention, the first charge packet applied according to the present invention to simulation cigarette contains than second And the less nicotine of subsequent charge.Therefore, in an embodiment of the invention, the first charge packet contains the cigarette less than about 1mg Alkali or its acceptable salts, more preferably from about preferably less than about 0.43mg, 0.02mg~0.3mg.In these embodiments, Two and subsequent charge can include about 0.1mg~1mg nicotine or its acceptable salts, or about 0.2mg~0.9mg or about 0.3mg~0.8mg or about 0.3mg~0.7mg or about 0.4mg~0.6mg or about 0.4mg~0.5mg or about 0.4~ 0.6mg nicotine or its acceptable salts, condition are that the nicotine content of the first charging is less than second and subsequent charge.Preferred In embodiment, the first charge packet containing than second and the less nicotine of subsequent charge or its acceptable salts, wherein second and Subsequent charge includes about 0.66mg~0.69mg nicotine or its acceptable salts, or about 0.43mg~0.45mg nicotine or Its acceptable salts, or about 0.21mg~0.23mg nicotine or its acceptable salts.

In a preferred embodiment of the invention, each charge packet is containing about 5 times~15 times suctions, preferably from about 6 times~12 times Suction, more preferably from about 7 times~10 times suctions, more preferably from about 8 times suctions or about 9 suctions.In a preferred embodiment, fill every time Material is sucked/2 minutes for/0.05 minute~1 time with about 1 suction, and/0.1 minute~1 time suction of preferably from about 1 time suction/1 minute is excellent / 0.2 minute~1 time suction of about 1 suction of choosing/0.5 minute, the speed of more preferably from about 1 time suction/0.25 minute is consumed. In the preferred embodiment of the present invention, charging was at most 10 minutes or at most 6 minutes or at most 5 minutes, preferably up to 4 every time Minute, more preferably up to 3 minutes, it is consumed in the time of more preferably up to 2 minutes.

In a preferred embodiment of the invention, oral suction-type preparation is included：

Nicotine or its medicinal acceptable derivative or salt；

Propellant；

Monohydric alcohol；With

Glycol and/or glycol ethers,

Characterized in that, monohydric alcohol:The weight ratio of glycol and/or glycol ethers is 6:1~1:1.

The dissolving of nicotine or its medicinal acceptable derivative or salt in glycol and/or glycol ethers auxiliary agent.This is avoided The presence of the sediment of nicotine in preparation (or such as other additives of saccharin, if there is), these sediments can be delivered to Cause stimulation during user.In addition, the presence of glycol or glycol ethers reduces the degraded that nicotine occurs over time, so that Improve long-time stability or " pot-life " of preparation.

Monohydric alcohol has the viscosity lower than glycol or glycol ethers.Therefore, compared with the preparation in the absence of monohydric alcohol, the system Agent can form the drop of smaller diameter.Inventors hereof have unexpectedly discovered that, above-mentioned monohydric alcohol and glycol or glycol ethers Ratio cause preparation and meanwhile have long-time stability (for example, 2 DEG C~40 DEG C temperature with it is single-phase keep at least one week) and The desirable combination of small drop sizes.

Advantageously, when with this monohydric alcohol:The nicotine formulation of the ratio of glycol or glycol ethers passes through conventional pressurization When metered dose inhaler (pMDI) is delivered to user, preparation is delivered in droplets, and some of them are (for example, at least 10 bodies Product %) there is the diameter for being less than 10 μm, being typically smaller than 5 μm.Generally, drop most of (for example, at least 50 volume %) has small In 5 μm of diameter, generally essentially all (for example, at least 90 volume %, or even at least 95 volume %) drop has small In 5 μm of diameter.Advantageously, upon oral administration, size is less than 10 μm of drop and tends to deposit on lung rather than such as In pars oralis pharyngis.Therefore, at least some (for example, at least 10 weight %), generally essentially all (for example, at least 90 weight %) cigarette Alkali enters blood by lung approach.It means that compared with the nicotine formulation of prior art, when oral suction, said preparation is more The Pharmacokinetic Characteristics of conventional cigarette can be imitated.Because said preparation can be by orally administering and can imitate the medicine of conventional cigarette For dynamic characteristic, thus use in NRT or the substitute of inhaling conventional cigarette as nature of leisure use it is especially effective.

More typically at least (for example, at least 10 volume %), drop has 0.5 μm~3 μm of size.This drop can be with Deep lung is deposited on, therefore enables in particular to enter blood by pulmonary route.More typically at least (for example, at least 10 bodies Product %) drop has 0.4 μm~0.5 μm of diameter.These drops enable in particular to imitate the Pharmacokinetic Characteristics of conventional cigarette, Because conventional cigarette smog has 0.4 μm~0.5 μm of average grain diameter.

When by one of following simulation cigarettes by the present invention formulation delivered to user when, drop can show following liquid Drip size characteristic：

Dv 90 is less than 20 μm, typically smaller than 5 μm, more typically less than 3 μm, and then more typically less than 2.9 μm, and/or

Dv 50 is less than 6 μm, typically smaller than 0.8 μm, more typically less than 0.7 μm, and then more typically less than 0.6 μm, and/or

Dv 10 is less than 2 μm, typically smaller than 0.3 μm, more typically less than 0.25 μm, and then is more typically less than 0.2 μm.

The certain droplet size characteristic is similar to the grain diameter characteristic of tobacco smoke.Therefore, the medicine of the preparation of delivering is for power Learn the Pharmacokinetic Characteristics that feature has closely imitated conventional cigarette.Particularly, preparation generates tool to the delivering of user There is shorter t_maxThe spreading peak of the high-nicotine concentration of (that is, the time that highest nicotine-blood plasma level is sucked into from first time).Therefore, The preparation is highly effective for the use in NRT, and can be with the lower cigarette of other suction-type patterns than NRT Alkaline agent amount effectively alleviates the craving for tobacco related to tobacco dependence or the withrawal symptom related with tobacco dependence.

Can be using any appropriate nicotine source.For example, nicotine can be nicotine free base, nicotine derivative and/or Nicotine salt.When using nicotine free base, it can be used in liquid form.When using nicotine salt, it can be with solution shape Formula is used.Appropriate nicotine salt includes the salt formed by following acid：Acetic acid, propionic acid, 1,2- butyric acid, methylbutanoic acid, valeric acid, bay Acid, palmitic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, alginic acid, hydrochloric acid, chloroplatinic acid, silico-tungstic acid, pyruvic acid, Glutamic acid and aspartic acid.Other nicotine salts, such as two tartaric acid nicotine dehydrates, can also be used.It can use two or more The mixture of nicotine salt.Nicotine salt can also be in liposome-encapsulated.This encapsulated nicotinic density for making preparation enters one Step is improved, without occurring nicotine precipitation.The weight of nicotine or its acceptable salts used herein refers to the free alkali of nicotine Form.Therefore, when using nicotine salt, the molar equivalent of free base weight should be calculated.

As described above, monohydric alcohol:The weight of glycol or glycol ethers is than producing stability and preferable drop size feature Combination.Preferably, monohydric alcohol:The weight ratio of glycol or glycol ethers is 5:1~1.5:1, preferably 4:1~2:1, more preferably 3:1~2.5:1, and then even more preferably about 2.8:1.

Glycol and/or glycol ethers can be selected from propane diols, polypropylene glycol and polyethylene glycol (PEG), or its is two or more Combination.It is appropriate that polyethylene glycol can have the molecular weight less than 20,000g/mol.One of appropriate polyethylene glycol Example is PEG 400.Preferably, glycol or glycol ethers are propane diols.Propane diols provides especially desirable drop chi for preparation Very little feature, and the enhanced solvation of excipient is provided, and reduce the decomposition of excipient.Preferably, based on the total of preparation Weight, preparation includes the weight % of 0.1 weight %~2 propane diols, the weight %, more preferably 0.2 weight % of preferably 0.1 weight %~1 ~0.5 weight % and then more preferably 0.25 weight %~0.4 weight %, even more preferably about 0.34 weight %.Known propane diols For the mankind using being safe, it is reported that, high-caliber suction propane diols is contacted for a long time can cause white blood cell count(WBC) Reduction.Therefore, in an embodiment of the invention, the propane diols that one or more pressurizing vessels are included can deliver a day agent Amount is less than 1000mg, more preferably less than preferably smaller than 500mg, more preferably less than 200mg, 150mg.

Preferably, monohydric alcohol is ethanol.Compared with glycol or glycol ethers, ethanol has especially low viscosity, therefore It is particularly effective in terms of the drop for making preparation formation small diameter.In addition, ethanol is cheap, relative harmless and easily obtain.It is preferred that , the gross weight based on preparation, preparation includes the weight % ethanol of 0.5 weight %~1.5, the weight of preferably 0.7 weight %~1.3 Measure %, the weight % of more preferably 0.9 weight %~1, and then more preferably from about 0.95 weight %.

Preferably, preparation also includes people's TAS2R bitterness receptors activators.The use of people's TAS2R bitterness receptors activators Bronchiectasis is induced, causes the cough level reduction that delivering is related.Therefore, because it causes very small stimulation, user Preparation can more be stood.

People's TAS2R bitterness receptors activator can be native compound or synthesis compound.Suitable native compound Example includes absinthin, aloin, amygdalin, andrographolide, arborescin, parthenolide derivative (Arglabin), south Argy wormwood alkene Inner esters (Artemorin), camphor, bitter fragrant alkali (Cascarillin), centaurin, Chris's Pohle moral (Crispolide), ethyl pyrazine, Fa Kalin glycol (Falcarindiol), helicin, humulone isomers, lemon Bitter principle, narcotine papaverine, parithenolide, guassin, sinigrin (Sinigrin) and thiamines.Suitable synthesis compound Example include acesulfame-K, styrax, carisoprodol, chloroquine, Cromoglycic acid, dapsone, denatonium benzoate, dimethyl disulfide For formamide, diphenhydramine, divinyl sulfoxide, famotidine, saccharin, sodium benzoate and cyclamate sodium.

Preferably, people TAS2R bitterness receptors activator is saccharin.Saccharin can be particularly effectively as people's TAS2R bitter tastes Receptor stimulating agent, can be soluble in preparation, it is easy to obtain, and for the taste profile needed for preparation is provided.Preferably, nicotine Or its medicinal acceptable derivative or salt:The weight ratio of saccharin is 12:1~5.5:1, preferably 11:1~6:1, more preferably 10:1~7:1, and then more preferably 9.5:1~8:1, even more preferably about 8.75:1.The saccharin of reduced levels causes preparation With unacceptable tolerance.The saccharin of higher level produces acceptable tolerance, but is unfavorable, because the saccharin Level may cause the sediment for forming saccharin in the formulation, and this is likely to result in stimulation when preparation is applied into user, or Person is likely to result in blocking when preparation is introduced into simulation cigarette.Such ratio also provides the taste profile of optimization for preparation.

Propellant can be HFC, preferably hydrofluoroalkane, and then more preferably 1,1,2,2- HFC-134a (HFA-134a) or 1,1,1,2,3,3- heptafluoro-propanes (HFC-227).These compounds can be particularly effectively as propellant, and for human body not With side effect.

Gross weight based on preparation, preparation can include at least 60 weight % propellants, the weight of preferably 90 weight %~99.5 Measure %, the weight % of preferably 96 weight %~99 weight %, more preferably 98 weight %~99.Propellant is preferably liquefied.

Preparation can also include flavouring ingredients.Nicotine lasting taste with pained, it can generally cause burning The sense of taste.The use of flavouring ingredients can cover this taste.Appropriate flavouring ingredients include generally making an addition to tobacco product Flavouring ingredients.Example includes carotenoid product, alcohol, aldehyde, ester and delta-lactone flavouring ingredients.Appropriate carotenoid Product include β-ionone, α-ionone, dorinone, beta -damascenone, oxo-Yi Dulan (edulan I), oxo-according to Du Lan II, theaspirone, 4- oxygen-β-ionone, 3- oxygen-α-ionone, dihydroactinidiolide (dihydroactinodiolide), 4- oxygen isophorone, safranal, β-cyclocitral.Appropriate alkenols includes C4~C10 Alkenols, preferably C5~C8 alkenols.Instantiation includes：Cis -2- amylene-1-ols, cis -2- hexen-1-ols, it is trans - 2- hexen-1-ols, trans -2- hexen-1-ols, cis-blatter alcohol, trans-blatter alcohol, trans -2- heptene -1- Alcohol, cis -3- heptene -1- alcohol, trans -3- heptene -1- alcohol, cis -4- heptene -1- alcohol, trans -2- octen-1-ols, it is cis - 3- octen-1-ols, cis -5- octen-1-ols, 1-OCOL and 3- octen-2-ols.Appropriate aldehyde includes benzaldehyde, grape Sugar and cinnamic acid.Appropriate ester includes allyl hexanoate, benzyl acetate, borneolacetate, butyl butyrate, ethyl butyrate, caproic acid Ethyl ester, ethyl cinnamate, Ethyl formate, cognac oil, ethyl isovalerate, ethyl lactate, ethyl pelargonate, ethyl valerate, acetic acid Geraniol ester, geranyl butyrate, isobutyl acetate, iso-butyl formate, isoamyl acetate, isopropyl acetate, bergamio, butyric acid Fragrant camphor tree ester, linalyl formate, methyl acetate, artificial neroli oil, methyl benzoate, methyl benzyl ester, methyl butyrate, cinnamic acid Methyl esters, methyl valerate, methyl phenyl ester, gaultherolin (wintergreen), nonyl caprylate, octyl acetate, n-octyl butyrate, acetic acid Pentyl ester (amyl acetate, pentyl acetate), amyl caproate, amyl valerate, propyl acetate, propyl isobutyrate, butyric acid Pine tar alcohol ester, Ethyl formate, ethyl acetate, ethyl propionate, ethyl butyrate, ethyl valerate, ethyl hexanoate, cognac oil, octanoic acid Ethyl ester, ethyl pelargonate, ethyl caprate, ethyl laurate, ethyl myristate, ethyl palmitate.Appropriate delta-lactone seasoning Agent composition includes δ-caprolactone, δ-octalactone, δ-nonalactone, δ-decalactone, delta-undeca lactone, δ-dodecalactone, Ma Suoyanei Ester, jasmine lactone and 6- amyl groups-α-pyranone.Flavouring ingredients can play a part of covering the undesirable taste of nicotine.

Flavouring ingredients are preferably menthol and/or vanillic aldehyde.Menthol exists together with saccharin reduces user's warp The stimulation received.Preferably, the gross weight based on preparation, preparation includes at most 0.1 weight % menthols, preferably 0.01 weight % The weight of the weight % of~0.08 weight %, more preferably 0.02 weight %~0.06, and then more preferably 0.03 weight %~0.05 Measure %, or even and then even more preferably about 0.04 weight %.

Gross weight based on preparation, preparation can be comprising the weight % nicotine of 0.001 weight %~0.045 or its is medicinal acceptable The weight % of derivative or salt, preferably 0.01 weight %~0.045 weight %, more preferably 0.015 weight %~0.04, and then The weight % of more preferably 0.02 weight %~0.035, or even and then the weight of more preferably 0.025 weight %~0.03 %, it is optimal Elect about 0.028 weight % as.Such preparation provides the effect similar to " low-intensity " nicotine cigarettes.

Gross weight based on preparation, preparation can comprising the weight % nicotine of 0.04 weight %~0.07 or its medicinal acceptable spread out Biological or salt, preferably 0.045 weight %~0.065 weight %, more preferably 0.05 weight %~0.06 weight %, Jin Ergeng The weight % of preferably 0.054 weight %~0.058, or even and then even more preferably about 0.056 weight %.Such preparation provide with The similar effect of " middle intensity " nicotine cigarettes.

Gross weight based on preparation, preparation can comprising the weight % nicotine of 0.065 weight %~0.1 or its medicinal acceptable spread out Biological or salt, preferably 0.07 weight %~0.095 weight %, more preferably 0.075 weight %~0.09 weight %, Jin Ergeng The weight % of preferably 0.08 weight %~0.088, or even and then even more preferably about 0.084 weight %.Such preparation provide with The similar effect of " high intensity " nicotine cigarettes.

Gross weight based on preparation, particularly preferred preparation is included：

The weight % of 0.03 weight %~0.05 menthol, preferably from about 0.04 weight %,

The weight % of 0.25 weight %~0.4 propane diols, preferably from about 0.34 weight %,

The weight % of 0.9 weight %~1 ethanol, preferably from about 0.95 weight %,

Saccharin, and

It is following any：

(i) the weight % nicotine of 0.025 weight %~0.03 or its medicinal acceptable derivative or salt, preferably from about 0.028 Weight %, or

(ii) the weight % nicotine of 0.054 weight %~0.058 or its medicinal acceptable derivative or salt, are preferably from about 0.056 weight %, or

(iii) the weight % nicotine of 0.08 weight %~0.088 or its medicinal acceptable derivative or salt, are preferably from about 0.084 weight %,

Surplus is HFA-134a, wherein, the weight ratio of nicotine and saccharin is 9.5:1~8:1, preferably from about 8.75:1.This The formulations display of sample goes out the especially desirable combination of above-mentioned advantage.

Preferably, the weight based on preparation, total solvent content, i.e. monohydric alcohol and glycol and/or glycol ethers always contain Amount, less than 35 weight %, the weight % of preferably smaller than 6 weight %, more preferably 0.1 weight %~2.5.Reduce the total solvent of preparation Content makes the reduction of its viscosity, it means that can more form more favourable drop size.

Preferably, the gross weight based on preparation, preparation includes the nicotinic acid less than 0.01 weight %, more preferably less than 0.005 Weight % and then more preferably less than 0.001 weight % nicotinic acid.Most preferably, preparation contains substantially no nicotinic acid.Nicotinic acid is deposited Sediment is formed in it can cause preparation.

The preparation of first aspect can " by " mentioned component " composition ".The preparation of first aspect can " by " mentioned component with Any inevitable impurity is common " composition ".Preparation can " substantially by " mentioned component with the function to preparation without notable shadow Loud any condition " composition ".

In another aspect, the present invention provides a kind of pressurizing vessel for accommodating the preparation for methods described herein.

The pressurizing vessel of another aspect of the present invention can be used for the air-flow that nicotine formulation is discharged to user.For example, pressurization Container can be provided with the means of the content delivery of container to user lung.

The pressurizing vessel of the present invention can be used for user's delivery formulations, without the single energy.For example, said preparation It can be discharged in the case of without the electric current of the heating of base material, the burning of material or battery-powered.As described above, this can be with Cause the reduction for being delivered to the harmful side product level of user.

The pressurizing vessel of the present invention can take the form of pressurized canister, for example, pressurization aluminium pot.The tank can be with wholly recyclable And/or reuse.The tank by automatic vending machine or can accommodate the larger container of required preparation in high pressure as needed Supplemented under gradient.In one embodiment, the tank is AW5052 aluminium pots.

Pressurizing vessel can dispense the mixture of preparation as atomized drop.Preferably, mixture has similar cigarette The particle diameter distribution of tobacco smoke.Mixture can have the outward appearance of steam or smog.

Pressurizing vessel can be forced into 3 × 10⁵Pa~1.5 × 10⁷Pa, preferably 5 × 10⁵Pa~2 × 10⁶Pa, more preferably 5.5×10⁵Pa~1 × 10⁶Pa and then more preferably from about 6 × 10⁵Pa pressure.

Pressurizing vessel can be used for supplementing simulation cigarette, the simulation cigarette of particularly following one aspect of the invention.

Pressurizing vessel content can include 16mg~18mg nicotine, preferably from about 17.18mg nicotine；7mg~9mg peppermints Alcohol, preferably from about 8.176mg menthols；1mg~3mg saccharin, preferably from about 1.963mg saccharin；68mg~72mg propane diols, preferably from about 69.5mg propane diols；190mg~200mg ethanol, preferably from about 194.2mg ethanol；With 18g~22g HFA-134a, preferably from about 20.15g HFA-134a.Alternatively, pressurizing vessel content can include 10mg~12mg nicotine, preferably from about 11.45mg nicotine；7mg~9mg menthols, preferably from about 8.176mg menthols；1.1mg~1.4mg saccharin, preferably from about 1.288mg Saccharin；68mg~72mg propane diols, preferably from about 69.5mg propane diols；190mg~200mg ethanol, preferably from about 194.2mg ethanol； With 18g~22g HFA-134a, preferably from about 20.16g HFA-134a.Alternatively, pressurizing vessel content can be with Include 5mg~7mg nicotine, preferably from about 5.73mg nicotine；7mg~9mg menthols, preferably from about 8.176mg menthols；0.5mg~ 0.8mg saccharin, preferably from about 0.654mg saccharin；68mg~72mg propane diols, preferably from about 69.5mg propane diols；190mg~200mg Ethanol, preferably from about 194.2mg ethanol；With 18g~22g HFA-134a, preferably from about 20.16g HFA-134a.Alternatively Selection, pressurizing vessel content can include about 7mg~9mg menthols, preferably from about 8.176mg menthols；0.1mg~0.3mg Saccharin, preferably from about 0.204mg saccharin；68mg~72mg propane diols, preferably from about 69.5mg propane diols；190mg~200mg ethanol, Preferably from about 194.2mg ethanol；With 18g~22g HFA-134a, preferably from about 20.17g HFA-134a.

Pressurizing vessel can be used for supplementing simulation cigarette.This " supplement " container can include 0.6mg~0.7mg cigarettes Alkali, preferably from about 0.672mg nicotine；0.2mg~0.4mg menthols, preferably from about 0.32mg menthols；0.07mg~0.09mg sugar Essence, preferably from about 0.077mg saccharin；2.5mg~2.9mg propane diols, preferably from about 2.72mg propane diols；7mg~9mg ethanol, preferably About 7.6mg ethanol；With 760mg~800mg HFA-134a, preferably from about 788.6g HFA-134a.Alternatively, this 0.4mg~0.5mg nicotine, preferably from about 0.448mg nicotine can be included by planting supplement；0.2mg~0.4mg menthols, preferably from about 0.32mg menthols；0.04mg~0.06mg saccharin, preferably from about 0.051mg saccharin；2.5mg~2.9mg propane diols, preferably from about 2.72mg propane diols；7mg~9mg ethanol, preferably from about 7.6mg ethanol；With 760mg~800mg HFA-134a, preferably from about 788.9g HFA-134a.Alternatively, each supplement can include 0.1mg~0.3mg nicotine, preferably from about 0.224mg nicotine；0.2mg~0.4mg menthols, preferably from about 0.32mg menthols；0.01mg~0.03mg saccharin, preferably from about 0.026mg saccharin；2.5mg~2.9mg propane diols, preferably from about 2.72mg propane diols；7mg~9mg ethanol, preferably from about 7.6mg second Alcohol；With 760mg~800mg HFA-134a, preferably from about 789.1g HFA-134a.Alternatively, this supplement About 0.2mg~0.4mg menthols, preferably from about 0.32mg menthols can be included；0.007mg~0.009mg saccharin, preferably from about 0.008mg saccharin；2.5mg~2.9mg propane diols, preferably from about 2.72mg propane diols；7mg~9mg ethanol, preferably from about 7.6mg second Alcohol；With 760mg~800mg HFA-134a, preferably from about 789.4mg HFA-134a.

Nicotine in above-mentioned pressurizing vessel content with its medicinal acceptable derivative or salt it is of course possible to being replaced.

In another aspect, the present invention provides a kind of simulation cigarette device (also referred to herein as simulation cigarette), and it includes：

Housing；

The pressurizing reservoir of suction-type preparation in the housing；

Suction-type preparation is flowed out the outlet of housing by reservoir, and the outlet is configured to discharge the suction-type of drops from it Preparation, at least some drops have less than 10 μm of diameter；With

For controlling outlet valve of the suction-type formulation flows by the outlet, wherein, the suction-type preparation such as first party Described in face.

For example, outlet may be constructed such that the suction-type preparation that drops are discharged from it, at least 1 volume % drop tool There is less than 10 μm of diameter.

Preferably, most of drop (for example, at least 50 volume %) has less than 10 μm of diameter, preferably substantially institute There is drop (for example, at least 90 volume %) that there is less than 10 μm of diameter.Preferably, at least some drops are (for example, at least 1 Volume %) there is less than 5 μm of diameter, preferably most of drop (for example, at least 50 volume %) has less than 5 μm of diameter, More preferably essentially all drop (for example, at least 90 volume %) has less than 5 μm of diameter.

Preferably, outlet valve is breath actuated valve.

Preferably, the simulation cigarette also includes extending about the capillary bolt into reservoir from outlet valve, and it is filled At least the 50% of reservoir volume, and be configured to wick suction-type preparation to outlet.

Preferably, the simulation cigarette has breath actuated valve, and housing has the port of export and opposite end, and this is imitative The cigarette that smells good also includes：

Preparation stream, it is used for going out for the port of export for making preparation be located at housing from reservoir along the flow path and outflow Mouthful；

Flexible baffle in housing, its define from air intake to the port of export positioned at housing air outlet slit air Stream；

Valve components, it can move through bias force with dividing plate and bias to its position for closing preparation stream；

Wherein, the suction of the port of export causes the flowing by air flow circuit, and it provides pressure difference in valve components, thus relatively Valve components are lifted in bias force, so as to open preparation stream；And

Wherein, bias force is arranged to close preparation stream if suction stops.

Preferably, simulation cigarette has breath actuated valve, and breath actuated valve is between outlet and reservoir Non-metering valve, breath actuated valve includes extending to the stream of the port of export from reservoir that (at least a portion of the stream is variable Shape pipe) and hold assembly, the hold assembly is clamped in no suction and puts on the deformable tube closed during the device, and is going out Mouth discharges the pipe to open stream when applying suction, so as to provide the continual flowing from reservoir to outlet.The emulation is fragrant Cigarette is hereinafter referred to as " pinch valve " simulation cigarette.

Preferably, the simulation cigarette also includes the replenishment valve connected with reservoir, and reservoir can pass through the replenishment valve And supplemented.The simulation cigarette can be supplemented by the pressurizing vessel of second aspect of the present invention.

Preferably, in reservoir the size of size, the pressure in reservoir and outlet at its most narrow point is set For when outlet valve is opened completely, reservoir will be discharged in less than 30 seconds.

Preferably, simulation cigarette is configured to discharge preparation drop from it, and the volume % of wherein at least 97 drop has Diameter less than 10 μm, preferably at least 98 volume %, more preferably at least 98.5 volume %, and then more preferably at least 99 bodies Product %.Diameter is less than 10 μm of droplet deposition in lung, it is meant that there is provided the Pharmacokinetic Characteristics of similar conventional cigarette.

Preferably, simulation cigarette is configured to from its preparation drop of the discharge with following size characteristic：

Dv 90 is less than 20 μm, preferably smaller than 5 μm, more preferably less than 3 μm, and then more preferably less than 2.9 μm, and/or

Dv 50 is less than 6 μm, preferably smaller than 0.8 μm, more preferably less than 0.7 μm, and then more preferably less than 0.6 μm, and/or

Dv 10 is less than 2 μm, preferably smaller than 0.3 μm, more preferably less than 0.25 μm, and then more preferably less than 0.2 μm.

Therefore, in one embodiment, simulation cigarette is configured to drop of the discharge with following size characteristic：Dv 90<20 μm, Dv 50<6 μm and Dv 10<2μm；It is preferred that with following size characteristic：Dv 90<5 μm, Dv 50<0.8 μm and Dv 10<0.3μm；More preferably there is following size characteristic：Dv 90<3 μm, Dv 50<0.7 μm and Dv 10<0.25μm；And then more It is preferred that with following size characteristic：Dv 90<2.9 μm, Dv 50<0.6 μm and Dv 10<0.2μm.

This size characteristic is similar to conventional cigarette, it is meant that the Pharmacokinetic Characteristics provided have closely imitated biography The Pharmacokinetic Characteristics of system cigarette.

The simulation cigarette can provide at most 15ng/ml, usual 2ng/ml~10ng/ml or even 4ng/ for user Ml~8ng/ml nicotine artery C_max.Greater than about 2ng/ml C_maxIt is worth what is experienced when being provided by user and inhaled conventional cigarette " drift (head rush) ".

Simulation cigarette can be these C_maxValue provides 10 seconds~20 minutes, normally about usual 5 minutes~15 minutes, 12 points The t of clock_max.Compared with the simulation cigarette device of prior art, such t_maxThe value that value is shown closer to conventional cigarette.Cause This, the present invention has closer imitated the Pharmacokinetic Characteristics of conventional cigarette, therefore using in NRT or as nature of leisure The use for inhaling the substitute of conventional cigarette is particularly effective.

Preferably, the simulation cigarette is configured to discharge system therefrom with 0.5 liter/min~3 liters/min of speed Agent.The speed is similar to the speed of the vapour discharge from conventional cigarette.Preferably, the simulation cigarette is configured to provide 1kPa ~7kPa, preferably from about 4kPa suction resistance.The suction resistance is similar to the suction resistance that conventional cigarette is provided.When emulation is fragrant When cigarette is configured to above rate of discharge and/or suction resistance, it is preferred that the simulation cigarette be configured to Nicotine is delivered to user by 0.01mg/ml~0.06mg/ml speed.This is lower than the speed of conventional cigarette.But, due to inhaling The habitual aspect of cigarette is imitated by above rate of discharge and suction resistance, thus user will experience with routinely give up smoking it is auxiliary Apparatus is helped to compare identical satisfactory level, and relatively low suction Nicotine levels.

In another aspect, the present invention provides a kind of method for manufacturing invention formulation, and this method includes：

Pre-composition is prepared, it includes polyalcohol and glycol and/or glycol ethers, and optional TAS2R taste receptors activators And/or flavor enhancement, wherein, polyalcohol:The weight ratio of glycol or glycol ethers is 6:1~1:1；

Nicotine or its medicinal acceptable derivative or salt are added to the pre-composition, to obtain mixture containing nicotine；With

Propellant is added to the mixture containing nicotine.

If adding nicotine before polyalcohol and glycol or glycol ethers merge, the precipitation that may occur nicotine.Equally, If said preparation includes such as flavoring ingredients or TAS2R taste receptors activator other compositions, these compositions should be in addition cigarette It is fully mixed to before alkali in pre-composition, to avoid the precipitation of nicotine.It was in particular found that when preparation includes menthol, Menthol should be fully dissolved in the pre-composition before addition nicotine, to avoid the precipitation of nicotine.

When preparation will include TAS2R taste receptors activator and/or flavoring ingredients, it is preferred that in addition TAS2R tastes Polyalcohol and glycol or glycol ethers are merged before feeling receptor stimulating agent and/or flavoring ingredients.This can avoid flavoring ingredients or The precipitation of TAS2R taste receptors activators.

In an embodiment of the invention, simulation cigarette is configured to provide at most 15ng/ml's to its user Nicotine vein C_maxAnd/or the t of 10 seconds~20 minutes_max。

The present invention is described by means of the example related to following non-limitative drawings.

Brief description of the drawings

Fig. 1 shows the average blood plasma nicotinic density by treatment over time from part B research；

Fig. 2 shows the average blood plasma nicotinic density by treatment over time from the research of D parts；

Fig. 3：Average craving for tobacco VAS scorings in part B by treatment over time；

Fig. 4：Average craving for tobacco VAS scorings in D parts by treatment over time；

Fig. 5 is the decomposition diagram of simulation cigarette device；

Fig. 6 is the axial cross section of simulation cigarette；

Fig. 7 is the section of the alternative spring assembly of simulation cigarette；

Fig. 8 is the perspective view of Fig. 7 spring；

Fig. 9 is the section of the system and device of pressurize supplement container and the simulation cigarette of open configuration；

Figure 10 is the view similar with Fig. 7, and wherein drawer is shown as closing；With

Figure 11 is the decomposition diagram of system.

* new nicotine inhaler device 0.45mg andSignificant difference (p=between inhalator (10mg) 0.05)

New nicotine inhaler device 0.67mg andSignificant difference (p=between inhalator (10mg) 0.05)

SE refers to standard error, the simulation scoring of VAS finger visions

Embodiment

These embodiment parts are from Nicotine and Tobacco Research, Manuscript ID:NTR- Entitled " Evaluation of Pharmacokinetics, the craving and for delivering is submitted in 2013-681.R2 What smoking urges when using a novel nicotine inhaler device " original copy was replicated.

The present invention is described by referring to following non-limiting example now.

Manufacture method

The preparation that the present embodiment is used is prepared using following raw material：

Saccharin (Ph.Eur)

Propane diols (EP grades)

Menthol (Ph Eur.)

Ethanol (100%BP, Ph.Eur.)

Nicotine (Ph.Eur)

HFA-134a(CPMP 1994)

Raw material is added to stainless steel in the following sequence：(i) 5.14g saccharin, (ii) 227.0g propane diols, (iii) 32.5g menthols and (iv) 774.0g ethanol.Then mixture is stirred 15 minutes with 600rpm, until menthol pellet is complete Fully dissolved simultaneously observes supernatant liquid.Then 45.6g nicotine is added to mixture, and continues to be stirred for 10 points with 600rpm Clock.Then the mixture of acquisition is added to the pressure vessel cleaned with HFA 134a.Then container is sealed, cooled down afterwards Until internal temperature reaches 8 DEG C~12 DEG C, temperature now is kept.Then about 40kg HFA-134a are discharged into container, it After start with 210rpm carry out magnetic agitation.Continuation discharges HFA into container, until added 80kg altogether, now with 210rpm is stirred for said preparation 110 minutes.In further whipping process, control pressure, to ensure to be no more than 4.5 bars, and Final pressure is the bar of 3 bars~4.After stirring, preparation is distributed into tank.

Change this method by adding nicotine before addition saccharin or before menthol fully dissolves, cause The precipitation of nicotine.

Drop size feature

Prepare following preparation：

0.04 weight % menthols,

0.006 weight % saccharin,

0.34 weight % propane diols,

0.95 weight % ethanol,

0.056 weight % nicotine, and

Remaining HFA-134a.

Preparation is inserted in nine pinch valve simulation cigarettes.5 dosage are discharged from each device, and use Malvern The respective drop size feature of Spraytec measurement devices.As a result arrange in table 1 below：

	MEAN	SD
			Dv 10(μm)	0.198758	0.010005
Dv 50(μm)	0.606342	0.094779
			Dv 90(μm)	2.806378	1.063722
Volume %<10μm	99.02222	0.77704

Table 1-drop size feature

Impurity

Prepare following preparation：

0.04 weight % menthols,

0.0032 weight % saccharin,

0.34 weight % propane diols, and

0.95 weight % ethanol,

0.028 weight % nicotine,

Remaining HFA-134a.

Then preparation is inserted in pressurizing vessel.In filling and after six months, impurities phase is assessed for cigarette by chromatogram The volume proportion of alkali concn.As a result it is listed in table 2 below：

2-stability data of table (reversely, 40 DEG C/75%RH).N=1,2 and 3 refer to add from the difference with a collection of preparation Pressure vessel.

Clinical research

Part B：The vein PK of the oral suction nicotine of two dosage levels (0.45mg and 0.67mg) of measure randomization, Non-blind, single blind, three crossing research.0.45mg dosage, which corresponds to study for drop size in simulation cigarette as described herein, to be made The once charging of standby preparation.0.67mg dosage (is referred to herein as corresponding to the simulation cigarette in the preferred embodiment for the present invention The present invention device) in higher intensity preparation once charging, wherein being prepared as drop chi using 0.084 weight % nicotine Preparation prepared by very little research.By the present invention dosage withInhalator (10mg) is compared.

D parts：By by the present invention nicotine inhalator system withInhalator (10mg) is compared to survey The random of vein PK, non-blind, the dual crossing of the oral suction nicotine of the fixed dosage level (0.45mg) delivered for part B Research.

Participant

At least inhale 10 finished cigarettes daily in the past year and be at the age that cigarette is inhaled in 1 hour of waking up Healthy volunteer's (sex) of 18~55 years old is eligible to participate in.Whole participants have in screening to be at least The carbon monoxide level of 10ppm exhalation simultaneously is required to give up smoking 12 hours before predetermined administration time.

Exclude it is known or suspect to inhalator orThe nicotine of inhalator or any other composition have allergies Participant.Also exclude with the chronic and/or serious PUD D (including asthma) or chronic obstructive lung disease made a definite diagnosis Medical history, myocardial infarction or the cerebrovas-cularaccident of disease, other clinically serious heart or kidney condition or participant can be in Risk or disturb this data explanation any disease medical history participant.

Research treatment

Before active treatment is received, participant is set to be familiar with the inhaler device of the present invention (hereafter using placebo preparation In be " inhaler device ") use.In addition to nicotine, placebo preparation is identical with active ingredient.Participant is studied to the research Each several part apply nicotine dosage it is ignorant.Participant is to suck the once charging of apparatus of the present invention with cigarette similar mode Content.Whole participants are indicated on the phase in the time of about 2 minutes once sucked with every 15 seconds and (amounted to 8 suctions) Same rate sucks the dosage.For 0.056 weight % nicotine formulation concentration (i.e. 35%~68% nicotine dosage), fine grained Dosage (<5m) specification is 160~305g.For 0.056 weight % and 0.084 weight % concentration, 0.8g preparations are (of the invention Single dose/supplement of device) in contained nicotine dosage be estimated as 0.45mg and 0.67mg respectively.Suction Device (10mg) is the NRT products orally sucked, and is chosen as comparative, because it is the immediate available exhibition of this inhaler device Show thing.Participant is carried out once for every 15 secondsThe suction of inhalator (10mg), with (i.e. 80 times suctions in no more than 20 minutes Enter) dosage is completed, it is consistent with scheme described in prescription information (McNeil Products Limited, 2010).The available nicotine dosage of each magazine of inhalator (10mg) is estimated as 4mg, but it is that temperature is related (McNeil Products Limited, 2010).Participant starts to be recorded the time that test product carries out first time suction For administration time (t=0).

In sectionb, continuous three days of each participant by new nicotine inhaler device with 0.45mg's and 0.67mg Dosage level receives the nicotine of single dose, and passes throughInhalator (10mg) receives single dose.

In D parts, each participant receives single dose in continuous two days by new nicotine inhaler device (0.45mg) Nicotine, and pass throughInhalator (10mg) receives the nicotine of single dose.For the device of the present invention, part B is surveyed First time supplement is tried, and the 4th supplement is detected in D parts.Early stage research, it is notable that for the first dosage The nicotine amount that (i.e. one full complement thing) is delivered by new inhaler device is only often about the 70% of subsequent dose.Grinding In the D parts studied carefully, filled out by using pump (Cole-Parmer), critical stream controller (TPK types) and dose uniformity sampling apparatus Fill and rinse the device 3 times to study the 4th supplement of apparatus of the present invention.The administration of inhalator (10mg) with Two study portion all sames.

Research is assessed

PK is analyzed

PK assessments are the primary outcome measures of this research.For part B and D parts, 5 minutes before administration (± 1 minute) With after administration 2 (i.e. since suction), 4,7,10 minutes (± 1 minute), 15,20,30,40,50,60 minutes (± 2 minutes) and 120th, 180, venous blood sample is collected within (± 5 minutes) 240 and 300 minutes, to be measured using Liquid Chromatography-Mass Spectrometry Plasma nicotine concentrations.This method demonstrates the linearity, precision and the degree of accuracy.Concentration be 3.0ng/ml, 7.5ng/ml and The sample of 37.5ng/ml quality control sample and 37.5ng/ml dilute quality controls (being diluted to 1/2) as low amounts sample Precision and internal accuracy and a degree of accuracy and the internal degree of accuracy between product are determined.The degree of accuracy is within 1% between average operation, and precision exists Within 5%.Derived PK parameters are collected by device and dosage level respectively.

Effect

Using following methods, by assessing test device is met to craving for tobacco and smoking is got excited influence and it is guarded against nicotine Effect is assessed in the influence of disconnected aspect：

1. the answer based on object to problem " your craving for tobacco to cigarette has how strong ", in 0 (no craving for tobacco) to 10 (strong cigarettes Addiction) yardstick on assess object craving for tobacco level visual analogue scale (VAS).This is assessed starts for 1 minute with administration before administration Afterwards 4,20,40,60,120,180, carry out within 240 and 300 minutes.In D parts, carry out within 2 minutes and 10 minutes after administration starts Extra assessment.

2. the reaction based on participant on the yardstick of 1 (being strongly opposed to) to 7 (strong to agree to) to 10 statements, assesses cigarette The smoking impulsion questionnaire (QSU1Brief) (Cox, Tiffany, ＆Christen, 2001) of addiction and smoking impulsion level.These are commented Estimate 20 after starting before administration with administration within 1 minute, carry out within 40,60,120,180,240 and 300 minutes.Determine " it is desirable that " and it is " pre- The component scores of phase " sub- scale.Using QSU-Brief " it is expected that " result the measuring as craving for tobacco of component scores.

Security

Compare device of the invention withThe security and tolerance of inhalator.Local tolerance is to this hair Bright device orThe assessment of inhalator and the contact area of participant's lip.Participant is asked about the device at it How are you feeling today in mouth or lip, it is also visually assessed.Tolerance is the assessment of symptom caused by orally being sucked from inhalator. It is reported as any symptom more even worse than before medication and is all registered as side effect (AE).AE is putd question to by neutrality and it is by researcher Record and be rated to test product " uncorrelated ", " may related ", the incidence of " being likely to related " and " clear and definite correlation " and Property and determine.The monitoring also carried out a medical examination with vital sign (blood pressure, heart rate, respiratory rate and temperature).

For part B and D parts, the assessment for carrying out local tolerance and vital sign in 20 minutes before administration.In administration Being assessed after the administration measured after beginning includes：Local tolerance at 4 minutes and 20 minutes；Physical examination at 300 minutes；With 4th, 20,40,60,120,180,240 and 300 minutes when vital sign and AE, SAE and concomitant drugs.Whole participants are grinding Study carefully after end by phone contact (9 ± 2 days), and record any AE, SAE and concomitant drugs.Assess and opened from test product administration Begin until security phone tracks the AE (TEAE) that the treatment accessed occurs.

Statistical analysis

The participant for receiving whole predetermined close nicotine is included into PK crowd.The participant for receiving a dosage nicotine is received Enter security treatment of purpose crowd.UseVersion 9.2 carries out statistical analysis.

PK is analyzed

Part B and D parts for this research, measure the plasma concentration of nicotine over time, and respectively by device and Dosage level collects derived PK parameters.After nicotine is applied using any device, the PK parameters of measure are from 0 moment to sample Harvest time terminates (AUC_all) and from 0 moment to mean maximum plasma nicotinic density (C when can finally quantify concentration_max), reach Average time (the T of maximum plasma nicotine concentrations_max) and plasma concentration-time graph under average area (AUC).Use profit Use C_maxLogarithmic transformed variance analysis (ANOVA) with AUC carry out new nicotine inhaler device andSuction Comparative analysis between two kinds of dosage levels of device (10mg).P=0.05 difference is considered as notable.Use PhoenixTMVersion 6.2 carries out PK analyses.

Effect

In the part B and D parts of research, collect craving for tobacco measurement and QSU- with the time by device and dosage level Brief overall scores and component scores.Examined using the student t of pairing come by device and the average craving for tobacco VAS of time point analysis The difference scored with QSU-Brief.Also scored by VAS-time graph under area assess craving for tobacco, wherein relatively low craving for tobacco AUC It is equal to more preferable craving for tobacco to decline.Using using the logarithmic transformed ANOVA of AUC carry out new nicotine inhaler device andComparative analysis between two kinds of dosage levels of inhalator (10mg).

Assuming that the coefficient of variation is that participant's quantity in 15%, part B and D parts suffices to show that and made in potential object With equivalence of 20% and 80% function of two method of testings of one side 5% at similar edge.

The weight for the preparation discharged by device and the target nicotinic density of preparation calculate each participant from the dress of the present invention Put the amount of suction nicotine.

As a result

Study population

24 participants are randomized into the part B of this research altogether, and 24 participants are divided into D parts in addition.Participant's Average age is 28.6 years old (part B) and 29.7 years old (D parts), and 58% (part B) and 54% (D parts) are male.

Part B

All 24 participants of part B receive to come fromThe single dose of inhalator (10mg), but only 23 Receive two kinds of respective single doses of dosage level of new nicotine inhaler device, because a participant is due to the limitation of research And exit.Average (standard deviation) weight of the preparation sucked from apparatus of the present invention is 0.9472g (0.2051g) and 0.8610g (0.3005g), it corresponds to the 0.5304mg and 0.7232mg of 0.45mg the and 0.67mg devices from the present invention nicotine respectively. Do not exited caused by AE.

D parts

All 24 participants of part B receive the single dose from 0.45mg devices of the present invention and come from The single dose of inhalator (10mg).In D parts, average (standard deviation) weight of the preparation sucked from apparatus of the present invention is 0.7074g (0.3028g), it corresponds to 0.3961mg nicotine.

PK is analyzed

Maximal plasma concentration

In sectionb, after all three treatment is applied, average venous plasma nicotinic density increase.Applying suction dress Set to 0 the average venous plasma C after .45mg and 0.67mg_maxRespectively 3.28ng/ml and 3.92ng/ml (referring to table 3).ApplyingAverage C after inhalator (10mg)_maxFor 6.57ng/ml (table 3).

The result of D parts is similar with those results of part B,Inhalator (10mg) is produced than present invention dress Put higher but more late peak.Apply the present invention 0.45mg devices andAverage C after inhalator (10mg)_max Respectively 3.52ng/ml and 7.63ng/ml (table 3).

Reach C_maxTime

ApplyingAfter inhalator (10mg), the average nicotine C calculated in part B_maxHigher than apparatus of the present invention Any one dosage (table 3).However,The T of inhalator (10mg)_maxIt is longer than apparatus of the present invention of any intensity (in sectionb for 38.0 minutes to 18.7 minutes and 19.2 minutes 0.45mg the and 0.67mg devices of the present invention [be respectively], For 36.3 minutes to 21.0 minutes [0.45mg devices of the invention] in D parts) (table 3).

The average blood plasma nicotinic density by treatment over time of part B and D parts is shown in fig 1 and 2.

Area below concentration-time graph

In sectionb,The average AUC of inhalator (10mg) is higher than this suction apparatus of any intensity.In D Visible similar results (table 1) in part.To the nicotine relative bioavailability carried out between the treatment in part B and D parts Relatively show, withInhalator (10mg) is compared, and device of the invention produces significantly lower C_max、AUC_lastWith AUC_all, and significantly shorter T_max(table 1).AUC from part B and D parts_0–10Analysis confirmation, withSuction Device (10mg) is compared, and device of the invention delivers the nicotine of higher amount in early stage.

Effect

Craving for tobacco VAS scores

Most of the time point in part B (Fig. 3) and D parts (Fig. 4), device of the invention is assessed by VAS Average craving for tobacco scoring ratioInhalator (10mg) is low (higher craving for tobacco is alleviated).In sectionb, for the present invention's 0.45mg devices andThe minimum scoring of inhalator (10mg) be all at 20 minutes, and for the present invention The minimum scoring of 0.67mg devices is at 4 minutes (Fig. 3).In D parts, put down for the minimum of 0.45mg devices of the present invention Equal craving for tobacco VAS scored at 20 minutes, and forThe scoring of inhalator (10mg) is at 40 minutes (Fig. 4).

Relatively showing for average craving for tobacco VAS scorings, it is in sectionb, 7 after being administered at 8 in time point, of the invention 0.45mg devices average score ratioInhalator (10mg) is low (higher craving for tobacco alleviate), and at 180 minutes and This difference reaches significance,statistical (Fig. 3) at the time point of 240 minutes.6 after being administered at 8 in time point, the present invention The average scores of 0.67mg devices be less thanInhalator (10mg), reaches that statistics shows at 180 minutes points Work property (Fig. 3).In D parts, at the time point after all 10 administrations, the average score of 0.45mg devices of the invention is less thanInhalator (10mg), and this difference reaches significance,statistical at 2 minutes, 4 minutes and 10 minutes point (Fig. 4).

The AUC of craving for tobacco VAS scorings

In part B and D parts, the average AUC ratios of apparatus of the present inventionInhalator (10mg) is low (to be shown more The craving for tobacco of big degree is alleviated).In sectionb, average (standard deviation) of the craving for tobacco VAS scorings of 0.45mg devices of the invention AUC minimum (1356.3 [789.4] cm*min), followed by the 0.67mg devices (1431.6 [769.0] cm*min) of the present invention.Meter CalculateThe maximum AUC (1566.3 [620.4] cm*min) of inhalator (10mg).It is of the invention in D parts The average AUC (1208.5 [724.4] cm*min) of the craving for tobacco VAS scorings of 0.45mg devices is less thanInhalator (10mg)(1402.3[815.2]cm*min)。

The craving for tobacco AUC carried out between treatment statistics relatively shows, in sectionb, 0.45mg devices of the invention AUC be substantially less thanInhalator (10mg) (p=0.029)；In D parts, 0.45mg devices of the invention AUC is less thanInhalator (10mg), and reach significance,statistical (p=0.059).These results indicate that withInhalator (10mg) is compared, and a greater degree of craving for tobacco is realized using the medium and high dose of the device of the present invention Alleviate.

QSU-Brief scores

For two parts, for whole treatment groups, in the average QSU-Brief general comments of the first time of measuring (20 minutes) Divide and reduce and (show that craving for tobacco is alleviated)；For the respective visible similar pattern of QSU-Brief component scores of " it is expected that " with " it is desirable that ".

The treatment of average QSU-Brief scorings, which is compared, to be shown, in sectionb, 120 minutes upon administration, 180 minutes and 240 minutes, the overall score of 0.45mg devices of the invention was statistically substantially less thanInhalator (10mg) is (complete Portion p=0.05).In D parts, the overall score of apparatus of the present invention is lower, although its difference does not have significance,statistical (p> 0.05)。

Security

In sectionb, 23/24 (96%) name participant reports 87 TEAE altogether.Wherein, 79 TEAE be considered as with Study medicine relevant.Actually major part TEAE is slight.Two TEAE are moderates, and one of them is relevant with research medicine (mono-anesthesia, its reporting for 4 minutes after inhalator is applied, and dissolved in 15 minutes).Utilize the present invention's in the presence of one Slight numb report in 20 minutes after the administration of 0.67mg devices.For the present invention device andInhalator, slight thorn Pain is the local tolerance symptom most often reported.

In D parts, 22/24 (92%) name participant reports 61 TEAE altogether.Wherein, altogether the 50 of 19 reports Individual TEAE is considered as relevant and entirely slight with research medicine.For the device and inhalator of the present invention, slight shouting pain It is the local tolerance symptom most often reported.

Whole AE actually seen in part B and D parts are slight or moderate, and the report without severe. There is no serious AE or death in whole research, and the person of being not engaged in stops treating because of AE.In general, most common AE For oral paresthesia, throat irritation, headache and oral hypoesthesia.For local tolerance, by two portions of the research The most common local AE of participant's report in point is mouth/lip shouting pain.

Within the duration of research, average life sign over time changes without clinically significant.

The pharmacokinetic parameter that table 3. is treated collects

Data are average value (standard deviations)

The new inhalator pharmacokinetic parameter of whole in addition to AUC and Reference Product (Inhalator) tool There were significant differences (p<0.05).

* for part B, N=23

AUC_all, the area below plasma concentration versus time curve terminated from 0 moment to the sample collection phase；AUC_last, from Area below 0 moment to the plasma concentration time curve for the time that can finally quantify concentration；AUC_0-10, from 0 moment to 10 points Area below the plasma concentration time curve of clock；C_max, maximal plasma concentration；T_max, reach the time of Cmax.

Described now with reference to Fig. 5~11 by simulation cigarette device and the supplement for forming simulation cigarette system, wherein The display simulation cigarette devices of Fig. 5 and 6, the alternative spring construction of the displays of Fig. 7 and 8, Fig. 9~11 illustrate how to be incorporated into supplement Device.

As shown in figure 1, device has the housing 1 being made up of master priming 2 and closing element 3.It passes through label (not shown) It is held in place by.There is the pressurizing reservoir 5 containing suction-type composition in housing.It can be such as WO2009/ It can be supplemented by filling-valve 6 described in 001082, or the device can be that device is intended for single use, or may be arranged so that storage Storage 5 is field-replaceable unit.

Breath actuated valve 7 is located between the port of export 8 and reservoir 5.Breath actuated valve is set to when user is in the port of export 8 During suction, breath actuated valve 7 is opened so that the suction-type composition from reservoir 5 is inhaled into.

Housing at the port of export has two holes.Wherein first hole is the chamber 10 with will be described in more detail below The suction hole 9 being connected；And second hole is the outlet opening 11 for the distribution suction-type composition being described in more detail below.Such as Shown in Fig. 2, outlet opening 11 is arranged on single part 12.

Outlet pathway 13 is defined between the reservoir 5 and outlet opening 11 provided by deformable tubular element 14.This pipe The very best part is moved between the closed position and open position as shown in now by the mechanism of description.

This mechanism includes the blade 15 and film 16 being pivotally mounted.The blade being pivotally mounted is near the port of export 8 End has pivot 17, and operation and the center ribs 18 being tapered away from the port of export along its length.Near midpoint, leaf Piece 15 is provided with the recess 19 for receiving spring 20, and spring 20 makes it be offset to closed position shown in Fig. 1 (although deformable tubulose Element is shown with its undeformed state).It is the mandible 21 with triangular-section under recess 19, it is configured in stenosis area The power for providing blade 15 on domain applies to deformable tube 14.Blade 15 is supported by dividing plate 16, and dividing plate 16 is at its end 22,23 Seal to housing.This seals the chamber 10 in addition to suction port 9 and the stomata in closing element 3.

24 pairs of the downside atmospheric pressure of film 16 is open, because existing across housing 1 when it extends around outlet pathway 1 Leakage paths (not shown in FIG.), it is and therefore not shown in Fig. 1 plane.

When user aspirates on the port of export 8, suction is connected by suction hole 9 with chamber 10, so as to reduce this intracavitary Pressure.This cause blade 15 resist spring 20 effect and lifted, make dividing plate deform and lift mandible 21 so that deformation tube opening, So that suction-type composition is discharged by deformable tube 14 and by outlet opening 11 from reservoir 5 along outlet pathway 13.Use The degree for the suction that person applies will determine the mobile degree of blade 15, and it is thus determined that the amount for the composition that user receives.One Denier user stops suction, and atmospheric pressure will be by the return cavity 10 of suction hole 9, and spring 20 will return to blade, so as to press from both sides Tight pipe 14 and close.

It is capillary bolt 30 in reservoir.Although as shown in Fig. 2 between existing between the end of bar and supplement valve 6 Gap 51, but it extends to the substantially whole length of reservoir.It is also shown from Fig. 2, bolt 30 is at least in the region away from valve 7 It is not filled with the whole cross section of reservoir.On the contrary, there is gap 32 along the top surface of bar.This allows supplement material along the gap Absorbed by and along the length of bar, rather than whole supplement liquid have to pass through the end of bar and entered.

Alternative spring construction will now be described.As shown in FIG. 7 and 8, spring 33 has a U-shape configuration, and the first arm 34 is from prominent Go out portion 35 along dividing plate 24 from the port of export 8 to stretch out so that the core of its supporting clapboard 24, must so as to provide dividing plate 24 The rigidity wanted simultaneously replaces blade 15 in Fig. 6.Dividing plate 24 that replaces the mandible 21 in Fig. 6 around protuberance 35.First arm 34 extend to top 36, extend in this spring away from dividing plate 24 and bend to the second arm 37 towards the wall of housing 1, the second arm court Valve components to return extension.Second arm 37 is engaged with the upper wall of housing 1, and is configured so as to produce between two arms 34,37 The compression bias force for keeping valve to close.This new spring design instead of blade 15 and helical spring 20 in Fig. 6.With Fig. 6 In example compare, its provide extra benefit, include easily operation and reduce part quantity.

The remainder of simulation cigarette system is supplementary device.It includes the main housing portion 42 as plastic shaped body. The part is surrounded by thin cutting ferrule 43, and the various information such as sales promotion information are printed on thin cutting ferrule.Housing be preferably dimensioned to be with The size of cigarette pack is similar, and can adjust to specific dimensions form is adapted to, for example, adjusting to 10 or 20 cigarette Package size.Housing 42 has recess 44, wherein accommodating the supplement tank 45 of pressurization supplement gas.Tank 45 has in its bottom There is outlet valve rod 46.Because tank 45 is in recess 44, nozzle 46 is located on supplement outlet opening 47.It is as detailed below , simulation cigarette device 1 is supplemented by being pressed relative to supplement outlet opening 47.Tank can simply be replaced by one solely Vertical cylinder, it can then have bigger capacity, because it is not limited by needing to be assemblied in the housing of cigarette pack size.

In general, housing 42 is divided into two halves, wherein a semi-inclusive supplement gas tank 45, and another part is comprising having The hinge drawer 48 of the relieving mechanism 49 biased by spring 50.This constructs the theme for forming WO 2011/095781.

Claims (17)

1. a kind of simulation cigarette system, it includes：

Oral suction-type preparation comprising nicotine or its acceptable salts and propellant,

Pressurization supplement container containing the suction-type preparation,

For the simulation cigarette of preparation described in pulmonary administration, the simulation cigarette has housing, is configured to receive and accommodates come From the reservoir and breath actuated outlet valve of the charging of the suction-type preparation of the pressurizing vessel, the outlet valve It is configured to discharge the suction-type preparation of drops therefrom, at least part of drop has less than 10 μm of diameter, And

Wherein, the supplement container includes 2mg~20mg nicotine or its acceptable salts, the nicotine or its medicinal connect It can be delivered by least the 60% of salt by pulmonary administration.

2. the system as claimed in claim 1, wherein, about 15~30 dresses of the pressurizing vessel comprising the simulation cigarette Material.

3. system as claimed in claim 1 or 2, wherein, second and subsequent charge include about 0.1mg~1mg nicotine or its medicine Use acceptable salt.

4. system as claimed in claim 3, wherein, second and subsequent charge is comprising about 0.2mg~0.7mg nicotine or its is medicinal Acceptable salt.

5. the system as any one of preceding claims, wherein, the first charge packet contains less than about 1mg nicotine or its is medicinal Acceptable salt, preferably less than about 0.43mg, more preferably from about 0.02mg~0.3mg.

6. the system as any one of preceding claims, wherein, the propellant is HFA, preferably HFA-134a.

7. the system as any one of preceding claims, wherein, the preparation is further included：

Monohydric alcohol；With

Glycol and/or glycol ethers,

Characterized in that, monohydric alcohol:The weight ratio of glycol or glycol ethers is 6:1~1:1.

8. system as claimed in claim 7, wherein, the monohydric alcohol is ethanol.

9. system as claimed in claim 7 or 8, wherein, the glycol and/or glycol ethers are propane diols.

10. the system as any one of preceding claims, wherein, based on the gross weight of the preparation, the preparation is included：

The weight % of 0.03 weight %~0.05 menthol,

The weight % of 0.25 weight %~0.4 propane diols,

The weight % of 0.9 weight %~1 ethanol,

Saccharin, and

It is following any：

(i) the weight % nicotine of 0.025 weight %~0.03 or its acceptable salts, or

(ii) the weight % nicotine of 0.054 weight %~0.058 or its acceptable salts, or

(iii) the weight % nicotine of 0.08 weight %~0.088 or its acceptable salts,

Surplus is HFA-134a, wherein, the weight ratio of nicotine or its acceptable salts and saccharin is 9.5:1~8:1.

11. the system as any one of preceding claims, wherein, the nicotine or its acceptable salts are at least 70% can be delivered by pulmonary administration.

12. the system as any one of preceding claims, wherein, the nicotine or its acceptable salts are at least 75% can be delivered by pulmonary administration.

13. the system as any one of preceding claims, wherein, the simulation cigarette further comprises capillary bolt, The capillary bolt is extended about into the reservoir from the outlet valve, fills at least the 50% of the reservoir volume, And be configured to wick suction-type composition to the outlet.

14. the system as any one of preceding claims, wherein, breath actuated valve has to be closed by spring and dividing plate biasing The valve components closed, it is configured to deform when applying suction to the port of export, producing low pressure above the dividing plate, thus relatively Lift the valve components in the bias force of the spring so that the selectively opened reservoir exit port, make preparation it is described go out Flow out the simulation cigarette in mouth end；Wherein, the spring is the elastic material rod to form U-shaped, and it has the first arm, described first Arm extends so as to by dividing plate branch from the position adjacent with the valve components on the direction away from the port of export along the dividing plate Support is to top, and at this, it is extended outwardly into towards the port of export in returning the second arm of extension from the dividing plate, second arm Engage to produce the bias force for promoting the valve components to close with housing.

15. a kind of method to Healthy People delivery of nicotine dosage, the described method comprises the following steps：

System any one of preceding claims is provided；

Nicotine daily dose less than 60mg is delivered by pulmonary delivery approach.

16. a kind of oral suction-type system for being used to treat Nicotine Dependence in the system any one of claim 1~14 Agent, it includes nicotine or its acceptable salts and propellant, wherein, user receives to be less than 60mg by pulmonary delivery approach Daily dose.

17. the system any one of claim 1~14 is used to pass through pulmonary administration by least 60% nicotine or its medicine The application of user is delivered to from the supplement container with acceptable salt.