UA104645C2 - Improved device (variants) and a method for delivering of a medicine - Google Patents

Abstract

Device for delivering nicotine in the human body comprises a housing, wherein the housing has an interconnected input and output holes formed so that it becomes possible to flow a carrier gas into the housing through the inlet, passing it through the body and out of the housing through the outlet. The device includes such zones arranged in series from the inlet to the outlet: b) connected with the inlet of the first internal zone which comprises a source compound for improving delivery c) coupled to the first inner area inside the second zone which includes a source of nicotine. The source of nicotine comprises nicotine and the compound forms an electrolyte, and both of these substances are in the aqueous solution.

Description

ИО001) This invention relates to devices and methods of delivering a medicinal product to the consumer.

In particular, this invention relates to devices and methods of delivering an aerosol of a medicinal product to the user's bronchopulmonary system. 0002) Pulmonary drug delivery systems have been used for decades to deliver drugs to treat respiratory diseases. The principle on which the method of delivering medicines to the lungs is built is the formation of an aerosol of the medicinal substance, which is to be delivered to the bronchioles and alveoli. Despite the complications associated with the need to optimize aerosol particle size and degradation, many companies have developed drug delivery technologies for the treatment of diabetes, migraine, osteoporosis, and cancer. 0003) Available drug delivery systems include metered dose inhalers (MOI5), dry powder inhalers (ORI5) and aerosol nebulizers. Dosing inhalers (MOI5) were among the first to be introduced in the United States in the mid-1950s. The inhaler-doser with propellant hydrofluoroalkane (NEA) (under increased pressure) was introduced in

United States in 1995. Despite the introduction of dry powder inhalers (ORiIb5) in the seventies of the twentieth century, their use was limited due to the undeniable predominance of MOiI5. Nebulizers are usually used in hospital settings. In the field of pulmonary drug delivery devices, the improvement of metered dose inhalers that do not use chlorofluorocarbon (CFC), dry powder inhalers (ORI5) and liquid inhalers (I VI5) is underway.

II0004| In the course of many preclinical and clinical studies, it has been shown that the delivery of drugs to the lungs is an effective method of treatment for both respiratory and systemic diseases. The many advantages of pulmonary drug delivery are well known, including rapid onset of action, patient self-administration, fewer side effects, ease of inhalation delivery, and elimination of the need for injection needles.

I0005) However, the delivery methods of most drugs have not undergone a significant deviation from delivery by traditional intravenous/intramuscular and oral routes towards pulmonary delivery by inhalation. The use of pulmonary delivery is limited mainly to the administration of drugs for the treatment of asthma.

I0006| It was reported that for the delivery of the powder directly to the lower respiratory tract, the size of the powder particles, as a rule, should not exceed 5 μm. In addition, it was found that powders with a particle size of 5-10 microns cannot penetrate to such a significant depth, instead they can affect areas of the upper respiratory tract.

I0007| In the manufacture of drug compositions for dry powder inhalers (DPIs), the mentioned drug must first be ground to obtain a powder with a particle size acceptable for pulmonary delivery. This stage of micronization can cause problems in the manufacturing process of the medicinal product. For example, the heat generated during grinding can cause the drug to break down. In addition, some mills can lose metal due to friction and contaminate the mentioned medicine. In addition to this, medicinal products in the form of dry powder, due to the small size of the particles, have a tendency to agglomerate, in particular, in the presence of moisture.

I0O008)| The consequence of agglomeration is the low fluidity of the powder particles, which reduces the effectiveness of the dry powder composition. As a result, the process of milling, mixing, powder flow, filling and even injection needs careful supervision to ensure the appropriate delivery of dry powder aerosols.

ИО009| Thus, there is a need for new methods of obtaining aerosols for drug delivery. This disclosure discloses, in part, a method of combining nicotine or other drugs with a delivery-enhancing compound in a gaseous carrier stream to create an aerosol for pulmonary delivery without the need for excipients or other additives, including solvents.

ИЙО0О10| In some embodiments, the present invention relates to a method of delivering nicotine to a patient by inhalation, which includes the following operations: a) first, introducing a gaseous carrier that contains a delivery-enhancing compound into contact with a nicotine source that contains nicotine, and p ) secondly, the introduction of a gaseous carrier containing nicotine into the patient's body. 0011) In some embodiments, this invention relates to the method described in paragraph (00101, which includes the additional step of contacting a gaseous carrier with a source of a delivery-enhancing compound that contains a delivery-enhancing compound. 0012) In some embodiments, this invention relates to of the method described in paragraph (00111), wherein the step of contacting the gaseous carrier with the source of the delivery-enhancing compound precedes the step of contacting the gaseous carrier containing the delivery-enhancing compound with the source of nicotine.

0013) In some embodiments, the present invention relates to the method described in paragraphs 00101, (0011) or (00121), wherein the source of the delivery-enhancing compound comprises a plurality of chambers containing two or more precursor compounds. 0014) In In some embodiments, this invention relates to the method described in paragraph (00131, wherein the delivery enhancing compound comprises ammonium chloride and two or more precursor compounds, including ammonia and hydrogen chloride. 0015) In some embodiments, this invention relates to methods , which are described in paragraphs (001 01-

I0O0131| or I0014|, in which the concentration of nicotine in the gaseous carrier is increased compared to the concentration of nicotine that the gaseous carrier would contain without the compound to improve delivery.

IO0O16) In some embodiments, the present invention relates to the methods described in paragraphs (00101-00141 or (00151), in which the compound for improving delivery comprises an acid.

I0017| In some embodiments, this invention relates to the method described in paragraph (00161, wherein said acid is an organic acid. 0018) In some embodiments, this invention relates to the method described in paragraph (00171, wherein said organic acid has a higher saturated vapor pressure than nicotine at a given temperature.

I0019) In some embodiments, the present invention relates to the method described in paragraph (00181), wherein said specific temperature is 25 "C, 30 "C, 40 "C, 45 "C, 70 "C or 100 "C.

I0020) In some embodiments, this invention relates to the methods described in paragraphs (00161|-

IOO181I or (00191), in which said acid is selected from the group consisting of 3-methyl-2-oxovaleric acid, pyruvic acid, 2-oxovaleric acid, 4-methyl-2-oxovaleric acid, 3-methyl-2-oxovaleric acid, 2-oxooctanoic acid, propionic acid, formic acid, acetic acid and combinations thereof One particular possible combination is propionic acid, formic acid and acetic acid, in a preferred embodiment with a ratio between acetic acid and formic acid of 2:1.

I0021| In some embodiments, the present invention relates to the methods described in paragraphs (00101-

I0019| or I0020|, in which the delivery-enhancing compound interacts with nicotine to form particles. 0022) In some embodiments, the present invention relates to the methods described in paragraphs (00211), in which the mass median aerodynamic diameter of the nicotine particles formed is less than b

MKM.

I0023) In some embodiments, this invention relates to the method described in paragraph (00211, in which the mass-median aerodynamic diameter of said nicotine particles is less than 1

MKM. 0024) In some embodiments, this invention relates to the method described in paragraph (00211, wherein the mass median aerodynamic diameter of at least some of said nicotine particles is from 0.5 μm to 5 μm. 0025) In some embodiments, this invention relates methods described in paragraphs (001 01-

IOO23| or (00241), which include the additional step of increasing the temperature of the delivery-enhancing compound, the source of the delivery-enhancing compound, the nicotine, the nicotine source, and/or the gaseous carrier. 0026) In some embodiments, the present invention relates to the method described in paragraph (00251, in which temperature is raised to at least 30 "C.

I0027| In some embodiments, the present invention relates to the methods described in paragraphs (00101-

I00O25I or (00261, in which the gaseous carrier contains at least 20 μg of nicotine in the volume of the gaseous carrier that is injected into the patient's body. 0028) In some embodiments, the present invention relates to the method described in paragraph (00271, in which the volume gaseous carrier, which is delivered to the patient's body, is introduced in the form of an indivisible volume.

I0029| In some embodiments, the present invention relates to a method of stopping the consumption of tobacco products using one or more of the methods described in paragraphs (00101-(002 71 or (10028)), which includes the additional operation of delivering to the patient's body a therapeutically effective amount of nicotine that is at least partially replaces nicotine obtained from the product.

ИЙОО30| In some embodiments, this invention relates to a method of treating diseases in which nicotine is useful as a therapeutic agent, using one or more of the methods described in paragraphs (00101-(0027| or (0028)), in which the patient is administered therapeutically effective amount of nicotine.

In some embodiments, the present invention relates to the method described in paragraph (00301), in which the disease is selected from the group of diseases consisting of nicotine addiction, obesity, Alzheimer's disease, Parkinson's disease, ulcerative colitis, multiple sclerosis, depression, schizophrenia, analgesia, attention deficit hyperkinetic syndrome (ADHD) and their combinations.

II0032| In some embodiments, this invention relates to a method of replacing the consumption of tobacco products, which involves delivering nicotine to the patient's body using the methods described in paragraphs (00101--(0027| or (0028)) to replace nicotine obtained from a tobacco product.

ІОО33| In some embodiments, this invention relates to a method of reducing the harmful effects of tobacco product consumption, which involves delivering nicotine to the patient's body using the methods described in paragraphs (00101-(0027| or (0028)) to replace nicotine obtained from the tobacco product .

I0034) In some embodiments, the present invention relates to a device that allows you to implement the methods described in paragraphs (00101-(00321) or (00331.

И00О35) In some embodiments, this invention relates to a device for delivering nicotine to the patient's body, which includes a housing, while the housing has: a) inlet and outlet openings that communicate with each other and are located so that a gaseous medium can enter the housing through the inlet opening, pass through the housing and exit the housing through the outlet opening, while the device includes in sequence from the inlet opening to the outlet opening: p) a first internal zone that communicates with the inlet opening, while the first internal zone includes a source compound to improve delivery, c) a second interior zone that communicates with the first interior zone, wherein the second interior zone includes a source of nicotine, and a) an optional third interior zone that communicates with the second interior zone and the outlet.

ИЙО036| In some embodiments, the present invention relates to the device described in para

IOOZ35I, in which a partial decrease in pressure at the outlet allows the gaseous medium to be pumped through the inlet, the first chamber, the second chamber, the third chamber (if present), and then through the outlet.

I0037| In some embodiments, the present invention relates to the device described in paragraphs

10OO35I or (0036), wherein the source of the delivery-enhancing compound comprises an adsorption element with the delivery-enhancing compound adsorbed thereon and/or wherein the nicotine source comprises an adsorption element with nicotine adsorbed thereon.

ИЙОО38| In some embodiments, the present invention relates to the device described in para

ИИОО37)Й, in which the adsorption element(s) includes at least one of such materials as glass, aluminum, polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polytetrafluoroethylene (RTEE or TERGOMU) , microporous, or foamed polytetrafluoroethylene (eRTEE) (description of eRTEE see, for example, US patent Mo 4,830,643), as well as VAKEHU.

II0039| In some embodiments, the present invention relates to the devices described in paragraphs

I00351-(00371 or (00381), which also includes a first reservoir that communicates with the first internal zone, wherein the first reservoir contains a compound to improve delivery.

II0040| In some embodiments, the present invention relates to the devices described in paragraphs

I00351-(00381 or (00391, which also includes a second reservoir that communicates with the second interior area, wherein the second reservoir contains nicotine. 0041) In some embodiments, the present invention relates to the devices described in paragraphs

I00351-(00391 or (0040), which include a third internal zone, while the third internal zone includes a structural element of the third internal zone. 0042) In some embodiments, the present invention relates to the device described in paragraph

ЙО041|, in which the mentioned structural element of the third internal zone includes a cleaning agent. 0043) In some embodiments, the present invention relates to the device described in paragraph 00421, in which the cleaning agent includes activated carbon. 0044) In some embodiments, the present invention relates to the devices described in paragraphs

IO0411, (00421 or (00431), in which said structural element in the third inner zone includes a flavoring agent. 0045) In some embodiments, the present invention relates to the devices described in paragraphs

I00411-(00431 or (0044), in which the mentioned structural element in the third internal zone includes a medicinal product.

I0046| In some embodiments, the present invention relates to the device described in paragraph 00451, in which the drug contains nicotine.

I0047| In some embodiments, the present invention relates to the devices described in paragraphs

I00351-(00451 or (0046), in which the body imitates a tobacco smoking product. 0048) In some embodiments, the present invention relates to the device described in paragraph 00471, in which said tobacco smoking product is a cigarette. 0049) In some embodiments, the present invention relates to the devices described in paragraphs

I00351-(00451 or (0046), in which the body imitates an inhalation device for the delivery of a pharmaceutical preparation.

ИЙОО50| In some embodiments, the present invention relates to the device described in paragraph 0049), wherein said simulated inhalation device for delivering a pharmaceutical preparation is selected from the group consisting of a metered-dose inhaler, a pressurized metered-dose inhaler, a dry powder inhaler, an aerosol nebulizer and a liquid inhaler.

IOO51| In some embodiments, the present invention relates to a method of increasing the concentration of nicotine in a gaseous carrier, which comprises the step of contacting a gaseous carrier that contains a delivery-enhancing compound with a source of nicotine that contains nicotine. 0052) In some embodiments, the present invention relates to the method described in paragraph (00511), which includes the additional step of contacting a gaseous carrier with a source of a delivery-enhancing compound that contains a delivery-enhancing compound.

I0053) In some embodiments, the present invention relates to the method described in paragraph (00521), wherein the step of contacting the gaseous carrier with the source of the delivery-enhancing compound precedes the step of contacting the gaseous carrier, which contains the delivery-enhancing compound, with the source of nicotine 0054) In some embodiments, the present invention relates to the method described in paragraphs

IOO511, (00521 or (0053), in which the source of the compound to improve delivery includes a number of chambers in which two or more precursor compounds are placed.

I0055) In some embodiments, the present invention relates to the method described in paragraph (00541), wherein the delivery enhancing compound comprises ammonium chloride and two or more precursor compounds, including ammonia and hydrogen chloride.

IOO56) In some embodiments, this invention relates to the methods described in paragraphs (00511-

I0O54| or I0055I, in which the concentration of nicotine in the gaseous carrier is increased compared to the concentration of nicotine that the gaseous carrier would contain without the delivery-enhancing compound.

I0057| In some embodiments, the present invention relates to the methods described in paragraphs (00511-

I0O55I or (00561) in which the compound for improving delivery contains an acid.

10OO58) In some embodiments, the present invention relates to the method described in paragraph (00571), wherein said acid is an organic acid.

I00O59) In some embodiments, this invention relates to the method described in paragraph (00581), in which said organic acid has a higher saturated vapor pressure than nicotine at a certain temperature.

I0O60) In some embodiments, the present invention relates to the method described in paragraph (00591, wherein said specific temperature is 25 "C, 30 "C, 40 "C, 45 "C, 70 "C, or 100 "C.

I00O61) In some embodiments, the present invention relates to the methods described in paragraph (00571, in which said acid is selected from the group consisting of 3-methyl-2-oxovaleric acid, pyruvic acid, 2-oxovaleric acid, 4-methyl-2 -oxovaleric acid, 3-methyl-2-oxobutanoic acid, 2-oxooctanoic acid, propionic acid, formic acid, acetic acid, and combinations thereof.One specific possible combination is propionic acid, formic acid, and acetic acid, optionally given preferably with a ratio of acetic acid to formic acid of 2:1. 0062) In some embodiments, the present invention relates to the methods described in paragraphs (00511-

IOO60OY or I0061|, in which the compound to improve delivery interacts with nicotine to form particles.

I0063) In some embodiments, this invention relates to the method described in paragraph (00621, in which the mass-median aerodynamic diameter of the formed nicotine particles is less than 6 μm. 0064) In some embodiments, this invention relates to the method described in paragraph ( 00621, in which the mass median aerodynamic diameter of said nicotine particles is less than 1

MKM.

I0065) In some embodiments, the present invention relates to the method described in paragraph (00621), in which the mass median aerodynamic diameter of at least some of said nicotine particles is from 0.5 μm to 5 μm.

ИЙОО66б| In some embodiments, the present invention relates to the method described in paragraphs

I00511--0064| or (0065), which includes the additional step of increasing the temperature of the delivery-enhancing compound, the source of the delivery-enhancing compound, the nicotine, the nicotine source, and/or the gaseous carrier.

I0067| In some embodiments, the present invention relates to the method described in paragraph (00661, in which the temperature is raised to at least 30 "C. 0068) In some embodiments, the present invention relates to the method described in paragraph (00671, in which the temperature is raised by multiple heating operations.

ИЙОО69| In some embodiments, the present invention relates to nicotine intended for cessation of use of a tobacco product, wherein said nicotine is delivered by a method described in paragraphs (00511-(00671 or (0068)), which includes the additional operation of introducing a gaseous carrier into the patient's body after surgery contacting a gaseous carrier containing a delivery-enhancing compound with a source of nicotine.

I0070) In some embodiments, this invention relates to nicotine described in paragraph (00691, wherein the gaseous carrier contains at least 20 mcg of nicotine in the volume of the gaseous carrier that is injected into the patient's body. 0071) In some embodiments, this invention relates to nicotine , which is described in paragraph (00701, while the volume of the gaseous carrier that is delivered to the patient's body is administered in the form of an indivisible volume. 0072) In some embodiments, the present invention relates to nicotine intended to reduce the harmful effects of smoking a tobacco product, in this case, the delivery of nicotine is carried out according to the method described in paragraphs I(00511-I(I0067| or (00681), which includes an additional operation of introducing a gaseous carrier into the patient's body after the operation of introducing a gaseous carrier, which contains a compound for improving delivery, into contact with a source of nicotine.

I0073) In some embodiments, this invention relates to the nicotine described in paragraph (00721, wherein the gaseous carrier contains at least 20 mcg of nicotine in the volume of the gaseous carrier that is injected into the patient's body. 0074) In some embodiments, this invention relates to nicotine , which is described in paragraph (00731, at the same time, the volume of the gaseous carrier, which is delivered to the patient's body, is introduced in the form of an indivisible volume.

I0075) In some embodiments, this invention relates to nicotine intended to replace the consumption of tobacco products, while the delivery of nicotine is carried out according to the method described in paragraphs I100511-(0067| or (0068), which includes the additional operation of introducing a gaseous carrier into the patient's body post-surgery, contacting a gaseous carrier containing a delivery-enhancing compound with a source of nicotine.

I0076) In some embodiments, this invention relates to nicotine, which is described in paragraph (00751), while the gaseous carrier contains at least 20 μg of nicotine in the volume of the gaseous carrier that is injected into the patient's body.

I0077| In some embodiments, the present invention relates to nicotine, which is described in paragraph (00761), while the volume of the gaseous carrier, which is delivered to the patient's body, is administered in the form of an indivisible volume.

I0078) In some embodiments, the present invention relates to nicotine for the treatment of a disease selected from the group consisting of nicotine addiction, obesity, disease

Alzheimer's disease, Parkinson's disease, nonspecific ulcerative colitis, multiple sclerosis, depression, schizophrenia, analgesia, attention deficit hyperkinetic syndrome (ADHD) and their combinations, while the delivery of nicotine is carried out according to the method described in paragraphs (00511-(0067| or

JOO68|, which includes the additional operation of introducing a gaseous carrier into the patient's body after the operation of introducing a gaseous carrier containing a compound to improve delivery into contact with a source of nicotine.

I0079) In some variants of implementation, this invention relates to a device, the design of which allows implementing a) the method described in paragraphs (00511-(00671| or (00681; and/or p)) provides the possibility of delivering nicotine according to the method described in paragraphs (00691 -(0077| or (00781.

IOO80| In some embodiments, this invention relates to the use of nicotine for the manufacture of a drug for delivery by the method described in paragraphs (00511-(0067) or (00681.

ИЙОО81| In some embodiments, this invention relates to the use of nicotine for the manufacture of a medicinal product for the cessation of the consumption of tobacco products, delivered by the method described in paragraphs (00511-(00671) or (00681.

ИО0О82| In some embodiments, the present invention relates to the use of nicotine for the manufacture of a medicinal product to reduce the harmful effects of smoking a tobacco product delivered by a method described in paragraphs (00511-(00671|) or (00681.

IOO83| In some embodiments, this invention relates to the use of nicotine for the manufacture of a medicinal product for the replacement of tobacco products delivered by the method described in paragraphs (00511-(00671) or (00681.

I0084| In some embodiments, the present invention relates to the use of nicotine for the manufacture of a medicament for the treatment of a disease selected from the group consisting of nicotine dependence, obesity, Alzheimer's disease, Parkinson's disease, ulcerative colitis, multiple sclerosis, depression, schizophrenia, analgesia, hyperkinetic syndrome with attention deficit hyperactivity disorder (ADHD) and their combinations, while nicotine delivery is carried out according to the method described in paragraphs 100511--0067| or (0068), which includes the additional operation of introducing a gaseous carrier into the patient's body after the operation of introducing a gaseous carrier that contains a compound to improve delivery into contact with a source of nicotine. 0085) In some embodiments, the present invention relates to a method of delivering a medicinal product to a patient's body, wherein said method includes: passing a gaseous stream over a first substance to produce a first vapor-containing gaseous stream; passing the first vapor-containing gaseous stream over the second substance to obtain particles in the gaseous stream; and delivering the gaseous stream containing the particles to the consumer.

I0O086| In some embodiments, the present invention relates to the method described in para

I0O85I, in which the operation of obtaining the first vapor-containing gas flow includes capturing the vapor of the first substance by the gaseous flow.

I0087| In some embodiments, the present invention relates to the method described in paragraph (0085) or I0086), wherein the operation of obtaining particles includes contacting a vapor of a second substance with a first vapor-containing gaseous stream. 0088) In some embodiments, the present invention relates to the method described in paragraph 00851, (00861) or (0087|), in which the operation of obtaining particles includes interaction between the first and second substances.

ИЙ0О089| In some embodiments, the present invention relates to the method described in para

IOO881I, while the mentioned interaction includes an acid-base reaction. 0090) In some embodiments, the present invention relates to the method described in paras

I00851-(00881 or (00891, wherein said first and second substances are volatile substances. 0091) In some embodiments, the present invention relates to the method described in para.

IO0O90Y, in which said first substance is more volatile at ambient temperature than the second substance. 0092) In some embodiments, the present invention relates to the method described in paras

I00851-(00901 or (0091), in which one of the substances, namely the mentioned first substance and/or the mentioned second substance, contains nicotine.

II0093| In some embodiments, the present invention relates to the method described in para

I0O0921, in which said nicotine contains nicotine in the form of a free base. 0094) In some embodiments, the present invention relates to the method described in paras

I00851-(00921 or (00931, wherein said particles comprise nicotine-containing particles. 0095) In some embodiments, the present invention relates to the method described in paragraphs

I00851-(00931| or (0094), in which the gaseous stream administered to the consumer contains more than 20 μg of nicotine-containing particles. 0096) In some embodiments, the present invention relates to the method described in paragraphs

I00851-(00941 or (00951), in which said particles contain nicotine salt particles.

I0097| In some embodiments, the present invention relates to the method described in paras

I00851-(00951 or (0096), in which the first substance contains an acid.

II0098| In some embodiments, the present invention relates to the method described in para

I0097|, in which said acid contains pyruvic acid. 0099) In some embodiments, the present invention relates to the method described in paras

I00851-(00971 or (00981), in which the particles contain nicotine pyruvate.

IO100| In some embodiments, the present invention relates to the method described in para

I0097|, in which said acid contains 3-methyl-2-oxobutanoic acid.

IO101) In some embodiments, the present invention relates to the method described in paras

I00851-(00991I or (01001), in which the particles contain 3-methyl-2-oxobutanoate of nicotine.

I0102) In some embodiments, the present invention relates to the method described in paragraphs

I00851-(01001 or (0101), wherein at least some of the particles are visible particles. 0103) In some embodiments, the present invention relates to the method described in paragraphs

I00851-(01011Й or (01021, in which at least some of the particles are delivered to the lungs of the consumer. 0104) In some embodiments, the present invention relates to the method described in paragraphs

I00851-(01021 or (0103), in which the diameter of the particles is less than 6 μm. 0105) In some embodiments, the present invention relates to the method described in paragraphs

I00851-(01031 or (0104), in which the diameter of at least some of the particles is in the range of 0.5 μm to 5 μm. 0106) In some embodiments, the present invention relates to the method described in paragraphs

I00101--0027| or (0028); or the method described in paragraphs (00511--0067| or (0068); or use according to the method described in paragraph (0080І, where the medicinal product specified in paragraph 01321, such as the compounds defined by numbers 1-70 in paragraph (0132), used instead of or in addition to nicotine specified in paragraphs (00101-(0027| or (00281; (00511-(0067| or (00681); or

IOO8O). 0107) In some embodiments, the present invention relates to the device described in paras

І00351-(0049| or І0О50І, wherein said device is designed to deliver a medicinal product specified in paragraph (01321, such as compounds defined by numbers 1-70 in paragraph (0132), instead of or in addition to said nicotine. 0108) In in some embodiments, the present invention relates to a method of administration of a medicinal product described in paragraph (01321, such as compounds identified by numbers 1-70 in paragraph (01321), for delivery by methods described in paragraphs (00101-(00271| or (0028 ); or paragraphs (00511-(00671) or paragraph (00681, for the treatment of a disease in which the said medicinal product has therapeutic value.

I0O109)| An improved source of nicotine

IO110| In some embodiments, the present invention relates to the method described in paras

I00101-(00321 or (0033); paragraphs (00511-(0067| or (0068); paragraphs (00691-(0077| or (0078)); paragraphs

I00801-(00831| or (0084); or the device presented above, which allows implementing the mentioned method, where the source of nicotine contains an aqueous solution of nicotine and a compound that forms an electrolyte.

О111) In some embodiments of the method described in paragraph (0110), the compound forming the electrolyte is a hydroxide or oxide of an alkali metal; or alkaline earth metal oxide; or a salt (including bases), or represents a compound selected from the group consisting of the compounds listed in Table 11 (paragraph (03741), for example, represents such bases as sodium hydroxide (maon), calcium hydroxide (Ca( OH)") and potassium hydroxide (KOH) and their combinations. 0112) In some embodiments, the nicotine according to the method described in paragraph (01101 or (01111) is selected from between nicotine base and nicotine salt, such as nicotine hydrochloride, bitartrate nicotine, nicotine ditartrate and their combinations.

ИО113) In some embodiments, nicotine according to the method described in paragraph (01101, (01111) or 0112) is selected from the group consisting of nicotine base and nicotine bitartrate and their combinations, and the compound forming the electrolyte is selected from the group consisting of hydroxide sodium (Maon), calcium hydroxide (Ca(OH)") and potassium hydroxide (KOH) and their combinations. 0114) In some variants of implementing nicotine according to the method described in paragraph (01101, (01111) or 01121, choose from- between the nicotine base and nicotine bitartrate and combinations thereof, and the electrolyte-forming compound contains KOH. 0115) In some embodiments, the method described in paragraphs (01101-(0113) or

I0114Y, the pH value of the aqueous solution is equal to or greater than 9.0, for example, equal to or greater than pH 10, 11, 12, 13 or 14.

ИО116)| In some variants of implementation according to the method described in paragraphs (01101-(0114) or

IO115) in which the electrolyte-forming compound is KOH, the ratio between KOH and nicotine base (or base equivalents) is 10:40, 10:60, 10:80 or 10:100, with a ratio of 10:60 being preferred . These values also define the limit points of various characteristic ranges within the limits of the present invention, such as the range from 10:40 to 10:100.

I0O117| In some embodiments of the method described in paragraphs (01101-(0113) or 0114), said method includes the additional operation of mixing the electrolyte-forming compound with nicotine in an aqueous solution.

IO118) In some embodiments of the method described in paragraph (01171, the dissolution of the electrolyte-forming compound in an aqueous solution is an exothermic reaction and, in a preferred embodiment, the electrolyte-forming compound is added in an amount sufficient to increasing the temperature of the aqueous solution of nicotine, for example, to about 80 "C or higher.

II0119| The above description rather broadly outlines the features and technical advantages of the present invention for a better understanding of the further detailed description of the present invention. Other advantages and features of the present invention, which form the subject of the formula of the present invention, will be described below.

It should be understood by those skilled in the art that the concept and its specific embodiment disclosed within the framework of this invention can easily be used as a basis for modification or development of other constructive solutions designed to implement the same objectives as this invention. Specialists should also understand that similar constructive solutions do not contradict the idea and do not go beyond the scope of the present invention defined by the claims. New features, which are considered to be characteristic features of the present invention, both from the point of view of the construction of devices and from the point of view of methods, as well as other objects and advantages will be better understood from the following description, in particular in combination with the accompanying figures. However, it should be clearly understood that each figure is provided for illustrative purposes only and is used to compile the description, without in any way limiting the scope of the present invention.

I0120)| A better understanding of the present invention should be provided by the following description, with the help of the accompanying figures, in which:

I0O121) Fig. 1 - a perspective view of an embodiment of a drug delivery device imitating a cigarette;

I0122| Fig. 2 - a perspective view of the interior of an embodiment of a drug delivery device imitating a cigarette;

IO123) Fig. C is a perspective view of an embodiment of the drug delivery device simulating a cigarette from FIG. 1 and fig. 2 in the process of application;

I0124| Fig. 4 - a section of the constituent elements of the variant of the implementation of the drug delivery device, which shows the stages of assembly and the final location of the constituent elements for the use of the device;

IO125) Fig. 5 is a perspective view of various design elements-sources for providing nicotine or other drug and compound for improving delivery;

I0O126| Fig. 6 - a section of the constituent elements of the variant implementation of the drug delivery device, showing parts of multiple and single use;

I0127| Fig. 7 is a cross-sectional view of the components of a multiple use embodiment of a drug delivery device showing the device and reloading unit for delivering nicotine or other drug and delivery-enhancing compounds;

I0128| Fig. 8 is a cross-sectional view of an embodiment of a reusable drug delivery device showing the device and a perspective view of a reloadable unit for delivering nicotine or other drug and delivery-enhancing compounds; and

I0129| Fig. 9 is a cross-section of an embodiment of a device for the delivery of a multi-use drug, showing the device and the reloading unit; Fig. 9A shows only the reset unit, FIG. 9B shows a drug delivery device placed in a reloading unit, and FIG. 9C shows a drug delivery device after compressing the reloading unit's metering pumps to re-deliver nicotine or other drug and delivery-enhancing compounds;

ИО130| Fig. 10 represents a section of an embodiment of a drug delivery device with a heating element placed therein, which is presented as a separate component element in a perspective view; also Fig. 10 represents an embodiment of a drug delivery device having an external heating unit, where a drug delivery device is placed to regulate the temperature of the mentioned device and/or its constituent elements;

ИО1311 Fig. 11 - cross-section of an embodiment of a drug delivery device imitating a metered-dose inhaler, which is traditionally used to deliver pharmaceutical drugs by inhalation; 01321 Fig. 12 - a section of an embodiment of a drug delivery device imitating a metered-dose inhaler, which is traditionally used to deliver pharmaceutical drugs by inhalation; 0133) Fig. 13 - a section of an embodiment of a drug delivery device imitating a metered-dose inhaler, which is traditionally used to deliver pharmaceutical drugs by inhalation; 01341 Fig. 14 - section of an embodiment of a drug delivery device imitating a metered-dose inhaler, which is traditionally used to deliver pharmaceutical drugs by inhalation; 0135) Fig. 15 is a cross-section of an embodiment of a drug delivery device that simulates a metered-dose inhaler, which is traditionally used to deliver pharmaceutical drugs by inhalation.

ИО136)| The term "particle" as used herein may refer to a liquid droplet, a solid particle, or a combination thereof, for example, a liquid droplet with a solid particle inside.

I0137| The term "therapeutically effective amount" in accordance with the context of this description can refer to any concentration or amount of nicotine or other drug that ensures the achievement of a therapeutic effect in the body of a patient, as a rule, in the body of a person. The patient has positive dynamics of the disease or improvement of the condition, which corresponds to the medical diagnosis. Positive dynamics or relief means any softening or disappearance of symptoms associated with the disease. Positive dynamics or relief is an obvious or measurable result of improvement. Accordingly, it is clear to a person skilled in the art that treatment can improve the course of the disease, but not provide a complete cure of the disease, that is, recovery. The therapeutic effect in some embodiments of the present invention may consist, for example, in reducing or eliminating nicotine cravings in a patient suffering from nicotine addiction, or in a patient experiencing withdrawal symptoms as a result of cessation of nicotine use.

I0138| The phrase "electrolyte-forming compound" as used herein may refer to a neutral or ionic substance that dissociates into ions in solution.

I0139| In order to facilitate the understanding of the concepts of the present invention, a description of examples of implementation with reference to devices and methods of nicotine delivery will be given below. One of ordinary skill in the art will appreciate that, in accordance with the ideas of the present invention, the drugs listed in paragraph (01321, may be used instead of or in addition to nicotine. 0140) The methods disclosed herein relate to unexpected discovery of a fact relating to the dose of nicotine received from nicotine delivery devices. The authors of the invention unexpectedly discovered ways to increase the dose of nicotine that enters the patient's body by inhalation. The importance of this fact lies in the increased ability to replace the delivery of nicotine to the patient's body when smoking cigarettes and similar tobacco products. Due to the improved dynamics of nicotine delivery, patients using the methods disclosed herein will receive high-quality nicotine replacement therapy when trying to quit smoking, with less harm to health and/or a better replacement effect. Taking into account the ongoing global health care challenges health effects resulting from smoking, the methods described are aimed at meeting the critical needs of healthcare professionals in helping smokers to quit smoking.0141) Without wishing to be bound by theory, it is believed that the effect of vapor passage of a volatile first substance (ie, a delivery-enhancing compound) over a nicotine source is to form particles in a liquid or solid state that then allow more nicotine to vaporize and combine with the first substance with additional particle formation Amount of Particle Formation (Delivered Mass) at this temperature will be greater than would be formed in the case of passage of nicotine vapor over second volatile substance. Similarly, the amount of particle formation at a given temperature will be greater than would be formed if a pair of two substances were combined in a parallel mixing apparatus (as disclosed in the prior art) due to the fact that the amount of particle formation is limited by the volatility of the less volatile substance , and as a result of dilution of the active substance by mixing with a volume of gas containing another substance. Thus, allowing one substance to pass sequentially over another substance can provide the ability to combine the two substances more effectively than parallel mixing known in the art. Another possibility is that the interaction between the first and second substances is an exothermic process. In other words, energy is released in the form of heat as a result of exothermic interaction. Without wishing to be bound by theory, it is believed that the heat generated may enhance the vaporization of nicotine. 0142) In some embodiments of the present invention, the mentioned methods involve the stage of introducing a gaseous carrier into interaction with the nicotine source. The gaseous carrier in these embodiments of the invention contains a delivery-enhancing compound that can increase the amount of nicotine in the gaseous carrier compared to the amount of nicotine that would be present in the gaseous carrier without said delivery-enhancing compound. In some embodiments of the present invention, the delivery-enhancing compound may react with the nicotine base or other drug to form a salt. In specific embodiments of the invention, the delivery-enhancing compound may react with the nicotine base to form salt particles. In preferred embodiments of the present invention, the mass-median aerodynamic diameter (Mav55

Mediap Aegodupatis Oiateiieg) of the particles is less than b micron, according to the variant, which is given more preference, the mass-median aerodynamic diameter is less than 1 micron. (Regarding the determination of the mass-median aerodynamic diameter, see the article by Kai; I.M., Zspgoeieg 3.0.,

Mapopep T.V. Rasiogyh5 apesiipu She aeroziyop oi aegozoiiigeai ipzyip, Oiarbeiie5 Tesppoiododu 4 Pegareshisv,

Mo. Z (3), 2001, pp. 387-397; the content of which is incorporated into this description by reference). 0143) The methods disclosed in this description can be prescribed for the use of a number of other drugs whose biophysical and/or chemical properties are similar to the biophysical and/or physical properties of nicotine. The following compounds are aliphatic or aromatic, saturated or unsaturated nitrogen-containing bases (nitrogen-containing compounds-acceptors of hydrogen ions or Lewis acids), where the nitrogen atom is present in a heterocyclic ring or in an acyclic chain (substitution). In addition to this, the compounds mentioned were selected based on their melting point (below 150 "C) or boiling point (below 300 "C) expected to facilitate vaporization: 1. 7-Hydroxymitragynine 2. Amphetamine 3. Arecoline 4. Atropine 5. Bupropion 6. Cathine (O-norpseudoephedrine) 7. Cathinone (VD-ketoamphetamine) 8. Chlorpheneramine 9. Dibucaine 10. Dimemorphan 11. Dimethyltryptamine 12. Diphenhydramine 13. Ephedrine 14. Hordenine 15. Hyoscyamine 16. Isoarecoline

17. Levorphanol 18. Lobeline 19. Mescaline 20. Mezembrine 21. Mitragynine 22. Muscarine 23. Parahydroxyamphetamine 24. Procaine 25. Pseudoephedrine 26. Pyrylamine 27. Raclopride 28. Ritodrine 29. Scopolamine 30. Sparteine (Lupinidine) 31. Ticlopidine

Components of tobacco smoke: 32. 1,2,3,4-tetrahydroisoquinolines 33. Anabazin 34. Anatabine 35. Cotinine 36. Myosmin 37. Nicotine 38. Norcotinine 39. Nornicotine

Antiasthmatic drugs 40. Orciprenaline 41. Propranolol 42. Terbutaline

Medicines against angina 43. Nicorandil 44. Oxprenolol 45. Verapamil

Antiarrhythmic drugs 46. Lidocaine

Agents of nicotinic receptors

A. Nicotinic receptor agonist 47. Epibatidine 48. 5-(28)-azetidinylmethoxy)-2-chloropyridine (АВТ-594) 49. (5)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole ( AVT 418) 50. (g)-2-(Z-pyridinyl)-1-azabicyclo|2.2.2|octane (EUB-2429)

B. Antagonist of nicotinic receptors: 51. Methyllicacotinine 52. Mecamylamine

C. Acetylcholinesterase inhibitors 53. Galantamine 54. Pyridostigmine 55. Physostigmine 56. Tacrine

Monoamine oxidase inhibitors 57. 5-methoxy-M,M-dimethyltryptamine 58. 5-methoxy-α-methyltryptamine 59. Alpha-methyltryptamine 60. Iproclozid 61. Iproniazid 62. Isocarboxazid 63. Linezolid 64. Meclobemid 65. M, M-dimethyltryptamine 66 Phenelzine 67. Phenylethylamine 68. Toloxatone 69. Tranylcypromine

70. Tryptamine 0144) Gaseous carrier and its source 0145) The gaseous carrier can be any gas capable of containing a nicotine base and a delivery-enhancing compound. One of ordinary skill in the art will readily be able to select an acceptable gaseous carrier based on its intended use, form of nicotine, and specific compound(s) to enhance delivery. In preferred embodiments of the present invention, the gaseous carrier is essentially inert to the form in which the nicotine and/or delivery-enhancing compounds carried by it exist, at least for the time period during which their delivery to the the patient's body. In some embodiments of the present invention, the gaseous carrier is ambient air. In other embodiments of the present invention, the gaseous carrier is a gas in essentially pure form, such as gaseous carbon dioxide or nitrogen, or a mixture of such gases. In such embodiments of the present invention, the gaseous carrier is supplied from a container designed to hold and deliver the gaseous carrier in a manner that enables the methods disclosed herein. For example, in those embodiments of the present invention that involve the use of metered dose inhalers, the gaseous carrier may contain hydrofluoric carbons, including hydrofluoric alkanes (NEAs), as propellants. In some of the mentioned embodiments of the present invention, the NEAs are one or more compounds of NEA 134a and NEA 227. 0146) Compounds to Improve Delivery

II0147| Delivery-enhancing compounds are compounds that are capable of increasing the total concentration of nicotine particles in a gaseous carrier when said gaseous carrier is brought into contact with a nicotine source. Nicotine has a saturated vapor pressure of 0.04 mm Hg. (5.33238 Pa) at 25 "C. Delivery-enhancing compounds are preferred that have a saturated vapor pressure greater than that of nicotine at the same temperature, particularly when operating at ambient temperature. Non-limiting examples include inorganic acids, such as hydrochloric acid, hydrobromic acid or sulfuric acid, as well as organic acids, including saturated and unsaturated aliphatic acids, saturated and unsaturated alicyclic acids, aromatic acids (including heterocyclic aromatic acids), polycarboxylic acids, hydroxy-, alkoxy- . In some of these embodiments of the invention, the carboxylic acid is to the class called "2-oxoacids". In some of these embodiments of the invention, the carboxylic acid belongs to the class of a-keto acids known as "2-keto acids." In some of these embodiments of the invention, the carboxylic acid is selected from the group consisting of 3-methyl-2-oxovaleric acid, pyruvic acid, 2-oxovaleric acid, 4-methyl-2-oxovaleric acid, 3-methyl-2-oxovaleric acid, 2-oxooctanoic acid and their combinations. In some embodiments of the present invention, the delivery-enhancing compound forms solid particles, such as salt particles. In other embodiments of the present invention, the delivery-enhancing compound forms an aerosol with a liquid dispersed phase. 0148) Alternatively, the delivery-enhancing compound forms an aerosol with a solid dispersed phase in which the solid particles are capable of, for example, adsorbing or absorbing a nicotine base. In specific embodiments of the present invention, the aerosol with a solid dispersed phase contains ammonium chloride particles. In embodiments of the present invention, which involve the formation of nicotine particles or the adsorption of nicotine on the surface or its absorption inside the particles, the formed particles, according to the preferred option, have a size of less than 6 μm; in a more preferred embodiment, their size is less than 1 µm or their size is less than 1 µm. 0149) Sources of nicotine (or other drug) 0150) In embodiments of the source of nicotine, a compound containing any chemical capable of providing nicotine in a volatile form is used, for example, nicotine base or nicotine salts (for example, nicotine hydrochloride, -bitartrate , -ditartrate). Although more than one form of nicotine can be used, free base nicotine is preferred. The nicotine source may contain other compounds such as antioxidants (eg BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene) and ascorbate) to stabilize the nicotine. In some embodiments, the nicotine is adsorbed on the structural element to provide a source of nicotine.

Adsorbed nicotine is retained on the surface of a relatively inert material. Non-limiting examples of materials for the manufacture of adsorption elements include glass, stainless steel, aluminum, PET (polyethylene terephthalate), PBT (polybenzthiazole), RTEE (polytetrafluoroethylene), eRTEE, VAVEX". Adsorption is a process that occurs when a gas , a liquid or solid solute accumulates on the surface of a solid or, less commonly, a liquid (adsorbent) to form a molecular or atomic film (adsorbate). Physical adsorption, as a rule,

is the result of the action of van der Waals forces and electrostatic forces between adsorbate molecules and atoms that form the surface of the adsorbent. Thus, adsorbents are characterized by such surface properties as surface plane and polarity.

ЙО151| A large plane of the specific surface is the predominant factor for ensuring a large adsorption capacity, but the formation of an inner surface of a large plane in a limited volume inevitably leads to the appearance of a large number of small pores between the adsorption surfaces. The size of micropores determines the degree of accessibility of adsorbate molecules to the internal adsorption surface, therefore, the distribution of micropore size is another important property for characterizing the adsorption capacity of adsorbents. The polarity of the surface corresponds to the affinity for polar substances, for example, water or alcohols. Due to this, polar adsorbents are called "hydrophilic" and examples of adsorbents of this type are aluminosilicates such as zeolites, porous aluminum oxide, silica gel or aluminosilicate. On the other hand, non-polar adsorbents are generally "hydrophobic". Carbon adsorbents, polymer adsorbents and silicalite are typical non-polar adsorbents. These adsorbents have a greater affinity for oil or hydrocarbons than for water. In some embodiments, the adsorbent surface also absorbs the adsorbed material by capillary action when the adsorbent is in liquid form. Absorption occurs when the adhesive intramolecular forces between the liquid and the adsorption surface are stronger than the intramolecular cohesive forces inside the liquid. The mentioned effect causes the formation of a concave meniscus at the point of contact of the substance and the vertical adsorption surface. Adsorption surfaces can be selected or designed to absorb hydrophilic or hydrophobic liquids.

I0152) In alternative embodiments of the present invention, the constructive element-source of nicotine may include an absorbent (porous or non-porous) material. Non-limiting examples of materials for the manufacture of absorbent elements in such embodiments of the present invention include polyethylene (PE) and polypropylene (PP).

II0153| The source of nicotine may, in some embodiments of the present invention, be a nicotine reservoir or be connected to such a reservoir. In some embodiments of the present invention, the reservoir contains a certain volume of nicotine in the form of a liquid, while the liquid reservoir is connected to an adsorption or absorption structural element-source. In other embodiments of the present invention, the nicotine reservoir is a source structural element or forms part of a source structural element. One non-limiting example of such a combination of source and reservoir can be a material (eg PE or PP) saturated with a nicotine solution. In specific embodiments of the present invention, the reservoir contains a sufficient amount of nicotine solution so that the drug delivery device can deliver therapeutically effective doses of nicotine to the body during the desired time.

Non-limiting examples may include devices capable of delivering from 0 mcg to 100 mcg of nicotine per puff of 35 cm" of gaseous carrier at a desired number of puffs per day (eg, 200) for a desired period of time (eg, 1 day to 7 In certain embodiments of the present invention, the amount of nicotine delivered is from 10 mcg to 110 mcg, from 20 mcg to 100 mcg, from 50 mcg to 100 mcg, or from 40 mcg to 60 mcg of nicotine per puff volume 35 cm3. 0154) Other medicinal products described in paragraph (0132) may be used instead of or in addition to nicotine to obtain sources of medicinal product(s) using the same principles as applied to the nicotine base in the examples above.0155) An improved source of nicotine

IO156) In embodiments of the invention of the application prior to this improved invention application, where the drug was nicotine, the delivery of nicotine was reduced to undesirably low levels after a certain number of puffs, while significant amounts of nicotine remained in the previous devices. The profile of reduced nicotine delivery was prevented by incorporating larger volumes of nicotine. However, this greater volume of nicotine left an even greater residual volume of nicotine in its source after aerosol delivery fell below acceptable levels. While the devices of the prior art were good at delivering nicotine to achieve a therapeutic effect, limitations such as: a) the amount of nicotine required and b) the residual nicotine content after application, caused problems in the development of an effective aerosol device for industrial production. For example, significant residual amounts of nicotine in the device could lead to legal compliance issues in some countries.

I0157| According to the previous application, one way to increase the efficiency of nicotine delivery and extend the beneficial delivery profile over more puffs per unit of nicotine content was to apply heat. When the authors heated the nicotine base, nicotine delivery increased significantly and so did the number of puffs that had acceptable levels of nicotine delivery. Based on this, the authors concluded that heating the nicotine base was a useful measure to enhance the delivery of nicotine in the aerosol form, and also helped to reduce the rate of decline of nicotine concentration per puff over time. The authors' goal, however, was to avoid the use of heating elements in nicotine-enhanced delivery devices, as such technology would increase the cost of production, which would ultimately affect the consumer and could also complicate the path to legislative approval.

ИЙО158| Thus, the authors sought alternatives to heating to improve delivery efficiency and reduce the amount of residual nicotine after device use. In the process of conducting experiments with nicotine sources, the authors unexpectedly found that the addition of electrolyte-forming compounds to nicotine salts or nicotine base in water/nicotine solutions resulted in a dramatic improvement in both delivery and reduction of residual nicotine compared to aqueous nicotine solutions. without electrolyte-forming compounds and in comparison with nicotine base without the addition of electrolyte-forming compounds. Typical electrolyte-forming compounds can be found in Table 11 below, and include strong bases such as sodium hydroxide (MAH) and potassium hydroxide (KOH), with KOH being particularly preferred. Preferred forms of nicotine for use in the improved source are nicotine base and/or nicotine bitartrate. Particular preference is given to combinations of nicotine base and KOH in water. These improved nicotine compositions with an additional amount of electrolyte-forming compound are fully compatible with the devices and compositions of the prior application. The significant and unexpected improvements observed with these modified nicotine sources are demonstrated in the sections "Improvement Experiments Mo 1-6" and "Constructions Mo 1-3" below. 0159) Compound sources to enhance drug delivery

ЙО160| In some embodiments of the aforementioned methods, a gaseous carrier is used pre-combined with the compound to improve delivery. Other embodiments of the methods disclosed herein include the step of mixing the gaseous carrier with the delivery-enhancing compound, which is performed prior to or simultaneously with passing the gaseous carrier over the nicotine source. In those embodiments of the invention that involve mixing a gaseous carrier with a delivery-enhancing compound, the delivery-enhancing compound is typically used as a source of the delivery-enhancing compound.

The gaseous carrier in these embodiments of the invention is typically brought into direct interaction with the source of the delivery enhancing compound such that the delivery enhancing compound is able to mix with the gaseous carrier as it is released from the source of the delivery enhancing compound. In some embodiments of the present invention, the source of the delivery-enhancing compound includes a source structural element, which in turn includes materials that adsorb or absorb the delivery-enhancing compound. The materials of the component-source component for delivery should generally be inert to the compound to improve delivery. In some embodiments of the present invention, the delivery enhancing compound is an acid as described above. Non-limiting examples of materials for the manufacture of adsorption elements in such variants of the implementation of the present invention include glass, stainless steel, aluminum, PET, RVT, RTEE, eRTEE and VAREH"U. Non-limiting examples of materials for the manufacture of absorption elements in such variants of the implementation of the present invention include polyethylene (PE) and polypropylene (PP).

I0161)| The source of the delivery-enhancing compound may, in some embodiments of the present invention, be a reservoir for placing the delivery-enhancing compound or communicate with such a reservoir. In some embodiments of the present invention, the reservoir contains, in liquid form, a certain volume of the delivery-enhancing compound, wherein the liquid reservoir communicates with an adsorptive or absorptive structural element-a source of the delivery-enhancing compound. In other embodiments of the present invention, the nicotine reservoir is a delivery-enhancing compound source component or forms part of said source component. One non-limiting example of such a combination of source and reservoir may be a material (eg, PE or PP) saturated with a solution of a compound to enhance delivery. In specific embodiments of the present invention, the reservoir contains a sufficient amount of solution of the delivery compound so that the drug delivery device can deliver a therapeutically effective dose of nicotine to the body for a desired period of time. Non-limiting examples may include devices capable of delivering sufficient delivery-enhancing compound to deliver between 0 mcg and 100 mcg of nicotine per 35 cc puff? gaseous carrier at the desired number of puffs per day (for example, 200) during the desired period of time (for example, from 1 day to 7 days). In certain embodiments of the present invention, the amount of delivered nicotine is from 10 mcg to 110 mcg, from 20 mcg to 100 mcg, from 50 mcg to 100 mcg, or from 40 mcg to 60 mcg of nicotine per puff with a volume of 35 cm3.

Variants of the implementation of the present invention, which provide for the introduction of 0 μg of nicotine, as a rule, are intended to be the limit points of the program of abandoning the consumption of tobacco products based on the gradual reduction of the amount of nicotine.

I0162)| Temperature

ЙО163| In some variants of implementation of these methods, the method involves the stage of increasing the temperature of one or more of such elements as: a gaseous carrier; nicotine source and/or delivery enhancer compound source (if applicable). Such temperature control operations are usually used to regulate or increase the amount of nicotine delivered to the body. In some variants of the implementation of the present invention, an increase in temperature is used only if, in another case, a reduction in the nicotine dose below the acceptable minimum level can be expected. In some embodiments of the present invention, this minimum level may be 20 μg; in preferred embodiments of the invention, it is equal to 30 mcg and in more preferred embodiments of the invention, the minimum nicotine dose level is 40 mcg per 35 cm3 puff. For example, the desired concentration of nicotine is 40-50 μg per puff of 35 cm3 volume, according to the widespread methods of analyzing the nicotine content in this field of technology. See Te ETS Sidagece Teb5zi MeiShtoi og

Oeiegptipipu Tag, Misoipe apa Sagbop Mopohide Mieii oi Sh.5. Sidagetsevs: Verop oi She MSI Ai Nos

Sottieye ZtoKipud apa Torasso Sopigoi Mopodgara 27). Oh A. Zporiapa (Ea.), bagru, RA: Oiape

Rybiyepipu So, 1996. In some embodiments of the present invention, a lower temperature is typically used initially, raising it later, in order to maintain the desired concentration of nicotine delivered to the lungs from the nicotine source. In other variants of the implementation of the present invention, a constant temperature is maintained during operation. In some variants of the implementation of the present invention, the temperature is increased to the maximum value of 100 C, 70 C, or the temperature is increased to 40-45 76.

For example, the temperature of pyruvic acid as a delivery-enhancing compound can be increased to 40°C to promote steady, continuous delivery of nicotine over many puffs while maintaining the nicotine concentration in a desired range (eg, 20 mcg to 50 mcg per puff). Temperature control in some embodiments of the present invention can be implemented by a temperature control element. Such elements can be any known mechanical device capable of achieving the desired target temperature of the carrier gas, nicotine and/or compound(s) to improve delivery. Specific examples of temperature control elements are provided below in the presented device embodiments. Alternatively, heat released from exothermic chemical reactions may be used to enhance nicotine delivery. For example, base compounds may be mixed with nicotine and/or water during aerosol formation to generate of heat during the course of the exothermic reaction and, thereby, to increase the efficiency of nicotine use and its continuous delivery to the body during an increased number of puffs compared to the formation of an aerosol at room temperature. An exothermic reaction mixture, such as a water-ConH mixture, can be separated from the nicotine source to produce only heat to raise the temperature. Said base may also be mixed with the nicotine of the nicotine source, either with or without water, but, in a preferred embodiment, with water, both to produce heat and to further enhance nicotine delivery, as described in the case of the improved source nicotine In any case, the heat obtained during the exothermic reaction can be used to increase the temperature of any component of the drug delivery device, for example, one or more of the following elements: a gaseous carrier, a source of nicotine, and/or a source of a compound for delivery improvements (if available); and other components, such as flavorings, to make the nicotine/gaseous carrier more palatable during inhalation. 0074) Devices

II0075| The methods disclosed in this description are generally carried out using specially adapted devices configured to implement during use the methods described in this description. Specialists in this field, guided by the recommendations described above, are able to develop and create a number of devices for delivering drugs into the body. However, the authors of the invention in this description provide a description of many variants of the arrangement of the device for delivering drugs into the body, to illustrate the methods disclosed in this description, as well as their practical application with specific examples. The gaseous carrier required for use of the device may contain a therapeutically effective dose of nicotine for smoking cessation, tobacco harm reduction and/or replacement therapy. Preferred embodiments of devices that deliver drugs into the body include pulmonary drug delivery systems. Pulmonary delivery systems are able to deliver fixed doses of drugs in the form of an aerosol with particles of the dispersed phase of an acceptable average size and with a small discrepancy (variability) of this size to the deep zones of the lungs. The advantages of pulmonary drug delivery are not limited to needle-free administration and the accompanying improvements in patient acceptability and compliance. Compared to the various available techniques and techniques for non-invasive drug delivery, including nasal, transdermal, buccal, and needle-free injections, pulmonary delivery offers unique opportunities to deliver new drugs and improve delivery techniques for existing drugs, including the ability to accurately measure dose, rapid absorption and high bioavailability of drugs, etc.

Methods of implementing the invention

I0076)| Finding an acceptable experimental design for the formation of nicotine aerosol

I0077| In order to quantify the process of formation of aerosol particles as a result of the reaction of acid with nicotine base in a vapor state, several experimental plans were tested, which are described below. 0168) EXPERIMENT Mo 1: Hydrochloric acid and ammonia were used to produce a vapor mixture in a U-shaped tube, which was then passed over free base nicotine

IO169| Goal:

The purpose of this experiment was to determine the effectiveness of a chemically stable acid/base system to produce a free base nicotine aerosol with characteristics sufficient for atomization.

I0170) Experimental design:

When conducting this experiment, two identical glass test tubes were used (Test tube A contained 5 ml of hydrochloric acid (HCl), and test tube B contained 5 ml of ammonia (MH333)), connected by a "XU"-shaped tube, the design of which provided the possibility of instant mixing in it vapor from two tubes with subsequent passage of said vapor over nicotine in the form of a free base using an Apparatus with Adjustable Puff Volume, SRMA (air volume 40 cm for 2 s (interval C s) 100 times (100 puffs)). The mixture of NSI and MNz steam formed a white thick fog visible to the naked eye. 0171) Results: (01721

Table 1

The amount of nicotine that was obtained after passing the NSI and MNz for nicotine.

Lichensitamnii ///77777777111111Ї11111111110111111Ї11111111111101 0173) Discussion: 0174) As shown in Table 1, the use of hydrochloric acid, ammonia and nicotine resulted in a significant improvement in nicotine delivery compared to nicotine alone. However, the chemical activity and aggressiveness of the acid and base chosen for this experiment forced the search for alternative components more acceptable to the human body, such as alternative non-aggressive acids, including volatile and low-volatile organic acids (for example, fatty acids). 0175 EXPERIMENT Mo 2: Search for suitable candidate acids for use in the development of an aerosol delivery device obtained by passing acid over a nicotine base

ИО176)| Goal:

I0177| The purpose of this experiment was to test the ability of a number of candidate acids to mix with nicotine in free base form to form an aerosol suitable for pulmonary delivery. For further experiments, the best candidates were selected, which formed aerosols containing the largest mass of nicotine in the form of the free base, which was reported in μg/puff. Volatile carboxylic acids were selected as the most suitable organic acids because of their relatively high volatility and because they are constituents of cigarettes and other commercially available products for human consumption, such as food additives, flavors and sweeteners. 0178) Experimental design: 0179) Two identical rectangular glass chambers (4 cmx2 cmx1 cm) were used, each equipped with two inlet/outlet channels that passed externally through the top of the chamber before turning 90? away from the center of the camera. These channels were placed on opposite sides and near the edge of the chambers. Inside, these channels were a hollow glass tube that extended almost to the bottom of the chamber. These channels are designed to provide a controlled passage of air through a certain volume of nicotine in the form of a free base ("chamber B") or a candidate acid (chamber "A"). For this experiment, chamber B was filled with 200 μl of free base nicotine and chamber A was filled with 200 μl of pyruvic acid.

Volumes of nicotine in the form of free base and pyruvic acid were added using an Eppendorf pipette. Pure nicotine in the form of a free base and pure pyruvic acid were stored at a temperature of 4 "С in an atmosphere of nitrogen gas. Working volumes of nicotine in the form of a free base and pyruvic acid were stored with refrigeration, but without nitrogen. The temperature of the working volumes before transfer to the chambers were brought to room temperature. Attainment of working volumes at room temperature was checked with a temperature sensor. Each chamber had a filling inlet located in the top center panel, which was intended to fill the chambers with the appropriate reagents. After adding the appropriate volume to the individual chamber, the mentioned entrance was sealed with a stopper made of RABARIIM"U film, the outer part of which was covered with Teflon (TER OM) tape. After that, the cameras were connected in series with a Teflon tube fixed with a RABARIIM film. After that, the outlet of the camera B was connected with a TUSOM tube to the filter holder, on which a filter produced by the Satgidde company (diameter 44 mm) was installed ), designed to collect the reaction product.

Look, RiIiYizrigu NS, ZtokKipd taspipe ragategieg5 Tog soPesiop oi gai ragiisciage taineg apa daze5 iot om idpiop-roiepiya! Sidagenev Opdeg sopigashi o She 0.5. Sopsiteg Rhodisi Zaiezu Sottivviop YAESRBSZO-5- 92-5472 | and Magsy 14, 1993. The opposite side of the filter housing using a TUSOM tube? connected with 100 cm? syringe The syringe was connected to an automated system, which was an Apparatus with

Adjustable Inhalation Volume (SRMA). See the detailed methodology in Hemip EO, Koze UE and Vept R.

Sopigoiipud ryi my m/ypoci aivgiriipd vtokKipu jurodgarnu. Vepamiog Nezeagsii Meinodz Inzigitepiv v

Sotriieg5, 21:383-386, 1989, which is incorporated herein by reference. The total time for preparing the installation from filling the first chamber to the beginning of the time interval after taking the first sample was approximately 5 min. The SRMA was programmed to pump 35 cm3 volumes of air 20 times (20 puffs) for 2 s (with 30 s intervals). Filled chambers were immersed to half their height in a water bath, and kept for equilibration at a temperature of 70 "C for minutes before sampling.

ИЙО180| Before testing the candidate acids, a control experiment was conducted, during which there was only nicotine in the form of a free base in the chamber, and nicotine vapor was pumped through a filter produced by the Satrbgidde company 20 times (20 puffs of 35 cm of air for 2 s with 30 s intervals between puffs) . Quantitative determination of all samples was carried out by means of gas chromatography (C) with the use of MPO (nitrogen-phosphorus detector).

ИО181| Results: 0182) The table below shows the results of the acid selection, as well as the data of the control experiment. The results are given as the amount of nicotine determined in each puff.

IO183I

Table 2

Delivery of nicotine when passing acid over the base at a temperature of 70 C mcg/puff

I0184| Discussion:

I0185) The results of the experiment show that at a temperature of approximately 70 "C, passing 3-methyl-2-oxovaleric acid over nicotine ensures delivery of the largest amount of nicotine (363.89 μg/puff), followed by pyruvic acid (362.28 μg/puff ), 2-oxovaleric acid (297.75 µg/puff), 4-methyl-2-oxovaleric acid (281.39 µg/puff), 3-methyl-2-oxobutanoic acid (213.99 µg/puff) and 2 -oxooctanoic acid (90.48 µg/puff) These candidates were tested under ambient conditions as described in the experimental description below 3-methyl-2-oxovaleric acid, pyruvic acid, 2-oxovaleric acid, 4-methyl-2 -oxovaleric acid, 3-methyl-2-oxobutanoic acid, and 2-oxooctanoic acid represent a family of carboxylic acids called “2-keto acids” or “alpha-keto acids.” 0186 EXPERIMENT Mo 3: Testing the most acceptable candidate acids at temperature environment

ИО187| Goal:

ИЙО188| The purpose of this experiment was to determine which of the most acceptable candidate acids selected in the experiment described above would deliver the greatest amount of nicotine under ambient conditions.

I0189| Test method:

IO190| This experiment was carried out according to the methodology described in the previous experiment, except that the glass chambers were not immersed in a heated water bath, and the samples were taken at ambient temperature. Separate experiments were conducted using selected candidate acids: 3-methyl-2-oxovaleric acid, pyruvic acid, 2-oxovaleric acid, 4-methyl-2-oxovaleric acid, 3-methyl-2-oxobutanoic acid, and 2-oxooctanoic acid. . During each experiment, various acids were introduced into Chamber A, as in the previous experiment, with nicotine in the form of a free base in Chamber B. As in the previous experiment, a control experiment was also conducted with nicotine in the form of a free base. 0191) Results: 0192) The table below presents the test results of the most acceptable candidate acids, samples of which were taken under ambient conditions. The results are given as the amount of nicotine determined in each puff.

IO193I

Table C

Delivery of nicotine by passing selected acids over the base (Ambient temperature) nicotine 'nicotine'

I0194| Discussion:

I0195| The results of the experiment at ambient temperature show that pyruvic acid is the best candidate for the formation of a nicotine aerosol with a delivery of 44.68 mcg/puff. 0196 EXPERIMENT Mo 4: Testing of the most acceptable candidate acids from previous experiments conducted at 70 C and at ambient temperature (Experiment 2 and Experiment 3, respectively) using a prior art design for aerosol generation

I0197| Purpose: 0198) The purpose of this experiment was to compare a previous experimental design for sequential acid and base targeting to determine which provides greater nicotine delivery. The two most acceptable candidate acids that provided the same nicotine delivery at a temperature of "70" C and one candidate acid that delivered the largest amount of nicotine at ambient temperature (from Experiments Me 2-3) were tested at a temperature of 70 C and under ambient conditions , respectively. 0199) Experimental design: 0200) Two identical rectangular glass chambers were used in this experiment, exactly the same as those used in Experiment Mo 2. Chamber A contained 200 μl of the most acceptable acid, and chamber B contained 200 μl of nicotine in free base form. The two chambers were connected by means of a U-shaped glass connector, which was connected to the same polytetrafluoroethylene housing that housed the Satrgidde filter as previously described. A pair of tubes could be instantly mixed in a U-shaped glass connector when pumped for 20 times (20 puffs) 35 cm 3 volumes of air for 2 s (with intervals of 30 s between puffs) using an apparatus with an adjustable puff volume (PSMA). To carry out experiments at elevated temperature, chambers with acid and nicotine were immersed to half their height in a water bath with a water temperature of approximately 70 C. Before sampling, the chambers were kept for equilibration for 10 min. For conducting experiments at ambient temperature, both cameras were placed on a laboratory stand. The collected samples were analyzed for nicotine content by means of gas chromatography with a nitrogen-phosphorus detector.

ИО201| Results: 02021) The table below shows the test results of the most acceptable candidate acids, which were sampled at elevated temperature (approximately 70 C) and under ambient conditions using state-of-the-art systems; for comparison, the results obtained by the method of sequential transmission of acid over the base are also given (p

Experiments Mo 2-3). The results are given as the mass of nicotine determined in each puff. (O2OZI

Table 4

Nicotine delivery using a U-shaped design (Prior art) the other day 800 YET t sequential (u-shaped connector) transmission (0204) Discussion:

I0205| Based on the above data, the delivery of nicotine by the known methods is significantly lower than in the case of using the sequential transmission technique and, thus, the sequential transmission technique is the best way to deliver the nicotine aerosol. (0206 EXPERIMENT Mo 5: Effectiveness of sequentially placing an acid reservoir and a base reservoir to allow the acid to pass over the base to produce an aerosol stream with sufficient nicotine concentrations

I02071| Goal:

I0208| The purpose of this experiment was to determine the effect of sequentially placing the acid and base reservoirs, allowing the acid vapor to rise into the free base nicotine chamber and pass over the nicotine to form an aerosol cloud containing sufficient amounts of free base nicotine. Pyruvic acid was chosen for this experiment.

I0209| Test Procedure: 0210) The procedure described in experiment Mo 2 was followed. This experiment was divided into two parts, A and B. The first part, A, included the evaluation of the application of free base nicotine (200 μl) and pyruvic acid (200 μl) in separate chambers with sample collection (20 puffs/sample). The second part of the experiment (part B) included a comparison of the above system tested at ambient temperature and tested at 40 "C to determine the effect of mild heating on aerosol formation and nicotine delivery.

ИО211) Results (Part A):

ИЙО212| The following tables present the results of an experiment on the passage of pyruvic acid over nicotine in the form of a free base under ambient conditions

(part A). The results are presented as the total weight of nicotine and the amount of nicotine determined in each puff. (0213

Table 5

Delivery of nicotine in the case of passing acid over the base. . Nicotine

Sample ID Total weight of nicotine (mcg)//sample (mcg)/puff

Passage of pyruvic acid over 782.16 39.11 nicotine in the form of a free base-1

Passage of pyruvic acid over nicotine in the form of a free base-2 623.02 ZY

Passage of pyruvic acid over nicotine in the form of a free base-3 533.73 26.69

Average (Coefficient of variation 32.31 (19.5 95)

SU

0214) Discussion (Part A): 0215) These results show an overall, approximately 32 95, decrease in nicotine yield from the first to the last test.

ИО216) Results (part B)

ИЙО217| The following table presents the results of an experiment with the passage of pyruvic acid over nicotine in the form of a free base at a temperature of 40 "C. The results are presented in the form of the total weight of nicotine and the amount of nicotine determined in each puff. (02181

Table 6

Delivery of nicotine in case of passing acid over the base at a temperature of 40 "C. Full weight of nicotine Nicotine

Sample identifier (μg)//sample (μg) in/tightening

Passage of pyruvic acid over 2341.09 117.05 nicotine in the form of free base-1

Passage of pyruvic acid over 214120 107.06 nicotine in the form of free base-2

Passage of pyruvic acid over nicotine in the form of a free base-3 213792 106.90 11111111 Average (SMu | 110.337 (5395

I0219| Discussion (Part B):

I0220| Under heating conditions, a 3-4-fold increase in the weight of nicotine/puff was observed compared to ambient conditions. In addition, the coefficient of variation has improved significantly (up to approximately 595), which indicates a good regulation of delivery dynamics. Moreover, there was no significant decrease in nicotine delivery during puffs. (0221| EXPERIMENT Me 6. Study of the formation of an aerosol of nicotine and its delivery by a sequential method with pyruvic acid using a miniature device the size of a cigarette (length 8 cm, internal diameter 8 mm) (0222) Materials and methods: (0223) Materials for manufacturing matrices: (0224| Samples of wick from an air freshener made of a mixture of polyethylene (PE) and polypropylene (PP) fibers (sold as X-40495 fiber from Rohech Tesppoiodiez) were used as a matrix for retaining pyruvic acid; as a matrix for retaining nicotine in in the form of a free base, the membrane CORE "M, intended for medical use (pore size 0.2 μm), was used, which includes a membrane intended for medical use from foamed polytetrafluoroethylene (PTEE) with a membrane base made of non-woven polyethylene terephthalate (PET) fabric (sold under brand 5MRI-MMT314 from the company UM.G.

Sboge 8 Av5osiae5, Ips.). The aforementioned membrane was rolled into a roller shape with a polyester inner wall and a Teflon (TER OM) outer wall with an inner diameter of 1.5 mm and cut into 4 cm long segments.

(0225) Experimental design: (0226| A piece of a wick from an air freshener was saturated with 180 μl of pyruvic acid (the structural element-source of pyruvic acid). On the inner walls (polyester side) of three pieces of rolled membrane for medical use, 4 cm long and 1 in. diameter, 5 mm was loaded with 90 μl (3x30 μl) of free-base nicotine. free base form was tightly inserted into a Teflon washer that had three holes (nicotine source construct).The nicotine source construct was inserted into a 9 cm long, 8 mm inner diameter Teflon tube with the pyruvic acid source construct with a 2 cm gap between constructive element-source of pyruvic acid and constructive e source of nicotine. The relative location of the structural elements-sources was such that a measured portion of air (a puff of 35 cm3 for 2 s with an interval between puffs of 30 s for 20 puffs), which was introduced using an automatic syringe pump, first passed through the structural element source of pyruvic acid, and then through the constructive element-source of nicotine, forming an aerosol. The proximal end of the device was connected to an adjustable volume inhalation device (ADV) equipped with a Satrbgidde filter (for collection of product in the form of an aerosol). To conduct the experiment at elevated temperature (40 "C), the 9-cm-long device (which includes both the structural element-source of pyruvic acid and the structural element-source of nicotine) was completely immersed in a water bath and equilibrated for 10 min before sampling The experiment was carried out under environmental conditions by placing the device on a laboratory stand.

I0227| Results: 0228) Samples were analyzed for nicotine content; the results are shown in Table 7 and Table 8. (0229)

Table 7

Nicotine delivery in an experiment using a miniature device at a temperature of 407 (μg/puff)

Permeation of pyruvic acid in air freshener wick over nicotine in three rolled sections of membrane for medical 103.58 application (0230

Table 8

Nicotine delivery in an experiment using a miniature device at ambient temperature

Permeation of pyruvic acid in air freshener wick over nicotine in three folded sections of membrane 29,20 for medical applications

ИО231| Discussion:

I0174| The experimental data indicate that in conditions where pyruvic acid and base are introduced into the matrix (in this case, wick from an air freshener was used as the acid source, and a membrane for medical use was used as the free base nicotine source), nicotine delivery was comparable with the delivery obtained in the laboratory setup described in experiment Mo 5. In addition, at a temperature of "40 "С, the delivery of nicotine significantly increases (approximately 3 times) in comparison with the delivery of nicotine under ambient conditions. 0233) Improvement experiments (0234 EXPERIMENT Mo 1: Finding Suitable Chemical Agents for Nicotine to Improve Aerosol Generation with Pyruvic Acid 02351 Purpose: (0236) This experiment was conducted to determine a suitable chemical agent for nicotine to effectively generate aerosol with pyruvic acid vapor.

I0237| Materials and methods: 02381) Nicotine bitartrate solutions: The nicotine base was obtained according to the following methods:

I0239| Approximately 16 mg of nicotine bitartrate (equivalent to 5 mg of nicotine base) was mixed with 200 mg of sodium hydroxide granules in a tube with a side tap, 1 ml of distilled water was added, and vigorously mixed (Imaon Nicotine Base). 0240) Approximately 16 mg of nicotine bitartrate (equivalent to 5 mg of nicotine base) was mixed with 200 mg of calcium hydroxide in a tube with a side tap, 1 ml of distilled water was added, and vigorously stirred (Ca(OH)»Nicotine base). 02411) Approximately 16 mg of nicotine bitartrate (equivalent to 5 mg of nicotine base) was mixed with 200 mg of potassium hydroxide granules in a tube with a side tap, 1 ml of distilled water was added, and intensively mixed (ICON Nicotine base).

I0242| Approximately 16 mg of nicotine bitartrate (equivalent to 5 mg of nicotine base) was dissolved in 1 ml of distilled water in a tube with a side tap, and heated to a temperature of 75-80" (a temperature corresponding to exothermic conditions) (Control for an exothermic reaction experiment.

I0243| Approximately 16 mg of nicotine bitartrate (equivalent to 5 mg of nicotine base) was dissolved in 1 ml of distilled water (Control for the experiment at ambient temperature) in a tube with a side tap.

I0244| Pyruvic acid: For each experiment, approximately 1 ml of pyruvic acid was measured into a glass tube with a side tap and a jet of air was injected into the tube using a Pasteur pipette. (0245) Test method: In this experiment, two identical test tubes with a side tap (Test tube A and B) were used. Tube A contained approximately 1 ml of pyruvic acid and tube B contained alkalized nicotine. A separate side-drain tube containing nicotine plus bases or nicotine alone (control) was immediately connected to a source of pyruvic acid (measuring the temperature as an indication of the exothermic process resulting from the addition of water to the selected base). To conduct the experiment at ambient temperature, the tube with nicotine was cooled to room temperature before being connected to the tube containing pyruvic acid. Vapor of pyruvic acid (from test tube A) was passed over nicotine mixed with a chemical agent (test tube B), and the outlet of test tube B was connected to a filter produced by Satrgidde company to collect the reaction product while pumping 35 cm3 of air volume for 2 s ( with intervals of 5 s) 5 times (5 puffs), 10 times (10 puffs), 20 times (20 puffs) or 50 times (50 puffs) using an automatic syringe pump. The vapor formed in test tube A was injected into test tube B using a jet of air from a glass pipette attached to test tube A. All samples were subjected to quantitative analysis by means of gas chromatography (C) with a nitrogen-phosphorus detector (NPD). 0246) Results:

I0247| The samples were analyzed for nicotine content, and the average amount of nicotine delivered in aerosol form is shown in Table TA and Table 18. (o248I

Table 1A

Delivery of nicotine in case of passage of pyruvic acid vapor over a mixture of nicotine bitartrate solutions and a base under heating conditions as a result of the course of the exothermic reaction of a pyruvic acid sample over:

Mahon and nicotine Ca(OH)» 5 nicotine KOH 8 nicotine Control Nicotine (average 20 (average 20 (average 20 (average 20 puffs) puffs) puffs) by puff)

Under heating conditions | Under heating conditions | Under heating conditions (heating to due to the course | due to the course | due to the course of temperature 75- exothermic exothermic exothermic exothermic 802) reactions reactions reactions 11111171 4061 17771711171712 | 77387 | 09 2 F F"

Table 1A

Delivery of nicotine in case of passage of pyruvic acid vapor over a mixture of nicotine bitartrate solutions and a base under heating conditions as a result of the course of the exothermic reaction of a pyruvic acid sample over:

Average nicotine content (100 puffs) μg x ZO 31.3325.86 0.66-0.35 29.7947.94 1.2550.35 (mean square deviation) (o249)I

Table 18

Delivery of nicotine by passing pyruvic acid vapor over a mixture of nicotine bitartrate and base solutions at ambient temperature acid sample over: maon 8 nicotine | Ca(OH)» 8 nicotine KOH 4 nicotine Control Nicotine (mean 20 (mean 20 puffs) puffs) (mean 20 puffs) (mean 20 puffs)

At room At room ry room At room - : temperature temperature temperature temperature 17113521 Я7111117108771117171111111342 | and

Average content Average content Average content Average nicotine content (100 nicotine (100 nicotine (100 nicotine (100 puffs) puffs) puffs) puffs) mcg - 50: mcg -50- mcg -50- mcg -50- 27.2656.21 0 ,4330.23 29.5755.29 0.55:20.55 (0250) Discussion:

ИО251) When conducting experiments on the delivery of nicotine aerosol by mixing three different bases (Maon, KOH and Ca (OH)2g) with the nicotine base, different results were obtained. In addition, when applying two experimental conditions (under conditions of heating due to the passage of an exothermic reaction and under ambient temperature conditions) also gave different results regarding the delivery of nicotine aerosol. 0252) Under heating conditions due to the course of the exothermic reaction, the average nicotine aerosol delivery was 31.33 μg/puff in the case of mixing nicotine base with sodium hydroxide (Maon), 0.66 μg /puff in the case of mixing the nicotine base with calcium hydroxide (Ca (OH)g) and 29.79 μg/puff in the case of mixing the nicotine base with potassium hydroxide (KOH). In the case of conducting a control experiment under identical experimental conditions without any chemical agent (base), the nicotine aerosol delivery rate was approximately 1.25 mcg/puff. pay attention to the fact that in the case of mixing Ca(OH)g| with water and nicotine base no heat was released, while the other two bases (MaonH and KOH) released heat. Sodium hydroxide and potassium hydroxide are known as "alkali metal hydroxides", while calcium hydroxide is known as "alkaline earth metal hydroxide". The results of this experiment show that nicotine aerosol delivery was significantly increased when nicotine base was mixed with alkali metal hydroxides, compared to alkaline earth metal hydroxide, under identical test conditions.

I0253| When conducting experiments at ambient temperature (room temperature), the average concentrations of nicotine aerosol were 27.26 μg/puff in the case of mixing nicotine base with sodium hydroxide (MAON), 0.43 μg/puff in the case of mixing nicotine base with calcium hydroxide ( Ca(OH)»gi and 29.57 mcg/puff when nicotine base was mixed with potassium hydroxide (KOH). In the case of a control experiment under identical experimental conditions without any base, the nicotine aerosol delivery level was approximately 0.55 mcg/ Interestingly, at room temperature, nicotine aerosol delivery was slightly higher when the nicotine base was mixed with KOH compared to Mmaon. (0254) Nicotine delivery in the potassium hydroxide (alkali metal hydroxide) experiment was slightly increased compared to Mmaon . For this reason, the following experiments were carried out using potassium hydroxide as the preferred agent. (0255 EXPERIMENT NT Me 2: Passage of pyruvic acid over a mixture of nicotine bitartrate and potassium hydroxide upon heating due to the passage of an exothermic reaction (0256) Purpose:

I0257| When conducting preliminary experiments, attention was paid to the fact that the heat released during the exothermic reaction played a significant role in enhancing the initial delivery of nicotine in the form of an aerosol. This experiment was conducted to test the constancy of the enhancement of nicotine aerosol delivery by the heat of exothermic reaction. In this experiment, nicotine bitartrate was used as a source of nicotine base. (0258) Materials and method:

I0259| Alkalized solutions of nicotine bitartrate: Alkalized nicotine base in two different concentrations was obtained according to the following procedure: 0260) Approximately 250 mg of nicotine bitartrate salt (equivalent to 81 mg of nicotine base) was mixed with 500 mg of potassium hydroxide granules in a test tube with a side tap, and 1 ml of distilled water, and thoroughly mixed. 0261) Approximately 125 mg of nicotine bitartrate salt (equivalent to 40 mg of nicotine base) was mixed with 250 mg of potassium hydroxide granules in a tube with a side tap, 1 ml of distilled water was added, and mixed thoroughly.

I0262| Pyruvic acid: For each experiment, approximately 1 ml of pyruvic acid was measured into a glass tube with a side tap and a jet of air was injected into the tube using a Pasteur pipette. (0263) Test method: An alkaline solution of nicotine base in a separate test tube with a side tap was connected to a source of pyruvic acid according to the method described in

Experiments Mo 1. (0264) Results: 0265) Samples were analyzed for nicotine content and Table 2 shows the average amount of nicotine delivered in each 50 puffs up to 150 puffs. (O266)

Table 2

Delivery of nicotine in the case of passing pyruvic acid vapor over alkalized solutions of nicotine bitartrate when heated by the heat of an exothermic reaction

Pyruvic acid Pyruvic acid is passed over 81 mg of alkalized is passed over 40 mg of alkalized nicotine base (Experiment- | nicotine base (Experiment-

And in

I0267| Discussion: (0268) The results showing the amount of nicotine delivered during the first 50 puffs (76.7 mcg/puff in Experiment-A and 57.8 mcg/puff in Experiment-B) suggest that the heat released in the process exothermic reaction (as a result of the reaction between potassium hydroxide and water), dramatically increases the formation of nicotine aerosol with pyruvic acid during the first 50 puffs; the time required for 50 puffs was approximately 30 min, during which the heat released in the exothermic reaction maintained the elevated temperature. The results of this experiment are significant and unique in that the external heating necessary to ensure improved nicotine delivery during the first 50 puffs was absent. This result again validates the use of heating in the authors' previous application to improve nicotine delivery and shows that this alternative heating mechanism can be used to improve delivery for a number of puffs that is practical and of commercial interest. With adequate insulation, the heat released in the exothermic reaction may be suitable to improve delivery for even more than the 50 puffs specified herein. (0269 EXPERIMENT Me 3: Passing pyruvic acid over a mixture of nicotine bitartrate and potassium hydroxide (0270) Purpose: This experiment was designed to investigate the delivery of nicotine in aerosol form by passing pyruvic acid vapor over an alkalized nicotine base.

Nicotine bitartrate was used as a source of nicotine base. (0271) Materials and methods:

I0272| Nicotine bitartrate salt solution: Approximately 500 mg of nicotine bitartrate salt (equivalent to 162 mg of nicotine base) was mixed with 1 g of potassium hydroxide granules in a side-vented tube, 2 mL of distilled water was added, and mixed thoroughly.

I0273| Pyruvic acid: For each experiment, approximately 1 ml of pyruvic acid was measured into a glass tube with a side tap and a jet of air was injected into the tube using a Pasteur pipette. (0274) Test method: 0275) An alkaline solution of the nicotine base in a separate test tube with a side tap was immediately (so that the heat of the exothermic reaction can be measured) combined with a source of pyruvic acid according to the method described in Experiment Mo 1. (0276) Results:

I0277| The samples were analyzed for nicotine content and Table C shows the average amount of nicotine delivered in each 50 puffs of 35 cc. These results were compared with data obtained when experiments were carried out using an identical design with a relatively equivalent amount (700 μl) of pyruvic acid and a much larger amount (700 mg) of unsalted nicotine base. (278)

Table C

Nicotine delivery by passing pyruvic acid vapor over an alkalized nicotine bitartrate solution at room temperature compared with nicotine delivery from a non-alkalinised nicotine base

Pyruvic acid Pyruvic acid is passed over 162 mg passed over 700 mg of alkalized nicotine bitartrate |unalkalized nicotine base (each point represents an average (each point represents a puff) average of 40 puffs) 200 puffs)x5O

I0279| Discussion:

ИО280| It should be noted that the nicotine delivery over 200 puffs (average 71.12 μg/puff) in this experiment was dramatically increased (approximately 3.5 times) compared to previous experimental results (average nicotine content was 21.66 μg/puff) puff). More importantly, the total amount of free base nicotine in this experiment was significantly lower (162 mg) than in the previous experiment (700 mg). Another important result was that the amount of nicotine delivered during the first 50 puffs was greater than in subsequent puffs. The authors drew attention to the fact that in the case of the reaction of nicotine salt with potassium hydroxide and water, a significant amount of energy was released in the form of heat (heat of exothermic reaction). The elevated temperature (approximately 80 "C) was maintained at a constant level for approximately 15-20 min. Thus, the improved nicotine delivery during the first 50 puffs was likely due to the heat of the exothermic reaction. Importantly, however, the improved nicotine delivery in puffs 100-200 cannot be simply attributed to a transient exothermic reaction. Rather, it appears that the sustained increase in nicotine aerosol release is due to the addition of alkali metal hydroxides to reg 5e nicotine (ie, some effect of base addition other than heating due to the exothermic reaction). Based on the data from this experiment, it can be concluded that the use of an agent selected from alkali metal hydroxides can help reduce the amount of nicotine base required for effective aerosol formation with significantly improved nicotine aerosol delivery compared to a control experiment (in which no alkali metal hydroxide was used).(02811) These post regulations indicated the need for the next series of experiments using small amounts of nicotine salts. (0282| EXPERIMENT Mo 4: Passing pyruvic acid over a reduced amount of a mixture of nicotine bitartrate and potassium hydroxide at room temperature 0283) Purpose: (0284) This experiment was designed to determine the smallest amount of nicotine bitartrate that could be used to produce an effective vapor aerosol pyruvic acid. To this end, three different amounts of nicotine bitartrate were used as a source of nicotine base to form an aerosol with pyruvic acid vapor. Aerosol samples were taken in the absence of heat released during the exothermic reaction, as they waited until the tubes cooled to room temperature. (0285) Materials and Methods: (0286) Nicotine Bitartrate Solutions: Three different concentrations of alkalized nicotine base for these experiments were prepared as follows:

I0287| Approximately 32 mg of nicotine bitartrate salt (equivalent to 10 mg of nicotine base) was mixed with 100 mg of potassium hydroxide granules in a tube with a side tap, 200 μl of distilled water was added, and mixed thoroughly. 0288) Approximately 20 mg of nicotine bitartrate salt (equivalent to 6.5 mg of nicotine base) was mixed with 100 mg of potassium hydroxide granules in a tube with a side tap, 200 μl of distilled water was added, and mixed thoroughly.

ИО289| Approximately 9 mg of nicotine bitartrate salt (equivalent to 2.9 mg of nicotine base) was mixed with 100 mg of potassium hydroxide granules in a tube with a side tap, 200 μl of distilled water was added, and mixed thoroughly.

I0290| The above-mentioned solutions in separate test tubes with a side tap were kept at room temperature for 20 min to reach the mentioned test tubes at room temperature.

I0O291| Pyruvic acid: For each experiment, approximately 1 ml of pyruvic acid was measured into a glass tube with a side tap and a jet of air was injected into the tube using a Pasteur pipette. (0292) Test Methodology: This experiment followed the methodology described in Experiment Mo 1. 0293) Results: Samples were analyzed for nicotine content and Table 4 shows the average amount of nicotine delivered in every 10 puffs during the first 100 puffs. (o2941

Table 4

Delivery of nicotine by passing pyruvic acid vapor over a solution of a mixture of nicotine (with lower concentrations) and potassium hydroxide at room temperature

Delivery of nicotine (mcg/puff) in the form of an aerosol (mcg) in/puff when:

Pyruvic acid Pyruvic acid Pyruvic acid passes over 10 mg passes over 6.5 mg acid passes nicotine in potassium hydroxide nicotine in hydroxide over 2.9 mg nicotine in potassium hydroxide potassium nicotine (in 100

Table 4

Delivery of nicotine by passing pyruvic acid vapor over a solution of a mixture of nicotine (with lower concentrations) and potassium hydroxide at room temperature

Identifier y y y

Delivery of nicotine (mcg/puff) in the form of an aerosol (mcg) in/puff when:

And burdensome ( '/ HER (0295) Discussion: (0296| Experimental results demonstrate that the average amount of nicotine delivered during the first 100 puffs of the aerosol was 35.55 mcg/puff with a small amount (10 mg) of nicotine in potassium hydroxide solution, 28.07 mcg/puff with a smaller amount (6.5 mg) of nicotine in potassium hydroxide solution and 25.10 mcg/puff with the smallest amount (2.9 mg) of nicotine in potassium hydroxide solution.

All three experiments demonstrated significant nicotine aerosol delivery even at a significantly lower nicotine level compared to the previous experiment, which used approximately 700 mg of nicotine base (Table 3). Coincidentally, delivery of the nicotine aerosol with the lowest amount (2.9 mg) of alkalized nicotine outperformed the experiment using 700 mg of nicotine base. It should be noted that the addition of potassium hydroxide to the nicotine bitartrate solution provides effective nicotine aerosol formation even when small amounts of nicotine are used.

I0297| It can be concluded that the combination of nicotine bitartrate with potassium hydroxide helps to overcome the deterioration of nicotine aerosol delivery during the first 100 puffs even at much lower concentrations of nicotine base. (0298| EXPERIMENT Mo 5: Determination of the mass balance of nicotine delivered with an aerosol in the case of passing pyruvic acid over a mixture of nicotine bitartrate and potassium hydroxide 0299 Purpose:

ИЙОЗО0О| The main objective of this experiment was to determine the amount of nicotine delivered in aerosol form and to calculate the percentage of nicotine recovery. A secondary objective was to determine the maintenance of the desired amount of nicotine delivered at two different concentrations of nicotine bitartrate solution and potassium hydroxide.

1) Materials and methods:

ИО3021| Nicotine bitartrate solutions: Two different concentrations of nicotine base were prepared as follows:

ИО303| Approximately 32 mg of nicotine bitartrate salt (equivalent to 10 mg of nicotine base) was mixed with 100 mg of potassium hydroxide granules in a tube with a side tap, 200 μl of distilled water was added, and mixed thoroughly. 0304) Approximately 9 mg of nicotine bitartrate salt (equivalent to 2.9 mg of nicotine base) was mixed with 100 mg of potassium hydroxide granules in a side-tube, 200 μl of distilled water was added, and mixed thoroughly. 0305) The above-mentioned solutions in separate tubes with a side tap were kept at room temperature for 20 min to prevent any effect of the heat released during the exothermic reaction on the formation of the nicotine aerosol.

ИЙО3О6| Pyruvic acid: For each experiment, approximately 1 ml of pyruvic acid was measured into a glass tube with a side tap and a jet of air was injected into the tube using a Pasteur pipette.

I0307| Test method: Alkalized solutions of the nicotine base in a separate test tube with a side tap were combined with a source of pyruvic acid according to the method described in

Experiments Mo 1.

ИОЗО8)| Results:

ЙО309| The samples were analyzed for nicotine content and Table 5 shows the average amount of nicotine delivered in each 10 puffs.

IOZ10I

Table 5

Delivery of nicotine by passing pyruvic acid vapor over solutions of a mixture of nicotine bitartrate and potassium hydroxide (10 puffs/sample) in the case of:

The passage of pyruvic transmission of pyruvinograde 0 YEE nicotine base of nicotine base of nippivinnshnshi: now tires now now echnnnshyshishyshishshishshshyshshshyshshhshshshyshshshshshyshshshyshishshshyshishshishshishshishshishshishshishshyshishshyshishshyshishshyshishshyshishshyshishshyshishshishshyshishshishshyshish.

Average amount of nicotine (in | Average amount of nicotine (in 120 280 puffs) puffs) mcg - 50- mcg 50 - 31.1328.21 24.03х9.43 111 Ash well and delivered over 280 |delivered over 120 puffs - puffs - 7 .9 mg 2.88 mg 11111101 Original 79095... | Exit 993954DshDsh Rr (u

ИО3111| Discussion:

ИО312)| The total amount of nicotine delivered during the first 280 puffs in an experiment using 10 mg of nicotine in potassium hydroxide was approximately 7.9 mg for an average nicotine amount of 31.13 µg/puff. The total amount of nicotine delivered (over 120 puffs) in an experiment using approximately 2.9 mg of alkalized nicotine base was 2.88 mg with an average nicotine amount of 24.03 mcg/puff. Aerosol generation and delivery still occurred (as evidenced by double-digit nicotine delivery rates observed at 280 puffs) in the experiment using approximately 10 mg of alkalized nicotine base, while aerosol generation only lasted for 120 puffs in the experiment using approximately 2 .9 mg of alkalized nicotine base. It should be noted that the yield was approximately 99.3 95 in the experiment using 2.88 mg of alkalized nicotine base and 79.0 95 when using 10 mg of alkalized nicotine base. Thus, the results of this experiment clearly demonstrated that most of the nicotine (more than 79 95) was effectively used to form the pyruvic acid aerosol. In addition to this, the results of this experiment showed that the consistency of nicotine aerosol delivery depends on the amount of nicotine in potassium hydroxide that was used. 0313 EXPERIMENT Mo 6: Experiments on the development of an acceptable device for the generation and delivery of an aerosol containing nicotine pyruvate

ИО314| Goal:

ИО315) The purpose of this series of experiments was to try to create a device suitable for production in industrial conditions from a device suitable for use in laboratory conditions. 0316 CONSTRUCTION Mo 1: Pyruvic acid in a test tube with a side tap; nicotine base in glass tubes with an inner diameter of 2 mm

ИО317| Materials and methods

IO318) Nicotine base solution: Approximately 10 μl (10 mg) of nicotine base was mixed with 30 μl of saturated potassium hydroxide solution. The solution was applied (4x10 μl) to the inner surfaces of 4 segments of glass tubes 10 cm long and with an inner diameter of 2 mm. The tubes with the applied solution were placed in a Teflon tube with an inner diameter of 8 mm (Structural element with a nicotine base).

ИЙО319| Pyruvic acid: For each experiment, approximately 1 ml of pyruvic acid (PA) was measured into a glass tube with a side tap and a jet of air was injected into the tube using a Pasteur pipette (Building element with pyruvic acid).

ИО320| Test method: A structural element with a nicotine base was combined with a structural element with pyruvic acid, and aerosol samples were taken according to the method described in Experiment Mo 1. (0321) CONSTRUCTION Mo 2: Pyruvic acid in a test tube with a side tap; nicotine in potassium hydroxide solution applied to the inner surface of glass tubes with an inner diameter of 2 mm 0322) Materials and methods

ИО323)| Nicotine base solutions:

I0324| Approximately 10 μl (10 mg) of nicotine base was mixed with 30 μl of saturated potassium hydroxide (KOH) solution. The solution was applied (4x10 μl) to the inner surfaces of 4 segments of glass tubes 10 cm long and with an inner diameter of 2 mm. The tubes with the applied solution were placed in a Teflon tube with an inner diameter of 8 mm (Constructive element with a nicotine base)-

Solution 1.

ИО325| Approximately 20 μl (10 mg) of nicotine base was mixed with 20 μl of saturated potassium hydroxide solution. The solution was applied (4x10 μl) to the inner surfaces of 4 segments of glass tubes 10 cm long and with an inner diameter of 2 mm. The tubes with the applied solution were placed in a Teflon tube with an inner diameter of 8 mm (Constructive element with a nicotine base)-

Solution 2.

ИО326| Approximately 30 μl (30 mg) of nicotine base was mixed with 10 μl of saturated potassium hydroxide solution. The solution was applied (4x10 μl) to the inner surfaces of 4 segments of glass tubes 10 cm long and with an inner diameter of 2 mm. The tubes with the applied solution were placed in a Teflon tube with an inner diameter of 8 mm (Constructive element with a nicotine base)-

Solution 3.

ИО327| Pyruvic acid: For each experiment, approximately 1 ml of pyruvic acid (PA) was measured into a glass tube with a side tap and a jet of air was injected into the tube using a Pasteur pipette (Building element with pyruvic acid).

ИО328| Test method: A structural element with a nicotine base was combined with a structural element with pyruvic acid, and aerosol samples were taken according to the method described in Experiment Mo 1, after waiting for 20 minutes, to dissipate the heat released during the exothermic reaction.

ИО329| Results:

IO330) Samples were analyzed for nicotine content and Table 6 shows the average amount of nicotine delivered in each 10 puffs of aerosol.

ИО3911

Table 6

Nicotine delivery by passing pyruvic acid vapor in a test tube with a side outlet over an alkalized nicotine base aerosolized on glass tubes using: 11111111 Solutions"! | Solution2" | Dissolve?

Passage of pyruvic acid over nicotine in KOH-1 67.8 62.0 734

Passing pyruvic acid over

Table 6

Nicotine delivery by passing pyruvic acid vapor in a tube with a side outlet over an alkalized nicotine base applied to glass tubes

Sample identifier Amount of nicotine (mcg/puff) delivered With an aerosol using: nicotine in KOH-With npshnnshshsh

Passage of pyruvic acid over nicotine in KOH-4 524 54.3 64.8

Passage of pyruvic acid over nicotine in KOH-5 47.6 47.6 bag

Passage of pyruvic acid over nicotine in KOH-6 43.3 zvi 67.3

Passage of pyruvic acid over nicotine in KOH-7 ЗА 40 64.8

Passage of pyruvic acid over nicotine in KOH-8 is 35.0 ba

Passage of pyruvic acid over nicotine in KOH-9 42 A Zb 60.2

Passage of pyruvic acid over nicotine in KOH-10 40.7 32.2 53.8

The average amount of nicotine (in 100 puffs) 50.37:9.5 47.14410.8 65.1045.4 μg - 50 "10 μl (10 mg) of nicotine base was mixed with 30 μl of saturated potassium hydroxide solution; 7520 μl (20 mg) of nicotine base was mixed with 20 μl of saturated potassium hydroxide solution; μl (30 mg) of nicotine base was mixed with 10 μl of saturated potassium hydroxide solution

I0332| CONSTRUCTION Mo 3: Pyruvic acid and nicotine in potassium hydroxide applied to the inner surface of a glass tube with an inner diameter of 2 mm 0333) Materials and methods

ИЙО334| Nicotine base solution: Approximately 2.7 mg of nicotine base was mixed with 20 μl of saturated potassium hydroxide solution. The solution was applied to the inner surface of a glass tube 10 cm long and with an inner diameter of 2 mm. The tube with the applied solution was placed in a Teflon tube with an inner diameter of 8 mm (Constructive element with a nicotine base).

ИО335| Pyruvic acid: Approximately 20 µL of pyruvic acid (PA) was applied to the inner surface of a 10 cm long glass tube with an inner diameter of 2 mm. The tube with the applied solution was placed in a Teflon tube with an inner diameter of 8 mm (Construction element with pyruvic acid).

ИЙО336| Test method: A structural element with a nicotine base was combined with a structural element with pyruvic acid, and aerosol samples were taken according to the method described in Experiment Mo 1, after waiting for 20 minutes to dissipate the heat released during the exothermic reaction.

ИО337| Results:

IO338) Samples were analyzed for nicotine content and Table 7 shows the average amount of nicotine delivered in each 5 puffs of the aerosol. The results were compared with the data obtained in an identical experiment, except that the nicotine base was not mixed with the potassium hydroxide solution. (OZ39

Table 7

Nicotine delivery when pyruvic acid applied to the surface of a glass tube is passed over a solution of nicotine in potassium hydroxide (KOH) applied to the surface of the glass tube

Sample ID Amount of nicotine (mcg/puff) delivered with aerosol 11111117 nicotinucone Nicotine without KOH

Passing pyruvic acid over

Table 7

Delivery of nicotine when pyruvic acid, applied to the surface of a glass tube, is passed over a solution of nicotine in potassium hydroxide (KOH), applied to the surface of a glass tube with an aerosol of 111111 nicotine-2

NOT yikissNY CURRENT LIN NYE CNN - 34.9 25.1 nicotine-3

ZO

I0340| CONSTRUCTION Me 4: The wick from the air freshener is saturated with pyruvic acid; nicotine is applied to the inner surface of glass tubes with an inner diameter of 2 mm 0341) Materials and methods 0342) Nicotine base: Approximately 5 mg of nicotine base is mixed with 15 μl of saturated potassium hydroxide solution. The solution is applied to the inner surface of two glass tubes cm long and with an inner diameter of 2 mm (placed in parallel). Add two more empty glass tubes (without applying the solution) of the same size to dilute the air. All tubes are placed in a Teflon tube with an inner diameter of 8 mm (Constructive element with a nicotine base). 0343) Pyruvic acid: Approximately 140 µL of pyruvic acid (PA) saturate an air freshener wick made from a mixture of polyethylene (PE) and polypropylene (PP) fibers (sold as X-40495 fiber from Rohech TesppoiIodieb5) which is inserted into a Teflon tube with an inner diameter of 6 mm (Construction element with pyruvic acid).

I0344| Test method: A structural element with a nicotine base was combined with a structural element with pyruvic acid, and aerosol samples were taken according to the method described in Experiment Mo 1, after waiting for 20 minutes to dissipate the heat released during the exothermic reaction.

ИО345)| Results: 0346) Samples were analyzed for nicotine content and Table 8 shows the average amount of nicotine delivered in each 10 puffs of aerosol. The results were compared with the data obtained during an identical experiment, except that the nicotine base was not alkalized (Unalkalisted nicotine).

IOZ471

Table 8

Nicotine delivery when pyruvic acid saturated with air freshener wick is passed over nicotine in potassium hydroxide aerosolized on glass tubes 11111111 nictinukon | NicotinbezkOnN:Ch nicotine - 1 Y Y

In iii NINI PON INNYA - 24.3 b2 nicotine-2

Nico NNI NI NNYA - 24.5 6.4 nicotine-3 iii NINI LIN NIE: ZV - 24.6 5.7 nicotine-4 nicotine-5 ' ' μg - 50

Table 8

Delivery of nicotine in the case when pyruvic acid, which was used to saturate the wick from the air freshener, is passed over nicotine in potassium hydroxide, applied to glass tubes with an aerosol μg 5 50

I0348| Discussion: The results of the Experiment would illustrate the application of the component parts of the device, similar to those that could be used in the designs of a real product for the delivery of a nicotine aerosol for inhalation. A sustained increase in nicotine yield, independent of any exothermic reaction, results from the use of alkali metal hydroxide with nicotine, as in

Constructions Mo 1-3, the description of which is given above. In all cases, the delivery of significant amounts of nicotine in the absence of exogenous heating elements demonstrates the utility of using alkali metal hydroxide in combination with nicotine to increase nicotine output.

I0349| EXPERIMENT Mo 7: Research on determining the appropriate ratio of nicotine and potassium hydroxide for the preparation and delivery of nicotine pyruvate aerosol

ИОЗ50И Purpose:

ИО351)| The purpose of this experiment was to determine the appropriate ratio of nicotine to potassium hydroxide for obtaining and delivering a constant amount of nicotine pyruvate aerosol.

ИО352)| Materials and methods

ИЙО353| Nicotine Base Solution: Approximately 10 µl (10 mg) of nicotine base was mixed in a side-drain tube with 200 µl of water containing 10 mg, or 20 mg, or 40 mg, or 60 mg, or 80 mg, or 100 mg, or 200 mg of potassium hydroxide (constructive element with a nicotine base).

Constructive elements with a nicotine base were kept at room temperature for an hour before the experiments (for cooling after the release of the heat of the exothermic reaction).

ИЙО354| Pyruvic acid: For each experiment, approximately 1 ml of pyruvic acid (PA) was measured into a glass tube with a side tap and a jet of air was introduced into the tube using a Pasteur pipette (constructive element with pyruvic acid).

ИЙО355| Test method: A structural element with a nicotine base was combined with a structural element with pyruvic acid, and aerosol samples were taken according to the method described in Experiment Mo 1.

ИОЗ356)| Results:

ИО357| The samples were analyzed for nicotine content and Table 10 shows the average amount of nicotine delivered in each 20 puffs of the aerosol. (oZ58)

Table 10

Nicotine delivery by passing pyruvic acid vapor over potassium hydroxide and nicotine base in different ratios of pyruvic acid vapor over nicotine (10 μl), water (200 μl) and:

Table 10

Nicotine delivery by passing pyruvic acid vapor over potassium hydroxide and nicotine base in different ratios of pyruvic acid vapor over nicotine (10 μl), water (200 μl) and:

I0359| Discussion:

ИОЗ36О| The results of Experiment 7 demonstrate the delivery of nicotine aerosol with different ratios of potassium hydroxide and nicotine base in water. It should be noted that consistent improvement in nicotine delivery was achieved at nicotine to potassium hydroxide ratios of 10:40, 10:60, 10:80, and 10:100, with 10:60 appearing to outperform the other three ratios. Thus, by adjusting the ratio between the concentration of potassium hydroxide and the nicotine base, the delivery of the nicotine aerosol can be adjusted, as needed, to an optimal level. Each increase in the amount of potassium hydroxide led to an increase in the pH value. Thus, the more alkaline pH of reg 5e did not correlate with nicotine delivery.

IOH361) At the same time, greater nicotine delivery at intermediate KOH concentrations correlated with the formation of an emulsion consisting of small nicotine beads suspended in an aqueous solution

CON. Low concentrations of KOH (eg, 10 mg KOH in 200 microliters of water) were insufficient to induce this phase separation. Very high concentrations (e.g., 200 mg of KOH in 200 microliters of water) induce phase separation but do not stabilize a nicotine-in-KOH emulsion consisting of small nicotine beads surrounded by a KOH solution. Instead, a continuous layer of nicotine was formed, possibly as a result of the increased surface tension of aqueous KOH solutions of high concentration (RM Yuipiar apa 5K Ragi5, Zipase Tepviop oi Adoeoi5 BoiYishiop5 oi Roiazzisht Nuagohiade,

Maishige 196, 1312-1313, 1962). Without a stable emulsion, there was no increase in nicotine release over many puffs under the tested conditions. That is, the improvement of nicotine delivery may depend on the sequestration of pyruvic acid in the KOH solution surrounding the small nicotine-containing beads. 0362 EXPERIMENT Mo 8: Search for additional chemicals for obtaining and effective delivery of nicotine pyruvate aerosol

ИО363| Purpose: (0364) The purpose of this experiment was to investigate the suitability of certain additional chemicals (preferred alkali metal hydroxides/oxides and alkaline earth metal hydroxides/oxides) and salts, as well as potassium hydroxide, to produce and deliver stable amount of nicotine pyruvate aerosol. 0365) Materials and methods

ИЙО366| Nicotine base solution: Approximately 10 µl (10 mg) of nicotine base was mixed in a side-drain tube with 300 µl of water containing 100 mg of the selected base and salt (nicotine building block). Before conducting the experiments, the structural element with nicotine was kept at room temperature for an hour (for cooling in case of the presence of exothermic reaction heat). The candidates listed below were tested for their ability to increase the sustained delivery of nicotine aerosol.

ИО367| Alkali metal hydroxides and oxides:

Potassium hydroxide (KOH)

Tertiary potassium butoxide (CH3)zSOkK

Potassium superoxide (KOg)

Sodium hydroxide (maon)

Sodium butoxide (СН3(СНег)зОМа|!

Sodium tertiary butoxide (CH3) zSOMa)

Lithium oxide (Gi20)

ИО368)| Alkaline earth metal oxides:

Calcium oxide (CaO)

Beryllium oxide (Ved)

Barium oxide (Vas)

Barium peroxide (Bag)

ИО369| Salts:

Potassium chloride (KSI)

Sodium chloride (mass)

Sodium carbonate (MgSO3)

Sodium citrate (HOS (СООМа) (СНаСООМа) gi

Ammonium sulfate (MNA) 2504I

ИО370| Pyruvic acid: For each experiment, approximately 1 ml of pyruvic acid (PA) was measured into a glass tube with a side tap. Using a Pasteur pipette, a jet of air was introduced into the test tube (Construction element with pyruvic acid).

I0O371| Test method: The structural element with nicotine was combined with the structural element with pyruvic acid, and aerosol samples were taken according to the method described in Experiment Mo 1.

ИО372| Results:

ИО373)| The samples were analyzed for nicotine content and Table 11 shows the average amount of nicotine delivered in each 60 puffs of the aerosol.

IOZ741

Table 11

Delivery of nicotine by passing pyruvic acid vapor over mixtures of nicotine with some alkali metal hydroxides/oxides, alkaline earth metal oxides and salts at room temperature

Sample identifier and end of nicotine (mcg)/puff experiment vs 1001

METALEV potassium sodium

OXIDILUHNOZEMELNYHMETALEV.DG//Z/ | :G / HER

OLE (111 sodium ammonium

CONTROL EXPERIMENT

I0O375| Discussion: The results of Experiment 8 clearly show that alkali metal hydroxides/oxides (potassium, sodium, and lithium) are the most effective group in terms of obtaining and delivering sustained and increased amounts of nicotine in an aerosol, compared to alkaline earth metal oxides (beryllium, calcium, and barium). . Among the alkali metal hydroxides/oxides tested, potassium and lithium hydroxides/oxides were found to be the best candidates to provide improved nicotine delivery in an aerosol.

ЙО376| In addition, it was found that nicotine aerosol delivered in experiments in which saline solutions were mixed with nicotine base showed an interesting result.

Although the control experiment (without water, salt, or alkali metal hydroxides/oxides and alkaline earth metal oxides) delivered approximately 25.62 μg/puff of nicotine in the aerosol, mixing selected saline solutions with the nicotine base may be beneficial in terms of enhancing nicotine delivery in aerosols, in comparison with the result of the control experiment, for two reasons:

I0377| 1) It is known that nicotine forms an azeotropic mixture with water, which can be separated into separate nicotine and water phases with certain ranges of nicotine concentration and temperature. (P. 5. Niazop, 7eiy. Rnuvz. Spet., 47, 113 (1904)). By causing the release of nicotine from an azeotropic aqueous solution,

as shown in Experiment Mo 7 above, nicotine delivery will be increased compared to nicotine diluted in the same volume of water; and 0378) 2) due to the use of a larger volume of solution than with a pure nicotine base, the solution can be distributed over a larger surface area, which stimulates more effective vaporization of nicotine.

ИЙО379| Without intending to bind myself to any specific theory of the mechanism of the phenomenon, the increased evaporation of nicotine from aqueous solutions of nicotine with, for example, KSI and KOH presented above, may be the result of the influence of electrolytes 3 "salting out" of the nicotine base from the solution. In general concept, in industrial chemistry this could correspond to salt distillation, for example the use of potassium acetate in the separation of azeotropic mixtures of water and ethanol. (Zsptia,

O., Modeironyi, A. (1983). OibviShayop oi eiShapoi!-maieg 5oYshiope ip She rgezepse oi roiazzisht aseiaiv. zZeragayop Zsiepse apa TesNpoiodu, 18 (6), 547-554). In general, this salting-out effect should be most effective when the electrolytes have extremely different solubilities in nicotine base and water, with high solubility in water and low solubility in nicotine base. The technology of salt distillation of ethanol from aqueous azeotropic mixtures, developed in the field of bioethanol production, provides an analytical basis for the evaluation of salts other than those tested in this experiment. (BK. T. R. Ripio, M. K. Umoi-Masiei, G. Ppiotep, Zaiiipe ehigasiime adiviiShayop rgosev55 og eiyapgoi! rigitisayop, Sotriiegt5 v Spetisa! Epaipeegipa, Moishte 24, Ivzzcez 2-7, 15 shu 2000, Radez 1689 - 1694; Mago Papo-Nezigero, Udayite Adiyag!-Agiav5, Moadeiipud apa vitshayop oi zaiiipe ehigasiime aibzshayop soishtpv og She rgodisiyop oi abzoitsie eiyapoi, Sotriieg5 5 Spetisa! Epaipeegipa, Moishte 27, Ivvce 4, 15

Art 2003, Radez 527-549).

ИЙО380| We investigated the dependence of nicotine aerosolization on concentration by calculating the molality of solutions of the substances in Table 11. The graph below demonstrates the existence of a good correlation (correlation coefficient /-0.76 and p-0.016). In comparison, insoluble compounds such as beryllium oxide or calcium oxide did not improve nicotine delivery compared to the aqueous control solution (data not shown). Other electrolyte-forming compounds tested include potassium tertiary butoxide, potassium superoxide, sodium butoxide, sodium tertiary butoxide, and barium peroxide.

Grass year of regression

Row of bulges: Dependence of "delivering a puff of nicotine - concentration" 43 40 . - 35 me

E ZO rai -- me

E 59 as sha ra ya) shchi -t same . bye to her

Z. ray in shk: 1 o and Ya ki B 10 12

Mopality

ИО381| In addition to the salting-out effect, it is well established that mild heating induces a shift to the biphasic state of the nicotine-water system. (P.5. Niazop, 2ei. Rpuz. Spet., 47, 113 (1904)). A sufficient increase in ionic strength can change the phase shift temperature such that heating to a lower temperature or no heating at all is required to induce this phase shift.

ИО382| Heating the salted mixture would generally also correspond to the salt distillation discussed above. This is consistent with the general trend of higher initial nicotine delivery for strong bases (KOH, Mahon) compared to salts (KSI, mass). Thus, for certain variants of the implementation of the present invention, preference is given to compounds that form an electrolyte, when dissolved in water, an exothermic reaction occurs.

IO383) In embodiments of the present invention where the delivery enhancing compound is an acid such as pyruvic acid, said acid may dissolve in the nicotine source over time and acidify it. This acidification is associated with decreased nicotine delivery over time, possibly due to neutralization of the nicotine base (protonated nicotine has a pKa of 8.5). Thus, in these variants of the implementation of the present invention, preferred are compounds that form an electrolyte, in case of dissolution of which in water an exothermic reaction occurs and which, in addition, are strong bases (that is, they provide the pH value of the nicotine/water mixture » 11, 12, 13 or 14). A particularly preferred compound in this regard is KOH.

ИО384| Examples of embodiments of devices adapted to implement the methods of the present invention

ИО385) Nicotine delivery devices in some embodiments of the present invention include a body that imitates a tobacco product. The case can imitate any tobacco smoking product in terms of size, shape and/or structure. Non-limiting examples of tobacco smoking products of the present invention include cigarettes, cigars, cigarillos, and pipes. 0386) Nicotine delivery devices in some embodiments of the present invention include a housing that imitates a medical-pharmaceutical inhaler. The housing can mimic in size, shape and/or construction any medical-pharmaceutical device used for inhalation. Non-limiting examples of medical-pharmaceutical inhalers according to the present invention include metered-dose inhalers, high-pressure metered-dose inhalers, dry powder inhalers, aerosol nebulizers, and liquid inhalers.

ИО387| Device implementation option 1

ИО388| In Fig. 1 presents a device for receiving and delivering nicotine aerosol to the consumer according to an embodiment of the present invention. In particular, a nicotine inhaler 10 having the size, shape and appearance of a cigarette is shown. Nicotine inhaler 10 consists of a hollow body 12, which has an elongated cylindrical shape. To ensure the passage of a gaseous flow through the inhaler 10, an inlet 14 for gas and an outlet 16 for gas are provided at the opposite ends of the housing 12.

I0O389| The part of the body 12 between the gas inlet 14 and the gas outlet 16 is divided into three chambers, in which a first, second and/or third substance can be placed. Said first, second or third substance can contain a vapor-forming drug , such as nicotine.

ИО390) As shown in Fig. 2, the nicotine inhaler 10 includes a first chamber 18, a second chamber 20, and a third chamber 22. Nicotine, in the preferred free base form, may be contained in any of these three chambers. Nicotine, for example, can be placed in the second chamber 20. A suitable drug delivery enhancing compound, such as an acid, is placed in the first chamber 18. Any suitable acid can be used. For example, pyruvic acid can be placed in the first chamber 18. Pyruvic acid is a volatile substance that has a significant saturated vapor pressure at room temperature. Thus, any free space within the first chamber 18 will be filled to some extent with pyruvic acid vapor, i.e. gaseous pyruvic acid. Although the saturated vapor pressure of nicotine is lower than the saturated vapor pressure of pyruvic acid, nicotine is also a volatile substance.

Well, in the same way, any free space within the second chamber 20 will be filled with nicotine vapor to some extent.

ИО391)| It should be understood that pyruvic acid is contained within a first chamber 18 on the compound source assembly to enhance delivery (not shown) and nicotine is contained within a second chamber 20 on the nicotine source assembly (not shown).

In addition, a third source component (not shown) within the third chamber 22 may contain a third substance. In addition to this, one or more structural elements-sources can be performed as a whole with the cameras 18, 20, 22, respectively, or form a component part of the mentioned cameras.

I0392| The delivery-enhancing compound source component can be of any size and shape that allows the gaseous stream to contact the acid vapor and pass through the first chamber 18. The nicotine source component can be of any size and shape that provides the possibility of contacting the gaseous stream with nicotine vapor and passing through the second chamber 20. The third structural element-source can have any size and shape that provide the possibility of contacting the gaseous stream with the third substance and passing through the third chamber 22. 0393) Structural element - the source of the compound to improve delivery may consist of any suitable material capable of retaining the acid on its surface while allowing the acid vapor to be released into the surrounding space. The nicotine source component can be made of any suitable material capable of retaining nicotine on its surface while allowing the release of nicotine vapor into the surrounding space. The structural element-source of the third substance can consist of any suitable material capable of holding the third substance. In specific embodiments of the present invention, the corresponding material holds the third substance on its surface while simultaneously ensuring the possibility of releasing the vapor of the third substance into the surrounding space.

ИО394| According to the preferred option, the corresponding material of the source structural element is inert to any substance intended to be placed on its surface. In addition to this, the corresponding material is, in a preferred embodiment, adsorbing to any substance intended to be placed on its surface, whereby said substance is adsorbed on the surface of said material. Although a material having both absorptive and adsorptive properties may be used, a material capable of adsorbing the delivery-enhancing compound(s), nicotine, and/or a third substance is preferred. Non-limiting examples of such material include glass, aluminum, PET, RVT, RTEE, eRTEE, and WAREX, preferably in the form of a fiber mesh.

I0395| The adsorbent material can function by capillary action to continuously deliver substances to the surface of the adsorbent material. 0396) The third chamber 22 may contain a cleaning agent. For example, activated carbon can be placed in the third chamber 22 using any method that provides the third chamber 22 with gas purification capability. Suitable methods are well known in the art. For example, coal can be placed inside the third chamber 22 in the form of a coal plug or filter.

I0397| In the operating mode, the user puffs through the gas outlet 16 of the nicotine inhaler 10, as shown in Fig. 3. A partial decrease in pressure as a result of the tightening pulls the gaseous flow into the housing 12 through the gas inlet 14. The gaseous stream enters the first chamber 18 and captures acid vapor as a result of passing over the pyruvic acid source structural element, which is placed in the first chamber 18. The gaseous stream that leaves the chamber 18 and later enters the second chamber 20 is an acid-containing gaseous stream. Said acid-containing gas stream forms a stream of nicotine-containing particles due to passing over the nicotine held by the nicotine source structural element in the second chamber 20. The stream of nicotine-containing particles passes through the third chamber 22 and exits through the outlet 16 for the gas to exit to the oral cavity of the user. Any unreacted acid is removed from the stream of nicotine-containing particles by an activated carbon filter in the third chamber 22. It should be understood that the pyruvic acid may be retained on the first structural element in the first chamber 18 and/or the nicotine may be retained on the second structural element in second chamber 20. In addition, a third substance, such as a cleaning agent or fragrance, may be retained on the third structural element in the third chamber 22. In addition, the first, second and third structural elements may be integral with the chambers 18, 20, 22 respectively, or form an integral part of the mentioned chambers.

IO398) Device embodiment 2 0399) This device embodiment is explained and described with reference to Figures 4-6. In Fig. 4 structural elements of the device are shown in the form of a diagram of the sequence of operations. The delivery enhancer compound source 30 and the nicotine source 40 are optionally manufactured and stored as separate components, which are typically equipped with frangible end caps 35 and 45, which are heat-welded to seal the ends of said component structural elements. The two mentioned structural elements 30 and 40 are inserted into the first housing 50. After that, the first housing 50, with the source 30 of compounds for improving delivery and the nicotine source 40 placed therein, is inserted into the second housing 100. The housings 50 and 100 and the structural elements 30 and 40 are, as a rule, extruded plastic tubes. A heating element 95 is also inserted into the second housing 100. The heating element 95 is typically a thin, flexible heating foil that is shaped to wrap around the housing 50 and that contacts the housing 50 sufficiently to heat the compound source 30 to improve delivery and /or the nicotine source 40 to a desired temperature (eg, "C). The heating element 95 is also adapted to contact the storage battery 130 to supply power to the foil heating element 95.

I0400| The filter element 80 is designed to be slidably inserted and latched and spring-loaded into the second housing 100. The filter element 80 has a filter cavity 75 adapted to accommodate the filter 70. The filter 70 is typically a carbon filter and may contain additional volatile compounds such as flavors that are traditionally used in cigarettes.

The filter element 80 may have a foil seal 150 to seal the assembled device 160 before use.

I0401) The filter element 80 has an opening 90 combined with an opening 110 of the second housing 100. In the folded form, an inlet opening 140 for air is formed. The filter element 80 and the second body 100 are given such a shape that provides the possibility of sliding rotation to select the required size of the inlet hole 140 for air. The air inlet 140 is formed when the filter element 80 is fully inserted into the second housing 100, as shown by position 170. When the filter element 80 is fully inserted, the structural elements 60 are also forced through the frangible plugs 35 and 45, depressurizing these structural elements for unimpeded passage. air flow from air inlet 140 to particle delivery port 180.

I0402| In Fig. 5 shows various alternative designs of the compound source 30 to improve delivery and the nicotine source 40. The delivery enhancer in such a design is typically a volatile acid that can be retained by adsorption on sintered plug 310, PE wick 320, fiber tow 330, multi-lumen tube 340 or 350, woven or nonwoven PET, PVT, or

RETO material 360, PET static mixer 370 or on a spiral channel 380 wrapped in a non-woven material. 0403) Fig. 6 shows some embodiments of this device, where said device includes reusable parts 210 and disposable parts 200. As shown in Fig. 1, the disposable part 200 includes a source 30 of the compound to improve delivery and a source 40 of nicotine, a first housing 50 and a filter element 80.

The reusable part 210 includes a second housing 100, a heating element 95, and a battery 130. (0404) Device embodiment C 0405) In FIG. 7 presents an embodiment of a reusable device in its entirety. Two alternative designs are presented where parts 410 and 420 or 430 and 440 are reversibly connected. For example, said parts may be extruded plastic products designed for multiple quick click-and-remove applications that have the appropriate dimensions. Removable parts 420 or 440 have holes 430 and 440 for communication with a source 445 of a compound to improve delivery and a source 435 of nicotine. Parts 420 or 440 are slidably introduced into reloadable structural element 450 through hole 460.

The structural elements 470 are annular gaskets for sealing the reservoir in the event of reloading of the source 445 of the compound to improve the delivery and the source 435 of nicotine. The shape of the loading ports 480 and 490 allows for communication with the delivery-enhancing compound source 445 and the nicotine source 435 after placement of the portion 420 in the reloading assembly 450. In some embodiments of the present invention, fluid flows from the delivery-enhancing compound reservoir 500 and the reservoir 510 for nicotine to source 445 compound to improve delivery and source 435 nicotine, respectively, occurs by gravity. In some variants of the implementation of the present invention, the flow of liquid from the mentioned tanks to the mentioned sources is partially determined by the suction of liquid from the tanks by the structural elements-sources. For example, the delivery-enhancing compound source 445 and the nicotine source 435 may be a PET-containing source design element to provide rapid absorption and thereby reload sources 445 and 435. 0406) Device Embodiment 4

I0407| Another embodiment of the device is shown in Fig. 8 and Fig. 9. This embodiment of the device is reloadable and mimics the shape of a typical cigarette pack. In Fig. 8, the shape of the delivery device 600 allows it to be inserted into the reloading unit 610 through the storage opening 620 and the reloading opening 630. After being fully seated in the reloading unit 610 on the reloading assembly 640, the device 600 is reloaded with the compound to enhance drug delivery and/or nicotine. 0408) In Fig. 9 shows in detail the reloading structural element 640. On

Fig. 9A, the injection structural element 650 having loading ports 660 and 670 is in hydraulic communication with reservoirs 720 and 730 through metering pumps 680 and 690 and tubes 700 and 710. In FIG. 9B, the delivery device 600 is shown positioned within the reloading unit 640. The injection assembly 650 passes through the reloading hole in the base of the delivery assembly and enters said assembly such that the openings 660 and 670 communicate with the nicotine source assembly 740 and the nicotine assembly assembly 650. source of 750 compounds to improve delivery. In Fig. 9C, the delivery device 600 is further inserted into the reloading unit 640 with actuation of pumps 680 and 690 to deliver defined doses (770) of nicotine and delivery enhancement compound (760) through apertures 660 and 670, respectively, to the nicotine source assembly 740 and structural element-source 750 compound to improve delivery, respectively. 04091) Device embodiment 5 (0410) This device embodiment is shown in Fig. 10. The design of this device includes a heating unit 850 positioned externally relative to the delivery device 800. After inserting the delivery device 800 into the heating unit 850, the electrical contacts 840 are in contact with the connecting wires 825, which enable the battery pack 830 to heat the foil heating element 860 to regulate the temperature of the source 870 of the compound to improve the delivery and the source 880 of the nicotine on levels, for example, 4025 C. In an alternative design, a foil heating element 860 is placed inside the delivery device 800, as shown in FIG. 4. 0411) Device implementation option 6

I0412| The devices corresponding to the above-mentioned embodiments are generally given a shape imitating a cigarette or a pack of cigarettes. Delivery devices suitable for use in the methods described are readily provided in a variety of forms. An example is presented in Fig. 11. This embodiment of the device mimics a metered dose inhaler, which is traditionally used to deliver pharmaceutical drugs by inhalation.

The delivery device 900 includes a first housing 910 and a second housing 920. The second housing 920 can slide outward (FIG. 11A) and inward (FIG. 118) to recharge or replace the battery 990. When the second housing 920 moves inward, the electrical contacts 1050 and 1060 are closed, causing the battery 990 to heat the foil heating element 950 , which regulates the temperature of the compound source 960 to improve delivery and the nicotine source 970 .

The design of the air intake switch 930 allows it to be moved from the position shown in FIG. 11A, in the position shown in fig. 118. Power to the foil heating element 950 may optionally be applied and turned off by the air intake switch 930 or by a separate switch (not shown). The air inlet 940 can be opened to a selected amount thereby regulating the volume of air per puff and thus the amount of nicotine. This feature is analogous to the adjustable air inlet 140 of FIG. 1. In operation, air is drawn through air inlet 940 to chamber 1000, passes through channel 1010, through delivery enhancer compound source 960, where the delivery enhancer compound is entrained in the air stream. For example, a vapor of pyruvic acid can be released from the PET of a structural element-source, on which liquid pyruvic acid is adsorbed. This vapor travels in the air flow through channel 1020 to source 970 of nicotine. The delivery-enhancing compound increases the concentration of nicotine in the air stream compared to the amount of nicotine vapor that would be contained in the same volume of air-flow in the absence of the delivery-enhancing compound. In the case of pyruvic acid, nicotine pyruvate salt particles can be formed to improve nicotine delivery to the patient. Delivery can be further improved by increasing the temperature of, for example, pyruvic acid and nicotine, using the heating element 950 to increase the saturated vapor pressure of these compounds. The air stream containing nicotine passes through the channel 1030, through the carbon filter 980 and exits through the inhalation hole 1040. 0413) FIG. 11C and O illustrate an embodiment of an inhaler device 900, wherein a portion of the device that houses a delivery-enhancing compound source 960 and a nicotine source 970 that is located within a reusable housing 1050 that is structurally movable in and out of the housing 1060 forms a device functionally identical to the 900 device.

The structural element 1070 for placing the battery is separated from the structural element 1050 of single use and, thanks to this, can be used repeatedly with the part 1060 and the replaceable structural element 1050. 0414) Device embodiment 7 0415) Fig. 12 A-C illustrate an inhalation device of another design. In this design, the source of the delivery-enhancing compound and the source of nicotine constitute the lower and upper surface planes of the folded inner tube 1100. In operation, as shown in FIG. 12A, an impermeable shell 1110 is placed over the nicotine reservoir 1120 and the compound reservoir 1130 to improve delivery. The impermeable shell 1110 reduces evaporation losses from said reservoirs and physically separates the reservoirs from the folded inner tube 1100. In operation, the sliding lower housing 1180 is pushed into the main housing 1190 until the first locking spring 1140 is locked in the position shown in FIG. 128. Thanks to this, the reservoirs 1120 and 1130 occupy a position parallel to the folded inner tube 1100 with a micro-window. As shown in Figure 9C, the lower housing 1180 is further inserted into the main housing 1190 until the second locking spring 1150 is locked in the position shown in FIG. 12C0. In this third position, the compression members 1160 press against the folded inner tube 1100, forcing the wall 1170 into contact with the reservoirs 1120 and 1130. Under this pressure, nicotine and a delivery-enhancing compound (e.g., pyruvic acid) are forced onto the inner surface of the wall 1170 so that , that said surface again becomes a source of nicotine and a source of compound to improve delivery. 0416) Device implementation option 8

I0417| In Fig. 13 shows a variant of the device shown in Fig. 12. In this embodiment, the lower housing 1250 presses against the conical spring 1230, forcing the nicotine reservoir 1210 and the delivery enhancement compound reservoir 1220 to travel through the reservoir cap 1200 and contact the inner surface of the conical inner tube 1240, thereby coating the surface with the nicotine and compound for delivery. improvement of delivery (Fig. 138B). 0418) Device implementation option 9 0419) In Fig. 14 shows another version of the device shown in Fig. 12. In this embodiment, the outer housing 1300 abuts the moving components, which are the switch 1310 and the various internal structural elements shown. The switch 1310 is connected to the socket structural element 1330 of the source by means of the connecting rod 1320. When the switch 1310 is moved up, the rigid socket element 1330 moves along the column 1360. In the loading position, the structural elements-reservoirs 1340 and 1350 collide with the deformable elements 1370, which also collide with the rigid nest element 1330. The dimensions of the rigid nest element 1330 are selected in such a way that it presses the deformable elements 1370 into contact with the structural elements-reservoirs 1340 and 1350 in the last part of the sliding movement (Fig. 14B). The effect of this action is to coat the top of the deformable element 1370 with, for example, a nicotine base solution from reservoir 1350, and the bottom of the deformable element 1370 with pyruvic acid from reservoir 1340 to form a source of nicotine and a source of delivery enhancer compound, respectively. The upper surface of the reservoir 1350 may be covered with an impermeable material to limit the rate of evaporation of the drug and compound to improve delivery from the reservoirs while in the operating position (FIG. 14A). From the structural elements 1320 or 1330, an annular flap of flexible impermeable material may depart to cover the volume under the reservoir 1350 to further limit evaporation. In the loaded position (Fig. 14B), the valve will be forced downward and away from the tanks by means of the deformable structural element 1370. (0420) Device embodiment 10 04211 In Fig. 15 shows a drug delivery device of another design. In Fig. 15A device 1400 is shown in operational mode. Air moves from inlet 1410 past delivery-enhancing compound source 1500, nicotine source 1490 and through outlet 1415. Nicotine and delivery-enhancing compound coat the sidewalls of the respective sources. A reservoir of delivery enhancing compounds 1430 and a reservoir of nicotine 1420 are provided for reloading said sources. The switch 1460 may be actuated by the user's thumb to reset the sources. When actuated by the switch 1460 , the base 1510 is induced to move along the guide rod 1470 in the direction of the source 1500 of the compound to improve delivery and the source 1490 of the nicotine. As shown in Fig. 15B, upon contact with the delivery enhancer compound source 1500, the nicotine source 1490, and the upper locking structure 1480, the impermeable plugs 1440 and 1450 compress the reservoirs forcing the delivery enhancer compound and nicotine from the reservoirs onto the surface of the sources 1490 and 1500. The reservoirs in this the devices may be made of any adsorbent or absorbent material capable of retaining solutions of nicotine or compounds to enhance delivery. The reservoirs will typically be automatically induced to move downward along the guide rod 1470 after the sources are reloaded, making this a convenient one-click device. Movement of tanks can be provided by any traditional devices. For example, a movable wire 1520 may be provided in the groove of the guide rod 1470. Said movable wire 1520 may be connected to the base 1510 and induced to move up and down the guide rod 1470 by a motor-rotated structural member (not shown). In some embodiments of this device, the upper outer part of the device 1400 can be rotated to determine the size of the inlet opening 1410, similar to the structural element 140 shown in FIG. 4. (0422) Suitability for use on an industrial scale

I0423| The devices and methods described herein are useful for delivering nicotine for therapeutic purposes, namely for smoking cessation, harm reduction and/or replacement therapy. In addition, the devices and methods disclosed herein are useful as alternative general purpose nicotine delivery systems instead of articles. As disclosed in this specification, the methods and devices described in this specification can also be used to deliver other drugs. (0424) Although the essence and advantages of the present invention are described in detail, it should be understood that various changes, substitutions and modifications may be made to it, which do not go beyond the essence and scope of the present invention, defined by the appended claims. Moreover, the authors of the invention do not intend that the scope of the present invention be limited to certain variants of technology, equipment, production, substance composition, means, methods and operations disclosed in this description. Any specialist in this field who has read the description of the present invention will easily understand that the technological processes, equipment, production conditions, options for the composition of the substance, means, methods or operations, both those that already exist and those that will subsequently developed, and which perform essentially the same function or achieve essentially the same results as the corresponding embodiments of the present invention disclosed herein, may be considered as being used in accordance with the present invention. Accordingly, the clauses of the formula of the present invention, which is attached, fully cover the following technological processes, equipment, production conditions, options for the composition of the substance, means, methods or operations. 0425) All references and other information cited herein, or otherwise used, are incorporated herein by reference in their entirety, just as if they were separately specifically incorporated. U.S. Provisional Patent Application Mo. 60/909,302, filed March 30, 2007, U.S. Provisional Patent Application Mo. 61/160,904, filed March 17, 2009, and

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Claims (43)

1. A device for delivering nicotine to the body of a person, which includes a housing, while the housing has: a) interconnected inlet and outlet holes, designed in such a way that the gaseous carrier enters the housing through the inlet hole, its passage through the housing 1 exit from the housing through the outlet opening, while the device includes the following zones located in series from the inlet opening to the outlet opening: b) a first internal zone connected to the inlet opening, which includes a source of the compound for improving delivery, c) connected to the first inner zone a second inner zone that includes a nicotine source, and) the nicotine source contains nicotine and an electrolyte-forming compound, 1 both of which are in an aqueous solution. 2. The device according to item I, which differs in that the compound forming the electrolyte is a hydroxide or oxide of an alkali metal, an oxide of an alkaline earth metal, or a salt. 3. The device according to claim 1, which is characterized in that the compound that forms the electrolyte is selected from the group that includes the compounds listed in Table 11 of paragraph (0374|, and their combinations. 4. The device according to claim 1, claim 2 or claim 3, characterized in that the nicotine is selected from the group consisting of a nicotine base, a nicotine salt such as nicotine hydrochloride, nicotine bitartrate, nicotine ditartrate, and combinations thereof. 5. The device according to claim 1, claim 2 or claim 3, characterized in that the nicotine is selected from the group consisting of nicotine base, nicotine bitartrate and combinations thereof, and that the electrolyte-forming compound is selected from the group consisting of sodium hydroxide (MaOH), calcium hydroxide (Ca(OH);»), potassium hydroxide (KOH) and their combinations. 6. The device according to claim 1, claim 2 or claim 3, characterized in that the nicotine is selected from the group consisting of nicotine base, nicotine bitartrate, and combinations thereof, and the electrolyte-forming compound includes KOH. 7. The device according to claim 1, claim 2 or claim 3, which is characterized by the fact that the pH of the aqueous solution is equal to or exceeds 9.0. 8. The device according to claim 6, characterized in that the ratio between KOH and nicotine base (or base equivalents) is in the range of 10:40 to 10:100. 9. The device of any one of claims 1-8, wherein the source of the delivery-enhancing compound comprises an acid. 10. The device according to claim 9, characterized in that the acid is an inorganic acid or a carboxylic acid. 11. The device according to claim 10, characterized in that the acid is a 2-keto acid. 12. The device according to claim 11, characterized in that the acid is selected from the group consisting of 3-methyl-2-oxovaleric acid, pyruvic acid, 2-oxovaleric acid, 4-methyl-2-oxovaleric acid, 3-methyl-2 -oxobutanoic acid, 2-oxooctanoic acid and their combinations. 13. The method of delivering nicotine to a person's body by inhalation, which includes the following operations: a) first, ensuring the interaction of a gaseous carrier containing a compound for improving delivery with a source of nicotine, and) and the source of nicotine contains nicotine and a compound that forms electrolyte, 1 both of these substances are in an aqueous solution, 1 b) secondly, providing a gaseous carrier with nicotine to the person. 14. The method according to claim 13, which is characterized by the fact that the compound forming the electrolyte is a hydroxide or oxide of an alkali metal, an oxide of an alkaline earth metal or a salt. 15. The method according to claim 13, which is characterized by the fact that the compound that forms the electrolyte is selected from the group that includes the compounds listed in Table 11 of paragraph (0374|, and their combinations. 16. The method according to claim 13, claim 14 or claim 15, which is characterized by the fact that the nicotine is selected from among nicotine base, nicotine salt, such as nicotine hydrochloride, nicotine bitartrate, nicotine ditartrate, and combinations thereof. 17. The method according to claim 13, claim 14 or claim 15, which is characterized by the fact that the nicotine is selected from the group consisting of nicotine base, nicotine bitartrate, and combinations thereof, and that the electrolyte-forming compound is selected from the group consisting of sodium hydroxide (MaOH), calcium hydroxide (Ca(OH);»), potassium hydroxide (KOH) and their combinations. 18. The method according to claim 13, claim 14 or claim 15, which is characterized in that the nicotine is selected from among the nicotine base, nicotine bitartrate and their combinations, and the compound forming the electrolyte includes KOH. 19. The method according to claim 13, claim 14 or claim 15, which is characterized by the fact that the pH of the aqueous solution is equal to or exceeds 9.0. 20. The method according to claim 18, which is characterized by the fact that the ratio between KOH and nicotine base (or base equivalents) is in the range from 10:40 to 10:100. 21. The method of any one of claims 13-20, wherein the source of the delivery-enhancing compound comprises an acid. 22. The method according to claim 21, which is characterized in that the acid is an inorganic acid or a carboxylic acid. 23. The method according to claim 22, which is characterized in that the acid is a 2-keto acid. 2A. The method according to claim 23, which is characterized by the fact that the acid is selected from the group consisting of 3-methyl-2-oxovaleric acid, pyruvic acid, 2-oxovaleric acid, 4-methyl-2-oxovaleric acid, 3-methyl-2-oxovaleric acid acid, 2-oxooctanoic acid and their combinations. 25. A device for delivering nicotine to the body of a person, which includes a housing, while the housing has: a) interconnected inlet and outlet openings, designed in such a way that the gaseous carrier enters the housing through the inlet opening, its passage through the housing 1 exit from the housing through the outlet opening, while the device includes the following zones located in series from the inlet opening to the outlet opening: b) a first internal zone connected to the inlet opening, which includes a source of the compound for improving delivery, c) connected to the first inner zone a second inner zone that includes a nicotine source, and) wherein the nicotine source comprises nicotine and an electrolyte-forming compound, 1 both of which are in an aqueous solution, wherein the source of the delivery-enhancing compound comprises an inorganic acid or a carboxylic acid. 26. The device according to claim 25, which is characterized in that the compound forming the electrolyte is a hydroxide or oxide of an alkali metal, an oxide of an alkaline earth metal, or a salt. 27. The device according to claim 25, characterized in that the compound forming the electrolyte is selected from the group that includes the compounds listed in Table 11 of paragraph (0374|, and combinations thereof. 28. The device of claim 25, claim 26 or claim 27, wherein the nicotine is selected from the group consisting of a nicotine base, a nicotine salt such as nicotine hydrochloride, nicotine bitartrate, nicotine ditartrate, and combinations thereof. 29. The device according to claim 25, claim 26 or claim 27, characterized in that the nicotine is selected from the group consisting of nicotine base, nicotine bitartrate, and combinations thereof, and that the electrolyte-forming compound is selected from the group consisting of sodium hydroxide (MaOH), calcium hydroxide (Ca(OH);»), potassium hydroxide (KOH) and their combinations. 30. The device according to claim 25, claim 26 or claim 27, characterized in that the nicotine is selected from nicotine base, nicotine bitartrate, and combinations thereof, and the electrolyte-forming compound includes KOH. 31. The device according to claim 25, claim 26 or claim 27, which is characterized in that the pH of the aqueous solution is equal to or greater than 9.0. 32. The device according to claim 30, characterized in that the ratio between KOH and nicotine base (or base equivalents) is in the range of 10:40 to 10:100. 33. The device according to any one of claims 25-32, characterized in that the acid is a 2-keto acid. 34. The device according to claim 33, characterized in that the acid is selected from the group consisting of 3-methyl-2-oxovaleric acid, pyruvic acid, 2-oxovaleric acid, 4-methyl-2-oxovaleric acid, 3-methyl-2 -oxobutanoic acid, 2-oxooctanoic acid and their combinations. 35. A device for delivering nicotine to the body of a person, which includes a housing, while the housing has: a) interconnected inlet and outlet openings, designed in such a way that the gaseous carrier enters the housing through the inlet opening, its passage through the housing 1 exit from the housing through the outlet opening, while the device includes the following zones located in series from the inlet opening to the outlet opening: b) a first internal zone connected to the inlet opening, which includes a source of the compound for improving delivery, c) connected to the first by inner zone, a second inner zone that includes a source of nicotine, and) wherein the source of nicotine comprises nicotine and an electrolyte-forming compound, 1 both of which are in an aqueous solution, wherein the source of the delivery-enhancing compound comprises 2-ketocarboxylic acid. 36. The device according to claim 35, which is characterized in that the compound that forms the electrolyte is a hydroxide or oxide of an alkali metal, an oxide of an alkaline earth metal, or a salt. 37. The device according to claim 35, characterized in that the compound forming the electrolyte is selected from the group that includes the compounds listed in Table 11 of paragraph (0374|, and combinations thereof. 38. The device of claim 35, claim 36 or claim 37, wherein the nicotine is selected from the group consisting of a nicotine base, a nicotine salt such as nicotine hydrochloride, nicotine bitartrate, nicotine ditartrate, and combinations thereof. 39. A device according to claim 35, claim 36 or claim 37, characterized in that the nicotine is selected from the group consisting of nicotine base, nicotine bitartrate, and combinations thereof, and that the electrolyte-forming compound is selected from the group consisting of sodium hydroxide (MaOH), calcium hydroxide (Ca(OH);»), potassium hydroxide (KOH) and their combinations. 40. The device according to claim 35, claim 36 or claim 37, characterized in that the nicotine is selected from the group consisting of nicotine base, nicotine bitartrate, and combinations thereof, and the electrolyte-forming compound includes KOH. 41. The device according to claim 35, claim 36 or claim 37, which is characterized by the fact that the pH of the aqueous solution is equal to or exceeds 9.0. 42. The device according to claim 40, characterized in that the ratio between KOH and nicotine base (or base equivalents) is in the range of 10:40 to 10:100. 43. Device according to any of claims 35-42, characterized in that the acid is selected from the group consisting of 3-methyl-2-oxovaleric acid, pyruvic acid, 2-oxovaleric acid, 4-methyl-2-oxovaleric acid , 3-methyl-2-oxobutanoic acid, 2-oxooctanoic acid and their combinations.