HK1192491B - Device and method for delivery of a medicament - Google Patents
Device and method for delivery of a medicament Download PDFInfo
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- HK1192491B HK1192491B HK14104595.5A HK14104595A HK1192491B HK 1192491 B HK1192491 B HK 1192491B HK 14104595 A HK14104595 A HK 14104595A HK 1192491 B HK1192491 B HK 1192491B
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Description
The present application is a divisional application of the chinese patent application having an application number of 200880017582.7, an application date of 2008/3/25 entitled "device and method for delivering a medicament".
Technical Field
The present invention relates to a device and a method for delivering a medicament to a user. More particularly, the present invention relates to devices and methods for delivering an aerosol of a medicament to the lungs of a user.
Background
Pulmonary drug delivery systems have been used for decades to deliver agents for the treatment of respiratory disorders. The principle behind pulmonary drug delivery is to aerosolize the drug compound to be delivered to the bronchioles and alveoli. Despite challenges such as particle size optimization and degradation, many companies have developed techniques to deliver therapeutic drugs for diabetes, migraine, osteoporosis, and cancer.
Delivery systems that may be used include Metered Dose Inhalers (MDIs), dry powder inhalers (MPIs) and nebulizers. MDI is one of the first delivery systems introduced in the united states in the mid 50's of the 20 th century. HFA (pressurized) based MDIs were introduced in 1995 in the united states. Although DPIs were introduced in the 70's of the 20 th century, the use of DPIs has been limited due to the overwhelming dominance of MDIs. Nebulizers are commonly used in hospital settings. Technological advances in the pulmonary drug delivery technology market are taking place in non-CFC based MDIs, DPIs and Liquid Based Inhalers (LBIs).
Numerous preclinical and clinical studies have shown that pulmonary delivery of agents is an efficient approach for treating both respiratory and systemic diseases. Many advantages of pulmonary delivery are well recognized and include rapid onset, patient self-management, reduced side effects, ease of delivery by inhalation, and elimination of needles.
However, the methods for managing most medicaments have not significantly deviated from the oral route by traditional intravenous/intramuscular delivery, and including pulmonary delivery via inhalation. The use of pulmonary delivery is primarily limited to the management of agents used to treat asthma.
It has been recorded that in order to deliver powder directly into the lower breathing zone, the powder must generally have a particle size of less than 5 μm. In addition, it has been found that powders in the range of 5-10 μm do not leak as deeply, but instead tend to irritate the upper respiratory tract area.
When manufacturing a drug formulation for a Dry Powder Inhaler (DPI), the medicament must first be ground to obtain a particle size acceptable for pulmonary delivery. This micronization step can create problems during manufacturing. For example, heat generated during grinding can cause degradation of the pharmaceutical agent. In addition, the metal may rub off some of the abrasive dust and contaminate the medicament. In addition, due to the small particle size, dry powder formulations tend to agglomerate, especially in the presence of moisture.
Agglomeration results in low flowability of the granules, which can reduce the efficacy of the dry powder formulation. Therefore, careful supervision is required during milling, mixing, powder flow, filling and even administration to ensure proper delivery of the dry powder aerosol.
Accordingly, there is a need for new methods for preparing aerosols for drug delivery. The present disclosure describes, in part, a method for combining nicotine or other agents with a delivery enhancing compound in a gas stream to produce an aerosol for pulmonary delivery without the need for excipients or other additives including solvents.
Brief description of the invention
In some embodiments, the present disclosure relates to a method of delivering nicotine to a subject by inhalation, the method comprising the steps of:
a) first placing a gaseous carrier comprising a delivery enhancing compound in communication with a nicotine source comprising nicotine, and
b) and secondly providing the gaseous carrier comprising nicotine to the subject.
In some embodiments, the present disclosure relates to the method of paragraph [0010], further comprising the step of placing a gaseous carrier in communication with a delivery enhancing compound source comprising a delivery enhancing compound.
In some embodiments, the present disclosure relates to the method of [0011], wherein the step of placing the gaseous carrier in communication with a delivery enhancing compound source precedes the step of placing the gaseous carrier comprising the delivery enhancing compound in communication with the nicotine source.
In some embodiments, the present disclosure relates to the method of [0010], [0011], or [0012], wherein the delivery enhancing compound source comprises a plurality of compartments, the compartments comprising two or more precursor compounds.
In some embodiments, the present disclosure relates to the method of [0013], wherein the delivery enhancing compound comprises ammonium chloride and the two or more precursor compounds comprise ammonia and hydrogen chloride.
In some embodiments, the present disclosure relates to [0010] - [0013] or [0014] methods wherein the concentration of nicotine in the gaseous carrier is increased relative to the concentration of nicotine that would be included in the gaseous carrier in the absence of the delivery enhancing compound.
In some embodiments, the present disclosure relates to the methods of [0010] - [0014] or [0015], wherein the delivery enhancing compound comprises an acid.
In some embodiments, the present disclosure relates to the method of [0016], wherein the acid is an organic acid.
In some embodiments, the present disclosure relates to the method of [0017], wherein the organic acid has a greater vapor pressure than the nicotine base at a given temperature.
In some embodiments, the present disclosure relates to the method of [0018], wherein the given temperature is 25, 30, 40, 45, 70, or 100 degrees celsius.
In some embodiments, the present disclosure relates to the methods of [0016] - [0018] or [0019], wherein the acid is selected from the group consisting of 3-methyl-2-oxopentanoic acid, pyruvic acid, 2-oxopentanoic acid, 4-methyl-2-oxopentanoic acid, 3-methyl-2-oxobutanoic acid, 2-oxooctanoic acid, and combinations thereof.
In some embodiments, the present disclosure relates to the methods of [0010] - [0019] or [0020], wherein the delivery enhancing compound reacts with the nicotine to form particles.
In some embodiments, the present disclosure relates to the method of [0021], wherein the mass median aerodynamic diameter of the particles is less than 6 microns.
In some embodiments, the present disclosure relates to the method of [0021], wherein the mass median aerodynamic diameter of the particles is less than 1 micron.
In some embodiments, the present disclosure relates to the method of [0021], wherein the mass median aerodynamic diameter of at least some of the particles is between 0.5 microns and 5 microns.
In some embodiments, the present disclosure relates to the methods of [0010] - [0023] or [0024], wherein the method further comprises the step of increasing the temperature of the delivery enhancing compound, the delivery enhancing compound source, nicotine source, and/or gaseous carrier.
In some embodiments, the present disclosure relates to the method of [0025], wherein the temperature is increased to at least 30 degrees celsius.
In some embodiments, the present disclosure relates to the methods of [0010] - [0025] or [0026], wherein the gaseous carrier comprises at least 20 micrograms of nicotine in a volume of gaseous carrier provided to the subject.
In some embodiments, the present disclosure relates to the method of [0027], wherein the volume of gaseous carrier delivered to the subject is provided as a single volume.
In some embodiments, the present disclosure relates to a method of stopping the use of a tobacco product, the method comprising one or more of the methods of [0010] - [0027] or [0028] and further comprising delivering a therapeutically effective amount of nicotine to a subject to at least partially replace nicotine derived from the tobacco product.
In some embodiments, the present disclosure relates to a method of treating a disease for which nicotine is therapeutically beneficial, the method comprising one or more of the methods of [0010] - [0027] or [0028], wherein a therapeutically effective amount of nicotine is provided to a subject.
In some embodiments, the present disclosure relates to the method of [0030], wherein the disease is selected from the group consisting of nicotine addiction, obesity, alzheimer's disease, parkinson's disease, ulcerative colitis, multiple sclerosis, and combinations thereof.
In some embodiments, the present disclosure relates to a method of replacing a tobacco product, the method comprising delivering nicotine to a subject by the method of [0010] - [0027] or [0028] to replace nicotine derived from the tobacco product.
In some embodiments, the present disclosure relates to a method of reducing harm to a tobacco product, the method comprising delivering nicotine to a subject by the method of [0010] - [0027] or [0028] in place of nicotine derived from the tobacco product.
In some embodiments, the present disclosure relates to an apparatus configured to perform the methods of [0010] - [0032] or [0033 ].
In some embodiments, the present disclosure relates to a device for delivering nicotine to a subject, the device comprising a housing comprising:
a) an inlet and an outlet in communication with each other and adapted such that a gaseous carrier can be conveyed into the housing through the inlet, through the housing, and out of the housing through the outlet, the apparatus comprising, in order from the inlet to the outlet:
b) a first interior region in communication with the inlet, the first interior region including a source of a transport enhancing compound,
c) a second interior region in communication with the first interior region, the second interior region including a nicotine source, an
d) Optionally, a third interior region in communication with the second interior region and the outlet.
In some embodiments, the present disclosure relates to the apparatus of [0035], wherein a partial vacuum at the outlet is capable of pulling the gaseous carrier through the inlet, the first compartment, the second compartment, the third compartment (if present), and then through the outlet.
In some embodiments, the present disclosure relates to the device of [0035] or [0036], wherein the delivery enhancing compound source comprises a sorption element having the delivery enhancing compound sorbed thereon, and/or wherein the nicotine source comprises a sorption element having nicotine sorbed thereon.
In some embodiments, the present disclosure relates to [0037]Wherein the one or more adsorbent elements comprise glass, aluminum, polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polytetrafluoroethylene (PTFE or PTFE), or a combination thereof) Expanded polytetrafluoroethylene (ePTFE) (ePTFE, e.g., as specified in the United states)As described in U.S. Pat. No.4,830,643) andat least one of (1).
In some embodiments, the present disclosure relates to [0035] - [0037] or [0038] the apparatus further comprising a first reservoir in communication with the first interior region, the first reservoir comprising a transport enhancing compound.
In some embodiments, the present disclosure relates to [0035] - [0038] or [0039] the device further comprising a second reservoir in communication with the second interior region, the second reservoir comprising nicotine.
In some embodiments, the present disclosure relates to [0035] - [0039] or [0040] devices comprising a third inner region element.
In some embodiments, the present disclosure relates to the apparatus of [0041], wherein the third inner zone element comprises a scavenger.
In some embodiments, the present disclosure relates to the apparatus of [0042], wherein the scavenger comprises activated carbon.
In some embodiments, the present disclosure relates to the device of [0041], [0042], or [0043], wherein the third inner region element comprises a flavoring agent.
In some embodiments, the present disclosure relates to the devices of [0041] - [0043] or [0044], wherein the third interior region element comprises an agent.
In some embodiments, the present disclosure relates to the device of [0045], wherein the pharmaceutical agent comprises nicotine.
In some embodiments, the present disclosure relates to the devices of [0035] - [0045] or [0046], wherein the housing simulates a tobacco smoking article.
In some embodiments, the present disclosure relates to the device of [0047], wherein the tobacco smoking article is a cigarette.
In some embodiments, the present disclosure relates to [0035] - [0045] or [0046] devices in which the housing simulates a drug inhalation device.
In some embodiments, the present disclosure relates to the device of [0049], wherein the simulated medicinal inhalation device is selected from the group consisting of a metered dose inhaler, a pressurized metered dose inhaler, a dry powder inhaler, a nebulizer, and a liquid-based inhaler.
In some embodiments, the present disclosure relates to a method of increasing nicotine concentration in a gaseous carrier comprising the step of placing a gaseous carrier comprising a delivery enhancing compound in communication with a nicotine source comprising nicotine.
In some embodiments, the present disclosure relates to the method of [0051], the method further comprising the step of placing a gaseous carrier in communication with a source of a delivery enhancing compound comprising the delivery enhancing compound.
In some embodiments, the present disclosure relates to the method of [0052], wherein the step of placing a gaseous carrier in communication with a delivery enhancing compound source precedes the step of placing a gaseous carrier comprising a delivery enhancing compound in communication with a nicotine source.
In some embodiments, the present disclosure relates to the method of [0051], [0052], or [0053], wherein the source of delivery-enhancing compound comprises a plurality of compartments comprising two or more precursor compounds.
In some embodiments, the present disclosure relates to the method of [0054], wherein the delivery-enhancing compound comprises ammonium chloride, and the two or more precursor compounds comprise ammonia and hydrogen chloride.
In some embodiments, the present disclosure relates to [0051] - [0054] or [0055] methods wherein the concentration of nicotine in the gaseous carrier is increased relative to the concentration of nicotine that would be contained in the gaseous carrier in the absence of the delivery enhancing compound.
In some embodiments, the present disclosure relates to the methods of [0051] - [0055] or [0056], wherein the delivery-enhancing compound comprises an acid.
In some embodiments, the present disclosure relates to the method of [0057], wherein the acid is an organic acid.
In some embodiments, the present disclosure relates to the method of [0058], wherein the organic acid has a greater vapor pressure than nicotine at a given temperature.
In some embodiments, the present disclosure relates to the method of [0059], wherein the given temperature is 25, 30, 40, 45, 70, or 100 degrees celsius.
In some embodiments, the present disclosure relates to [0057] the method, wherein the acid is selected from the group consisting of 3-methyl-2-oxopentanoic acid, pyruvic acid, 2-oxopentanoic acid, 4-methyl-2-oxopentanoic acid, 3-methyl-2-oxobutanoic acid, 2-oxooctanoic acid, and combinations thereof.
In some embodiments, the present disclosure relates to [0051] - [0060] or [0061] methods wherein a delivery enhancing compound is reacted with nicotine to form a particle.
In some embodiments, the present disclosure relates to the method of [0062], wherein the mass median aerodynamic diameter of some or all of the particles is less than 6 microns.
In some embodiments, the present disclosure relates to the method of [0062], wherein the mass median aerodynamic diameter of some or all of the particles is less than 1 micron.
In some embodiments, the present disclosure relates to the method of [0062], wherein the mass median aerodynamic diameter of at least some of the particles is between 0.5 microns and 5 microns.
In some embodiments, the present disclosure relates to the methods of [0051] - [0064] or [0065], wherein the methods further comprise the step of increasing the temperature of the delivery enhancing compound, the delivery enhancing compound source, nicotine source, and/or gaseous carrier.
In some embodiments, the present disclosure relates to a method of [0066], wherein the temperature is increased to at least 30 degrees celsius.
In some embodiments, the present disclosure relates to a process of [0067], wherein the temperature is increased by multiple heating steps.
In some embodiments, the present disclosure relates to nicotine for cessation of use of a tobacco product, the nicotine delivered by the method of [0051] - [0067] or [0068], the method further comprising the step of providing a gaseous carrier comprising a delivery enhancing compound to a subject after the step of placing the gaseous carrier in communication with a nicotine source.
In some embodiments, the present disclosure relates to [0069] nicotine wherein the gaseous carrier comprises at least 20 micrograms of nicotine in a volume of gaseous carrier provided to the subject.
In some embodiments, the present disclosure relates to [0070] nicotine in which the volume of gaseous carrier delivered to the subject is provided as a single volume.
In some embodiments, the present disclosure relates to nicotine for reducing harm in a tobacco product, the nicotine delivered by the method of [0051] - [0067] or [0068], further comprising the step of providing a gaseous carrier comprising a delivery enhancing compound to a subject after the step of placing the gaseous carrier in communication with a nicotine source.
In some embodiments, the present disclosure relates to [0072] nicotine wherein the gaseous carrier comprises at least 20 micrograms of nicotine in a volume of gaseous carrier provided to the subject.
In some embodiments, the present disclosure relates to [0073] nicotine in which the volume of gaseous carrier delivered to the subject is provided as a single volume.
In some embodiments, the present disclosure relates to nicotine for use in a tobacco product replacement, the nicotine delivered by the method of [0051] - [0067] or [0068], further comprising the step of providing a gaseous carrier comprising a delivery enhancing compound to a subject after the step of placing the gaseous carrier in communication with a nicotine source.
In some embodiments, the present disclosure relates to [0075] nicotine, wherein the gaseous carrier comprises at least 20 micrograms of nicotine in a volume of gaseous carrier provided to the subject.
In some embodiments, the present disclosure relates to [0076] nicotine in which the volume of gaseous carrier delivered to the subject is provided as a single volume.
In some embodiments, the present disclosure relates to nicotine for use in treating a disorder selected from the group consisting of nicotine addiction, obesity, alzheimer's disease, parkinson's disease, ulcerative colitis, multiple sclerosis, and combinations thereof, the nicotine delivered by the method of [0051] - [0067] or [0068], the method further comprising the step of providing a gaseous carrier comprising a delivery enhancing compound to a subject after the step of placing the gaseous carrier in communication with a nicotine source.
In some embodiments, the present disclosure relates to a device configured to perform a) [0051] - [0067] or [0068] method; and/or b) nicotine configured to be capable of delivery [0069] - [0077] or [0078 ].
In some embodiments, the present disclosure relates to the use of nicotine for the manufacture of an agent delivered by the methods of [0051] - [0067] or [0068 ].
In some embodiments, the present disclosure relates to the use of nicotine for the manufacture of an agent delivered by the methods of [0051] - [0067] or [0068] for cessation of use of a tobacco product.
In some embodiments, the present disclosure relates to the use of nicotine for the manufacture of an agent for reducing harm to a tobacco product delivered by the methods of [0051] - [0067] or [0068 ].
In some embodiments, the present disclosure relates to the use of nicotine for the manufacture of an agent for replacement of a tobacco product delivered by the methods of [0051] - [0067] or [0068 ].
In some embodiments, the present disclosure relates to the use of nicotine delivered by the method of [0051] - [0067] or [0068] for the manufacture of a medicament for treating a disease selected from the group consisting of nicotine addiction, obesity, alzheimer's disease, parkinson's disease, ulcerative colitis, multiple sclerosis, and combinations thereof, the method further comprising the step of providing a gaseous carrier comprising a delivery enhancing compound to a subject after the step of placing the gaseous carrier in communication with a nicotine source.
In some embodiments, the present disclosure relates to a method for delivering a medicament to a user, the method comprising:
passing the gas stream over a first substance to produce a first gas stream comprising a vapor;
passing the first vapor-containing gas stream over the second material to produce particles in the gas stream; and
the gas stream containing the particles is delivered to a user.
In some embodiments, the present disclosure relates to the method of [0085], wherein the step of generating a first gas stream comprising a vapor comprises capturing a vapor of a first substance in the gas stream.
In some embodiments, the present disclosure relates to the method of [0085] or [0086], wherein the step of generating particles comprises contacting the vapor of the second material with a first stream of gas comprising vapor.
In some embodiments, the present disclosure relates to a method of [0085], [0086] or [0087], wherein the step of generating particles comprises an interaction between a first substance and a second substance.
In some embodiments, the present disclosure relates to the method of [0088], wherein the interaction comprises an acid-base reaction.
In some embodiments, the present disclosure relates to methods of [0085] - [0088] or [0089], wherein the first substance and the second substance are volatile substances.
In some embodiments, the present disclosure relates to the method of [0090], wherein the first substance is more volatile than the second substance at ambient temperature.
In some embodiments, the present disclosure relates to methods of [0085] - [0090] or [0091], wherein one of the first and/or second substances comprises nicotine.
In some embodiments, the present disclosure relates to the method of [0092], wherein the nicotine comprises free base nicotine.
In some embodiments, the present disclosure relates to methods of [0085] - [0092] or [0093], wherein the particles comprise nicotine-containing particles.
In some embodiments, the present disclosure relates to methods of [0085] - [0093] or [0094], wherein the gas stream delivered to the user comprises greater than 20 micrograms of particles comprising nicotine.
In some embodiments, the present disclosure relates to [0085] - [0094] or [0095] methods, wherein the particles comprise nicotine salt particles.
In some embodiments, the present disclosure relates to methods of [0085] - [0095] or [0096], wherein the first material comprises an acid.
In some embodiments, the present disclosure relates to the method of [0097], wherein the acid comprises pyruvic acid.
In some embodiments, the present disclosure relates to [0085] - [0097] or [0098] methods wherein the particles comprise nicotine pyruvate.
In some embodiments, the present disclosure relates to the method of [0097], wherein the acid comprises 3-methyl-2-oxobutanoic acid.
In some embodiments, the present disclosure relates to methods of [0085] - [0099] or [0100], wherein the particles comprise nicotine 3-methyl-2-oxobutyrate.
In some embodiments, the present disclosure relates to methods of [0085] - [0100] or [0101], wherein at least some of the particles are visible particles.
In some embodiments, the present disclosure relates to methods of [0085] - [0101] or [0102], wherein at least some of the particles are delivered to the lungs of the user.
In some embodiments, the present disclosure relates to methods of [0085] - [0102] or [0103], wherein the particles are less than 6 microns in diameter.
In some embodiments, the present disclosure relates to methods of [0085] - [0103] or [0104], wherein at least some of the particles have a diameter between 0.5 microns and 5 microns.
In some embodiments, the present disclosure relates to methods of [0010] - [0027] or [0028 ]; or [0051] - [0067] or [0068 ]; or [0080], wherein the agents listed in [0132], such as the compounds identified by numerals 1 to 66 in [0132], are used in place of or in addition to nicotine described in [0010] - [0027] or [0028], [0051] - [0067] or [0068], or [0080 ].
In some embodiments, the present disclosure relates to a device of [0035] - [0049] or [0050], wherein the device is adapted to deliver the agents listed in [0132], such as the compounds identified by numbers 1-66 in [0132], in place of or in addition to nicotine.
In some embodiments, the present disclosure relates to the use of an agent in [0132] (e.g., a compound identified by numerals 1-66 in [0132 ]), delivered by the methods of [0010] - [0027] or [0028], or [0051] - [0067] or [0068], for the treatment of a disease for which the agent is therapeutically beneficial.
The foregoing has outlined rather broadly the features and technical advantages of the present invention in order that the detailed description of the invention that follows may be better understood. Additional features and advantages of the invention will be described hereinafter which form the subject of the claims of the invention. It should be appreciated by those skilled in the art that the conception and specific embodiment disclosed may be readily utilized as a basis for modifying or designing other structures for carrying out the same purposes of the present invention. It should also be realized by those skilled in the art that such equivalent constructions do not depart from the spirit and scope of the invention as set forth in the appended claims. The novel features which are believed to be characteristic of the invention, both as to its organization and method of operation, together with further objects and advantages will be better understood from the following description when considered in connection with the accompanying figures. It is to be expressly understood, however, that each of the figures is provided for the purpose of illustration and description only and is not intended as a definition of the limits of the present invention.
Brief Description of Drawings
For a more complete understanding of the present invention, reference is now made to the following descriptions taken in conjunction with the accompanying drawing, in which:
FIG. 1 is a perspective view of the exterior of an exemplary delivery device simulating a cigarette;
FIG. 2 is a perspective view of the interior of an exemplary delivery device simulating a cigarette;
FIG. 3 is a perspective view of the exemplary delivery device from FIGS. 1 and 2 in use;
FIG. 4 is a cross-sectional view of subcomponents of an exemplary delivery device, illustrating the assembly stages and final configuration of the components used in the device;
figure 5 is a perspective view of various source elements for providing nicotine or other agents and delivery enhancing compounds;
FIG. 6 is a cross-sectional view of a subcomponent of an exemplary delivery device, showing a reusable portion and a disposable portion;
FIG. 7 is a cross-sectional view of a subcomponent of an exemplary reusable delivery device, showing a refill unit and device for supplying nicotine or other agents and delivery enhancing compounds;
FIG. 8 is a cross-sectional view of an exemplary reusable delivery device showing the device, and a perspective view of a refill unit for supplying nicotine or other medicament and delivering an enhancement compound; and
FIG. 9 is a cross-sectional view of an exemplary reusable delivery device showing the device and a refill unit; 9A shows only the refill unit, 9B shows the delivery device housed in the refill unit, and 9C shows the delivery device after compressing the dosing pump of the refill unit to re-supply nicotine or other medicament and delivery enhancing compound;
FIG. 10 illustrates a cross-sectional view of an exemplary delivery device having a heating member therein, shown in perspective as a separate member; and an exemplary delivery device having an external heating unit in which the delivery device is mounted for temperature control of the device and/or its constituent parts;
FIG. 11 is a cross-sectional view of an exemplary device of a metered dose inhaler simulating the medical delivery of medicaments typically used for inhalation;
FIG. 12 is a cross-sectional view of an exemplary device of a metered dose inhaler simulating the medical delivery of medicaments typically used for inhalation;
FIG. 13 is a cross-sectional view of an exemplary device of a metered dose inhaler simulating the medical delivery of medicaments typically used for inhalation;
FIG. 14 is a cross-sectional view of an exemplary device of a metered dose inhaler simulating the medical delivery of medicaments typically used for inhalation;
FIG. 15 is a cross-sectional view of an exemplary device of a metered dose inhaler simulating the medical delivery of medicaments typically used for inhalation;
Detailed Description
As used herein, "particle" may refer to a liquid droplet, a solid particulate, or a combination of both, such as a liquid droplet with a core provided by a solid particulate.
As used herein, a "therapeutically effective amount" may refer to the concentration or amount of nicotine or other agent that achieves a therapeutic effect in a subject, typically a human subject. The subject has improved in a disease state or medically defined condition. An improvement is any improvement or correction of the symptoms associated with the disease. The improvement is an observable or measurable improvement. Thus, one skilled in the art recognizes that treatment may improve the condition, but may not completely cure the disease. The therapeutic effect may in some embodiments include reducing or eliminating craving for nicotine in a subject suffering from nicotine addiction or experiencing withdrawal from nicotine use.
To aid in understanding the concepts of the present invention, embodiments will be described herein with reference to devices and methods for nicotine delivery. It will be appreciated by those skilled in the art that the agents listed at [0132] may be used in place of or in addition to nicotine according to the teachings herein.
The methods described herein relate to surprising findings regarding nicotine dosages obtained from nicotine delivery devices. The inventors have unexpectedly determined a method for increasing the dose of nicotine delivered to a subject by inhalation. The importance of this finding is to improve the ability of replacing nicotine delivery subjects to experience while smoking cigarettes and similar tobacco products. With an improved nicotine delivery profile, superior nicotine replacement therapy will be provided to subjects applying the methods described herein during attempts to stop smoking, reduce smoking harm, and/or replace (smoking). For the continuing global problem of health issues related to smoking, the methods described herein address the critical need for medical efforts to assist smokers in quitting smoking.
Without wishing to be bound by theory, it is believed that passing the vapour of the volatile first substance (i.e. the delivery enhancing compound) over the nicotine source results in the formation of liquid or solid particles which then allow more nicotine to evaporate and combine with the first substance, thereby creating further particles. The amount of particles formed (mass delivered) at a given temperature will be greater than the amount of particles formed when the vapour of nicotine passes over the second volatile substance. Similarly, the amount of particles formed at a given temperature will be greater than the amount of particles formed when vapors of two substances are combined in a parallel mixing apparatus (as disclosed in the prior art), since the amount of particles formed is limited by the volatility of the less volatile substance, and since the active substance is diluted by mixing with a volume of gas containing the other substance. Moreover, allowing one substance to pass continuously over a second substance may allow the two substances to be combined more efficiently than parallel mixing as disclosed in the prior art. Another possibility is that the interaction between the first and second substances is a heat generating process. In other words, energy is released in the form of heat due to exothermic interactions. Without wishing to be bound by theory, it is believed that the released heat may promote vaporization of nicotine.
In some embodiments, the method comprises the step of communicating a gaseous carrier with a nicotine source. The gaseous carrier in these embodiments comprises a delivery enhancing compound that is capable of increasing the amount of nicotine in the gaseous carrier relative to the amount of nicotine that would be present in a gaseous carrier without the delivery enhancing compound. In some embodiments, the delivery enhancing compound is capable of reacting with a nicotine base or other agent to form a salt. In particular embodiments, the delivery enhancing compound is capable of reacting with nicotine base to form salt particles. In a preferred embodiment, the mass median aerodynamic diameter of the particles is less than 6 microns, more preferably less than 1 micron. (for determination of mass median aerodynamic diameter, see KatzIM, Schroeter JD, Martonen TB, Factors influencing the deposition of Aerosol insulin, Diabetes technology & Therapeutics, vol.3(3),2001, pp387-397, incorporated by reference in the present teachings).
The methods disclosed herein may be adapted for use with many other agents having biophysical and/or chemical properties similar to nicotine. The following compounds are aliphatic or aromatic, saturated or unsaturated nitrogen-containing bases (base compounds containing nitrogen) in which the nitrogen atom is present in a heterocyclic ring or a non-cyclic chain (substitution). In addition, the compounds are selected based on the melting point (below 150 ℃) or boiling point (below 300 ℃) that is expected to contribute to volatilization:
medicament-other than nicotine
1, 7-hydroxy hattaceous lignines
2. Arenarine
3. Atropine
4. Bupropion derivatives
5. Aminophylline (D-norpseudoephedrine)
6. Chlorpheniramine
7. Dibucaine
8. Dimemorfan
9. Dimethyl tryptamine
10. Diphenhydramine
11. Ephedrine hydrochloride
12. Hordenine
13. Scopolamine
14. Isoarecoline
15. Levorphanol
16. Lobeline
17. Dendrantherine
18. Cap column wood alkali
19. Muscarine
20. Procaine
21. Pseudoephedrine
22. Mepiramine
23. Raclepride
24. Ritodrine
25. Scopolamine
26. Cytisine (sparteine) 27 ticlopidine
Tobacco smoke composition:
28.1, 2,3, 4-tetrahydroisoquinoline
29. Anabacin
30. Ananatane
31. Cotinine
32. Mioxinamine
33．Nicotrine
34. Jiangkening (Norcotinine)
35. Nicotine reduction
Anti-asthma medicine
36. Ocinalin
37. Propranolol (Propranolol)
38. Terbutaline
Medicine for treating pharyngalgia
39. Nicorandil
40. Oxprenolol
41. Verapamil
Antiarrhythmic agents
42. Lidocaine
Nicotine receptor agents
A. Nicotine agonists
43. Sea-buckthorn frog hormone
44.5- (2R) -azetidinylmethoxy) -2-chloropyridine (ABT-594)
45. (S) -3-methyl-5- (1-methyl-2-pyrrolidinyl) isoxazole (ABT418)
(±) -2- (3-pyridyl) -1-azabicyclo [2.2.2] octane (RJR-2429)
B. Nicotine antagonists
47．Methyllycacotinine
48. Mecamylamine
C. Acetylcholinesterase inhibitors
49. Galanthamine
50. Pyridostigmine
51. Physostigmine
52. Tacrine (D)
MAO inhibitors
53.5-methoxy-N, N-dimethyltryptamine
54.5-methoxy-alpha-methyltryptamine
55. Alpha-methyl tryptamine
56. Isopropylchlorohydrazine
57. Isopropylisoniazid
58. Isoazodicarbonamide
59. Lizolidinide
60. Moclobemide
61. N, N-dimethyltryptamine
62. Phenylethydrazine
63. Phenylethylamine
64. Toloxanone
65. Tranylcypromine
66. Tryptamine
Gas carrier and source therefor
The gaseous carrier can be any gas capable of containing the nicotine base and the delivery enhancing compound. One skilled in the art will be readily able to select an appropriate gaseous carrier based on the intended use, the form of nicotine, and the particular delivery enhancing compound. In a preferred embodiment, the gaseous carrier is substantially inert with respect to the form of nicotine and/or delivery enhancing compound delivered, at least over the period of time expected for delivery to the subject. In some embodiments, the gaseous carrier is ambient air. In other embodiments, the gaseous carrier is a substantially pure gas, such as carbon dioxide or nitrogen, or a mixture of such gases. In such embodiments, the gaseous carrier is supplied from a container designed to hold and deliver the gaseous carrier in a manner that renders the methods described herein effective. For example, in embodiments using metered dose inhaler devices, the gaseous carrier may comprise a hydrofluorocarbon including a Hydrofluoroalkane (HFA) as the propellant. In some of these embodiments, the HFA is one or more of HFA134a and HFA 227.
Delivery enhancing compounds
Delivery enhancing compounds are those compounds that are capable of increasing the total concentration of nicotine in the gaseous carrier when the gaseous carrier is placed in communication with a nicotine source. The nicotine has a vapor pressure of 0.04 mm hg at 25 ℃. If ambient temperature is used, a delivery enhancing compound having a greater vapor pressure than nicotine at a given temperature is preferred. Non-limiting examples include inorganic acids such as hydrochloric acid, hydrobromic acid, or sulfuric acid; and organic acids including saturated and unsaturated fatty acids, saturated and unsaturated alicyclic acids, aromatic acids (including heterocyclic aromatic acids), polycarboxylic acids, hydroxyl, alkoxy, keto, and oxo acids, thio acids, amino acids, and each of the foregoing may optionally be replaced with one or more heterocyclic atoms, including but not limited to halogen. In some embodiments, the transport enhancing compound is a carboxylic acid. In some of these embodiments, the carboxylic acid is in the class referred to as a "2-oxo acid". In some of these embodiments, the carboxylic acid is in an alpha-keto acid class known as "2-keto acids". In some of these embodiments, the acid is selected from the group consisting of 3-methyl-2-oxopentanoic acid, pyruvic acid, 2-oxopentanoic acid, 4-methyl-2-oxopentanoic acid, 3-methyl-2-oxobutanoic acid, 2-oxooctanoic acid, and combinations thereof. In some embodiments, the transport enhancing compound forms solid particles, such as salt particles. In other embodiments, the delivery enhancing compound forms an aerosol of droplets.
Alternatively, the delivery enhancing compound forms a particulate aerosol, the particles of which can, for example, adsorb or absorb nicotine base. In a particular embodiment, the particulate aerosol comprises ammonium chloride salt particles. In embodiments including nicotine particulate forms or nicotine sorption/absorption onto particles, the size of the formed particles is preferably less than 6 microns, more preferably less than 5 microns or less than 1 micron.
Sources of nicotine (or other agents)
Examples of nicotine sources use such compounds: the compound includes any chemical capable of providing nicotine in a volatile form such as nicotine base or nicotine salt (e.g., nicotine-HC 1, -bitartrate). Although more than one form of nicotine may be used, free base nicotine is preferred. The nicotine source may comprise other compounds for stabilizing nicotine, such as antioxidants (BHA, BHT, ascorbate). In some embodiments, nicotine is adsorbed on the element to provide a nicotine source. The adsorbed nicotine remains on the surface of the relatively inert material. Non-limiting examples of adsorbent element materials include glass, stainless steel, aluminum, PET, PBT, PTEE, ePTFE, andadsorption is a process that occurs when a gaseous, liquid or solid solute accumulates on the surface of a solid, or more rarely a liquid (adsorbent), forming a molecular or atomic film (adsorbate). Physical adsorption is generally the molecular and constitutive adsorption of adsorbatesVan der waals and electrostatic forces between atoms of the agent surface. Thus, adsorbents are characterized by surface properties, such as surface area and polarity.
A large specific surface area is preferred for providing a large adsorption capacity, but the creation of a large internal surface area in a limited volume inevitably results in a large number of small-sized pores between the adsorption surfaces. The size of the micropores determines the accessibility of the adsorbate molecules to the internal adsorption surface, so the pore size distribution of the micropores is another important characteristic characterizing the adsorbability of the adsorbent. The surface polarity corresponds to the affinity to polar substances such as water or alcohol. Polar adsorbents are therefore referred to as "hydrophilic" and aluminosilicates, such as zeolites, porous alumina, silica gel or silica-alumina are examples of this type of adsorbent. Non-polar adsorbents, on the other hand, are typically "hydrophobic". Carbonaceous adsorbents, polymeric adsorbents and silicalite are typical non-polar adsorbents. These adsorbents have a better affinity for oil or hydrocarbons than water. In some embodiments, when the adsorbent is in liquid form, the adsorption surface is also adsorbed by capillary action absorption (wick). Absorption occurs when the intermolecular adhesion between the liquid and the adsorption surface is stronger than the intermolecular cohesion inside the liquid. This action causes a concave meniscus to form where the substance contacts the vertical adsorption surface. The adsorption surface may be selected or designed to absorb hydrophilic or hydrophobic liquids by capillary action.
In alternative embodiments, the nicotine source element may comprise an absorbent (porous or non-porous) material. Non-limiting examples of nicotine source element materials include Polyethylene (PE) and polypropylene (PP).
In some embodiments, the nicotine source may be a nicotine reservoir, or may be in communication with a nicotine reservoir. In some embodiments, the reservoir contains a volume of nicotine in liquid form, and the liquid reservoir is in communication with the adsorbing or absorbing nicotine source element. In other embodiments, the nicotine reservoir is, or forms part of, a nicotine source element. Non-limiting examples of such combined sources and reservoirs may be materials (e.g., PE or PP) impregnated with nicotine solution. In certain embodiments, the reservoir provides sufficient nicotine solution to enable the delivery device to provide a therapeutically effective dose of nicotine over a desired time frame. Non-limiting examples may be such devices: the device is capable of delivering 0-100 micrograms of nicotine per 35 cubic centimeter volume of gaseous carrier "puff" for a desired number of puffs (e.g., 200) per day over a desired number of days (e.g., 1-7 days). In certain embodiments, the amount of nicotine delivered is between 10 and 110 micrograms, 20 and 100 micrograms, 50 and 100 micrograms, or 40 and 60 micrograms of nicotine per 35 cubic centimeter volume "puff.
Other agents listed in [0132] may be used in place of or in addition to nicotine to form a source of the agent using the same principles as applied to nicotine base as the above example categories.
Delivery enhancing compound source
In some embodiments of the method, a gas carrier is provided that is pre-combined with a delivery enhancing compound. Other embodiments of the methods described herein include the step of loading the gaseous carrier with a delivery enhancing compound prior to or simultaneously with passing the gaseous carrier over the nicotine source. In embodiments that include the step of loading the gaseous carrier with a delivery enhancing compound, the delivery enhancing compound is typically provided in the form of a source of the delivery enhancing compound. In these embodiments, the gaseous carrier is typically in direct communication with the delivery enhancing compound source such that the delivery enhancing compound may enter the gaseous carrier from the delivery enhancing compound source. In some embodiments, the transport enhancing compound source comprises a transport enhancing compound source element comprising a material that adsorbs or absorbs the transport enhancing compound. The transport enhancing compound source element material will generally be inert with respect to the transport enhancing compound. In some embodiments, the transport enhancing compound is an acid as described above. Non-limiting examples of adsorbent element materials for use in such embodiments include glass, stainless steel, aluminum, PET,PBT, PTFE, ePTFE andnon-limiting examples of adsorbent element materials for such embodiments include PE and PP.
The delivery enhancing compound source may be, or may be in communication with, a delivery enhancing compound reservoir in some embodiments. In some embodiments, the reservoir contains a volume of the delivery enhancing compound in liquid form, and the liquid reservoir is in communication with an adsorption or absorption delivery enhancing compound source element. In other embodiments, the nicotine reservoir is, or forms part of, the delivery enhancing compound source element. A non-limiting example of such a combined source and reservoir may be a material (e.g., PE or PP) impregnated with a solution of the delivery enhancing compound. In certain embodiments, the reservoir provides a sufficient solution of the delivery enhancing compound to enable the delivery device to provide a therapeutically effective dose of nicotine over a desired time period. Non-limiting examples may be such devices: the device is capable of delivering 0-100 micrograms of nicotine per 35 cubic centimeter volume of the gaseous carrier "puff" for a desired number of puffs (e.g., 200) per day over a desired number of days (e.g., 1-7 days). In certain embodiments, the amount of nicotine delivered is between 10 and 110 micrograms, 20 and 100 micrograms, 50 and 100 micrograms, or 40 and 60 micrograms of nicotine per 35 cubic centimeter volume "puff. Embodiments delivering 0 micrograms of nicotine are generally intended to be the end point of a gradual nicotine stop program.
Temperature of
In some embodiments of the method, the method involves the step of increasing the temperature of one or more of the gaseous carrier, nicotine source and/or enhancer source (when present). Such a temperature control step is typically used to adjust or further enhance the nicotine delivery. In some embodiments, the temperature increase is used only when the level of nicotine delivered would otherwise be expected to fall below a desired minimum value in general. In some embodiments, it may be more than 20 micrograms of nicotine, preferably more than 30 micrograms of nicotine, and more preferably more than 40 micrograms of nicotine per 35cc volume burst. For example, a common target delivery concentration is 40-50 micrograms of nicotine per 35 cubic centimeter volume "puff as measured by techniques known in the nicotine delivery art. See The FTC Cigarette Test Method for Determining Tar, Nicotine and carbon monoxide production in U.S. cigarettes, Report of The national cancer institute Special Committee, Report of The NCI Ad Hoc Committee, Smokeing and Tobacco Control Monograph #7, R.Shoplad (Ed.). Darby Phd, Diane publishing Co., 1996. In some embodiments, a lower temperature is generally used first, wherein the temperature is increased over time to maintain a desired nicotine delivery concentration from the nicotine source. In other embodiments, a constant temperature is maintained during use. In some embodiments, the temperature is raised to a maximum of 100 degrees Celsius, a maximum of 70 degrees Celsius, or the temperature is raised to 40 ± 5 degrees Celsius. For example, pyruvic acid as a delivery enhancing compound can be heated to 40 degrees celsius to facilitate sustained nicotine delivery over multiple bursts at a desired nicotine concentration range (e.g., 20-50 micrograms per burst). In some embodiments, temperature control may be achieved by a temperature control element. Such elements may be any known mechanism capable of achieving a desired target temperature for the gaseous carrier, nicotine and/or delivery enhancing compound. Specific examples of temperature control elements are shown below in the exemplary devices provided.
Device for measuring the position of a moving object
The methods described herein are typically performed using a specially modified delivery device configured to perform the methods described herein during operation of the device. Those skilled in the art, using the foregoing guidance, will be able to design and produce a variety of delivery devices. The inventors provide herein a number of delivery device configurations to further illustrate the methods herein and their practical application by way of specific examples. The gaseous carrier delivered to the user of the device can include a therapeutically effective dose of nicotine for stopping smoking, reducing smoking harm, and/or replacing smoking. A preferred embodiment of the delivery device is a pulmonary delivery system. The pulmonary delivery system has the ability to deliver consistent doses with appropriate particle size and low particle size variability deep into the lungs. Among the various non-invasive drug delivery technologies available, including nasal, transdermal, buccal and needle-free injection, pulmonary delivery offers the unique possibility of accurate dose titration, rapid absorption, and high bioavailability for providing novel therapies and improving delivery of existing compounds.
Modes for carrying out the invention
Screening of suitable assay designs for aerosol formation of nicotine
Several experimental designs were tested as described below to evaluate the generation of aerosol particles by allowing the acid vapor to immediately react with the base vapor.
Experiment # 1: a mixture of vapors was generated using hydrogen chloride and ammonia in a "Y" tube which was then passed over nicotine free base.
The purpose is as follows:
the objective was to evaluate the effectiveness of a chemically robust acid/base system to produce an aerosol with sufficient characteristics to aerosolize nicotine free base.
Experiment design:
the experimental design included two identical glass test tubes connected by a "Y" tube (tube a containing 5 ml hydrochloric acid (HCI) and tube B containing 5 ml ammonia (NH)3) Designed to allow the vapors from the two test tubes to blend immediately in the "Y" tube and then pass over the nicotine by the CPVA (40cc of air 2 seconds duration (3 second interval) 100 times (100 bursts)) using a controlled burst volume device. The blend of HC1 and NH3 vapor produced a white, dense and visible cloud.
As a result:
TABLE 1 amount of nicotine obtained after passing HC1 and NH3 over nicotine3
| Sample number | Nicotine (μ g)/sample | Nicotine (μ g)/hair spray |
| Only HC1 and NH3 | 0 | 0 |
| Nicotine, HCL and NH3 | 3796.265 | 37.963 |
| Only nicotine | 1291.924 | 12.919 |
Discussion:
the use of hydrochloric acid, ammonia and nicotine only resulted in significant nicotine delivery vs. nicotine as shown in table 1. However, due to the chemical reactivity and corrosive nature of the acids and bases selected for this experiment, candidate components that are more amenable to human use, such as non-corrosive acid candidates, including volatile and low-volatile organic acids (e.g., fatty acids), were evaluated.
Experiment # 2: screening for suitable candidate acids for use in developing an "acid over nicotine aerosol delivery arrangement
The purpose is as follows:
the purpose of this experiment was to evaluate a series of candidate acids for their ability to be blended with nicotine free base to form an aerosol suitable for pulmonary delivery. Good candidates were selected to produce aerosols containing the maximum nicotine free base mass recorded in μ g/puff for further evaluation. Volatile carboxylic acids are chosen as the organic acids of choice because of their relatively high volatility and because of the fact that they are components of cigarettes and other commercial products for human consumption, such as food additives, flavors, and sweeteners.
Experiment design:
for this experiment, chamber B contained 200 μ L nicotine free base and chamber A contained 200 μ L pyruvic acid free base and pyruvic acid volumes added by Eppendorf pipette tubesOf beltsThe plug seals the fill port. Then use byFixedThe tubes connect the chambers sequentially. Then theThe tube connects the outlet of chamber B to a filter holder containing a Cambridge filter (44 mm diameter) for collecting the reaction product. See the Smokem machine parameters for the collection of particulate matter and gases from low-flame cigarettes according to Pillsbury HC of contract # CPSC-S-92-5472I i, 3, 14.1993 for Consumer Product Safety Commission (American Consumer Safety Commission) (Smoking machine parameters for collecting total particulate matter and gases from low-flame cigarettes). Opposite sides of the filter housing passThe tube was connected to a 100cc syringe. The syringe is secured to an automated system that supplements a "controlled burst volume device" (CPVA). For a detailed approach, see Levin ED, Rose JE and Behm F, Controlling puffs with distinguishing strokes topographies (Controlling the burst volume without disrupting the smoking morphology).Behavior Research methods Instruments & Computers(means for studying behavior&Computer), 21: 383-. The total time from filling the first chamber to initiating the first sampling interval to prepare for setting is about 5 minutes. The CPVA was programmed to draw a 35cc volume of air for a total of 20 bursts (20 bursts) for a2 second duration (30 second intervals). Half the height of the filled chamber was immersed in a water bath and the chamber was allowed to equilibrate at 70 ℃ for 10 minutes before sampling.
Prior to evaluation of the candidate acid, a control experiment was conducted in which only nicotine free base remained in the chamber and nicotine vapour was drawn through the Cambridge filter 20 times (20 bursts of 35cc air lasting 2 seconds and with 30 second burst intervals). All samples were quantified by Gas Chromatography (GC) using NPD (nitrogen phosphorus detector).
As a result:
the following table shows the results of the acid screening and control experiments. The results are recorded as the amount of nicotine measured in each burst.
TABLE 2 acid-base nicotine delivery at-70 ℃
| Sample number | Nicotine (μ g)/hair spray |
| Nicotine control | 46.12 |
| 4-methyl-2-oxopentanoic acid via nicotine | 281.39 |
| Isovaleric acid is processed through nicotine | 25.00 |
| Nicotinic acid-caprylic acid (caprylic acid) | 29.44 |
| 2-oxooctanoic acid via nicotine | 90.48 |
| Glycolic acid via nicotine | 35.32 |
| Hexanoic acid is passed through nicotine | 14.97 |
| Acetylpropionic acid via nicotine | 39.93 |
| 2-oxopentanoic acid via nicotine | 297.75 |
| Propionic acid via nicotine | 09.68 |
| Nicotine-containing pyroligneous acid | 32.54 |
| 2-mercaptopropionic acid via nicotine | 19.29 |
| 4-pentenoic acid via nicotine | 24.92 |
| 2-nonenoic acid via nicotine | 39.84 |
| Geranic acid via nicotine | 40.54 |
| 3-methyl-2-oxopentanoic acid via nicotine | 363.89 |
| 2-methyl-4-pentenoic acid via nicotine | 26.03 |
| 3-cyclohexane-1-carboxylic acid via nicotine | 48.24 |
| Glyoxylic acid through nicotine | 35.17 |
| Lactic acid via nicotine | 39.88 |
| Oleic acid via nicotine | 48.45 |
| Trimethylpropyruvic acid via nicotine | 26.69 |
| Pyruvic acid is nicotine | 362.38 |
| 3-methyl-2-oxobutanoic acid via nicotine | 213.99 |
Discussion:
the experimental results show that at about 70 ℃, the maximum amount of nicotine was delivered by 3-methyl-2-oxopentanoic acid of nicotine (363.89 μ g/burst), followed by pyruvic acid (362.28 μ g/burst), 2-oxopentanoic acid (297.75 μ g/burst), 4-methyl-2-oxopentanoic acid (281.39 μ g/burst), 3-methyl-2-oxobutanoic acid (213.99 μ g/burst) and 2-oxopentanoic acid (90.48 μ g/burst). These candidates were evaluated under ambient conditions as described in the experiments below. 3-methyl-2-oxopentanoic acid, pyruvic acid, 2-oxopentanoic acid, 4-methyl-2-oxopentanoic acid, 3-methyl-2-oxobutanoic acid and 2-oxooctanoic acid represent carboxylic acids referred to as "2-keto acids" or "alpha-keto acids".
Experiment # 3: evaluation of major acid candidates at ambient temperature
The purpose is as follows:
the purpose of this experiment was to assess which of the major candidate acids selected from the above experiments would deliver the greatest amount of nicotine under ambient conditions.
Experiment design:
the current experiment was performed as described in the previous experiment, except that the glass chamber was not immersed in a heated water bath, but was sampled at ambient temperature. Using the selected candidate acids: 3-methyl-2-oxopentanoic acid, pyruvic acid, 2-oxopentanoic acid, 4-methyl-2-oxopentanoic acid, 3-methyl-2-oxobutanoic acid and 2-oxooctanoic acid, to perform a single experiment. For each experiment, a different acid was placed in chamber a and nicotine free base was placed in chamber B as in the previous experiment. The nicotine free base control experiment was also performed as in the previous experiment.
As a result:
the following table shows the results of the evaluation of the primary candidate acids sampled at ambient conditions. The results are recorded as the amount of nicotine measured in each burst.
TABLE 3 nicotine delivery via base using selected acids (ambient temperature)
| Sample number | Nicotine (μ g)/hair spray |
| Nicotine base control | 8.76 |
| 3-methyl-2-oxopentanoic acid via nicotine | 12.93 |
| Pyruvic acid is nicotine | 44.68 |
| 2-oxopentanoic acid via nicotine | 18.96 |
| 4-methyl-2-oxopentanoic acid via nicotine | 13.63 |
| 2-oxooctanoic acid via nicotine | 04.46 |
| 3-methyl-2-oxobutanoic acid via nicotine | 18.65 |
Discussion:
data from ambient temperature shows that pyruvic acid is a good candidate acid for forming nicotine aerosols at 44.68 μ g/burst delivery.
Experiment # 4: evaluation of the Primary acid candidates from previous 70 ℃ and ambient temperature experiments (experiments 2 and 3, respectively) using a Prior Art design for Aerosol Generation
The purpose is as follows:
the purpose of this experiment was to compare prior art configurations with the sequential orientation of acid and base to determine which would result in higher nicotine delivery. Two major candidate acids that yielded similar nicotine delivery at-70 ℃ and one candidate acid that delivered the maximum amount of nicotine at ambient temperature (from experiments #2-3) were tested at-70 ℃ and ambient conditions, respectively.
Experiment design:
in this experiment, two identical rectangular glass chambers identical to those used in experiment #2 were used. Chamber a contained 200 μ L of the primary acid and chamber B contained 200 μ L of nicotine free base. The two chambers were connected by a "Y" glass connector which was then attached to the same PTFE housing containing the Cambridge filter as previously described. After a 35cc volume of air was drawn for 20 bursts (20 bursts) for a2 second duration (30 second intervals) using a controlled burst volume device (CPVA), the vapor from the tube was allowed to blend immediately in the "Y" shaped glass connector. For the temperature rise experiments, the acid and nicotine chambers were immersed at half height in a water bath with a water temperature of about 70 ℃. The chamber was allowed to equilibrate for 10 minutes before sampling. For ambient room temperature experiments, both chambers were placed on the laboratory bench. The collected samples were analyzed for nicotine using gas chromatography with a nitrogen phosphorus detector.
As a result:
the following table shows the evaluation results of the major candidate acids sampled at elevated temperature (approximately at 70 ℃) and ambient conditions and using the prior art system; also recorded for comparison are the results of using the sequential acid-via-base design (from experiments # 2-3). The results are reported as the mass of nicotine measured in each burst.
TABLE 4 Nicotine delivery Using "Y" shaped design (Prior Art)
Discussion:
based on current data, nicotine delivery in prior art designs is significantly lower than sequential designs, and thus sequential designs are superior methods of delivering nicotine aerosols.
Experiment # 5: sequential arrangement of acid and base reservoirs provides for the effectiveness of acid in passing through a base environment in developing an aerosol plume having sufficient nicotine concentration
The purpose is as follows:
the purpose of this experiment was to determine the effect of the sequential arrangement of the acid and base reservoirs that allowed the acid vapour to rise into the nicotine free base chamber and pass over the nicotine to produce a plume cloud with sufficient amounts of nicotine free base. Pyruvic acid was selected for use in these experiments.
Experiment design:
this experimental design was the same as in experiment # 2. This experiment was divided into two parts, a and B. The first part a included an assessment of the use of 200 μ L each of nicotine free base and pyruvic acid in separate chambers collected on 3 samples (20 bursts per sample). The second part of the experiment (part B) included a comparison of the above-described systems tested at ambient temperature and 40 ℃ conditions to evaluate the effect of moderate heat on aerosol formation and nicotine delivery.
Results (part a):
the table below shows the results of pyruvic acid tested with nicotine free base under ambient conditions (part a). The results are reported as the total mass of nicotine and the amount of nicotine measured in each burst.
TABLE 5 acid-base nicotine delivery
Discussion (part a):
these results indicate a total decrease in nicotine production from the first sample to the last sample of about 32%.
Results (part B):
the table below shows the results of the nicotine free base assay of pyruvic acid at 40 ℃. The results are reported as the total mass of nicotine and the amount of nicotine measured in each burst.
TABLE 6 acid-base nicotine delivery at 40 deg.C
| Sample number | Total nicotine (μ g)/sample | Nicotine (μ g)/hair spray |
| Pyruvic acid is processed by nicotine free base-1 | 2341.09 | 117.05 |
| Pyruvic acid is processed by nicotine free base-2 | 2141.20 | 107.06 |
| Pyruvic acid is processed by nicotine free base-3 | 2137.92 | 106.90 |
| Mean (CV) | 110.337(5.3%) |
Discussion (part B):
a 3 to 4 fold increase in the nicotine/puff mass under heated conditions was observed when compared to ambient conditions. In addition, the coefficient of variation improves significantly to about 5%, indicating good control over the transport dynamics. Moreover, nicotine delivery across the burst is not significantly reduced.
Experiment # 6: studies of nicotine aerosol formation and delivery by use of sequential arrangement (realization) using pyruvic acid in a miniaturized/cigarette-sized device (8 cm long, 8 mm inner diameter)
Materials and methods
Matrix materials used:
a sample of air freshener core (wick) made of a mixture of PE and PP fibers (X-40495 fibers sold by Porex Technologies) was used as a matrix on which pyruvic acid was loaded, and a sample made of a polymer film having a nonwoven PET film support (w.l&SMPL-MMT314 sold by Associates limited) of expanded PTFE medical filmsTMA medical film (pore size of 0.2 microns) was used as a matrix to load the nicotine free base. The film is rolled into a straw configuration to provide a straw having an ID dimension of about 1.5 mmOuter wall and inner polyester wall and cut into pieces 4cm long.
Experiment design:
one piece of air freshener wick contained 180 μ L pyruvic acid (pyruvate source element), three pieces of 4cm long medical film rolled to an inside diameter of 1.5 mm, the inside wall (polyester side) of which was coated with 90 μ L (3 × 30 μ L) nicotine free base, the pyruvic acid-loaded air freshener was inserted into a clean, 8 mm inside diameter and 9 cm long piece of air freshenerThe distal end of the tube, and a three-piece medical film with nicotine free base is tightly inserted into the tube with three holesIn the gasket (nicotine source element). Inserting a nicotine source element into a 9 cm long by 8 mm Inner Diameter (ID) container having a pyruvate source elementIn the tube, a 2cm separation was left between the pyruvate source element and the nicotine source element. The source was arranged so that a measured volume of air (35cc, 2 second duration and 30 second burst interval, 20 times) drawn by an automated syringe pump first passed through the pyruvic acid source, and thenAnd then passed through the nicotine source element to form an aerosol. The proximal end of the device was attached to a controlled burst volume device (CPVA) containing a Cambridge filter (to collect aerosol product). For the elevated temperature experiment (40 ℃), a 9 cm long device (with both pyruvic acid and nicotine source elements) was completely immersed in the water bath and equilibrated for 10 minutes before sampling. The environmental condition experiment was performed by placing the chamber on a laboratory bench.
As a result:
the samples were analyzed for nicotine content and recorded in tables 7 and 8.
TABLE 7 Nicotine delivery in miniaturized device experiments at 40 deg.C
TABLE 8 Nicotine delivery in miniaturized device experiments at ambient temperature
Discussion:
the data show that when both acid and base were loaded onto the substrate (in this case, the acid was loaded on the air freshener wick and the nicotine free base was loaded on the medical film), a nicotine delivery comparable to the previous experimental set-up used in experiment 5 was obtained. In addition, the-40 ℃ condition shows significantly higher amounts of nicotine delivery (approximately three times) when compared to ambient conditions.
Exemplary devices suitable for use with the methods herein
The delivery device of some embodiments comprises a housing that simulates a tobacco smoking article. The housing may simulate the size, shape and/or configuration of any article for smoking a tobacco article. Non-limiting examples of smoking articles according to the present invention include cigarettes, cigars, cigarillos and pipes.
The delivery device of some embodiments includes a housing that simulates a medicinal inhalation device. The housing may simulate the size, shape and/or configuration of any medical device for inhalation. Non-limiting examples of medicinal inhalation devices according to the present invention include metered dose inhalers, pressurized metered dose inhalers, dry powder inhalers, nebulizers, and liquid-based inhalers.
Exemplary device 1
Attention is directed to fig. 1, which shows a device for forming and delivering a nicotine aerosol to a user in accordance with one example of the invention. In particular, a nicotine inhaler 10 having the size, shape and appearance of a cigarette is shown. The nicotine inhaler 10 includes a housing 12, the housing 12 having an elongated cylindrical shape and being hollow. To allow gas to flow through the inhaler 10, the housing 12 includes a gas inlet 14 and a gas outlet 16 on the opposite end.
The portion of the housing 12 between the gas inlet 14 and the gas outlet 16 is divided into three compartments capable of holding a first substance, a second substance and/or a third substance. The first, second or third substance may comprise a vapour forming medicament, such as nicotine.
As shown in fig. 2, the nicotine inhaler 10 includes a first compartment 18, a second compartment 20, and a third compartment 22. Nicotine, preferably in the form of the free base, may be placed in any of the three compartments. For example, nicotine may be placed in the second compartment 20. A suitable delivery enhancing compound, such as an acid, is placed in the first compartment 18. Any suitable acid may be used. For example, pyruvic acid can be placed in the first compartment 18. Pyruvic acid is a volatile substance with substantial vapor pressure at room temperature. Thus, any free space within the first compartment 18 will be somewhat filled with pyruvic acid vapour, i.e. gaseous pyruvic acid. Although the vapour pressure of nicotine is less than that of pyruvic acid, nicotine is also a volatile substance. Likewise, any free space within the second compartment 20 will be somewhat filled with nicotine vapour.
It will be appreciated that pyruvic acid is retained within the first compartment 18 on a delivery enhancing compound source element (not shown) and nicotine is retained within the second compartment 20 on a nicotine source element (not shown). Additionally, a third substance may be retained on a third source element (not shown) within the third compartment 22. Furthermore, one or more of the source elements may be integral with the compartments 18, 20 and 22, respectively, or part of the compartments 18, 20 and 22, respectively.
The transport enhancing compound source element may be any size and shape that allows the gas stream to contact the vapor of the acid and pass through the first compartment 18. The nicotine source element may be of any size and shape that allows the gas stream to contact the vapour of nicotine and pass through the second compartment 20. The third source element may be any size and shape that allows the gas flow to contact the third substance and pass through the third compartment 22.
The transport enhancing compound source element may be constructed of any suitable material capable of retaining acid on its surface while allowing acid vapor to permeate into the surrounding area. The nicotine source element may be constructed of any suitable material capable of retaining nicotine on its surface while allowing nicotine vapors to permeate into the surrounding area. The third source element may be constructed of any suitable material capable of retaining the third substance. In particular embodiments, the suitable material retains the third substance on its surface while allowing vapor of the third substance to permeate into the surrounding area.
Preferably, a suitable source element material is inert with respect to any substance to be arranged on its surface. In addition, suitable materials are preferably adsorptive with respect to any substance to be disposed on the surface thereof, such that the substance adsorbs onto the surface of the material. While materials having both absorption and adsorption properties may be employed, materials capable of retaining the delivery enhancing compound, nicotine and/or third substance by adsorption are preferred. Non-limiting examples include glass, aluminum, PET, PBT, PTFE, ePTFE, and
the adsorbent material may act by capillary action to continuously provide the substance to the surface of the adsorbent material.
The third compartment 22 may contain a purging agent. For example, any method of providing gas purification capabilities to the resulting third compartment 22 may be used to incorporate activated carbon into the third compartment 22. Suitable methods are known in the art. For example, charcoal may be placed in the third compartment 22 as a charcoal plug or filter.
In operation, a user ejects a gas over the gas outlet 16 of the nicotine inhaler 10, as shown in fig. 3. The partial vacuum created by the gas injection action draws a gas stream into the housing 12 through the gas inlet 14. The gas stream enters the first compartment 18 and captures the acid vapor by passing over a pyruvic acid source element held in the first compartment 18. The gas stream exiting the first compartment 18 and subsequently entering the second compartment 20 is a gas stream comprising an acid. The acid containing gas stream is passed over nicotine held in the second compartment 20 by the nicotine source element to produce a particulate stream comprising nicotine. The flow of particles comprising nicotine passes through the third compartment 22 and exits through the gas outlet 16 and into the mouth of the user. Any unreacted acid is removed from the nicotine-containing particulate stream by the carbon filter in the third compartment 22. It should be understood that pyruvic acid may be retained on a first element in the first compartment 18 and/or nicotine may be retained on a second element in the second compartment 20. Additionally, a third substance, such as a cleansing agent or flavoring agent, may be retained on the third element in the third compartment 22. Further, the first, second, and third elements may be integral with compartments 18, 20, and 22, respectively, or may be part of compartments 18, 20, and 22, respectively.
Exemplary device 2
The exemplary apparatus is illustrated and described with reference to fig. 4-6. In fig. 4, the elements of the device are shown in an assembly flow diagram. The delivery enhancing compound source 30 and nicotine source 40 are optionally manufactured and stored as separate components that are generally heat sealed on the ends with frangible separator end caps 35 and 45. The two elements 30 and 40 are inserted into the first housing 50. The first housing 50 containing the delivery enhancing compound source 30 and nicotine source 40 is then inserted into the second housing 100. The housings 50 and 100 and the elements 30 and 40 are generally extruded plastic tubes. The heating element 95 is also inserted into the second housing 100. The heating element 95 is generally a thin flexible heating foil configured to wrap around the housing 50 and sufficiently contact the housing 50 to enable heating of the delivery enhancing compound source 30 and/or nicotine source 40 to a desired temperature (e.g., 40 degrees celsius). The heating element 95 is further adapted to contact the battery 130 to provide power to the heating foil element 95.
The filter element 80 is adapted to be inserted and snap-locked into the second housing 100. The filter element 80 includes a filter cavity 75 adapted to receive the filter 70. The filter 70 is generally a charcoal filter and may contain additional volatile compounds such as flavors commonly used in cigarettes. The filter element 80 may have a foil seal 150 to seal the assembled pre-use configuration 160.
The filter element 80 has an aperture 90 that is aligned with an aperture 110 of the second housing 100. When assembled, the air inlet 140 is formed. The filter element 80 and the second housing 100 are configured to allow rotation to select a desired air inlet 140 orifice size. When the filter element 80 is fully inserted into the second housing 100 as shown at 170, the air inlet 140 is formed. Full insertion of the filter element 80 also forces the perforating element 60 through the frangible partitions 35 and 45 to unseal these elements for an unobstructed airflow path from the air inlet 140 to the particle transport orifice 180.
Figure 5 shows various alternative configurations of the delivery enhancing compound source 30 and nicotine source 40. The transport enhancing compound is generally a volatile acid in this configuration, which may be maintained by adsorbing the volatile acid to sintered plug 310, PE core 320, fiber bundle 330, multi-lumen tube 340 or 350, woven or non-woven PET, PBT, or PETG fabric material 360, PET static mixer 370, or on a spiral path wrapped in non-woven material 380.
Fig. 6 shows some embodiments of this device, wherein the device comprises a reusable portion 210 and a disposable portion 200. Referring to fig. 1, disposable portion 200 includes delivery enhancing compound source 30 and nicotine source 40, first housing 50 and filter element 80. The reusable part 210 comprises the second housing 100, the heating element 95 and the battery 130.
Exemplary device 3
An exemplary device that is fully reusable is shown by fig. 7. Two alternative configurations are shown, in which portions 410 and 420 or 430 and 440 can be reversibly attached. For example, the portion may be extruded plastic adapted and dimensioned to allow repeated snap-lock and removal. The removable portion 420 or 440 includes apertures 430 and 440 to communicate with a delivery enhancing compound source 445 and a nicotine source 435. Either portion 420 or 440 is inserted through aperture 460 in refill 450. Element 470 is a sealing O-ring that is used to seal the reservoir when the delivery enhancing compound source 445 and nicotine source 435 are recharged. The loading apertures 480 and 490 are configured to communicate with the delivery enhancing compound source 445 and nicotine source 435 once the portion 420 is installed in the refill 450. In some embodiments, gravity drives the flow from the delivery enhancing compound reservoir 500 and the nicotine reservoir 510 to the delivery enhancing compound source 445 and the nicotine source 435, respectively. In some embodiments, the flow from the reservoir to the source portion is due in part to the source element absorbing the reservoir liquid by capillary action. For example, the delivery enhancing compound source 445 and nicotine source 435 may include source elements comprising PET to produce rapid capillary absorption and thereby recharge the sources 445 and 435.
Exemplary device 4
Fig. 8 and 9 illustrate another exemplary apparatus. This exemplary device is refillable and is configured to simulate a typical cigarette pack. Referring to fig. 8, the conveyor 600 is configured to be inserted into a refill unit 610 through a storage orifice 620 and a refill orifice 630. When fully loaded into the refill unit 610 on the refill unit 640, the device 600 is recharged with the delivery enhancing compound and/or nicotine.
Fig. 9 shows the refill unit 640 in detail. In fig. 9A, an injection element 650 having loading orifices 660 and 670 is in flow communication with reservoirs 720 and 730 through dosing actuator pumps 680 and 690 and tubes 700 and 710. In fig. 9B, the delivery device 600 is shown installed in a refill unit 640. Injection element 650 passes through a refill orifice at the base of the delivery device and into the device such that orifices 660 and 670 are in communication with nicotine source element 740 and delivery enhancing compound source element 750. In fig. 9C, the delivery device 600 is further inserted into the refill unit 640 to actuate the pumps 680 and 690 to deliver the metered nicotine 770 and the metered delivery enhancing compound 760 through the orifices 660 and 670, respectively, and into the nicotine source element 740 and the delivery enhancing compound source element 750, respectively.
Exemplary device 5
Fig. 10 illustrates this exemplary apparatus. This device configuration has a heating unit 850 external to the delivery device 800. Upon insertion of the delivery device 800 into the heating unit 850, the electrical contacts 840 contact the wires 825, and the wires 825 allow the battery 830 to heat the foil heating element 860, thereby controlling the temperature of the delivery enhancing compound source 870 and nicotine source 880 to, for example, 40 ± 5 degrees celsius. An alternative configuration places the heating foil 860 within the delivery device 800. As shown in fig. 4.
Exemplary device 6
The foregoing exemplary devices are generally configured to simulate cigarettes and cigarette packets. A delivery device suitable for use with the methods herein is readily constructed in various ways. An example is shown in fig. 11. This exemplary device simulates a metered dose inhaler commonly used for medical delivery of inhaled medicaments. The delivery device 900 includes a first housing 910 and a second housing 920. The second housing 920 is removable (fig. 11A) and installable (fig. 11B) to refill the battery 990 or to replace the battery 990. The loading position places the electrical contacts 1050 and 1060 in communication, allowing the battery 990 to heat the foil heating element 950 to then control the temperature of the delivery enhancing compound source 960 and nicotine source 970. The intake actuator 930 is configured to slide anywhere from the position in fig. 11A to 11B. The power supply for heating the foil element 950 may be selectively switched on or off using the air intake actuator 930 or a separate switching device (not shown). The air intake apertures 940 may then be opened to a selected degree to control the volume of air and subsequent amount of nicotine per inhalation. This feature is similar to the adjustable intake aperture 140 of fig. 1. In operation, air is drawn through the intake orifice 940, down to the chamber 1000, through the conduit 1010, and through the source 960 of the transport enhancing compound (wherein the transport enhancing compound is trapped in the air stream). For example, pyruvic acid vapor can be emitted from a PET source element having liquid pyruvic acid adsorbed thereon. The air flow moves this vapor through the conduit 1020 into the nicotine source 970. Here, the delivery enhancing compound increases the concentration of nicotine in the airflow relative to the amount of nicotine vapor that would be contained in the same volume of airflow without the delivery enhancing compound. With respect to pyruvic acid, nicotine pyruvate particles can be formed to enhance delivery of nicotine to a subject. Delivery may be further enhanced by raising the temperature of, for example, pyruvic acid and nicotine by means of heating element 950, so as to increase the vapor pressure of those compounds. The nicotine-containing airflow now passes through the conduit 1030, through the charcoal filter 980, and out the suction orifice 1040.
Fig. 11C and D illustrate one embodiment of an exemplary inhaler device 900, wherein a portion of the device has a delivery enhancing compound source 960 and a nicotine source 970 in a disposable housing 1050, the disposable housing 1050 configured to slide into and out of a reusable housing 1060 to form a functionally identical device to the device 900. The battery housing element 1070 is detachable from the disposable element and is therefore reusable with the portion 1060 and the replacement element 1050.
Exemplary device 7
Figures 12A-C illustrate another configuration of an inhalation device. In this configuration, the delivery enhancing compound source and nicotine source are separate upper and lower surface regions of the inner tube 1100. In use of configuration 12A, impermeable cover 1110 is in place over nicotine reservoir 1120 and delivery enhancing compound reservoir 1130. The impermeable cover 1110 reduces the evaporation loss of the reservoir and physically separates the reservoir from the separate inner tube 1100. In use, bottom housing 1180 is pushed into main housing 1190 until first catch spring 1140 locks into the position shown in fig. 12B. This allows the reservoirs 1120 and 1130 to be arranged in parallel adjacent to the separate inner tube 1100. As shown in fig. 9C, the bottom housing 1180 is further inserted into the main housing 1190 until the second catch spring 1150 locks into position as shown in fig. 12C. In this third position, the pressure element 1160 compresses the separated inner tubes 1100 to force the wall 1170 into contact with the reservoirs 1120 and 1130. This action pushes the nicotine and delivery enhancing compound (e.g., pyruvic acid) onto the inner surface of the wall 1170, recharging this surface as a nicotine source and a delivery enhancing compound source.
Exemplary device 8
Fig. 13 shows a variant of the device of fig. 12. In this version, bottom housing 1250 is pressed against conical spring 1230 to force nicotine reservoir 1210 and delivery enhancing compound reservoir 1220 through reservoir cap 1200 and into contact with the inner surface of conical inner tube 1240, coating the surface with nicotine and delivery enhancing compound (fig. 13B).
Exemplary device 9
Fig. 14 shows another version of the device of fig. 12. In this aspect, the outer housing 1300 is adjacent to the moving components, which are the switch 1310 and the various internal elements shown. Switch 1310 is connected to source socket element 1330 by a connecting strip 1320. When the switch 1310 moves upward, the rigid socket element 1330 moves along the stem 1360. In the loading position, the reservoir elements 1340 and 1350 are in contact with the flexible element 1370, and the flexible element 1370 is also in contact with the rigid socket element 1330. The rigid socket element 1330 is sized to press the flexible element 1370 into contact with the reservoir elements 1340 and 1350 during the final portion of the sliding motion (fig. 14B). This action coats an upper portion of the flexible element 1370 with, for example, nicotine base solution from the reservoir 1350 and coats a lower portion of the flexible element 1370 with pyruvic acid from 1340, thereby generating a nicotine source and a delivery enhancing compound source, respectively. The top surface of the reservoir 1350 may be covered by an impermeable material to limit the amount of volatilization of the medicament and the delivery enhancing compound from the reservoir when in the operating position (fig. 14A). A flexible disc of impermeable material may extend from the element 1320 or 1330 to close the volume under the reservoir 1350 and further limit evaporation. In the filled position (fig. 14B), the flexible element 1370 will force the sheet downward and away from the reservoir.
Exemplary device 10
Fig. 15 shows another delivery device configuration. Fig. 15A shows the device 1400 in a use mode. Air moves from the inlet 1410, through the delivery enhancing compound source 1500, the nicotine source 1490, and through the outlet 1415. The nicotine and the delivery enhancing compound are coated on the side walls of their respective sources. To recharge the source, a delivery enhancing compound reservoir 1430 and a nicotine reservoir 1420 are provided. The switch 1460 may be actuated to recharge the source. When activated by the switch 1460, the base 1510 is moved along the guide rod 1470 toward the delivery enhancing compound source 1500 and the nicotine source 1490. As shown in fig. 15B, impermeable caps 1440 and 1450 compress the reservoir when in contact with delivery enhancing compound source 1500, nicotine source 1490 and upper stop element 1480 to force the delivery enhancing compound and nicotine out onto the surfaces of sources 1490 and 1500. The reservoir in such a device may be made of any flexible absorbent or absorbent material capable of retaining nicotine or delivering an enhanced solution. After recharging the source, the reservoir will typically be automatically urged back down the index rod 1470, making the device a "one click" device for convenient operation. Movement of the reservoir may be achieved by any convenient means. For example, push wires 1520 may be provided in grooves on guide rod 1470. The push wire 1520 may be attached to the base 1510 and moved up and down along the guide bar 1470 by an element (not shown) rotated by a motor. In some versions of this device configuration, the top exterior portion of the device 1400 may be rotated to define a similar size of inlet 1410 as the element 140 shown in FIG. 4.
Industrial applicability
The methods and devices herein are useful for therapeutic delivery of nicotine for smoking cessation, smoking harm reduction, and/or smoking replacement. In addition, the devices and methods herein are useful as alternative general nicotine delivery systems in place of tobacco-based products. The devices and methods herein are additionally useful for the delivery of other agents described herein.
Although the present invention and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims. Moreover, the scope of the present application is not intended to be limited to the particular embodiments of the process, machine, manufacture, composition of matter, means, methods and steps described in the specification. As one of ordinary skill in the art will readily appreciate from the disclosure of the present invention, processes, machines, manufacture, compositions of matter, means, methods, or steps, presently existing or later to be developed that perform substantially the same function or achieve substantially the same result as the corresponding embodiments described herein may be utilized according to the present invention. Accordingly, the appended claims are intended to include within their scope such processes, machines, manufacture, compositions of matter, means, methods, or steps.
All references and other information cited or otherwise identified herein are hereby incorporated by reference in their entirety to the same extent as if each had been individually so incorporated. The priority application, U.S. provisional patent application serial No.60/909,302 filed on 30.3.2007, is also incorporated by reference in its entirety.
The invention discloses the following embodiments:
embodiment 1. a method of increasing the concentration of nicotine in a gaseous carrier comprising the step of placing said gaseous carrier comprising a delivery enhancing compound in communication with a nicotine source comprising said nicotine.
Embodiment 2. the method of embodiment 1, further comprising the step of placing the gaseous carrier in communication with a delivery enhancing compound source comprising the delivery enhancing compound.
Embodiment 3. the method of embodiment 2, wherein the step of placing the gaseous carrier in communication with the delivery enhancing compound source precedes the step of placing the gaseous carrier comprising the delivery enhancing compound in communication with the nicotine source.
Embodiment 4. the method of embodiment 3, wherein the delivery enhancing compound source comprises a plurality of interior regions comprising two or more precursor compounds.
Embodiment 5 the method of embodiment 4, wherein the transport enhancing compound comprises ammonium chloride and the two or more precursor compounds comprise ammonia and hydrogen chloride.
Embodiment 6. the method of any of embodiments 1-5, wherein the nicotine concentration in the gaseous carrier is increased relative to a nicotine concentration that would be contained in the gaseous carrier in the absence of the delivery enhancing compound.
Embodiment 7. the method of any of embodiments 1-5, wherein the transport enhancing compound comprises an acid.
Embodiment 8 the method of embodiment 7, wherein the acid is an organic acid.
Embodiment 9 the method of embodiment 8, wherein the organic acid has a greater vapor pressure than nicotine at a given temperature.
Embodiment 10. the method of embodiment 9, wherein the temperature is 25, 30, 40, 45, 70, or 100 degrees celsius.
Embodiment 11 the method of embodiment 7, wherein the acid is selected from the group consisting of 3-methyl-2-oxopentanoic acid, pyruvic acid, 2-oxopentanoic acid, 4-methyl-2-oxopentanoic acid, 3-methyl-2-oxobutanoic acid, 2-oxooctanoic acid, and combinations thereof.
Embodiment 12 the method of any of embodiments 1-5, wherein the delivery enhancing compound reacts with the nicotine to form particles.
Embodiment 13 the method of embodiment 12, wherein the particles comprise particles having a mass median aerodynamic diameter of less than 6 microns.
Embodiment 14 the method of embodiment 12, wherein the particles comprise particles having a mass median aerodynamic diameter of less than 1 micron.
Embodiment 15 the method of embodiment 12, wherein at least some of the particles have a mass median aerodynamic diameter between 0.5 and 5 microns.
Embodiment 16. the method of any of embodiments 1-5, further comprising the step of increasing the temperature of the delivery enhancing compound, the delivery enhancing compound source, the nicotine source, and/or the gaseous carrier.
Embodiment 17. the method of embodiment 16, wherein the temperature is increased to at least 30 degrees celsius.
Embodiment 18 the method of embodiment 16, wherein the temperature is increased by a plurality of heating steps.
Embodiment 19. nicotine for cessation of use of a tobacco product, the nicotine being delivered by the method of any one of embodiments 1-5, the method further comprising the step of providing the gaseous carrier comprising the delivery enhancing compound to a subject after the step of placing the gaseous carrier in communication with the nicotine source.
Embodiment 20 the method of embodiment 19, wherein the gaseous carrier comprises at least 20 micrograms of nicotine in the volume of gaseous carrier provided to the subject.
Embodiment 21 the method of embodiment 20, wherein the volume of gaseous carrier delivered to the subject is provided as a single volume.
Embodiment 22 nicotine for use in reducing tobacco product damage, the nicotine being delivered by a method according to any of embodiments 1-5, the method further comprising the step of providing the gaseous carrier comprising the delivery enhancing compound to a subject after the step of placing the gaseous carrier in communication with the nicotine source.
Embodiment 23 the method of embodiment 22, wherein the gaseous carrier comprises at least 20 micrograms of nicotine in the volume of gaseous carrier provided to the subject.
Embodiment 24. the method of embodiment 23, wherein the volume of gaseous carrier delivered to the subject is provided as a single volume.
Embodiment 25. nicotine for use in place of tobacco products, the nicotine delivered by the method of any of embodiments 1-5, the method further comprising the step of providing the gaseous carrier comprising the delivery enhancing compound to a subject after the step of placing the gaseous carrier in communication with the nicotine source.
Embodiment 26 the method of embodiment 25, wherein the gaseous carrier comprises at least 20 micrograms of nicotine in the volume of gaseous carrier provided to the subject.
Embodiment 27 the method of embodiment 26, wherein the volume of gaseous carrier delivered to the subject is provided as a single volume.
Embodiment 28 nicotine for use in treating a disorder selected from the group consisting of nicotine addiction, obesity, alzheimer's disease, parkinson's disease, ulcerative colitis, multiple sclerosis, and combinations thereof, said nicotine delivered by the method of any of embodiments 1-5, further comprising the step of providing said gaseous carrier comprising said delivery enhancing compound to a subject after said step of placing said gaseous carrier in communication with said nicotine source.
Embodiment 29. an apparatus configured to perform the method of any of embodiments 1-5.
Embodiment 30 a device configured to deliver nicotine as described in embodiment 19.
Embodiment 31 a device configured to deliver nicotine as described in embodiment 22.
Embodiment 32 a device configured to deliver nicotine as described in embodiment 25.
Embodiment 33 a device configured to deliver nicotine as described in embodiment 28.
Embodiment 34. a device for delivering a medicament to a subject, the device comprising a housing, the housing comprising:
an inlet and an outlet in communication with each other and adapted such that a gaseous carrier can pass into the housing through the inlet, through the housing, and out of the housing through the outlet, the apparatus comprising, in order from inlet to outlet:
a first interior region in communication with the inlet, the first interior region including a source of a transport enhancing compound,
a second interior region in communication with the first interior region, the second interior region comprising a nicotine or other agent source, and
optionally, a third interior region in communication with the second interior region.
Embodiment 35. the apparatus of embodiment 34, wherein a partial vacuum at the outlet is capable of drawing the gaseous carrier through the inlet, the first interior region, the second interior region, where present, through the third interior region, and then through the outlet.
Embodiment 36 the device of embodiment 34, wherein the enhancer source comprises an adsorbent element having the delivery enhancing compound adsorbed thereon, and/or wherein the nicotine or other medicament source comprises an adsorbent element having the nicotine adsorbed thereon.
Embodiment 37 the device of embodiment 36, wherein one or more of the adsorbent elements comprises at least one of glass, aluminum, PET, PBT, PTFE, ePTFE, and barix.
Embodiment 38. the device of any of embodiments 34-37, wherein the device further comprises a first reservoir in communication with the first interior region, the first reservoir comprising the transport enhancing compound.
Embodiment 39 the device of any of embodiments 34-37, wherein the device further comprises a second reservoir in communication with the second interior region, the second reservoir comprising nicotine or other agent.
Embodiment 40. the device of any of embodiments 34-37, wherein the device comprises a third inner region comprising a third inner region element.
Embodiment 41 the apparatus of embodiment 40, wherein the third inner zone component comprises a decontaminant.
Embodiment 42 the apparatus of embodiment 41, wherein the scavenger comprises activated carbon.
Embodiment 43 the device of embodiment 42, wherein the third inner region element comprises a flavoring agent.
Embodiment 44 the device of embodiment 43, wherein the third inner region element comprises a pharmaceutical agent.
Embodiment 45 the device of embodiment 44, wherein the agent comprises nicotine.
Embodiment 46. the device of any of embodiments 34-37, wherein the housing simulates a tobacco smoking article.
Embodiment 47 the device of embodiment 46, wherein the tobacco smoking article is a cigarette.
Embodiment 48 the device of any one of embodiments 34-37, wherein the housing simulates a medicinal inhalation device.
Embodiment 49 the device of embodiment 48, wherein the medicinal inhalation device is selected from the group consisting of a metered dose inhaler, a pressurized metered dose inhaler, a dry powder inhaler, a nebulizer, and a liquid based inhaler.
Embodiment 50. a medicament for delivery to a subject by inhalation, the delivery method comprising the steps of:
a) first placing a gaseous carrier comprising a delivery enhancing compound in communication with a medicament source comprising said medicament, and
b) and secondly providing said gaseous carrier comprising said pharmaceutical agent to the subject.
Embodiment 51 the agent of embodiment 50, wherein the agent is selected from the group consisting of: nicotine, 7-hydroxycapetalin, arecoline, atropine, bupropion, theophylline (D-norpseudoephedrine), chlorpheniramine, dibucaine, dimemorfan, dimethyltryptamine, diphenhydramine, ephedrine, hordenine, hyoscyamine, isoarecoline, levorphanol, lobeline, monocrotaline, capecitabine, muscarine, procaine, pseudoephedrine, mepyramine, raclopride, ritodrine, scopolamine, laburnine (sparteine), ticlopidine, 1,2,3, 4-tetrahydroisoquinoline, anabacin, anabetadine, cotinine, mugwort, Nicotrine, Norcotinine (Norcotinine), nornicotine, oxcinaline, propranolol, terbutaline, nicoruxol, vinoresinomin, lidocaine, echinocaine, 5- (2-chloro-butyl) -pyridine (ABR-2-N-butyl) -pyridine, (S) -3-methyl-5- (1-methyl-2-pyrrolidinyl) isoxazole (ABT418), (±) -2- (3-pyridyl) -1-azabicyclo [2.2.2] octane (RJR-2429), Methylocetonine, mecamylamine, galantamine, pyridostigmine, physostigmine, tacrine, 5-methoxy-N, N-dimethyltryptamine, 5-methoxy- α -methyltryptamine, iprochlorhydrazine, isopropylisoniazine, isoxazole, linazolirtide, moclobemide, N, N-dimethyltryptamine, phenelzine, phenylethylamine, toloxanone, tranylcypromine, tryptamine, and combinations thereof.
Embodiment 52 the agent of embodiment 50 or 51, wherein the agent is delivered in a therapeutically effective amount for the treatment of a disease for which the agent is therapeutically beneficial.
Embodiment 53 the method of any one of embodiments 50 to 52, wherein the agent is an aliphatic or aromatic, saturated or unsaturated, nitrogenous base, wherein the nitrogen atom is present in a heterocyclic or acyclic chain.
Embodiment 54 the agent of embodiment 53, wherein the agent has a melting point of less than 150 ℃ and/or a boiling point of less than 300 ℃.
Embodiment 55 the method of any one of embodiments 50-54, wherein the agent is a "tobacco smoke component".
Embodiment 56 the method of any one of embodiments 50-54, wherein the agent is a nicotine receptor agent.
Embodiment 57 the method of embodiment 56, wherein the nicotine receptor agent is a nicotine agonist.
Embodiment 58 the method of embodiment 56, wherein the nicotine receptor agent is a nicotine antagonist.
Embodiment 59 the method of embodiment 56, wherein the nicotine receptor agent is an acetylcholinesterase inhibitor.
Embodiment 60 the method of any one of embodiments 50-54, wherein the agent is an MAO inhibitor.
Embodiment 61 the method of any one of embodiments 50 to 54, wherein the agent is an anti-asthma drug.
Embodiment 62. the method of any one of embodiments 50-54, wherein the agent is an anti-sore throat drug.
Embodiment 63 the method of any one of embodiments 50-54, wherein the agent is an antiarrhythmic drug.
Embodiment 64. an apparatus configured to perform the method of any of embodiments 50-63.
Claims (17)
1. A device for delivering nicotine to a subject, the device comprising a housing comprising:
an inlet and an outlet in communication with each other and adapted such that a gaseous carrier can pass into the housing through the inlet, through the housing, and out of the housing through the outlet, the apparatus comprising, in order from inlet to outlet:
a first interior region in communication with the inlet, the first interior region comprising a source of a delivery enhancing compound comprising a 2-ketocarboxylic acid, a second interior region in communication with the first interior region, the second interior region comprising a nicotine source, and
optionally, a third interior region in communication with the second interior region.
2. The apparatus of claim 1, wherein a partial vacuum at the outlet is capable of drawing the gaseous carrier through the inlet, the first interior region, the second interior region, if present, through the third interior region, and then through the outlet.
3. The device of claim 1, wherein the delivery enhancing compound source comprises an adsorption element having the delivery enhancing compound adsorbed thereon, and/or wherein the nicotine source comprises an adsorption element having the nicotine adsorbed thereon.
4. The device of claim 3, wherein the adsorption element having the delivery enhancing compound adsorbed thereon and/or the adsorption element having the nicotine adsorbed thereon comprises at least one of glass, aluminum, PET, PBT, PTFE, ePTFE, and BAREX.
5. The device of any one of claims 1-4, further comprising a first reservoir in communication with the first interior region, the first reservoir comprising the transport enhancing compound.
6. The device of any one of claims 1-4, further comprising a second reservoir in communication with the second interior region, the second reservoir comprising nicotine.
7. The device of any of claims 1-4, wherein the device comprises a third inner region comprising a third inner region element.
8. The apparatus of claim 7, wherein the third inner zone element contains a decontaminant.
9. The apparatus of claim 8, wherein the scavenger comprises activated carbon.
10. The device of claim 7, wherein the third inner region element comprises a flavoring agent.
11. The device of claim 7, wherein the third inner region element contains a medicament.
12. The device of claim 11, wherein the agent comprises nicotine.
13. The device of any one of claims 1 to 4, wherein the housing simulates a tobacco smoking article.
14. The device of claim 13, wherein the tobacco smoking article is a cigarette.
15. A device according to any of claims 1 to 4, wherein the housing simulates a medicinal inhalation device.
16. The device of claim 15, wherein the medicinal inhalation device is selected from the group consisting of a metered dose inhaler, a dry powder inhaler, a nebulizer, and a liquid-based inhaler.
17. The device of claim 15, wherein the medicinal inhalation device is a pressurized metered dose inhaler.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60/909,302 | 2007-03-30 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HK11108912.5A Addition HK1156262B (en) | 2007-03-30 | 2008-03-25 | Device and method for delivery of a medicament |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HK11108912.5A Division HK1156262B (en) | 2007-03-30 | 2008-03-25 | Device and method for delivery of a medicament |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1192491A HK1192491A (en) | 2014-08-22 |
| HK1192491B true HK1192491B (en) | 2018-04-06 |
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