Nicotine delivery composition

Abstract

Aspects of this disclosure provide compositions and methods for administering nicotine to the respiratory system of a subject. Accordingly, aspects of this specification include nicotine-containing compositions comprising nicotine in combination with L-lactic acid and water. Aspects of this specification also include methods for producing the compositions of this specification, methods for delivering the compositions of this specification, and methods for treating a subject by administering one or more of the compositions of this specification.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 470,254, filed on June 1, 2023, with the title "Composition for Nicotine Delivery", the content of which is hereby incorporated by reference in its entirety into this specification.

[0002] Technical Field Aspects of this disclosure generally relate to compositions and methods for administering nicotine and nicotine - containing compositions to the respiratory system.

Background Art

[0003] In nature, chiral compounds are usually produced by organisms in optically pure forms. In many cases, one of the optical isomers is harmless, while the other isomer can be toxic and / or interfere with important pathways in the body. However, some isomers do not cause significant problems. Optical isomers (enantiomers) have been known for a long time, but laboratory tests are complex and expensive (see, for example, Biomed Res Int. Jun 17, 2020 "D - Lactic as a Metabolite: Toxicology, Diagnosis, and Detection", which is hereby incorporated by reference in its entirety).

[0004] L - Lactate exists in human blood at a concentration of 0.5 - 1 mmol / L. D - Lactate is not found naturally in the blood or is not involved in the basic metabolism of most organisms. In conclusion, D - Lactate is not a highly toxic compound, but it is a toxic metabolite that can cause health problems and exacerbate other medical conditions. However, further research is still needed.

Summary of the Invention

[0005] Aspects of this disclosure relate to methods and compositions for administering nicotine to a target respiratory system. In some aspects, this disclosure provides compositions which may contain nicotine, lactic acid, water, or a combination thereof. In some aspects, the compositions may further contain ethanol and / or menthol.

[0006] In some respects, lactic acid contains a racemic mixture of L-lactic acid and D-lactic acid.

[0007] In some respects, lactic acid contains L-lactic acid. In some respects, the composition consists essentially of L-lactic acid and does not contain any detectable amount of D-lactic acid. In some respects, the composition consists essentially of L-lactic acid and contains only trace amounts of D-lactic acid.

[0008] In some embodiments, the compositions of this specification do not contain D-lactic acid. In some embodiments, the D-lactic acid contained in the compositions of this specification is trace. In some embodiments, the D-lactic acid contained in the compositions of this specification is undetectable.

[0009] In some aspects, the compositions of this specification may contain about 0.1% (w / w) to about 5% (w / w) of nicotine. In some aspects, the compositions of this specification may contain about 1.8% (w / w) to about 2.2% (w / w) of nicotine. In some aspects, the compositions of this specification may contain about 2.0% (w / w) of nicotine.

[0010] In some aspects, the compositions of this specification may contain about 0.1% (w / w) to about 5% (w / w) of lactic acid. In some aspects, the compositions of this specification may contain about 1.6% (w / w) to about 2.0% (w / w) of lactic acid. In some aspects, the compositions of this specification may contain about 1.8% (w / w) of lactic acid.

[0011] In some aspects, the compositions of this specification may contain about 0.1% (w / w) to about 5% (w / w) of L-lactic acid. In some aspects, the compositions of this specification may contain about 1.6% (w / w) to about 2.0% (w / w) of L-lactic acid. In some aspects, the compositions of this specification may contain about 1.8% (w / w) of L-lactic acid. In some aspects, the compositions are D-lactic acid-free or contain no detectable amount of D-lactic acid.

[0012] In some embodiments, the compositions of this specification may contain water. In some embodiments, the compositions of this specification may contain water, which may be type I water, deionized water, distilled water, or a combination thereof. In some aspects, the water may be type I water.

[0013] In some embodiments, the compositions of this specification may contain ethanol. The concentration of ethanol may be about 10% (w / w) or less.

[0014] In some embodiments, the compositions of this specification may contain propylene glycol. The concentration of propylene may be about 15% (w / w) or less.

[0015] In some embodiments, the compositions of this specification may contain menthol. The concentration of menthol may be about 0.9% (w / w) or less. The menthol may be L-menthol.

[0016] In some embodiments, the compositions of this specification may be compositions inhaled by the subject. In some embodiments, the compositions of this specification may be delivered to the respiratory system of the subject.

[0017] In some embodiments, this disclosure provides a method for producing the compositions disclosed in this specification.

[0018] In some embodiments, this disclosure provides a method for delivering the compositions disclosed in this specification to the respiratory system of a user. In some embodiments, the method of the specification can deliver the compositions disclosed in this specification to the respiratory system of a user as a jet of droplets and vapors within an inhalable range. In other embodiments, the method of the specification can deliver the compositions disclosed in this specification to the respiratory system of a user as a jet of droplets without vapors within an inhalable range.

[0019] In some embodiments, the method of the specification can deliver a nicotine-containing composition to a user. In some embodiments, the method of the specification may deliver a nicotine-containing composition to a user to treat or improve one or more diseases, conditions or disorders.

[0020] In some embodiments, the method of delivering the compositions disclosed in this specification as droplets and vapor jets is provided. In other embodiments, the method of this specification can deliver the compositions disclosed in this specification to the user's respiratory system as a vapor-free droplet jet that is inhalable.

[0021] In some embodiments, the composition may contain cyclodextrin to assist in the solubilization of flavor components. The concentration of cyclodextrin may be 5% (w / w) or less.

[0022] In some embodiments, the compositions of this specification may contain the coolant WS-23 (2-isopropyl-N,2,3-trimethylbutylamide). The concentration of WS-23 may be about 0.5% (w / w) or less. In some embodiments, the compositions of this specification may contain concentrated fruit juice. The fruit extraction method involves removing all water from the fruit juice by heating and filtering the remaining material. Other methods, but not limited to, use organic solvents such as ethanol, supercritical carbon dioxide, and glycerin. These extractions can be facilitated by sonication or reflux of the fruit in the solvent. After the fruit flavor compounds have been extracted, the solvent can be removed by evaporation and / or liquid-liquid extraction using water as the final solvent. The concentration of the concentrated fruit extract is about 5% (w / w) or less.

[0023] Unless otherwise defined in the specification, terms have the meanings that are commonly understood by those of ordinary skill in the art or that can be applied by those of ordinary skill in the art with respect to some of the aspects disclosed in the specification.

[0024] Unless otherwise indicated, all drugs and / or compounds, properties such as molecular weight, reaction conditions, and all numbers representing what is disclosed in this specification are intended to be modified by the term "about" in all cases. Thus, unless otherwise indicated, the numerical parameters in the specification and claims are values that can vary by ± about 10% to about 15% depending on the desired properties disclosed in the specification. The numerical values shown in this specification inherently include the standard deviation that necessarily results from the error found in its measured values.

[0025] In this specification, "individual", "subject", "host", and "patient" are used in the same sense and refer to a mammalian subject, particularly a human, for whom diagnosis, treatment, prevention, or therapy is desired.

[0026] In this specification, "treatment" or "therapy" may refer to the treatment, reversal, improvement, prevention of onset, or prevention of progression of a health condition or a disease or the symptoms of a health condition or a disease.

[0027] Unless otherwise defined, all technical terms used in the specification have the same meaning as commonly understood by those of ordinary skill in the technical field to which this disclosure pertains. **Modes for Carrying Out the Invention**

[0028] In this section, specific representative compositions and methods are described to detail some aspects of the invention. In the implementation of some aspects, it is not necessary to adopt all or some of the specific matters outlined in the specification. Rather, it is obvious to those of ordinary skill in the art that concentrations, times, and other specific matters can be changed by routine experimentation. In some cases, well-known methods or components are not described in the specification.

[0029] In some aspects, this disclosure generally relates to a method of delivering a fluid composition containing nicotine to a user's respiratory system as a spray of inhalable droplets. In some aspects, the fluid composition containing nicotine may be delivered at high concentrations and potencies compared to other administration routes and standard inhalation techniques. In some aspects, the fluid composition containing nicotine may be delivered to the user with low levels of contaminants, undesirable compounds, etc. compared to other administration routes and standard inhalation techniques. In some aspects, the fluid composition containing nicotine may contain L-lactic acid. In some aspects, the fluid composition containing nicotine may contain no detectable amount of D-lactic acid or may contain a trace amount of D-lactic acid.

[0030] I. Composition Some aspects of this specification provide a composition containing nicotine. In some aspects, the compositions of this specification may contain nicotine, lactic acid, water, or a combination thereof. In some aspects, the lactic acid is L-lactic acid. In some aspects, the composition further contains ethanol and / or menthol. In some aspects, the compositions of this specification may be a solution for delivering nicotine to the target respiratory system.

[0031] In some aspects, the compositions disclosed in this specification may include nicotine.

[0032] In some embodiments, the compositions disclosed in this specification may contain about 1% to about 80%, about 5% to about 50%, or about 10% to about 40% of the weight of the composition in nicotine. In some embodiments, the compositions disclosed in this specification may contain about 0.1%, about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80% (w / w) of nicotine. In some embodiments, the compositions disclosed in this specification may contain about 0.1% (w / w) to about 5% (w / w) of nicotine. In some embodiments, the compositions disclosed in this specification may contain about 0.1% (w / w) to about 5% (w / w) of nicotine. In some aspects, the compositions of this specification may contain about 1.8% (w / w) to about 2.2% (w / w) of nicotine. In some respects, the compositions of this specification may contain about 2.0% (w / w) nicotine.

[0033] In some embodiments, the compositions disclosed in this specification may contain nicotine with a purity of at least about 85%. In some embodiments, the compositions disclosed in this specification may contain nicotine with a purity of about 85% to 99% (e.g., about 85%, 90%, 95%, 96%, 97%, 98%, 99%). In some embodiments, the compositions disclosed in this specification may contain at least pure nicotine. The purity of the nicotine in this specification can be determined using methods known in the art, including but not limited to high-performance liquid chromatography (HPLC).

[0034] In some embodiments, the compositions disclosed in this specification may contain nicotine in amounts ranging from about 0.1 mg / mL to about 20 mg / mL (e.g., about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 mg / mL).

[0035] In some embodiments, the compositions disclosed in this specification contain lactic acid. In some embodiments, the lactic acid is L-lactic acid (L-(+)-lactic acid).

[0036] In some embodiments, the compositions disclosed in this specification may contain about 1% to about 80%, about 5% to about 50%, or about 10% to about 40% (w / w) of L-lactic acid. In some embodiments, the compositions disclosed in this specification may contain about 0.1%, about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80% (w / w) of L-lactic acid. In some embodiments, the compositions disclosed in this specification may contain about 0.1% (w / w) to about 5% (w / w) of L-lactic acid. In some embodiments, the compositions disclosed in this specification may contain about 0.1% (w / w) to about 5% (w / w) of L-lactic acid. In some aspects, the compositions of this specification may contain about 1.6% (w / w) to about 2.0% (w / w) of L-lactic acid. In some aspects, the compositions of this specification may contain about 1.8% (w / w) of L-lactic acid.

[0037] In some embodiments, the compositions of this specification do not contain D-lactic acid. In some embodiments, the D-lactic acid contained in the compositions of this specification is trace. In some embodiments, the compositions of this specification do not contain a detectable amount of D-lactic acid. In some embodiments, the compositions of this specification contain lactic acid, wherein the lactic acid consists essentially of L-lactic acid.

[0038] In some embodiments, the compositions of this specification may contain water. In some embodiments, the compositions of this specification may contain deionized water. In some embodiments, the compositions of this specification may contain distilled water. In some embodiments, the compositions of this specification may contain type I water. Type I water is defined by the American Society for Testing and Materials (ASTM) as having a resistivity greater than 18 MΩ-cm, an conductivity less than 0.056 μS / cm, and a total organic carbon (TOC) of less than 50 ppb.

[0039] In some embodiments, the compositions disclosed in this specification further contain ethanol. The terms “ethanol” and “ethyl alcohol” are understood to be synonymous and are used interchangeably in this specification. In some embodiments, the compositions in this specification may contain ethanol of about 180 to about 200 (e.g., about 180, 185, 190, 195, 200) proof. In this specification, proof is defined as twice the volume content of alcohol (ethanol). For example, 180 proof ethanol contains about 90% ethanol, and 200 proof ethanol contains about 100% (i.e., 99.5% or more) ethanol. In some embodiments, the compositions in this specification may contain pure ethanol (i.e., 200 proof ethanol). In some embodiments, the compositions in this specification may contain about 200 proof ethanol.

[0040] In some aspects, the compositions disclosed in this specification may contain about 1% to about 95%, about 5% to about 50%, or about 10% to about 40% (w / w) of ethanol. In some aspects, the compositions disclosed in this specification may contain about 0.1%, about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% (w / w) of ethanol. In some aspects, the compositions disclosed in this specification may contain about 0.1% (w / w) to about 20% (w / w) of ethanol. In some aspects, the compositions disclosed in this specification may contain about 1% (w / w) to about 15% (w / w) of ethanol. In some aspects, the compositions of this specification may contain about 10% (w / w) of ethanol.

[0041] In some embodiments, the compositions disclosed in this specification may also contain menthol. The menthol may be L-menthol.

[0042] In some embodiments, the compositions disclosed in this specification may contain about 0.01% (w / w) to about 95% (w / w) of menthol. In some embodiments, the compositions disclosed in this specification may contain about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% (w / w) of menthol. In some embodiments, the compositions disclosed in this specification may contain about 0.01% (w / w) to about 0.1% (w / w) of menthol. In some aspects, the compositions disclosed in this specification may contain about 0.05% (w / w) to about 0.1% (w / w) of menthol. In some aspects, the compositions in this specification may contain about 0.09% (w / w) of menthol.

[0043] In some embodiments, the compositions of this specification may include at least one additional pharmaceutically acceptable carrier or diluent. In some embodiments, the compositions or solutions of this specification may further include a variety of emulsifiers, surfactants, solubilizers, stabilizers, flavoring agents, and other pharmaceutically acceptable carriers suitable for delivery to the respiratory system. In these embodiments, the pharmaceutically acceptable carrier and / or diluent used in the compositions of this specification may be a liquid carrier or diluent comprising water, propylene glycol, and at least one of a pharmaceutically acceptable fluid. The pharmaceutically acceptable fluid used in this specification may include, but is not limited to, polar solvents, and the polar solvent is, but is not limited to, a compound having a hydroxyl group or other polar group. The solvent used in this specification may include, but is not limited to, water or alcohol (e.g., ethanol, isopropanol, glycols (including propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerin, and polyoxyethylene alcohol)). Polar solvents include protic solvents, which include, but are not limited to, water, saline solutions containing one or more pharmaceutically acceptable salts, alcohols, glycols, or mixtures thereof. In some embodiments, the amount of water used in the composition may meet or exceed the applicable regulatory requirements for use in inhaled drugs.

[0044] In some embodiments, the pH of the composition of this specification may be about 4 to 6. In some embodiments, the pH is about 4.5 to about 5.5. In some embodiments, the pH is about 5.0 to about 5.4. In some embodiments, the pH is about 5.2.

[0045] In some embodiments, the compositions of this specification may be solutions. In some embodiments, the compositions of this specification may be organic solutions or aqueous solutions. In some embodiments, the compositions of this specification may be solutions inhaled by a subject. In some embodiments, the compositions of this specification may be solutions for delivering nicotine to the respiratory system of a subject. In some embodiments, the compositions of this specification may be solutions for intranasal administration. In some embodiments, the compositions of this specification may not be suspensions.

[0046] In some embodiments, the compositions of this specification may contain one or more nicotine, L-lactic acid and / or water. The composition may contain 2% (w / w) nicotine, about 1.8% (w / w) L-lactic acid and type I water. In some embodiments, the composition may further contain ethanol and / or menthol. In some embodiments, the composition may contain about 10% (w / w) ethanol and / or about 0.9% (w / w) menthol. In some embodiments, the composition does not contain D-lactic acid. In some embodiments, the pH of the composition is about 5.2.

[0047] II. Method The effective and efficient delivery of substances to the user's respiratory system, and the synchronization of substance administration to the user's respiratory system with the user's inspiratory / expiratory cycle, have always been challenges. For example, the aerodynamic diameter of droplets required for optimal deposition in the alveolar airways is generally 1–6 μm, with droplets smaller than approximately 4 μm shown to reach the alveolar region of the lungs more effectively, and larger droplets greater than approximately 6 μm shown to typically deposit on the tongue or hit the throat and cover the bronchi. Smaller droplets, for example, less than approximately 1 μm, tend to penetrate deep into the lungs and be exhaled. Therefore, methods for delivering nicotine-containing fluid compositions according to the disclosed aspects as a jet stream of inhalable droplets require the ability to precisely set the droplet size to suit specific applications.

[0048] In some embodiments, this disclosure provides a method for delivering a nicotine-containing fluid composition, subject to disclosed aspects requiring the ability to precisely set the droplet size to suit a particular application, as an inhalable droplet jet stream. In some embodiments of this disclosure, droplets with a diameter of less than about 5-6 μm, e.g., less than about 3.2 μm, are typically required for the droplet jet stream of the nicotine-containing fluid composition to effectively deposit in the user's lungs. While not intended to be theoretically bound, for the droplet jet stream to be delivered to the lungs, the droplet delivery device needs to impart momentum that is high enough to be released from the device and low enough to prevent deposition on the tongue or back of the throat. Droplets with a diameter of less than about 5-6 μm are transported almost entirely by the movement of the airflow carrying the droplet, rather than by their own momentum.

[0049] In some embodiments, the method of this disclosure minimizes or eliminates irritation to the mouth or throat. In some embodiments, the method involves generating a release flow of droplets of a nicotine-containing fluid composition at a precise timing coordinated with the user's inspiratory cycle, in order to maximize delivery to the respiratory system, while minimizing or eliminating irritation to the mouth or throat. While not intended to be theoretical, as described in the specification, the small droplets generated by the method of this disclosure are transported almost entirely by the movement of the airflow carrying the droplets. By using this airflow movement and a controlled droplet size, the release of droplets may be concentrated to be released during the peak flow of the inspiratory cycle, optimizing inhalation to target sites in the respiratory system (e.g., deep lungs) while minimizing unintended delivery to undesirable sites in the respiratory system (e.g., mouth, throat).

[0050] As discussed previously, effective delivery of droplets to the deep airways requires droplets with a diameter of less than approximately 5-6 microns, specifically, droplets with a mass-average aerodynamic diameter (MMAD) of less than approximately 5 microns. However, for certain drugs and applications, droplets of less than approximately 1 μm may be desirable for rapid adsorption to the deep lungs. For example, to deliver nicotine to the deep lungs, it may be desirable to use droplets of less than 4 μm, less than 3.2 μm, less than 3 μm, less than 2 μm, and less than 1 μm. The mass-average aerodynamic diameter is defined as the diameter where 50% of the total mass of the droplet is greater than or equal to that value, and 50% is less than or equal to that value. In some aspects of this disclosure, for deposition in the alveolar airways, the momentum of droplets of this size must be large enough to allow release from the droplet delivery device, but small enough to prevent deposition on the tongue (soft palate) or pharynx.

[0051] In some embodiments, a method is provided for generating a droplet stream from a nicotine-containing fluid composition and delivering it to the user's respiratory system. In some embodiments, the droplet stream is generated within a controllable, predetermined droplet size range. For example, the droplet size range includes at least approximately 50%, at least approximately 60%, at least approximately 70%, at least approximately 85%, at least approximately 90%, approximately 50% to approximately 90%, approximately 60% to approximately 90%, approximately 70% to approximately 90% of the ejected droplets, and is within the range of inhalable droplets, such as less than approximately 5 μm, less than approximately 4 μm, less than approximately 3.7 μm, less than approximately 3.5 μm, less than approximately 3.2 μm, less than approximately 3.0 μm, approximately 2 μm, approximately 0.7 μm to approximately 4 μm, approximately 0.7 μm to approximately 3.2 μm, approximately 0.7 μm to approximately 3 μm, approximately 0.7 μm to approximately 2.5 μm, approximately 0.7 μm to approximately 2.0 μm, approximately 0.7 μm to approximately 1.5 μm, approximately 0.7 μm to approximately 1.0 μm, etc.

[0052] In another embodiment, the diameter of the droplet ejection stream may be one or more, and droplets of varying diameters are generated to target multiple regions of the airway (mouth, tongue, throat, upper airway, lower airway, deep lungs, etc.). For example, the droplet diameter may be approximately 0.7 μm to 200 μm, approximately 0.7 μm to 100 μm, approximately 0.7 μm to 60 μm, approximately 0.7 μm to 40 μm, approximately 0.7 μm to 20 μm, approximately 0.7 μm to 5 μm, approximately 0.7 μm to 4.7 μm, approximately 0.7 μm to 4 μm, approximately 0.7 μm to 3.0 μm, approximately 0.7 μm to 2.5 μm, approximately 0.7 μm to 2.0 μm, approximately 0.7 μm to 1.5 μm, approximately 0.7 μm to 1.0 μm, approximately 5 μm to 20 μm, approximately 5 μm to 10 μm, or a combination thereof. In a special embodiment, the diameter of at least a portion of the droplet may be within the inhalable range, while other droplets may be of a different size (e.g., greater than approximately 5 μm) to target areas that cannot be inhaled. In this regard, a typical droplet ejection stream may have 50% to 70% of the droplets within the inhalable range (less than approximately 5 μm) and 30% to 50% outside the inhalable range (approximately 5 μm to approximately 10 μm, approximately 5 μm to approximately 20 μm, etc.).

[0053] In some embodiments, the specification provides a method for delivering a safe, appropriate, and repeatable dose of a nicotine-containing fluid composition to the respiratory system of a user. Such methods may deliver a droplet jet stream to a desired site within the user's respiratory system. In some embodiments, the method may deliver a predetermined amount of fluid in the form of a droplet jet stream so that an appropriate and repeatable high proportion of droplets are delivered to a desired site within the airway, e.g., the alveolar airway of the user during use.

[0054] In some embodiments, the method of the specification may include delivering a nicotine-containing fluid composition to the user's respiratory system as a droplet jet stream within an inhalable range. In some embodiments, the method includes (a) generating a droplet jet stream from the fluid composition by a droplet delivery device, wherein at least about 50% of the droplet jet stream has an average droplet diameter of less than about 6 μm, and (b) delivering the droplet jet stream to the user's respiratory system such that at least about 50% of the mass of the droplet jet stream is delivered within an inhalable range to the user's respiratory system during use.

[0055] In some embodiments, the methods of this disclosure may be used to deliver a nicotine-containing fluid composition to the respiratory system of a user to treat various diseases, disorders and conditions, promote or regulate various physiological activities, and to perform combinations thereof. In this regard, the methods of this disclosure may be used to deliver nicotine locally to the respiratory system and / or systemically.

[0056] Appropriate droplet delivery devices can be used in connection with this disclosure in accordance with this disclosure. Examples of droplet delivery devices that may be used in the manner described in the specification include PCT / US2017 / 030913 (International Publication No. 2017 / 192767), PCT / 2017 / 030917 (International Publication No. 2017 / 192771), PCT / 2017 / 030919 (International Publication No. 2017 / 192773), PCT / US2017 / 030921 (International Publication No. 2017 / 192774), and PCT / US2017 / 030929 (International Publication No. 2017 / 192782). PCT / 2017 / 030925 (International Publication No. 2017 / 192778), PCT / US2018 / 054417 (International Publication No. 2019 / 071008), PCT / US2018 / 056300 (International Publication No. 2019 / 079461), PCT / 2018 / 059874 (International Publication No. 2019 / 094628), PCT / 2019 / 012691 (International Publication No. 2019 / 136437), PCT / US2019 / 25321 (International Publication No. 2019 / 1952 (No. 39), PCT / 2019 / 054042 (International Publication No. 2020 / 072478), PCT / US2020 / 014785 (International Publication No. 2020 / 154497), PCT / US2020 / 032383 (International Publication No. 2020 / 227717), PCT / US2020 / 040132 (International Publication No. 2020 / 264501), PCT / US2022 / 035492, PCT / US2022 / 026176, PCT / US2022 / 034552, US Patent Application This includes, but is not limited to, the disclosures contained in U.S. Provisional Applications No. 17 / 846,902, 63 / 256,245, 63 / 318,202, 63 / 323,770, 63 / 346,794, 63 / 337,885, 63 / 390,170, 63 / 390,209, and 63 / 390,228 (these disclosures are incorporated into this specification in their entirety by reference).

[0057] In some embodiments, the compositions disclosed herein may be used in a “push-mode” droplet delivery device, which preferably does not include a heating element that could produce undesirable byproducts, and comprises a container assembly having a mouthpiece port, a reservoir disposed within or in fluid communication with the container assembly to supply a fixed amount of the composition fluid, and an ejector bracket in fluid communication with the reservoir, wherein the ejector bracket includes a mesh having a membrane operably connected to an electronic transducer (preferably such as an ultrasonic transducer containing a piezoelectric material), the membrane being between the transducer and the mesh, the mesh having a plurality of openings formed through the thickness direction of the mesh, the transducer being connected to a power source and operable to vibrate the membrane to generate a jet stream of droplets of the composition passing through the mesh, and an ejection channel within the container assembly is configured to guide the jet stream of droplets from the mesh to an outlet. The vibrating membrane “pushing” the liquid composition through the mesh is called “push-mode” ejection, and devices in embodiments of the push-mode invention are sometimes called push-mode devices. Examples of such devices, though not limited to them, are described in U.S. Patent Application No. 17 / 846,902 and PCT / US2022 / 034552, which are incorporated in whole by reference into this specification.

[0058] In one embodiment, the droplet delivery device may be configured to provide droplet ejection after a breathing initiation time (e.g., 0.1–0.5 seconds). The device may also be configured to detect the start of an inspiratory cycle, which can form a stable inspiratory flow in a short time (e.g., 0.1–0.5 seconds). Once the device detects a stable inspiratory flow, it may activate an ejector mechanism to begin ejecting small droplets for inhalation to a target site in the respiratory system. If necessary, the device may control the ejector mechanism to stop droplet generation at a specific end of the inspiratory cycle to allow for complete inhalation of droplets to a target site in the respiratory system. Such a device provides an improved method for delivering droplets to the user's respiratory system with minimal or no irritation to the mouth or throat.

[0059] In some embodiments, the method described in the specification includes generating a droplet jet stream from a nicotine-containing fluid composition by a droplet delivery device equipped with an ejector mechanism having an opening plate (or mesh), wherein the opening plate (or mesh) has a plurality of openings formed through its thickness direction, and the droplet delivery device is configured to generate a droplet jet stream by directly or indirectly vibrating the opening plate (or mesh) at a certain frequency, wherein the average ejected droplet diameter of at least about 50% of the droplet jet stream is less than about 6 μm; and delivering the droplet jet stream to the user's respiratory system such that at least about 50% of the mass of the droplet jet stream is delivered in a range that can be inhaled into the user's respiratory system during use.

[0060] In some embodiments, the ejection flow of droplets of the nicotine-containing fluid composition described in the specification may be generated by an ejector mechanism configured to provide coordinated and precise control of droplet size. In some embodiments, the ejector mechanism of the droplet delivery device may comprise at least one opening plate (or mesh) having a plurality of openings formed through its thickness direction for ejecting droplets, wherein at least one surface of the opening plate (or mesh) is configured to provide a desired surface contact angle. In some embodiments, the opening plate (or mesh) may be configured such that at least one surface is configured to have a desired surface contact angle and to facilitate the generation of droplets with a desired droplet size distribution, e.g., less than 4 μm, less than about 3.2 microns, less than about 3 microns, less than about 2 microns, less than about 1.5 microns, about 1 micron, etc.

[0061] In some embodiments, the opening plate (or mesh) has a plurality of openings formed through its thickness, and at least one of the fluid inlet sides of the plurality of openings is configured such that the surface contact angle is less than 90 degrees. In some embodiments, the average ejected droplet diameter of at least about 50% of the droplets is less than about 6 microns during use. In some embodiments, at least a portion of the interior of at least one opening near the fluid inlet side is configured such that the surface contact angle is less than 90 degrees.

[0062] In another embodiment, the opening plate (or mesh) is configured such that at least one of the fluid outlet sides of the plurality of openings has a surface contact angle greater than 90 degrees. In some embodiments, at least a portion of the interior of at least one opening near the fluid outlet side is configured such that the surface contact angle greater than 90 degrees.

[0063] In some embodiments, the fluid inlet surface of at least one or more openings in the opening plate (or mesh) and the fluid outlet surface of at least one or more openings in the opening plate (or mesh) are configured to provide a desired surface contact angle (e.g., treatment, coating, surface modification, or a combination thereof). In some embodiments, at least a portion of the interior of at least one opening near the fluid inlet side is configured to provide a desired surface contact angle. For example, the surface contact angles of the fluid inlet surface and / or inner surface of one or more openings in the opening plate (or mesh) may be configured to be less than about 80 degrees, less than about 70 degrees, less than about 50 degrees, less than about 55 degrees, less than about 50 degrees, less than about 40 degrees, less than about 35 degrees, less than about 30 degrees, less than about 20 degrees, about 10 degrees, about 10 degrees to about 80 degrees, about 10 degrees to about 60 degrees, about 20 degrees to about 55 degrees, about 10 degrees to about 35 degrees, about 15 degrees to about 35 degrees, etc. As another example, the surface contact angles of the fluid outlet surface and / or inner surface of one or more openings in the opening plate (or mesh) may be configured to be greater than 90 degrees, such as 90 to 140 degrees, 90 to 135 degrees, 100 to 140 degrees, 100 to 135 degrees, 90 to 110 degrees, etc.

[0064] In some aspects, the droplet delivery device can deliver a predetermined amount (fixed dose) of fluid in the form of a droplet jet stream with a small average jet diameter, so that a suitable and repeatable high proportion of droplets are delivered to a desired site in the airway, e.g., the alveolar airway of the user during use. In some embodiments, the average droplet diameter may be about 0.7 μm to about 5 μm, about 0.7 μm to about 4.7 μm, about 0.7 μm to about 4 μm, about 0.7 μm to about 3.2 μm, about 0.7 μm to about 2.5 μm, about 0.7 μm to about 1.3 μm, etc. In some embodiments, the average droplet diameter may be less than about 4 microns, less than about 3.2 microns, less than about 3 microns, less than about 2 microns, less than about 1.5 microns, less than about 1 micron, etc. In some embodiments, the average droplet diameter may be approximately 1 μm to approximately 2 μm (e.g., approximately 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0 μm). In some embodiments, the average droplet diameter may be approximately 3 μm to approximately 4 μm (e.g., approximately 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0 μm). Those skilled in the art will understand that the average droplet diameter may be optimized to meet clinical needs within an acceptable range for inhalation.

[0065] In some embodiments, one or more surfaces of the opening plate (or mesh) may be modified, treated, coated, or a combination thereof to achieve a desired surface contact angle. In some embodiments, one or more surfaces of the opening plate (or mesh) may be modified, treated, coated, or a combination thereof so as to affect the hydrophobicity of the surface. As some examples, one or more surfaces of the opening plate (or mesh) may be modified, treated, coated, or a combination thereof so as to result in at least one hydrophilic surface on the opening plate (or mesh), at least one hydrophobic surface on the opening plate (or mesh) if necessary, or a combination thereof. In some embodiments, at least the fluid inlet side and, if necessary, the fluid outlet surface may be configured to have a desired surface contact angle. In some embodiments, at least a portion of the inner surface of one or more openings may be configured to have a desired surface contact angle.

[0066] In addition to the contact angle of the aperture plate (or mesh) surface, several features of the ejector mechanism enable the precise dispensing of droplets of a specific size. For example, the droplet size is determined in part by the diameter of the precisely formed opening of the aperture plate (or mesh). As an example, the size of the opening on the fluid outlet side of the aperture plate (or mesh) may be 1 μm to 6 μm, 2 μm to 5 μm, 3 μm to 5 μm, 3 μm to 4 μm, approximately 1.7 μm, approximately 2.0 μm, approximately 3.5 μm, approximately 3.9 μm, etc. In some embodiments, the aperture plate (or mesh) may have openings of various cross-sectional shapes or diameters, thereby generating ejected droplets with different average ejected droplet diameters. The ejection velocity also affects the droplet size. The ejection velocity (droplets / second) is determined by the vibration frequency of the aperture plate (or mesh), for example, 108 kHz.

[0067] In some aspects of this disclosure, a desired surface contact angle may be formed by creating a hydrophilic surface through treatment, coating, surface modification, or a combination thereof. A surface is considered hydrophilic when the angle is less than approximately 80 degrees, less than approximately 70 degrees, less than approximately 60 degrees, less than approximately 55 degrees, less than approximately 50 degrees, etc., and may be considered superhydrophilic when the angle is less than approximately 10 to 20 degrees (where droplets tend to spread across the entire surface). The strength of the hydrophilic effect may be determined by the angle between the edge of the water droplet and the surface of the opening plate (or mesh).

[0068] For example, the opening plate (or mesh) can be formed from a metal such as stainless steel, nickel, cobalt, titanium, iridium, platinum or palladium, or an alloy thereof, and can be configured to achieve the desired contact angle described in the specification. Alternatively, the opening plate (or mesh) can be formed from a suitable polymer material and can be configured to achieve the desired contact angle described in the specification. For example, the opening plate (or mesh) may be composed of a material selected from the group consisting of polyethylene naphthalate (PEN), polyetheretherketone (PEEK), polyimide, polyetherimide, polyvinylidene fluoride (PVDF), ultra-high molecular weight polyethylene (UHMWPE), polysulfone, nickel, nickel-cobalt, nickel-palladium, palladium, platinum, an alloy thereof, and combinations thereof. Furthermore, in some aspects, the opening plate (or mesh) may include a dome shape.

[0069] As an example, a desired surface contact angle may be generated on the surface of an aperture plate (or mesh) by increasing the surface energy due to the formation of a polar surface. Typical methods for increasing surface energy include forming an oxide surface on an aperture plate (or mesh) of a polar metal ejector. According to the disclosed aspects, typical methods for forming a hydrophilic surface contact angle on an aperture plate (or mesh) include immersion coating, etching, and chemical vapor deposition. Immersion coating involves immersing the aperture plate (or mesh) in a solution containing the desired coating and solvent, which forms a hydrophilic coating on the surface as the solvent evaporates. Chemical vapor deposition includes known deposition methods (e.g., plasma etching, plasma coating, plasma deposition, CVD, electroless plating, electroplating, etc.), where chemical vapor deposition uses plasma or vapor to break down the bonds on the surface of the aperture plate (or mesh) and bond oxygen or hydroxyl groups to make the surface polar. Etching methods include non-chemical etching methods by surface roughening.

[0070] In some embodiments, the deposited hydrophilic layer is significantly thinner than the size of the opening so as not to affect the size of the droplets produced. In some embodiments, the surface treatment may extend to at least a portion of one or more openings such that a hydrophilic surface is formed inside at least a portion of one or more openings of the opening plate (or mesh).

[0071] In some embodiments, the desired surface contact angle may be obtained by surface roughening, for example, achieved by non-chemical etching. While not intended to be theoretically constrained, the surface contact angle may be estimated as an approximation using Wenzel's contact angle formula ("Apparent Contact Angles on Rough Surfaces: the Wenzel Contact Angle Revisited", Wolansky and Marmur, Colloids and Surfaces A, 156 (1999) pp. 381-388). Wenzel's formula calculates the contact angle of a droplet on a rough surface. It assumes no hysteresis in the contact angle and is therefore an approximation.

[0072] In some embodiments, the surface of the aperture plate (or mesh) may be sputtered with a thin layer of precious metal such as gold (Au), palladium (Pd), platinum (Pt), silver (Ag), and precious metal alloys (e.g., thick sputtering of about 30 to 150 nm, about 60 to 100 nm, about 30 nm, about 60 nm, about 80 nm, about 100 nm, etc., as needed). In some embodiments, the surface may be sputtered with a thin layer of palladium. The precious metal layer may then be etched with various etching forces (e.g., low, medium, or high etching forces) to provide a desired surface contact angle. Etching may be performed once, twice, three times, four times, etc., to achieve the desired contact angle.

[0073] In another embodiment, the opening plate (or mesh) may be coated with a hydrophilic polymer at least on its fluid inlet side to achieve a desired surface contact angle. In yet another embodiment, the opening plate (or mesh) may be coated with at least a portion of the inner surface of one or more openings, all of the inner surface of one or more openings, the fluid inlet side and fluid ejection surface of the opening plate (or mesh), and combinations thereof. Known hydrophilic polymers suitable for medical use may be used.

[0074] A suitable hydrophilic coating may be used on the fluid inlet side of the ejector opening plate (or mesh) to achieve the desired surface contact angle. Typical hydrophilic coating materials include, but are not limited to, siloxane-based coatings, isocyanate-based coatings, ethylene oxide-based coatings, polyisocyanate-based coatings, hydrocyclosiloxane-based coatings, hydroxyalkyl methacrylate-based coatings, hydroxyalkyl acrylate-based coatings, glycidyl methacrylate-based coatings, propylene oxide-based coatings, N-vinyl-2-pyrrolidone-based coatings, latex-based coatings, polyvinyl chloride-based coatings, and polyurethane-based coatings.

[0075] As a non-limiting example, a suitable hydrophilic coating may include a single layer of hydrophilic surface formed by cleaning the surface with a low-pressure plasma and then immersing it in a solution of organophosphates that self-assemble into a polar monolayer (see, for example, Aculon Patent No. 8,658,258, incorporated by reference in this specification). The thickness of these layers is typically less than 10 nm, significantly thinner than micron-sized holes. Such coatings can achieve a low contact angle of 10 degrees.

[0076] In another embodiment, the opening plate (or mesh) may be coated with a hydrophobic coating on the fluid outlet side as needed. Known hydrophobic polymers suitable for medical applications may be used, such as polytetrafluoroethylene (Teflon®), siloxane-based coatings, paraffin, polyisobutylene, and polysulfone. If necessary, the surface of the hydrophobic coating can be chemically or structurally modified or treated to further improve or control the surface contact angle.

[0077] In some embodiments, the opening plate (or mesh) may be coated with a siloxane-based coating to form an initial hydrophobic coating, which is then masked or shielded on the fluid outlet side in an appropriate manner. After masking, the masked opening plate (or mesh) may be oxidized to make the exposed (unmasked) portion, i.e., the siloxane coating on the fluid inlet side, hydrophilic. In this way, in some embodiments of this disclosure, the same siloxane-based coating can impart both hydrophilic and hydrophobic coatings to the surface of the opening plate (or mesh). As an example, such a siloxane-based coating can be selected from siloxanes known for medical use, such as 2,4,6,8-tetramethylcyclotetrasiloxane and 1,1,3,3-tetramethyldisiloxane.

[0078] The aperture plate (or mesh) may be made of metal or polymer having an opening approximately the same size as the diameter of the desired droplet (as further described in the specification). As an example, though not limited to these, the aperture plate (or mesh) may be formed of silicon, silicon carbide, nickel palladium, or a rigid polymer such as polyether ether ketone (PEEK), polyamide, Kapton®, or ultra-high molecular weight polyethylene (UHMWPE). When using a polymer aperture plate (or mesh), the opening may be manufactured by rolling, stamping, laser ablation, bulk etching, or other known micromachining. When silicon or SiC is used for the aperture plate (or mesh), the opening may be formed by common semiconductor manufacturing processes. These silicon materials can be formed by bulk micromachining, such as wet etching, though not limited to these processes. Furthermore, the opening region of the aperture plate (or mesh) may be formed in a dome shape to increase the rigidity of the aperture plate (or mesh) and generate a uniform ejection acceleration.

[0079] The opening plate (or mesh) may have, for example, 100 to 10,000 openings, 500 to 10,000 openings, etc. The diameter of the opening on the fluid outlet side is generally about the same as the diameter of the desired droplet, for example, as further described in the specification, it may be 0.5 μm to 100 μm, 1 μm to 20 μm, 1 μm to 10 μm, 1 μm to 5 μm, 1 μm to 4 μm, etc. The diameter on the fluid inlet side may be about 30 μm to 300 μm, about 75 μm to about 200 μm, about 100 μm to about 200 μm, etc. The thickness of the opening plate (or mesh) may be formed to be about 100 μm to about 925 μm, about 100 μm to about 300 μm.

[0080] As described above, the opening plate (or mesh) may have various treatments, coatings, surface modifications, or combinations thereof on one or more of its surfaces. For example, in some embodiments, the opening plate (or mesh) may have various combinations of hydrophilic coatings on one or more surfaces, hydrophobic coatings on one or more surfaces as needed, an untreated surface, or surface etching. In some embodiments, the opening plate (or mesh) may have an etched, hydrophobic coated, or untreated fluid inlet side (facing the fluid reservoir) of the opening plate (or mesh), or a non-chemically etched side. In other embodiments, the opening plate (or mesh) may have a hydrophilic coating on at least the fluid inlet side (facing the fluid reservoir) of the opening plate (or mesh), or a hydrophilic coating on at least a portion of the interior of one or more openings, or a combination thereof. In yet another embodiment, the opening plate (or mesh) may have a hydrophobic coating on the droplet outlet side of the opening plate (or mesh), either alone or in combination with one or more hydrophilic coatings. Hydrophobic and hydrophilic surfaces may be formed using gaseous or liquid methods. For example, hydrophilic and hydrophobic surfaces can be formed by liquid coating, sputtering, CVD, plasma deposition, ion implantation, etc.

[0081] The opening plate (or mesh) may be manufactured, for example, by semiconductor technology, stamping, rolling, or laser ablation. Rolling may be preferred because it allows for precise shaping and continuous production from rolls can reduce manufacturing costs. Since the stiffness of polymers (especially UHMWPE) is lower than that of metals such as stainless steel or palladium nickel, ribs on the fluid side or air side of the opening plate (or mesh) may be formed during rolling or before laser ablation. Similarly, metal annular members may be used to increase the stiffness of the edges of the opening plate (or mesh) against deflection. Furthermore, the opening plate (or mesh) region can be formed into a dome shape to increase the stiffness of the opening plate (or mesh) and generate a uniform ejection acceleration.

[0082] All publications and patent applications referenced in this specification are incorporated by reference in such a manner as it is specifically and individually indicated that each individual publication or patent application is incorporated by reference. [Examples]

[0083] Examples are given below to illustrate some aspects. Those skilled in the art will understand that the techniques disclosed in the following examples represent techniques that have been found to function well in the implementation of the methods, compositions and apparatus described in the claims. However, in view of this disclosure, those skilled in the art will understand that modifications can be made to some of the disclosed aspects to obtain similar or comparable results without departing from the spirit and scope of the aspects of this invention.

[0084] Example 1 As one example, a nicotine-containing preparation was manufactured. The preparation contained 2% (w / w) nicotine and 1.75 ± 0.5% (w / w) L-(+)-lactic acid (Cas # 79-33-4) in type I water. The pH of the preparation was approximately 5.2.

[0085] Example 2 As one example, a nicotine-containing preparation was manufactured. The preparation contained 2% (w / w) nicotine, 1.75±0.5% (w / w) L-(+)-lactic acid (Cas # 79-33-4), 10% (w / w) ethanol, and 0.088% (w / w) L-menthol (Cas # 2216-51-5) in Type I water. The pH of the preparation was approximately 5.2.

[0086] Various aspects of this invention have been described. However, it is clear that various modifications and changes, as well as additional aspects, are possible without departing from the broad scope of the disclosed invention. This specification should be interpreted as illustrative, not restrictive.

Claims

1. A composition containing approximately 0.1% (w / w) to approximately 5% (w / w) of nicotine; approximately 0.1% (w / w) to approximately 5% (w / w) of L-lactic acid; and water.

2. The composition according to claim 1, wherein the concentration of nicotine is approximately 2% (w / w).

3. The composition according to claim 1, wherein the concentration of L-lactic acid is approximately 1.8% (w / w).

4. The composition according to claim 1, wherein the pH of the composition is approximately 5.

2.

5. The composition according to claim 1, wherein the composition is substantially free of D-lactic acid.

6. The composition according to claim 1, further comprising ethanol.

7. The composition according to claim 6, wherein the concentration of the ethanol is approximately 10% (w / w).

8. The composition according to claim 1, further comprising menthol.

9. The composition according to claim 8, wherein the concentration of menthol is approximately 0.09% (w / w).

10. The composition according to claim 8, wherein the menthol is L-menthol.

11. The composition according to claim 1, wherein the composition is in the form of droplets and is suitable for delivery to the respiratory system of a target.

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