RU2770039C2 - Inhaled nicotine-based compositions and methods for production and application thereof - Google Patents

Abstract

FIELD: simulated smoking devices.

SUBSTANCE: group of inventions relates to a dry powder inhaled composition for simulating the effects of smoking. Dry powder nicotine-based composition containing particles, wherein the particles comprise: nicotine salt, at least one sugar, and at least one amino acid selected from the group consisting of glycine, lysine, leucine, and a combination thereof, wherein the particles have a size from 1 to 7 mcm, wherein the concentration of nicotine is from 0.5 to 10 wt.%, and the concentration of at least one sugar is from 50 to 99 wt.%, and wherein the composition is suitable for inhalation for simulating the effects of smoking. Dry powdered nicotine-based composition consisting of particles containing nicotine, at least one sugar, menthol, and at least one amino acid selected from the group consisting of glycine, lysine, and leucine, wherein the particles have a size from 1 to 7 mcm, wherein the concentration of nicotine is from 0.5 to 10 wt.%, and the concentration of at least one sugar is from 50 to 99 wt.%, wherein the composition is suitable for inhalation for simulating the effects of smoking. Dry powder nicotine-based composition containing from 0.5 to 10 wt.% of nicotine, from 50 to 99 wt.% of at least one sugar, and leucine, wherein the dry powder nicotine-based composition comprises a flavouring component and nicotine-containing particles, at least one sugar, and leucine, wherein the particles have a size from 1 to 7 mcm, and wherein the composition is suitable for inhalation for simulating the effects of smoking.

EFFECT: above compositions are effective for simulating the effects of smoking, including for quitting smoking, introduction of an amino acid reduces the degradation of the composition, improves the fluidity of the powder.

12 cl, 6 dwg

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under US Patent Application 15/452,133, filed March 7, 2017, which is a continuation of US Patent Application No. 14/856,102, currently US Patent No. 9,585,835, filed September 16, 2015, each of which are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

Smoking is an addictive habit that has been found to be a concomitant or causative factor in a number of diseases, including respiratory diseases such as emphysema, chronic bronchitis, lung infections and lung cancer, but also various heart conditions. With the growing public awareness of the dangers of smoking for human health, the number of smokers trying to quit this habit has increased. It is now accepted in scientific and medical circles that nicotine in cigarette smoke causes addiction through the effects it has on nicotinic receptors in the brain. Individuals who use cigarettes most regularly become dependent on or addicted to the pharmacological effects of nicotine in tobacco smoke. A common strategy in overcoming nicotine addiction in general and nicotine addiction in particular is to mimic the effects of cigarette smoking followed by a gradual decrease and eventually elimination.

There are several effects of smoking that a potential therapeutic formulation or method would help mimic. Among the most important effects of smoking are the chemical and mechanical effects of cigarette smoke on the smoker's airways and the absorption of nicotine into the smoker's blood. The chemical and mechanical effects of cigarette smoke on the smoker's airways result in a certain level of satisfaction experienced by the smoker. Absorption of nicotine into the smoker's blood results in the nicotine reaching various receptors in the smoker's nervous system, which in turn affects the smoker's perceived craving for nicotine. Both effects can potentially be mimicked by administering doses of nicotine-based formulations to a subject in need of smoking cessation therapy. Treatment of nicotine addiction can be achieved by gradually reducing doses until they are completely discontinued.

Leucine is an amino acid having an aliphatic isobutyl side chain. As a consequence, leucine is usually classified as a hydrophobic amino acid. Leucine is an essential amino acid because the human body is unable to synthesize it and must be provided from exogenous sources. Leucine plays a number of roles in metabolism and is involved, among other things, in the formation of sterols and the stimulation of muscle protein synthesis. Lysine is a basic amino acid with a side amino chain. Lysine is also an essential amino acid that is essential for calcium absorption. The terminal amine of the lysine may be chemically modified. Glycine, which has no side chain, is the smallest amino acid. Glycine is essential for the biosynthesis of the structural protein collagen and is also used as a sweetener.

Lactose is a disaccharide found in milk that has two residues: galactose and glucose. Lactose is used in the fields of pharmacology, for example, as a filler, due to its physical properties (for example, the ability to undergo compression). Tartaric acid is a diprotic acid found naturally in many plants, such as grapes and bananas. Tartrates are salts of tartaric acid with basic compounds such as nicotine. Phospholipids are the main components of cell membranes due to their amphiphilic nature. Phospholipids are also natural components of lung surfactant and are found in high concentrations in egg yolk and cow's milk.

Menthol is a well-known and widely used local anesthetic, decongestant and cough suppressant. Almost all cigarettes contain menthol to regulate flavor and reduce coughing. If the concentration of menthol in a cigarette is greater than 3%, then the label indicates that it is a menthol cigarette. Methods for using menthol in cigarettes include adding to the tobacco leaf. A plastic ball filled with menthol can be stored in a cigarette filter and then crushed before smoking the cigarette. When lighting a cigarette, the heated smoke helps vaporize and transport the menthol into the smoker's airways.

There is a need in the art for improved nicotine formulations, in particular dry powder formulations suitable for inhalation. The present invention satisfies this need.

BRIEF DESCRIPTION OF THE PRESENT INVENTION

In one aspect of the present invention, a nicotine-based dry powder formulation suitable for inhalation is described. This composition contains nicotine, at least one sugar and at least one amino acid selected from the group consisting of glycine and lysine, or combinations thereof. In one embodiment, the formulation further comprises at least one phospholipid. In one embodiment, the formulation further comprises menthol. In another embodiment, the formulation further comprises mint. In one embodiment, the nicotine is nicotine tartrate. In one embodiment, the nicotine concentration is from 0.5% to 10%. In one embodiment, the sugar concentration is between 50% and 99%. In one embodiment, the amino acid concentration is from 0.5% to 50%.

In another aspect of the present invention, a nicotine dry powder formulation suitable for inhalation is described. This composition contains nicotine, at least one sugar, mint and at least one amino acid selected from the group consisting of glycine, lysine and leucine. In one embodiment, at least 40% of the nicotine and amino acid particles are 3 to 4 microns in size. In another embodiment, at least about 80% of the nicotine and amino acid particles are 1 to 7 microns in size. In one embodiment, the particle size of the sugar is at least about 50 microns. In one embodiment, the mint particle size is at least about 20 microns.

In another aspect of the present invention, a nicotine dry powder formulation suitable for inhalation is described. This composition contains particles of nicotine, particles of at least one sugar and particles of at least one amino acid selected from the group consisting of glycine, lysine and leucine. In this formulation, the amino acid particles are essentially unrelated to the nicotine particles. In one embodiment, the formulation further comprises at least one phospholipid. In one embodiment, the formulation further comprises mint.

BRIEF DESCRIPTION OF THE DRAWINGS

The following detailed description of the preferred embodiments of the present invention will be better understood when read in conjunction with the accompanying drawings. For purposes of illustrating the present invention, the drawings show embodiments which are currently preferred. However, it should be understood that the present invention is not limited to the particular circuits and means of the embodiments shown in the drawings.

Figure 1 is a flow chart depicting an exemplary method for delivering the required amount of nicotine and the required amount of menthol to a subject.

Figure 2 is a flow chart depicting an exemplary method for delivering reduced or increased dosages of nicotine to a subject in multiple doses while maintaining a constant level of menthol per dose.

Figure 3 is a diagram depicting exemplary formulations of the present invention delivering consistent amounts of nicotine with increasing amounts of menthol.

Figure 4 is a diagram depicting exemplary formulations of the present invention delivering decreasing amounts of nicotine while maintaining a constant amount of menthol.

Figure 5 is a flowchart depicting an exemplary method for the manufacture of the composition of the present invention, involving dry mixing.

Figure 6 is a flowchart depicting an exemplary method for making a composition of the present invention involving wet mixing.

DETAILED DESCRIPTION

The present invention provides dry powder formulations containing nicotine, methods for their use and methods for their preparation. Dry powder formulations may additionally contain excipients, therapeutic agents and flavoring components. Dry powder formulations can be made using dry methods and wet methods.

Definitions

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as they are commonly understood by those skilled in the art to which the present invention pertains. While any methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present invention, preferred methods and materials are described.

Each of the following terms used in this document has the meaning associated with it in this section.

Singular nouns are used herein to refer to one or more than one (i.e., at least one) noun grammatical object. By way of example, "element" means one element or more than one element.

"Approximately" used in this document for a measured value such as quantity, time period, etc., is intended to cover deviations of ±20%, ±10%, ±5%, ±1%, and ±0.1% of the specified value if such deviations are appropriate.

As used herein, the term "composition" refers to a mixture of at least one compound or molecule useful in the present invention with one or more different compound, molecule or material.

As used herein, the term “formulation amount” refers to the total or partial amount of a dry powder nicotine formulation packaged in a disposable container, such as a capsule or blister pack, for use with a dry powder inhaler, or to the total or partial amount of a dry powder nicotine formulation. a nicotine-based powder formulation that can be loaded into a delivery chamber or dry powder inhaler compartment.

As used herein, the term "puff" refers to the effect of an inhaled amount of a nicotine dry powder formulation, typically from a dry powder inhaler, and may mean, for example, a single puff or multiple puffs.

As used herein, "educational material" includes a physical or electronic publication, recording, diagram, or any other means of expression that can be used to inform the applicability of the composition and method of the present invention for their intended purpose. The training material of the kit of the present invention, for example, may be attached to a container that contains the composition, or supplied with a container that contains the composition. Alternatively, the educational material may be delivered separately from the container so that the educational material and composition are shared by the recipient.

The term "pharmaceutically acceptable" refers to those properties and/or substances that are acceptable to the patient from a pharmacological/toxicological standpoint, and to a pharmaceutical chemist in the workplace from a physical/chemical standpoint, with respect to composition, composition, stability, patient acceptability, and bioavailability. "Pharmaceutical acceptable" may also refer to a carrier, meaning a medium that does not affect the efficacy of the biological activity of the active ingredient(s) and is not toxic to the host to which it is administered. Other additional ingredients that may be included in pharmaceutical compositions useful in the practice of the present invention are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which incorporated into this document by reference.

Unless otherwise indicated, the particle size or size range described should be taken as the mass median aerodynamic diameter (MMAD) of the particle or group of particles. These values are based on the distribution of aerodynamic particle diameters, defined as the diameter of a sphere with a density of 1 g/cm ³ that has the same aerodynamic characteristics as the particle being characterized. Since the particles described herein may have different densities and shapes, the particle size is expressed as MMAD and not the actual particle diameter.

Throughout the present invention, various aspects of the present invention may be represented in a range format. It should be understood that the description in range format is for convenience and brevity only and should not be construed as an inflexible limitation on the scope of the present invention. Accordingly, a description of a range should be considered as specifically disclosing all possible subranges as well as individual numerical values within that range. For example, a description of a range such as 1 to 6 should be considered to include specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 up to 6, etc., as well as individual numbers within this range, such as 1, 2, 2.7, 3, 4, 5, 5.3, 6, and any integer and partial increments in between. This applies regardless of the range width.

Compositions and compounds

In one aspect, the present invention relates to a dry powder nicotine formulation suitable for inhalation. In one embodiment, the nicotine is present in the formulation as a free base. In another embodiment, the formulation contains a nicotine salt. In one such embodiment, the nicotine salt is nicotine tartrate. In another embodiment, the nicotine salt is nicotine bitartrate. In other embodiments, the nicotine salt may be derived from any suitable non-toxic acid, including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, hexafluorophosphoric, citric, gluconic, benzoic, propionic, butyric, sulfosalicylic, maleic, lauric, malic, fumaric, succinic, tartaric, amsonic, pamoic, etc. -toluenesulfonic and mesylic acids. Suitable organic acids may be selected, for example, from the classes of aliphatic, aromatic, carboxylic and sulfonic organic acids, examples of which are formic, acetic, propionic, succinic, camphorsulfonic, citric, fumaric, gluconic, isethionic, lactic, malic, mucinic, tartaric, para-toluenesulfonic, glycolic, glucuronic, maleic, furancarboxylic, glutamic, benzoic, aminobenzoic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic (besylate), stearic, sulfanilic, alginic, galacturonic acids, etc. . P.

In another aspect, the present invention relates to a dry powder formulation suitable for inhalation based on nicotine, additionally containing sugar. In one embodiment, the sugar is a disaccharide. In one embodiment, the disaccharide is selected from the group consisting of sucrose, lactose, maltose, trehalose, and cellobiose. In one embodiment, the sugar is lactose.

In one aspect, the present invention relates to a nicotine-based dry powder formulation suitable for inhalation further comprising at least one amino acid. In one embodiment, the amino acid is selected from the group consisting of histidine, alanine, isoleucine, arginine, leucine, asparagine, lysine, aspartic acid, methionine, cysteine, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, glycine, valine, pyrrolysine, proline , selenocysteine, serine and tyrosine. In one embodiment, the amino acid is leucine. In one embodiment, the amino acid is a lysine. In one embodiment, the amino acid is glycine.

In one aspect, the present invention relates to a dry powder nicotine formulation suitable for inhalation further comprising at least one phospholipid. Phospholipids that can be used in the present invention include, without limitation, phosphatidic acids, phosphatidylcholines of both saturated and unsaturated lipids, phosphatidylethanolamines, phosphatidylglycerols, phosphatidylserines, phosphatidylinositols, lysophosphatidyl derivatives, cardiolipin, and β-acyl-y-alkylphospholipids. Examples of phosphatidylcholines include dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine (DMPC), dipentadekanoilfosfatidilholin, dilauroylphosphatidylcholine, dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), diarahidoilfosfatidilholin (DAPC), dibegenoilfosfatidilholin (DBPC), ditrikozanoilfosfatidilholin (DTPC), dilignotseroilfosfatidilholin (DLPC) and phosphatidylethanolamines such as dioleoylphosphatidylethanolamine or 1-hexadecyl-2-palmitoylglycerophosphoethanolamine. Examples of phosphatidylethanolamines include dicaprylphosphatidylethanolamine, dioctanoylphosphatidylethanolamine, dilauroylphosphatidylethanolamine, dimyristoylphosphatidylethanolamine (DMPE), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoleoylphosphatidylethanolamine, distearoylphosphatidylethanolamine (DSPE), dioleoylphosphatidylethanolamine and dilineoylphosphatidylethanolamine. Examples of phosphatidylglycerols include dicaprylphosphatidylglycerol, dioctanoylphosphatidylglycerol, dilauroylphosphatidylglycerol, dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphosphatidylglycerol (DPPG), dipalmitoleoylphosphatidylglycerol, distearoylphosphatidylglycerol (DSPG), dioleoylphosphatidylglycerol and dilineoylphosphatidylglycerol. You can also use synthetic phospholipids with asymmetric acyl chains (for example, with one acyl chain of 6 carbon atoms and another acyl chain of 12 carbon atoms). Additional examples of phospholipids include modified phospholipids, for example, phospholipids with a modified end group, for example, alkylated or polyethylene glycol (PEG)-modified, hydrogenated phospholipids, phospholipids with different end groups (phosphatidylmethanol, phosphatidylethanol, phosphatidylpropanol, phosphatidylbutanol, etc.), dibromophosphatidylcholines , mono- and diphytanoyl phosphatides, mono- and diacetylenic phosphatides and PEG-phosphatides.

In one aspect, the present invention relates to a nicotine-based dry powder formulation suitable for inhalation further comprising a flavor component. In one embodiment, the flavor component is derived from natural flavors, natural identical flavors, or artificial flavors. Non-limiting examples of flavors or flavors include banana, cherry, cinnamon, fruit, grape, orange, peach, pineapple, vanilla, wintergreen, strawberry, and mint. In one embodiment, the flavor component is menthol. In another embodiment, the flavor component is mint.

One of skill in the art will appreciate that mint in general is, without limitation, any and all flavors associated with the plant genus in the Lamiaceae family. In one embodiment, mint is a natural extract. In another embodiment, the mint is a commercially available formulation such as Coolmint Trusil Flavoring Powder available from International Flavors & Fragrances. In one embodiment, mint is a single substance. In another embodiment, the mint is a mixture of substances. In one embodiment, the mint contains menthol. In another embodiment, the mint contains trans-menthone. In another embodiment, the mint contains pinene. In another embodiment, the mint contains isomentone. In another embodiment, the mint contains limonene. In another embodiment, the mint contains eucalyptol. In another embodiment, mint contains pin-2(3)-ene. In another embodiment, the mint contains menthyl acetate. In another embodiment, the mint contains cineole. In another embodiment, the mint contains 4,5,6,7-tetrahydro-3,6-dimethylbenzofuran. In another embodiment, mint contains pin-2(10)-ene. In another embodiment, the mint contains dipentene. In another embodiment, mint contains d limonene. In another embodiment, mint contains (R)-p-menta-1,8-diene.

In one aspect, the present invention relates to a dry powder nicotine formulation suitable for inhalation further comprising a cough suppressant. In one embodiment, the cough suppressant is menthol. In another embodiment, the cough suppressant is mint.

One of skill in the art will appreciate that menthol and/or mint can serve multiple functions in a formulation. In one embodiment, menthol is a flavor component. In another embodiment, the menthol is a therapeutic agent such as, for example, a cough suppressant. In one embodiment, mint is a flavor component. In another embodiment, mint is a therapeutic agent such as, for example, a cough suppressant.

Lineups

The present invention relates to dry powder formulations based on nicotine suitable for inhalation. In one embodiment, the formulation contains nicotine particles. In another embodiment, the formulation further comprises excipients. In another embodiment, the formulation further comprises therapeutic agents. In another embodiment, the composition further comprises flavoring components.

As provided herein, any form of nicotine may be used as the nicotine-based component. Preferably, a form of nicotine is used that allows rapid absorption into the patient's lungs. Preferred is the form of nicotine, which can be formulated in the form of particles. You can also use a form of nicotine that can be ground or ground together with sugar or other ingredients. In another embodiment, the nicotine is mixed with sugar or other ingredients. In one embodiment, nicotine is a salt that is a solid at room temperature. Nicotine may additionally be a pharmacologically active analog or derivative of nicotine, or a substance that mimics the effect of nicotine, either alone or in combination with other active substances. If nicotine is a base, then it can be added to a liquid carrier such as water and mixed to form a generally homogeneous liquid mixture, which can then be dried using various methods to form a dry particulate composition. In other embodiments, a form of nicotine that is soluble or miscible with a liquid carrier may also be used. For example, nicotine may be a nicotine base which is a water-miscible liquid at room temperature. Alternatively, the nicotine base may be an oil formulation.

In one aspect, the present invention relates to a nicotine dry powder formulation suitable for inhalation, wherein the nicotine concentration is from about 0.5% to about 10%. In one embodiment, the nicotine concentration is about 0.5%. In another embodiment, the nicotine concentration is about 1%. In another embodiment, the nicotine concentration is about 1.5%. In another embodiment, the nicotine concentration is about 2%. In another embodiment, the nicotine concentration is about 2.5%. In another embodiment, the nicotine concentration is about 3%. In another embodiment, the nicotine concentration is about 3.5%. In another embodiment, the nicotine concentration is about 4%. In another embodiment, the nicotine concentration is approximately 4.5%. In another embodiment, the nicotine concentration is about 5%. In another embodiment, the nicotine concentration is approximately 5.5%. In another embodiment, the nicotine concentration is about 6%. In another embodiment, the nicotine concentration is about 6.5%. In another embodiment, the nicotine concentration is about 7%. In another embodiment, the nicotine concentration is about 7.5%. In another embodiment, the nicotine concentration is about 8%. In another embodiment, the nicotine concentration is approximately 8.5%. In another embodiment, the nicotine concentration is about 9%. In another embodiment, the nicotine concentration is approximately 9.5%. In another embodiment, the nicotine concentration is about 10%.

In one embodiment, the formulation contains nicotine particles (also referred to herein as the nicotine-based component) that are essentially about 1-10 microns in size, based on the MMAD of the particles. In yet another embodiment, the formulation contains nicotine particles that are essentially about 1-7 microns in size. In another embodiment, the formulation contains nicotine particles that are essentially about 2-5 microns in size. In yet another embodiment, the formulation contains nicotine particles that are essentially about 2-3 microns in size. By selectively restricting or removing nicotine particles smaller than about 1 micron or smaller than about 2 microns, the compositions of the present invention eliminate or at least reduce the ability of a subject to exhale nicotine back into the environment, thereby effectively reducing or eliminating the emission of nicotine contained in the smoke. with passive smoking. In addition, by selectively restricting or removing non-respirable nicotine particles, the compositions of the present invention provide a reduction in unwanted irritation caused by nicotine particles trapped in the larger airways, oropharynx, vocal cords in the glottis, and other more proximal or closer anatomical sites. to the oral cavity. Accordingly, in some embodiments, the smallest particle size in the nicotine particle size range is at least about 1 micron, at least about 1.1 microns, at least about 1.2 microns, at least about 1.3 microns, at least about 1.4 microns, at least about 1.5 microns, at least about 1.6 microns, at least about 1.7 microns, at least about 1.8 microns, at least about 1, 9 microns, at least about 2 microns, at least about 2.1 microns, at least about 2.2 microns, at least about 2.3 microns, at least about 2.4 microns, at least about 2.5 microns, at least about 2.6 microns, at least about 2.7 microns, at least about 2.8 microns, at least about 2.9 microns, and or at least about 3 microns. In some embodiments, the largest particle size within the nicotine particle size range is no more than about 10 microns, no more than about 7 microns, no more than about 6 microns, no more than about 5 microns, no more than about 4.5 microns, no more than about 4 micron, not more than about 3.5 microns, or not more than about 3 microns. In certain embodiments, no more than about 10% of the nicotine particles are less than about 1 micron in size. In certain embodiments, no more than about 10% of the nicotine particles are less than about 2 microns in size. In other embodiments, at least 90% of the nicotine particles are less than about 10 microns in size. In other embodiments, at least 90% of the nicotine particles are less than about 7 microns in size. In other embodiments, at least 90% of the nicotine particles are less than about 5 microns in size. In one embodiment, no more than about 10% of the nicotine particles are less than about 1 micron, and at least 90% of the nicotine particles are less than about 10 microns. In one embodiment, no more than about 10% of the nicotine particles are less than about 1 micron, and at least 90% of the nicotine particles are less than about 7 microns. In one embodiment, no more than about 10% of the nicotine particles are less than about 2 microns, and at least 90% of the nicotine particles are less than about 5 microns. In one embodiment, no more than about 10% of the nicotine particles are less than about 2 microns, and at least 90% of the nicotine particles are less than about 3 microns.

In one embodiment, the mass median aerodynamic diameter (MMAD) of the particles is approximately 2.0 microns. In one embodiment, the MMAD of the particles is approximately 2.1 microns. In one embodiment, the MMAD of the particles is approximately 2.2 microns. In one embodiment, the MMAD of the particles is approximately 2.3 microns. In one embodiment, the MMAD of the particles is approximately 2.4 microns. In one embodiment, the MMAD of the particles is approximately 2.5 microns. In one embodiment, the MMAD of the particles is approximately 2.6 microns. In one embodiment, the MMAD of the particles is approximately 2.7 microns. In one embodiment, the MMAD of the particles is approximately 2.8 microns. In one embodiment, the MMAD of the particles is approximately 2.9 microns. In one embodiment, the MMAD of the particles is approximately 3.0 microns. In one embodiment, the MMAD of the particles is approximately 3.1 microns. In one embodiment, the MMAD of the particles is approximately 3.2 microns. In one embodiment, the MMAD of the particles is approximately 3.3 microns. In one embodiment, the MMAD of the particles is approximately 3.4 microns. In one embodiment, the MMAD of the particles is approximately 3.5 microns. In one embodiment, the MMAD of the particles is approximately 3.6 microns. In one embodiment, the MMAD of the particles is approximately 3.7 microns. In one embodiment, the MMAD of the particles is approximately 3.8 microns. In one embodiment, the MMAD of the particles is approximately 3.9 microns. In one embodiment, the MMAD of the particles is approximately 4.0 microns. In one embodiment, the MMAD of the particles is approximately 4.1 microns. In one embodiment, the MMAD of the particles is approximately 4.2 microns. In one embodiment, the MMAD of the particles is approximately 4.3 microns. In one embodiment, the MMAD of the particles is approximately 4.4 microns. In one embodiment, the MMAD of the particles is approximately 4.5 microns. In one embodiment, the MMAD of the particles is approximately 4.6 microns. In one embodiment, the MMAD of the particles is approximately 4.7 microns. In one embodiment, the MMAD of the particles is approximately 4.8 microns. In one embodiment, the MMAD of the particles is approximately 4.9 microns. In one embodiment, the MMAD of the particles is approximately 5.0 microns.

One skilled in the art will appreciate that the particle size ranges described herein are not absolute ranges. For example, a mixture of nicotine particles of the present invention with a size range of about 2-5 microns may contain a proportion of particles that are less than or greater than the range of about 2-5 microns. In one embodiment, the particle size value provided for any particular component of the formulations according to the present invention, is the D90 value, where 90% of the particle sizes in the mixture is less than the D90 value. In another embodiment, the particle size range is a particle size distribution (PSD), where the percentage of particles in the mixture is within the specified range. For example, a nicotine particle size range of about 2-5 microns may be a mixture of nicotine particles containing at least 50% of particles in the range of about 2-5 microns, but more preferably a higher percentage, e.g., without limitation : 60%, 70%, 80%, 90%, 95%, 97%, 98% or even 99%.

It should be understood that the particles of the nicotine-based component may be spherical or have any other desired shape. In one embodiment, the particles may have an uneven or "corrugated" surface. In such embodiments, the uneven surface may enhance the ability of the additional components to adhere to the nicotine particles and form a uniform coating. For example, the additional component may be a therapeutic agent, such as menthol, ensuring that each nicotine particle that acts on the cough receptor is coated with menthol, which will suppress the cough reflex. An uneven surface can also provide relative turbulence as the particles move with the air, thereby imparting aerodynamic lift to the particles. In such embodiments, particles shaped in this way can be more easily captured and retained in the air breathed in by the subject, thereby improving the ability of the nicotine component particles to travel and remain in the subject's airways.

In one embodiment, the composition contains at least one amino acid. In one embodiment, the amino acid acts as a stabilizer by reducing to some extent the degradation of the composition of the present invention. In one embodiment, the amino acid acts as a carrier. In another embodiment, the amino acid prevents degradation of the composition of the present invention by acting as a buffer through its buffering properties. In another embodiment, the amino acid acts as a powder flow enhancer. In another embodiment, the amino acid in the composition of the present invention improves the flowability of the powder. In another embodiment, the amino acid in the composition of the present invention provides easier capture and retention of particles of the powder composition in the air inhaled by the subject, thereby improving the ability of the particles of the composition to move and stay in the respiratory tract. In one embodiment, the percentage of amino acid in the composition is from 0.5% to 10%. In some embodiments, the implementation of the percentage of amino acids in the composition is from 1.5% to 2.5%. In other embodiments, the implementation of the percentage of amino acids in the composition is from 0.5% to 2.5%. In yet other embodiments, the implementation of the percentage of amino acids in the composition is from 1.5% to 5%. In one embodiment, the percentage of amino acid in the composition is approximately 2.5%. In another embodiment, the percentage of amino acid in the formulation is about 5%. In another embodiment, the percentage of amino acid in the formulation is about 7.5%. In another embodiment, the percentage of amino acid in the formulation is about 10%. In another embodiment, the amino acid percentage is about 20%. In another embodiment, the amino acid percentage is about 30%. In another embodiment, the amino acid percentage is about 40%. In another embodiment, the amino acid percentage is about 50%. In another embodiment, the amino acid percentage is about 60%. In another embodiment, the amino acid percentage is about 70%. In another embodiment, the amino acid percentage is about 80%. In another embodiment, the amino acid percentage is about 90%. In another embodiment, the amino acid percentage is about 95%. In another embodiment, the amino acid percentage is about 97.5%. In another embodiment, the amino acid percentage is about 99%. In one embodiment, the amino acid is leucine. In another embodiment, the amino acid is a lysine. In another embodiment, the amino acid is glycine.

In one embodiment, the formulation further comprises excipients. It is contemplated herein that one embodiment of the excipient is a bulking agent. Bulking agents may include respirable sugars, which are generally solids at room temperature. Sugar can be milled directly into a particulate formulation, or separately, or milled together with the nicotine component. Also, the sugar may be soluble in a liquid carrier such as water. Without limitation, examples of suitable sugars are lactose, sucrose, raffinose, trehalose, fructose, dextrose, glucose, maltose, lecithin, mannitol, or combinations thereof. In one embodiment, the sugar is lactose. In another embodiment, the lactose is lactose coarse. In another embodiment, the sugar is lactose alpha monohydrate. The sugar may be natural or synthetic sugar and may include any sugar analogs or derivatives. It should be understood that any form of sugar approved for use as an excipient may be used as a carrier in the preparation of the nicotine component. Although not intended, the sugar is preferably of pharmaceutical grade, as will be understood by those skilled in the art. Preferably, the pharmaceutical grade sugar used alone for grinding, grinding together with the nicotine component, or for creating a flowable mixture is an unspheronized sugar. Pharmaceutical grade sugar can be obtained in non-spheronized form prior to dry or wet mixing with nicotine. For example, pharmaceutical grade sugar can first be obtained in a non-spheronized form by lyophilization, milling, micronizing, or the like. In certain embodiments, pharmaceutical grade sugar may be subjected to grinding, splitting, milling, crushing, cutting, sieving, or other physical disruption method known to those skilled in the art that ultimately reduces the size of the sugar particle and results in the formation of an unspheronized Sahara. In one embodiment, the particle size of the sugar is at least about 60 microns. In one embodiment, the particle size of the sugar is from 60 to 90 microns. In one embodiment, the particle size of the sugar is greater than about 90 microns. In one embodiment, the particle size of the sugar is about 60 microns.

It should be understood that there are no restrictions on the ratio of nicotine to sugar used, and the actual ratio used will depend on the concentration of nicotine required in the nicotine component particles. Accordingly, in one embodiment, the sugar concentration is at least about 50%. In another embodiment, the sugar concentration is from about 50% to about 99%.

In another embodiment, the formulation may further comprise an excipient, which is any pharmaceutically acceptable material, composition, or carrier such as a liquid or solid excipient, stabilizer, dispersant, suspending agent, diluent, thickener, solvent, or encapsulating material involved in the transfer or transporting a compound useful in the present invention within or to a subject so that it can perform its intended function. In one embodiment, the formulation further comprises a stabilizing agent. Each material must be "acceptable" in the sense that it is compatible with the other ingredients of the formulation, including nicotine, and is not harmful to that subject. Some materials that may be applicable in the composition of the present invention include pharmaceutically acceptable carriers, for example, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; surfactants; amino acids such as leucine, L-leucine, D-leucine, DL-leucine, isoleucine, lysine, valine, arginine, aspartic acid, threonine, methionine, phenylalanine, glycine; alginic acid; amino acid derivatives such as an amino acid derivative such as aspartame or acesulfame K; phospholipids such as dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, diarachidoylphosphatidylcholine, dibegenoylphosphatidylcholine or diphosphatidylglycerol; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solutions and other non-toxic compatible substances used in pharmaceutical formulations. Other pharmaceutically acceptable materials that may be applicable in this composition include any and all coating materials, antibacterial and antifungal agents and absorption delay agents and the like, which are compatible with the activity of nicotine or any other compound useful in the present invention, and are physiologically acceptable to the subject. Complementary active compounds, including pharmaceutically acceptable salts of these compounds, may also be included in the compositions. Other additional ingredients that may be included in the compositions used in the practice of the present invention are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is included to this document by reference. In one embodiment, the carrier is an amino acid.

In one embodiment, the composition of the present invention may further contain therapeutic agents. In one embodiment, the therapeutic agent is a cough suppressant. In one embodiment, the cough suppressant component is menthol. In one embodiment, the concentration of menthol in the composition is from about 0.5% to about 20%. As contemplated herein, any form of menthol, such as a solid form of menthol, can be used to process menthol particles, powder, solution, or suspension useful in the present invention. Non-limiting examples of solid forms of menthol include powders, crystals, solidified distillates, flakes, and press-formed articles. In one embodiment, the menthol is in the form of crystals. Menthol can be processed to particle sizes ranging from about 5 microns (µm) to about 10 µm using any method known in the art. In some embodiments, the menthol is mixed with additional liquid or solid processing aids. In addition, particulate additives may also be used. In one embodiment, menthol is mixed with silica. In another embodiment, the menthol is mixed with a sugar such as lactose. In some embodiments of the wet process, the menthol is treated in a carrier liquid. In another embodiment, the additional cough suppressant component is mint. In one embodiment, the concentration of mint in the formulation is from about 0.5% to about 20%. As contemplated herein, any form of mint, such as solid mint, can be used to process mint particles, powder, solution, or suspension useful in the present invention. In one embodiment, the composition of the present invention does not contain a therapeutic agent. In one embodiment, the therapeutic agent is an anticancer agent.

In one embodiment, the therapeutic agent may comprise a cough suppressant component having particles substantially between 5 and 10 microns in size. In another embodiment, the additional component, which is a cough suppressant, may include benzocaine. It should be understood that the additional cough suppressant component may include any compound approved for cough suppression. By selectively incorporating 5-10 micron menthol particles, such non-respirable menthol particles can reduce cough in the subject's upper respiratory tract. Accordingly, in some embodiments, the smallest particle size within the particle size range of the cough suppressant accessory component is at least about 5 microns, at least about 6 microns, at least about 7 microns, or at least about 8 microns. In some embodiments, the largest particle size within the particle size range of the cough suppressant additive is no more than about 10 microns, no more than about 9 microns, no more than about 8 microns, or no more than about 7 microns. In certain embodiments, no more than about 10% of the additional cough suppressant particles are less than about 5 microns in size. In other embodiments, at least 90% of the particles of the additional cough suppressant are less than about 10 microns. In other embodiments, at least 90% of the particles of the additional cough suppressant are less than about 8 microns. In one embodiment, no more than about 10% of the particles of the additional cough suppressant are less than 4 microns, and at least 90% of the particles of the additional cough suppressant are less than about 10 microns. In one embodiment, no more than about 10% of the particles of the additional cough suppressant are less than about 5 microns, and at least 90% of the particles of the additional cough suppressant are less than about 8 microns. While in a preferred embodiment, the cough suppressant accessory component is comprised of particles generally in the 5-10 micron size range, the cough suppressant accessory component may contain particles in a wider range of sizes. In one embodiment, the additional component, which is a cough suppressant, may contain particles in the size range of 5-25 microns. In another embodiment, the additional component, which is a cough suppressant, contains particles, the size of which is essentially in the range of 5-50 microns. In yet another embodiment, the additional component, which is a cough suppressant, contains particles, the size of which is essentially in the range of 5-100 microns.

In another embodiment, the composition of the present invention may further comprise an additional component, which is a cough suppressant, having particles, the size of which is essentially 10-200 microns. This additional cough suppressant component may be added to the formulation in addition to or instead of the additional cough suppressant component in the previously discussed range of 5-10. Accordingly, the composition of the present invention may contain two additional cough suppressant components, where each additional cough suppressant component has a substantially different particle size distribution. An additional cough suppressant component of 10-200 microns can reduce cough caused by irritation of the oropharynx, vocal cords in the glottis and other anatomical sites located more proximally or closer to the oral cavity that contain receptors that initiate cough or initiating other unwanted sensations. As provided in this document, these larger particles are not allowed to enter the airways below the folds of the glottis. Accordingly, in some embodiments, the smallest particle size within the particle size range of the cough suppressant accessory component is at least about 10 microns, at least about 12 microns, at least about 20 microns, at least about 30 microns, or at least about 50 microns. In some embodiments, the largest particle size within the particle size range of the cough suppressant additive is no more than about 200 microns, no more than about 150 microns, no more than about 120 microns, no more than about 100 microns, no more than about 90 microns or no more than about 80 microns. In certain embodiments, no more than about 10% of the cough suppressant accessory particle size is less than about 10 microns. In certain embodiments, no more than about 10% of the cough suppressant accessory particle size is less than about 20 microns. In other embodiments, the implementation of the particle size of at least 90% of the additional component, which is a cough suppressant, is less than about 200 microns. In other embodiments, the implementation of the particle size of at least 90% of the additional component, which is a cough suppressant, is less than about 150 microns. In other embodiments, at least 90% of the cough suppressant accessory particle size is less than about 100 microns. In one embodiment, no more than about 10% of the particles of the additional cough suppressant component are less than 10 microns, and at least 90% of the particles of the additional cough suppressant component are less than about 200 microns. In one embodiment, no more than about 10% of the particles of the additional cough suppressant component are less than about 12 microns, and at least 90% of the particles of the additional cough suppressant are less than about 100 microns in size. . In one embodiment, the additional component, which is a cough suppressant, includes particles of menthol with a size of approximately 10-200 microns. In another embodiment, the additional component, which is a cough suppressant, with a particle size of approximately 10-200 microns, may include benzocaine. It should be understood that the additional component, which is a cough suppressant, with a particle size of approximately 10-200 microns, may include any compound approved for cough suppression. In another example, the addition of at least one component to the composition of the present invention, other than the nicotine component, can lead to liquefaction of the particles containing nicotine and to the reduction of cough caused by nicotine, which irritates the oropharynx, vocal cords in the glottis and other anatomical areas located proximal to the trachea.

In one embodiment, the compositions of the present invention may optionally contain a flavor component with a particle size that is essentially about 10-1000 microns. In one embodiment, the flavor component consists of particles essentially in the range of approximately 10-200 microns. In a preferred embodiment, the flavor component consists of particles essentially in the range of approximately 10-100 microns. This flavoring component uses such included larger particles that can act on the subject in the oral cavity to provide the desired taste and aroma. In addition, by limiting the size of these flavoring component particles to greater than about 10 microns, the ability of these particles to enter the lungs of a subject is limited. Accordingly, in some embodiments, the smallest particles within the particle size range of the flavor component are at least about 10 microns, at least about 12 microns, at least about 20 microns, at least about 30 microns, or at least approximately 50 microns. In some embodiments, the size of the largest particles that fall within the particle size range of the flavor component is no more than about 1000 microns, no more than about 500 microns, no more than about 200 microns, no more than about 150 microns, no more than about 120 microns, no greater than about 100 microns, no greater than about 90 microns, or no greater than about 80 microns. In certain embodiments, no more than about 10% of the flavor particles are less than about 10 microns in size. In certain embodiments, no more than about 10% of the flavor particles are less than about 20 microns in size. In other embodiments, at least 90% of the flavor particles are less than about 1000 microns in size. In other embodiments, at least 90% of the flavor particles are less than about 500 microns in size. In other embodiments, at least 90% of the flavor particle size is less than about 200 microns. In other embodiments, at least 90% of the flavor particles are less than about 150 microns in size. In other embodiments, at least 90% of the flavor particles are less than about 100 microns in size. In one embodiment, no more than about 10% of the flavor component particles are less than 10 microns in size, and at least 90% of the flavor component particles are less than about 1000 microns in size. In one embodiment, no more than about 10% of the flavor component particles are less than 10 microns in size, and at least 90% of the flavor component particles are less than about 200 microns in size. In one embodiment, no more than about 10% of the flavoring particle size is less than about 10 microns, and at least 90% of the flavoring particle size is less than about 100 microns. In one embodiment, the flavor component is mint. In another embodiment, the flavor component is menthol. In other embodiments, the flavor component may include tobacco, fruit flavors, or food flavors used in confectionery or baked goods. It should be understood that the flavoring compound may be any flavoring compound known in the art, preferably a flavoring compound approved by regulatory authorities.

The present invention includes a composition consisting of nicotine, sugar and amino acid. The present invention also includes a composition consisting of nicotine, sugar, flavor component and amino acid. The present invention includes a composition consisting of nicotine, sugar, amino acid and excipient. The present invention includes a composition consisting of nicotine, sugar, amino acid and a cough suppressant. The present invention also includes a composition consisting of nicotine, sugar, flavor component, amino acid and excipient. The present invention also includes a composition consisting of nicotine, sugar, flavor component, amino acid, excipient and cough suppressant. The present invention also includes a composition consisting of nicotine, sugar, flavor component, amino acid and excipient. The present invention also includes a composition consisting of nicotine, sugar, flavor component, amino acid and cough suppressant. In one embodiment, the sugar is lactose. In one embodiment, the amino acid is selected from the group consisting of glycine and lysine. In one embodiment, the excipient is a phospholipid. In one embodiment, the flavor component is menthol. In one embodiment, the cough suppressant is selected from the group consisting of menthol and mint.

In various embodiments, the relative percentage by weight of each component in the composition of the present invention can be varied to achieve different characteristics. Thus, one of ordinary skill in the art will appreciate that the percentage by weight of the components can be modified for a number of reasons, such as, without limitation, to achieve a certain level of nicotine blood concentration while modulating the level of astringency to the subject's airways, to achieve some the level of astringency while modulating the level of satisfaction felt by the subject of therapy, achieving better absorption of nicotine in the lungs of the patient, achieving faster blood nicotine kinetics, optimizing the effectiveness of the composition in suppressing cough, changing or improving the taste of the composition and adjusting the relative dose of nicotine. In certain embodiments, the composition may contain about 1-20% by weight of flavoring component, with the preferred weight of flavoring component being 1-5%. In certain embodiments, the composition may contain from about 1% to about 10% by weight of a cough suppressant, with the preferred weight of cough suppressant being from about 0.5% to about 5%. In various embodiments, the remainder of the composition, in addition to any flavor components, cough suppressant components, carriers, or other components, is a nicotine component. In one embodiment, the formulation may contain about 10% nicotine component.

In one embodiment, the percentage of lactose in the composition is from 50% to 99%. In one embodiment, the percentage of lactose in the composition is from 50% to 80%. In some embodiments, the implementation of the percentage of lactose in the composition is from 75% to 90%. In other embodiments, the implementation of the percentage of lactose in the composition is from 75% to 85%. In still other embodiments, the implementation of the percentage of lactose in the composition is from 80% to 90%. In still other embodiments, the implementation of the percentage of lactose in the composition is from 80% to 99%. In one embodiment, the percentage of lactose in the composition is approximately 50%. In one embodiment, the percentage of lactose in the composition is approximately 60%. In one embodiment, the percentage of lactose in the composition is approximately 70%. In one embodiment, the percentage of lactose in the formulation is approximately 80%. In another embodiment, the percentage of lactose in the composition is approximately 90%. In another embodiment, the percentage of lactose in the formulation is approximately 95%. In another embodiment, the percentage of lactose in the formulation is approximately 99%. In some embodiments, any carrier at any concentration may be substituted with lactose.

In one embodiment, the percentage of menthol in the composition is from 0% to 20%. In some embodiments, the implementation of the percentage of menthol in the composition is from 5% to 20%. In other embodiments, the implementation of the percentage of menthol in the composition is from 5% to 15%. In still other embodiments, the implementation of the percentage of menthol in the composition is from 10% to 20%. In one embodiment, the percentage of menthol in the composition is approximately 5%. In another embodiment, the percentage of menthol in the composition is approximately 20%.

In one embodiment, the percentage of mint in the composition is from 0% to 20%. In some embodiments, the implementation of the percentage of mint in the composition is from 5% to 20%. In other embodiments, the implementation of the percentage of mint in the composition is from 5% to 15%. In yet other embodiments, the percentage of mint in the composition is from 10% to 20%. In one embodiment, the percentage of mint in the composition is approximately 5%. In another embodiment, the percentage of mint in the composition is approximately 20%.

Methods of application

In one aspect, the present invention relates to methods for controlling the amount of nicotine and the amount of menthol inhaled by a subject, including increasing, decreasing, or maintaining the amount of nicotine and the amount of menthol in a powder formulation inhaled by a subject. For example, Figure 1 shows that method 100 includes the steps of 110: determining the concentration of nicotine to be inhaled by the subject, 120: determining the total dose of nicotine to be inhaled by the subject, 130: determining the concentration of menthol to be inhaled by the subject, 140: determining the total dose of menthol, to be inhaled by the subject. Finally, in step 150, the subject is provided with an amount of a formulation containing nicotine particles at a specific nicotine concentration and containing menthol particles at a specific menthol concentration such that the total amount of nicotine particles and menthol particles in the formulation is equal to the total dose of nicotine and the total dose of menthol.

In another embodiment, as shown in Figure 2, method 200 includes the steps of reducing the amount of nicotine while maintaining the amount of menthol inhaled by the subject. The method 200 includes the steps 210: determining the concentration of nicotine in a nicotine-based composition to be inhaled by a subject containing a basic concentration of menthol, 220: providing a first dose containing an amount of a composition containing nicotine particles with a determined nicotine concentration and menthol particles with a basic concentration of menthol, and 230: providing at least one additional dose containing an amount of a nicotine particle composition, wherein at least one additional dose contains fewer nicotine particles than the composition in the first dose and contains the same base concentration of menthol as the first dose.

Next, with reference to figure 3, three different compositions are indicated, where each composition is designed to deliver the same dose of nicotine (1 mg). To achieve baseline nicotine delivery (formulation 1), the total nicotine dose is a fraction of 20 mg of the total powder formulation containing 5% leucine and 90% lactose, resulting in a 5% nicotine concentration in the formulation. Assuming that about 1 mg of powder can be inhaled per breath, then approximately 0.05 mg of nicotine is inhaled per breath, with the total dose of nicotine being administered after about 20 separate breaths with an intake of 20 mg of the powder formulation. To achieve an increased level of menthol delivery when delivering 1 mg of nicotine, the total dose of nicotine is a fraction of 20 mg of the total powder formulation containing 5% leucine, 85% lactose and 5% menthol, resulting in a nicotine concentration of 5% (formulation 2) . Assuming that about 1 mg of powder can be inhaled per breath, then approximately 0.05 mg of nicotine is inhaled per breath, with the total dose of nicotine being administered after about 20 separate breaths with an intake of 20 mg of the powder formulation. When ingesting this amount of menthol per breath, the user experiences an increased level of cough suppression compared to formulation 1. To achieve an additional increased level of cough suppression when delivering 1 mg of nicotine, the total dose of nicotine is a fraction of 20 mg of the total powder formulation containing 5% leucine, 70 % lactose and 20% menthol, resulting in a nicotine concentration of 5% (formulation 3). Assuming that about 1 mg of powder can be inhaled per breath, then approximately 0.05 mg of nicotine is inhaled per breath, with the total dose of nicotine being administered after about 20 separate breaths with an intake of 20 mg of the powder formulation. Upon ingestion of an increased amount of menthol per breath, the user experiences an increased level of cough suppression compared to formulations 1 and 2. The formulations shown in Figures 3 and 4 are illustrative and any constituent may be replaced by a comparable substitute or adjuvant described herein. .

In another embodiment, the total dose of nicotine can be gradually reduced. For example, as shown in Figure 4, three different formulations are indicated, where each formulation is designed to deliver a different (lower) total dose of nicotine while maintaining the same level of cough suppression. Starting with formulation 4, the total nicotine dose of 1 mg is a fraction of 20 mg of the total powder formulation containing 5% leucine, 80% lactose and 10% menthol, resulting in a nicotine concentration of 5%. Assuming that about 1 mg of powder can be inhaled per breath, this means that approximately 0.05 mg of nicotine is inhaled per breath, and the total dose of nicotine is delivered after about 20 separate breaths at the initial dose of nicotine. Formulation 5 is designed to deliver a total dose of nicotine of 0.5 mg at the same level of cough suppression. Accordingly, a total dose of 0.5 mg nicotine may be a fraction of 20 mg of the total powder formulation containing 5% leucine, 82.5% lactose and 10% menthol, resulting in a nicotine concentration of approximately 2.5%. Assuming that about 1 mg of powder can be inhaled per breath, this means that approximately 0.025 mg of nicotine is inhaled per breath, and the total dose of nicotine is administered after about 20 separate breaths with the same level of cough suppression. Formulation 6 is designed to deliver a total dose of 0.3 mg nicotine again with the same level of cough suppression. Accordingly, a total nicotine dose of 0.3 mg may be a fraction of 20 mg of the total powder formulation containing 5% leucine, 83.5% lactose and 10% menthol, resulting in a nicotine concentration of approximately 1.5%. Assuming that about 1 mg of powder can be inhaled per breath, this means that approximately 0.015 mg of nicotine is inhaled per breath, and the total dose of nicotine is administered after about 20 separate breaths with the same level of cough suppression. Thus, the subject can gradually reduce the total dose of nicotine administered through the sequential administration of Formulations 4-6 while experiencing cough suppression at a constant level as the level of nicotine delivered decreases. In one embodiment, formulations with decreasing concentrations of nicotine may be used in a smoking cessation regimen. Similarly, the subject may gradually increase the total dose of nicotine administered by sequential administration of formulations with increasing concentrations of nicotine while experiencing cough suppression at a constant level as the level of nicotine delivered increases. The compositions described in the drawings are illustrative and any constituent may be replaced by a comparable substituent or excipient as described herein.

It should be understood that any method of increasing, decreasing, or maintaining the total dose of nicotine in a nicotine formulation can be combined with any method of increasing, decreasing, or maintaining the amount of menthol in the formulation.

As provided herein, there is no limitation as to the specific amount of the powder formulation or the concentration of nicotine within the total amount of the formulation, however, the present invention relates to the ability to vary one or both of these parameters when delivering a total dose of nicotine to a subject via a dry powder inhaler. In addition, there is no restriction on the actual amount of powder delivered per breath. Such amounts may depend on the functionality of the dry powder inhaler used, or they may depend on the user's actions, namely if the user decides to take a shallower or deeper breath through the dry powder inhaler used. Furthermore, by administering the total dose of nicotine over multiple puffs, the subject can more consistently absorb the total dose of nicotine, since any user error that occurs during one puff is eventually corrected by one or more subsequent puffs.

Manufacturing methods

The present invention also relates to methods for preparing the compositions of the present invention. In one embodiment, the methods involve dry blending. In one embodiment, the methods involve wet mixing.

Next, with reference to figure 5 shows an illustrative dry method or method 300 to obtain any of the compositions described in this document. For example, in step 310, the nicotine tartrate is dry ground. In step 312, nicotine is mixed with lactose and leucine. Optionally, at step 313, a therapeutic agent such as menthol is added. In some embodiments, the nicotine or nicotine salt is not associated with any other components of the formulation. That is, the composition contains individual particles of nicotine or nicotine salts and individual particles of other components of the composition, such as sugar. In one embodiment, nicotine is not associated with sugar. In one embodiment, nicotine is not associated with amino acid particles. In one embodiment, the nicotine is not bound to the leucine particles. In one embodiment, the nicotine is not bound to the glycine particles. In one embodiment, the nicotine is not bound to the lysine particles. In one embodiment, the nicotine is not associated with the carrier. In one embodiment, nicotine is not bound to lactose and leucine particles. In another embodiment, the nicotine is not bound to the menthol particles. In another embodiment, the nicotine is at least partially bound to the menthol particles. Alternatively, the nicotine tartrate, lactose, and leucine may first be dry blended, such as at step 314, and ground together at step 316. In another embodiment, the nicotine tartrate, lactose, leucine, and a therapeutic agent, such as menthol, are first blended into dry, for example, at step 318, and grind together at step 320. At step 330, the resulting particles of the composition are filtered, for example, using a sieve, to remove any particles exceeding the size threshold. In step 340, the resulting composition particles are refiltered to remove any particles that are smaller than a size threshold, resulting in a final dry powder composition 350. In some embodiments, only one filtration step is required. In other embodiments, two or more filtration steps are required. Optionally, at step 360, the flavoring component can be added to the final composition 350. Step 360 may include any number of processing steps necessary to obtain particles of the desired size (for example, 10-1000 microns) of the added flavoring component.

Any method of mixing particles in accordance with the methods and compositions of the present invention is considered in this document. Mixing can be carried out using one or more stages through a continuous, batch or semi-batch process. For example, if two or more excipients are used, they may be mixed together before or simultaneously with mixing with the pharmaceutical microparticles.

Mixing can be carried out using essentially any technique or any device suitable for combining microparticles with one or more other materials (eg, excipients) effective to achieve a homogeneous mixture. The mixing process can be carried out using various mixers. Illustrative examples of suitable mixers include V-blenders, tilt-cone drum mixers, cube drum mixers, hopper mixers, stationary continuous mixers, dynamic continuous mixers, rotary auger mixers, planetary mixers, Forberg mixers, horizontal two-blade mixers. mixers, horizontal high speed agitators, vertical high speed agitators, paddle agitators, double cone agitators, drum agitators and tumbling drum agitators. Preferably, the mixer is of a rigorously designed, hygienic design required for pharmaceutical products.

Tumbler mixers are often preferred for batch operations. In one embodiment, mixing is accomplished by aseptically combining two or more components (which may include both dry components and small amounts of liquid components) in a suitable container. One example of a tumbling drum mixer is TURBULA™ sold by Glen Mills Inc., Clifton, NJ, USA, and manufactured by Willy A. Bachofen AG, Maschinenfabrik, Basel, Switzerland.

For continuous or semi-continuous process operations, the mixer may optionally be equipped with a rotary feeder, screw conveyor, or other feed mechanism for controlled feeding of one or more dry powder components into the mixer.

The grinding step is used to break up and/or deagglomerate the mixed particles in order to achieve the desired particle size and size distribution, as well as to improve the distribution of particles within the mixture. One skilled in the art will appreciate that any milling method can be used to form the particles of the present invention. Various grinding methods and equipment known in the art can be used. Examples include hammer mills, ball mills, roller mills, disc grinders, jet mills, and the like. A dry grinding process is preferably used.

Next, with reference to Figure 6, an exemplary wet process or process 400 for making any of the formulations described herein is shown. For example, in step 410, nicotine tartrate is mixed with excipients such as lactose and leucine to form a fluid mixture. At step 412, the mixture is sprayed. Alternatively, at step 414, nicotine tartrate can be mixed with excipients such as lactose and leucine, as well as a therapeutic agent such as menthol, to form a fluid mixture. This document provides that any liquid carrier can be used in a process for preparing a solution or suspension. In one embodiment, the liquid carrier is water. Preferably, the liquid carrier is one in which the components of the composition are either soluble or suspendable. Accordingly, the liquid carrier may be any liquid or liquids with which the components of the composition, either alone or in combination, form a fluid mixture or suspension, which preferably constitute a generally homogeneous composition.

At step 416, the mixture is sprayed. At step 420, the mixture is dried, for example by means of a spray dryer. Alternatively, the process may optionally be carried out by fluid bed drying, where the nicotine tartrate may instead be spray dried onto the adjuvant mixture. In step 430, the resulting nicotine particles are filtered, for example with a sieve, to remove any particles above a size threshold. In step 440, the resulting nicotine particles are again filtered to remove any particles that are smaller than the size threshold, resulting in the final dry powder composition 450. In some embodiments, only one filtering step is required. In other embodiments, two or more filtration steps are required. Optionally, at step 460, the flavoring component may be added to the final composition 450. Step 460 may include any number of processing steps necessary to obtain particles of the desired size (eg, 10-1000 microns) of the added flavoring component.

Fluid mixtures are dried, for example, by means of a spray dryer, to obtain complex particles of fluid mixtures that are suitable for delivery to the alveoli and lower respiratory tract of the subject. It should be understood that there is no limitation on the method of drying the fluid mixtures. Although a spray dryer is used in the preferred method, other drying techniques capable of producing appropriately sized particles, such as fluid bed drying, can be used. In one embodiment, the mixture is finely ground by passing through a spray dryer inlet. In another embodiment, the fluid mixture may be passed through an atomizer, such as a rotary atomizer, to supply the fluid to a spray dryer. In addition, any drying rate can be used (eg, drying at low or high speed), provided that such a drying rate results in the formation of dry particles with a size in the desired range. Before separating the desired particle size of the nicotine component, the resulting particles formed by the spray dryer may have a particle size of from about 0.1 to about 5 microns.

Additional separation/filtering of particles of a selected size can be carried out by both dry and wet methods. In the wet process, the operating parameters of the spray dryer can be adjusted to obtain particles having sizes suitable for transport into the alveoli and smaller airways of the lungs. For example, a rotary nebulizer may operate at a fluid delivery rate of about 2 to about 20 ml/min, or 2 to about 10 ml/min, or about 2 to about 5 ml/min. In addition, the rotary atomizer can be operated at about 10,000 to about 30,000 rpm, from about 15,000 to about 25,000 rpm. or from about 20,000 to about 25,000 rpm. It should be understood that particles of various sizes can be obtained by spray drying and particles having the desired particle size can be more accurately selected by filtration, for example, through one or more of the screening steps described elsewhere in this document. The spray dryer can operate at temperatures high enough to cause rapid release of the liquid carrier without raising the temperature of the sugar and nicotine in the mixture to the point where these compounds begin to break down. Accordingly, the spray dryer can be operated at an inlet temperature of about 120°C to about 170°C and an outlet temperature of about 70°C to about 100°C.

It should be understood that there is no limitation on the method of drying the fluid mixtures. Examples of methods for drying fluid mixtures include, but are not limited to, spray drying, vacuum drying, and lyophilization. In addition, any drying rate can be used (eg, drying at a low or high speed), provided that such a drying rate results in the formation of dry particles with a size in the desired range.

As previously mentioned, in the wet method, the carrier liquid is dried, for example by means of a fluid bed dryer, to produce menthol-coated complex nicotine particles that are suitable for delivery to the alveoli and lower respiratory tract of the subject. It should be understood that there is no limitation on the method of drying the fluid mixture. While the preferred method uses a fluid bed dryer, other drying techniques can be used that are capable of removing the carrier liquid and leaving a uniform menthol-based coating on the nicotine particles.

This document provides that the particles of the present invention can be obtained in relatively narrow size ranges by using at least one screening step. In such an embodiment, the screening step includes using a sieve corresponding to the minimum or maximum value in the required particle size range to remove particles from the mixture that are smaller or larger than the desired range. For example, to obtain nicotine particles in the range of approximately 1-5 microns, a mixture of nicotine particles obtained using the grinding method described herein can be provided. The mixture of nicotine particles will have a size distribution that depends on the grinding conditions used and/or the characteristics of the mixture entering the mill. The mixture of nicotine particles can first be passed through a 5 micron sieve, where essentially all particles less than 5 microns pass through the sieve and are collected. Particles passing through the sieve can then be transferred to a 1 micron sieve, where essentially all particles larger than 1 micron do not pass through the sieve. Particles larger than 1 micron can be collected from the sieve, where the collected particles will essentially have a size in the range of 1-5 microns. Accordingly, such a method can be used to narrow any mixture of particles to any desired particle size range described throughout this document.

In another embodiment, a mixture of particles can be provided that substantially meets either the minimum or maximum criteria for the desired particle size range. For example, if a nicotine particle size range of approximately 2-5 microns is required, then a mixture of nicotine particles can be provided where substantially all of the particles are less than 5 microns in size. Such a mixture can be obtained by modifying the grinding conditions, or if the particles are spray dried, by grinding the spray-dried material, resulting in a mixture of particles that are generally less than 5 microns in size. The mixture can then be passed through a 2 micron sieve where particles not passing through the sieve are collected and where the collected particles are substantially within the required range of 2-3 microns.

It is expected that the percentage of particles that are within the required particle size range of any of the components of the composition of the present invention may depend on the technique used to obtain this component. For example, if the target size of the nicotine component is in the range of 2-5 microns, it should be understood that more than 90% of this component will be within the required range when using a relatively small scale spray drying production technique. However, using a relatively large scale milling technique, only more than 70% of the nicotine component can be produced within this target range.

Kits of the present invention

The present invention also relates to nicotine-containing kits, including, without limitation, nicotine-containing therapeutic kits and smoking cessation kits. In one embodiment, the kit may contain multiple doses of a powdered nicotine formulation contained in a sealed storage chamber, such as a capsule or blister pack. This document provides that at least two of the doses of the composition have equal amounts of total nicotine content, but at different concentrations of nicotine. In other embodiments, the kit contains at least two sets of nicotine-based bulk powder containing various concentrations of nicotine, and means for measuring predetermined amounts of powders, such as a measuring spoon or graduated measuring container, which can be used to load into a storage chamber. dry powder inhaler.

In another embodiment, the kit includes prefilled powder capsules for a prescribed course of nicotine therapy or treatment, such as, for example, a 30 day course of treatment. The capsules can be filled with different amounts of powder with different concentrations of nicotine according to the therapy regimen. In other embodiments, the kit includes educational materials that describe the steps of a nicotine therapy method, including, but not limited to, smoking cessation therapy. The method steps may include an initial dose, subsequent regular doses such as multiple daily doses, for example, and a final dose to be administered by loading doses of the dry powder formulation into the dry powder inhaler.

In another embodiment, the educational materials may instruct the user regarding the prescribed number of days of a course of nicotine therapy, in which the daily dose of nicotine can be modulated. In one embodiment, the course of nicotine therapy lasts from about 7 days to about 30 days. In another embodiment, the course of nicotine therapy lasts from about 10 days to about 45 days. In another embodiment, the course of nicotine therapy lasts from about 15 days to about 60 days. In another embodiment, the course of nicotine therapy lasts from about 30 days to about 90 days. In a preferred embodiment, the course of nicotine therapy lasts approximately 30 days. In another preferred embodiment, the course of nicotine therapy lasts approximately 45 days. In another preferred embodiment, the course of nicotine therapy lasts approximately 60 days. In another preferred embodiment, the course of nicotine therapy lasts approximately 90 days.

The disclosure of all patents, patent applications, and publications referenced herein is hereby incorporated herein by reference in its entirety. Although the present invention has been disclosed with reference to specific embodiments, it is obvious that other embodiments and variations of the present invention may be developed by others skilled in the art without departing from the actual spirit and scope of the present invention. The appended claims are to be construed as including all such embodiments and equivalents.

Claims (21)

1. Dry powder composition based on nicotine containing particles, where the particles contain: nicotine salt, at least one sugar, and at least one amino acid selected from the group consisting of glycine, lysine, leucine, and combinations thereof, where the particles have a size of 1 to 7 microns, where the concentration of nicotine is from 0.5% to 10% by weight, and the concentration of at least one sugar is from 50% to 99% by weight, and where the composition is suitable for inhalation to mimic the effects of smoking. 2. Composition according to claim 1, additionally containing at least one phospholipid. 3. Composition according to claim 1, wherein the nicotine salt is nicotine tartrate. 4. The composition of claim. 1, where the concentration of sugar is from 50% to 80% by weight. 5. Composition according to claim 1, additionally containing menthol. 6. Composition according to claim 1, additionally containing mint. 7. Dry powder composition based on nicotine, consisting of particles containing nicotine, at least one sugar, menthol and at least one amino acid selected from the group consisting of glycine, lysine and leucine, where the particles have a size of 1 to 7 microns, where the concentration of nicotine is from 0.5% to 10% by weight, and the concentration of at least one sugar is from 50% to 99% by weight, where the composition is suitable for inhalation to mimic the effects of smoking. 8. The composition of claim. 7, where at least 40% of the particles have a size of 3 to 4 microns. 9. Dry powder composition based on nicotine containing from 0.5% to 10% by weight of nicotine, from 50% to 99% by weight of at least one sugar and leucine, where the dry powder composition based on nicotine contains a flavor component and particles containing nicotine, at least one sugar and leucine, wherein the particles are 1 to 7 microns in size, and the formulation is suitable for inhalation to mimic the effects of smoking. 10. Composition according to claim 9, additionally containing at least one phospholipid. 11. Composition according to claim 9, additionally containing menthol. 12. Composition according to claim 9, additionally containing mint.

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