KR20190126772A - Inhalable nicotine formulations, and methods of making and using the same - Google Patents

Abstract

The present invention provides a dry powder formulation comprising nicotine, a method of using the same, and a method of preparing the same. Dry powder formulations may further comprise excipients, therapeutics and flavoring ingredients. Dry powder formulations can be prepared by dry and wet processes.

Description

Inhalable nicotine formulations, and methods of making and using the same

The present invention relates to inhalable nicotine formulations and methods of making and using the same.

Smoking is an addictive habit that has been found to contribute to or cause various cardiac pathological conditions, as well as several diseases including respiratory diseases such as emphysema, chronic bronchitis, lung infections and lung cancer. As public awareness of the harmful effects of smoking on human health has increased, the number of smokers attempting to stop habits has increased. Now, the fact that nicotine in cigarette smoke forms addiction through the effect on brain nicotine receptors is widely accepted in the scientific and medical community. Most regular smokers become addicted or dependent on the pharmacological effects of nicotine in cigarette smoke. In general, a common strategy of overcoming nicotine addiction, and in particular nicotine netting, follows mimicking the effects of cigarette smoking, followed by a gradual decrease followed by complete elimination.

There are several smoking effects that the potential therapeutic formulation or method may attempt to mimic. Among the most important effects of smoking are the chemical and mechanical effects of cigarette smoke on smokers 'airways and the absorption of nicotine into smokers' blood. The chemical and mechanical effects of cigarette smoke on smokers' airways result in some level of satisfaction experienced by smokers. The absorption of nicotine into the smoker's blood causes nicotine to reach various receptors in the smoker's nervous system, which in turn affects the perceived nicotine craving experienced by the smoker. Both effects can be potentially mimicked by administering a dosage of nicotine formulation to a subject seeking a smoking cessation regimen. The dose can be gradually reduced to treat nicotine addiction until it is completely gone.

Leucine is an amino acid with aliphatic isobutyl side chains. As a result, leucine is usually classified as a hydrophobic amino acid. Leucine is an essential amino acid because the human body cannot synthesize it and must be provided from external sources. Leucine has a variety of metabolic roles and is particularly involved in stimulating sterol formation and muscle protein synthesis. Lysine is a basic amino acid with an amine side chain. Lysine is also an essential amino acid important for calcium absorption. Terminal amines of lysine can be chemically modified. Without side chains, glycine is the smallest amino acid. Glycine is important for the biosynthesis of structural protein collagen and has been used as a sweetener.

Lactose is a disaccharide found in milk and has two residues: galactose and glucose. Lactose is used as a pharmaceutical application, for example as a filler due to its physical properties (eg compressibility). Tartaric acid is a diuretic that occurs naturally in many plants, such as grapes and bananas. Tartarate is a salt of tartaric acid with a basic compound, such as nicotine. Phospholipids are the main components of cell membranes due to their amphiphilic nature. Phospholipids are also a natural component of pulmonary surfactants and are found at high concentrations in egg whites and milk.

Menthol is a known and widely used topical analgesic, decongestant and cough suppressant. Almost all cigarettes contain menthol to adjust flavor and reduce cough. When the menthol concentration in the cigarette exceeds 3%, it is labeled with menthol cigarettes. Methods of using menthol in cigarettes include adding to tobacco leaves. Plastic balls filled with menthol can be stored in the filter of the cigarette and then crushed before smoking the cigarette. When a cigarette is lit, heated smoke is volatilized to transport menthol into the smoker's airways.

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

In one aspect of the invention, a dry powder nicotine formulation suitable for inhalation is described. The formulation comprises 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 comprises nicotine tartarate. In one embodiment, the concentration of nicotine is 0.5% to 10%. In one embodiment, the concentration of sugar is 50% to 99%. In one embodiment, the concentration of amino acid is 0.5% to 50%.

In another aspect of the invention, dry powder nicotine formulations suitable for inhalation are described. This formulation comprises 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 3-4 μm. In another embodiment, at least about 80% of the nicotine and amino acid particles are 1-7 μm. In one embodiment, the sugar particle size is at least about 50 μm. In one embodiment, the mint particle size is at least about 20 μm.

In another aspect of the invention, dry powder nicotine formulations suitable for inhalation are described. Such formulations comprise nicotine particles, 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 such formulations, the amino acid particles are not substantially bound to nicotine particles. In one embodiment, the formulation further comprises at least one phospholipid. In one embodiment, the formulation further comprises mint.

The following detailed description of the preferred embodiment of the invention will be better understood when read in conjunction with the accompanying drawings. For purposes of illustrating the invention, presently preferred embodiments are shown in the drawings. However, it should be understood that the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings.
1 is a flow diagram illustrating an exemplary method for delivering a desired amount of nicotine and a desired amount of menthol to a subject.
FIG. 2 is a flow diagram illustrating an exemplary method for delivering a reduced or increased dose to a subject over multiple doses while maintaining a level of menthol per dose.
FIG. 3 is a chart illustrating an exemplary formulation of the present invention delivering an amount of nicotine while increasing the amount of menthol.
4 is a chart showing an exemplary formulation of the present invention delivering a decreasing amount of nicotine while maintaining a certain amount of menthol.
5 is a flow chart illustrating an exemplary method of making a formulation of the present invention comprising dry mixing.
FIG. 6 is a flow diagram illustrating an exemplary method of making a formulation of the present invention comprising wet mixing.

The present invention provides a dry powder formulation comprising nicotine, a method of using the same, and a method of preparing the same. Dry powder formulations may further comprise excipients, therapeutics and flavoring ingredients. Dry powder formulations can be prepared by dry and wet processes.

Justice

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.

As used herein, each of the following terms has the meaning associated with that of this section.

The article “a” and “an” are used herein to refer to one or more than one (ie, at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

As used herein, when referring to measurable values such as amount and duration, “about” means ± 20%, ± 10%, ± 5%, ± 1%, and ± 0.1 from the specified values. This means that the% deviation is included (as appropriate).

As used herein, the term "composition" refers to a mixture of at least one compound or molecule and one or more different compounds, molecules or substances useful within the present invention.

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

As used herein, the term “inhalation” refers to the act of inhaling a nicotine dry powder formulation, typically from a dry powder inhaler, and can mean, for example, single inhalation or multiple inhalations.

As used herein, an “instructional material” is any physical or electronic publication, record, diagram, or any that can be used to convey utility for its designed use of the compositions and methods of the present invention. Contains other expression media. Instructions of the kits of the invention may be attached, for example, to a container containing the composition or may be delivered with a container containing the composition. Alternatively, the instructions may be delivered separately from the container with the intention that the instructions and the composition should be used in concert by the recipient.

The term “pharmaceutically acceptable” is acceptable to a patient from a pharmacological / toxicological point of view, and is acceptable to a pharmacologist who manufactures from a physical / chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability and / or Or refers to a substance. “Pharmaceutically acceptable” may also refer to a carrier, which means a medium that is not toxic to the host to be administered without interfering with the effects of the biological activity of the active ingredient (s). Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the present invention are known in the art and described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA). This document is incorporated herein by reference.

Unless stated otherwise, the stated size or size range of a particle should be considered as the mass median aerodynamic diameter (MMAD) of the particle or set of particles. This value is based on the distribution of aerodynamic particle diameters defined as the diameter of a sphere having the same aerodynamic behavior as the particle being characterized and having a density of 1 gm / cm 3. Since the particles described herein can be of various densities and shapes, the size of the particles is expressed as MMAD, not the actual diameter of the particles.

Throughout this disclosure, various aspects of the invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity, and should not be considered as limiting without the flexibility of the scope of the invention. Accordingly, the description of a range should be considered to specifically disclose all possible subranges as well as individual numerical values within that range. For example, descriptions of ranges such as 1 to 6 include subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, and the like, as well as individual numbers within that range, such as For example, 1, 2, 2.7, 3, 4, 5, 5.3, 6 and the full and partial increments therebetween should be considered specifically disclosed. This applies regardless of the width of the range.

Compositions and Compounds

In one aspect, the invention relates to a dry powder nicotine formulation suitable for inhalation. In one embodiment, nicotine is present in the formulation as a free base. In another embodiment, the formulation comprises a nicotine salt. In one such embodiment, the nicotine salt is nicotine tartarate. In another embodiment, the nicotine salt is nicotine hydrogen tartarate. In other embodiments, the nicotine salt can be prepared from any suitable nontoxic acid, including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof. Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, hexafluorophosphoric acid, citric acid, gluconic acid, benzoic acid, propionic acid, butyric acid, sulfosalic acid, maleic acid, lauric acid, malic acid, fumaric acid, Succinic acid, tartaric acid, cownic acid, palmic acid, p-toluenesulfonic acid and mexilic acid. Suitable organic acids can be selected from, for example, aliphatic, aromatic, carboxyl and sulfone series organic acids, for example formic acid, acetic acid, propionic acid, succinic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, isethionic acid, lactic acid , Malic acid, slime acid, tartaric acid, para-toluenesulfonic acid, glycolic acid, glucuronic acid, maleic acid, puroic acid, glutamic acid, benzoic acid, anthranilic acid, salicylic acid, phenylacetic acid, mandelic acid, embonic acid (phamoic acid), methane Sulfonic acid, ethanesulfonic acid, pantothenic acid, benzenesulfonic acid (besylate), stearic acid, sulfanilic acid, alginic acid, galacturonic acid, and the like.

In another aspect, the invention relates to a dry powder nicotine formulation suitable for inhalation which further comprises a 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 invention relates to a dry powder nicotine formulation suitable for inhalation further comprising at least one amino acid. In one embodiment, the amino acids are histidine, alanine, isoleucine, arginine, leucine, asparagine, lysine, aspartic acid, methionine, cysteine, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, glycine, valine, pyrrolysine, proline, seleno Cysteine, serine, and tyrosine. In one embodiment, the amino acid is leucine. In one embodiment, the amino acid is lysine. In one embodiment, the amino acid is glycine.

In one aspect, the invention relates to a dry powder nicotine formulation suitable for inhalation which further comprises at least one phospholipid. Phospholipids that can be used in the present invention include phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, lysophosphatidyl derivatives, cardiolipin and β-acyl-y with both phosphatidic acid, saturated and unsaturated lipids. -Alkyl phospholipids, including but not limited to. Examples of phosphatidylcholine include dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine (DMPC), dipentadecanoylphosphatidylcholine, dilauroylphosphatidylcholine, dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC) Doylephosphatidylcholine (DAPC), dibehenoylphosphatidylcholine (DBPC), ditricosanoylphosphatidylcholine (DTPC), dilignoceroylpatidylcholine (DLPC); And phosphatidylethanolamines such as dioleoylphosphatidylethanolamine or 1-hexadecyl-2-palmitoylglycerophosphoethanolamine. Examples of phosphatidylethanolamine include dicaprylphosphatidylethanolamine, dioctanoylphosphatidylethanolamine, dilauroylphosphatidylethanolamine, dimyristoylphosphatidylethanolamine (DMPE), dipalmitoylphosphatidylethanolamine (DPPE), dipalmi Toleoylphosphatidylethanolamine, distearoylphosphatidylethanolamine (DSPE), dioleoylphosphatidylethanolamine, and dilinoylphosphatidylethanolamine. Examples of phosphatidylglycerols include dicaprylphosphatidylglycerol, dioctanoylphosphatidylglycerol, dilauroylphosphatidylglycerol, dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphosphatidylglycerol (DPPG), dipalmitoleoylphosphatidylglycerol, Distearoylphosphatidylglycerol (DSPG), dioleoylphosphatidylglycerol, and dilinoylphosphatidylglycerol. Synthetic phospholipids with asymmetric acyl chains (eg with one acyl chain of six carbons and another acyl chain of twelve carbons) can also be used. Further examples of phospholipids include modified phospholipids, eg, phospholipids with modified head groups such as alkylated or polyethylene glycol (PEG) -modified, hydrogenated phospholipids, phospholipids with various head groups (phosphatidylmethanol, phosphatidyl Ethanol, phosphatidylpropanol, phosphatidylbutanol, etc.), dibromo phosphatidylcholine, mono and dipitanoli phosphatides, mono and diacetylene phosphatides, and PEG phosphatides.

In one aspect, the invention relates to a dry powder nicotine formulation suitable for inhalation which further comprises a flavor component. In one embodiment, the flavor component is derived from a natural flavor material, a natural-like flavor material, or an artificial flavor material. Non-limiting examples of flavor ingredients or flavors include bananas, cherries, cinnamon, fruits, grapes, oranges, pears, pineapples, vanilla, wintergreens, strawberries and mints. In one embodiment, the flavor component is menthol. In another embodiment, the flavor component is mint.

As will be appreciated by those skilled in the art, mint is generally not limited to any and all flavors associated with Lamiaceae and the genus of plants. In one embodiment, the mint is a natural extract. In another embodiment, the mint is a commercial formulation, such as, for example, Coolmint Trusil Flavouring Powder, supplied by International Flavors & Fragrances. In one embodiment, mint is one substance. In another embodiment, mint is a mixture of materials. In one embodiment, the mint comprises menthol. In another embodiment, the mint comprises trans-menthone. In another embodiment, the mint comprises pinene. In another embodiment, the mint comprises isomentone. In another embodiment, the mint comprises limonene. In another embodiment, the mint comprises eucalyptol. In another embodiment, the mint comprises pin-2 (3) -ene. In another embodiment, the mint comprises menthyl acetate. In another embodiment, the mint comprises cineole. In another embodiment, the mint comprises 4,5,6,7-tetrahydro-3,6-dimethylbenzofuran (4,5,6,7-tetrahydro-3,6-dimethylbenzofuran). In another embodiment, the mint comprises pin-2 (10) -ene. In another embodiment, the mint comprises dipentene. In another embodiment, the mint comprises d-limonene. In another embodiment, the mint comprises (R) -p-menta-1,8-diene ((R) -p-mentha-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.

As will be appreciated by those skilled in the art, menthol and / or mint can play a number of roles in the formulation. In one embodiment, menthol is a flavor component. In another embodiment, menthol is a therapeutic such as, for example, a cough suppressant. In one embodiment, the mint is a flavor component. In another embodiment, the mint is a therapeutic such as, for example, a cough suppressant.

Formulation

The present invention relates to dry powder formulations of nicotine suitable for inhalation. In one embodiment, the formulation comprises nicotine particles. In another embodiment, the formulation further comprises an excipient. In another embodiment, the formulation further comprises a therapeutic agent. In another embodiment, the formulation further comprises a flavor component.

As contemplated herein, any form of nicotine may be used as the nicotine based component. Preferably, the form of nicotine used is one that achieves rapid absorption into the lungs of the patient. Preferred forms of nicotine that can be formed into particles. Forms of nicotine that can be milled or co-milled with sugars or other ingredients can also be used. In other embodiments, nicotine is combined with sugars or other ingredients. In one embodiment, nicotine is a salt that is a solid at room temperature. Nicotine may be a pharmacologically active analog or derivative of a substance that mimics the effects of nicotine alone or in combination with other active substances. If nicotine is the base, it can be added to a liquid carrier, such as water, mixed to produce a generally homogeneous liquid mixture, and then dried by various methods to form a dry particulate formulation. In other embodiments, forms of nicotine that can be dissolved or miscible in the liquid carrier can also be used. For example, nicotine may be nicotine base, a liquid that can be miscible with water at room temperature. Alternatively, the nicotine base may be an oil formulation.

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

In one embodiment, the formulation comprises nicotine particles (also referred to herein as nicotine-based components) that are substantially about 1-10 μm in size, based on the MMAD of the particles. In yet another embodiment, the formulation comprises nicotine particles that are substantially about 1 to 7 μm in size. In another embodiment, the formulation comprises nicotine particles that are substantially about 2 to 5 μm in size. In yet another embodiment, the formulation comprises nicotine particles that are substantially about 2-3 microns in size. By selectively limiting or excluding nicotine particles that are less than about 1 μm, or less than about 2 μm in size, the formulations of the present invention eliminate or at least reduce the ability of a subject to release nicotine back to the environment, thereby reducing nicotine contained in secondhand smoke Effectively reduce or eliminate the production of In addition, by selectively limiting or excluding non-respirable nicotine particles, the formulations of the present invention are trapped in larger airways, oro-pharynx, glottis vocal cords and other anatomical regions closer or closer to the mouth. Reduces unwanted irritation caused by nicotine particles. Thus, in some embodiments, the minimum particles within the nicotine particle size range are at least about 1 μm, at least about 1.1 μm, at least about 1.2 μm, at least about 1.3 μm, at least about 1.4 μm, at least about 1.5 μm, at least about 1.6 μm, at least About 1.7 μm, at least about 1.8 μm, at least about 1.9 μm, at least about 2 μm, at least about 2.1 μm, at least about 2.2 μm, at least about 2.3 μm, at least about 2.4 μm, at least about 2.5 μm, at least about 2.6 μm, at least about 2.7 μm, at least about 2.8 μm, at least about 2.9 μm or at least about 3 μm. In some embodiments, the largest particles in the nicotine particle size range are about 10 μm or less, about 7 μm or less, about 6 μm or less, about 5 μm or less, about 4.5 μm or less, about 4 μm or less, about 3.5 μm or less or about 3 μm or less. In certain embodiments, less than about 10% of nicotine particles are less than about 1 μm. In certain embodiments, less than about 10% of nicotine particles are less than about 2 μm. In other embodiments, at least 90% of the nicotine particles are less than about 10 μm. In other embodiments, at least 90% of the nicotine particles are less than about 7 μm. In other embodiments, at least 90% of the nicotine particles are less than about 5 μm. In one embodiment, less than about 10% of nicotine particles are less than about 1 μm and at least 90% of the nicotine particles are less than about 10 μm. In one embodiment, up to about 10% of nicotine particles are less than about 1 μm and at least 90% of nicotine particles are less than about 7 μm. In one embodiment, less than about 10% of nicotine particles are less than about 2 μm and at least 90% of the nicotine particles are less than about 5 μm. In one embodiment, less than about 10% of nicotine particles are less than about 2 μm and at least 90% of the nicotine particles are less than about 3 μm.

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

As will be appreciated by those skilled in the art, the particle size ranges described herein are not absolute. For example, the nicotine particle mixture of the present invention having a size range of about 2-5 μm may contain portions of particles smaller or larger than the range of about 2-5 μm. In one embodiment, the particle size values presented for any particular component of the formulations of the invention represent a D90 value, wherein 90% of the particle size of the mixture is less than the D90 value. In another embodiment, the particle size range represents a particles size distribution (PSD), wherein the percentage of particles in the mixture is within the listed ranges. For example, the nicotine particle size range of about 2-5 μm is at least 50% of the particles in the range of about 2-5 μm, but more preferably, it may represent a mixture of nicotine particles having a higher percentage as follows: 60%, 70%, 80%, 90%, 95%, 97%, 98% or even 99%.

It should be understood that nicotine based component particles may have a spherical or any other shape desired. In one embodiment, the particles may have an uneven or “dimpled” surface. In such embodiments, the uneven surface may increase the ability of additional components to stick to the nicotine particles and create a uniform coating. For example, the additional component may be a therapeutic agent such as menthol that ensures that all nicotine particles that hit the cough receptor are coated with menthol that inhibits cough reflex. The uneven surface can also produce relative turbulence as the particles run through the air, thereby providing the particles with an aerodynamic lift. In such embodiments, particles having such a shape can be more easily entrained and remain entrained in the air inhaled by the subject, such that nicotine-based component particles can travel and be retained in the subject's airways. Improve your ability to

In one embodiment, the formulation comprises at least one amino acid. In one embodiment, the amino acids reduce to some extent the degradation of the compositions of the present invention, acting as stabilizers. In one embodiment, the amino acids act as carriers. In another embodiment, the amino acids act as buffers by the buffering capacity to prevent sensitization of the compositions of the present invention. In other embodiments, the amino acids serve as powder flow enhancers. In another embodiment, the amino acids in the composition of the present invention improve the flow of the powder. In another embodiment, the amino acids in the composition of the present invention allow particles of the powder formulation to more easily entrain and remain entrained in the air inhaled by the subject, whereby the composition particles can travel and be retained in the airways Improve your skills. In one embodiment, the percentage of amino acids in the formulation is 0.5% to 10%. In some embodiments, the percentage of amino acids in the formulation is 1.5% to 2.5%. In another embodiment, the percentage of amino acids in the formulation is 0.5% to 2.5%. In yet other embodiments, the percentage of amino acids in the formulation is 1.5% to 5%. In one embodiment, the percentage of amino acids in the formulation is about 2.5%. In another embodiment, the percentage of amino acids in the formulation is about 5%. In another embodiment, the percentage of amino acids in the formulation is about 7.5%. In another embodiment, the percentage of amino acids in the formulation is about 10%. In other embodiments, the percentage of amino acids is about 20%. In another embodiment, the percentage of amino acids is about 30%. In other embodiments, the percentage of amino acids is about 40%. In another embodiment, the percentage of amino acids is about 50%. In other embodiments, the percentage of amino acids is about 60%. In another embodiment, the percentage of amino acids is about 70%. In other embodiments, the percentage of amino acids is about 80%. In other embodiments, the percentage of amino acids is about 90%. In other embodiments, the percentage of amino acids is about 95%. In another embodiment, the percentage of amino acids is about 97.5%. In other embodiments, the percentage of amino acids is about 99%. In one embodiment, the amino acid is leucine. In other embodiments, the amino acid is lysine. In other embodiments, the amino acid is glycine.

In one embodiment, the formulation further comprises an excipient. As contemplated herein, one embodiment of an excipient is a bulking agent. Extenders may include inhalable sugars which are generally solid at room temperature. The sugar may itself be milled into a particulate formulation or co-milled with the nicotine component. Sugars can also be dissolved in liquid carriers such as water. Examples of suitable sugars include, but are not limited to, 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 coarse lactose. In another embodiment, the sugar is alpha monohydrate lactose. The sugar can be a natural or synthetic sugar and can include any sugar analog or derivative. It should be understood that any form of sugar approved as an excipient may be used as a carrier in the production of nicotine-based components. Although not required, the sugar is preferably of pharmaceutical grade, as will be understood by one skilled in the art. Preferably, the pharmaceutical grade sugars that are milled on their own, co-milled with the nicotine component, or used to produce a flowable mixture are non-spheronized sugars. Pharmaceutical grade sugars may be prepared in non-spherical form prior to dry or wet mixing with nicotine. For example, pharmaceutical grade sugars may first be prepared in non-spherical form by freeze drying, milling, micronization, and the like. In certain embodiments, the pharmaceutical grade sugar is subjected to milling, bashing, grinding, crushing, cutting, sieving, or other physical degradation processes as understood by those skilled in the art. This can ultimately reduce the particle size of the sugars and produce non-globular sugars. In one embodiment, the sugar particle size is at least about 60 μm. In one embodiment, the sugar particle size is 60 to 90 μm. In one embodiment, the sugar particle size is greater than about 90 μm. In one embodiment, the sugar particle size is about 60 μm.

There is no limit to the ratio of nicotine to sugar used, and it should be appreciated that the actual ratio used will be based on the desired nicotine concentration in the nicotine based component particles. Thus, in one embodiment the sugar concentration is at least about 50%. In another embodiment, the sugar concentration is about 50% to about 99%.

In other embodiments, the formulation is any pharmaceutically acceptable material, composition or carrier, such as a liquid or solid, associated with transporting or transporting a compound useful within the present invention or to a subject to perform the intended function. It may further comprise fillers, stabilizers, dispersants, suspending agents, diluents, thickeners, solvents or encapsulating materials. In one embodiment, the formulation further comprises a stabilizer. Each substance must be in an "acceptable" state in the sense of being compatible with the other ingredients of the formulation, including nicotine, and not harmful to the subject. Some materials that may be useful in the formulation of the present invention include pharmaceutically acceptable carriers such as sugars such as lactose, glucose and sucrose; Starches such as corn starch and potato starch; Cellulose, and derivatives thereof such as 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 glycerin, sorbitol, mannitol and polyethylene glycol; Esters such as ethyl oleate and ethyl laurate; Agar; Buffers such as magnesium hydroxide and aluminum hydroxide; Surface active agents; 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 for example aspartame or acesulfame K, derivatives of amino acids; Phospholipids such as dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, diarachidoylphosphatidylcholine, dibehenoylphosphatidylcholine, or diphosphatidyl glycerol; Pyrogen-free water; Isotonic saline; Ringer's solution; ethyl alcohol; Phosphate buffer solution; And other non-toxic compoundable materials used in pharmaceutical formulations. Other pharmaceutically acceptable materials that may be useful in the formulation include any and all coatings, antimicrobial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of nicotine or any other compound useful in the present invention, and the like. Physiologically acceptable to the subject. Supplementary 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 described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA). This document is incorporated herein by reference. In one embodiment, the carrier is an amino acid.

In one embodiment, the formulation of the present invention may further comprise a therapeutic agent. 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 formulation is about 0.5% to about 20%. As contemplated herein, any form of menthol, such as menthol in solid form, may be used for processing into menthol particles, powders, solutions or suspensions useful in the present invention. Non-limiting examples of menthol in solid form include powders, crystals, solidified distillates, flakes, and pressurized articles. In one embodiment, menthol is in the form of crystals. Menthol can be processed into particles ranging in size from about 5 μm to about 10 μm using any method known in the art. In some embodiments, menthol is mixed with additional liquid or solid additives for processing. Particulate additives may also be used. In one embodiment, menthol is mixed with silicon dioxide. In another embodiment, menthol is mixed with a sugar such as lactose. In some embodiments of the wet process, menthol is processed in a liquid carrier. In another embodiment, the additional cough suppressant component is mint. In one embodiment, the concentration of mint in the formulation is about 0.5% to about 20%. As contemplated herein, any form of mint, such as mint in solid form, may be used for processing into mint particles, powders, solutions or suspensions useful in the present invention. In one embodiment, the formulation of the present invention does not comprise 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 having a size of substantially 5-10 μm. In other embodiments, the additional cough suppressant component may comprise benzocaine. It is to be understood that the additional cough suppressant component may include any compound approved for suppressing cough. By optionally including 5-10 μm of menthol particles, these non-breathable menthol particles can reduce coughing in the subject's upper airways. Thus, in some embodiments, the minimum particles within the additional cough inhibitor component particle size range are at least about 5 μm, at least about 6 μm, at least about 7 μm, or at least about 8 μm. In some embodiments, the maximum particle within the additional cough suppressant component particle size range is about 10 μm or less, about 9 μm or less, about 8 μm or less, or about 7 μm or less. In certain embodiments, less than about 10% of the additional cough suppressor particles are less than about 5 μm. In other embodiments, at least 90% of the additional cough suppressant particles are less than about 10 μm. In other embodiments, at least 90% of the additional cough suppressant particles are less than about 8 μm. In one embodiment, less than about 10% of the additional cough suppressor particles are less than 4 μm and at least 90% of the additional cough suppressor particles are less than about 10 μm. In one embodiment, less than about 10% of the additional cough suppressor particles are less than about 5 μm and at least 90% of the additional cough suppressor particles are less than about 8 μm. In a preferred embodiment, the additional cough suppressant component consists of particles substantially in the range of 5-10 μm, although the additional cough suppressant component may comprise a wider range of particles. In one embodiment, the additional cough suppressant component may comprise particles in the range of 5-25 μm. In another embodiment, the additional cough suppressant component comprises particles substantially in the range of 5-50 μm. In another embodiment, the additional cough suppressant component comprises particles substantially in the range of 5-100 μm.

In another embodiment, the formulations of the present invention may further comprise an additional cough suppressant component having particles having a size of substantially 10 to 200 μm. Such additional cough suppressant component may be added to the formulation instead of or in addition to the additional cough suppressant component in the range of 5 to 10 previously discussed. Thus, the formulations of the present invention may comprise two additional cough suppressant components, wherein each additional cough suppressant component has a substantially different particle size distribution. An additional cough suppressant component of 10 to 200 μm contains oro-pharynx, glottis vocal cords and other anatomical regions closer or closer to the mouth containing receptors that can cause coughing or other unwanted sensations. Reduces cough caused by irritation. As contemplated herein, these large particles are substantially blocked from entering the sub-glottic airway. Thus, in some embodiments, the minimum particles within the additional cough inhibitor component particle size range are at least about 10 μm, at least about 12 μm, at least about 20 μm, at least about 30 μm, or at least about 50 μm. In some embodiments, the maximum particle within the additional cough inhibitor component particle size range is about 200 μm or less, about 150 μm or less, about 120 μm or less, about 100 μm or less, about 90 μm or less, or about 80 μm or less. In certain embodiments, less than about 10% of the additional cough suppressant component particles are less than about 10 μm. In certain embodiments, less than about 10% of the additional cough suppressant component particles are less than about 20 μm. In other embodiments, at least 90% of the additional cough suppressant component particles are less than about 200 μm. In other embodiments, at least 90% of the additional cough suppressant component particles are less than about 150 μm. In other embodiments, at least 90% of the additional cough suppressant component particles are less than about 100 μm. In one embodiment, less than about 10% of the additional cough suppressor component particles are less than 10 μm and at least 90% of the additional cough suppressor component particles are less than about 200 μm. In one embodiment, less than about 10% of the additional cough suppressor component particles are less than about 12 μm and at least 90% of the additional cough suppressor component particles are less than about 100 μm. In one embodiment, the additional cough suppressant component comprises menthol particles of about 10-200 μm in size. In another embodiment, the additional cough suppressant component having particles about 10 to 200 μm in size may comprise benzocaine. It should be understood that the additional cough suppressant component having particles of about 10-200 μm in size may include any compound approved to inhibit cough. In another embodiment, the addition of at least one component to the formulation of the present invention in addition to the nicotine component dilutes the nicotine containing particles and causes oro-pharynx, glottis vocal cords and other anatomical regions close to the mouth. It can reduce the cough caused by nicotine that stimulates it.

In one embodiment, the formulations of the present invention may optionally include a flavor component having particles that are about 10 to 1000 μm in size. In one embodiment, the flavor component consists of particles substantially in the range of about 10 to 200 μm. In a preferred embodiment, the flavor component consists of particles substantially in the range of about 10 to 100 μm. This flavor component utilizes these embedded large particles that can affect the subject in the oral cavity to produce the desired flavor. In addition, these flavor component particles are limited to more than about 10 μm in size, which limits their ability to enter the subject's lungs. Thus, in some embodiments, the minimum particles within the flavor component particle size range are at least about 10 μm, at least about 12 μm, at least about 20 μm, at least about 30 μm, or at least about 50 μm. In some embodiments, the maximum particles within the flavor component particle size range are about 1000 μm or less, about 500 μm or less, about 200 μm or less, about 150 μm or less, about 120 μm or less, about 100 μm or less, about 90 μm or less, or About 80 μm or less. In certain embodiments, less than about 10% of the flavor component particles are less than about 10 μm. In certain embodiments, less than about 10% of the flavor component particles are less than about 20 μm. In other embodiments, at least 90% of the flavor component particles are less than about 1000 μm. In other embodiments, at least 90% of the flavor component particles are less than about 500 μm. In other embodiments, at least 90% of the flavor component particles are less than about 200 μm. In other embodiments, at least 90% of the flavor component particles are less than about 150 μm. In other embodiments, at least 90% of the flavor component particles are less than about 100 μm. In one embodiment, less than about 10% of the flavor component particles are less than 10 μm and at least 90% of the flavor component particles are less than about 1000 μm. In one embodiment, less than about 10% of the flavor component particles are less than 10 μm and at least 90% of the flavor component particles are less than about 200 μm. In one embodiment, less than about 10% of the flavor component particles are less than about 10 μm and at least 90% of the flavor component particles are less than about 100 μm. 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 grade spices used for candy or baking. It is to be understood that the flavor compound can be any flavor compound known in the art, preferably a regulated flavor compound.

The present invention includes formulations consisting of nicotine, sugars, and amino acids. The present invention also includes formulations consisting of nicotine, sugars, flavor components and amino acids. The present invention includes formulations consisting of nicotine, sugars, amino acids and excipients. The present invention includes formulations consisting of nicotine, sugars, amino acids and cough suppressants. The present invention also includes formulations consisting of nicotine, sugars, flavor components, amino acids and excipients. The invention also includes formulations consisting of nicotine, sugars, flavor components, amino acids, excipients, and cough suppressants. The present invention also includes formulations consisting of nicotine, sugars, flavor components, amino acids and excipients. The present invention also includes formulations consisting of nicotine, sugars, flavor components, amino acids and cough suppressants. 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 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 weight percentages of each component in the formulations of the invention can be varied to achieve different properties. Thus, as will be appreciated by those skilled in the art, the relative weight percentages of the components may be modified for a variety of reasons, including but not limited to certain levels of blood while controlling the coarseness of the subject's airways. Achieving nicotine concentration, achieving a certain level of roughness while adjusting the level of satisfaction perceived by the subject of therapy, better absorbing nicotine in the patient's lungs, achieving faster blood nicotine kinetics, Optimizing the cough suppressant performance of the formulation, changing or improving the taste of the formulation, and adjusting the relative dose of nicotine. In certain embodiments, the formulation can be about 1 to 20% by weight flavor component, with a preferred weight of 1 to 5% flavor component. In certain embodiments, the formulation may be about 1% to about 10% by weight cough suppressant, and the preferred weight is about 0.5% to about 5% cough suppressant. In various embodiments, in addition to any flavor ingredients, cough suppressant ingredients, carriers, or other ingredients, the remainder of the formulation is a nicotine ingredient. In one embodiment, the formulation may be approximately 10% nicotine component.

In one embodiment, the percentage lactose in the formulation is 50% to 99%. In one embodiment, the percentage lactose in the formulation is 50% to 80%. In some embodiments, the percentage lactose in the formulation is 75% to 90%. In other embodiments, the lactose percentage in the formulation is 75% to 85%. In yet other embodiments, the percentage lactose in the formulation is 80% to 90%. In yet other embodiments, the percentage lactose in the formulation is 80% to 99%. In one embodiment, the percentage lactose in the formulation is about 50%. In one embodiment, the percentage lactose in the formulation is about 60%. In one embodiment, the percentage lactose in the formulation is about 70%. In one embodiment, the percentage lactose in the formulation is about 80%. In another embodiment, the percentage lactose in the formulation is about 90%. In another embodiment, the percentage lactose in the formulation is about 95%. In another embodiment, the lactose percentage in the formulation is about 99%. In some embodiments, any carrier at any concentration may be substituted for lactose.

In one embodiment, the percentage of menthol in the formulation is 0% to 20%. In some embodiments, the percentage of menthol in the formulation is 5% to 20%. In other embodiments, the percentage of menthol in the formulation is 5% to 15%. In yet other embodiments, the percentage of menthol in the formulation is 10% to 20%. In one embodiment, the percentage of menthol in the formulation is about 5%. In another embodiment, the percentage of menthol in the formulation is about 20%.

In one embodiment, the percentage of mint in the formulation is 0% to 20%. In some embodiments, the percentage of mint in the formulation is 5% to 20%. In other embodiments, the percentage of mint in the formulation is 5% to 15%. In yet other embodiments, the percentage of mint in the formulation is 10% to 20%. In one embodiment, the percentage of mint in the formulation is about 5%. In another embodiment, the percentage of mint in the formulation is about 20%.

How to use

In one aspect, the invention relates to a method for controlling the amount of nicotine and menthol inhaled by a subject, including increasing, decreasing or maintaining the amount of nicotine and menthol in a powder formulation inhaled by the subject. For example, as shown in FIG. 1, the method 100 includes identifying a concentration of nicotine for inhalation 110 by a subject, identifying a total dose of nicotine for inhalation by a subject 120, Identifying the concentration of menthol to be inhaled (130), and identifying the total dose of menthol to be inhaled by the subject (140). Finally, step 150 comprises nicotine particles having the concentration of nicotine identified above and the concentration of the identified menthol 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. The subject is provided with an amount of the formulation that includes menthol particles having.

In another embodiment, as shown in FIG. 2, the method 200 includes steps to reduce the amount of nicotine while maintaining the amount of menthol inhaled by the subject. The method 200 includes identifying 210 the concentration of nicotine in the nicotine formulation to be inhaled by the subject having a base menthol concentration, comprising nicotine particles having a concentration of nicotine identified above and menthol particles having a base menthol concentration; Providing 220 a first dose comprising an amount of a formulation present, and providing at least one additional dose comprising an amount of a formulation comprising nicotine particles, wherein at least one additional dose Comprises step 230, which comprises less nicotine particles than the formulation in the first dose and contains the same base menthol concentration in the first dose.

Referring now to FIG. 3, three different formulations are outlined, where each formulation is designed to deliver the same dose of nicotine (1 mg). To achieve the base level of nicotine delivery (Formulation 1), the total dose of nicotine forms part of a 20 mg total formulation amount of powder containing 5% leucine and 90% lactose, which is a nicotine concentration of 5% in the formulation. Results in. Assuming that about 1 mg of powder can be inhaled per single inhalation, about 0.05 mg of nicotine is inhaled per single inhalation and after about 20 single inhalations are completed, the total dose of nicotine is administered to consume 20 mg of formulation powder. . To achieve increased levels of menthol delivery when delivering 1 mg of nicotine, the total dose of nicotine is part of a 20 mg total formulation amount of powder containing 5% leucine, 85% lactose and 5% menthol, which is 5 Results in a nicotine concentration of% (Formulation 2). Assuming that about 1 mg of powder can be inhaled per single inhalation, about 0.05 mg of nicotine is inhaled per single inhalation and after about 20 single inhalations are completed, the total dose of nicotine is administered to consume 20 mg of formulation powder. . By taking the amount of menthol per inhalation, the user will experience increased cough suppression levels compared to Formulation 1. To achieve even higher cough suppression levels when delivering 1 mg of nicotine, the total dose of nicotine forms part of a 20 mg total formulation amount of powder containing 5% leucine, 70% lactose, and 20% menthol. This results in a nicotine concentration of 5% (Formulation 3). Assuming that about 1 mg of powder can be inhaled per single inhalation, about 0.05 mg of nicotine is inhaled per single inhalation and after about 20 single inhalations are completed, the total dose of nicotine is administered to consume 20 mg of formulation powder. . By increasing the amount of menthol per inhalation, the user will experience increased levels of cough suppression compared to formulations 1 and 2. The formulations provided in FIGS. 3 and 4 are exemplary and any component may be substituted with the comparable substituents or excipients described herein.

In other embodiments, the total dose of nicotine may be gradually reduced. For example, as shown in FIG. 4, three different formulations are outlined, where each formulation is designed to deliver different (smaller) total doses of nicotine while maintaining the same amount of cough suppression. Starting with Formulation 4, the 1 mg total dose of nicotine forms part of the 20 mg total formulation amount of powder 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 single inhalation, this means that about 0.05 mg of nicotine is inhaled per single inhalation and the total dose of nicotine is administered after about 20 single inhalations have been completed at the initial nicotine dose. . Formulation 5 is designed to deliver a total dose of 0.5 mg nicotine with the same level of cough suppression. Thus, a total dose of 0.5 mg nicotine may form part of a 20 mg total formulation amount of powder containing 5% leucine, 82.5% lactose and 10% menthol, resulting in a nicotine concentration of about 2.5%. Assuming that about 1 mg of powder can be inhaled per single inhalation, this indicates that about 0.025 mg of nicotine is inhaled per single inhalation and the total dose of nicotine is administered after about 20 single inhalations are completed with the same level of cough suppression. it means. Formulation 6 is again designed to deliver a total dose of 0.3 mg nicotine with the same level of cough suppression. Thus, a total dose of 0.3 mg nicotine may form part of a 20 mg total formulation amount of powder containing 5% leucine, 83.5% lactose and 10% menthol, resulting in a nicotine concentration of about 1.5%. Assuming that about 1 mg of powder can be inhaled per single inhalation, this indicates that about 0.015 mg of nicotine is inhaled per single inhalation and the total dose of nicotine is administered after about 20 single inhalations are completed with the same level of cough suppression. it means. Thus, a subject can gradually progressively reduce the total dose of nicotine administered by sequentially administering Formulations 4-6, while experiencing a certain level of cough suppression throughout the decrease in delivered nicotine. In one embodiment, nicotine concentration reducing formulations can be used for smoking cessation therapy. Likewise, a subject may gradually incrementally increase the total dose of nicotine administered by administering sequentially increasing nicotine concentration formulations, while experiencing a constant level of cough suppression throughout the increased nicotine delivered. The formulations described in the figures are exemplary and any component may be substituted with the comparable substituents or excipients described herein.

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

As contemplated herein, there is no restriction on the specific formulation amount of the powder or the concentration of nicotine within the total formulation amount; rather, the present invention does not provide any of these variables when delivering the total dose of nicotine to the subject through a dry powder inhaler. It is about the possibility of changing one or both. In addition, there is no limit to the actual amount of powder inhaled per inhalation. This amount may vary depending on the function of the dry powder inhaler used, or may depend on user performance if the user chooses to inhale shallower or deeper through the dry powder inhaler used. In addition, by administering a total dose of nicotine over multiple inhalations, any user error occurring during a single inhalation will ultimately be corrected through one or more sequential inhalations, thereby subjecting the subject to more consistently ensure absorption of the total dose of nicotine. Can be.

Manufacturing method

The invention also relates to a method of preparing the formulation of the invention. In one embodiment, the method comprises dry mixing. In one embodiment, the method comprises wet mixing.

Referring now to FIG. 5, an exemplary dry process or method 300 for producing any of the formulations described herein is shown. For example, in step 310, nicotine tartarate is dry milled. In step 312 nicotine is mixed with lactose and leucine. Optionally, in step 313 a therapeutic agent such as menthol is added. In some embodiments, the nicotine or nicotine salt is not bound to any other component of the formulation. That is, the formulation contains separate particles of nicotine or nicotine salt, and separate particles of other components of the formulation, such as sugars. In one embodiment, nicotine is not bound to sugars. In one embodiment, nicotine is not bound to amino acid particles. In one embodiment, nicotine is not bound to the leucine particles. In one embodiment, nicotine is not bound to glycine particles. In one embodiment, nicotine is not bound to the lysine particles. In one embodiment, nicotine is not bound to the carrier. In one embodiment, nicotine is not bound to lactose and leucine particles. In another embodiment, nicotine is not bound to the menthol particles. In another embodiment, nicotine is at least partially bound to menthol particles. Alternatively, nicotine tartarate, lactose and leucine may be first dry mixed and co-milled in step 316, as in step 314. In another embodiment, the therapeutic agents such as nicotine tartarate, lactose, leucine, and menthol are first dry mixed and co-milled in step 320, as in step 318. In step 330, the particles of the resulting formulation are filtered, such as a sieve, to remove any particles larger than the threshold size value. In step 340, the particles of the resulting formulation are filtered again to remove any particles smaller than the threshold size value, resulting in a final dry powder formulation (350). In some implementations, only one filtering step is necessary. In other implementations, more than one filtering step is required. Optionally, at 360, flavoring ingredients may be added to the final formulation 350. Step 360 can include any number of processing steps necessary to obtain the desired particle size (eg, 10-1000 μm) for the flavor component being added.

Any method of incorporating particles into and for the methods and formulations of the invention is contemplated herein. The compounding can be carried out in one or more steps, in a continuous, batch, or semi-batch process. For example, if two or more excipients are used, they may be combined together before or simultaneously with the pharmaceutical formulation microparticles.

Formulation may be performed using essentially any technique or device suitable for combining microparticles with one or more other materials (eg, excipients) effective to achieve uniformity of the formulation. The compounding process can be performed using various blenders. Representative examples of suitable blenders include V-blenders, slant-cone blenders, cube blenders, bin blenders, static continuous blenders, Dynamic continuous blender, orbital screw blender, planetary blender, forberg blender, horizontal double-arm blender, horizontal high intensity mixer (horizontal high intensity mixer), vertical high intensity mixer, stirring vane mixer, twin cone mixer, drum mixer, and tumble blender. It is included. The blender preferably has the strict hygienic design required for pharmaceutical products.

Tumble mixers are often preferred for batch operations. In one embodiment, the formulation is achieved by aseptically blending two or more components (which may include both dry and small portions of the liquid components) in a suitable container. One example of a tumble blender is TURBULA ™, supplied by Glen Mills Inc. of Clifton, NJ, and manufactured by Willy A. Bachofen AG, Masseen Fabric, Basel, Switzerland.

For continuous or semi-continuous operation, the blender may optionally have a rotary feeder, a screw conveyor, or other feeder mechanism for controlled introduction of one or more of the dry powder components into the blender.

The milling step is used to break and / or deaggregate the blended particles to achieve the desired particle size and size distribution and to improve the distribution of the particles in the blend. Any milling method can be used to form the particles of the present invention, as will be appreciated by those skilled in the art. Various milling processes and equipment known in the art can be used. Examples include hammer mills, ball mills, roller mills, disk grinders, jet mills, and the like. Preferably, a dry milling process is used.

Referring now to FIG. 6, an exemplary wet process or method 400 for making any of the formulations described herein is shown. For example, in step 410, nicotine tartarate is mixed with excipients such as lactose and leucine to form a fluid mixture. In step 412, the mixture is sprayed. Alternatively, in step 414, nicotine tartarate may be mixed with excipients such as lactose and leucine, as well as therapeutic agents such as menthol, to form a fluid mixture. As contemplated herein, any liquid carrier can be used in the process of producing a solution or suspension. In one embodiment, the liquid carrier is water. Preferably, the liquid carrier is one in which the components of the formulation are soluble or suspended. Thus, the liquid carrier may be any liquid or liquids in which the components of the formulation alone or in combination form a flowable mixture or suspension, which is preferably a generally uniform composition.

In step 416, the mixture is sprayed. In step 420, the mixture is dried, for example via a spray dryer. Alternatively, the process can optionally be carried out via fluid bed drying, where nicotine tartarate can instead be spray dried onto the excipient mixture. In step 430, the resulting nicotine particles are filtered, such as with a sieve, to remove any particles larger than the threshold size value. In step 440, the resulting nicotine particles are filtered again to remove any particles smaller than the threshold size value, producing a final dry powder formulation (450). In some implementations, only one filtering step is necessary. In other implementations, more than one filtering step is required. Optionally, in step 460, flavor components may be added to the final formulation 450. Step 460 may include any number of processing steps necessary to obtain the desired particle size (eg, 10-1000 μm) for the flavor component being added.

The flowable mixture is dried, for example through a spray dryer, to produce composite particles of the flowable mixture suitable for delivery to the alveoli and lower airways of the subject. It should be appreciated that there is no limit to the method of drying the flowable mixture. While the preferred method uses a spray dryer, other drying techniques can be used that can produce particles of suitable size, such as fluidized bed drying. In one embodiment, the mixture is finely divided through the passage through the orifice when entering the spray dryer. In another embodiment, the flowable mixture may pass through a sprayer, such as a rotary sprayer, to supply the flowable liquid into the spray dryer. In addition, any drying rate may be used, provided that the drying rate results in the formation of dry particles in the desired size range (eg, slow rate or fast rate drying). Prior to separating the desired particle size of the nicotine based component, the resulting particles formed through the spray dryer may have a particle size of about 0.1 to about 5 μm.

Further separation / filtering of the selected particle size can be performed in both dry and wet processes. In a wet process, the operating conditions of the spray dryer can be adjusted to produce particles sized to travel into the alveoli of the lungs and smaller airways. For example, the rotary nebulizer may be operated at a liquid feed rate of about 2 to about 20 ml / min, or 2 to about 10 ml / min, or about 2 to about 5 ml / min. The rotary nebulizer may also be operated at about 10,000 to about 30,000 rpm, about 15,000 to about 25,000 rpm, or about 20,000 to about 25,000 rpm. Particles of various sizes may be obtained by spray drying, and particles having the desired particle size may be more specifically selected when filtered, such as through one or more sieving steps, as described elsewhere herein. It should be understood. The spray dryer can be operated at a temperature high enough to allow the liquid carrier to develop rapidly without raising the temperature of sugars and nicotine in the mixture to the point where these compounds begin to degrade. Thus, the spray dryer may 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 appreciated that there is no limit to the method of drying the flowable mixture. Examples of methods for drying the flowable mixture include, but are not limited to, spray drying, vacuum drying and freeze drying. In addition, any drying rate may be used, provided that the drying rate results in the formation of dry particles in the desired size range (eg, slow rate or fast rate drying).

As mentioned above, in a wet process, such as through a fluidized bed dryer, the liquid carrier dries to produce composite particles of nicotine coated with menthol suitable for delivery to the subject's alveoli and lower airways. It should be understood that there is no limit to the method of drying the flowable mixture. While the preferred method uses a fluidized bed drier, other drying techniques may be used that remove the liquid carrier and leave a uniform menthol coating on the nicotine particles.

As contemplated herein, the particles of the invention can be produced in a relatively narrow size range through the use of at least one sieving step. In this embodiment, the sieving step comprises removing the particles from the mixture smaller or larger than the desired range using a sieve corresponding to the minimum or maximum of the desired particle size range. For example, to obtain nicotine particles in the range of about 1-5 μm, a mixture of nicotine particles produced using the milling process described herein can be provided. The mixture of nicotine particles will have a size distribution depending on the milling conditions used and / or the properties of the input mixture for the mill. The mixture of nicotine particles may first pass through a 5 μm sieve, where substantially all of the particles below 5 μm pass through the sieve and are collected. Subsequently, the particles passing through the sieve can be delivered to a 1 μm sieve, where substantially all of the particles larger than 1 μm do not pass through the sieve. Particles larger than 1 μm may be collected from a sieve, where the collected particles will have a substantially size ranging from 1 to 5 μm. Thus, such a process can be used to narrow the range of any mixture of particles to any desired particle size range as generally described herein.

In other embodiments, a mixture of particles may be provided that substantially meets the minimum or maximum criteria of the desired particle size range. For example, if a nicotine particle size range of about 2-5 μm is desired, a mixture of nicotine particles may be provided wherein substantially all of the particles are less than 5 μm. Such mixtures may modify the milling conditions or, if the particles are spray dried, mill the spray dried material to produce a mixture of particles, typically less than 5 μm. The mixture can then be delivered through a 2 μm sieve, where particles that do not pass through the sieve are collected, where the collected particles are substantially within the desired 2-3 μm range.

It is contemplated that the percentage of particles within the desired particle size range for any component of the formulations of the present invention may depend on the technology used to produce that component. For example, if the target size of the nicotine component is in the range of 2-5 μm, it will be understood that more than 90% of the component falls within the desired range when using a spray drying production technique on a relatively small scale. However, using a relatively large milling production technique can produce in excess of 70% of the nicotine component within this target range.

Kit of invention

The invention also relates to nicotine kits, including but not limited to nicotine treatment kits and smoking cessation kits. In one embodiment, the kit may comprise a plurality of nicotine based powder formulation doses contained in a sealed storage chamber, such as a capsule or blister pack. As contemplated herein, at least two formulation doses are equal to the total nicotine amount, but at different nicotine concentrations. In other embodiments, the kit measures at least two sets of bulk nicotine based powders with different concentrations of nicotine, and a set amount of powder measurement, such as a scoop or graduated measuring container, which can be mounted in a storage chamber of a dry powder inhaler. It includes a means.

In another embodiment, the kit includes a prefilled powder capsule for nicotine therapy or a set course of treatment, such as for example a 30 day treatment course. Capsules may be filled in varying powder amounts of varying nicotine concentrations to suit a therapeutic regimen. In other embodiments, the kit includes an instruction that describes steps for a method for treating nicotine, including but not limited to smoking cessation therapy. The steps of the method may include a starting dose, subsequent regular doses such as multiple daily doses, and final dose to be administered by means of loading the dry powder formulation dose into a dry powder inhaler.

In another embodiment, the indication can instruct the user about the number of sets of daily course of nicotine treatment, where the daily nicotine dose can be adjusted. In one embodiment, the nicotine treatment course lasts about 7 days to about 30 days. In another embodiment, the course of nicotine treatment lasts about 10 days to about 45 days. In another embodiment, the course of nicotine treatment lasts about 15 days to about 60 days. In another embodiment, the course of nicotine treatment lasts about 30 days to about 90 days. In a preferred embodiment, the nicotine treatment course lasts about 30 days. In another preferred embodiment, the nicotine treatment course lasts about 45 days. In another preferred embodiment, the nicotine treatment course lasts about 60 days. In another preferred embodiment, the nicotine treatment course lasts about 90 days.

The disclosures of all patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety. Although the present invention has been described with reference to specific embodiments, it is apparent that other embodiments and variations of the present invention can be devised by other persons skilled in the art without departing from the true spirit and scope of the present invention. The appended claims are intended to be embraced as including all such embodiments and variations of the same.

Cross Reference to Related Application

This application is filed on September 16, 2015, now US Patent No. 9,585,835, part of US Patent Application No. 14 / 856,102, filed March 7, 2017, US Patent Application No. 15 / 452,133 All of which are hereby incorporated by reference in their entirety.

Claims (17)

A dry powder nicotine formulation comprising at least one amino acid, nicotine, and at least one sugar selected from the group consisting of glycine and lysine or combinations thereof, wherein the formulation is suitable for inhalation. The formulation of claim 1, further comprising at least one phospholipid. The formulation of claim 1, wherein the nicotine comprises nicotine tartarate. The formulation of claim 1, wherein the concentration of nicotine is 0.5% to 10%. The formulation of claim 1, wherein the sugar concentration is between 50% and 99%. The formulation of claim 1, wherein the concentration of amino acid is 0.5% to 50%. The formulation of claim 1, further comprising menthol. The formulation of claim 1, further comprising mint. A dry powder nicotine formulation consisting of at least one amino acid, nicotine, at least one sugar, and mint selected from the group consisting of glycine, lysine and leucine, wherein the formulation is suitable for inhalation. The formulation of claim 9, wherein at least about 40% of the nicotine and amino acid particles are between 3 and 4 μm. The formulation of claim 9, wherein at least about 80% of the nicotine and amino acid particles are between 1 and 7 μm. The formulation of claim 9, wherein the sugar particle size is at least about 50 μm. The formulation of claim 9, wherein the mint particle size is at least about 20 μm. A dry powder nicotine formulation comprising particles of at least one amino acid, nicotine particles, and particles of at least one sugar selected from the group consisting of glycine, lysine and leucine, wherein the amino acid particles are not substantially bound to the nicotine particles, and The formulation is suitable for inhalation. The formulation of claim 14, further comprising at least one phospholipid. The formulation of claim 14 further comprising menthol. The formulation of claim 14 further comprising mint.

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