US20120042886A1

US20120042886A1 - Method of producing a nicotine medicament and a medicament made by the method

Info

Publication number: US20120042886A1
Application number: US13/270,682
Authority: US
Inventors: Hanna Piskorz
Original assignee: Individual
Current assignee: Sansa Corp Barbados Inc
Priority date: 1998-03-11
Filing date: 2011-10-11
Publication date: 2012-02-23

Abstract

A method of producing a nicotine medicament for use in an inhaler comprises combining nicotine, a non-spheronized sugar and a liquid carrier including water to produce a flowable mixture and spray drying the flowable mixture at conditions to produce particles of the nicotine medicament suitable for delivery to the alveoli and lower airways of the person. Also disclosed is a nicotine medicament made by the method. The nicotine composition produced by this method is a composite particle suitable for tobacco replacement or withdrawal therapy.

Description

This application is a continuation-in-part of application Ser. No. 11/673,813 filed Feb. 12, 2007 which is still pending, which is a continuation of application Ser. No. 10/320,479 filed Dec. 17, 2007 which is abandoned, which is a division of application Ser. No. 09/759,304 filed on Jan. 16, 2001 and which is abandoned, which is a continuation of Ser. No. 09/265,367 filed Mar. 10, 1999, which is abandoned, all of which is incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to nicotine medicaments. In particular, the invention relates to a method of producing a nicotine medicament which is suitable for inhalation.

BACKGROUND OF THE INVENTION

Smoking has been determined to be a contributory or causative factor in a number of diseases including respiratory diseases such as emphysema, chronic bronchitis, lung infections and lung cancer. Most regular smokers become addicted to, or dependent upon, the pharmacological effects of nicotine in tobacco smoke. Nicotine is rapidly absorbed across the blood/brain barrier and exerts a direct action on nicotine receptors in the spinal cord, autonomic ganglia and adrenal medulla.
Various nicotine replacement therapies have been developed. Some of these utilize a nicotine substitute. Nicotine substitutes generally contain nicotine in a solid form, in a vapour or in solution. For example, nicotine replacement therapy has included the use of nicotine gum. One disadvantage with nicotine gum is that lower steady state nicotine levels are achieved from chewing nicotine gum compared to smoking cigarettes and the rate of rise of blood nicotine levels is substantially lower as compared to smoking cigarettes. Further, the gum has been associated with gastrointestinal side effects, hiccups, mouth ulcers and sore throat. The amount of nicotine absorbed is also highly variable and is dependent upon the chewing and swallowing actions of the user over a prolonged period of time.
Nicotine patches have also been developed. One disadvantage of nicotine patches is that they have been associated with skin irritation at the site of application. Further, they result in a slow absorption of nicotine which may not be effective in satisfying a person's craving for cigarettes.
Self-propelled aerosols (also known as pressurized aerosols) which contain nicotine in solution have been proposed as cigarette substitutes. An example is the self-propelled formulation of Jacobs (U.S. Pat. No. 4,635,651). As shown in Jacobs, these delivery systems contain a water based aerosol formulation and a propellant such as freon which are stored in a pressurized container. When actuated, Jacobs delivers nicotine and a solid carrier to the mouth of the user. Thus the aerosol created by Jacobs contains, in combination, a mixture of nicotine and the solid carrier. The nicotine is not formed as a composite part of the solid carrier. Further, the particle size of the aerosol created by Jacobs was variable. Therefore, the dose which is administered by using such pressurized aerosols may not be accurately controlled.
It has also been proposed to produce a dry powder inhaler for delivering a nicotine containing medicament via inhalation (see PCT application PCT/CA95/00562). While nicotine formulations in the form of salts and complexes have been developed, there is still a need for a nicotine formulation which is adapted for inhalation into the alveoli and smaller airways of the lungs.

SUMMARY OF THE INVENTION

Cigarette smoke is an aerosol comprising discrete particles of tar with which the nicotine is associated. The tar particles are of a size, which makes them capable of traveling to the alveoli and lower airways of a person. Upon study, it has been determined that the nicotine is effectively conveyed to the alveoli and lower airways of a person by the tar particles. Current tobacco replacement therapies have not been effective in satisfying a person's craving for cigarettes. According to the instant invention, a nicotine formulation, which more closely simulates cigarette smoke, is provided which may be used with existing inhaler technology so as to improve the effectiveness of tobacco replacement or withdrawal therapies.
In accordance with the method of the instant invention, there is provided a composite material comprising discrete particles. which are a mixture of nicotine and a carrier. As with cigarette smoke, the composite material is a physical combination of both the nicotine and the carrier. The carrier effectively provides a particle having a size and density such that it will be conveyed on inhalation to the alveoli and lower airways of a person. The nicotine is combined with the carrier such that it will be conveyed to the alveoli and lower airways of a person with the carrier. In contrast, in prior art formulations, the nicotine and the carrier were merely associated or aggregated with each other such that they separated from each other in the air stream. Thus the carrier did not act in general to transport a dose of the nicotine to the alveoli and lower airways of a person. In accordance with the instant invention, the nicotine and carrier form a composite material which are physically combined in such a way that they will not separate during inhalation.
In accordance with the method of the instant invention, there is provided a method of producing a nicotine medicament for use in an inhaler comprising:
a) combining nicotine, a non-spheronized pharmaceutical grade sugar and a liquid carrier to produce a flowable mixture; and,
b) spray drying the flowable mixture to form spray dried particles.
The flowable mixture is spray dried at conditions to produce composite particles of a nicotine medicament suitable for delivery to the alveoli and lower airways of a person.
In accordance with another the method of the instant invention, there is provided a method for conducting a tobacco replacement or withdrawal therapy comprising:
a) preparing a flowable mixture consisting essentially of nicotine, a non-spheronized pharmaceutical grade sugar and a liquid carrier;
b) spray drying the flowable mixture to produce a composite material at conditions to produce particles of the nicotine medicament which are suitable for delivery to the alveoli and lower airways of a person and which simulate cigarette smoke when aerosolized and inhaled; and,
c) packaging the composite material in a container for use with an inhaler suitable for delivering a medicament to the lungs.
The inhaler is preferably non-pressurized. Such inhalers, which may be referred to as breath activated inhalers, utilize the inhalation of a person to produce the air flow through the inhaler.
In one embodiment, the liquid carrier may comprise water and preferably consists of water.
In another embodiment, the liquid carrier additionally comprises alcohol, particularly where the nicotine is a nicotine salt such as a nicotine sulphate or a nicotine tartrate. In this case, alcohol may be added as a cosolvent, to expedite the solubility of the nicotine in the flowable mixture. In such a case, the liquid carrier preferably comprises a minor proportion of the alcohol and a major proportion of water. The ratio of alcohol to water in the liquid carrier may be from about 1:1 to 1:10, preferably from about 1:2 to 1:8 and more preferably from about 1:5 to 1:7 parts by weight.
In another embodiment of the invention, the flowable mixture is atomized prior to being dried.
The flowable mixture is preferably dried at conditions to form substantially spherical particles. More preferably, the flowable mixture is dried at conditions to form spherical particles, which have a dimpled surface. In one embodiment, the flowable mixture is dried at a temperature sufficiently high so that the liquid carrier is rapidly removed from the atomized particles of the flowable mixture in the spray drier.
An advantage of the instant invention is that the medicament particles produced by the method disclosed herein are well adapted for absorption into the bloodstream of a person via the alveoli and small airways of the lungs. The particles are a composite structure. Accordingly, the nicotine will not separate from the sugar (the carrier) during inhalation. Thus the sugar will convey the nicotine to the lungs in a manner to mimic cigarette smoke. By controlling the conditions at which the flowable mixture is spray dried, particles having a size from about 0.1 to about 5 μm, more preferably from about 0.5 to about 3 μm may be produced.
Nicotine, if it impacts upon the throat or upper airways of the person may cause irritation. Thus, the method of the instant invention may be used to produce a powdered medicament formulation, which, by inhalation, may reach the alveoli and smaller airways of a person's lungs without causing undue, and preferably, no irritation.
The method may also be used to produce particles, which, not only are spherical, but have an uneven or a “dimpled” surface. The spherical shape of the dried particles reduces aggregation of the particles while in the inhaler, thus rendering it easier to aerosolize the particles upon inhalation by the user. Further, by having a dimpled surface, the aerodynamics of the medicament particles are improved whereby the particles may by more easily entrained in the air inhaled by the user.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other advantages of the instant invention will be more fully and completely understood in accordance with the following description of a preferred embodiment of the invention, taken together with the drawings in which:

FIG. 1 is a micrograph of exemplary non-spheronized particles of a pharmaceutical grade sugar used in processes of the present disclosure;

FIG. 2 is a graph illustrating the particle size of an exemplary non-spheronized pharmaceutical grade sugar, used in processes of the present disclosure;

FIG. 3 is a micrograph of a second embodiment of exemplary non-spheronized particles of a pharmaceutical grade sugar used in processes of the present disclosure;

FIG. 4 is a micrograph of a third embodiment of exemplary non-spheronized particles of a pharmaceutical grade sugar used in processes of the present disclosure;

FIG. 5 is a graph illustrating, in a second embodiment, the particle size of an exemplary non-spheronized pharmaceutical grade sugar, used in processes of the present disclosure;

FIG. 6 is a graph, in a third embodiment, illustrating the particle size of an exemplary non-spheronized pharmaceutical grade sugar, used in processes of the present disclosure;

FIG. 7 is a micrograph of a fourth embodiment of exemplary non-spheronized particles of a pharmaceutical grade sugar used in processes of the present disclosure;

FIG. 8 is a micrograph of a fifth embodiment of exemplary non-spheronized particles of a pharmaceutical grade sugar used in processes of the present disclosure

FIG. 9 is a graph illustrating, in a fourth embodiment, the particle size of an exemplary non-spheronized pharmaceutical grade sugar, used in processes of the present disclosure;

FIG. 10 is a graph illustrating, in a fifth embodiment, the particle size of an exemplary non-spheronized pharmaceutical grade sugar, used in processes of the present disclosure;

FIG. 11 (A, B and C) are graphs illustrating, in a sixth embodiment, the particle sizes of exemplary non-spheronized pharmaceutical grade sugars, used in processes of the present disclosure;

FIG. 12 is a graph of nicotine concentration in a finished product made in accordance with the present invention versus nicotine concentration in the flowable mixture prior to being spray dried; and,

FIG. 13 is a graph of nicotine concentration in the finished product versus the ratio of nicotine to lactose in the flowable mixture prior to being spray dried.

DESCRIPTION OF THE PREFERRED EMBODIMENT

According to the method of the instant invention, a composite medicament comprising nicotine and a pharmaceutical grade sugar is produced in a form suitable for inhalation by a user. In particular, the medicament comprises solid discrete flowable particles, which may be entrained in the air inhaled by a person so as to travel to the alveoli and smaller airways of the lungs.
According to a method of the instant invention, a non-spheronized pharmaceutical grade sugar and nicotine are mixed with a liquid carrier so as to form a flowable mixture which may then be dried. The liquid carrier is an agent, which mixes with the sugar and the nicotine to a degree sufficient to form a flowable mixture which may be rapidly dried such as in a spray drier. The nicotine, sugar and liquid carrier may be combined in any order. The liquid carrier may be utilized to solubilize one or both of the nicotine and the sugar. If one of the reagents is not soluble in the liquid carrier, then the liquid mixture may be blended or homogenized to produce a liquid mixture having a generally consistent composition.
In accordance with the present disclosure, the Applicants have unexpectedly found that the form or shape of the pharmaceutical grade sugar that is combined with the nicotine before spray drying aids in the preparation of a composite material which is not deposited in the upper airways of a user upon inhalation. In particular, if spheronized sugar is utilized in the process, then the resultant spray dried product tends to form as string shaped particles and not spherical particles. Unexpectedly, non-spheronized sugar, when solubilized and mixed with the nicotine, will form spherical particles when spray dried. As the non-spheronized pharmaceutical grade sugar is further processed by solubilizing the sugar and combining it with the nicotine formulation in liquid carrier, followed by spray drying, it is unexpected that the initial form or shape of the sugar would influence the final powdered medicament.
A person skilled in the art would understand that non-spheronized particles are non-spheroidal irregularly shaped particles (such as wedge-shaped), as opposed to spheronized particles produced by the spheronization process resulting in rounded or spherical particles. Such non-spheronized particles may be prepared by freeze drying or physical particle size reduction such as by milling, micronizing or the like.
Accordingly, in one embodiment of the disclosure, there is included a method of producing a nicotine medicament for use in an inhaler comprising:

- a) combining nicotine, a non-spheronized pharmaceutical grade sugar and a liquid carrier to produce a flowable mixture;
- b) spray drying the flowable mixture to produce spray dried particles.

The spray dried particles may be spray dried at conditions to produce composite particles of a nicotine medicament that are suitable for delivery to the alveoli and lower airways of a person.
In one embodiment, the non-spheronized pharmaceutical grade sugar comprises a micronized pharmaceutical grade sugar, such as micronized lactose as seen in FIG. 1 having a particle size distribution as seen in FIG. 2.
In another embodiment, the non-spheronized pharmaceutical grade sugar comprises a milled or fine milled sugar, such as milled or fine-milled lactose as seen in FIGS. 3 and 4, having particle size distributions as seen in FIGS. 5 and 6.
In another embodiment, the non-spheronized pharmaceutical grade sugar comprises a sieved or coarse-sieved pharmaceutical grade sugar, such as sieved or coarse-sieved lactose as seen in FIGS. 7 and 8 having a particle size distribution as seen in FIGS. 9 and 10.
In another embodiment, the non-spheronized pharmaceutical grade sugar have particle sizes as illustrated in FIG. 11.
In one embodiment, the non-spheronized pharmaceutical grade sugar may be micronized, milled or sieved using processes known to those skilled in the art. For example, the non-spheronized pharmaceutical grade sugar may be subjected to milling, bashing, grinding, crushing, cutting or other physical degradation or any combination thereof which reduces the particle size of the sugar, resulting in the non-spheronized sugar. For example, in a milling process, a drum containing steel spheres is rotated and the steel spheres collide with the nicotine or sugar particles to reduce particle size.
In one embodiment, the non-spheronized pharmaceutical grade sugar comprise non-spherical or irregularly shaped particles of the sugar, having a d₅₀value of less than about 200 μm, preferably less than 100 um, or preferably less than 50 um, or preferably less than 10 μm, or preferably less than about 5 μm, and a d₉₀value of less than about 300 μm, or preferably less than 200 μm, or preferably less than 100 μm, or preferably less than 50 μm, or preferably less than 15 μm, or preferably less than about 10 μm. In one embodiment, the non-spheronized pharmaceutical grade sugar is wedge-shaped.
In one embodiment, the non-spheronized sugar is an inhalable sugar and is preferably selected from lactose, dextrose, glucose, maltose or combinations thereof, and is most preferably lactose, for example alpha monohydrate lactose. The sugar may be a natural or a synthetic sugar and may include analogs or derivatives of sugars. It will be appreciated that references herein are made to lactose, although one or more of the other sugars mentioned could similarly be employed. The non-spheronized lactose acts as a carrier and, therefore, any form of non-spheronized lactose approved as an excipient may be used. The non-spheronized lactose is preferably of a pharmaceutical grade such as CP, USP, NF, BP or BPC. The non-spheronized lactose which is used as a starting material is therefore in the form of a dry powder which is readily soluble in water.
The nicotine formulation may be any form of nicotine which is soluble in or miscible with the liquid carrier. For example, the nicotine may be a nicotine base, which, at room temperature, is a liquid that is miscible in water. Alternately, or in addition, the nicotine may be a salt, which, at room temperature, is a solid. The nicotine base is typically an oil formulation. Preferably, the nicotine comprises nicotine base. The nicotine may be pharmacologically active analogs or derivatives of nicotine or substances which mimic the effect of nicotine, either alone or in combination with other active substances. If the nicotine is a base, then it may be added to the water and mixed to produce a generally homogeneous liquid mixture. The liquid carrier may be any liquid or liquids with which the nicotine may be mixed and the lactose may be dissolved to form a flowable mixture which is preferably of a generally uniform composition. Nicotine bases are generally miscible in water and nicotine salt formulations are generally soluble in water. Further, non-spheronized lactose is soluble in water. Accordingly, whether the nicotine is a base and/or a salt formulation, the liquid carrier may comprise water. When a salt is used, the liquid carrier solubilizes the nicotine and the lactose. When a nicotine base is used, the liquid carrier solubilizes the non-spheronized lactose and mixes (e.g. homogenizes) with the liquid base to create a generally uniform solution (e.g. it is miscible with the liquid base). While water is the preferred liquid carrier, other liquids in combination with or in place of water may be used. For example, alternate liquids may be used, either by themselves or in combination to water, to solubilize the solid material or to disperse the nicotine base in the liquid carrier.
In a further preferred embodiment, the liquid carrier may comprise a mixture of alcohol and water. The water and the alcohol form an azeotropic mixture. Nicotine base formulations are readily soluble in an alcohol. However, the non-spheronized lactose is not soluble in the alcohol. Pursuant to this embodiment, the solution may comprise less water thus assisting in the rate of drying of the solution and/or the amount of water in the dried product.
Preferably, the alcohol is a primary alcohol. Further, the alcohol is preferably a lower alkyl alcohol (i.e. C₁to C₅). A particularly preferred alcohol which may be used as a solvent for the nicotine base solution is ethanol. The ethanol may be CP grade, and preferably, is, USP grade. However, it will be appreciated that it is preferable, where possible, to avoid the use of alcohol in the base solution.
This liquid carrier preferably contains an excess amount of water compared to alcohol where alcohol is used as a cosolvent. In such an embodiment, the mixture preferably comprises a minor proportion of alcohol and a major proportion of water. Where alcohol is required, the ratio of alcohol to water in the liquid carrier may be from about 1:1 to 1:10, preferably from about 1:2 to 1:8 and more preferably from about 1:5 to 1:7 parts by weight.
The liquid carrier (e.g., water and/or alcohol) may be mixed with the nicotine to produce a liquid mixture to which the non-spheronized sugar may then be added. Accordingly, the non-spheronized lactose and a nicotine salt may be dissolved in water (and optionally a water/alcohol mixture) to form the flowable mixture. Alternately, the non-spheronized lactose may be dissolved in water (and optionally a water/alcohol mixture) and the nicotine base may be mixed with the water (and optionally a water/alcohol mixture) to form the flowable mixture. It will be appreciated that the nicotine, liquid carrier and non-spheronized sugar may be combined together in any desired order to produce the dry flowable mixture.
The amount of liquid mixture which is utilized is sufficient to produce a flowable mixture. Pursuant to the preferred embodiment, the mixture is finely divided (such as passing the flowable mixture through an orifice) on entry to a spray dryer. The flowable mixture preferably has a viscosity comparable to that of water and may readily be finely divided such as by passing the liquid through an atomizer (preferably a rotary atomizer).
The ratio of nicotine to non-spheronized lactose which is combined with the liquid carrier to produce the flowable mixture will vary upon the desired concentration of nicotine in the spray dried product. Due to product handling limitations, it is typical in the field that the carrier comprises a substantial portion of the weight of a powdered sugar as compared to the active ingredient. The amount of non-spheronized sugar (e.g. lactose) which is utilized, compared to the amount of nicotine, must be sufficient such that the spray dried product can be used in association with dry powder inhalers which are known in the art. Accordingly, the ratio of non-spheronized lactose to nicotine in the flowable mixture may vary from about 1:10 to about 10:1, more preferably from about 3:7 to about 3:2 and, most preferably, about 4:6 parts by weight. Further, the concentration of sugar in the flowable mixture may vary from about 1 to about 10, more preferably from about 2 to about 5 and, most preferably, about 3% (w/v, i.e. g/100 ml).
The flowable mixture is dried so as to produce particles which are sized so as to be able to travel to the alveoli and smaller airways of the lungs. Preferably, the particles have a particle size from about 0.1 to about 5 μm, more preferably from about 0.5 to about 5 μm and, most preferably from about 0.5 to about 3 μm based on the mass median aerodynamic diameter (MMAD) of the particles. The flowable mixture is preferably rapidly dried such as by using a spray drier. However, other drying techniques capable of producing appropriately sized particles (e.g., the use of fluidized bed drying) may be used.
The flowable liquid is preferably rapidly dried so as to produce spherical or substantially spherical particles. Such particles may be achieved by using a rotary atomizer to feed the flowable liquid into a spray dryer.
The operating conditions of the spray dryer are adjusted so to produce particles which are sized so as to be able to travel to the alveoli and smaller airways of the lungs. The rotary atomizer may be operated at a liquid feed rate from about 2 to about 20, more preferably from 2 to about 10, and most preferably from about 2 to about 5 ml/min. The rotary atomizer may be operated from about 10,000 to about 30,000, more preferably from about 15,000 to about 25,000, and most preferably from about 20,000 to about 25,000 rpm. It will be appreciated that particles of various sizes may be obtained by spray drying and particles having the desired particle size may be selected.
The spray dryer is operated at temperatures sufficiently high to cause the liquid carrier to rapidly evolve without raising the temperature of the lactose and nicotine to a point at which these compounds commence to degrade. Accordingly, the spray dryer may be operated with an inlet temperature from about 120 to about 170° C. and an outlet temperature from about 70 to about 100° C.
The medicament particles are spherical or of another aerodynamic shape. Such particles will tend not to aggregate when stored in a bulk form. Further, by evolving the liquid carrier sufficiently rapidly during the spray drying process, the medicament particles may be produced with an uneven or a “dimpled” surface. The uneven surface produces turbulence as the particles travel through the air, thus providing the particles with aerodynamic lift. This assists the particles to be entrained, and to remain entrained, in the air inhaled by a user thus improving the ability of the medicament particles to travel to the alveoli and smaller airways.
The following examples are intended to be illustrative only, and do not limit the scope of the invention.

EXAMPLES

3 g of nicotine and 27 g of lactose were added to 200 g of water. The mixture was stirred until the solution was clear (approximately 10 minutes). The mixture was spray dried in a Buchi Mini Spray Dryer 190, with an air flow rate of 500 ml/minute, an inlet temperature of 165° C. and an outlet temperature of 87° C. The nicotine and lactose solution was fed into the atomizer at a rate of 7 ml/min. The results are set out in Table 1.
This experimental procedure was repeated under each of the sets of conditions set out in Table 1. Determination of the nicotine content in the nicotine lactose composite product was determined by using UV spectrophotometry at a wavelength of 262 nm. Particle size was determined using laser diffraction methods known in the art.
A concentration of 3% (w/v) of nicotine in solution, with a 4:6 ratio of nicotine to lactose (w/w) produced the highest concentration in the finished product. An air flow higher than 750 ml/min. resulted in a wet powder being produced which was detrimental to the flow characteristics.
FIG. 12 is a graph setting out the concentration of nicotine in the finished product as a function of the nicotine concentration in solution for experiments 1-5. “Series 1” is the concentration of nicotine in the finished product after spray drying. “Series 2” is the concentration of nicotine in solution prior to spray drying. It will be seen that a higher concentration of nicotine in solution did not always result in a higher concentration of nicotine in the finished product.
FIG. 13 is a graph setting out the concentration of nicotine in the finished product as a function of the ratio of nicotine to lactose in the solution, for experiments 6-8. It will be seen that the higher nicotine to lactose ratio in solution did not necessarily produce a higher concentration of nicotine in the finished product. The highest ratio of nicotine to lactose in solution was determined to be approximately 3:7. “Series 1” in FIG. 13 shows the concentration of nicotine in the finished product after spray drying, while “Series 2” shows the ratio of nicotine to lactose in solution prior to spray drying.
The results show that the highest concentration of nicotine in the finished product were achieved with a nicotine concentration of approximately 3% (w/v) in solution, and a nicotine:lactose ratio of approximately 4:6 in solution.

TABLE 1

	Nicotine	Particle size

concentra-

Solution

1.

% under

Nicotine

Lactose

Water

Nicotine:

tion in

Feed

Inlet

Outlet

5.72

Nicotine

added

Lactose

solution

Air Flow

Rate

Temp

2.

Median

in F.P.

No.

(g)

Ratio

% (w/v)

Spray Dryer Type

ml/min

(ml/min)

(° C.)

D(v, 0.5)

% (w/w)

1	3	27	200	1:9	1.5	Buchi Mini Spray Dryer	500	7	165	87	Not done	8.5
						190
2	6	24	220	2:8	2.73	Buchi Mini Spray Dryer	500	7	167	83	Not done	16.6
						190

3	9	21	200	3:7	4.5	Buchi Mini Spray Dryer	500	7	167	83	1).	38.14	23.6
						190					2).	7.56

4	15	15	200	5:5	7.5	Buchi Mini Spray Dryer	500	4.3	126	70	Not done	15.3
						190
5	21	9	220	7:3	9.55	Buchi Mini Spray Dryer	500	4.3	126	75	Not done	16.7
						190
6	9	21	300	3:7	3	Buchi Mini Spray Dryer	600	6.6	150	98	Not done	25
						B-191

7	12	18	400	4:6	3	Buchi Mini Spray Dryer	600	6.6	150	94	1).	82.09	26.7
						B-191					2).	3.25
8	15	15	500	5:5	3	Buchi Mini Spray Dryer	600	6.6	150	98	1).	90.02	24.7
						B-191					2).	2.94
9	12	18	400	4:6	3	Buchi Mini Spray Dryer	700	6.6	155	92	1).	86.93	27.6
						B-191					2).	3.25
10	12	18	400	4:6	3	Buchi Mini Spray Dryer	750	6.6	150	90	1).	87.95	27.9
						B-191					2).	3.12

Claims

1. A method of preparing a nicotine formulation suitable for inhalation comprising:

(a) combining nicotine, a non-spheronized pharmaceutical grade sugar and a liquid carrier to produce a flowable mixture; and,

(b) spray drying the flowable mixture to form spray dried particles.

2. The method as claimed in claim 1 wherein the liquid carrier comprises water.

3. The method as claimed in claim 1 wherein the particles are from about 0.1 to 5 μm in diameter and are physically joined together by spray drying such that the nicotine and sugar remain physically joined together during inhalation

4. The method as claimed in claim 1 wherein the flowable mixture has a ratio of non-spheronized sugar to nicotine which varies from about 1:10 to about 10:1 parts by weight.

5. The method as claimed in claim 1 wherein the flowable mixture has a ratio of non-spheronized sugar to nicotine which varies from about 3:7 to about 3:2 parts by weight.

6. The method as claimed in claim 1 wherein the flowable mixture has a concentration of non-spheronized sugar which varies from about 1 to about 10 w/v.

7. The method as claimed in claim 6 wherein the concentration of non-spheronized sugar in the flowable mixture varies from about 2 to about 5 w/v.

8. The method as claimed in claim 1 wherein the flowable mixture is dried by spray drying and produces particles that are about 0.1 to about 5 μm in diameter.

9. The method as claimed in claim 8 wherein the flowable mixture is atomized prior to being spray dried.

10. The method as claimed in claim 1 wherein the flowable mixture is dried at conditions to form spherical particles.

11. The method as claimed in claim 1 wherein the flowable mixture is dried at conditions to form spherical particles that have a dimpled surface and are about 0.5 to about 3 μm in diameter.

12. The method of claim 1 wherein the nicotine comprises a nicotine base and the pharmaceutical grade sugar is selected from the group consisting of lactose, dextrose glucose, maltose or combinations thereof.

13. The method as claimed in claim 1 wherein the flowable mixture is dried at conditions to form spherical particles that have a dimpled surface.

14. A method for conducting a tobacco replacement or withdrawal therapy comprising:

(a) preparing a flowable mixture consisting essentially of nicotine, a non-spheronized pharmaceutical grade sugar and a liquid carrier;

(b) spray drying the flowable mixture to produce a composite material at conditions to produce particles of the nicotine medicament which are suitable for delivery to the alveoli and lower airways of a person and which simulate cigarette smoke when aerosolized and inhaled; and,

(c) packaging the composite material in a container for use with an inhaler suitable for delivering a medicament to the lungs.

15. The method as claimed in claim 14 wherein the liquid carrier comprises water.

16. The method as claimed in claim 14 wherein the liquid carrier consists essentially of water.

17. The method as claimed in claim 14 wherein the flowable mixture has a ratio of non-spheronized sugar to nicotine which varies from about 1:10 to about 10:1 parts by weight.

18. The method as claimed in claim 14 wherein the flowable mixture has a ratio of non-spheronized sugar to nicotine which varies from about 3:7 to about 3:2 parts by weight.

19. The method as claimed in claim 14 wherein the flowable mixture has a concentration of non-spheronized sugar which varies from about 1 to about 10 w/v.

20. The method as claimed in claim 19 wherein the concentration of non-spheronized sugar in the flowable mixture varies from about 2 to about 5 w/v.

21. The method as claimed in claim 14 wherein the flowable mixture is dried by spray drying and produces particles that are about 0.1 to about 5 μm in diameter.

22. The method as claimed in claim 21 wherein the flowable mixture is atomized prior to being spray dried.

23. The method as claimed in claim 14 wherein the flowable mixture is dried at conditions to form spherical particles.

24. The method as claimed in claim 14 wherein the flowable mixture is dried at conditions to form spherical particles that have a dimpled surface are about 0.5 to about 3 μm in diameter.

25. The method of claim 14 wherein the nicotine comprises a nicotine base and the pharmaceutical grade sugar is selected from the group consisting of lactose, dextrose glucose, maltose or combinations thereof.

26. The method of claim 14 wherein the pharmaceutical grade sugar is selected from the group consisting of lactose, dextrose glucose, maltose or combinations thereof.

27. The method as claimed in claim 14 wherein the spray drying is operated to produce particles that are about 0.1 to about 5 μm in diameter.