Nicotine particles

Abstract

A method includes combining nicotine with a liquid carrier to form a liquid mixture and spray drying the liquid mixture to form a first plurality of particles. The first pluralities of particles are then milled to form a second plurality of particles.

Claims

1. A method, comprising: combining nicotine salt, sugar, and leucine with a liquid carrier, wherein the liquid carrier is water, to form a liquid mixture consisting of the liquid carrier, the nicotine salt, the sugar, and the leucine; and spray drying the liquid mixture to form a first plurality of particles; and milling the first plurality of nicotine particles to form a second plurality of particles, wherein the first plurality of nicotine particles comprises about 90% by volume of the particles having a particle size of about 4.5 micrometres or less, and about 50% by volume of the particles having a particle size of less than about 2.5 micrometres and about 10% by volume of the particles having a particle size of less than about 0.85 micrometres, and wherein the second plurality of nicotine particles comprises about 90% by volume of the plurality of particles having a particle size of less than about 2.8 micrometres, and about 50% of the plurality of particles have a particle size of less than about 1.35 micrometres, and about 10% of the second plurality of particles having a particle size of less than about 0.65 micrometres.

2. The method according to claim 1, wherein the milling step comprises fluid energy milling and the fluid energy milling decreases a mass median aerodynamic diameter of the first plurality of particles to a mass median aerodynamic diameter of the second plurality of particles by a ratio of about 1.2:1 to about 5:1.

3. The method according to claim 1, wherein the nicotine salt comprises nicotine lactate, nicotine pyruvate, nicotine citrate, or nicotine aspartate.

4. The method according to claim 1 further comprising packaging the second plurality of particles in an inhalation delivery consumable element.

5. The method of claim 1, wherein the spray drying comprises an inlet temperature of 140 degrees Celsius or less.

6. The method of claim 1, wherein the spray drying comprises an outlet temperature of 30 degrees Celsius to 90 degrees Celsius.

7. The method of claim 1, wherein the spray drying comprises an outlet temperature of 40 degrees Celsius to 85 degrees Celsius.

8. The method of claim 1, wherein the second plurality of particles comprises from 1 wt % to 10 wt % nicotine.

9. The method of claim 1, wherein the second plurality of particles comprises from 70 wt % to 90 wt % sugar.

10. The method of claim 1, wherein the sugar comprises lactose, sucrose, raffinose, trehalose, fructose, dextrose, glucose, maltose, mannitol, or a combination thereof.

Description

EXAMPLES

(1) All the examples (except Table 3 examples) are formulated by combining nicotine base and acid in water (at the specified ratio) to form a stable nicotine salt solution. Then the sugar and amino acid (leucine) is combined with the nicotine salt solution to form a liquid mixture. Then the liquid mixture is atomized and dried to form dry particles that are collected to from the dry powder composition.

(2) The Table 3 examples are formulated by combining a nicotine free base with sugar and amino acid (leucine) to form a liquid mixture. Then the liquid mixture is atomized and dried to form dry particles that are collected to from the dry powder composition.

(3) The spray dryer was a Buchi B-290 spray dryer (available from Buchi Corp., DE, USA). The liquid mixture was provided to the spray dryer at a flow rate of 2 ml/min at 5 bar atomization pressure. The outlet temperature was about 80 degrees Celsius for examples utilizing trehalose. Table 1 below describes lactic acid nicotine powder formulations. Table 2 below describes pyruvic acid nicotine powder formulations. Table 3 below describes no acid nicotine powder formulations. Table 4 reports the particle size distribution of various examples.

(4) TABLE-US-00001 TABLE 1 Lactic Acid Nicotine Powder Formulations pH of powder Example Formulation solution Comments L1 10% Nicotine, Lactic acid (1:1), 7.3 Small amount of powder adhering 85% Trehalose to spray dryer surface L2 15% Nicotine, Lactic acid (1:1), 7.0 Small amount of powder adhering 77% Trehalose to spray dryer surface L3 10% Nicotine, Lactic acid (1:1), 7.5 Free flowing powder - no 80% Trehalose, 5% Leucine adherence L4 15% Nicotine, Lactic acid (1:1), 7.1 Free flowing powder - no 72% Trehalose, 5% Leucine adherence L5 20% Nicotine, Lactic acid (1:1), — Free flowing powder - no 64% Trehalose, 5% Leucine adherence

(5) TABLE-US-00002 TABLE 2 Pyruvic Acid Nicotine Powder Formulations pH of powder Example Formulation solution Comments P1 10% Nicotine, Pyruvic acid (0.6:1), 7.5 Powder adhering to spray dryer 87% Trehalose surface, cohesive powder P2 15% Nicotine, Pyruvic acid (0.6:1), 7.8 Cohesive powder, some static 80% Trehalose charge P3 10% Nicotine, Pyruvic acid (0.6:1), 7.7 Free flowing powder - no 82% Trehalose, 5% Leucine adherence, some static charge P4 15% Nicotine, Pyruvic acid (0.6:1), 7.8 Free flowing powder - no 75% Trehalose, 5% Leucine adherence P5 20% Nicotine, Pyruvic acid (0.6:1), 7.7 Free flowing powder - no 68% Trehalose, 5% Leucine adherence

(6) TABLE-US-00003 TABLE 3 No Acid Nicotine Powder Formulations pH of powder Example Formulation solution Comments N1 10% Nicotine, 90% Trehalose 9.3 Some powder adhering to spray dryer surface N2 15% Nicotine, 85% Trehalose 9.5 Some powder adhering to spray dryer surface N3 10% Nicotine, 85% Trehalose, 5% 8.6 Free flowing powder - no Leucine adherence, some static charge N4 15% Nicotine, 80% Trehalose, 5% 8.7 Free flowing powder - no Leucine adherence N5 20% Nicotine, 75% Trehalose, 5% 8.8 Free flowing powder - no Leucine adherence

(7) TABLE-US-00004 TABLE 4 Particle Size Distribution - reported in micrometres Example X.sub.10 X.sub.50 X.sub.90 VMD L1 0.65 1.43 3.54 1.81 L2 0.68 1.62 3.75 1.97 L3 0.76 1.89 3.86 2.14 L4 0.92 2.14 3.99 2.35 L5 0.78 1.95 3.90 2.19 P1 0.67 1.54 3.47 1.85 P2 0.67 1.53 3.54 1.86 P3 0.66 1.48 3.54 1.84 P4 0.72 1.78 3.79 2.06 P4 0.65 1.43 3.54 1.81 N1 0.68 1.62 3.75 1.97 N2 0.76 1.89 3.86 2.14 N3 0.92 2.14 3.99 2.35 N4 0.78 1.95 3.90 2.19 N5 0.67 1.54 3.47 1.85

(8) X.sub.10 refers to size of particle where 10% of particles, by volume, are less than this size.

(9) X.sub.50 refers to size of particle where 50% of particles, by volume, are less than this size.

(10) X.sub.90 refers to size of particle where 90% of particles, by volume, are less than this size. VMD refers to volume mean diameter.

(11) Particle size distribution described herein was determined by Sympatec laser sizing, Andersen Cascade Impactation, and scanning electron microscopy.

(12) TABLE-US-00005 TABLE 5 Further Formulations Example Formulation X.sub.10 X.sub.50 X.sub.90 VMD MMAD 1 10% Nicotine, Lactic 0.92 2.17 4.15 2.4 3.8 Acid (1:1), 80% Trehalose, 5% Leucine 2 10% Nicotine, Pyruvic 1.04 2.56 5.08 2.9 4.0 Acid (1:0.6), 82% Trehalose, 5% Leucine 3 10% Nicotine, Citric 0.81 2.34 5.48 2.8 3.5 Acid (1:0.25), 82% Trehalose, 5% Leucine 4 10% Nicotine, Aspartic 0.82 2.24 4.96 2.6 4.2 Acid (1:0.6), 80% Trehalose, 5% Leucine
Fluid Energy Milling Examples

(13) The following examples are formulated as described above. Example 5 includes 5% wt menthol that is dissolved in ethanol and added to the liquid mixture. Example 6 is free of menthol.

(14) The liquid mixture is atomized and dried with a spray dryer to form dry particles that are then fluid energy milled to from the dry powder composition.

(15) The spray dryer was a Buchi B-290 spray dryer (available from Buchi Corp., DE, USA). The liquid mixture was provided to the spray dryer at a flow rate of 2 ml/min at 5 bar atomization pressure. The outlet temperature was about 80 degrees Celsius for examples utilizing trehalose.

(16) The fluid energy mill was an Atritor M3 Fluid Energy Mill (available from Atritor Limited, England). The feed rate to the mill was about 3 grams per minute, using a compressed air driven venture feed at a pressure of about 7 bar and a milling pressure of about 4 bar, at room temperature. Example 5 was milled to create Example 5M and Example 6 was milled to create Example 6M.

(17) TABLE-US-00006 TABLE 6 Nicotine Powder Formulations pH of Example Formulation powder solution 5 5% Nicotine, Lactic Acid (1:1), 7.3 82% Trehalose, 5% Leucine, 5% Menthol 6 5% Nicotine, Lactic Acid (1:1), 7.2 82% Trehalose, 5% Leucine

(18) Example 5 and Example 6 are then fluid energy milled as described above. Prior to fluid energy milling Example 6 had a respirable particle fraction of 52% (able to reach the lungs during inhalation). After fluid energy milling Example 6M had a respirable particle fraction of 70% (able to reach the lungs during inhalation).

(19) TABLE-US-00007 TABLE 7 Particle Size Before and After Fluid Energy Milling Example MMAD 5 3.24 6 3.74 5M 2.16 6M 2.54

(20) Table 8 reports particle size distribution immediately following (t=0) and 7 days (t=7) following spray drying and fluid energy milling. Storage conditions were 40 degrees Celsius and 75% relative humidity (RH) for seven days.

(21) TABLE-US-00008 TABLE 8 Moisture Example X.sub.10 X.sub.50 X.sub.90 VMD Content 5 t = 0 0.74 1.79 3.61 2.02 2.59 5 t = 7 0.74 1.80 3.66 2.05 2.32 5M t = 0 0.62 1.14 2.32 1.33 2.32 5M t = 7 0.62 1.19 2.50 1.14 2.98 6 t = 0 0.82 2.03 4.03 2.27 2.77 6 t = 7 0.80 2.03 4.05 2.27 3.02 6M t = 0 0.65 1.34 2.80 1.56 2.94 6M t = 7 0.64 1.32 2.80 1.56 2.99

(22) Expert panel tests were conducted on Example 5 and Example 6 and Example 6M. Example 6M and Example 5 were deemed to be substantially equal in perceived inhalation feel as compared to Example 6.