ANATABINE POWDER COMPOSITIONS

Abstract

Anatabine powder compositions include a sugar or adhesion reducing compound and are suitable for inhalation and methods of forming the same. Sugar and an anatabine compound may be spray dried to form a dry anatabine powder composition. The anatabine powder may have a particle size of about 20 micrometres or less, 10 micrometres or less, or from about 1 to about 4 micrometres, measured as mass medium aerodynamic diameter. A powder may include a plurality of particles comprising an anatabine compound and a sugar or adhesion reducing compound and the plurality of particles have a particle size of about 20 micrometres to about 200 micrometres, measured as mass medium aerodynamic diameter.

Claims

1. An inhalable powder composition comprising: a plurality of particles comprising an anatabine compound and a sugar or adhesion reducing compound, the plurality of particles having a particle size of about 20 micrometres or less measured as mass medium aerodynamic diameter.

2. A powder composition comprising: a plurality of particles comprising an anatabine compound and a sugar or adhesion reducing compound, the plurality of particles having a particle size of about 20 micrometres to about 200 micrometres, measured as mass medium aerodynamic diameter.

3. The powder composition according to claim 1, wherein the anatabine compound comprises an anatabine salt.

4. The powder composition according to claim 1, wherein the anatabine compound comprises an anatabine glutarate.

5. The powder composition according to claim 1, wherein the plurality of particles comprise an amorphous sugar.

6. The powder composition according to claim 5, wherein the sugar comprises lactose, sucrose, raffinose, trehalose, fructose, dextrose, glucose, maltose, or combinations thereof.

7. The powder composition according to claim 1, wherein the adhesion reducing compound comprises an amino acid or peptide.

8. The powder composition according to claim 1, wherein the adhesion reducing compound comprises histidine, alanine, isoleucine, arginine, leucine, asparagine, lysine, aspartic acid, methionine, cysteine, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, glycine, valine, pyrrolysine, proline, selenocysteine, serine, tyrosine, or a combination thereof.

9. The powder composition according to claim 1, wherein the plurality of particles comprise from 50 to 99% sugar by weight.

10. The powder composition according to claim 1, wherein the plurality of particles comprise from 0.5 to 20% anatabine compound by weight.

11. The powder composition according to claim 1, wherein the plurality of particles comprise from 0.5 to 20% amino acid by weight.

12. The powder composition according to claim 1, wherein the plurality of particles comprise 0.5 to 20% anatabine glutarate, from 70 to 90% sugar, and from 0 to 20% leucine, all by weight.

13. The powder composition according to claim 1, wherein the plurality of particles comprise 0.5 to 20% anatabine glutarate, from 70 to 90% sugar, and from 1 to 20% leucine, all by weight.

14. The powder composition according to claim 1, further comprising a second plurality of particles having a particle size of 20 micrometers or greater measured as mass medium aerodynamic diameter.

15. A method of forming a powder composition, comprising: combining an anatabine compound and a sugar, in a liquid carrier, to form a liquid mixture; and spray drying the liquid mixture to form a plurality of particles, or spray drying the liquid mixture to form a plurality of particles having a first size, and then micronizing the plurality of particles having a first size to a reduced size.

16. The powder composition according to claim 1, the plurality of particles having a particle size of about 1 to about 4 micrometres, measured as mass medium aerodynamic diameter.

17. The powder composition according to claim 1, wherein the plurality of particles comprise from 70 to 90% sugar by weight.

18. The powder composition according to claim 1, wherein the plurality of particles comprise from 1 to 10% anatabine compound by weight.

19. The powder composition according to claim 1, wherein the plurality of particles comprise from 1 to 15% amino acid by weight.

20. The powder composition according to claim 1, wherein the plurality of particles comprise 1 to 10% anatabine glutarate, from 70 to 90% sugar, and from 1 to 10% leucine, all by weight.

Description

[0154] The Examples will now be further described with reference to the figure in which:

[0155] FIG. 1 is an X-ray powder diffraction pattern (CuKα) of a preferred polymorph of anatabine gluterate.

[0156] The schematic drawings are presented for purposes of illustration and not limitation.

EXAMPLES

Preparation of Anatabine Glutarate

[0157] Anatabine free base was converted to 1:1 anatabine glutarate by the following methods:

[0158] a) To a solution of glutaric acid (16.5 g, 125 mmol, 1.00 eq) in acetonitrile (500 mL) was added anatabine (20.0 g, 125 mmol, 1.00 eq) drop-wise at 25° C., and the mixture was stirred at 25° C. for 1 hour. TLC (Dichloromethane: Methanol = 20:1) showed anatabine (Rf = 0.5) was consumed. The mixture was filtered. The filter cake was collected and concentrated to dryness to give anatabine glutarate (30.0 g, 103 mmol, 82.2% yield, 100% purity) as an off-white solid.

[0159] b) To a solution of anatabine (11.6 g, 72 mmol) in acetonitrile (700 ml) was added glutaric acid (9.6 g, 72 mmol). The reaction mixture became cloudy. The reaction mixture was then heated until a clear yellow solution was obtained. The mixture was allowed to cool to room temperature (20° C.) and was stirred for 2 hours. A gummy solid appeared which was scratched with a spatula. The mixture was stirred for a further 30 minutes, and the resulting pale-yellow solid was filtered under an atmosphere of argon, washed with acetonitrile (500 ml) and dried under reduced pressure at 45° C. for 45 minutes to give anatabine glutarate (18.3 g, 87%) as a pale yellow solid.

[0160] .sup.1HNMR (D.sub.2O), δ: 8.84-8.45 (m, 2H), 7.99 (d, J = 7.8 Hz, 1H), 7.59-7.55 (m, 1H), 6.08 (d, J = 8.4 Hz, 1H), 5.85 (d, J = 10.4 Hz, 1H), 4.63-4.59 (m, 1H), 3.97-3.87 (m, 1H), 3.81-3.70 (m, 1H), 2.80-2.53 (m, 2H), 2.25 (t, J = 7.6 Hz, 4H), 1.82-1.74 (m, 2H). The chemical purity of anatabine glutarate was assessed using Waters Acquity UPLC H-class with PDA detector and SQD mass spectrometer, column BEH C18, 2.1 x 50 mm, 1.7 .Math.M running a gradient with detection at 261 nM. The retention time of anatabine glutarate was 1.125 min and purity 99.41%, [M+H]+ 161.0. Comparison of FTIR spectra of anatabine glutarate and anatabine free base indicates change of N-H band suggesting confirmation of salt formation.

[0161] The anatabine glutarate obtained in this manner was recrystallized from 2.5 mL actonitrile while cooling down after having been heated to reflux. The solid phase was recovered and dried.

[0162] The anatabine glutarate salt was analyzed by X-ray powder diffraction (XRPD) between 2-40° 2θ using zero background silicone wafers (with 9 mm cavities). It was found to have a purity higher than 99% by uHPLC. FIG. 1 is an X-ray powder diffraction pattern (CuKα) of a preferred polymorph of anatabine gluterate.

Preparation of Anatabine Powder Compositions

[0163] Anatabine glutarate is a solid salt. The use of such solid salt during spray drying helps to limit losses, stabilizes the powder obtained, and enables production of powders with high effective content of anatabine glutarate.

[0164] Two different batches of spray dried anatabine powder formulation were produced and the results are provided below.

[0165] For the manufacture of these spray dried formulations, the following raw materials were used:

[0166] 1) Anatabine glutarate solid salt; a 2% (effective) anatabine (3.62% of anatabine glutarate) formulation (i.e. for a multiple inhalation use=> i.e. 50 mg of powder to deliver 1 mg of anatabine) and a 10% (effective) anatabine (18.17% anatabine glutarate) formulation (i.e. for single straight inhalation use => i. e. 10 mg of powder in the capsule to deliver 1 mg) were made. Stoichiometric ratio of anatabine and glutaric acid is 1:1.

[0167] 2) L-Leucine; its use is beneficial for the powder flowability, but it is not compulsory. It is possible to manufacture an anatabine powder formulation with/without leucine (optional). 10% w/w L-Leucine.

[0168] 3) Trehalose Dihydrate; used as excipient. 86.35% w/w Trehalose or 71.76% w/w Trehalose.

[0169] Spray drying feed solutions were prepared in deionised (DI) water and spray dried immediately after preparation. Spray drying was performed using a Buchi B-290 spray dryer fitted with a Buchi two-fluid nozzle, and standard Buchi cyclone. Feed solutions were protected from light during processing. All powders were handled under reduced humidity (<30% RH) and stored in sealed glass amber jars at 2-8° C.

[0170] Spray drying conditions on Buchi B-290 spray dryer. Atomization Pressure 6 bar. Target Outlet Temperature 80° C. Aspirator 100%. Feed rate 3 g/min.

[0171] Particle size analysis of spray dried powders was performed using a Sympatec HELOS particle size analyser equipped with an R3 lens (range 0.5 to 175 micrometers) and an ASPIROS dispersion unit. Dispersal was achieved using compressed air at a pressure of 1 bar. Measurements were made in triplicate and mean data reported.

[0172] Blending and Micronisation. 6.500 g of spray dried formulation was blended with 1.147 g of leucine for five minutes at 36 rpm using a turbula mixer. The resulting blend, 85% w/w spray dried formulation and 15% w/w leucine, was micronised using an Atritor M3 fluid energy mill under the following conditions: Venturi Pressure 8.0 bar. Grinding Pressure 3 - 4 bar. Feed rate 2.4 g/min.

[0173] Two spray dryer feed solutions were prepared according to Table 1 below. Trehalose was added as trehalose dihydrate, the loss of the water of hydration during processing was compensated for in all calculations.

TABLE-US-00001 Example Total Solids (g) DI water (ml) Anatabine Gluterate (g) L-Leucine (g) Trehalose (g) 1 25 250 0.912 2.5 23.9 2 25 250 4.561 2.5 19.8

TABLE-US-00002 Results Example Formulation X.sub.10 (.Math.m) X.sub.50 (.Math.m) X.sub.90 (.Math.m) VMD (.Math.m) 1 Anatabine Glutarate (3.65%); leucine (10%); Trehalose (86.35%) 0.99 2.89 6.04 3.31 2 Anatabine Glutarate (18.24%); leucine (10%); Trehalose (71.76%) 0.99 2.77 5.63 3.09

[0174] Both Example 1 and Example 2 spray dried successfully with processing yields of about 85%. The spray dried materials of Example 1 and Example 2 were both noted as fine, free-flowing white powder.

[0175] For the purpose of the present description and of the appended claims, except where otherwise indicated, all numbers expressing amounts, quantities, percentages, and so forth, are to be understood as being modified in all instances by the term “about.” Also, all ranges include the maximum and minimum points disclosed and include any intermediate ranges therein, which may or may not be specifically enumerated herein. In this context, therefore, a number “A” is understood as A ±2% of A. Within this context, a number A may be considered to include numerical values that are within general standard error for the measurement of the property that the number A modifies. The number A, in some instances as used in the appended claims, may deviate by the percentages enumerated above provided that the amount by which A deviates does not materially affect the basic and novel characteristic(s) of the claimed invention. Also, all ranges include the maximum and minimum points disclosed and include any intermediate ranges therein, which may or may not be specifically enumerated herein.