CYTISINE SALTS

Abstract

Salts of cytisine have been prepared and incorporated in stable pharmaceutical compositions, including compositions comprising lactose. The salts are prepared by adding acid stock solutions to solutions of cytisine with heating, followed by cooling to ambient temperature. The salts and compositions are indicated in the treatment of nicotine addiction.

Claims

1.-9. (canceled)

10. A gentisate salt of cytisine.

11. A solvate or hydrate of a salt according to claim 10.

12. A method for making a gentisate salt of cytisine, the method comprising: preparing a first solution, of an acid salt former, of gentisic acid; (ii) preparing a second solution, of cytisine; (iii) adding said solution the acid salt former to said solution of cytisine; (iv) maintaining the solution obtained in step (iii) at an elevated temperature for a fixed period of time; (v) allowing the solution to cool to ambient temperature; (vi) filtering the cooled solution; and (vii) drying the obtained solids.

13. A pharmaceutical composition comprising a salt according to claim 10, or a solvate or hydrate thereof, and a pharmaceutically acceptable carrier.

14. A pharmaceutical composition according to claim 13, wherein the pharmaceutically acceptable carrier selected from lactose, corn starch, wheat starch, microcrystalline cellulose, or a mixture thereof

15. A pharmaceutical composition according to claim 13, wherein the composition is a unit dosage form.

16. A pharmaceutical composition according to claim 13, wherein the composition is in a form of a tablet or capsule.

17. A method of treating nicotine addiction in a subject, said method comprising administering to said subject an effective amount of a salt according to claim 10 or a solvate or hydrate thereof

18. The method of claim 17, wherein the salt or solvate or hydrate thereof, is administered in a composition comprising a pharmaceutically acceptable carrier.

19. The method of claim 18, wherein the pharmaceutically acceptable carrier is selected from lactose, corn starch, wheat starch, microcrystalline cellulose, or a mixture thereof.

20. The method of claim 18, wherein the composition is a unit dosage form.

21. The method of claim 18, wherein the composition is in a form of a tablet or capsule.

Description

FIGURES

[0039] FIG. 1 shows the XRPD profile for cytisine mesylate.

[0040] FIG. 2 shows the combined DSC/TGA profile for cytisine mesylate.

[0041] FIG. 3 shows the XRPD profile for cytisine gentisate.

[0042] FIG. 4 shows the combined DSC/TGA profile for cytisine gentisate.

[0043] FIG. 5 shows the XRPD profile for cytisine maleate.

[0044] FIG. 6 shows the combined DSC/TGA profile for cytisine maleate.

[0045] The various embodiments of the present invention will now be further explained with reference to the following examples.

EXAMPLES

Example 1—Salt Formation

[0046] Stock solutions of acid salt formers were prepared in the carrier solvents and having the molarities detailed in the following Table 1 below:

TABLE-US-00001 TABLE 1 List of acid solution for screening cytisine salt formation Acid Solvent mix Molarity Acetic EtOH 1 Ascorbic 9:1 EtOH:Water 0.5 Benzoic EtOH 1 Gentisic EtOH 0.5 Glucuronic Water 0.5 Maleic EtOH 1 Methansulphonic EtOH 1
Stock solutions of cytisine API (non-synthetic) were also prepared in CH.sub.3CN and in Me-THF. 2.4 g of cytisine was dissolved in 60 ml of 2-Me-THF heated to a temperature of 60° C.2.4 g of cytisine was dissolved in 24 ml of CH.sub.3CN heated to a temperature of 40° C.

[0047] 200 ml capacity tubes heated to 40° C. were charged with 2 ml or 5 ml of the cytisine stock solution. The acid stock solutions were then added to the heated tubes in equimolar amounts. The solutions were held at 40° C. for one hour and then allowed to cool to ambient temperature (˜18° C.) for 18 hours. Where solid formation did not spontaneously occur, successive secondary manipulations were carried out in order to induce crystallisation, namely: i) gradual blow down under nitrogen to induce crystallisation, ii) charging antisolvent/triturate, and iii) second blow down under nitrogen and trituration with 3 ml TBME and 1 ml acetone.

[0048] Filtration of the obtained solids was then carried out using a PTFE fritted column and the obtained solids were dried at 50° C. for 48 hours. The properties of the obtained products were then analysed, and the outcome of this screen and the properties of the obtained products are summarised in Table 2 below:

TABLE-US-00002 TABLE 2 Salt preparation API Stock Solution Salt-type Assessment CH.sub.3CN Acetate Secondary precipitations, unstable salt 2-MeTHF Acetate Secondary precipitations, unstable salt CH.sub.3CN Ascorbate Secondary precipitations, unstable salt 2-MeTHF Ascorbate Secondary precipitations, unstable salt CH.sub.3CN Benzoate Failed to yield solid 2-MeTHF Benzoate Failed to yield solid CH.sub.3CN Gentisate Excellent salt profile 2-MeTHF Gentisate Excellent salt profile CH.sub.3CN Glucuronate Failed to yield solid 2-MeTHF Glucuronate Failed to yield solid CH.sub.3CN Maleate Excellent salt profile 2-MeTHF Maleate Excellent salt profile CH.sub.3CN Mesylate Excellent salt profile 2-MeTHF Mesylate Excellent salt profile

[0049] As can be seen, suitable salts could not be formed with the common acid salt formers acetic acid and benzoic acid, as well as with the more exotic salt formers ascorbic acid and glucoronic acid. However, the mesylate, gentisate, and maleate salts were readily formed, exhibiting advantageous properties.

Example 2—Characterisation Tests

[0050] The obtained salts were subjected to XRPD, DSC and TGA analysis, using the apparatus and parameters outlined below. The results are presented in Tables 3-5 below and illustrated in FIGS. 1-6 as described above.

X-Ray Powder Diffraction (XRPD)

[0051] X-Ray Powder Diffraction patterns were collected on a PANalytical™ diffractometer using Cu Kα radiation (45 kV, 40 mA), θ-θ goniometer, focusing mirror, divergence slit (½″), soller slits at both incident and divergent beam (4 mm) and a PIXceI™ detector.

[0052] The software used for data collection was X'Pert™ Data Collector, version 2.2f and the data was presented using X'Pert™ Data Viewer, version 1.2d.

[0053] XRPD patterns were acquired under ambient conditions via a transmission foil sample stage (polyimide—Kaplan, 12.7μm thickness film) under ambient conditions using a PANalytical™ X'Pert™ PRO. The data collection range was 2.994-35°2θ with a continuous scan speed of 0.202004°s-1.

Differential Scanning Calorimetry (DSC)

[0054] DSC data was collected on a PerkinElmer Pyris™ 6000 DSC equipped with a 45 position sample holder. The instrument was verified for energy and temperature calibration using certified indium. A predefined amount of the sample, 0.5-3.0 mg, was placed in a pin holed aluminium pan and heated at 20° C.min-1 from 30 to 350° C., or varied as experimentation dictated. A purge of dry nitrogen at 20 ml.min-1 was maintained over the sample. The instrument control, data acquisition and analysis were performed with Pyris™ Software v11.1.1 Revision H.

Thermo-Gravimetric Analysis (TGA)

[0055] TGA data were collected on a PerkinElmer Pyris™ 1 TGA equipped with a 20 position auto-sampler. The instrument was calibrated using a certified weight and certified Alumel and Perkalloy for temperature. A predefined amount of the sample, 1-5 mg, was loaded onto a pre-tared aluminium crucible and was heated at 20° C.min-1 from ambient temperature to 400° C. A nitrogen purge at 20ml.min-1 was maintained over the sample.

[0056] The instrument control, data acquisition and analysis were performed with Pyris™ Software v11.1.1 Revision H.

TABLE-US-00003 TABLE 3 Cytisine Mesylate Characterization Properties Cytisine Mesylate XRPD Crystalline. Peaks at: 5.3, 5.6, 6.6, 9.6, 10.6, 11.3, 11.8, 12.3, 13.0, 13.4, 14.7, 15.1, 15.7, 16.4, 16.8, 17.3, 17.8, 18.2, 18.9, 19.3, 19.7, 20.3, 20.6, 21.0, 21.3, 21.8, 22.8, 23.0, 23.6, 23.8, 24.2, 24.8, 25.4, 25.9, 26.7, 27.0, 27.5, 27.7, 28.2, 28.8, 29.7, 30.2, 30.8, 31.0, 31.7, 32.0, 32.9, 33.2, 33.3, 33.9 2θ DSC Sharp endotherm at 238° C. TGA Decomposition from 238° C.

TABLE-US-00004 TABLE 4 Cytisine Gentisate Characterization Properties Cytisine Gentisate XRPD Crystalline, Peaks at: 5.5, 9.2, 9.6, 12.0, 12.4, 13.5, 14.4, 14.7, 15.7, 16.5, 16.7, 18.5, 19.2, 19.9, 21.0, 21.4, 21.6, 22.4, 22.7, 23.7, 24.2, 25.1, 25.5, 25.9, 26.1, 26.6, 27.5, 27.7, 28.0, 29.0, 29.3, 29.8, 30.7, 31.0, 31.2, 31.9, 32.4, 32.8, 33.4, 33.7, and 34.1 2θ DSC Sharp endotherm at 230° C. TGA Decomposition from 230° C.

TABLE-US-00005 TABLE 5 Cytisine Maleate Characterization Properties Cytisine Maleate XRPD Crystalline. Peaks at: 5.4, 9.9, 10.6, 12.0, 13.3, 13.6, 13.8, 14.6, 15.2, 15.4, 15.9, 16.6, 17.1, 17.9, 18.1, 18.7, 19.3, 20.1, 20.3, 20.9, 21.2, 22.2, 22.7, 23.2, 23.7, 24.2, 24.4, 25.1, 25.3, 25.7, 26.0, 26.6, 27.0, 27.4, 28.3, 29.4, 30.3, 31.2, 31.8, 32.4, 33.0 and 34.3 2θ DSC Sharp endotherm at 169° C. TGA Decomposition from 169° C.

Example 3—Lactose Compatibility

[0057] The stability of formulations of cytisine and the present cytisine salts with lactose was investigated. Samples were stored at 25° C. and 60% relative humidity (RH) and at 40° C. and 75% RH and evaluated after 7 and 14 days. As can be seen from the data in Tables 6 and 7, when present in the form of its mesylate or gentisate salt, cytisine is degraded at a substantially lower rate than when present in free base form. Thus, these salts effectively improve the stability of cytisine and facilitates its formulation with compositions comprising lactose.

TABLE-US-00006 TABLE 6 Stability evaluation of cytisine salts in the presence of lactose following storage at 25° C. and 60% RH: Cytisine by HPLC, Cytisine by HPLC, Formulation area % - 7 days area % - 14 days Cytisine with 98.77 94.99 lactose Cytisine mesylate 99.54 99.66 with lactose Cytisine gentisate 97.98 98.37 with lactose

TABLE-US-00007 TABLE 7 Stability evaluation of cytisine salts in the presence of lactose following storage at 40° C. and 75% RH: Cytisine by HPLC, Cytisine by HPLC, Formulation area % - 7 days area % - 14 days Cytisine with 78.71 59.76 lactose Cytisine mesylate 99.20 99.89 with lactose Cytisine gentisate 96.67 97.45 with lactose

[0058] The invention is further defined with reference to the following claims.