Method of making particles for use in a pharmaceutical composition

Abstract

The invention relates to a method for making composite active particles for use in a pharmaceutical composition for pulmonary administration, the method comprising a milling step in which particles of active material are milled in the presence of particles of an additive material which is suitable for the promotion of the dispersal of the composite active particles upon actuation of an inhaler. The invention also relates to compositions for inhalation prepared by the method.

Claims

1. A pharmaceutical composition comprising: (i) composite active particles, each composite active particle comprising (a) a particle of active material; and (b) particles of magnesium stearate on the surface of said particle of active material; and (ii) carrier particles; wherein said composite active particles have a mass median aerodynamic diameter of not more than 10 μm; and wherein said composition is used for pulmonary administration.

2. The pharmaceutical composition of claim 1 wherein magnesium stearate comprises about 0.25 to 30% of the pharmaceutical composition by weight.

3. The pharmaceutical composition of claim 2 wherein magnesium stearate comprises about 0.25 to 2% of the pharmaceutical composition by weight.

4. The pharmaceutical composition of claim 3 wherein said carrier particles comprise lactose.

5. The pharmaceutical composition of claim 4 wherein lactose comprises more than 95% of the pharmaceutical composition by weight.

6. The pharmaceutical composition of claim 5 wherein the active material is a (3 agonist or (32 agonist.

7. The pharmaceutical composition of claim 6 wherein said composite active particles have a mass median aerodynamic diameter of not more than 5 μm.

8. The pharmaceutical composition of claim 6 wherein said composite active particles have a mass median aerodynamic diameter of not more than 3 μm.

9. The pharmaceutical composition of claim 6 wherein said composite active particles have a mass median aerodynamic diameter of not more than 1 μm.

10. The pharmaceutical composition of claim 6 wherein said composite active particles possess a fine particle fraction (FPF) greater than the FPF of particles of active material that have not been incorporated into said composite active particles or otherwise processed with magnesium stearate or other additive material.

11. The pharmaceutical composition of claim 1 wherein the particles of magnesium stearate on the surface of the particle of active material form a coating which is a continuous coating or a discontinuous coating.

12. The pharmaceutical composition of claim 11 wherein the coatings on the composite active particles cover on average at least 50% of the total surface area of the particles of active material.

13. A pharmaceutical composition comprising: (i) composite active particles, each composite active particle comprising (a) a particle of active material; and (b) particles of magnesium stearate on the surface of said particle of active material; and (ii) carrier particles; wherein said composite active particles have a mass median aerodynamic diameter of not more than 10 μm; wherein magnesium stearate comprises about 0.25 to 2% of the pharmaceutical composition by weight; wherein the carrier particles are lactose; wherein the lactose comprises more than 95% of the pharmaceutical composition by weight; wherein the active material comprises a β agonist or β2 agonist; and wherein said composition is used for pulmonary administration.

14. The pharmaceutical composition of claim 13 wherein said composite active particles have a mass median aerodynamic diameter of not more than 5 μm.

15. The pharmaceutical composition of claim 13 wherein said composite active particles have a mass median aerodynamic diameter of not more than 3 μm.

16. The pharmaceutical composition of claim 13 wherein said composite active particles have a mass median aerodynamic diameter of not more than 1 μm.

17. The pharmaceutical composition of claim 13 wherein said composite active particles possess a fine particle fraction (FPF) greater than the FPF of particles of active material that have not been incorporated into said composite active particles or otherwise processed with magnesium stearate or other additive material.

18. The pharmaceutical composition of claim 13 wherein the particles of magnesium stearate on the surface of the particle of active material form a coating which is a continuous coating or a discontinuous coating.

19. The pharmaceutical composition of claim 18 wherein the coatings on the composite active particles cover on average at least 50% of the total surface area of the particles of active material.

20. A pharmaceutical composition comprising: (i) composite active particles, each composite active particle comprising (a) a particle of active material; and (b) particles of magnesium stearate on the surface of said particle of active material; and (ii) carrier particles; wherein said composite active particles have a mass median aerodynamic diameter of not more than 10 μm; wherein said composite active particles possess a fine particle fraction (FPF) greater than the FPF of particles of active material that have not been incorporated into said composite active particles or otherwise processed with magnesium stearate or other additive material; and wherein said composition is used for pulmonary administration.

21. The pharmaceutical composition of claim 20 wherein magnesium stearate comprises about 0.25 to 30% of the pharmaceutical composition by weight.

22. The pharmaceutical composition of claim 20 wherein magnesium stearate comprises about 0.25 to 2% of the pharmaceutical composition by weight.

23. The pharmaceutical composition of claim 22 wherein said carrier particles comprise lactose.

24. The pharmaceutical composition of claim 19 wherein lactose comprises more than 95% of the pharmaceutical composition by weight.

25. The pharmaceutical composition of claim 16 wherein the active material comprises a β agonist or β2 agonist.

26. The pharmaceutical composition of claim 20 wherein the particles of magnesium stearate on the surface of the particle of active material form a coating which is a continuous coating or a discontinuous coating.

27. The pharmaceutical composition of claim 26 wherein the coatings on the composite active particles cover on average at least 50% of the total surface area of the particles of active material.

Description

(1) Embodiments of the invention will now be described for the purposes of illustration only with reference to the 5 Figures in which:

(2) FIGS. 1 and 2 are scanning electron micrographs of the composite active particles of Example 1;

(3) FIG. 3 is a scanning electron micrograph of the composite active particles of Example 1a;

(4) FIG. 4 is a scanning electron micrograph of the composite particles of Example 2;

(5) FIG. 5 is a scanning electron micrograph of the same sample of particles shown in FIG. 4 but at a higher magnification;

(6) FIG. 6 is a scanning electron micrograph of the composite particles of Example 3;

(7) FIG. 7 is a scanning electron micrograph of the same sample of particles shown in FIG. 6 but at a higher magnification;

(8) FIG. 8 is a schematic drawing of part of a Mechano-Fusion machine; and

(9) FIGS. 9 and 10 are electromicrographs of composite active particles according to the invention comprising salbutamol sulphate and magnesium stearate in a ratio of 19:1 (Example 4).

(10) All percentages are by weight unless indicated otherwise.

Example 1

(11) 5g of micronised salbutamol sulphate (particle size distribution: 1 to 5 μm) and 0.5 g of magnesium stearate were added to a 50cm.sup.3 stainless steel milling vessel together with 20 cm.sup.3 dichloromethane and 124 g of 3 mm stainless steel balls. The mixture was milled at 550 rpm in a Retsch S100 Centrifugal Mill for 5 hours. The powder was recovered by drying and sieving to remove the mill balls. An electron micrograph of the powder is shown in FIG. 1. This was repeated 3 times using leucine in place of the magnesium stearate and an electron micrograph of the powder is shown in FIG. 2. The powders shown in FIGS. 1 and 2 appear to have particles in the size range 0.1 to 0.5 μm.

Example 1a

(12) Micronised salbutamol sulphate and magnesium stearate were combined as particles in a suspension in the ratio 10:1 in propanol. This suspension was processed in an Emulsiflex C50 high pressure homogeniser by 5 sequential passes through the system at 25,000 psi. This dry material was then recovered by evaporating the propanol. The particles are shown in FIG. 3.

Example 2

(13) It was found that, on drying, the powder prepared in Example 1 including magnesium stearate as additive material formed assemblies of primary particles which were hard to deagglomerate. A sample of this powder was re-dispersed by ball milling for 90 minutes at 550 rpm in a mixture of ethanol, polyvinylpyrolidone (PVPK30) and HFA227 liquid propellant to give the following composition:

(14) 0.6% w/w Salbutamol sulphate/magnesium stearate composite particles

(15) 0.2% w/w PVPK30

(16) 5.0% w/w Ethanol

(17) 94.2% w/w HFA 227

(18) (The PVP was included to stabilise the suspension of the composite particles in the ethanol/HFA227).

(19) The suspension could be used directly as in a pMDI. In this example, however, the composition was sprayed from a pressurised can through an orifice −0.4 mm in diameter to produce dried composite active particles of salbutamol sulphate and magnesium stearate with PVP. Those particles (shown in FIGS. 4 and 5) were collected and examined and 10 were found to be in the aerodynamic size range 0.1 to 4 μm.

Example 3

(20) The process of Example 2 was repeated except that the 15 composition was as follows:

(21) 3% w/w Salbutamol sulphate/magnesium stearate composite particles

(22) 1% w/w PVPK30

(23) 3% w/w Ethanol

(24) 93% w/w HFA 227

(25) The particles produced are shown in FIGS. 6 and 7.

Example 4

Salbutamol Sulphate/Magnesium Stearate Blends

(26) a) Homogenised Magnesium Stearate

(27) 240g magnesium stearate (Riedel de Haen, particle size by Malvern laser diffraction:dso=9.7 μm) was suspended in 2150 g dichloroethane. That suspension was then mixed for 5 minutes in a Silverson high shear mixer. The suspension was then processed in an Emulsiflex C50 high pressure homogeniser fitted with a heat exchanger at 10000 psi for 20 minutes in circulation mode (300 cm.sup.3/min) for 20 minutes. The suspension was then circulated at atmospheric pressure for 20 minutes allow it to cool. The next day, the suspension was processed in circulation mode (260 cm.sup.3/min) at 20000 psi for 30 minutes. The dichloroethane was removed by rotary evaporation followed by drying in a vacuum over at 37° C. overnight. The resulting cake of material was broken up by ball milling for 1 minute. The homogenised magnesium stearate had a particle size of less than 2μ.

(28) b) A 9:1 by weight blend of salbutamol sulphate and homogenised magnesium stearate having a particle size of less than 2 μm was prepared by blending the two materials with a spatula. An electron micrograph of the blended material showed that the blend was mostly in the form of agglomerated particles, the agglomerates having diameters of 50 μm and above. The blend was then processed in a Mechano-Fusion mill (Hosokawa) as follows:

(29) TABLE-US-00001 Machine data: Hosokawa Mechano-Fusion: AMS-Mini Drive: 2.2 kW Housing: stainless steel Rotor: stainless steel Scraper: None Cooling: Water Gas purge: None

(30) The Mechano-Fusion device (see FIG. 8) comprises a cylindrical drum 1 having an inner wall 2. In use, the drum rotates at high speed. The powder 3 of the active and additive particles is thrown by centrifugal force against the inner wall 2 of the drum 1. A fixed arm 4 projects from the interior of the drum in a radial direction. At the end of the arm closest to the wall 2, the arm is provided with a member 5 which presents an arcuate surface 6, of radius of curvature less than that of inner wall 2, toward that inner wall. As the drum 1 rotates, it carries powder 3 into the gap between arcuate surface 6 and inner wall 2 thereby compressing the powder. The gap is of a fixed, predetermined width A. A scraper (not shown in FIG. 8) may be provided to scrape the compressed powder from the wall of the drum.

(31) All samples were premixed for 5 minutes by running the machine at 1000 rpm. The machine speed was then increased to 5050 rpm for 30 minutes. The procedure was repeated for salbutamol sulphate/magnesium stearate in the following weight ratios: 19:1, 3:1, 1:1.

(32) Electronmicrographs of the 19:1 processed material are shown in FIGS. 9 and 10 and indicate that the material was mostly in the form of simple small particles of diameter less than 5 gm or in very loose agglomerates of such particles with only one agglomerate of the original type being visible.

(33) The 3:1 and the 19:1 blends were then each loaded into a 20mg capsule and fired from a twin stage impinger. A sample of unprocessed salbutamol sulphate was also fired from the TSI to provide a comparison.

(34) The fine particle fractions were then calculated and are given in table 1.

(35) TABLE-US-00002 TABLE 1 Fine Particle Fraction results for salbutamol sulphate blends. Composition Fine Particle Fraction % salbutamol sulphate 28 salbutamol sulphate/magnesium stearate 19:1 66 salbutamol sulphate/magnesium stearate 3:1 66

Example 5

(36) Micronised glycopyrrolate and homogenised magnesium stearate (as described in Example 4) were combined in a weight ratio of 75:25. This blend (−20 g) was then milled in the Mechano-Fusion AMS-Mini system as follows. The powder was pre-mixed for 5 minutes at −900 rpm. The machine speed was then increased to −4,800 rpm for 30 minutes. During the milling treatment the Mechano-Fusion machine was run with a 3 mm clearance between element and vessel wall, and with cooling water applied. The powder of composite active particles was then recovered from the drum vessel.

(37) The experiment was repeated using the same procedure but the active particle and homogenised magnesium stearate were 15 combined in the ratio 95:5, and milled for 60 minutes at 4,800 rpm.

(38) This above process was repeated using the same procedure with a sample of sodium salicilate as a model drug and homogenised magnesium stearate in the ratio 90:10, where the sodium salicilate had been produced as approximately micron sized spheres by spray drying from a Buchi 191 spray dryer. It was believed that the spherical shape of these particles may be advantageous in the coating process. Milling was for 30 minutes at 4,800 rpm