NEW COMPOSITION COMPRISING AMORPHOUS NANOPOROUS SILICA PARTICLES

Abstract

According to the invention, there is provided a pharmaceutical composition suitable for administration to the lung, which composition comprises a plurality of amorphous nanoporous silica particles, in which N-butyloxycarbonyl-3-(4-imidazol-1-yl-methylphenyl)-5-iso-butylthiophene-2-sulfonamide or a pharmaceutically-acceptable salt thereof is loaded into the pores of said silica particles, and wherein the silica particles have: (a) a mass median aerodynamic diameter that is between about 0.1 μm and about 10 μm; and (b) a geometric standard deviation that is less than about 4. Such compositions find particular utility in the treatment of an interstitial lung diseases, such as idiopathic pulmonary fibrosis and sarcoidosis, which diseases may be treated with such compositions for example by way of pulmonary administration.

Claims

1. A pharmaceutical composition suitable for administration to the lung, which composition comprises a plurality of amorphous nanoporous (mesoporous) silica particles, in which N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide or a pharmaceutically-acceptable salt thereof is loaded into the pores of said silica particles, and wherein the silica particles have: (a) a mass median aerodynamic diameter that is between about 0.1 μm and about 15 μm (e.g. about 10 μm); and (b) a geometric standard deviation that is less than about 4.

2. The composition as claimed in claim 1, wherein the loaded silica particles have a mass density that is less than about 0.4 g/cm.sup.3.

3. The composition as claimed in claim 1, wherein the mass median aerodynamic diameter is between about 3 μm and about 5 μm.

4. The composition as claimed in claim 1, wherein the geometric standard deviation is between about 1 and about 1.5.

5. The composition as claimed in claim 1, wherein the silica particles have a pore size that is between about 10 nm and about 20 nm.

6. The composition as claimed in claim 1, wherein the silica particles have a pore volume that is between 0.2 and 3 cm.sup.3/g.

7. The composition as claimed in claim 1, wherein the silica particles have a surface area that is between about 150 and about 1200 m.sup.2/g.

8. The composition as claimed in claim 1, wherein the silica particles are essentially spherical.

9. The composition as claimed in claim 1, wherein up to about 45% of the total weight of the loaded silica particles is N-butyloxycarbonyl-3 -(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide, or a pharmaceutically-acceptable salt thereof.

10. The composition as claimed in claim 1, wherein N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide or pharmaceutically-acceptable salt thereof is essentially amorphous.

11. The composition as claimed in claim 1, wherein the silica particles consist essentially of a synthetic biodegradable amorphous mesoporous silica.

12. A process for the production of a composition as defined in claim 1, which process comprises providing porous silica particles either: (a) having a mass median aerodynamic diameter and/or a geometric standard deviation as defined in the relevant preceding claims; or (b) at least in part not having a mass median aerodynamic diameter and/or a geometric standard deviation as defined in the relevant preceding claims, and thereafter separating silica particles so as to obtain particles having a mass median aerodynamic diameter and/or a geometric standard deviation within those ranges; followed by, in either case, (c) loading the obtained particles with N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide or pharmaceutically-acceptable salt thereof

13. The process as claimed in claim 12, which process further comprises one or more of the steps of: (i) prior to step (b), calcining the mesoporous silica particles at a temperature of between about 650° C. and about 750° C. in order to provide silica particles; and/or (ii) after step (b) (and/or after step (i) above), surface modifying said silica particles by chemical reaction thereof with a reagent that provides at least one organic group; and/or (iii) after step (c), admixing the loaded silica particles with a fatty acid- or a lipid-based surfactant.

14. The process as claimed in claim 12, wherein the silica particles are separated and classified into the desired particle size range using an air classifier or via an elutriation step.

15. The process as claimed in claim 12, wherein the silica particles are loaded with N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide or pharmaceutically-acceptable salt thereof using a process of solvent evaporation.

16. The process as claimed in claim 12, wherein the silica particles are manufactured by reacting tetraethyl orthosilicate with a template made of micellar structures.

17. The process as claimed in claim 12, wherein the silica particles are manufactured by a sol-gel method comprising a condensation reaction of an aqueous suspension of silica nanoparticles with a non-miscible organic solution, oil, or liquid polymer, followed by gelation by means of change in pH and/or evaporation of the aqueous phase.

18. A pharmaceutical composition obtained by the process as defined in claim 12.

19. A pharmaceutical formulation comprising a composition as defined in claim 1 in admixture with one or more pharmaceutically-acceptable excipients.

20. The pharmaceutical formulation as claimed in claim 19, wherein the excipient is a hydrocarbon, a fluorocarbon and/or a hydrogen-containing fluorocarbon propellant.

21. The pharmaceutical formulation as claimed in claim 19, which is a dry powder formulation in which the excipient is of larger particle size.

22. A process for the production of a composition, which process comprises admixing the composition as defined in claim 1, with the one or more pharmaceutically-acceptable excipients.

23-24. (canceled)

25. A method of treatment of an interstitial lung disease, which method comprises the administration of a pharmacologically-effective amount of a composition as defined in claim 1, to a patient in need of such treatment.

26. The method of treatment as defined in claim 25, wherein the interstitial lung disease is idiopathic pulmonary fibrosis.

27. The method of treatment as defined in claim 25, wherein the interstitial lung disease is sarcoidosis.

28. The method of treatment as defined in claim 25, wherein the composition is administered by the pulmonary route.

Description

EXAMPLES

Example 1

Silica Particle Manufacture I

[0139] Pluronic 123 (triblock co-polymer, E020P070E020, Sigma-Aldrich; 4 g; templating agent) and 1,3,5-trimethylbenzene (TMB; mesitylene, Sigma-Aldrich; 3.3 g; swelling agent) were dissolved in 127 mL of distilled H.sub.2O.sub.2and 20 mL of hydrochloric acid (HCl, 37%, Sigma-Aldrich) while stirring at room temperature for 3 days.

[0140] The solution was preheated to 40° C. before adding 9.14 mL of tetraethyl orthosilicate (TEOS; Sigma-Aldrich). The mixture was stirred for another 10 minutes at a speed of 500 rpm, then kept at 40° C. for 24 hours, and then hydrothermally treated in the oven at 100° C. for another 24 hours. Finally, the mixture was filtered, washed and dried at room temperature.

[0141] The product was calcined to remove the surfactant template and swelling agent. The calcination was conducted by heating to 600° C. with a heating rate of 1.5° C./min and kept at 600° C. for 6 hours, followed by cooling to ambient conditions. The resultant product was a white powder comprising porous silica particles.

Example 2

Silica Particle Manufacture II

[0142] A dispersion (14 wt %) of silica nanoparticles (10 nm) in water (pH 9) (400 mL) was poured into benzyl alcohol (800 mL) warmed to 50° C. and stirred at 300 rpm with an overhead stirrer (Silverson, UK) for 20 minutes.

[0143] A drop of acetic acid was added and vacuum (200 bar) was applied during heating at 80° C. to remove the aqueous phase. The resulting particles were collected by filtration and washing with acetone.

[0144] The product was calcined by heating to 600° C. with a heating rate of 1.5° C./min and kept at 600° C. for 6 hours, followed by cooling to ambient conditions. The resultant product was a white powder comprising porous silica particles in the size range 2 to 4 microns measured by scanning electron microscope (JEOL, Japan) and by electrical sensing zone method (Elzone, Micromeretics USA). The particles were further treated by refluxing in ammonium hydroxide overnight followed by filtering and refluxing in nitric acid overnight and finally filtered and washed in water and oven dried at 80° C.

Example 3

Silica Particle Separation

[0145] 100 g of nanoporous silica particles (preparable and/or prepared as described in Example 1 and/or Example 2 above) were fed into an air classifier (TTS, Hosokawa-Alpine), with the air flow adjusted from 53 to 42 m.sup.3/h and the speed set at between 2,475 and 13,500 rpm. 11 g of fines and 8 g of course materials were collected. The particle size distribution calculated as (D.sub.90/D.sub.10) was reduced from 4.5 to 1.8.

Example 4

Nanoporous Silica Particle Properties

[0146] Two porous silica particle types with different porosities and densities (1.2 mL/g and 0.9 mL/g, and 0.18 mg/mL and 0.33 mg/mL, respectively) were prepared essentially as described in Example 1 and/or Example 2, and were characterised to determine their MMAD, GSD and GPS (mean particle size) using an 8-Stage Cascade Impactor (Marple), as shown in Table 1 below.

TABLE-US-00001 TABLE 1 Bulk Density D.sub.10 D.sub.50 D.sub.90 MMAD GPS (mg/mL) (μm) (μm) (μm) (μm) (μm) GSD Silica 1 0.18 3.0 4.1 5.5 4.33 3.8 1.354 Silica 2 0.33 2.6 3.8 5.1 3.6 4.1 1.401

[0147] By optical observation, it could be seen that, in small quantities, the above particles aggregated and had poor flow properties.

[0148] Attempts were made to reduce particle aggregation for formulation by using the well-known glidant magnesium stearate. This is an approved excipient for inhalation products. The particles were mechanically mixed with magnesium stearate (Sigma) at several different weight ratios in the range 1-5% magnesium stearate, but the flow properties of the particles did not improve.

Example 5

Loading of C21 in Silica

[0149] C21 was encapsulated into the porous silica particles of Example 4 above (those with the bulk density of 0.18 mg/mL and the MMAD of 4.33 μm) by a solvent impregnation and evaporation method. A concentrated solution of C21 was made in a chosen good solvent for the drug, and various known masses of nanoporous silica particles were added to the solution. The solvent was removed by evaporation.

[0150] In one example, C21 as the sodium salt (450 mg) was dissolved in methanol (15 mL; VWR) at room temperature in a round-bottomed flask. Nanoporous silica particles (1050 mg) were added to the C21 solution.

[0151] The mixture was stirred for 30 minutes at 40° C. The solvent was evaporated with controlled evaporation under a reduced pressure of 200 mbar in a rotary evaporator, with a water bath temperature of 40° C. The resultant dry powder that was collected was free flowing. The samples were further dried at 40° C. under vacuum for 12 hours. The resulting loaded silica particles were free flowing and showed good handling properties.

[0152] The samples were characterized by thermogravimetric analysis (TGA) to evaluate drug loading. In FIG. 1, an analysis of mass loss from free C21 and C21-loaded silica particles is shown. The main degradation of C21 appears between 300 and 600° C. A loading amount of 30 wt % (calculated as mass of drug/mass of loaded particles) was determined.

[0153] The physical state of the drug (crystalline vs amorphous) was measured with differential scanning calorimetry (DSC) and is shown in FIG. 2. FIG. 2 shows DSC measurements of free C21 and C21 loaded into porous silica particles. C21 has a clear melting peak in DSC of around 230° C. It can be seen from FIG. 2 that the melting peak was completely absent when C21 was loaded into porous silica particles, showing that the C21 is stabilized in an amorphous state in the samples with a drug loading of up to 30 wt %.

[0154] Analysis by light microscopy showed that the free drug is fully encapsulated in the porous silica particles. This is shown in FIG. 3 (empty silica particles on the left, and C21 silica particles (30% loading) on the right). No C21 was detected around the outside of the silica particles.

Example 6

Dissolution Kinetics of C21-Loaded Silica Particles

[0155] The dissolution kinetics of the C21-loaded silica described in Example 5 were characterized in SLF (pH 7.4; Gamble's solution: made up with the salts NaCl, NaHCO.sub.3, KCl, MgCl.sub.2, CaCl.sub.2, Na.sub.2SO.sub.4, sodium citrate dihydrate, sodium acetate, NaH.sub.2PO.sub.4 (all from Sigma-Aldrich)) at 37° C. (Reference: Simulated Biological Fluids with Possible Application in Dissolution Testing, Marques et al,. Dissolution technologies August 2011, p15-28) using a USP 2 dissolution apparatus with stirring speed 75 rpm. Free, unloaded C21-sodium salt was used as control. Concentration of drug at set times after release was measured by a UV/vis spectrometer (Cecil 3021) at 267 nm.

[0156] The dose of C21 was calculated as 25 mg of C21 in 500 mL of SLF. The data are shown in FIG. 4. The C21 sodium salt is readily soluble in SLF conditions and show immediate dissolution. The dissolution kinetics of free C21 shows a rapid dissolution profile with 96% released in the first 2 minutes. The loaded C21 is fully released and dissolved from the silica particles in around 10 minutes.