Process for producing of inorganic particulate material

Abstract

The present invention is directed to a process for producing inorganic particulate material, the material obtainable by such process, a modified release delivery system comprising the material and the use of the material for the administration of a bioactive agent.

Claims

1. Inorganic particulate material composed of silicon oxide, wherein the particulate material comprises macropores and mesopores wherein the macropores have a mean diameter >0.1 m and the mesopores have a mean diameter between 2 and 100 nm, which is obtained by a process for producing inorganic particulate material mainly composed of silicon oxide, wherein the particulate material comprises mesopores and macropores and the process includes the steps of: (a) dissolving a water-soluble polymer or another pore forming agent and a precursor for a matrix dissolving agent in a medium that promotes the hydrolysis of a metalorganic compound; (b) mixing a metalorganic compound or a mixture of metalorganic compounds which contains hydrolyzable ligands to promote a hydrolysis reaction; (c) solidifying the mixture through a sol-gel transition, wherein a gel is prepared which has three dimensional interconnected phase domains, one rich in solvent and the other rich in inorganic component, in which surface pores are contained; (d) disintegrating the gel into particles 15 to 120 minutes after the phase separation of step (c), wherein a uniform particle size distribution is determined by controlling the time from phase separation to disintegration, resulting in particles having a mean diameter from 1 m to 2000 m; (e) setting the matrix dissolving agent free from its precursor, wherein the matrix dissolving agent modifies the structure of said inorganic component; and (f) removing the solvent by evaporation drying and/or heat-treatment.

2. Inorganic particulate material composed of silicon oxide, wherein the particulate material comprises macropores and mesopores wherein the macropores have a mean diameter >0.1 m and the mesopores have a mean diameter between 2 and 100 nm, which is obtained by a process for producing inorganic particulate material mainly composed of silicon oxide, wherein the particulate material comprises mesopores and macropores and the process includes the steps of: (a) dissolving a water-soluble polymer or another pore forming agent and a precursor for a matrix dissolving agent in a medium that promotes the hydrolysis of a metalorganic compound; (b) mixing a metalorganic compound or a mixture of metalorganic compounds which contains hydrolyzable ligands to promote a hydrolysis reaction; (c) solidifying the mixture through a sol-gel transition, wherein a gel is prepared which has three dimensional interconnected phase domains, one rich in solvent and the other rich in inorganic component, in which surface pores are contained; (d) disintegrating the gel into particles 15 to 120 minutes after the phase separation of step (c), wherein the mean diameter of the particles is from 1 m to about 2000 m; (e) setting the matrix dissolving agent free from its precursor, wherein the matrix dissolving agent modifies the structure of said inorganic component; and (f) removing the solvent by evaporation drying and/or heat-treatment.

3. The inorganic mesoporous particulate material according to claim 1, wherein said material has an irregular non-spherical shape.

4. A modified release delivery system comprising a bioactive agent and inorganic mesoporous particulate material according to claim 1.

5. A modified release delivery system according to claim 4, wherein the bioactive agent is a pharmaceutical drug.

6. A modified release delivery system according to claim 4, wherein the bioactive agent has a water-solubility of <about 10 mg/ml.

7. A modified release delivery system according to claim 4, wherein the bioactive agent is present in an amount of from about 0.1 to about 90% by weight.

8. A modified release delivery system according to claim 4, wherein said system is an oral or a topical or a parenteral administration form.

9. A modified release delivery system according to claim 8, wherein the oral administration form is a tablet or capsule, a powder, or a drage, the topical administration form is an ointment, a cream, a powder or a suspension and the parenteral administration form is a microparticle or an implant.

10. A method for the administration of at least one bioactive agent to a mammal, comprising administering the bioactive agent as part of a modified release system of claim 4.

11. Method according to claim 10, wherein said administration to the mammal is an oral or a topical or a parenteral administration.

12. The inorganic mesoporous particulate material according to claim 1, wherein the process further includes the step (g) calcining the particles.

13. The inorganic mesoporous particulate material according to claim 1, wherein the macropores have a mean diameter >0.1 m and the mesopores have a mean diameter between 2 and 100 nm.

14. The inorganic mesoporous particulate material according to claim 1, wherein in the process said precursor of the matrix dissolving agent is a compound having an amido group or an alkylamido group.

15. The inorganic mesoporous particulate material according to claim 1, wherein in the process step (d) is executed by stirring with an agitator.

16. The inorganic mesoporous particulate material according to claim 1, wherein in the process the pore forming agent is a non-ionic surfactant.

17. The inorganic mesoporous particulate material according to claim 1, wherein in the process said precursor of the matrix dissolving agent is a compound having a urea group.

18. The inorganic mesoporous particulate material according to claim 1, wherein in the process the mean diameter of the particles is from about 1 m to about 500 m.

19. The inorganic mesoporous particulate material according to claim 1, wherein in the process the particles made have an irregular non-spherical shape.

20. The inorganic mesoporous particulate material according to claim 1, wherein in the process step (d) is the disintegrating of the gel into particles 15 to 30 minutes after the phase separation of step (c).

Description

EXAMPLE 1

(1) In a three necked flask (equipped with an overhead stirrer with a small blade, 7.6 cm diameter) 30.45 g PEO and 27.00 g urea are dissolved in 300 mL of 0.01 M acetic acid and mixed at room temperature for 10 min. The solution is then cooled down to 5.0 C. followed by the addition of 150 mL TMOS without stirring. The resulting mixture is then stirred for 30 min at 5.0 C. and subsequently heated up to 30 C. for another 20 minutes. The stirring is then stopped and a phase separation takes place (solution changes from transparent to a white colour). 15 min after the phase separation the semi solid silica gel is stirred with a speed of 450 rpm for 3.5 h and with 300 rpm over night. Afterwards the silica gel is poured into a pressure resistant glass bottle and aged in a steam autoclave for 4 h at 110 C. The solvent is exchanged over a glass suction filter in four steps: purified water, nitric-acid, purified water and water/ethanol (2:1). The silica is washed four times with about 200 mL of each solvent and filtered to dryness. The semi-dried silica gel is replaced into an evaporating dish which is covered by a paper filter followed by a drying step in an oven for 5 days at 40 C.

(2) The dried gel is calcined for 4 h at 600 C. with a heating rate of 50 K/h. The calcined gel is analysed by Hg-Intrusion and N.sub.2-Adsorption/Desorption (BET-measurement). Further, the particle size distribution is measured by the Malvern Laserbeugung method.

(3) Particle measurement of this and all other Examples was performed using the following Instruments: Hg-Intrusion: PoreMaster 60 from Quantachrome Instruments, 1900 Corporate Drive Boynton Beach, Fla. 33426 USA; BET: Accelerated Surface Area and Porosimetry System ASAP 2420 from Micromeritics Instrument Corporation, 4356 Communications Drive, Norcross, Ga. 30093-2901, USA; Malvern Mastersizer 2000 from Malvern Instruments Ltd, Enigma Business Park, Grovewood Road, Malvern, Worcestershire WR14 1XZ, United Kingdom. Macropore size: 4.81 m Mesopore size: 10.1 nm Surface area: 322 m.sup.2/g Particle size distribution: d.sub.10=6 m, d.sub.50=22 m, d.sub.90=92 m

EXAMPLE 2

(4) In a three necked flask (equipped with an overhead stirrer with a large blade, 8.8 cm) 30.45 g PEO and 27.00 g urea are dissolved in 300 mL of 0.01 M acetic acid and mixed at room temperature for 10 min. The solution is then cooled down to 5.0 C. followed by the addition of 150 mL TMOS without stirring. The resulting mixture is then stirred for 30 min at 5.0 C. and subsequently heated up to 30 C. for another 20 minutes. The stirring is then stopped and a phase separation takes place (solution changes from transparent to a white colour). 15 min after the phase separation the semi solid silica gel is stirred with a speed of 450 rpm for 3.5 h and with 300 rpm over night. Afterwards the silica gel is poured into a pressure resistant glass bottle and aged in a steam autoclave for 4 h at 110 C. The solvent is exchanged over a glass suction filter in four steps: purified water, nitric-acid, purified water and water/ethanol (2:1). The silica is washed four times with about 200 mL of each solvent and filtered to dryness. The semi-dried silica gel is replaced into an evaporating dish which is covered by a paper filter followed by a drying step in an oven for 5 days at 40 C.

(5) The dried gel is calcined for 4 h at 600 C. with a heating rate of 50 K/h. The calcined gel is analysed by Hg-Intrusion and N.sub.2-Adsorption/Desorption (BET-measurements). Further, the particle size distribution is measured by the Malvern Laserbeugung method.

(6) Macropore size: 3.99 m

(7) Mesopore size: 10.2 nm

(8) Surface area: 321 m.sup.2/g

(9) Particle size distribution: d.sub.10=5 m, d.sub.50=11 m, d.sub.90=21 m

EXAMPLE 3

(10) In a three necked flask (equipped with an overhead stirrer with a large blade, 8.8 cm) 30.45 g PEO and 27.00 g urea are dissolved in 300 mL of 0.01 M acetic acid and mixed at room temperature for 10 min. The solution is then cooled down to 5.0 C. followed by the addition of 150 mL TMOS without stirring. The resulting mixture is then stirred for 30 min at 5.0 C. and subsequently heated up to 30 C. for another 20 minutes. The stirring is then stopped and a phase separation takes place (solution changes from transparent to a white colour). 30 min after the phase separation the semi solid silica gel is stirred with a speed of 450 rpm for 3.5 h and with 300 rpm over night. Afterwards the silica gel is poured into a pressure resistant glass bottle and aged in a steam autoclave for 4 h at 110 C. The solvent is exchanged over a glass suction filter in four steps: purified water, nitric-acid, purified water and water/ethanol (2:1). The silica is washed four times with about 200 mL of each solvent and filtered to dryness. The semi-dried silica gel is replaced into an evaporating dish which is covered by a paper filter followed by a drying step in an oven for 5 days at 40 C.

(11) The dried gel is calcined for 4 h at 600 C. with a heating rate of 50 K/h. The calcined gel is analysed by Hg-Intrusion and N.sub.2-Adsorption/Desorption (BET-measurements). Further, the particle size distribution is measured by the Malvern Laserbeugung method.

(12) Macropore size: 1.7 m

(13) Mesopore size: 10.1 nm

(14) Surface area: 321 m.sup.2/g

(15) Particle size distribution: d.sub.10=5 m, d.sub.50=166 m, d.sub.90=501 m

EXAMPLE 4

(16) In a three necked flask (equipped with an overhead stirrer with a small blade, 7.6 cm) 30.45 g PEO and 27.00 g urea are dissolved in 300 mL of 0.01 M acetic acid and mixed at room temperature for 10 min. The solution is then cooled down to 5.0 C. followed by the addition of 150 mL TMOS without stirring. The resulting mixture is then stirred for 30 min at 5.0 C. and subsequently heated up to 30 C. for another 20 minutes. The stirring is then stopped and a phase separation takes place (solution changes from transparent to a white colour). 2 hours after the phase separation the semi solid silica gel is roughly cracked with a spatula and afterwards stirred with a speed of 450 rpm for 3.5 h and with 300 rpm over night. Afterwards the silica gel is poured into a pressure resistant glass bottle and aged in a steam autoclave for 4 h at 110 C. The solvent is exchanged over a glass suction filter in four steps: purified water, nitric-acid, purified water and water/ethanol (2:1). The silica is washed four times with about 200 mL of each solvent and filtered to dryness. The semi-dried silica gel is replaced into an evaporating dish which is covered by a paper filter followed by a drying step in an oven for 5 days at 40 C.

(17) The dried gel is calcined for 4 h at 600 C. with a heating rate of 50 K/h. The calcined gel is analysed by Hg-Intrusion and N.sub.2-Adsorption/Desorption (BET-measurements). Further, the particle size distribution is measured by the Malvern Laserbeugung method.

(18) Macropore size: 1.7 m

(19) Mesopore size: 10.1 nm

(20) Surface area: 321 m.sup.2/g

(21) Particle size distribution: d.sub.10=5 m, d.sub.50=166 m, d.sub.90=501 m

EXAMPLE 5

(22) In a three necked flask (equipped with an overhead stirrer with a large blade, 8.8 cm) 30.45 g PEO and 27.00 g urea are dissolved in 300 mL of 0.01 M acetic acid and mixed at room temperature for 10 min. The solution is then cooled down to 5.0 C. followed by the addition of 150 mL TMOS without stirring. The resulting mixture is then stirred for 30 min at 5.0 C. and subsequently heated up to 30 C. for another 20 minutes. The stirring is then stopped and a phase separation takes place (solution changes from transparent to a white colour). 30 min after the phase separation the semi solid silica gel is stirred with a speed of 450 rpm for 3.5 h and with 300 rpm over night. Afterwards the silica gel is poured into a pressure resistant glass bottle and aged in a steam autoclave for 4 h at 110 C. The solvent is exchanged over a glass suction filter in four steps: purified water, nitric-acid, purified water and water/ethanol (2:1). The silica is washed four times with about 200 mL of each solvent and filtered to dryness. The semi-dried silica gel is replaced into an evaporating dish which is covered by a paper filter followed by a drying step in an oven for 5 days at 40 C.

(23) The dried gel is calcined for 4 h at 600 C. with a heating rate of 50 K/h. The calcined gel is analysed by Hg-Intrusion and N.sub.2-Adsorption/Desorption (BET-measurements). Further, the particle size distribution is measured by the Malvern Laserbeugung method.

(24) For the purpose of a subsequent rehydroxylation of the silica surface (transformation of siloxane groups to hydrophilic silanol groups) the calcined silica gel is suspended in a beaker with water which is placed in an autoclave for 3 h at 130 C. Afterwards the rehydroxylated gel is washed with methanol over a glass suction filter until all solvent is removed. The silica gel is then placed in an evaporating dish covered with a paper filter and dried in an oven for 5 days at 40 C.

(25) The resulting material possess hydrophilic properties due to a maximization of silanol groups.

(26) Macropore size: 1.43 m

(27) Mesopore size: 11.1 nm

(28) Surface area: 328 m.sup.2/g

(29) Particle size distribution: d.sub.10=3 m, d.sub.50=25 m, d.sub.90=562 m

(30) Example for Drug Loading

(31) Itraconazole, a synthetic triazole antifungal agent, which is poorly soluble in aqueous solutions (1 ng/mL at pH 7 and 4 g/mL at pH 1; see Six, K. et al., Eur J Pharm Sci 24 (2005) 179-186), was used as model drug.

(32) The silica material of the present invention was drug loaded with itraconazole by using wetness impregnation. For this purpose 1.0 g of itraconazole was dissolved in 130 mL of acetone at 53 C. A 250 mL three necked flask (heated by a water bath at 60 C.; equipped with an overhead stirrer and paddle) was filled with 2.3 g of silica material synthesized in accordance to Example 5. The itraconazole solution was added pro rata (10 mL per impregnation step) to the flask while acetone was evaporated by a nitrogen stream under stirring. The procedure of impregnating and subsequently evaporating was repeated until the entire itraconazole solution was evaporated. Additionally, the obtained powder was dried under vacuum at 40 C. over night. The resulting drug load aimed to 30% by weight.

(33) The dissolution rates of itraconazole loaded formulation prepared as set forth above and pure crystalline itraconazole was tested using USP Apparatus II (rotating paddle) dissolution tester with on-line UV sampler and measurement system (conditions: simulated gastric fluid (SGF) without pepsin; 1000 mL vessel; 37 C.; 75 rpm; 0.1% sodium dodecyl sulphate (SDS)).

(34) The itraconazole loaded samples tested contained 50 mg of itraconazole which was confirmed by high performance liquid chromatography (HPLC) with UV detector, pure crystalline itraconazole was tested in the same amount (50 mg).

BRIEF DESCRIPTION OF THE DRAWING

(35) FIG. 1 summarizes the dissolution rates of the samples tested.