MESOPOROUS POLYMERIC PARTICULATE MATERIAL

Abstract

A particulate material comprising porous polymeric particles is described. The porous polymeric particles have an average pore diameter of from 2 to 50 nm and a volume mean particle diameter D[4,3] of less than 100 μm. The material is obtained or obtainable by spray-drying a polymer solution. The particles find use as a solubility-enhancing carrier for active pharmaceutical compounds. Methods of manufacturing the particulate material and pharmaceutical compositions including the particulate material loaded with one or more active pharmaceutical compounds are also described.

Claims

1. A particulate material comprising porous polymeric particles, the average pore diameter being from 2 to 50 nm, wherein the porous polymeric particles have a volume mean particle diameter D[4,3] of less than 100 μm and the material is obtained or obtainable by spray-drying a polymer solution.

2. The particulate material according to claim 1, wherein the volume mean particle diameter D[4,3] of the particles is less than 50 μm.

3. The particulate material according to claim 1, wherein the volume of pores in the material is greater than 0.10 cm.sup.3/g.

4. The particulate material according to claim 1, wherein the surface area of the material is greater than 10 m.sup.2/g.

5. The particulate material according to claim 1, wherein the average pore diameter is from 10 to 30 nm.

6. The particulate material according to claim 1, wherein the particles comprise cellulosic polymer and the polymer solution is a solution comprising the same cellulosic polymer.

7. The particulate material according to claim 6, wherein the cellulosic polymer is selected from one or more of cellulose esters and cellulose ethers.

8. The particulate material according to claim 6, wherein the cellulosic polymer is selected from one or more of cellulose acetate butyrate, cellulose acetate, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose.

9. The particulate material according to claim 8, wherein the cellulosic polymer is cellulose acetate butyrate.

10. The particulate material according to claim 1, wherein the inlet temperature during spray-drying of the polymer solution is lower than the glass transition temperature T.sub.g of the polymer in the polymer solution.

11. The particulate material according to claim 1, wherein the glass transition temperature T.sub.g of the polymer in the polymer solution is greater than 100° C.

12. The particulate material according to claim 1, wherein the solution comprises a solvent mixture comprising water and acetone.

13. A pharmaceutical composition comprising a particulate material according to claim 1 loaded with one or more active pharmaceutical compounds.

14. (canceled)

15. A method of treatment of the human or animal body, comprising administration of a therapeutically effective amount of the pharmaceutical composition according to claim 13.

16. A method of manufacturing a particulate material comprising spray-drying a polymer solution, the particulate material comprising porous polymeric particles, the average pore diameter being from 2 to 50 nm, wherein the porous polymeric particles have a volume mean diameter D[4,3] of less than 100 μm.

17. The method according to claim 16, wherein the polymer solution is a solution comprising cellulosic polymer.

18. The method according to claim 17, wherein the cellulosic polymer is selected from one or more of cellulose esters and cellulose ethers.

19. The method according to claim 17, wherein the cellulosic polymer is selected from one or more of cellulose acetate butyrate, cellulose acetate, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose.

20. The method according to claim 19, wherein the cellulosic polymer is cellulose acetate butyrate.

21. The method according to claim 16, wherein the inlet temperature during spray-drying of the polymer solution is lower than the glass transition temperature T.sub.g of the polymer in the polymer solution.

22. The method according to claim 16, wherein the glass transition temperature T.sub.g of the polymer in the polymer solution is greater than 100° C.

23. The method according to claim 16, wherein the solution comprises a solvent mixture comprising water and acetone.

24. The method according to claim 16, wherein the solution comprises one or more active pharmaceutical compounds.

25. The method according to claim 16, wherein the spray-drying is carried out in a spray-dryer under closed-mode with nitrogen, an inlet temperature of from 60 to 180° C. and an atomisation pressure of from 100 to 500 KPa.

26. Use of a particulate material according to claim 1 as a solubility-enhancing carrier for one or more active pharmaceutical compounds.

Description

SUMMARY OF THE FIGURES

[0143] So that the invention may be understood, and so that further aspects and features thereof may be appreciated, embodiments illustrating the principles of the invention will now be discussed in further detail with reference to the accompanying figures, in which:

[0144] FIG. 1 shows SEM images of mesoporous cellulose acetate butyrate particles according to the invention, prepared by a spray drying process, including (a) a CAB particle cross-section at a magnification of ×5000 and a scale bar of 1 μm and (b) the internal mesoporous structure of a particle at a magnification of ×30,000 and a scale bar of 100 nm.

[0145] FIG. 2 shows SEM images of mesoporous cellulose acetate butyrate particles according to the invention, prepared by a spray drying process, including (a) a CAB particle surface at a magnification of ×5000 and a scale bar of 1 μm, and (b) a CAB particle surface at a magnification of ×33,000 and a scale bar of 100 nm.

[0146] FIG. 3 shows DSC thermograms of Felodipine raw material (solid line) and Felodipine-loaded mesoporous CAB particles (dashed line), under a scanning rate of 10° C./min and a scanning range of 50-250° C.

[0147] FIG. 4 shows DSC thermograms of Ibuprofen raw material (solid line) and Ibuprofen-loaded mesoporous CAB particles (dashed line), under a scanning rate of 10° C./min and a scanning range of 40-250° C.

[0148] FIG. 5 shows DSC thermograms of Furosemide raw material (solid line) and Furosemide-loaded mesoporous CAB particles (dashed line), under a scanning rate of 10° C./min and a scanning range of 100-300° C.

[0149] FIG. 6 shows dissolution profiles of Felodipine raw material (solid line) and Felodipine-loaded mesoporous CAB particles (dashed line). Testing conditions: phosphate buffer pH 6.5+0.25% SLS, 500 mL, USP apparatus 1 (rotating basket), 50 rpm, HPLC method (mobile phase: pH 3 phosphate buffer:acetonitrile:methanol (30:45:25); column: C18, 15 cm×4.6 mm, 5 μm; flow rate: 1 mL/min; injection volume: 40 μL; detector: UV, 362 nm).

[0150] FIG. 7 shows dissolution profiles of Ibuprofen raw material (solid line) and Ibuprofen-loaded mesoporous CAB particles (dashed line). Testing conditions: HCL-NaCl medium pH 3+0.25% SLS, 900 mL, USP apparatus 1 (rotating basket), 100 rpm, HPLC method (mobile phase: pH 3 phosphate buffer:acetonitrile (60:40); column: C18, 15 cm×4.6 mm, 5 μm; flow rate: 2 mL/min; injection volume: 20 μL; detector: UV, 254 nm).

[0151] FIG. 8 shows dissolution profiles of Furosemide raw material (solid line) and Furosemide-loaded mesoporous CAB particles (dashed line). Testing conditions: HCL-NaCl medium pH 3+0.25% SLS, 900 mL, USP apparatus 1 (rotating basket), 100 rpm, HPLC method (mobile phase: pH 3 phosphate buffer:acetonitrile (60:40); column: C18, 15 cm×4.6 mm, 5 μm; flow rate: 1 mL/min; injection volume: 10 μL; detector: UV, 234 nm).

[0152] FIG. 9 shows dissolution profiles of Felodipine raw material (dotted line with triangular markers), spray-dried raw Felodipine (dotted line with square markers) and Felodipine-loaded mesoporous CAB particles prepared by co-spray drying a solution containing CAB and three different levels of Felodipine: 5 wt %, 15 wt % and 25 wt % (solid lines). Testing conditions: phosphate buffer pH 6.5+0.25% SLS, 500 mL, USP apparatus 1 (rotating basket), 50 rpm, HPLC method (mobile phase: pH 3 phosphate buffer:acetonitrile:methanol (30:45:25); column: C18, 15 cm×4.6 mm, 5 μm; flow rate: 1 mL/min; injection volume: 40 μL; detector: UV, 362 nm).

[0153] FIG. 10 shows SEM images of mesoporous cellulose acetate butyrate particles according to the invention, prepared by co-spray drying a solution of CAB and Felodipine, including (a) drug loading of 5 wt %, (b) drug loading of 10 wt % and (c) drug loading of 25 wt %. SEM images were taken at 30,000× magnification with a scale bar of 100 nm.

[0154] FIG. 11 shows CLSM images of mesoporous cellulose acetate butyrate particles loaded with fluorescein by two different methods (a) post-loading with fluorescein, and (b) co-spray drying with fluorescein.

[0155] FIG. 12 shows plots of (a) cumulative distribution of pore volume of particles of Sample 8, and (b) the pore size distribution curve for the particles of Sample 8 determined according to the BJH method.

EXAMPLES

[0156] Aspects and embodiments of the present invention will now be discussed in the following examples. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.

Characterisation of Particle Properties

[0157] In the Examples below, the pore size, pore volume and specific surface area of polymeric mesoporous particles were analysed by gas adsorption porosimetry using pore size analyser Quantachrome Nova 4200e. Each sample was degassed under vacuum at 100° C. for 24 h before obtaining nitrogen adsorption-desorption measurements.

[0158] Morphology of mesoporous particles was examined by scanning electron microscopy (SEM) in JEOL JSM-7800F operating at 1 kV under a high vacuum. The samples were not gold-coated to retain sample integrity, i.e. original surface features. Approximately 1 mg of each sample was placed onto a double-sided adhesive strip on a sample holder.

[0159] Particle size of samples was determined by laser diffraction using particle size analyser Sympatec HELOS/BR and dry disperser RODOS with feeder VIBRI. The measuring range was 0-195 μm. Approximately 0.2 g of each sample was placed in the feeder tray. The time of each measurement was 10 s with powder dispensing pressure of 300 kPa. The results were obtained as volume mean diameter (VMD; D[4,3]) and given as the average of three analyses for each sample.

[0160] To assess the level of drug loading of the particles, a known amount of drug-loaded mesoporous particles were dissolved in 25 ml of acetone and diluted with a corresponding dissolution medium to 500 ml, then sonicated for 30 min.

[0161] The concentrations of dissolved drug were then determined using HPLC in a C18 column (15 cm×4.6 mm, 5 μm) and UV detector at 362 nm in an Agilent 1200 HPLC system.

Example 1—Preparation of Cellulosic Mesoporous Particles

[0162] 4 g of cellulose acetate butyrate (CAB) or cellulose acetate (CA), or ethyl cellulose (EC) were dissolved in 200 mL of either the acetone:water or ethyl acete:isopropanol mixtures prepared at a volume ratio of 90:10. The resulting polymer solutions were then spray dried with a two-fluid nozzle. A mini spray dryer Buchi B-290 in closed mode with nitrogen in the Inert Loop Buchi B-295 (Flawil, Switzerland) was used with a feed rate of 5 mL/min, nitrogen flow rate of 600 L/h, atomization pressure of 200 KPa, and a drying gas flow rate of 30 m.sup.3/h. The spray drying process was operated with an inlet temperature of 100° C. All materials and solvent were pharmaceutical grade.

[0163] Table 1 below shows the results of measurements taken on the particulate material produced in the spray drying.

TABLE-US-00001 TABLE 1 Average Surface pore Pore Particle area diameter volume size Polymer Sample # Solvent mixture (cm.sup.2/g) (nm) (cm.sup.3/g) (μm) Mesoporous 1 Acetone:water 12.8 16.3 0.05 48.8 ethyl cellulose (EC) Mesoporous 2 Acetone:water 32.6 24.9 0.18 22.5 cellulose acetate butyrate (CAB) Mesoporous 3 Acetone:water 15.7 24.8 0.09 32.6 cellulose acetate (CA) Mesoporous 4 Ethyl  6.6 15.1 0.02 19.3 cellulose acetate:isopropanol acetate butyrate (CAB)

[0164] FIG. 1 shows SEM images of the particles of Sample 2. FIG. 1(a) is a cross-section of a broken particle showing the porous internal structure at a magnification of ×5000. FIG. 1(b) shows the same particle cross-section at a magnification of ×30,000, which shows the mesoporous internal structure in greater detail.

[0165] FIG. 2 shows SEM images of the particles of Sample 2. FIG. 2(a) is the external surface of a particle showing the porous surface structure at a magnification of ×5000. FIG. 2(b) shows the same particle surface at a magnification of ×33,000, which shows the mesoporous surface structure in greater detail.

Example 2—Preparation of CAB Polymeric Mesoporous Particles

[0166] Polymeric mesoporous particles were manufactured from various types of CAB having a butyryl content ranging from about 15% to about 60%, an acetyl content ranging from about 1% to about 30%, and a hydroxyl content ranging from about 0.5% to about 5% (ex Eastman Chemical). Solvent mixtures of acetone:water were prepared at volume ratios of 80:20, 85:15 and 90:10. 4 g of CAB were dissolved in 200 mL of solvent mixtures. Polymer solutions were then spray dried with a two-fluid nozzle. A mini spray dryer Buchi B-290 in closed mode with nitrogen in the Inert Loop Buchi B-295 (Flawil, Switzerland) was used with a feed rate of 5 mL/min, nitrogen flow rate of 600 L/h, atomization pressure of 200 kPa, and drying gas flow rate of 30 m.sup.3/h. The spray drying process was operated with inlet temperature in the range of 60-140° C. All materials and solvents were pharmaceutical grade.

[0167] Table 2 below shows details of the various samples produced:

TABLE-US-00002 TABLE 2 Average Inlet Solvent ratio Surface pore Pore temp. (v/v) area diameter volume Sample (° C.) (acetone:water) (cm.sup.2/g) (nm) (cm.sup.3/g) 5 60 80:20 45.6 ± 2.1 24.9 ± 0.6 0.29 ± 0.01 6 100 80:20 42.5 ± 0.6 22.6 ± 2.2 0.24 ± 0.04 7 140 80:20 42.8 ± 3.3 20.4 ± 0.7 0.22 ± 0.01 8 60 85:15 56.7 ± 6.9 20.8 ± 2.3 0.32 ± 0.03 9 100 85:15 44.3 ± 1.3 22.0 ± 1.3 0.25 ± 0.02 10 140 85:15 38.6 ± 5.9 23.9 ± 0.6 0.23 ± 0.03 11 60 90:10 42.5 ± 2.9 27.2 ± 0.1 0.29 ± 0.02 12 100 90:10 32.6 ± 1.0 24.1 ± 1.2 0.18 ± 0.01 13 140 90:10 19.0 ± 3.6 27.0 ± 1.3 0.13 ± 0.01

Example 3—Preparation of Felodipine-Loaded Mesoporous Particles

[0168] Mesoporous CAB particles of Sample 8 in Table 2 were added to a solution of Felodipine (FELO, complies with USP 36, purity >98%) in ethanol (10 mg/mL) to form a suspension at an initial drug load of 15% (w/w). The suspension was gently stirred for 12 h, then spray-dried at inlet temperature of 100° C. using a mini spray dryer Buchi B-290 and inert loop Buchi B-295 in closed mode with nitrogen flow rate of 600 L/min, feed rate of 5 mL/min, and drying gas flow rate of 30 m.sup.3/h. All materials and solvent were pharmaceutical grade.

Example 4—Preparation of Ibuprofen-Loaded Mesoporous Particles

[0169] Mesoporous CAB particles of Sample 8 in Table 2 were added to a solution of Ibuprofen (IBU, purity >98%) in ethanol (10 mg/mL) to form a suspension at an initial drug load of 20% (w/w). The suspension was gently stirred for 12 h, then spray-dried at inlet temperature of 80° C. using a mini spray dryer Buchi B-290 and inert loop Buchi B-295 under the same process parameters as Example 3. All materials and solvent were pharmaceutical grade.

Example 5—Preparation of Furosemide-Loaded Mesoporous Particles

[0170] Mesoporous CAB particles of Sample 8 in Table 2 were added to a solution of Furosemide (FURO, complies with USP 38, purity >99%) in ethanol (10 mg/mL) to form a suspension at an initial drug load of 21% (w/w). The suspension was gently stirred for 12 h, then spray-dried using the same apparatus and under the same process parameters as Example 3. All materials and solvent were pharmaceutical grade.

Example 6—Co-Spray Dried Felodipine-CAB Polymeric Particles for Extended Release

[0171] 4.0 g of CAB was mixed with 0.2 g, 0.6 g and 1.0 g of Felodipine to produce mixtures of polymer and drug with 5, 15 and 25% drug loading (w/w), respectively (i.e. drug loading in % w/w herein is calculated by dividing the mass of drug compound added to the solution by the mass of polymeric particles added to the solution, then multiplying by 100). These mixtures were then each dissolved in 200 mL of acetone:water at ratio of 85:15 (v/v) and co-spray dried using a mini spray dryer Buchi B-290 in closed mode with nitrogen in the Inert Loop Buchi B-295 (Flawil, Switzerland), inlet temperature of 100° C., nitrogen flow rate of 600 L/min, feed rate of 5 mL/min, and drying gas flow rate of 30 m.sup.3/h. All materials and solvent were pharmaceutical grade.

[0172] Table 3 below sets out the properties of the co-spray dried Felodipine-CAB porous particles (n=3; mean±standard deviation).

TABLE-US-00003 TABLE 3 Average Felodipine Surface pore Sample loading area diameter Pore volume # (% w/w) (cm.sup.2/g) (nm) (cm.sup.3/g) 14 5 46.3 ± 2.5 23.7 ± 0.6 0.28 ± 0.02 15 15 14.2 ± 3.4 17.2 ± 2.5 0.06 ± 0.01 16 25 10.4 ± 0.4 13.7 ± 1.4 0.04 ± 0.01

[0173] SEM images of the particles having different levels of drug loading are shown in FIG. 10.

Example 7—Thermal Analysis of Drug-Loaded Mesoporous Particles

[0174] Thermal properties of the drug-loaded mesoporous particles made in Examples 3-5 were characterised by DSC instrument TA Q 200. Samples were accurately weighed (approximately 3-5 mg) into Tzero aluminium pans and heated in the temperature range of 50-300° C. at a scanning rate of 10° C./min under nitrogen. TA universal analysis 2000 software (version 4.5) was employed to analyse the resulting DSC graphs.

[0175] FIGS. 3-5 show the DSC thermograms for each of Examples 3-5 respectively, alongside the thermograms for the raw materials.

[0176] FIG. 3 shows DSC curves for Felodipine raw material (solid line) and Felodipine-loaded mesoporous particles (dotted line). A strong endothermic phase transition occurs at 146.3° C. for the raw material, which demonstrates its crystalline nature. No corresponding phase transitions are evident for the Felodipine adsorbed onto the mesoporous particles, showing that it is in amorphous form, which explains the enhanced solubility described below.

[0177] FIG. 4 shows DSC curves for Ibuprofen raw material (solid line) and Ibuprofen-loaded mesoporous particles (dotted line). A strong endothermic phase transition occurs at 75.24° C. for the raw material, which demonstrates its crystalline nature. Only a very weak corresponding phase transition is evident for the Ibuprofen adsorbed onto the mesoporous particles, showing that the majority of the material is in amorphous form, which explains the enhanced solubility described below.

[0178] FIG. 5 shows DSC curves for Furosemide raw material (solid line) and Furosemide-loaded mesoporous particles (dotted line). Phase transitions occur at around 220° C. and 265° C. for the raw material, which demonstrates its crystalline nature. No corresponding phase transitions are evident for the Furosemide adsorbed onto the mesoporous particles, showing that it is in amorphous form, which explains the enhanced solubility described below.

Example 8—Dissolution Profiles of FELO-Loaded Mesoporous Particles

[0179] Dissolution testing was performed using USP I apparatus (rotating basket, 50 rpm) in an Erweka DT 126 dissolution tester. Samples of the material as prepared in Example 3 containing 20 mg of FELO were loaded into a HPMC hard-shell capsule and tested in 500 mL of USP pH 6.5 medium with 0.25% sodium lauryl sulfate (SLS) at 37° C. (adapted from USP 36 monograph with a reduction of SLS concentration from 1.0 to 0.25%). Samples were withdrawn during a 120-min period at the following timepoints: 15, 30, 60, 90, and 120 min. The concentrations of dissolved FELO were determined according to a HPLC method described in United States Pharmacopoeia (USP version 36) with mobile phase of USP pH 3 phosphate buffer:acetonitrile:methanol (30:45:25), C18 column (15 cm×4.6 mm, 5 μm), flow rate of 1 mL/min, injection volume of 40 μL, and UV detector at 362 nm in an Agilent 1200 HPLC system.

[0180] The results are shown in FIG. 6 for the FELO-loaded particles of Example 3 alongside the results for dissolution of the FELO raw material. As can be clearly seen from the plot, the dissolution of Felodipine is greatly enhanced by adsorbing the compound onto the mesoporous particulate material. After 120 mins the dissolution of Felodipine is 10× that seen after the same period for the raw material (i.e. the compound not adsorbed onto any carrier). Indeed, all of the Felodipine adsorbed onto the mesoporous particulate material is fully dissolved after 120 mins, compared with only around 10% of the raw material after the same time period.

Example 9—Dissolution Profiles of IBU-Loaded Mesoporous Particles

[0181] Dissolution testing of IBU-loaded mesoporous particles as prepared in Example 4 was performed by using USP I apparatus (rotating basket, 100 rpm) in an Erweka DT 126 dissolution tester. Samples containing 50 mg of IBU were loaded into a HPMC hard-shell capsule and tested in 900 mL of pH 3.0 medium with 0.25% SLS at 37° C. The pH 3 medium was prepared by dissolving 2 g of sodium chloride and 2.5 g of SLS in 400 mL of deionised water, then adding 0.1 mL of hydrochloric acid 37%, and diluting with deionised water to 1000.0 mL. The concentrations of dissolved IBU were determined using a HPLC method with mobile phase of phosphate buffer pH 3: acetonitrile (60:40), C18 column (15 cm×4.6 mm, 5 μm), flow rate of 2 mL/min, injection volume of 20 μL, and UV detector at 254 nm in an Agilent 1200 HPLC system.

[0182] The results are shown in FIG. 7 for the IBU-loaded particles of Example 4 alongside the results for dissolution of the IBU raw material. After 120 mins, all of the Ibuprofen which was adsorbed onto the mesoporous particulate material was dissolved, compared with only 73.4% for the Ibuprofen raw material. Furthermore, a high dissolution rate (97.4%) is achieved for the adsorbed Ibuprofen after a relatively short period of time (60 mins).

Example 10—Dissolution Profiles of FURO-Loaded Mesoporous Particles

[0183] Dissolution testing of FURO-loaded mesoporous particles as prepared in Example 5 was performed by using USP I apparatus (rotating basket, 100 rpm) in an Erweka DT 126 dissolution tester. Samples containing 40 mg FURO were loaded into a HPMC hard-shell capsule and tested in 900 mL of HCl—NaCl pH 3.0 medium with 0.25% SLS at 37° C. The concentrations of dissolved FURO were determined using a HPLC method with mobile phase of phosphate buffer pH 3: acetonitrile (60:40), C18 column (15 cm×4.6 mm, 5 μm), column temperature of 35° C., flow rate of 1 mL/min, injection volume of 10 μL, and UV detector at 234 nm in an Agilent 1200 HPLC system.

[0184] The results are shown in FIG. 8 for the FURO-loaded particles of Example 5 alongside the results for dissolution of the FURO raw material. A significantly higher dissolution rate (87.6%) is achieved for the Furosemide when adsorbed onto the mesoporous particulate material of the invention, compared with only 65.3% for the Furosemide raw material, after 120 mins.

Example 11—Dissolution Profiles of Co-Spray Dried Felodipine-CAB Polymeric Particles

[0185] Dissolution testing of the FELO-loaded mesoporous particles as prepared in Example 6 by the co-spray drying of polymer and Felodipine was performed by using USP I apparatus (rotating basket, 50 rpm) in an Erweka DT 126 dissolution tester. Samples of the material as prepared in Example 6 containing 20 mg of FELO were loaded into a HPMC hard-shell capsule and tested in 500 mL of USP pH 6.5 medium with 0.25% sodium lauryl sulfate (SLS) at 37° C. (adapted from USP 36 monograph with a reduction of SLS concentration from 1.0 to 0.25%). Samples were withdrawn during a 10-hour period at the following timepoints: 0.5, 1, 2, 6, and 10 hours. The concentrations of dissolved FELO were determined according to a HPLC method described in United States Pharmacopoeia (USP version 36) with mobile phase of USP pH 3 phosphate buffer:acetonitrile:methanol (30:45:25), C18 column (15 cm×4.6 mm, 5 μm), flow rate of 1 mL/min, injection volume of 40 μL, and UV detector at 362 nm in an Agilent 1200 HPLC system.

[0186] The results are shown in FIG. 9. From the dissolution plots it is evident that both Felodipine raw material and spray-dried raw Felodipine (dotted lines) exhibit poor dissolution, as also evidenced in FIG. 6. By contrast, mesoporous polymeric particles produced by co-spray drying solutions of Felodipine and CAB show much higher dissolution rates after a given period of time, across a range of drug loadings (5%, 15% and 25%). Thus it is evident that the solubility of the compound is enhanced by its loading onto the mesoporous particles.

[0187] Additionally, a comparison of FIG. 9 with FIG. 6 reveals that sustained-release properties are imparted on the Felodipine-loaded particles of Example 6 (FIG. 9) relative to those of Example 3 (FIG. 6). When Felodipine is co-spray dried with the polymer, the drug is released more slowly from the particles over an extended period. More specifically, for the 5%, 15% and 25% loaded particles, after 2 hours around 44%, 64% and 66% of the loaded Felodipine had dissolved, respectively, rising to 59%, 81% and 87% respectively after 10 hours. This compares with around 100% dissolution after 2 hours for the post-loaded Felodipine-containing particles of Example 3 (FIG. 6).

Example 12—Confocal Laser Scanning Microscopy (CLSM) of Mesoporous Particles Loaded with Fluorescein

[0188] CLSM was performed on some of the mesoporous particles loaded with a model poorly-soluble compound, fluorescein, to demonstrate the distribution of the model compound.

[0189] The mesoporous CAB particles of Sample 8 (Table 2) were post-loaded with fluorescein by following a procedure equivalent to that of Example 3, but substituting fluorescein for felodipine. Mesoporous CAB particles of Sample 8 in Table 2 were added to a solution of Fluorescein (Sigma-Aldrich, analytical reagent) in ethanol (2 mg/mL) to form a suspension at an initial drug load of 20% (w/w). The suspension was gently stirred for 12 h, then spray-dried at inlet temperature of 100° C. using a mini spray dryer Buchi B-290 and inert loop Buchi B-295 in closed mode with nitrogen flow rate of 600 L/min, feed rate of 5 mL/min, and drying gas flow rate of 30 m.sup.3/h. These particles post-loaded with fluorescein were denoted Sample 17.

[0190] Fluorescein-loaded mesoporous particles were also prepared by co-spray drying. 4.0 g of CAB was mixed with 0.8 g of fluorescein. These mixtures were then each dissolved in 200 mL of acetone:water at ratio of 85:15 (v/v) and co-spray dried using a mini spray dryer Buchi B-290 in closed mode with nitrogen in the Inert Loop Buchi B-295 (Flawil, Switzerland), inlet temperature of 100° C., nitrogen flow rate of 600 L/min, feed rate of 5 mL/min, and drying gas flow rate of 30 m.sup.3/h. The spray-dried particles were denoted Sample 18.

[0191] The distribution of fluorescein in Samples 17 and 18 was qualitatively evaluated by using Leica confocal microscope TCS SP5 II (Wetzlar, Germany) with 10× and 20× dry objective lens. Excitation and emission wavelength for fluorescein samples were 488 and 525 nm, respectively. Confocal images of fluorescein samples were obtained at 515-535 nm. Scanning depth was 2 μm for both samples with scanning speed was 200 Hz.

[0192] Images obtained from the CLSM are shown in FIG. 11. FIG. 11(a) shows a particle of Sample 17 and FIG. 11(b) shows a particle of Sample 18. The CLSM image of Sample 18 shows that co-spray drying with the poorly soluble compound leads to a distribution of the compound both entrapped within the particles and adsorbed at the particle surface. By contrast, post-loading of particles leads to deposition of the poorly soluble compounds only within the surface pores and the total drug loading is lower.

Example 13—Determination of Pore Size Distribution

[0193] The pore volume and pore size distribution of polymeric mesoporous particles of Sample 8 were analysed by gas adsorption porosimetry using pore size analyser Quantachrome Nova 4200e under the BJH theory according to the method set out in ISO 15901-2 of 2006. Each sample was degassed under vacuum at 100° C. for 24 h before obtaining nitrogen adsorption-desorption measurements.

[0194] The results are set out in Table 4 below:

TABLE-US-00004 TABLE 4 dV/dD Cumulative Pore Cumulative Pore Pore Diameter, [(cm.sup.3/nm/g) × Volume, V.sub.cum Volume Fraction D (nm) 10.sup.−3] (cm.sup.3/g) (%) 0.0000 0.00 0.0000 0.0% 1.1960 0.961 0.0002 0.1% 1.3222 5.08 0.0005 0.2% 1.4339 6.55 0.0016 0.5% 1.5494 7.79 0.0021 0.7% 1.7745 6.65 0.0046 1.6% 2.0238 6.75 0.0054 1.9% 2.2210 6.06 0.0071 2.4% 2.4822 4.79 0.0083 2.8% 2.7720 4.39 0.0097 3.3% 3.0842 3.15 0.0106 3.7% 3.4220 3.01 0.0118 4.1% 3.8656 3.39 0.0135 4.6% 4.3895 2.01 0.0146 5.0% 4.9998 2.33 0.0162 5.6% 5.7476 1.90 0.0177 6.1% 6.5752 2.45 0.0198 6.8% 8.0070 2.49 0.0248 8.5% 9.8003 3.13 0.0297 10.2% 11.2361 3.29 0.0340 11.7% 12.5497 4.05 0.0393 13.5% 14.3762 4.49 0.0499 17.1% 16.8172 5.60 0.0641 22.0% 19.7873 5.18 0.0817 28.0% 22.8421 5.08 0.0954 32.8% 25.5916 5.52 0.1108 38.0% 29.0798 5.57 0.1342 46.0% 33.9831 4.14 0.1574 54.0% 40.2092 4.76 0.1900 65.2% 50.0931 3.08 0.2298 78.9% 65.6605 2.18 0.2694 92.5% 91.9799 0.636 0.2913 100.0%

[0195] The cumulative distribution of pore volume is plotted in FIG. 12a. The pore size distribution, presented graphically as a plot of dV/dD versus pore size, is shown in FIG. 12b.

[0196] The features disclosed in the foregoing description, or in the following claims, or in the accompanying drawings, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for obtaining the disclosed results, as appropriate, may, separately, or in any combination of such features, be utilised for realising the invention in diverse forms thereof.

[0197] While the invention has been described in conjunction with the exemplary embodiments described above, many equivalent modifications and variations will be apparent to those skilled in the art when given this disclosure. Accordingly, the exemplary embodiments of the invention set forth above are considered to be illustrative and not limiting. Various changes to the described embodiments may be made without departing from the spirit and scope of the invention.

[0198] For the avoidance of any doubt, any theoretical explanations provided herein are provided for the purposes of improving the understanding of a reader. The inventors do not wish to be bound by any of these theoretical explanations.

[0199] Any section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0200] Throughout this specification, including the claims which follow, unless the context requires otherwise, the words “have”, “comprise”, and “include”, and variations such as “having”, “comprises”, “comprising”, and “including” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0201] It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment. The term “about” in relation to a numerical value is optional and means, for example, +/−10%.

[0202] The words “preferred” and “preferably” are used herein refer to embodiments of the invention that may provide certain benefits under some circumstances. It is to be appreciated, however, that other embodiments may also be preferred under the same or different circumstances. The recitation of one or more preferred embodiments therefore does not mean or imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the disclosure, or from the scope of the claims.