POROUS SILICA MATERIAL FOR USE AS A PHARMACEUTICAL OR DIETARY ACTIVE INGREDIENT

Abstract

A porous silica material for use as a pharmaceutical or dietary active ingredient having pores in the mesoscale range (2-50 nm), wherein the average pore size of the pores in the mesoscale range is in the range of 2 to 25 nm, and the pore size distribution (PSD) in the mesoscale range is such that at least 80% of the pores fall within the range of 2 to 25 nm.

Claims

1-18. (canceled)

19. A method of the prophylaxis or treatment of: metabolic syndrome, type 2 diabetes, insulin resistance, or hyperglycemia in a human or animal in need thereof, comprising administering to the human or animal an effective amount of a porous silica material having pores in the mesoscale range of 2-50 nm, wherein the average pore size of the pores in the mesoscale range is in the range of 2 to 25 nm, and the pore size distribution (PSD) in the mesoscale range is such that at least 80% of the pores fall within the range of 2 to 25 nm.

20. A method of lowering glucose levels in the blood in a human or animal in need thereof, comprising administering to the human or animal an effective amount of a porous silica material having pores in the mesoscale range of 2-50 nm, wherein the average pore size of the pores in the mesoscale range is in the range of 2 to 25 nm, and the pore size distribution (PSD) in the mesoscale range is such that at least 80% of the pores fall within the range of 2 to 25 nm.

21. The method of claim 19, wherein the porous silica material is the sole active ingredient being administered to the human or animal for the prophylaxis or treatment of: metabolic syndrome, type 2 diabetes, insulin resistance or hyperglycemia.

22. The method of claim 19, wherein the prophylaxis or treatment of: metabolic syndrome, type 2 diabetes, insulin resistance, or hyperglycemia in a human or animal is achieved by reduction of adipose tissue in the human or animal.

23. The method of claim 19, wherein the porous silica material is orally administered.

24. The method of claim 19, wherein the human or animal is obese.

25. The method of claim 19, wherein the average pore size is in the range of 7 to 15 nm.

26. The method of claim 19, wherein the average pore size is in the range of 10 to 12 nm.

27. The method of claim 19, wherein the BET (Brunauer-Emmett-Teller theory) surface area is between 300 and 1300 m.sup.2/g

28. The method of claim 27, wherein the BET surface area is between 500 and 900 m.sup.2/g.

29. The method of claim 19, wherein the pore volume measured by nitrogen adsorption is in the range of 0.3 to 1.7 cm.sup.3/g.

30. The method of claim 19, wherein the porous silica material additionally has a hierarchical porous structure containing both pores in the range of 2 to 50 nm and pores larger than 50 nm.

31. The method of claim 19, wherein the porous silica material has a minimum particle size distribution of 300 nm.

32. The method of claim 20, wherein, wherein the porous silica material is the sole active ingredient being administered to the human or animal for lowering glucose levels in the blood.

33. The method of claim 20, wherein the lowering glucose levels in the blood in a human or animal is achieved by reduction of adipose tissue in the human or animal.

34. The method of claim 20, wherein the porous silica material is orally administered.

35. The method of claim 20, wherein the human or animal is obese.

36. The method of claim 20, wherein the average pore size is in the range of 7 to 15 nm.

37. The method of claim 20, wherein the average pore size is in the range of 10 to 12 nm.

38. The method of claim 20, wherein the BET (Brunauer-Emmett-Teller theory) surface area is between 300 and 1300 m.sup.2/g.

39. The method of claim 38, wherein the BET surface area is between 500 and 900 m.sup.2/g.

40. The method of claim 20, wherein the pore volume measured by nitrogen adsorption is in the range of 0.3 to 1.7 cm.sup.3/g.

41. The method of claim 20, wherein the porous silica material additionally has a hierarchical porous structure containing both pores in the range of 2 to 50 nm and pores larger than 50 nm.

42. The method of claim 20, wherein the porous silica material has a minimum particle size distribution of 300 nm.

Description

TABLES AND FIGURES

[0068] The present invention is not limited to the tables and figures listed below, but these are included in order to exemplify the present invention.

[0069] Table 1. Example of a porous silica composition that may be used in the present invention as an active ingredient or as part of a formulation. The method of characterization is also included as defined by the Pharmacopeia.

[0070] Table 2. Examples of textural properties of porous silica materials that may be suitable for the present invention.

[0071] FIGS. 1, 2 and 3, Example 2A. The example is included to show the effect of a typical Silica 2 material (Table 2) on lowering of body fat composition and body weight.

[0072] FIG. 1. Scanning electron microscopy image (FIG. 1A) and pore size distribution (FIG. 1B) of a mesoporous silica material included in the present invention.

[0073] FIG. 2. Development of female mice body weight, body fat composition and lean during the study described in Example 2A. The figure shows a significant effect of the silica particles with an average pore size of about 11 nm (FIG. 1) on lowering body fat composition and body weight.

[0074] FIG. 3. Development of male mice body weight, body fat composition and lean during the study described in Example 2A. The figure shows a significant effect of the silica particles with an average pore size of about 11 nm (FIG. 1) on lowering body fat composition and body weight.

[0075] FIGS. 4, 5 and 6, Example 2B. The example is included to show that a material with structural properties typical for a Silica 1 (Table 2) material has a weaker effect than a typical Silica 2 (Table 2) material on lowering body fat composition and body weight.

[0076] FIG. 4. Scanning electron microscopy image (FIG. 4A) and pore size distribution (FIG. 4B) of a mesoporous silica material included in the present invention.

[0077] FIG. 5. Development of female mice body weight, body fat composition and lean during the 20 weeks study described in Example 2B. The figure shows the effect of the silica particles with an average pore size of about 3 nm (FIG. 4) on lowering body fat composition and body weight.

[0078] FIG. 6. Development of male mice body weight, body fat composition and lean during the study described in Example 2B. The figure shows the effect of the silica particles with an average pore size of about 3 nm (FIG. 4) on lowering body fat composition and body weight.

[0079] FIGS. 7 and 8, Example 2C. The example is included to show that a material with structural properties typical for a Silica 5-type (Table 2) material has a weaker effect than a typical Silica 2 (Table 2) material on lowering body fat composition and body weight.

[0080] FIG. 7. Scanning electron microscopy image (FIG. 7A) and pore size distribution (FIG. 7B) of a mesoporous silica material included in the present invention.

[0081] FIG. 8. Development of male mice body weight, body fat composition and lean during the study described in Example 2B. The figure shows the effect of the silica particles with an average pore size of about 3 nm (FIG. 4) on lowering body fat composition and body weight.

[0082] FIG. 9. Food intake and silica concentration in blood (measured by inductively coupled plasma technique) of mice included in Example 2A and 2B.

[0083] FIG. 10. Lipid (Cholesterol, HDL and tryglicerides) and glucose levels in blood from female mice receiving Particle 2 material (representative of Silica 2 as described in Table 2) in the diet, compared to control mice not receiving mesoporous silica in the diet.

[0084] FIG. 11. Lipid (Cholesterol, HDL and tryglicerides) and glucose levels in blood from female mice receiving Particle 1 material (representative of Silica 1 as described in Table 2) in the diet, compared to control mice not receiving mesoporous silica in the diet.

[0085] FIG. 12. Lipid (Cholesterol, HDL and tryglicerides) levels in blood from male mice receiving Particle 1, Particle 2 and Particle 3 in the diet (representative of respectively Silica 1, 2 and 3 as described in Table 2), compared to control mice not receiving mesoporous silica in the diet.

[0086] FIG. 13. Example of a Bimodal Pore Mesoporous material with macropores (which is representative for Silica 5 described in Table 2).

EXAMPLES

Example 1: Examples of Textural Properties of Porous Silica Materials that May be Suitable for the Present Invention

[0087] The textural properties of materials that may be suitable for the present invention were determined and are included in Table 2.

[0088] The pore structure.

[0089] The pore structure was determined based on diffraction patterns recorded utilizing low-angle X-ray powder diffraction using CuKa radiation (=1.5418 at 45 kV and 40 mA) and/or transmission electron microscopy (TEM) with a TEM microscope operating at 300 kV (Cs 0.6 mm, resolution 1.7).

[0090] BET (Brunauer-Emmett-Teller) Surface Area

[0091] The BET surface area, pore volume and pore size distribution (PSD) is determined by nitrogen adsorption technique. Nitrogen adsorption/desorption isotherms were measured at liquid nitrogen temperature (196 C.) using a Micromeritics ASAP2020 volumetric adsorption analyzer for mesoporosity determination. The material samples were outgassed before the measurement. The BET equation was used to calculate the surface area from adsorption data obtained in the relative pressure (p/p) range of 0.05 and 0.3. The pore volume was calculated from the amount of gas adsorbed at p/p=0.91. The mesopores pore size distribution curves were derived using the density functional theory (DFT) assuming a cylindrical pore model; the pore size and PSD range of the mesopores were obtained from those curves according to the methodology described in Gas Adsorption Equilibria: Experimental Methods and Adsorptive Isotherms by Jrgen U. Keller, Springer, 2006.

[0092] The macropores size (defined as pores larger than 50 nm) was determined using mercury porosimetry technique and/or by scanning electron microscopy (SEM) by measuring the pore width on SEM images recorded with an SEM microscope with no gold coating

TABLE-US-00002 TABLE 2 Silica 1 Silica 2 Silica 3 Silica 4 Silica 5 Pore structure 2-d-cylindrical 2-d-cylindrical hierarchical hierarchical Worm-like hexagonal hexagonal BET surface 653 709 300 550 685 area (m.sup.2/g) Pore size by 2 nm 11 nm 12 nm 12 nm 30 nm DFT mesopores, and mesopores, and 2 m*\ 1.5 m macropores macropores Pore volume 0.32 1.17 1 0.9 1.6 (cm.sup.3/g) PSD range 2-3.5 nm 8-13 nm 10-15 nm and, 10-15 nm and, 5-33 nm 1-3 m 1-3 m

Example 2A: A Large Pore Mesoporous Silica Material (Particle 2 which is Representative for Silica 2 Described in Table 2)

[0093] Example of the effect of oral administration of mesoporous silica particles of about 10 nm pore size (Particle 2) on body weight, body fat composition and lean mass as compared to No silica particles (Control) in obese mice.

[0094] FIG. 1A shows a scanning electron microscopy (SEM) image of the material (named Particle 2) utilized in the study, which is representative for Silica 2 described in Table 2. The material's pore size distribution measured by nitrogen adsorption experiments is shown in FIG. 1B indicating a sharp pore size distribution in the range of about 8 to 12 nm.

[0095] Particle 2 material is utilized to exemplify the effect of mesoporous silicas on body weight and body fat composition (adipose tissue) when administered orally in a well-known obesity murine model.

[0096] From week 0 to 7.5 the animals were high fat fed in order to make them obese; from week 7.5 to 12 silica particles (Particle 2) were added into the high fat diet; from week 12 to 20 the animals received standard diet ad libitum with two extra high fat meals per week containing silica particles.

[0097] FIGS. 2 A, C and E show the development of body weight, body fat composition and lean respectively during the 20-week long study for female animals.

[0098] FIGS. 2 B, D and F shows only the data from the last eight weeks of the experiment. The stars indicate statistically significant differences between mice receiving particles in the diet compared to control mice not receiving particles in the diet.

[0099] FIG. 3 shows the same as FIG. 2 for a study with the same experimental set-up, but performed on males.

[0100] Both body fat composition and body weight decrease is observed in the animal groups receiving mesoporous silica in the diet, as compared to the control group not receiving porous silica, in both female and male mice (FIGS. 2 and 3 respectively).

[0101] A mesoporous material with pore sizes in the order above 10 nm, was utilized to exemplify the positive weight and cholesterol lowering properties of a porous silica. The effect of silica mesoporous particles with large pores, above 10 nm intake on blood lipid levels in obese black 6 mice (C57BL/6J) with elevated lipid/cholesterol blood levels and healthy animals is analyzed. Particles are embedded in the food pellets and given to the animals during a period of time of about 12 weeks. Blood levels of cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides are analyzed during the 12 weeks of particle intake. Levels of silica in blood are measured at the end of the experiment.

Example 2B: A Small Pore Mesoporous Silica Material (Particle 1 which is Representative for Silica 1 Described in Table 2)

[0102] Another study was performed as described in Example 2A, but utilizing a mesoporous silica material with a pore width of about 3 nm (Particle 1) instead of the material named Particle 2. FIG. 4A shows the SEM image of Particle 1 which is representative for Silica 1 described in Table 2. The material's pore size distribution measured by nitrogen adsorption experiments is shown in FIG. 4B, indicating a narrow distribution in the range of about 2.5 to 3.7 nm. FIGS. 5 and 6 show the development of body weight, body fat composition and lean in this study. FIGS. 5 and 6 are equivalent to FIGS. 2 and 3 as described in Example 2A, respectively.

[0103] No differences in body fat composition or body weight are observed in the female obese mice receiving silica particles in the diet compared to the control (FIG. 5).

[0104] Both body fat composition and body weight show a tendency to decrease in the group receiving porous silica in the diet compared to the control group not receiving porous silica in the experiment utilizing male mice (FIG. 6).

[0105] A mesoporous material with pore sizes in the order above 3 nm was utilized to exemplify the positive weight and cholesterol lowering properties of a porous silica. The effect of silica mesoporous particles with large pores, above 10 nm intake on blood lipid levels in obese black 6 mice (C57BL/6J) with elevated lipid/cholesterol blood levels and healthy animals is analyzed. Particles are embedded in the food pellets and given to the animals during a period of time of about 12 weeks. Blood levels of cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides are analyzed during the 12 weeks of particle intake. Levels of silica in blood are measured at the end of the experiment. Example 2C: A larger pore mesoporous silica material (Particle 3 which is representative for Silica 5 described in Table 2) Another study was performed as described in Example 2A, but utilizing a mesoporous silica material with a pore width of about 25 nm (Particle 3) instead of the material named Particle 2. FIG. 7A shows the SEM image of the material utilized in this study, Particle 3. The material's pore size distribution measured by nitrogen adsorption is shown in FIG. 7B indicating the distribution to be in the range of about 10 to 35 nm.

[0106] Both body fat composition and body weight show a tendency to decrease in the group receiving porous silica in the diet compared to the control group not receiving porous silica (FIG. 8).

Example 3: Food Intake and Adsorbed Silica for Particle 1 and Particle 2

[0107] The food intake of mice included in Example 2A and 2B was measured. The daily food intake is the same for mice receiving particles in the diet as in the control animals not receiving silica particles in the diet (FIGS. 9 A and C for Particle 1 and Particle 2 respectively).

[0108] The silica concentration in blood was measured by inductively coupled plasma technique at the end of the studies (after about 12 weeks of silica particle administration in the diet). No differences in blood silica content are observed between mice receiving porous silica in the diet and control mice not receiving porous silica in the diet after about 12 weeks of oral administration (FIGS. 9 B and D for Particle 1 and Particle 2 respectively).

Example 4: Cholesterol, HDL, P Glucose and Triglyceride Levels in Blood for Particle 1, Particle 2 and Particle 3

[0109] The Cholesterol, HDL, Glucose and Triglyceride levels in blood were analyzed at the end of the studies described in examples 2A, 2B and 2C.

[0110] No differences in blood lipid or glucose levels are observed between female mice receiving Particle 2 or Particle 1 in the diet, compared to control mice not receiving mesoporous silica in the diet after about 12 weeks of oral administration (respectively FIG. 10 and FIG. 11). Similar results are obtained for male mice, where no differences in blood lipid levels are observed between mice receiving Particle 1, Particle 2 or Particle 3 in the diet, compared to the control mice not receiving mesoporous silica in the diet after about 12 weeks of oral administration (FIG. 12).

Example 5: Example of a Bimodal Pore Mesoporous Material with Macropores (which is Representative for Silica 5 Described in Table 2)

[0111] FIG. 13A shows an SEM image of a material representative for Silica 5 as described in Table 2.

[0112] FIG. 13B shows a transmission electron microscopy (TEM) image of the same material. A more detailed description of the material is summarized in the table in FIG. 13 C.