Materials and Methods Relating to Stabilised Polymeric Silicate Compositions

Abstract

Stabilised and aquated polymeric silicate compositions are described in which the compositions are poorly condensed compositions in which the silicates are resorbable and are capable of undergoing efficient dissolution to provide bioavailable soluble silicic acid. In particular, stabilised and aquated polymeric silicates are described that are capable of intravenous delivery, useful in the treatment of cancer or systemic infection, or for topical administration, e.g. in the form of a solid or semi-solid ointment useful in the treatment of wounds or the prevention of bacterial infection.

1 . A process for producing a stabilised polymeric silicate composition comprising polymeric silicic acid and nanosilicate particles having mean diameters of 20 nm or less, the process comprising the steps of:
 (a) providing an aqueous solution of a soluble silicate at a pH greater than or equal to 9.5;   (b) reducing the pH of the silicate solution to cause polymerisation of the silicate to form polymeric silicic acid and nanosilicate particles; and   (c) simultaneously or sequentially with steps (a) and/or (b) adding to the silicate solution a stabilising agent that comprises a polyalkylene glycol and/or a sugar thereby producing a stabilised silicate composition in which the stabilising agent inhibits formation of condensed silicates;   wherein the stabilised polymeric silicate composition is aquated and wherein the process does not involve drying the composition or heating it above 100° C.   
     
     
         2 . The process of  claim 1 , wherein the stabilised polymeric silicate composition comprises at least 5% water. 
     
     
         3 . The process of  claim 1  or  claim 2 , wherein the process does not involve drying the composition or heating it above 70° C. 
     
     
         4 . The process of any one of  claims 1  to  3 , wherein the stabilised polymeric silicate composition is resorbable as determined in an in vitro dissolution assay in which at least 25%, and optionally at least 35%, of the composition dissolves in 24 hours in HEPES buffer. 
     
     
         5 . The process of  claim 4 , wherein the in vitro dissolution assay is a molybdic acid assay for determining the soluble silicic acid fraction. 
     
     
         6 . The process of any one of the preceding claims, which comprises the further step after steps (b) and (c) of raising the pH of the composition to a final pH by adding a base, and optionally waiting for average particle size grow to the desired size and then optionally adding further stabiliser and or dropping the pH. 
     
     
         7 . The process of  claim 6 , wherein the final pH is in the range pH 3.0 to 9.0. 
     
     
         8 . The process of  claim 6  or  claim 7 , wherein the base is sodium hydroxide or sodium carbonate. 
     
     
         9 . The process of any one of the preceding claims, further comprising formulating the stabilised polymeric silicate composition as a cream or ointment for topical administration to a subject. 
     
     
         10 . The process of  claim 8  or  claim 9 , wherein sodium hydroxide is added to adjust the pH of the composition prior to formulating the stabilised polymeric silicate composition as a cream or ointment by mixing with polyalkylene glycol. 
     
     
         11 . The process of  claim 9  or  claim 10 , wherein formulating the stabilised polymeric silicate composition as a cream or ointment comprises mixing it with a solid or semi-solid matrix. 
     
     
         12 . The process of  claim 11 , wherein the solid or semi-solid matrix comprises one or more polyalkylene glycol polymers or one or more hydroxyethyl cellulose gels. 
     
     
         13 . The process of any one of  claims 1  to  8 , further comprising formulating the stabilised polymeric silicate composition so that it is formulated for oral administration or parenteral administration of silicic acid to a subject. 
     
     
         14 . The process of any one of the preceding claims, wherein in step (a) the aqueous alkaline silicate solution is a Group 1 or Group 2 metal silicate such as sodium silicate or potassium silicate. 
     
     
         15 . The process of any one of the preceding claims, wherein in step (b) the pH is reduced to less than or equal to pH 4.0 by adding an acid. 
     
     
         16 . The process of any one of the preceding claims, wherein in step (c) the pH is reduced to less than or equal to pH 3.0. 
     
     
         17 . The process of any one of the preceding claims, wherein the concentration of the silicate solution is between 5 mM and 3.0 M. 
     
     
         18 . The process of any one of the preceding claims, wherein the concentration of the silicate solution is between 0.1 M and 1.5 M. 
     
     
         19 . The process of any one of the preceding claims, wherein stabilised polymeric silicate composition is stable for 1 month or more, 2 months or more, 3 months or more, 6 months or more. 
     
     
         20 . The process of any one of the preceding claims, wherein the nanosilicate particles have a mean diameter of 10 nm or less. 
     
     
         21 . The process of any one of the preceding claims, wherein the nanosilicate particles have a mean diameter of 5 nm or less. 
     
     
         22 . The process of any one of the preceding claims, wherein the concentration of the silicate solution is more than 30 mM. 
     
     
         23 . The process of any one of the preceding claims, wherein in step(a) the pH of the alkaline silicate solution is above pH 11.5. 
     
     
         24 . The process of any one of the preceding claims, wherein two, three, four or five stabilising agents are added in step (c). 
     
     
         25 . The process of any one of the preceding claims, wherein the stabilising agent is sucrose or polyethylene glycol (PEG). 
     
     
         26 . The process of any one of the preceding claims, wherein the stabilising agent is not lactose or mannitol. 
     
     
         27 . The process of any one of the preceding claims, wherein in step (b) the pH of the composition is lowered to a pH less than or equal to pH 1.5. 
     
     
         28 . The process of any one of the preceding claims, further comprising adding a metal cation to the composition. 
     
     
         29 . The process of  claim 28 , wherein the metal cation is Cu 2+ , Ag + , Ca 2+ m Mg 2+ , Fe 3+  and/or Zn 2+ . 
     
     
         30 . The process of  claims 28  or  claim 29 , wherein the metal cation inhibit dissolution of the composition. 
     
     
         31 . The process of  claims 28  or  claim 29 , wherein the metal cation provides the composition with antibacterial properties. 
     
     
         32 . The process of any one of  claims 29  to  31 , wherein the metal cation is added to provide a Si to metal ratio of between 100:1 and 10:1, and optionally to provide a Si to metal ratio of 20:1. 
     
     
         33 . The process of any one of the preceding claims, wherein in step (b) the pH is lowered over a period of less than 60 seconds, less than 30 seconds, less that 10 seconds, or less than 5 seconds 
     
     
         34 . A stabilised polymeric silicate composition comprising polymeric silicic acid and nanosilicate particles having mean diameters of 20 nm or less as obtainable by the process of any one of  claims 1  to  33 . 
     
     
         35 . A stabilised polymeric silicate composition comprising polymeric silicic acid and nanosilicate particles having mean diameters of 20 nm or less as obtainable by the process of any one of  claims 1  to  33  for use in a method of treatment. 
     
     
         36 . The stabilised polymeric silicate composition for use in a method of treatment of  claim 35 , wherein the composition is formulated for parenteral administration. 
     
     
         37 . The stabilised polymeric silicate composition for use in a method of treatment of  claim 36 , wherein the parenteral administration is intravenous (IV), intraperitoneal (IP) or intramuscular (IM) administration. 
     
     
         38 . The stabilised polymeric silicate composition for use in a method of treatment of  claim 36  or  claim 37 , wherein the parenteral administration is intravenous (IV) administration via an intravenous drip. 
     
     
         39 . The stabilised polymeric silicate composition for use in a method of treatment of any one of  claims 36  to  38 , wherein the stabilising agent is sucrose and/or polyethylene glycol (PEG). 
     
     
         40 . The stabilised polymeric silicate composition for use in a method of treatment of any one of  claims 36  to  39 , wherein the composition is diluted or neutralised to a physiologically acceptable pH for administration. 
     
     
         41 . A stabilised polymeric silicate composition for use in a method of treatment, wherein the composition comprising polymeric silicic acid and nanosilicate particles having mean diameters of 20 nm or less and a stabilising agent comprising sucrose and/or a polyalkylene glycol, wherein composition is formulated for intravenous (IV) administration via an intravenous drip. 
     
     
         42 . A stabilised polymeric silicate composition comprising polymeric silicic acid and nanosilicate particles having mean diameters of 20 nm or less as obtainable by the process of any one of  claims 1  to  33  for use in a method of promoting wound healing and/or treating or preventing bacterial infection, wherein the composition is formulated for topical administration. 
     
     
         43 . A stabilised polymeric silicate composition for use in a method of treatment, wherein the composition comprising polymeric silicic acid and nanosilicate particles having mean diameters of 20 nm or less and a stabilising agent comprising a polyalkylene glycol, wherein composition is formulated for topical administration, the composition is for use in a method of promoting wound healing and/or treating or preventing bacterial infection. 
     
     
         44 . The stabilised polymeric silicate composition for use in a method of treatment of  claim 42  or  claim 43 , wherein the composition is formulated as a cream or an ointment, optionally wherein the cream or ointment comprises a polyalkylene glycol. 
     
     
         45 . The stabilised polymeric silicate composition for use in a method of treatment of any one of  claims 42  to  44 , wherein the polyalkylene glycol is polyethylene glycol (PEG). 
     
     
         46 . The stabilised polymeric silicate composition for use in a method of treatment of any one of  claims 34  to  45 , wherein the pH is between 3.0 and 9.0. 
     
     
         47 . The stabilised polymeric silicate composition for use in a method of treatment of any one of  claims 34  to  46 , wherein the composition has a concentration of silicon of 2.5 mM or more, 5.0 mM or more, 25 mM or more, 40 mM or more. 
     
     
         48 . The stabilised polymeric silicate composition for use in a method of treatment of any one of  claims 34  to  47 , wherein composition is for treating a human subject. 
     
     
         49 . The stabilised polymeric silicate composition for use in a method of treatment of any one of  claims 34  to  47  for veterinary administration. 
     
     
         50 . A silicate-containing supplement comprising a stabilised polymeric silicate composition comprising polymeric silicic acid and nanosilicate particles having mean diameters of 20 nm or less as obtainable by the process of any one of  claims 1  to  33  for use in the delivery of silicic acid to a human or animal subject. 
     
     
         51 . The silicate-containing supplement of  claim 50 , wherein the composition is in the form of a liquid filled capsule. 
     
     
         52 . The silicate-containing supplement of  claim 50  or  claim 51 , wherein the composition is for direct oral administration. 
     
     
         53 . The silicate-containing supplement of any one of  claims 50  to  52 , wherein the composition is a silicate supplement for improving the appearance of hair, skin or nails. 
     
     
         54 . A composition comprising a stabilised polymeric silicate composition comprising polymeric silicic acid and nanosilicate particles having mean diameters of 20 nm or less as obtainable by the process of any one of  claims 1  to  33  for use therapy. 
     
     
         55 . The stabilised polymeric silicate composition for use in therapy of  claim 54  for use in method of treating osteoporosis, osteopenia, musculoskeletal and joint disorders, cancer, skin conditions, vascular diseases, cardiovascular diseases, coronary heart diseases, inflammatory diseases, autoimmune diseases, Alzheimer's disease, cognitive impairment, infections, wounds, ulcers, gastrointestinal disorders, liver disease, kidney disease, immune related disorders or hormone related disorders. 
     
     
         56 . The stabilised polymeric silicate composition for use in therapy of  claim 54 , wherein the composition is for oral delivery to bind cations in the gut, such as iron. 
     
     
         57 . The stabilised polymeric silicate composition for use in therapy of  claim 54 , wherein the composition is for intravenous delivery for the treatment of cancer 
     
     
         58 . The stabilised polymeric silicate composition for use in therapy of  claim 54 , wherein the composition is for intravenous delivery for the treatment of infections 
     
     
         59 . A silicate-containing supplement comprising a stabilised polymeric silicate composition comprising polymeric silicic acid and nanosilicate particles having mean diameters of 20 nm or less as obtainable by the process of any one of  claims 1  to  33  for use in the delivery of transiently stable silicate polymers to a human or animal subject. 
     
     
         60 . The silicate-containing supplement comprising a stabilised polymeric silicate composition of  claim 59 , wherein the composition is for oral supplementation and comprises particles have mean diameters of 5 nm or less (uSANS).