Starch

Abstract

Production of purified, parenterally administrable starch by washing starch containing more than 85% amylopectin in order to remove surface-localized proteins, lipids and endotoxins, subjecting the starch to a molecular weight reduction by acid hydrolysis, and optionally removing residual water-soluble proteins. Purified starch and microparticles based on such starch.

1 . A process for the production of a starch that is pharmaceutically acceptable, especially for parenteral administration, for example by means of injection, to a mammal, especially a human, which comprises 
 a) starting from starch in solid form, especially particles, for example granules, and with an amylopectin content in excess of 85 percent by weight, expressed as dry weight of starch,    b) subjecting said solid starch to washing(s) under conditions such that proteins, lipids and endotoxins surface-localized on the starch are dissolved whilst the starch remains undissolved, and separating the starch from the dissolved material,    c) subjecting the starch and to a molecular weight reduction by acid hydrolysis such that a molecular weight distribution is obtained in which at least 80 percent by weight of the material lies within the range of 10-10000 kDa.    
     
     
         2 . A process according to  claim 1 , which comprises removing residual water-soluble proteins from the starch.  
     
     
         3 . A process according to  claim 2 , which comprises removing said water-soluble proteins after performing step c) to reduce the molecular weight of the starch.  
     
     
         4 . A process according to  claim 1 , in which step a) is performed using starch with an amylopectin content in excess of 95 percent by weight, preferably in excess of 98 percent by weight, expressed as dry weight of starch.  
     
     
         5 . A process according to  claim 4 , in which said starch is waxy maize starch, preferably native or acid-hydrolyzed starch.  
     
     
         6 . A process according to  claim 1 , in which step a) is undertaken using starch particles with an average diameter in the range 5-25 μm, based on weight distribution.  
     
     
         7 . A process according to  claim 1 , in which the washing in step b) is performed under alkaline conditions, preferably using sodium hydroxide as alkali, and in one or more stages.  
     
     
         8 . A process according to  claim 7 , in which the washing or washings in step b) is/are performed at a pH value in the range of 11-14, preferably in two stages with a first stage using aqueous alkali solution at pH 11.5-13 and a second stage which is performed under conditions in which the input pH value in the aqueous phase is in the range of 12.5-13.5.  
     
     
         9 . A process according to  claim 8 , in which the washing comprises a stage with an aqueous alkaline solution for dissolving water-soluble proteins, lipids and endotoxins and a stage with an aqueous solvent with the ability to dissolve zein for dissolving more sparingly soluble proteins.  
     
     
         10 . A process according to  claim 9 , in which the solvent with the ability to dissolve zein is selected from aqueous solutions of monovalent or divalent alcohols and ketones, preferably alkanols or alkylene glycols containing a total of up to 4 carbon atoms or dialkyl ketones with a total of up to 5 carbon atoms.  
     
     
         11 . A process according to  claim 10 , in which the solvent is selected from aqueous solutions of ethanol, isopropanol, ethylene glycol, propylene glycol and acetone.  
     
     
         12 . A process according to  claim 11 , in which the solvent is an aqueous ethanol solution.  
     
     
         13 . A process according to  claim 1 , in which the acid hydrolysis in step c) is carried out such that a molecular weight distribution is obtained in which at least 80% of the material is in the range of 100-4000 kDa, preferably 200-1000 kDa, especially 300-600 kDa.  
     
     
         14 . A process according to  claim 1 , in which the acid hydrolysis in step c) is carried out at a temperature within the range of 20-70° C., preferably 30-60° C., more preferably 45-55° C., and most preferably around 50° C.  
     
     
         15 . A process according to  claim 1 , in which the hydrolysis in step c) is carried out with a duration less than 3 days, preferably less than 2 days, more preferably less than 1 day, and most preferably 1-12 hours.  
     
     
         16 . A process according to  claim 1 , in which the hydrolysis in step c) is carried out at an acid concentration of 0.1-20%, preferably 0.5-15% and more preferably 1-10%.  
     
     
         17 . A process according to  claim 1 , in which the hydrolysis in step c) is carried out at a starch concentration of 1-40%, preferably 5-35%.  
     
     
         18 . A process according to  claim 1 , in which the hydrolysis in step c) is terminated by making a neutralization and/or a lowering of temperature.  
     
     
         19 . A process according to  claim 2 , in which said removal of residual water-soluble proteins from the starch is performed by subjecting the starch solution to ion exchange chromatography, preferably anion exchange chromatography.  
     
     
         20 . A process according to  claim 2 , in which said removal of residual water-soluble proteins from the starch is performed by electrophoresis.  
     
     
         21 . A process according to  claim 1 , in which prior to the washings in step b) non-starch material is removed from the starting starch, preferably by sieving and/or sedimentation.  
     
     
         22 . A process according to  claim 21 , in which material that is larger than the starch particles is removed by wet sieving and material that is smaller than the starch particles is removed by sedimentation.  
     
     
         23 . A process according to  claim 21 , in which non-starch material that is larger than 40 μm is removed, and preferably also non-starch material that is smaller than 5 μm.  
     
     
         24 . A process according to  claim 1 , in which after the acid hydrolysis in step c) any residual particulate non-starch material is removed by filtering of the solution, preferably through a 20 μm filter and optionally thereafter through a 0.5 μm filter.  
     
     
         25 . A process according to  claim 2 , in which, after the removal of residual water-soluble proteins from the starch, filtering is carried out, preferably through a 5 μm pre-filter and a 0.5 μm filter, to remove any particulate contamination.  
     
     
         26 . A process according to  claim 19 , in which at least 0.4, preferably at least 0.8, ml of sedimented, bed volume of ion exchange material per gram of starch is used in the ion exchange chromatography.  
     
     
         27 . A process according to  claim 1 , in which the purified starch is subjected to a final drying stage, preferably by means of spray drying.  
     
     
         28 . A process according to  claim 1 , in which the washing in step b) comprises washing with a thioglycolate solution to remove sparingly soluble proteins.  
     
     
         29 . A pharmaceutically acceptable starch, especially for parenteral administration, preferably by way of injection, to a mammal, especially a human, which 
 a) has an amylopectin content in excess of 85 percent by weight, in which the molecular weight of said amylopectin has been reduced, by acid hydrolysis such that at least 80 percent by weight of the material lies within the range of 10-10 000 kDa,    b) has a purity of at most 50 μg amino acid nitrogen per gram dry weight of starch, preferably at most 20 μg, more preferably at most 10 μg, and most preferably at most 5 μg, amino acid nitrogen per gram dry weight of starch,    c) can be dissolved in a concentration exceeding 25 percent by weight in water.    
     
     
         30 . A pharmaceutically acceptable starch, especially for parenteral administration, preferably by way of injection, to a mammal, especially a human, which 
 a) has an amylopectin content in excess of 85 percent by weight, in which the molecular weight of said amylopectin has been reduced by acid hydrolysis such that at least 80 percent by weight of the material lies within the range of 10-10000 kDa,    b) has a purity of at most 50 μg amino acid nitrogen per gram dry weight of starch, preferably at most 20 μg amino acid nitrogen, more preferably at most 10 μg, and most preferably at most 5 μg amino acid nitrogen per gram dry weight of starch,    c) lacks covalently bonded additional chemical groups of the type that occur in hydroxyethyl starch.    
     
     
         31 . A starch according to  claim 30 , which can be dissolved in a concentration exceeding 25 per cent by weight in water.  
     
     
         32 . A starch according to  claim 30 , which exhibits the ability to gel in vitro.  
     
     
         33 . A starch according to  claim 30 , which exhibits the ability to form microparticles in an emulsion system, especially a two-phase aqueous system.  
     
     
         34 . A starch according to  claim 30 , which has an endotoxin content of less than 25 EU/g and contains fewer than 100 microorganisms per gram.  
     
     
         35 . A starch according to  claim 30 , which is obtainable by means of a process according to  claim 1 .  
     
     
         36 . A starch according to  claim 30 , in which said molecular weight of the amylopectin is within the range of 100-40,00 kDa, preferably 200-1000 kDa and more preferably 300-600 kDa.  
     
     
         37 . A starch according to  claim 30 , which can be dissolved in water in a concentration exceeding 30%, preferably exceeding 40%, and more preferably exceeding 45%, by weight.  
     
     
         38 . A starch according to  claim 30 , which remains in solution at a temperature of at most 60° C., preferably 20-45° C., especially 30-37° C., for a period sufficiently long to allow combining with a substance that is temperature sensitive and/or unstable in organic solvents, especially a protein.  
     
     
         39 . A starch according to  claim 38 , wherein said combining is performed at conditions which are able to retain the bioactivity of said substance.  
     
     
         40 . A starch according to  claim 30 , which when dissolved in water solidifies at a temperature of 1-55° C., especially 4-37° C.  
     
     
         41 . A starch according to  claim 40 , which solidifies when exposed to an initial temperature of 1-10° C., especially about 4° C., and subsequently to a temperature of 20-55° C., preferably 25-40° C., especially about 37° C.  
     
     
         42 . Microparticles based on starch as a carrier for a biologically active substance, especially for parenteral administration, preferably by way of injection, to a mammal, especially a human, in which said starch is the starch as defined in  claim 30 .  
     
     
         43 . Microparticles according to  claim 42 , which have a mean particle diameter in the range of 10-200 μm, preferably 20-100 μm, especially 20-80 μm.  
     
     
         44 . Microparticles according to  claim 42 , which exhibit the ability to be dissolved by enzymatic action in vitro or eliminated from biological tissue in vivo.  
     
     
         45 . Microparticles according  claim 42 , in which the biologically active substance is a protein.