IL24513A - Iron-containing therapeutic preparations - Google Patents

Description

therapeutic preparations present invention relates to new therapeutically parenteral readily absorbed preparations of iron more to preparations of iron containing a of inventio also relates to a for the production Parenteral preparations comprisin a complex of trivaient iron are already For the iron are sugar as a complex products are widely used for intravenous they cannot be readily used for intramuscular ministration because aqueous solutions thereof highly a iron dextrins and iron may be stered these products have a high average molecular weight ranging generally between 100 and are absorbed only incompletely in the and animal the administration of these products causes an undesired coloration at the side of Trivaient iron in the form ferric hydroxide has furthermore already bee converted into complex thereof by means of a mixture of gluconic acid and one of hydroxide has been reacted with at least one half mol of gluconic and at least one half mol of sorbitol patent these complex products do not have a sufficient complex compounds of iron have been duced in a form la particle about 5 000 means of a hexitol such as sorbitol and a hydroxycarboxylic such as citric or gluconic these products being stabilized by means dextrins having an average molecular weight of about 1 000 to 5 000 patent 659 420 These products sorbed about the iron administered are excreted again within short time through the kidneys by urination Pringle Lancet 1 962 7259 The iron excreted in this way is lost for the curing effect in the in a rapid absorption is contrasted by a high rate unutilized these products a rather high The in white mice ranges 36 taneous 50 upon toneal and upon venous administration first line of page of Canadian patent 659 420 the high toxicity of these products is caused by the fact that they do not have a uniform composition and contain considerable amounts of readily ionizable which amounts exert a toxic the human According to Canadian patent 659 420 the hydroxycarboxylic acid and the hexitol component are bound to the iron atom while the dextrin is present a free form and serves as a stabilizing agent for the ficiently stable dispersion of the salt in When subjecting this product to about 6 of the iron contained in these products migrates to the with a higher speed than the remaining amount the product is not uniform in is object of the invention to a new therapeutically useful parenteral preparation of a readily absorbed complex of trivalent iron by the use of a mixture of gluconic acid and certain oligosaccharides as complex forming agent complex of trivalent iron is has a uniform position and a low toxicity and at the same has a high rate utilization of the iron to the h or animal Further objects of the present invention and advantages thereof will become apparent as the description The therapeutically useful preparations of iron in present invention comprise a phonetically complex of trivalent iron as ferric hydroxide with a complex forming agent consisting of gluconic acid and certain oligosaccharides in very particular and The plex forming agent consists of gluconic acid as third a dextrin or dextran having an average viscosity of about to about at and an average molecular weight of from about 500 to 1200 or a dextrin or dextran having said average viscosity and average molecular weight and being substantially to the i or mixtures a molar of about of sorbitol about of gluconic acid mol of the above About of said complex forming is present in the iron preparation to present invention per each mol of trivalent iron or ferric hydroxide The dextrans and dextrins such an average molecular obtained by known such as by growing under fully controlled conditions of appropriate ganism in a suitable nutrient medium containing a high proportion of sucrose or by controlled acid hydrolysis of native dextrans and or they may be obtained as described for instance in US Patent and 4th column The hydrogenated dextrans and dextrins may be produced ing to known such as by subjecting a dextran or dextrin of the average molecular weight defined hereinabove to reaction with sodium in an aqueous medium or by catalytic hydrogenation as described for instance in US Patents or or in 74 The Somogyi reagent is defined for instance in 607 The iron preparations according to the present invention are prepared hy subjecting 1 mol of a compound of trivalent iron in a form to reaction with about 2 tools of the comple agent above however containing its ingredients in a molar ratio of about of bitol about mol of gluconic acid about mol of above in an aqueous medium and heating the resulting after an is thereto until a pH of or somewhat is Complex ation may take place both at an alkaline pH and at an acid pH with the intermediate formation of an acid an alkali metal preferably droxide is as The word as herein is to be understood in such a way that changes ranging to about 20 in the ratio of the components of the complex forming agent among each other and in the ratio between the ferric hydroxide and the complex forming agent are The process according to the invention with the other respects should be carried out for fulfilling the objects of the invention in such a way that electrophoretically low molecular complexe are obtained wherein all of three complex forming agents are bound in a complex The trivalent iron compounds used as starting materials in the process according to the present invention correspond to the trivalent iron compounds which been used already in similar known ferric chloride is used as starting material which in the alkaline complex formation is converted into trivalent iro hydroxide by reaction with bicarbonate or aqueous sodium hydroxide and is further reacted with the complex forming agent in a freshly reactive preferably after being formation of the iron hydroxide is carried out according to known method such a way tha its reactive polynuclear is formed to an extent as large as possible and the formation of its less reactive polynuclear is In the formation of the iron the alkali such as the aqueous sodium hydroxide is added the solution of the iron compound in such an amount that the acid deriving from the iron compound is neutralized complete an excess of about per 1 gram atom remains in the reaction She of the reaction mixture should be at about during the alkaline complex the reaction a small amount of alkali is After the termination of the reac ion it should be possible to determine of by using as starting preferably of are used per one of the complex preferably the solution of the complex forming agents in water is placed in the vessel and is heated at the solution of the iron for the ferric as well as the aqueous sodium hydroxide is duced into the reaction mixture as separate solutions solution of ferric chloride and the other solution of sodium in the calculated the a clear solution is produced very Only during the is proven by the addition of methanol to sample the thus obtained producing precipitate containing both iron complex forming a solution chloride which does contain the comple forming agent or lution of the eomplex forming contain chloride does hot produce a precipitate lent the salt of iron the of the complex forming agent in these essays They sta in solution even if very methyl alcohol is When now the of acid complex obtained in the first step from about which for instance may be effected by adding ponding amounts aqueous sodium a precipitate is formed a pH of which precipitate however almost during further addition of the alkali hydroxide until pH This addition sodium hydroxide from pH is carried out at room perature After the pH of about reaction mixture is heated boiling a short immediatel brought to a of about by addition of a physiologically harmless acid such as ably hydrochloric acid and is worked The ratio between water and materials in the alkaline and acid procedure should be preferably and until free from in 200 of wit rapid The pH the reaction mixtur is brought to a value of by the addition of 50 of 10 N aqueous hydroxide and is then heated to the iron hydroxide dissolves starting from and at a complete solution is obtained which is heated to boiling for 15 The pH of the cooled solution is brought to a value of by the addition of hydrochloric acid and the iron complex isolated therefrom by tation with methanol in a ratio of part of solution per parts of 99 The precipitate is filtered off and the complex is The iron content of the dried preparation amounts to An aqueous solution ing 5 of iron is prepared from this dry preparationwhich solution is filled into ampoules and is sterilized by ing the ampoules 30 minutes in a current of Example 3 42 of 12 of sodium and 16 of a hydrpgenated oligomeric dextrin having an average molecular weight of about 1000 and an average intrinsic viscosity of are dissolved in such an amount of water to yield a solution of 250 The solution is heated to 95 of 10 aqueous sodium hydroxide and 184 of a 30 weight by weight aqueous solution of ferric chloride added simultaneously with rapid stirring in such a way that the reaction mixture always has a pH between to When proceeding in this way the ferric hydroxide is the reaction mixture is heated to immediately thereafter cooled to temperature and neutralized to a pH of by the of hydrochloric and is worked up as described in ample The iron content of the preparation is proceeding as described in Example 2 and using 108 of a dextrin having an average molecular weight of about 1000 and an average intrinsic viscosity of about in place of the hydrogenated dextrin a dry preparation is contains of trivalent It is solved in into ampoules and is sterilized as described in Example The with an intrinsic viscosity of about is obtained by acid lization and precipitation of the neutralized solution with methanol of a dextrin having an intrinsic viscosity of about US patent derived from tato Example 6 42 of 12 of gluconic and 16 of a dextran having an average molecular weight of about 1000 and an average intrinsic viscosity about reacted with ferric hydroxide prepared in situ as described in Example This dextran is obtained by acid and precipitation of the neutralized solution with a dextran having an average intrinsic viscosity greater than at see US Patent 7 A dextran having an average molecular weight of abou 1Ό00 an intrinsic about is as described in Example 6 in place the in order to prepare a dry preparation containing by weight of The hydrogenated dextran obtained from a dextran as described in Example 6 by hydrogenation according to Example The resulting product is to According to Example a product is the iron tent of which amounts to 7 This corresponds to an content of residual are the complex forming compounds in relation mol sorbitol mol gluconic acid mol This molar relationship corresponds to the following weight relationship sorbitol gluconic acid insufficientOCRQuality

Claims (1)

1. A therapeutically usefu preparation of iron prising a complex of ferric hydroxide and 1 of a agent per mol of ferric the complex forming agent consisting of a mixture of gluconic acid and a polyglueose comprising a dextrin or a dextran which dextrin o has an average intrinsic viscosity of to at and an average molecular weight of 500 to or a hydrogenated dextrin or dextran having an a intrinsic viscosit of to at and an average molecular weight of from 500 to 1200 and being substantially to the in a molar ratio of about of sorbitol to about mol of gluconic acid to about mol of A preparatio as claimed in Claim 1 containing to by weight of trivalent A preparation as claimed in G 1 or Claim 2 cluding water and containing to by weight of trivalent A preparation as claimed in any of Claims 1 to substantially as herein described with reference to any one of Examples 2 to A process of preparing a therapeutically useful preparation of iron as claimed in Claim 1 which comprises treating 1 mol of a compound of trivalent iron in a reactive form with about 2 in an aqueous a agent consisting of a mixture of sorbitol and acid 18 and a polyglucose comprising a dextrin or dextraa having an average intrinsic viseosity of to at and an average molecular weight of from 500 to 1200 or a dextrin dextran having an average intrinsic cosity of to at and an average molecular weigh of from 500 to 1200 and being substantially to Somogyi in a molar ratio of about of sorbitol to about mol of gluconic acid to mol of and the resulting mixture at an alkaline 6 A process according to Claim 5 which comprises heating 1 rao of freshly precipitated ferric hydroxide in a reactive form together with about 2 of the complex forming agent in an aqueous alkaline until the ferric hydroxide is A process as claimed in Claim 5 which comprises adding 2 mols of the agent to an acid aqueous solution 1 mol of a ferric adding slowly at room an alkali to the acid solution thus obtained until a pH of about is adding further alkali thereto until a pH of and nesting the alkaline solution so obtained to boiling for 5 to 30 A process for the preparation of iron preparations as claimed in 1 substantially as herein described with reference to any one of Examples 2 to insufficientOCRQuality