Patent Application
20120214986
The present invention relates to novel processes for the preparation of iron (III) carboxymaltose complex.
Water-soluble iron carbohydrate complexes are used for the prophylaxis or treatment of iron deficiency anaemia. The medicaments are especially useful for parenteral application.
Ferric carboxymaltose complex, also known as iron (III) carboxymaltose, is indicated for the treatment of iron deficiency anaemia, and which is marketed by Vifor under the brand name Ferinject®.
U.S. Patent Application Publication No. 2006/0205691 discloses water-soluble iron carbohydrate complexes (ferric carboxymaltose complexes) obtainable from an aqueous solution of an iron (III) salt, preferably iron (III) chloride, and an aqueous solution of the oxidation product of one or more maltodextrins using an aqueous hypochlorite solution.
The process for the preparation of ferric carboxymaltose complex described in the aforementioned prior art suffers from disadvantages since it involves the use of excess amounts of sodium carbonate and iron (III) chloride, thereby generating a large quantity of chemical waste which is difficult to treat. Moreover, the use of highly corrosive and toxic reagents like iron (III) chloride and excess amounts of sodium carbonate in the final stage of complex formation is not advisable since the resulting complex is contaminated with unacceptable amounts of impurities like sodium carbonate and sodium chloride, and thus resulting in a poor product quality.
Similar process for the preparation of ferric carboxymaltose complex is also mentioned in PCT Publication No. WO 2007/081744. The '744 publication describes a method of treating iron-associated diseases comprising administering to a subject in need thereof an iron carbohydrate complex in a single dosage unit of at least about 0.6 grams of elemental iron, wherein the iron carbohydrate complex has a substantially non-immunogenic carbohydrate component and substantially no cross reactivity with anti-dextran antibodies.
Hence, the ferric carboxymaltose complex obtained by the process described in the prior art is not suitable for the preparation of medicaments without further purification.
Based on the aforementioned drawbacks, the prior art processes have been found to be unsuitable for the preparation of ferric carboxymaltose at lab scale and in commercial scale operations.
We have surprisingly discovered novel, improved and environmentally friendly processes for the preparation of iron (III) carboxymaltose complex substantially free of impurities using ferric hydroxide. The novel processes avoid the use of excess amounts of reagents like sodium carbonate and iron (III) chloride and thereby resolving the problems associated with the processes described in the prior art, and which are more convenient to operate at lab scale and in commercial scale operations. Desirable process properties include use of non-hazardous, environmentally friendly and easy to handle reagents in the final stage of complex formation, reduced quantities of reagents and base, reduced cost, greater simplicity, increased quality and increased yield of the product, and thereby enabling the commercially viable and environmentally friendly production of ferric carboxymaltose. The iron (III) carboxymaltose complexes obtained by the processes described herein can be directly used for the production of medicaments even without further purification.
In one aspect of the present invention, there is provided a process for the preparation of water soluble iron (III) carboxymaltose complex on the basis of the oxidation products of maltodextrins, which comprises:
In another aspect of the present invention, there is provided a process for the preparation of water soluble iron (III) carboxymaltose complex on the basis of the oxidation products of maltodextrins, which comprises adding sodium hypochlorite to a mixture of one or more maltodextrins and ferric hydroxide in the presence of water to obtain iron (III) carboxymaltose complex where, when one maltodextrin is applied, its dextrose equivalent lies between 4 and 20, and when a mixture of several maltodextrins is applied, the dextrose equivalent of the mixture lies between 4 and 20 and the dextrose equivalent of each individual maltodextrins contained in the mixture lies between 2 and 40.
In another aspect of the present invention, there is provided a process for the preparation of iron (III) carboxymaltose complex, which comprises:
wherein, when one maltodextrin is applied, its dextrose equivalent lies between 4 and 20, and when a mixture of several maltodextrins is applied, the dextrose equivalent of the mixture lies between 4 and 20 and the dextrose equivalent of each individual maltodextrins contained in the mixture lies between 2 and 40.
According to one aspect of the present invention, there is provided a process for the preparation of water soluble iron (III) carboxymaltose complex on the basis of the oxidation products of maltodextrins, which comprises:
In order to prepare the liginds of the complex of the invention, the maltodextrins are oxidized in an aqueous solution with a sodium hypochlorite solution.
In one embodiment, the oxidation reaction in step-(a) is carried out in an alkaline solution at a pH of 8 to 12. In another embodiment, the oxidation reaction is carried out at a temperature of 15 to 40° C., and preferably at a temperature of 25 to 35° C. In another embodiment, the oxidation reaction is carried out for 10 minutes to 4 hours, and preferably for 1 hour to 1 hour 30 minutes.
Optionally, the oxidation reaction is carried out in the presence of a catalyst such as alkali bromides, for example sodium bromide. The amount of catalyst is not critical. Specifically, the amount of catalyst is kept as low as possible in order to achieve an end product (Fe-complex) which can easily be purified, and more specifically catalytic amounts are sufficient.
In order to prepare the complex of the invention, the obtained oxidized maltodextrins are reacted with ferric hydroxide. In order to do so, the oxidized maltodextrins can be isolated and re-dissolved. However, it is also possible to use the obtained aqueous solutions of the oxidized maltodextrins directly for the further reaction with ferric hydroxide. For instance, the aqueous solution of the oxidized maltodextrin can be mixed with ferric hydroxide in order to carry out the reaction.
Preferably, a freshly prepared ferric hydroxide is used in step-(b).
In one embodiment, the reaction in step-(b) is carried out at a pH between 5 and 14. If necessary, the pH of the reaction is adjusted with a strong base. Examples of strong bases are alkali or alkaline earth metal hydroxides such as sodium hydroxide.
In another embodiment, the reaction in step-(b) is carried out at a temperature of 15° C. to 125° C. It is preferred to raise the temperature gradually. Thus, for example, it is preferable to heat the reaction mixture at a temperature of about 15 to 70° C. and then raise the temperature gradually up to 125° C.
Optionally, the reaction is carried out under pressure.
The reaction is preferably carried out for 15 minutes to 4 hours depending on the reaction conditions.
In a preferred embodiment, the reaction in step-(b) is initially maintained at a pH of 10 to 12 and at a temperature of 40 to 60° C., followed by adjusting the pH between 4 to 7 and maintaining the reaction at a temperature of 85° C. to 125° C.
The pH can be lowered, if necessary, by the addition of an acid. It is preferable to use inorganic or organic acids or a mixture thereof, specifically hydrohalic acids such as aqueous hydrochloric acid.
After completion of the reaction, the obtained solution can be cooled to room temperature and then optionally diluted and filtered. After cooling, the pH is adjusted to 5 to 7 by the addition of an acid or a base. It is preferable to use the acids and bases which have been mentioned for carrying out the reaction. The solutions obtained are purified and can directly be used for the production of medicaments. However, it is also possible to isolate the iron (III) complex from the solution by precipitation with an alcohol such as an alkanol, for example, ethanol.
According to another aspect of the present invention, there is provided a process for the preparation of water soluble iron (III) carboxymaltose complex on the basis of the oxidation products of maltodextrins, which comprises adding sodium hypochlorite to a mixture of one or more maltodextrins and ferric hydroxide in the presence of water to produce iron (III) carboxymaltose complex wherein, when one maltodextrin is applied, its dextrose equivalent lies between 4 and 20, and when a mixture of several maltodextrins is applied, the dextrose equivalent of the mixture lies between 4 and 20 and the dextrose equivalent of each individual maltodextrins contained in the mixture lies between 2 and 40.
In order to prepare the iron (III) carboxymaltose complex of the invention, the mixture of maltodextrins and ferric hydroxide in an aqueous solution is oxidized with a sodium hypochlorite solution.
Preferably, a freshly prepared ferric hydroxide is used.
In one embodiment, the oxidation reaction is carried out in an alkaline solution at a pH of 8 to 12. In another embodiment, the oxidation reaction is carried out at a temperature of 15 to 40° C., and preferably at a temperature of 25 to 35° C. In another embodiment, the oxidation is carried out for 10 minutes to 4 hours and preferably 1 hour to 1 hour 30 minutes.
Optionally, the oxidation reaction is carried out in the presence of a catalyst such as alkali bromide, for example sodium bromide. The amount of catalyst is not critical. In one embodiment, the amount of the catalyst is kept as low as possible in order to achieve an end product (Fe-complex) which can easily be purified, and specifically catalytic amounts are sufficient.
In one embodiment, the pH of the reaction is raised to values in between 5 to 14 using a strong base. Examples of strong bases are alkali- or alkaline earth metal hydroxides such as sodium hydroxide.
In one embodiment, the reaction is carried out at a temperature of 15° C. to 125° C. It is preferred to raise the temperature gradually. Thus, for example, it is preferable to heat the reaction mixture at a temperature of about 15 to 70° C. and then raise the temperature gradually up to 125° C.
Optionally, the reaction is carried out under pressure.
The reaction is preferably carried out for 15 minutes to 4 hours depending on the reaction conditions.
In a preferred embodiment, the reaction is initially maintained at a pH of 10 to 12 and at a temperature of 40 to 60° C., followed by adjusting the pH at 4 to 7 and maintaining the reaction at a temperature of 85° C. to 125° C.
The pH can be lowered, if necessary, by the addition of an acid. It is preferable to use inorganic or organic acids or a mixture thereof, specifically hydrohalic acids such as aqueous hydrochloric acid.
After completion of the reaction, the obtained solution can be cooled to room temperature and then optionally diluted and filtered. After cooling, the pH is adjusted 5 to 7 by the addition of an acid or a base. It is preferable to use the acids and bases which have been mentioned for carrying out the reaction. The solutions obtained are purified and can directly be used for the production of medicaments. However, it is also possible to isolate the iron (III) complex from the solution by precipitation with an alcohol such as an alkanol, for example, ethanol.
According to another aspect of the present invention, there is provided a process for the preparation of iron (III) carboxymaltose complex, which comprises:
wherein, when one maltodextrin is applied, its dextrose equivalent lies between 4 and 20, and when a mixture of several maltodextrins is applied, the dextrose equivalent of the mixture lies between 4 and 20 and the dextrose equivalent of each individual maltodextrins contained in the mixture lies between 2 and 40.
In one embodiment, the heating in step-(a) is carried out at a temperature of 50° C. to the boiling point while maintaining the pH between 5 and 14. Preferably, the heating is carried out at a temperature of 70 to 90° C., and more preferably at a temperature of about 90° C.
Preferably, a freshly prepared ferric hydroxide is used in step-(a).
In one embodiment, the oxidation reaction in step-(b) is carried out in an alkaline solution at a pH of 8 to 12. In another embodiment, the oxidation reaction is carried out at a temperature of 15 to 40° C. and preferably at 25 to 35° C. In another embodiment, the oxidation reaction is carried out for 10 minutes to 4 hours and preferably for 1 hour to 1 hour 30 minutes.
Optionally, the oxidation is carried out in presence of a catalyst such as alkali bromide, for example sodium bromide. The amount of catalyst is not critical. In one embodiment, the amount is kept as low as possible in order to achieve an end product (Fe-complex) which can easily be purified, and specifically catalytic amounts are sufficient.
In one embodiment, the pH of reaction in step-(c) is adjusted with a strong base. Examples of strong bases are alkali- or alkaline earth metal hydroxides such as sodium hydroxide.
In another embodiment, the reaction in step-(c) is carried out at a temperature of 25° C. to 125° C. It is preferred to raise the temperature gradually. Thus, for example, it is preferable to heat the reaction mixture at a temperature of about 25 to 70° C. and then raise the temperature gradually up to 125° C.
Optionally, the reaction is carried out under pressure.
The reaction is preferably carried out for 15 minutes to 4 hours depending on the reaction conditions.
In a preferred embodiment, the reaction in step-(c) is initially maintained at a pH of 10 to 12 and at a temperature of 40 to 60° C., followed by adjusting the pH between 4 to 7 and maintaining the reaction at a temperature of 85° C. to 125° C.
The pH can be lowered, if necessary, by the addition of an acid. It is preferable to use inorganic or organic acids or a mixture thereof, specifically hydrohalic acids such as aqueous hydrochloric acid.
After completion of the reaction, the obtained solution can be cooled to room temperature and then optionally diluted and filtered. After cooling, the pH is adjusted to 5 to 7 by the addition of an acid or a base. It is preferable to use the acids and bases which have been mentioned for carrying out the reaction. The solutions obtained are purified and can directly be used for the production of medicaments. However, it is also possible to isolate the iron (III) complex from the solution by precipitation with an alcohol such as an alkanol, for example, ethanol.
According to the processes of the present invention, the iron content of the obtained iron (III) carboxymaltose complexes is 10 to 40% weight/weight, and specifically 20 to 35% weight/weight. Iron content is measured by using Atomic Absorption Spectrophotometer (AAS). The complexes can easily be dissolved in water. It is possible to prepare neutral aqueous solutions which have an iron content of 1% weight/volume to 20% weight/volume. Such solutions can be sterilised by general methods. The weight average molecular weight of the obtained complexes is in between 80 kDa to 700 kDa, preferably 80 kDa to 350 kDa, and more preferably up to 300 kDa. The weight average molecular weight of the complexes is measured by the following method:
Allow each standard solution to stand at or below 25° C. for a minimum of 12 hours.
After the agglomerate particles of each standard solution have swelled to their fullest extent, gently swirl each standard solution until dissolved.
The resolution between high molecular weight dextran and glucose should not be less than 4.0.
The following examples are given for the purpose of illustrating the present invention and should not be considered as limitations on the scope and spirit of the invention.
Ferric chloride (61.5 gm) was dissolved in water (750 ml) and the solution was filtered to remove undissolved material. The resulting solution was cooled to 5 to 10° C. Sodium carbonate solution (61.5 gm dissolved in 750 ml water) was slowly added to the above solution at 5 to 10° C. The reaction mixture was stirred for 10 minutes at 5 to 10° C. and then again stirred for 1 hour at ambient temperature. The separated solid was filtered and washed with water to obtain ferric hydroxide.
Maltodextrin (50 gm, 14.2 dextrose equivalent), water (100 ml) and sodium bromide (0.35 gm) were added to a sodium hypochlorite solution (68 gm) containing 2.79 gm of active chlorine. The resulting solution was stirred for 5 minutes at ambient temperature and then the pH of the reaction mass was adjusted to 11 with dilute sodium hydroxide solution, and maintained for 1 hour 30 minutes. The resulting mass was added to a mixture of freshly prepared ferric hydroxide (obtained in example 1 from 61.5 g of ferric chloride) and water (100 ml). The pH of the reaction mass was then adjusted to 11 with dilute sodium hydroxide solution. The resulting mixture was heated to 50° C. and maintained for 30 minutes, and then the pH of the reaction mass was adjusted to 6 with dilute hydrochloric acid. The reaction mass was maintained for 30 minutes at 50° C., followed by maintaining for 30 minutes at 96 to 98° C. The resulting solution was cooled to ambient temperature to produce iron carboxymaltose complex.
Molecular Weight=3,00,000 Da
Iron carboxymaltose solution (50 gm, obtained in example 2) was added to ethanol (1400 ml) and then stirred for 3 hours at ambient temperature. The resulting solid was collected by filtration, washed with ethanol and the solid was dried at 50° C. under vacuum for 2 hours to obtain iron carboxymaltose powder.
Example 2 was repeated using maltodextrin (6 dextrose equivalent) instead of maltodextrin (14.2 dextrose equivalent) to obtain iron carboxymaltose complex.
Example 2 was repeated using a mixture of maltodextrin (6 dextrose equivalent, 24 gm) and maltodextrin (14.2 dextrose equivalent, 28 gm) instead of maltodextrin (14.2 dextrose equivalent) to obtain iron carboxymaltose complex.
Molecular Weight=1,76,597 Da
About 50 percent of the volume was distilled from the above solution under vacuum to obtain iron carboxymaltose complex.
Example 2 was repeated using maltodextrin (16 dextrose equivalent) instead of maltodextrin (14.2 dextrose equivalent) to obtain iron carboxymaltose complex.
A solution of maltodextrin (50 gm, 14.2 dextrose equivalent) in water (100 ml) was added to a mixture of ferric hydroxide (obtained in example 1 from 61.5 gm of ferric chloride) and water (100 ml). The pH of the resulting mixture was adjusted to 11 with dilute sodium hydroxide solution, followed by the addition of sodium hypochlorite solution (70 gm) containing 3.1 gm of active chlorine and sodium bromide (0.5 gm) at ambient temperature. The pH of the reaction mixture was adjusted to 11 and then stirred for 1 hour at ambient temperature. The mixture was heated to 50° C. and maintained for 30 minutes. The pH of the resulting mass was adjusted to 6 with diluted hydrochloric acid and maintained for 30 minutes at 50° C. The reaction mass was heated at 96 to 98° C. and maintained for 1 hour. The solution was cooled to ambient temperature to produce iron carboxymaltose complex.
The iron carboxymaltose complex obtained in example 6 was precipitated by using ethanol. Iron carboxymaltose solution (50 gm, obtained in example 6) was added to ethanol (1400 ml) and then stirred for 3 hours at ambient temperature. The resulting solid was collected by filtration, washed with ethanol and then dried at 50° C. under vacuum for 2 hours to obtain iron carboxymaltose powder.
Example 6 was repeated using maltodextrin (6 dextrose equivalent) instead of maltodextrin (14.2 dextrose equivalent) to obtain iron carboxymaltose complex.
Example 6 was repeated using a mixture of maltodextrin (6 dextrose equivalent, 24 gm) and maltodextrin (14.2 dextrose equivalent, 28 gm) instead of maltodextrin (14.2 dextrose equivalent) to obtain iron carboxymaltose complex.
About 50 percent of the volume was distilled from the above solution under vacuum to obtain iron carboxymaltose complex.
Example 6 was repeated using maltodextrin (16 dextrose equivalent) instead of maltodextrin (14.2 dextrose equivalent) to obtain iron carboxymaltose complex.
A solution of maltodextrin (50 gm, 14.2 dextrose equivalent) in water (100 ml) was added to a mixture of ferric hydroxide (obtained in example 1 from 61.5 gm of ferric chloride) and water (100 ml). The pH of the resulting mixture was adjusted to 11 with dilute sodium hydroxide solution, followed by the addition of sodium hypochlorite solution (70 gm) containing 3.1 gm of active chlorine and sodium bromide (0.5 gm). The pH of the reaction mixture was adjusted to 11 and stirred for 1 hour at ambient temperature. The mixture was heated to 50° C. and maintained for 30 minutes. The pH of the resulting mass was adjusted to 6 with dilute hydrochloric acid and maintained for 30 minutes. The mixture was taken in autoclave and maintained for 1 hour at 121° C. under 1.1 kg/cm2 pressure. The solution was cooled to ambient temperature to produce iron carboxymaltose complex.
The above solution was precipitated by using ethanol. Iron carboxymaltose solution (50 gm, obtained above) was added to ethanol (1400 ml) and then stirred for 3 hours at ambient temperature. The solid obtained was collected by filtration, washed with ethanol and then dried at 50° C. under vacuum for 2 hours to obtain iron carboxymaltose powder.
Example 10 was repeated using maltodextrin (6 dextrose equivalent) instead of maltodextrin (14.2 dextrose equivalent) to obtain iron carboxymaltose complex.
Example 10 was repeated using a mixture of maltodextrin (6 dextrose equivalent, 24 gm) and maltodextrin (14.2 dextrose equivalent, 28 gm) instead of maltodextrin (14.2 dextrose equivalent) to obtain iron carboxymaltose complex.
Example 10 was repeated using maltodextrin (16 dextrose equivalent) instead of maltodextrin (14.2 dextrose equivalent) to obtain iron carboxymaltose complex.
A solution of maltodextrin (50 gm, 14.2 dextrose equivalent) in water (100 ml) was added to a mixture of ferric hydroxide (obtained in example 1 from 61.5 gm of ferric chloride) and water (100 ml), followed by adjusting the pH to 11 with dilute sodium hydroxide solution. The reaction mixture was heated to 90° C. and maintained for 30 minutes at 90° C. The solution was cooled to ambient temperature to produce iron maltodextrin complex (Molecular weight: 2,40,000 Da).
Sodium hypochlorite solution (70 gm) containing 3.1 gm of active chlorine and sodium bromide (0.5 gm) were added to the iron (III) maltodextrin complex obtained above and then the pH was adjusted to 11. The solution was maintained for 1 hour at ambient temperature and heated to 50° C., and then maintained for 30 minutes. The pH was adjusted to 6 with dilute hydrochloric acid and maintained for 30 minutes at 50° C. The reaction mass was heated to 96 to 98° C. and maintained for 30 minutes. The solution was cooled to ambient temperature to produce iron carboxymaltose complex.
Iron carboxymaltose solution (50 gm, obtained in example 14) was added to ethanol (1400 ml) and then stirred for 3 hours at ambient temperature. The solid obtained was collected by filtration, washed with ethanol and then dried at 50° C. under vacuum for 2 hours to produce iron carboxymaltose powder.
Example 14 was repeated using maltodextrin (6 dextrose equivalent) instead of maltodextrin (14.2 dextrose equivalent) to obtain iron carboxymaltose complex.
Example 14 was repeated using a mixture of maltodextrin (6 dextrose equivalent, 24 gm) and maltodextrin (14.2 dextrose equivalent, 28 gm) instead of maltodextrin (14.2 dextrose equivalent) to obtain iron carboxymaltose complex.
About 50 percent of the volume was distilled from the above solution under vacuum to obtain iron carboxymaltose complex.
Example 14 was repeated using maltodextrin (16 dextrose equivalent) instead of maltodextrin (14.2 dextrose equivalent) to obtain iron carboxymaltose complex.
| Number | Date | Country | Kind |
|---|---|---|---|
| PCT/IN2009/000624 | Nov 2009 | IN | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/IN2009/000624 | 11/4/2009 | WO | 00 | 4/30/2012 |
