WO2007062546A1

WO2007062546A1 - Iron-saccharide complexs easy to reconstitute and the method for manufacture them

Info

Publication number: WO2007062546A1
Application number: PCT/CN2005/002056
Authority: WO
Inventors: Jinmai Xiao; Jie Deng; Bo Xiao; Jin Feng
Original assignee: Chongqing Pharmaceutical Research Institute Co., Ltd.
Priority date: 2005-11-30
Filing date: 2005-11-30
Publication date: 2007-06-07

Abstract

The present invention discloses a new pharmaceutical composition comprising, in well-distributed powder form : iron-saccharide complex and salt agent in a suitable amount or other excipient . It also discloses the process for preparation the composition , wherein the salt or other excipient is added before iron-saccharide complex is being dried . This improved process make API manufacturer prepare the hematinic powder which can be used just mixed with water , moreover , the powder is easy to reconstitute in water by the ordinary manufacturer .

Description

Iron-sugar composition capable of reconstitution and preparation method thereof

The present invention relates to a powdered pharmaceutical composition, in particular to a powder composition comprising a therapeutically effective amount of an active pharmaceutical ingredient iron hydroxide-sugar complex and at least one additive, and to prepare a novel injectable iron having therapeutic activity - A method of carbohydrate complex. The complex can be injected to treat iron deficiency. The complex can be conveniently reconstituted in water prior to administration. Background technique

Iron-saccharide complexes and their derivatives are one of several FDA-approved blood-suppressive drugs for the treatment of iron deficiency. Iron deficiency is a blood disorder that can be caused by congenital genetic defects or other medical abnormalities. It is known that kidney disease, repeated renal dialysis, and certain cancer therapies can cause iron deficiency. "Blood medicine," means an agent that stimulates the formation of blood cells and/or increases the level of hemoglobin in the blood.

Depending on the route of administration, the treatment of iron deficiency can be divided into two categories: oral supplementation and injection supplementation. The oral supplemental administration method is to improve the symptoms of iron deficiency by oral administration of a simple iron salt such as ferrous sulfate and ferrous gluconate. If oral supplementation does not achieve the desired results, consider the use of supplemental administration as the next stage of treatment, with intravenous and intramuscular injections being two common methods of administration.

A variety of treatments for the treatment of iron deficiency have been developed. To this end, the FDA has approved two types of chemical drugs. The first type is iron dextran, which is a complex of iron hydroxide and dextran. Once injected into the body, iron dextran is rapidly absorbed by the cells and decomposed into iron and dextran, and then enters different metabolic pathways.

Because iron dextran can cause serious side effects in some patients, the second type of supplement, an iron-saccharide complex, is particularly useful as a safer drug for the treatment of iron deficiency. Unlike iron dextran containing a polydextrose structure, the iron-saccharide complex does not contain polymonosaccharides. The two types of iron-saccharide complexes currently available on the market have a skeleton structure formed by gluconate and/or sucrose in combination with ferric ions. The first type of iron-saccharide complex is sodium iron gluconate-sucrose complex (SFGCS). SFGCS is a macromolecular complex with an apparent molecular weight greater than 350,000 Daltons. In comparison, another type of iron-saccharide complex is much smaller, with an apparent molecular weight of less than 80,000 Daltons. Such iron-saccharide complexes are chemically referred to as iron hydroxide-sugar complexes (FHSC).

The prior art methods for preparing iron-saccharide complexes either lack a final drying step or require an additional purification step to adequately remove the excipients prior to drying. This additional purification step not only reduces the overall yield but also increases the total cost of production. Therefore, it is necessary to improve the process so that the iron-saccharide complex is dried into a powder after completion of the reaction without removing the excipient.

In the United States Pharmacopoeia, there is a limited range of cr ion content in iron-saccharide complexes, especially iron-sucrose complexes. How to control the content of cr ions has not been reported in the literature. We are studying iron-saccharide complexes. In particular, in the course of the iron-sucrose complex, it has been found that the purpose of controlling the Cr ion content is achieved by adding NaCl in the process of preparing the iron-sucrose complex, thereby completing the present invention. Summary of the invention

The method of the present invention solves the above problems and provides a method of preparing an iron-saccharide composite dry powder. An advantage of the present invention is that it makes the necessary salts or other excipients, here mainly referred to as inorganic chlorides, especially NaCl which can be added to the iron-saccharide complex prior to drying.

In one aspect, the iron-saccharide complex can be dried after the reaction is completed without prior removal of salts or other excipients. According to this scheme, the concentration of salt or other excipients will be maintained after drying.

The method is applicable to both iron-saccharide complexes of SFGCS and FHSC, as well as derivatives and mixtures thereof. Since the iron-saccharide complex is unstable in solution, it is advantageous to store and transport these compounds in the form of a dry powder. Although there have been various methods for preparing these two iron-saccharide complexes, few methods for preparing dry powders of such compounds have been disclosed.

A defined, repeatable amount of the necessary salt or other excipient can be added to the final dried product. In theory, these inactive ingredients can be added after the pure active pharmaceutical ingredient has dried. However, the introduction of these inactive ingredients prior to drying allows these ingredients to be more homogeneously mixed with the active pharmaceutical ingredients. Evenly. It is advantageous to add the necessary excipients prior to drying because the excipients do not have sterility requirements. This improvement is significant because it allows the drug manufacturer to make the blood-blend into an easily miscible powder, and the generic drug manufacturer can conveniently reconstitute the drug powder in water prior to sale. After the bulk drug is made, only purified water needs to be added. Thus, the method reduces the likelihood of errors by removing additional purification steps.

In one embodiment, the amount of salt or excipient that is added is determined by determining the salt content of the reaction mixture. According to the solution of the present invention, the salt and other excipients are dried together with the active ingredient, i.e., the iron-saccharide complex. The salt referred to herein mainly refers to an inorganic chloride, preferably NaCL, which is a new and improved method for the drug manufacturer to make the blood-mixing drug into an easily-mixable powder. The generic drug manufacturer can deliver it for clinical use before delivery. The powder is conveniently reconstituted in water.

It is an object of the present invention to provide a pharmaceutical composition in the form of a dry powder comprising a therapeutically effective amount of an active pharmaceutical ingredient iron hydroxide-saccharide complex and at least one additive and optionally an excipient, wherein the additive As the inorganic chloride such as potassium chloride, sodium chloride or the like, sodium chloride is preferred. The iron hydroxide-sugar complex is preferably an iron hydroxide-sucrose complex or a sodium iron gluconate-sucrose complex. Wherein the formula of the iron hydroxide-sucrose complex is [Na ₂ Fe ₅ 0 ₈ (OH).3(H ₂ 0)] _n m(C ₁₂ H ₂₂ Ou), wherein n is any integer from 1 to 30 m is any integer from 1-360. Preferably n is any integer from 5 to 20, and m is any integer from 60 to 240. The effective therapeutic amount of the iron hydroxide-sugar complex herein means that the iron content is 1-20% by weight, preferably 5-10% by weight, of the iron hydroxide-sugar complex. The dosage range is from 500 mg to 4 g, preferably from 1 to 3 g, more preferably from 1.5 to 2 g.

In the preparation of the composition of the present invention, an additive such as sodium chloride is added to the reaction mixture before the synthesis of the iron hydroxide-sugar complex or during the synthesis of the iron hydroxide-saccharide complex, and after the reaction is completed, no separation is required. Impurities, the reaction mixture containing the reaction product iron hydroxide-sugar complex may be directly subjected to freeze drying or spray drying, preferably spray drying.

The amount of the additive such as sodium chloride in the pharmaceutical composition of the present invention is calculated according to the following Equation I.

Equation I: 1.06%- C reverse) /35.5,

G reaction solution: good i G water: total dissolved water;

G »: Sucrose dosage G, : Ferric hydroxide dosage

G Sodium hydroxide feed amount G : Net weight of distilled water at the time of sampling

G supplemental sodium chloride amount C reaction; reaction liquid iron content (%)

G reaction liquid gas:

( % ) ,

The amounts are all by weight.

Another object of the present invention is to provide an iron hydroxide suitable for injection by a human or an animal.

- a method for preparing a carbohydrate complex, the method comprising the following steps:

At least one sugar or sugar derivative or a mixture thereof is contacted with Fe(III) ions and inorganic chloride in the presence of OH- ions. The term "contacting" as used herein refers to mixing together for chemical reaction or chemical reaction. The reactants of the process react in an aqueous medium. The Fe(m) ion referred to in the method of the present invention is preferably present in the form of iron hydroxide, and the iron hydroxide can be prepared by mixing an aqueous alkaline solution with a solution containing Fe(III) ions.

The aqueous alkaline solution referred to in the process of the present invention is selected from the group consisting of sodium hydroxide, sodium carbonate and aqueous sodium hydrogencarbonate, preferably sodium carbonate or sodium hydrogencarbonate.

The method of the present invention may further comprise, according to actual needs, drying unreacted sodium chloride together with a reaction product, such as an iron hydroxide-sucrose complex, to form a final product, i.e., a powder composition.

The amount of sodium chloride used in the process of the present invention is calculated according to Equation I above.

A further object of the present invention is to provide a process for the preparation of an iron-saccharide complex suitable for parenteral administration to humans or animals, which method comprises the following steps:

a) contact

i) at least one sugar or sugar derivative or a mixture thereof, and

Ii) Fe(III) ions in the presence of OH' ions,

b) adding sodium chloride; and C) The final reaction mixture comprising the iron-saccharide complex is dried to make it in powder form.

The reaction of the method is carried out in an aqueous medium, wherein the Fe(m) ion is preferably present in the form of iron hydroxide, and the iron hydroxide is prepared by mixing an aqueous alkaline solution with a solution containing Fe(III) ions, wherein The aqueous alkaline solution is selected from the group consisting of sodium hydroxide, sodium carbonate and aqueous sodium hydrogencarbonate, preferably sodium carbonate or hydrogencarbonate. The final reaction mixture of the process is dried by a freeze or spray drying process, preferably a spray drying process. The air temperature during spray drying is about 70 ° C to 100 ° C, where the air feed rate is between 30 Hz and 50 Hz. The pre-cleaning of air before entering the spray drying chamber should reach 100,000 level. The speed is between approximately 1 Hz and 3 Hz. The sodium chloride added in the process is dried with a reaction product such as an iron hydroxide-sucrose complex to form a dry powder product which can be rapidly reconstituted in a suitable solvent prior to administration. The amount of sodium chloride used in the process is calculated according to Equation I above.

In the method for preparing an active blood-enriching ingredient (iron-saccharide complex) which is powdered and mixed with a suitable excipient, the "iron" ion refers not only to iron ions in a solution, but also to other complexes such as a hydroxyl group. Forms of iron ions. Similarly, OPT includes OH_ in the iron hydroxide precipitate.

"Complex" refers to a complex or polymer of molecules, iron and certain sugars. "Auxiliary material" means any molecule, component, compound or complex that has no blood-filling activity. Thus, excipients in a broad sense include unreacted starting materials, by-products, degradation products, buffers, diluents, preservatives, salts, and the like. Excipients can also be added to the reaction mixture to adjust the chemical and/or physical properties of the final product. Such excipients may also be referred to as "additives" or "excipients".

The iron-saccharide complex of the present invention may be composed of a skeleton structure formed of a sugar or a derivative thereof and iron. The process of the invention can be used to prepare powdered iron-sugar complexes. A useful reagent should contain at least one sugar and a substance that provides a source of ferric ions.

The term "sugar" as used in the present invention refers to monosaccharides and oligosaccharides. "Monosaccharide" refers to a single sugar unit without a glycosidic bond. These include aldoses, disaccharides, aldoses, ketoses and diketoses, as well as deoxysaccharides and amino sugars, as well as derivatives thereof. Examples of monosaccharides include dihydroxyacetone, glyceraldehyde, Red sugar, ribose, sorbose, pentose, arabinose, levulose, galactose and manose. "Oligosaccharide" refers to a sugar in which ten or more monosaccharides are combined. Oligosaccharides include, but are not limited to, sucrose, maltose, cellobiose, isomaltose, gentiobiose, melibiose, rutose, primrose, trehalose, lactose, and derivatives thereof. Preferred is sucrose.

"Sugar derivative" means a compound derived from the monosaccharide or oligosaccharide. A sugar comprising one or more terminal groups which are oxidized to a carboxyl group, a thiol group is reduced, and one or more hydroxyl groups are replaced by a hydrogen, an amino group, a sulfhydryl group or the like. For example, oxidized sugars include gluconate salts obtained by oxidation of glucose. These oxidized sugar groups can be ionized based on their ionization constant and pKa value. The ionized sugar is called a sucrose salt or a sugar acid, and its protons remain on the ionized sugar. If the ionized carboxyl group is combined with a cation such as sodium ion, a sugar salt is formed. Other suitable sugar or sugar derivatives include those which are similar in nature to the sugars described above. A preferred sugar derivative is a gluconate such as sodium gluconate.

Typical sugars and derivatives thereof useful in the present invention must be sufficiently soluble in water. Naturally occurring or synthetic sugars and derivatives thereof, including the sugars of the D and L optical isomers or their racemic mixtures, are suitable for use in the present invention. Derivatives of sugars may include sugar based acids, salts, methyl esters, amines and alcohol derivatives. Acids include, but are not limited to, gluconic acid, dextrose diacid, hydroxy acid fructose, alpha-mercapto tyrosine, uronic acid, sucrose diacid, mannoic acid, saccharide acid, galacturonic acid, glucuronic acid, mannose Uronic acid, xylic acid, tartaric acid, galactonic acid, glyceric acid, lactic acid, arabinose dihydroxy acid, mannose dihydroxy acid, glucose dihydroxy acid, maltoic acid, and lactanoic acid. The salt may be composed of uronic acid and an alkali metal or alkaline earth metal including, but not limited to, lithium, sodium, potassium, rubidium, magnesium, calcium, strontium and barium. A particularly useful salt therein is sodium gluconate. Amines include, but are not limited to, fucosylamine (2-amino-2,6-dideoxygalactose), galactosamine (2-amino-2-deoxygalactose), acosamine (3-amino-2,3, 6-tripaoxy-L-wood-hexose), bacitracin (2,4-diamino-2,4,6-trideoxy-0-glucose), glucosamine (2-amino-2-deoxyglucose), etc. . Alcohols include, but are not limited to, mannitol, glucose alcohol, arabitol, xylitol, fucitol, rhamitol, erythritol, ribitol, galactitol, glycerol, and the like.

Polymeric sugars or polysaccharides such as starch, cellulose, dextran and dextrin are not suitable for use in the present invention. In fact, the iron-saccharide complex of the present invention does not contain a significant amount of polysaccharide. For the purpose of the present invention In terms of "significant quantity" is defined as the concentration of polysaccharide that causes an adverse reaction, such as an allergic reaction caused by an iron-saccharide complex when administered to a patient parenterally.

Therefore, the iron-saccharide complex referred to in the present invention is preferably an iron-sucrose complex or a sodium iron gluconate complex.

The reaction for preparing the iron-saccharide complex is preferably carried out in an aqueous phase or an environment which is actually an aqueous phase. "Substantially aqueous phase" means that a portion of the reaction medium can include a non-aqueous liquid, and the reaction to form an iron-saccharide complex within this extent is not significantly affected. More suitably, the reaction medium is almost entirely water.

The iron ion is preferably a ferric ion, not a divalent iron ion. A soluble or dispersible trivalent iron-containing compound can be used as a source material of Fe(m). These materials include, but are not limited to, iron chloride, ferric nitrate, ferric sulfate, iron carbonate, ferric citrate, and iron hydroxide. Iron hydroxide is particularly useful in the present invention, but the other iron salts described above can be used to prepare iron hydroxide. Although most of the iron salts are available, it is best to use iron salts which are slightly soluble in water.

The iron hydroxide is preferably in a solid precipitated state or in a dispersed colloidal state. The colloid is composed of a substance divided into fine particles (gel particles) dispersed in another substance. A colloid is considered to be a physical state between a solution and a suspension. The size of the ferric hydroxide colloid is in the range of 1 nm to 100 nm. "True solution" means a homogeneous mixture of two or more substances. In "true solution", the particle size of the solute approximates the size of the molecule, which is much smaller than the particle size of the colloid or suspension. Based on the present invention, "solution" refers to a wide range, including true solutions and colloids, and mixtures thereof. Therefore, the reaction mixture solution may refer to an iron hydroxide colloid mixed with an unreacted substance dissolved in a "true solution".

Typically, an aqueous solution of an iron salt can be used to prepare iron hydroxide. Or, buy iron hydroxide directly from the market. A wide variety of bases or salts which hydrolyze to produce (OH)-ions can be used to prepare iron hydroxide intermediates. Such bases or salts include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydrogencarbonate. Ferric chloride hexahydrate is the best source of Fe(III) ions. Sodium carbonate is the best raw material for the preparation of iron hydroxide by reaction with iron salts.

If iron hydroxide is prepared by reacting an iron salt with a base or a basic compound such as sodium carbonate, the iron salt and the base or basic compound may be mixed in the form of a solid or a solution. It is best to completely dissolve the iron salt first. In water, the sodium carbonate solution was slowly added dropwise to the iron salt solution. Stirring for 10-30 minutes gives the iron hydroxide intermediate. The iron hydroxide can be used directly in the subsequent reaction with sugar. The sugar is added as a solid or a solution to the iron hydroxide which has been dispersed or colloidal.

Based on the present invention, the reaction is preferably terminated by centrifugation and washed with water to collect the filter cake. The iron hydroxide is preferably washed with water to facilitate determination of its weight. The water content of the wet iron hydroxide was measured to determine the net weight of the iron hydroxide. The sugar in the form of a solid or solution is mixed with iron hydroxide in the presence of water. A certain amount of sodium hydroxide solution was added dropwise to adjust the pH of the reaction solution. The reaction was stirred and heated slowly to promote dissolution. The amount of sugar, water and sodium hydroxide charged is calculated based on the amount of iron hydroxide added.

The feed ratio (w/w) is:

Iron hydroxide : sucrose : sodium hydroxide : total water =1: a : b : c

among them:

a is any number in the range 5-12, a is preferably between 8-9; b is any number between 0.1-0.3, b is preferably between 0.15-0.25; c is 10- Any number between 15 and c is preferable between 12-13. Weight of iron hydroxide (dry) = weight of iron hydroxide intermediate X iron content of iron hydroxide intermediate X 106.86/55.84

In the present invention, the iron hydroxide intermediate means a wet product of iron hydroxide (aqueous iron hydroxide).

The feed ratio (w/w) in one example of the present invention is:

Iron hydroxide: sucrose: sodium hydroxide: total water = 1: 8.4906: 0.2076: 12.2642 The total water comprises water of the iron hydroxide intermediate, which corresponds to the total weight of the intermediate minus the net weight of the iron hydroxide. The total water also includes sodium hydroxide solution and water from other solutions.

After all ingredients have been completely dissolved, the solution should be sampled for chlorine and iron content to determine the weight of sodium chloride to be added. The weight of sodium chloride is calculated by the following equation:

G Reaction solution ⁼ G total water + (sucrose + G) + G sodium hydride - G distillate

G supplemental chlorine == G reaction wave ^x 58.5 X (C reaction solution X 1.06% - C reaction liquid gas) /35·5, G reaction solution: total amount of reaction solution G total water: total amount of dissolved water;

G «: Sucrose dosage G,: Ferric hydroxide dosage

G Sodium hydroxide feed amount G _it water: Net weight of distilled water during sampling

G ^: Additional sodium chloride amount C Reaction liquid Reaction liquid iron content (%)

C reaction liquid chlorine content (%),

The amounts are all by weight.

The amount of sodium chloride added is obtained according to the above calculation formula.

The total reaction mixture was filtered while the filtrate was distilled at 100 ° C to 120 ° C. The temperature of the distillation tank and the cloud point of the reaction mixture should be monitored. When the cloud point reaches a set value, which is any value between 4.6 and 5.1, the distillation is stopped. A small amount of water was added while the reaction mixture was still hot. The reaction mixture was agitated and then the specific gravity of the solution was measured. If the specific gravity is above 1.35 g/ml, add water until the specific gravity of the solution is between 1.25-1.35 g/ml. The prepared iron-sucrose solution was cooled and dried.

It is not necessary to remove unreacted reactants or reaction by-products prior to drying. The final product can also be dried using other drying methods, and the final iron-sucrose solution is preferably dried by spray drying. Pre-cleaning of compressed air and hot air should reach the 100,000 level. During the drying process, the material in the dryer should be fluidized. The fluidized liquid is first passed through a peristaltic pipetting pump and then atomized into a very fine droplet by compressed air and then injected into the dryer through a sprayer. Hot air is also used to promote drying.

The drying parameters are as follows: The material input speed is between l-3Hz. The air temperature is approximately 70. C to 100. C. The material temperature is approximately 50. C to 75. C. The air input speed is 30-50Hz.

The dried material was cooled and weighed. Preferably, the dried iron-sucrose complex is comminuted through a 40 mesh screen. The screened composite is preferably remixed to obtain a uniform iron-sucrose complex powder. The dry powdered composite was loaded into a two-layer PE bag and then sealed. Put the sealed PE bag into the aluminum-plastic composite bag and seal it, then put it into the aluminum to listen, seal and label. The dry iron-sucrose complex can be packaged in 10kg, 5kg, lkg, 500g, 250g, 50g or packaged according to customer needs. The range of chemicals, compounds, and amounts supplied is provided as a general guide. For example, the sucrose in the saccharides used herein is for illustrative purposes only. It is possible for a person skilled in the art to find other similar chemicals or ranges that can be completed without departing from the spirit of the invention. detailed description

The following examples are intended to explain and understand the technical solutions of the present invention, but are not intended to limit the scope of the invention.

Example 1

Preparation of iron hydroxide intermediates:

Anhydrous sodium carbonate 9.30 g was weighed and dissolved in 100 g of purified water. Another weighed 14.50g of ferric chloride hexahydrate, added to 60g of purified water, stirred and dissolved. After the ferric chloride is completely dissolved, the prepared sodium carbonate solution is added to the ferric chloride solution. After the sodium carbonate solution is added, stirring is continued for a while, centrifuged with a centrifuge, and washed with purified water. The precipitate is collected to obtain an iron hydroxide intermediate.

Preparation of iron-sucrose complex:

The reactants were placed in the flask in the following proportions:

Iron hydroxide: Sucrose: Sodium hydroxide: Dissolved total water = 5.4g: 50g: l.Og: 75g, slowly heated to warm up; When the material is completely dissolved, sample and check the chlorine content and iron content, and restart stirring after sampling. Continue to heat. According to the test results, the amount of sodium chloride added was calculated according to the above equation I, and the calculated amount of sodium chloride was weighed and added to the reaction liquid. After adding sodium chloride, stop heating. The reaction temperature is controlled between 100 and 120 ° C; the reaction is carried out while distilling until the cloud point reaches between 4.6 and 5.1 and the reaction is completed.

Example 2

Free-drying preparation of solid powder of iron-sucrose complex

The iron-sucrose complex solution obtained in Example 1 was added, purified water was added to a specific gravity of 1.26 g/ml, placed in a stainless steel tray, placed in a lyophilizer, and vacuum-dried for 30 hours to obtain a water-soluble solution. A tan powder containing a predetermined amount of chloride ions. Example 3

Anhydrous sodium carbonate 139.5 g was weighed and dissolved in 1500 g of purified water. Further, 217.5 g of ferric chloride hexahydrate was added, and it was added to 900 g of purified water, and stirred to dissolve. After the ferric chloride was dissolved, the prepared sodium carbonate solution was added to the ferric chloride solution, and then stirred for 10 minutes, centrifuged with a centrifuge, and washed with purified water. The precipitate is collected to obtain the intermediate iron hydroxide.

The reactants were added to the flask in the following proportions: Iron hydroxide: Sucrose: Sodium hydroxide: Total dissolved water = 79.5 g: 755.2 g: 19.9 g: 975 g, slowly heated to warm up; The content and the iron content, restart the stirring after sampling, and continue to heat. According to the test results, the amount of sodium chloride added is calculated according to the above equation I, and the calculated amount of sodium chloride is weighed and added to the reaction liquid. Keep the temperature at 100-12 (TC, when the cloud point reaches 5.0, the reaction reaches the end point.

Purified water was added to the obtained iron-sucrose complex solution to adjust the specific gravity to 1.33 g/ml, and spray-drying was carried out to control the inlet speed of 1.0 HZ, the inlet air temperature of 70 to 100 ° C, and the material temperature of 50 to 75 °C. Finally, a tan powder is obtained which contains a predetermined amount of chloride ions. Example 4

Preparation of iron hydroxide intermediate

Weigh 9.30 kg of anhydrous sodium carbonate, add to 100 kg of purified water, stir and dissolve, and then pump into the measuring tank. 14.50 kg of ferric chloride hexahydrate was weighed, added to 60 kg of purified water, and dissolved by stirring. After the ferric chloride is completely dissolved, the prepared sodium carbonate solution is added dropwise to the ferric chloride solution, and the feeding time is controlled to about 30 minutes. After the sodium carbonate solution was added dropwise, stirring was continued for a while, and the resulting solution was filtered with a centrifuge and washed with purified water. The filter cake is collected to obtain an iron hydroxide intermediate.

Preparation of iron-sucrose complex stock solution:

Feeding ratio (weight):

Iron hydroxide: sucrose: sodium hydroxide: dissolved total water = 5.3kg: 45kg: 1.1kg: 65kg Weigh sucrose, dissolved water and sodium hydroxide according to the above ratio; from the dissolved water, take the appropriate amount The purified water dissolves the sodium hydroxide; the dissolved water, sucrose, and the intermediate are sequentially added to the solution tank; the stirring is turned on; then the sodium hydroxide solution is added to close the feed port. Slow heating Temperature; When the material is completely dissolved, sample and check the chlorine content and iron content, restart the stirring after sampling, and continue heating. According to the test result, the amount of additional sodium chloride is calculated according to the above equation I, and the calculated amount of sodium chloride is calculated and added to the reaction liquid. The heating steam pressure is controlled, and the reaction temperature is controlled between 100 and 120 ° C; the reaction is carried out while distilling. When the cloud point reached 5.0, the reaction reached the end point. When the reaction reaches the end point, it is diluted with an appropriate amount of purified water, and the specific gravity of the solution is adjusted between 1.25 and 1.35 g/ml.

Spray drying:

The iron-sucrose complex stock solution is dried by spray drying, and the compressed air and hot air used in the drying process are purified and up to the requirements of 100,000 cleanliness. In order to prevent fine particles or fine powder from being drawn into the air and causing pollution to the outside, a trap bag is placed on the upper portion of the dryer.

Control the liquid inlet speed of 1.0 ~ 3.0HZ, the inlet air temperature of 70 ~ 100 °C, the material temperature of 50 ~ 75 °C and the main fan frequency of 30 ~ 50HZ, the dry material is first crushed, then sieved, mixed, with double-layer polyethylene plastic Bags are packed.

Claims

Rights request

A powder pharmaceutical composition comprising: a therapeutically effective amount of an active pharmaceutical ingredient iron-saccharide complex and at least one additive and optionally an excipient, wherein the additive is an inorganic chloride.

2. The pharmaceutical composition of claim 1, wherein the iron-saccharide complex is selected from the group consisting of a ferric hydroxide-sucrose complex and a sodium iron gluconate-sucrose complex.

3. The pharmaceutical composition according to claim 1 or 2, wherein the inorganic chloride is sodium chloride.

4. The pharmaceutical composition of claim 3, wherein the amount of sodium chloride is calculated according to the following equation I:

Equation I:

G Reaction Solution = G Total Water + G Sucrose + Gi + G Sodium Nitride - G Distillate

G qi = G reaction solution ^x 58.5 X (C reaction solution iron 1.06% - C reaction liquid gas) / 35 · 5,

among them:

G total amount of reaction solution G ^: total amount of dissolved water;

G m: sucrose feed amount G _{1 :} ferric hydroxide feed amount

G Helium: Sodium hydroxide feed G Water: Net weight of distilled water during sampling

G Supplement ^ Additional sodium chloride amount C Reaction liquid iron. Reaction liquid iron content (%)

C : chlorine content (%) of the reaction solution,

The amounts are all by weight.

5. A method for preparing an iron-saccharide complex composition suitable for human or animal injection administration, comprising:

i) at least one sugar or sugar derivative or a mixture thereof, and

ϋ) Fe(III) ions in contact with inorganic chloride in the presence of cerium ions.

6. The method of claim 5 wherein said contacting is carried out in an aqueous medium.

The method of claim 5, wherein the inorganic chloride is added to the reaction mixture prior to the synthesis of the iron-saccharide complex or during the synthesis of the iron-saccharide complex.

8. The method of claim 5 wherein Fe(m) is present in the form of iron hydroxide.

9. The method of claim 8 wherein the iron hydroxide is prepared by mixing an aqueous alkaline solution with a solution containing Fe(III) ions.

10. The method of claim 9 wherein the aqueous alkaline solution is selected from the group consisting of sodium hydroxide, sodium carbonate and aqueous sodium hydrogencarbonate.

11. The method of claim 10, wherein the aqueous alkaline solution is an aqueous solution of sodium carbonate.

12. The method of claim 10, wherein the aqueous alkaline solution is an aqueous solution of sodium hydrogencarbonate.

13. The method of claim 5, further comprising the step of drying the unreacted inorganic chloride together with the reaction product iron-saccharide complex.

14. The method of claim 5 wherein the inorganic chloride is sodium chloride and the amount is calculated according to Equation I below:

Equation I:

G reaction solution = G total water + G sucrose + + G nitrogen 3⁄4_ sodium - G distillate

G qi = G reaction solution ^x 58.5 X (C reaction solution & ^x 1.06% - C reaction liquid gas) / 35.5,

among them:

G ^ _3⁄4 : total amount of reaction solution G dissolved total water amount;

G wire: sucrose feed amount G _{1 :} iron hydroxide feed amount

G Sodium hydroxide feed amount G saturated water: Net weight of distilled water during sampling

G _A : Additional sodium chloride amount C Reaction liquid iron. Reaction liquid iron content (%)

C reaction reaction liquid chlorine content (%),

The amounts are all by weight.

15. The method of claim 5, wherein the sugar or sugar derivative is selected from the group consisting of sucrose and sodium gluconate.

16. A method of preparing an iron-saccharide complex composition suitable for parenteral administration to a human or animal, comprising:

a) contact

i) at least one sugar or sugar derivative or a mixture thereof, and

Ii) Fe(III) ions in the presence of OH- ions;

17. The method of claim 16 wherein step (a) is accomplished in an aqueous medium.

18. The method of claim 16 wherein Fe(III) is present substantially in the form of iron hydroxide.

19. The method of claim 18, wherein the iron hydroxide is prepared by mixing an aqueous alkaline solution with a solution containing Fe(III) ions.

20. The method of claim 19, wherein the aqueous alkaline solution is selected from the group consisting of sodium hydroxide, sodium carbonate, sodium hydrogencarbonate or mixtures thereof.

21. The method of claim 20 wherein the aqueous alkaline solution is selected from the group consisting of sodium carbonate and sodium bicarbonate.

22. The method of claim 16 wherein the final reaction mixture is dried by lyophilization or spray drying.

23. The method of claim 16 wherein the added sodium chloride and the reaction product of step a) are dried together to form a dry powder product.

24. The method of claim 16 wherein the amount of sodium chloride is calculated according to Equation I below:

Equation I:

G reaction solution = G total water + G sucrose + + G sodium sulphate - G distillate

G qi = G reaction solution ^x 58.5 X (C reaction block ^x 1.06% - C reaction liquid chlorine) / 35.5,

among them:

G Total amount of reaction solution G . : Total dissolved water amount;

G ^: sucrose dosage G _{1 :} ferric hydroxide dosage

: Sodium hydroxide feed amount G _3⁄4 effluent: Net weight of distilled water during sampling

G supplemental sodium chloride amount C reaction liquid iron. reaction liquid iron content (%)

C reaction liquid chlorine content (%),

The amounts are all by weight.

25. The method of claim 16 wherein the sugar or sugar derivative is selected from the group consisting of sucrose, sodium gluconate.