CN105193844A - Method for preparing delta-hydroxyl contained ferric oxide (multinuclear) and medicine compositions of delta-hydroxyl contained ferric oxide, as well as application to field of hyperphosphatemia - Google Patents
Method for preparing delta-hydroxyl contained ferric oxide (multinuclear) and medicine compositions of delta-hydroxyl contained ferric oxide, as well as application to field of hyperphosphatemia Download PDFInfo
- Publication number
- CN105193844A CN105193844A CN201510290939.0A CN201510290939A CN105193844A CN 105193844 A CN105193844 A CN 105193844A CN 201510290939 A CN201510290939 A CN 201510290939A CN 105193844 A CN105193844 A CN 105193844A
- Authority
- CN
- China
- Prior art keywords
- phosphate
- multinuclear
- tablet
- phosphate adsorbent
- ferrum
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Abstract
The invention relates to a method for preparing delta-hydroxyl contained ferric oxide (multinuclear) and medicine compositions of delta-hydroxyl contained ferric oxide, as well as application to the field of hyperphosphatemia, in particular to preparation and separation methods of a Fe (III)-based phosphate absorbent as well as medicine compositions of the Fe (III)-based phosphate absorbent. The absorbent shows valuable pharmacological properties.
Description
Technical field
The present invention relates to for the preparation of containing δ-FeOOH (multinuclear) and the method for pharmaceutical composition thereof and the application in hyperphosphatemia field.
Background of invention
The invention provides the preparation method for the preparation of the phosphate adsorbent based on δ-FeOOH (multinuclear).Specifically, the method for form (such as the dried powder being suitable for directly the filling folliculus) preparation being easy to pack and the phosphate adsorbent be separated based on δ-FeOOH (multinuclear) is provided.
Phosphorus is crucial for bone mineralising, cellularity, genetic coding and energy metabolism.There is multiple organic and inorganic form.Phosphorus is present in nearly all food, and it is very effective that the GI of diet form absorbs.Phosphorus homeostasis is maintained by several mechanisms (release of renal excretion, cell, hormone control etc.) usually.When phosphorus load (from GI absorb, exogenous use or cell release) exceed renal excretion and tissue resorption time, then there is hyperphosphatemia.
Owing to there is relatively low absorbability containing obtainable or described phosphate adsorbent in high-caliber phosphate and prior art in diet, be thus necessary to use such adsorbent effectively to control phosphatic blood level with high dose.Therefore, need to provide the phosphate adsorbent with high phosphate binding capacity that can be used as medicine.
And, also need to provide the phosphate adsorbent that the emission and absorption being characterised in that ferrum in physiological conditions reduces.And, also need to provide such preparation method; It produces all even stable and can by the adsorbent easily prepared and/or pack, and can when do not affect adsorbent character, namely its phosphate binding capacity to carry out on a large scale.
Having been surprisingly found that: by using special reaction condition during the preparation process of multinuclear ferrum, its phosphate binding capacity can be prepared higher than the phosphate adsorbent of prior art, particularly higher than the phosphate adsorbent based on multinuclear ferrum (III) of the phosphate adsorbent based on ferrum recorded in prior art.
In order to obtain the complex based on ferrum that can be used as medicine, acquisition produces the preparation method with the product of reproducible high phosphate binding capacity and is necessary.This needs must be met especially when extensive amplification.Have been surprisingly found that, by adopting suitable reaction condition, namely by using stabilizing agent as sucrose and/or by being separated product as spraying dry or bed spray are dry through gentle method during heat stress, a large amount of uniform phosphate adsorbents based on ferrum (III) can be prepared, such as, from several grams until commercial scale.
Summary of the invention
According to the present invention, pharmaceutical composition of the present invention refers to the pharmaceutical composition containing the phosphate adsorbent based on ferrum (III) of the present invention.
The present invention includes the method preparing compositions, the method comprises the following steps:
I the aqueous solution of ferrum (II) salt mixes with the aqueous solution of alkali as alkali, such as mixes simultaneously by (), form the suspension that pH is 3 to 10, such as 4 to 9, such as 7 to 9, preferably about 8.5; This suspension is left standstill; Add rapidly appropriate EDTA.Logical oxygen, until pH value is about 5.
(ii) be separated the precipitation formed, optionally carry out washing, such as washing with water;
(iii) by precipitation suspendible, be such as suspended in water, the suspension that to obtain with the Weight computation iron content of suspension be about 3 to 16%;
(iv) add one or more carbohydrates and/or humic acid, the iron content obtaining institute's separating solids is the suspension of about 10 to about 50% weight iron;
V () is dry by filtration, decantation, spraying dry or bed spray drying, preferably spray drying or bed spray, most preferably bed spray is dry, separating obtained phosphate adsorbent.
In step (i), first the aqueous solution of ferrum (II) salt and the aqueous solution of alkali are oxidized generation nucleation, and the precipitation of hydroxyl oxygen ferrum (ironoxidehydroxide) then occurs.Nucleation can be carried out under insoluble carbohydrate is as the existence of starch, or can add described carbohydrate after nucleation and before precipitation.
In an embodiment of the present invention, the aqueous solution of ferrum (II) salt is mixed after being oxidized with the aqueous solution of alkali under insoluble carbohydrate is as the existence of starch.Then other insoluble carbohydrate is optionally added.In another embodiment of the present invention, only after mixed with iron salt by the aqueous solution of alkali, such as, after iron salt has started to precipitate, add insoluble carbohydrate.
Iron salt can be ferrous chloride (II), ferrous nitrate (II) or ferrous sulfate (II), ferric oxalate, and preferred iron salt is ferrous sulfate.
The aqueous solution of ferrum (II) salt can the particularly solution of ferrum (II) salt in water as hereinbefore defined.Based on the total weight of iron salt, iron salt solutions can comprise the iron salt of about 3 to about 35wt/wt, such as about 3 to about 25wt/wt, the preferably iron salt of about 3 to about 16wt/wt%.Preferred use comprises about 3 to about 35wt/wt, such as about 3 to about 25wt/wt, preferably about 3 to iron sulfate (II) solution of about 16wt/wt% iron salt based on the total weight of iron salt.
Alkali for using can be hydroxide or the carbonate of alkali metal or alkaline-earth metal.Preferred alkali metal carbonate, alkali metal hydrogencarbonate and alkali metal hydroxide (carbonate of such as sodium, bicarbonate and hydroxide).Specifically, alkali can be selected from LiOH, KOH, NaOH, NaHCO
3, Na2CO
3, Ca (OH)
2, Mg (OH)
2, Li
2cO
3, K
2cO
3, CaCO
3, MgCO3, preferred NaOH.Cumulative volume based on solution calculates, and aqueous slkali can comprise about 20 to about 30, the alkali of such as about 22 to about 27, such as about 25.5vol%.
The aqueous solution of alkali can comprise the aqueous solution containing alkali as hereinbefore defined.
Select to alkali number the pH obtaining expection, the pH regulator of the solution such as obtained by the mixture by the aqueous solution with ferrum (II) salt is about 3 to about 10, preferably about 6 to the pH of about 9, more preferably from about 8.5.
In a preferred embodiment of the invention, in step (i), the pH of solution under the pH of about 6 to about 9, preferably about 8.5, is 5 after oxidation, keeps constant between whole mixing period.By adding iron salt and alkali simultaneously, can by pH regulator to and in this process whole, remain on desired value.
According to the present invention, reaction, particularly step (i) are preferably carried out at the temperature of about 20 DEG C about 1 to about 30, preferably about 5 to about 25, preferably.In another embodiment, (1} carries out step at ambient temperature.
According to wood invention, can by the washing of precipitate of acquisition in step (i) at least one times.
According to the present invention, in step (ii), by gained precipitate and separate, such as by decantation, filtration, centrifugal, preferably by decantation be separated, then wash.Slurry, preferably to carry out with water.Water washing and NaHCO can be adopted
3the associating of washing.By washing of precipitate once or for several times, preferably for several times.Can carry out washing until the level of impurity drops to predeterminated level.Preferably carry out 2 to 5 times washing, more preferably 3 to 5 times.After each washing operation, by decantation, filtration, centrifugal, preferably by decantation except anhydrating or wash solution.Preferred product is not completely dried.
Then product is suspended in water again.Need minimum water can process suspension.Such as, the ratio of the amount of water/final phosphate adsorbent can be about 0.8 to about 2, preferably 1.1 to 1.5, more preferably from about 1.
The aqueous suspension of the phosphate adsorbent of gained approximately has the iron content of about 2 to about 16% weight, preferably about 3 to about 8% and preferably has the pH value of about 5 to 7.
After step (ii), suspension can be made to place a period of time, such as more than 1 hour, preferably 1 to 5 hour.During this period, can stir suspension.
According to the present invention, in step (iv), carbohydrate comprises solubility or insoluble carbohydrate or its mixture.
According to the present invention, soluble-carbohydrate can be glucosan derivative.Glucosan derivative can be selected from agarose, glucosan, dextrin, glucan derivative, cellulose, cellulose derivative, sucrose, maltose, lactose, mannitol and composition thereof.Preferred glucosan derivative is sucrose, maltodextrin and composition thereof.Most preferred glucosan derivative is sucrose.
According to the present invention, based on the Weight computation of phosphate adsorbent, the soluble-carbohydrate added in step (iv) such as the amount of glucosan derivative can be about 5 to about 25 % by weight, preferably about 5 to about 20 % by weight.The sucrose of preferred use about 5 to about 15 % by weight or about 5 to about 10 % by weight sucrose.
According to the present invention, insoluble carbohydrate can be starch.Starch can be selected from corn starch, wheaten starch, rice starch, corn starch, pea starch or potato starch and composition thereof.Starch can also contain some soluble starch (such as maltodextrin).Such as, starch can be the potato starch and 20 % by weight or the mixture of following soluble starch of 80 % by weight or more, the potato starch of such as 80 % by weight or more and 20 % by weight or the mixture of following maltodextrin.In another embodiment of the present invention, starch can replace with dietary fiber.Preferred starch is potato starch.
For every about 0.5 to about 30g iron salt, such as often about 1.0 to about 20g iron salt, such as often about 1.5 to about 10g iron salt, such as often for about 2.0 to about 15g iron salt, preferably add the insoluble carbohydrate of such as 1g as starch.
In step (iv), antiseptic can be added, such as solubility antiseptic, such as chlorhexidine or p-Hydroxybenzoate; Or alcohol, such as ethanol, methanol, 2-propanol or its combination.Preferred preservative is alcohol.Preferred alcohol is ethanol.
Step (v) comprises separation phosphate adsorbent.This separation can be undertaken by filtration, decantation, spraying dry or bed spray drying.Preferably carry out that spraying dry or bed spray are dry, such as bed spray is dry.Have been surprisingly found that; Such technology causes creating well granular, free-pouring and not containing the powder of dust, it is suitable for directly filling folliculus and does not use excipient, and its storage stability is significantly excellent.This powder can be easily handled, such as, be easily handled during processing or packaging.
According to the present invention, provide the method with the adsorbent in ferrum (III) of high phosphate binding capacity of preparation dry powdered form as described above, wherein said method also comprises the step by spraying dry or the dry separated product of bed spray.The bed spray of the method parameter that preferred employing is suitable is dry.
Have been surprisingly found that; Bed spray drying is particularly suitable for directly and continuously producing well granular, free-pouring and not containing the powder of dust, described powder is suitable for directly filling folliculus or can being easily pelletized to produce granule.
The invention discloses the method preparing compositions, the method comprises the following steps:
I ferrous sulfate (II) mixes with at least one alkali by (), forming pH is the suspension of 7 to 9, adds rapidly appropriate EDTA.
(ii) logical oxygen, until pH value is about 5.Be separated the precipitation formed;
(iii) precipitation is suspended in aqueous solution;
(iv) starch and sucrose is added, and;
V () is by the prepared product of the dry separating step (iv) of spraying dry or bed spray.
In addition, formulation process can be carried out after step (v).Such as can mix phosphate adsorbent, granulate, encapsulate and/or tabletting, carry out with suitable excipient if necessary.
According to the present invention, provide the phosphate adsorbent based on ferrum, it comprises carbohydrate and/or humic acid; Such as solubility or insoluble carbohydrate or its mixture.The example of soluble-carbohydrate comprises sucrose, maltodextrin, agarose, glucosan, dextrin, cellulose, maltose, lactose, mannitol or its mixture.Preferred soluble-carbohydrate is sucrose.The example of insoluble carbohydrate comprises starch, agarose, glucosan, dextrin, cellulose.Preferred insoluble carbohydrate is starch.
One or more calcium salts can be added as calcium acetate.The example of suitable calcium salt comprises mineral acid or organic acid salt, particularly calcium acetate.
In an embodiment of the present invention, phosphate adsorbent based on ferrum can be defined as the complex formed with multinuclear FeOOH (III), starch and glucosan derivative (such as sucrose or maltodextrin, preferably sucrose).In a preferred embodiment, multinuclear FeOOH is combined with adsorbent based metallic substance such as starch.
In an embodiment of the present invention, complex of the present invention comprises and to be covered by δ-FeOOH (multinuclear) and optionally by starch granules that water soluble carbohydrates is stable.
In another aspect of this invention, provide the new phosphate adsorbent containing FeOOH (III), based on the total weight of product, this adsorbent contain at least about 20 % by weight ferrum, such as at least about the ferrum of 25 % by weight, such as about 30 % by weight.In another aspect of this invention, based on the total weight of product, the iron content of complex of the present invention is about 20 to about 50 % by weight, such as about 40 to about 50 % by weight.
Preferred phosphate adsorbent of the present invention comprises the ferrum (III) optionally mixed with ferrihydrite (feroxyhyte).In preferred embodiments, the multinuclear FeOOH (III) of phosphate adsorbent is made up of δ-FeOOH or beta-hydroxy ferrum oxide, preferably δ-FeOOH or its mixture and ferrihydrite.
Phosphate adsorbent based on δ-FeOOH (multinuclear) of the present invention can be used for treating and/or preventing hyperphosphatemia, hypercalcemia, hyperparathyroidism, minimizing cardiovascular disease incidence and death, renal osteodystrophy, calciphylaxis and soft tissue calcification.Phosphate adsorbent based on δ-FeOOH (multinuclear) of the present invention is particularly suitable for treating and/or preventing hyperphosphatemia in people and homoiothermic animal, particularly companion animals are as Canis familiaris L. order particularly cat.
Detailed description of the invention
Preparation
Phosphate adsorbent of the present invention and the pharmaceutical composition containing it more particularly can be used for the patient suffering from hyperphosphatemia, such as can be used for the patient relying on dialysis, such as hemodialysis, or suffer from advanced chronic kidney disease (CKD), the patient of chronic renal failure, chronic renal insufficiency, end-stage renal disease.
Phosphate adsorbent of the present invention and being particularly used in containing its pharmaceutical composition needs control serum phosphate and Serum Calcium Phosphorus product (calcium-phosphateproduct) level by the phosphate adsorbent based on ferrum (III) of the present invention using effective dose to described curee in the patient of the curee of this treatment, such as chronic hemodialysis and maintain normal serum calcium level simultaneously.
In another embodiment of the present invention, phosphate adsorbent of the present invention and the pharmaceutical composition containing it also can be used for from dialysis solution, whole blood or blood plasma, optionally removing inorganic phosphate or eliminating inorganic phosphate, such as in dialysis patient, such as Patients in Hemodialysis, it is undertaken by the phosphate adsorbent based on δ-FeOOH (multinuclear) of the present invention using effective dose to described curee.
Pharmaceutical composition of the present invention can be mixed with any conventional form, preferred oral dosage form, such as powder, granule, granule, capsule, little wafer, excellent bag agent (stickpacks), bottle (optionally with suitable drug-supplying system as together with scale spoon), tablet, dispersible tablet, film coated tablet or unique coated tablet (uniquelycoatedtablet).
Pharmaceutical composition of the present invention can also be mixed with semi-solid preparation, such as aqueous and non aqueous gels, can swallow gel, chewable bar, fast dispersing dosage form, emulsifiable paste ball can chewable dosage forms, can chewable dosage forms or the little wafer of edible (as hereafter define).
Preferred preparation is that powder, granule, tablet are as dispersible tablet and chewable tablet.
In a preferred embodiment of the invention, with the form pharmaceutical compositions of powder or granular product (i.e. particulate powder or granule), described product is optionally packed into powder container as in bottle, capsule, little wafer or rod bag.This little wafer or rod bag optionally have the stubborn character of child.
Can add as hereafter the lubricant that defines, such as, when phosphate adsorbent of the present invention (such as obtaining according to preparation method defined above) is packed in capsule.
Granular product can by dry granulation if rolling process or wet granulation be as obtained in fluid bed or high shear mixer.Granulation can carry out the mechanical stability improving granule under the existence of binding agent as MCC.Then can by particles filled in such as bottle, capsule, little wafer or rod bag.In an embodiment of the present invention, this filling can be carried out by automatic working system.Little wafer or rod bag can containing the granular products of 0.5 to the 10g that has an appointment, such as about 0.5 to 5g.
Pharmaceutical composition of the present invention can contain binding agent, such as dry adhesives, such as sucrose or microcrystalline Cellulose (MCC).
In another embodiment of the present invention, pharmaceutical composition of the present invention can contain lubricant, such as magnesium stearate or hydrophilic lubricant as PEG6000 or PEG4000.The invention provides containing based on δ-FeOOH (multinuclear) phosphate adsorbent (such as powder or granule) and optionally comprise the capsule of lubricant in addition.
According to an embodiment of the present invention, pharmaceutical composition is the form of tablet.In order to apply better or be easy to distinguish, film coating can be carried out to tablet subsequently.
Can by pure powder (namely not containing any excipient) tabletting of phosphate adsorbent, such as direct compression be produced tablet.
In another embodiment of the present invention, by not suppressing together with suitable excipient containing the phosphate adsorbent powder of excipient prepare tablet by pure powder, namely, described excipients is selected from the excipient of filler, binding agent, disintegrating agent, flowable, lubricant and composition thereof in this way.
In another embodiment of the present invention, obtain tablet by particulate powder (i.e. " interior phase ") being suppressed together with other excipient.Pharmaceutical composition of the present invention interior can comprise the excipient that phosphate adsorbent and at least one are selected from filler, binding agent, disintegrating agent and composition thereof mutually.The foreign minister of pharmaceutical composition of the present invention can comprise the excipient that at least one is selected from flowable, lubricant, filler, disintegrating agent and composition thereof.Preferred foreign minister (additional) comprises flowable, lubricant and optionally comprises filler and/or disintegrating agent.
Pharmaceutical composition of the present invention can comprise filler to provide machinability.
Suitable filler material is well known in the art, it comprises microcrystalline Cellulose, lactose and other carbohydrate, starch, pregelatinized Starch as starch, corn starch, dicalcium phosphate, potassium bicarbonate, sodium bicarbonate, cellulose, calcium phosphate dibasic anhydrous, sugar, sodium chloride and composition thereof, wherein, lactose, microcrystalline Cellulose, pregelatinized Starch and composition thereof are preferred.Microcrystalline Cellulose and to comprise microcrystalline Cellulose and one or more other filleies as useful especially due to the disintegrate of its excellence and compacting character in the mixture of corn starch or pregelatinized Starch.Preferred filler is microcrystalline Cellulose.
Based on the total weight of pharmaceutical composition, filler can with about 10 to 60 % by weight, the amount of preferably 20 to 40 % by weight, more preferably from about 30 % by weight exists.
Pharmaceutical composition of the present invention can also contain the excipient of following classification:
The mixture of the tabletting binding agent a) known (such as hydroxypropyl emthylcellulose, starch, pregelatinized Starch, gelatin, sugar, natural and rubber polymer are as hydroxypropyl cellulose, ethyl cellulose, polyvinyl acetate, polyacrylate, gelatin, the natural and rubber polymer of carboxymethyl cellulose, methylcellulose, polyvinylpyrrolidone, low replacement), microcrystalline Cellulose and aforementioned substances.In preferred embodiments, binding agent is made up of the hydroxypropyl cellulose HPC of low replacement or hydroxypropyl emthylcellulose HPMC, such as 3 or 6cps.Based on the total weight of pharmaceutical composition, tabletting binding agent can account for about 1 to about 10 % by weight, preferably about 1 to about 5 % by weight.In preferred embodiments, based on the total weight of pharmaceutical composition, use binding agent with about 3 % by weight.
B) disintegrating agent, such as carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, crospovidone, primojel.Preferred disintegrating agent is crospovidone and cross-linking sodium carboxymethyl cellulose.Based on the total weight of pharmaceutical composition, disintegrating agent can account for about 3 to about 15 % by weight, preferably about 5 to about 10 % by weight.Such as, disintegrating agent is crospovidone, cross-linking sodium carboxymethyl cellulose or its mixture, and the total weight based on pharmaceutical composition is involved with about 10 % by weight.
C) lubricant, such as magnesium stearate, stearic acid, calcium stearate, glyceryl behenate, hydrogenated vegetable oil, cohune put wax etc., Polyethylene Glycol as PEG6000 or PEG4000.In preferred embodiments, lubricant is magnesium stearate.Based on the total weight of pharmaceutical composition, lubricant such as magnesium stearate can exist to about 5wt, preferably about 2 to about 3wt% with about 0.5 to about 5wt, such as about 3.
D) flowable, such as silicon dioxide or Pulvis Talci, preferably silica sol.Based on the total weight of pharmaceutical composition, flowable such as silica sol can exist with about 0.1-2 % by weight, such as 0.5 % by weight.
E) antitack agent or fluidizer, such as Pulvis Talci;
F) sweeting agent;
G) shading or coloring medium, such as titanium dioxide, ferrum oxide or aluminum color form sediment;
H) taste masking medium;
I) antioxidant.
According to the present invention, provide containing based on the phosphate adsorbent of ferrum (III) and lubricant and the optional tablet being selected from the other excipient of filler, binding agent, disintegrating agent and flowable as described above containing at least one.Tablet can comprise the excipient that at least one is selected from antitack agent as described above, fluidizer, sweeting agent, shading or coloring medium and taste masking medium in addition.
Tablet by coating, such as, can comprise film coating.Such as Polyethylene Glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydrophilic polymer is comprised as containing the cationic polymer (such as EudragitE and EPO) of dimethylaminoethyl methacrylate as functional group at the example for being applied to the suitable filmogen in the film coated composition of pharmaceutical composition of the present invention, hypromellose, hydroxy methocel and hydroxypropyl emthylcellulose etc., wherein, hydroxypropyl emthylcellulose is preferred.
Film coating composition ingredients comprises plasticizer, and the glycerol of such as Polyethylene Glycol (such as polyethylene glycol 6000), triethyl citrate, ethyl phthalate, propylene glycol, convention amount and above-mentioned opacifier are if titanium dioxide and coloring agent are as ferrum oxide, aluminum color lake etc.Preferred use dry mixture is as Sepifilm or Opadry mixture, and the latter is standby by Colorcon Inc..These products can be the dry premixs of the independent preparation of film forming polymer, opacifier, coloring agent and plasticizer, and they are further processed into aqueous film coating suspensions.
Based on the total weight of pharmaceutical composition, film coating usually can be applied to reach tablet weight increase about 1 to 10 % by weight, preferred about 2 to 6 % by weight.
Film coating can use water and/or conventional organic solvent (such as methanol, ethanol, isopropyl alcohol), ketone (acetone) etc. to carry out by routine techniques in suitable coating pan or fluid unit.
In another embodiment of the present invention, the phosphate adsorbent based on ferrum ferrum (III) is formulated into unique coated tablet.
Tablet of the present invention can be prepared based on the phosphate (drug substance) of ferrum ferrum (III) with by adding high concentration magnesium stearate (such as about 3 to about 5%) by direct pressing.
Tablet can also comprise binding agent, such as HPMC3cps.
Electrostatic dry powder end deposition process can increase the structural intergrity of tablet and not add a large amount of materials, and provides the chance of unique dosage form outward appearance.
Coating can be carried out by electrostatic dry powder end deposition process to tablet, such as, carry out as follows:
By by polymer, (preferred Eudragits is as E, RS.L, RL type and other PVP/VA, HPMPC, HPMCAS), the mixture of coloring agent (such as titanium dioxide) and other additive (such as PEG3000) carries out melt extruding obtained coating blend.Optionally other micronization step is carried out to produced melt extrudate, such as, there are about 7 to 10 microns.
Coating process can comprise: i) be fixed on wheel by core core (such as passing through vacuum), make electrically charged, be conveyed through coating room, the coating powder of oppositely charged is made to be attached to core wicking surface, ii) the core core of coating powders is transported on the wheel of IR lamp, make coating melting, iii) core core is transferred on second adjacent wheel, repeat the method to bottom label.Typical coat weight is the 3-4% of core core weight, and about 20-50um is thick.
Heat fixation step: it is different that product circulates from the melting of product, but normally every side is about 80s.This comprises and being heated from room temperature by tablet, thus the temperature of tablet surface reaches the peak value of about 100 DEG C and the peak value that the temperature of sheet in-core reaches about 70 DEG C reaches about 20s.
According to the present invention, the phosphate adsorbent based on ferrum (III) of the present invention can also be mixed with semi-solid preparation.Said composition is comfortable for swallowing, particularly for old people and child so, can consider them as day supplement instead of medicine.In addition, this semisolid dosage form tool has the following advantages: they can be filled in many or single-dose containers.
In an embodiment of the present invention, compositions of the present invention is the form of aqueous gel preparation.This aqueous gel can contain viscosifier (it preferably has wetting property) or thickening agent.Viscosifier can be selected from polyoxyethylene sorbitan fatty acid ester, Polyethylene Glycol and glycerol.Thickening agent can be selected from starch (such as corn starch, potato starch, pea starch) (starch is preferably heated), cellulose derivative (such as hydroxypropyl emthylcellulose), alginate (such as sodium alginate), carbomer, silica sol become paste (such as PVP, polyacrylic acid, arabic gum, xanthan gum and composition thereof) with other.
In addition, antiseptic can be added, such as methyl parahydroxybenzoate and salt thereof, propyl p-hydroxybenzoate and salt, sorbic acid and salt thereof, benzoic acid and salt thereof or chlorhexidine.Correctives and sweeting agent can also be added.Aqueous gel can containing buffer system if citrate or acetate buffer be to guarantee the antimicrobial efficacy of protective system.
Aqueous gel can also be selected from sweeting agent if saccharin sodium, aspartame, sucralose and correctives are as grass poison or the material of Herba Passiflorae Caeruleae (passion) containing at least one.
Aqueous gel can be prepared as follows: be dissolved in purified water by all excipient except thickening agent, phosphate adsorbent is disperseed until acutely mix, then adds thickening agent.
Possible semi-solid preparation includes but not limited to swallow gel, such as aqueous or non aqueous gels (phosphate adsorbent is encapsulated or granulation optionally); Chewable bar, such as grain rod; Fast dispersing dosage form, such as per os discrete sheet; Emulsifiable paste ball can chewable dosage forms; Can chewable dosage forms, such as confection, soft capsule or block; Or the little wafer of edible.In this kind of semi-solid preparation, the phosphate adsorbent based on ferrum (III) containing dietary fiber as insoluble carbohydrate, such as, can replace starch with dietary fiber.
Semi-solid preparation has and as day supplement instead of the advantage of medicine, can this means that sizable dosage form is acceptable for patient.Preferably give old age and pediatric patients by these preparations.
Can swallow gel have swallow comfortable and may as day supplement instead of the advantage of medicine.In addition, for taste masking option, there is wide selection.Non aqueous gels is preferred.The encapsulating of hydrated ferric oxide. and/or granulation step are preferably included to overcome sensory issues as grittiness.
According to the present invention, chewable bar can containing being selected from following composition: Fructus Hordei Germinatus extract, defatted milk powder, low fat cocoa, glucose syrup, egg, sclerosis palm fibre put oil (such as based on the total weight about 30 % by weight of rod), yeast, sodium chloride (such as based on the total weight about 0.1 % by weight of rod), vitamin (such as vitamin E), spice (such as vanilla flavor), one or more stabilizing agents (such as E339, E435, E472b, E475, soybean lecithin), thickening agent (such as carob flour, E460).Rod can cover by milk chocolate layer, described milk chocolate layer such as containing sugar, cocoa, cocoa butter, whole milk, defatted milk powder, ear of maize, butterfat, soybean lecithin.Cover layer can be 33% weight of chewable bar gross weight.Preparation method can comprise and be mixed in mixer by all the components at elevated temperature and be filled in mould by mixture.Be cooled to room temperature and from mould after taking-up, chewable bar can be packed.
Chewable bar as cereal bars chew be a kind of easily with the using of patient close friend, can as a part for day routine, namely as day supplement instead of medicine.This dosage form only has less restriction for size.In addition, for taste masking option, there is wide selection.
Per os discrete sheet is general fast dispersing dosage form.Containing phosphate adsorbent of the present invention, be such as particularly suitable for department of pediatrics and elderly population based on the phosphatic per os discrete sheet of ferrum (1II), because they are comfortable and can as day supplement instead of medicine for swallowing.
According to the present invention, fast dispersing dosage form can discharge its active component, namely based on the phosphate adsorbent of ferrum (III) within the time being shorter than about 90 seconds.These dosage forms can have 3D shape, and it can be kept in suitable storage, but easily disperse under the existence of excess humidity.
According to the present invention, fast dispersing dosage form such as per os discrete sheet can be prepared by solid free fo manufacture (solidfree-formfabrication) technology, and wherein object builds by succession adding figuratum thin layer, such as three-dimensional print (3DP) in a hierarchical manner.
According to the present invention, semisolid dosage form can be that emulsifiable paste ball can chewable dosage forms.In an embodiment of the present invention, phosphate adsorbent is suspended in emulsifiable paste or gel, then coating on core core.Various spice can be used.This form can provide than other can chewable dosage forms better can chewiness and mouthfeel.This prepared product is comfortable for swallowing, and can be used as order supplement instead of medicine.
According to the present invention, such as confection, soft capsule and block can be comprised by chewable dosage forms.The spice of wide selection can be used.Novel shape and color can be designed.Can may be packaged in tablet dispenser or packed separately by chewable dosage forms.
According to the present invention, can chewable dosage forms can containing being selected from following composition: corn syrup, sugar, partially hydrogenated soya oil and Oleum Gossypii semen, defatted milk powder, soybean lecithin, natural or artificial flavors, citric acid, glyceryl monostearate, carrageenin, red 40, vitamin (such as vitamin D3 or Kl), tricalcium phosphate, alpha-tocopherol, salt, nicotiamide, calcium pantothenate, pyridoxine hydrochloride, riboflavin and thiamine mononitrate.
Composition can be formed syrup in soluble in water or milk, syrup can be boiled until it reaches the concentration of expection or sugar starts caramelization.Then can, by liquid filling in mould, cool dosage form is hardened.
According to the present invention, phosphate adsorbent can be mixed with the little wafer of edible.Edible little wafer be a kind of easily with the using of patient close friend, can as a part for day routine, namely as day supplement instead of medicine.
The implant of the little wafer of edible can be made up of granule, such as be made up of granule, and described granule can by as made the material as described in chewable bar above.Such as, the implant of the little wafer of edible can be prepared by rod being taken out from mould rear pulverizing.Folliculus agent material can by water soluble polysaccharide as starch, the plant ground or fruit be optionally made together with lipid.Can produce little wafer as follows: fruit or vegetable puree are sprayed on atwirl teflonated dish, it forms thin film there, and thin film is dried in the next step.
In another embodiment of the present invention, be dietary fiber based on insoluble carbohydrate contained in the phosphate adsorbent of δ-FeOOH (multinuclear).Such as, the step I in preparation method as described above) and/or step I i) in, starch is replaced by dietary fiber.This prepared product combines phosphate in conjunction with benefit and dietary fiber benefit in a product.
Purposes
Phosphate adsorbent based on δ-FeOOH (multinuclear) of the present invention shows valuable pharmacological properties, the phosphate such as adsorbing inorganic phosphate from body fluid or food or be combined with food, such as indicated in vitro and in vivo test, therefore show to can be used for treatment.
Therefore, the phosphate adsorbent based on ferrum δ-FeOOH (multinuclear) of the present invention can be used for treating and/or preventing hyperphosphatemia, hypercalcemia, hyperparathyroidism, minimizing cardiovascular disease incidence and death, renal osteodystrophy, calciphylaxis and soft tissue calcification.Phosphate adsorbent based on ferrum (III) of the present invention is particularly suitable for treating and/or preventing hyperphosphatemia in people and homoiothermic animal, particularly companion animals as Canis familiaris L. and particularly cat.
Phosphate adsorbent of the present invention and the pharmaceutical composition containing it more particularly can be used for the patient suffering from hyperphosphatemia, such as can be used for the patient relying on dialysis, such as hemodialysis, or suffer from advanced chronic kidney disease (CKD), the patient of chronic renal failure, chronic renal insufficiency, end-stage renal disease.
Phosphate adsorbent of the present invention can by any conventional route, particularly enteral, such as oral, such as use with the form of tablet or capsule.In some cases, phosphate adsorbent can by nasogastric tube as department of pediatrics nasogastric tube be used.
The pharmaceutical composition comprising complex of the present invention and at least one pharmaceutically suitable carrier or diluent can in a usual manner by preparing with pharmaceutically suitable carrier or mixing diluents.
For Orally administered unit dosage forms contain such as about 0.5g to about 7g, such as about 0.5 to about 5g, such as about 1.0 to about 3g, preferably about 1 to about 1.5, more preferably from about 1 to about 1.5g, even more preferably from about 1 to the phosphate adsorbent of about 1.25g.
Phosphate adsorbent of the present invention also can be used for adsorbing the phosphate be combined with food.They can be mixed with food.
Phosphate adsorbent based on δ-FeOOH (multinuclear) of the present invention effect in treatment hyperphosphatemia can animal experiment method and clinical in, such as proved according to method hereinafter described.
A-phosphate binding capacity can measure according to the method for disclosed method as described in W02007/088343 (its content is incorporated herein by reference) or the experiment carried out according to the embodiment 2 of the application.
B-clinical trial: the study on the transformation of the open-label of carrying out in CKD (chronic renal disease) patient of hemodialysis, time lag, multiple dose.
According to above, the invention provides:
1.1 based on the phosphate adsorbent of δ-FeOOH (multinuclear), it is characterized in that the phosphate binding capacity improved.Binding ability is that the absorption of 1g phosphate adsorbent is at least about 50mg phosphate, preferred 1g phosphate adsorbent adsorbs about 120mg phosphate, most preferably 1g phosphate adsorbent adsorbs about 140mg phosphate, and even most preferably 1g phosphate adsorbent adsorbs about 200mg phosphate.
1.2 based on the phosphate adsorbent based on multinuclear ferrum (III) of ferrum (III), comprise i) δ-FeOOH (multinuclear), ii) adsorbent based metallic substance, preferred insoluble carbohydrate, and iii) soluble-carbohydrate, such as glucosan derivative, and optionally comprise iv) carbonate, wherein soluble-carbohydrate is partly incorporated in δ-FeOOH (multinuclear).
1.3 based on the phosphate adsorbent of δ-FeOOH (multinuclear), comprise i) δ-FeOOH (multinuclear), and ii) glucosan derivative, be selected from sucrose, maltodextrin and composition thereof, preferably sucrose, wherein glucosan derivative is partly incorporated in δ-FeOOH (multinuclear), and iii) starch.Multinuclear FeOOH optionally stablize by described glucosan derivative.
1.4 based on the phosphate adsorbent of δ-FeOOH (multinuclear), comprise i) δ-FeOOH (multinuclear), and ii) glucosan derivative, be selected from sucrose, maltodextrin and composition thereof, preferably sucrose, wherein multinuclear FeOOH (III) is containing δ-FeOOH (multinuclear), and iii) insoluble carbohydrate, preferred starch, and optional ferrihydrite.Optionally glucose derivant is partly incorporated in multinuclear FeOOH (III).
1.5 based on the phosphate adsorbent of δ-FeOOH (multinuclear), comprise i) δ-FeOOH (multinuclear), ii) adsorbent based metallic substance, preferred insoluble carbohydrate (such as starch), and iii) glucosan derivative, be selected from sucrose, maltodextrin or its mixture, preferably sucrose, wherein multinuclear iron oxide hydroxide stablize by described glucosan derivative.
According to above, present invention also offers:
The method of the phosphate adsorbent based on ferrum (III) of 2.1 preparations containing δ-FeOOH (multinuclear), the method comprises the following steps:.
I ferrous sulfate (II) mixes with at least one alkali by (), forming pH is the suspension of 7 to 9, adds rapidly appropriate EDTA.
(ii) logical oxygen, until pH value is about 5.Be separated the precipitation formed;
(iii) precipitation is suspended in aqueous solution;
(iv) one or more carbohydrates and/or humic acid is added, and;
V () is by the prepared product of the dry separating step (iv) of spraying dry or bed spray.
The method of the phosphate adsorbent based on ferrum (III) of 2.2 preparations containing δ-FeOOH (multinuclear), insoluble carbohydrate (preferred starch) and glucosan derivative, the method comprises the following steps;
I ferrous sulfate (II) mixes with at least one alkali by (), forming pH is the suspension of 7 to 9, adds rapidly appropriate EDTA.Such as mix simultaneously, form the suspension that pH is 5 to 10, such as 7 to 9, preferably about 8.5; This suspension is left standstill;
(ii) logical oxygen, until pH value is about 5.Be separated the precipitation formed, optionally carry out washing, such as washing with water;
(iii) by precipitation suspendible, be such as suspended in water, the suspension that to obtain with the Weight computation iron content of suspension be about 3 to 16%;
(iv) add one or more carbohydrates and/or humic acid, obtaining take the total weight iron content of the solid of institute's suspendible as the suspension of 10-50% at the most, and;
V () is dry by filtration, decantation, spraying dry or bed spray drying, preferably spray drying or bed spray, be separated phosphate adsorbent.
The method of the phosphate adsorbent based on ferrum (III) of 2.3 preparations containing δ-FeOOH (multinuclear), insoluble carbohydrate (preferred starch) and glucosan derivative, the method comprises the following steps:
I) aqueous solution of ferrum (II) salt is mixed with the aqueous solution of alkali as alkali, such as mixed simultaneously, forming pH is the suspension of 3 to 10; The aqueous solution of ferrum (II) salt mixes with the aqueous solution of alkali as alkali, such as mixes simultaneously, and forming pH is the suspension of 3 to 10;
(ii) logical oxygen, until pH value is about 5.Be separated the precipitation formed, optionally carry out washing, such as washing with water;
Wherein step I ii) to v) as in 2.1 define carry out.
2.4 as 2.1 to 2.3 the method that defines, wherein the method also comprises the steps; Optionally under at least one is selected from the existence of the excipient of binding agent and lubricant, powder is granulated, obtain the phosphate adsorbent based on δ-FeOOH (multinuclear) as granule.
2.5 as 2.1 to 2.4 the method that defines, wherein the method also comprises following step viii): by step vi) in the powder of gained or step vii) in the granule of gained carry out tabletting, wherein tableting step optionally carries out under the existence of excipient being selected from filler as above, binding agent, disintegrating agent, flowable, lubricant and composition thereof.
According to above, present invention also offers:
3.1 in needing curee, i.e. people or homoiothermic animal, the particularly companion animals of this treatment as Canis familiaris L. and cat prevention or treatment such as above indication those disorder or the method for disease, the method comprises the phosphate adsorbent based on δ-FeOOH (multinuclear) of the present invention using effective dose to described curee.
3.2 control serum phosphate and Serum Calcium Phosphorus product level and maintain the method for normal serum calcium level simultaneously in the patient needing the curee of this treatment, such as chronic hemodialysis, and the method comprises the phosphate adsorbent based on δ-FeOOH (multinuclear) of the present invention using effective dose to described curee.
3.3 are needing optionally to remove inorganic phosphate in the curee of this treatment, such as dialysis patient, such as Patients in Hemodialysis or are eliminating inorganic phosphate, such as, from dialysis solution, whole blood or blood plasma, optionally remove inorganic phosphate or eliminate the method for inorganic phosphate, and the method comprises the phosphate adsorbent based on ferrum (III) of the present invention using effective dose to described curee.
3.4 optionally remove the method for inorganic phosphate be combined with food.
3.5 are used as medicine, such as the phosphate adsorbent of the present invention of the either method above described in 2.1 to 2.3.
4. be used as the compositions of pharmaceutical preparation optionally eliminating inorganic phosphate from liquid, wherein said compositions is water-insoluble and containing, for example the phosphate adsorbent based on δ-FeOOH (multinuclear) defined in aforementioned any opinion.
5.1 pharmaceutical composition, such as above 2.1 to 2.3 the pharmaceutical composition of either method, it comprises the phosphate adsorbent based on δ-FeOOH (multinuclear) of the present invention and the pharmaceutically acceptable diluent for it or carrier, such as, comprise the excipient that at least one is selected from antiseptic and binding agent.
5.2 pharmaceutical composition, such as be used as from liquid as optionally eliminated the pharmaceutical composition of the pharmaceutical preparation of inorganic phosphate dialysis solution, whole blood or blood plasma, wherein said compositions contains the phosphate adsorbent material based on δ-FeOOH (multinuclear) of the present invention.
5.3 are suitable for Orally administered pharmaceutical composition, such as solid or semisolid dosage form, and it contains the phosphate adsorbent based on δ-FeOOH (multinuclear) of the present invention.
5.4 solids or semisolid dosage form, it contains the phosphate adsorbent based on δ-FeOOH (multinuclear) of the present invention.
5.5 pharmaceutical composition, preferred powder or granule, it comprises the phosphate adsorbent based on δ-FeOOH (multinuclear) of the present invention and comprises antiseptic (such as alcohol, preferred alcohol) and optionally comprise binding agent (such as sucrose, microcrystalline Cellulose or its mixture).
5.6 pharmaceutical compositions of the present invention, it is tablet form, and comprises lubricant and optionally comprise the other excipient that at least one is selected from filler, binding agent, disintegrating agent and flowable.
6. for the preparation of above 2.1 to 2.3 either method in the phosphate adsorbent based on δ-FeOOH (multinuclear) of the present invention of pharmaceutical composition that uses.
6.1 phosphate adsorbents based on δ-FeOOH (multinuclear) of the present invention, are used for the treatment of or prevent little good, the calciphylaxis of hyperphosphatemia, hypercalcemia, hyperparathyroidism, minimizing cardiovascular disease incidence and death, kidney osteotrophy and soft tissue calcification and associated disease and disorder.
According to the present invention, described phosphate adsorbent can be used as independent active component, or reduces agent with other phosphate and use together with sevelamer, fosrenol, calcium acetate or calcium carbonate.It also can with calcium simulant (calcimimetic) as CNC, vitamin D or calcitriol combined administration.
According to above, the present invention additionally provides on the other hand:
7. as method defined above, comprise jointly use, such as phosphate adsorbent of the present invention that is parallel or administering therapeutic effective dose successively and the second drug substance, described the second drug substance is that other phosphate reduces agent, calcium simulant, vitamin D or calcitriol, such as indicated above.
8. therapeutic combination product, such as medicine box, its comprise a) phosphate adsorbent of the present invention and b) at least one be selected from the second medicine that other phosphate reduces agent, calcium simulant, vitamin D and calcitriol.Component a) and components b) can walk abreast or use successively.Medicine box can comprise for using description.
When phosphate adsorbent of the present invention and other phosphate reduce agent as sevelamer, fosrenol, calcium acetate or calcium carbonate, calcium simulant as CNC or with vitamin D or calcitriol combined administration, such as prevent or treat hyperphosphatemia or Other diseases as described above or disorderly time, the dosage of the compound jointly used is certainly different by the type according to concomitant medication used, the disease for the treatment of etc.
The pharmaceutical composition comprising complex of the present invention and at least one pharmaceutically suitable carrier or diluent can in a usual manner by preparing with pharmaceutically suitable carrier or mixing diluents.
In this description claims in the whole text and subsequently, unless the context requires otherwise, otherwise word " comprises " and will be understood to mean the set of integer or step or integer or the step comprising indication, but do not get rid of the set of other integer or step or integer or step arbitrarily.
Following examples explain clear the present invention.
Embodiment 1:
Get the FeSO of certain volume
4; Be placed in the beaker of 250mL with ring-like bubbler, drip under fast stirring when 6mol/LNaOH to pH is about 8.5 and obtain Fe (OH) suspension; Add rapidly the EDTA10mL of people 0.015mol/L, add water and be dissolved to 150mL, make Fe
2+concentration is the concentration of 0.30mol/L, EDTA is 1.0mmol/L; Oxygen-supply speed is 0.06m
3/ h, the temperature of whole course of reaction controls 20 ± and DEG C 2 DEG C; (when no longer changing) (be now pure amorphous δ-FeOOH, amorphous state is that maximized surface is long-pending) when the pH value of question response system is about 5.2, timing sampling between the reaction period, sucking filtration, washing, vacuum drying 10h,
Subsequently 225g sucrose and 225g starch are joined in the suspension of above-mentioned sample, obtain end product by spraying dry (SD).The iron content (being recorded by flame AAS) of SD product is 22.2%.
Embodiment 2:
By 1 gram of sample is placed in the Phosphate Adsorption that 25mL volumetric flask measures the product of embodiment 1 gained.Add in flask containing 170.92mg phosphate (PO
4 3-) 20mL aqueous solution, with salt acid for adjusting pH to pH2.0 (+/-0.05).Then flask is filled to scale with water.Then sample is stirred 2 hours in 37 DEG C.Afterwards, by sample filtering, by the chromatography of ions, quantitative assay is carried out to the phosphate dissolved.The phosphatic amount adsorbed is placed in the phosphatic amount of flask and the difference of measured phosphatic amount.Result is to represent as the % (m/m) of " quality of institute's phosphate adsorption "/" quality for the Spray dried products of absorption " X100.
Result:
The complex of embodiment 1 has adsorbed 21.9%m/m phosphate as SD product.
Embodiment 3: sachet
In embodiment 1 by 90%, the product of preparation mixes to prepare final mixture with corn starch (10%).Subsequently final mixture is filled in sachet.
Embodiment 4: capsule (with lubricator directly filling)
The product of preparation in the embodiment 1 by 90% loads in mixer.The premix of the preparation same product of 7-8% and the magnesium stearate of 2-3%.Described premix is crossed by screen cloth (1000 micron mesh size) and is sieved in mixer, prepares final mixture with original Product mix.Described final mixture is filled in hard gelatin capsule subsequently.
Embodiment 5: capsule (with lubricator directly filling with other excipient)
The product of preparation in the embodiment 1 by 80% mixes with MCC (10%) or preferred corn starch (10%).The premix of the preparation same product of 7-8% and the magnesium stearate of 2-3%.Described premix is crossed by screen cloth (1000 micron mesh size) and is sieved in mixer, prepares final mixture with original Product mix.Described final mixture is filled in hard gelatin capsule subsequently.
Embodiment 6: sachet, bar-shaped packaging or capsule (suppressed by dry method and granulate)
In embodiment 1 by 68%, the product of preparation mixes with MCC (20-30%).Magnesium stearate (2%) is sieved by screen cloth (1000 micron mesh size) and is added in premix.Prepare final mixture, suppress subsequently and/or compress.By suppressing with the tablet machine of large-scale perforator or cylinder tablet machine.Compacting thing is milled by screen cloth (sieve mesh 2mm) and is sieved subsequently, subsequently, particles filled in sachet or bar-shaped packaging by what sieve.
Described granule also can be filled in capsule together with lubricant.
Embodiment 7: sachet, bar-shaped packaging or capsule (wet granulation)
By in embodiment 1 preparation product with granulate in High-shear mixers relative to the water of dry powder about 15%.Subsequently by particle drying until LOD (loss on drying) is about 6-7%.Subsequently by the pellet through sieves (sieve mesh 2mm) of drying.Finally, particles filled to bar-shaped packaging by what sieve.Optionally, described granule also can be filled in capsule together with lubricant.
Embodiment 8: sachet, bar-shaped packaging or capsule (wet granulation carried out with other binding agents)
The product of preparation in the embodiment 1 using about 97% and about 2% mix as binding agent through propyl methocel-HPMC-3-cps (2910 grades), granulate with the water relative to dry powder about 10%.Binding agent adds as a solution after being dissolved in the water of respective amount.Step is subsequently as described in above-described embodiment.
Embodiment 9: tablet (direct pressing with lubricator carried out)
In embodiment 1 by about 90%, the product of preparation is placed in mixer.Preparation contains the premix of the same product of 7% and the magnesium stearate of 3%.Premix sieves, and (1000 microns of meshes), in mixer, prepares final mixture with original Product mix.Final mixture is pressed into the heavy tablet (product 1 corresponding to 625mg) of 644mg subsequently on tablet machine.
Embodiment 10: tablet (with lubricator with other excipient direct pressings)
In embodiment 1 by 50%, the product of preparation, the microcrystalline Cellulose of 30% load in mixer together with the crospovidone of about 10%.Preparation contains the premix of the same product of about 7% and the magnesium stearate of 3%.Premix sieves, and (1000 microns of meshes), in mixer, prepares final mixture with original Product mix.Final mixture is pressed into the heavy oval tablet (product corresponding to 625mg) of 1100mg subsequently on tablet machine.The aqueous suspension that described tablet thin film forms polymer (HPMC-3cps), coloring agent, titanium dioxide (antholeucin), Talk (fluidizer) and plasticizer carries out coating.
Embodiment 11: tablet (dry compaction is granulated)
Undertaken by described in embodiment 6, but also containing disintegrating agent in granule.In sieved granule, add the foreign minister comprising filler, disintegrating agent, fluidizer and lubricant equally, subsequently final mixture is pressed into tablet, it can subsequently by coating.
Embodiment 12: tablet (carrying out wet granulation with other binding agent and other excipient)
The product of preparation in the embodiment 1 by 50% is with the microcrystalline Cellulose of about 20% and the crospovidone of about 5% and granulate in a high shear mixer relative to the water of dry powder about 18%.Dried particles subsequently, until LOD (loss on drying) is about 6-7%.Sieved together with the microcrystalline Cellulose of 10% and the crospovidone of about 5% by the granule of drying subsequently, sieve aperture is about 1.25mm.Preparation contains the premix of this mixture of about 7% and the magnesium stearate of about 2%.Premix is sieved (1000 microns of meshes) in mixer, prepare final mixture with original Product mix.Final mixture is pressed into the oval tablet (product corresponding to 625mg) of 1100mg subsequently on tablet machine.The aqueous suspension of described tablet HPMC3cps, titanium dioxide, Talk and plasticizer or corresponding Opadry mixture carries out coating.
Embodiment 13: tablet (carrying out wet granulation with other binding agent)
As mentioned above, but interior mutually in add about 3% hydroxypropyl emthylcellulose-HPMC-3cps (2910 grades), wherein binding agent adds with drying regime or the form in granulation liquid of being partially or completely dissolved in; In granule, the amount of the amount filler of binding agent compensates.Subsequent step is as described in above-described embodiment.
Embodiment 14: gel
(smooth aqueous gel) heats 80mL water to about 70-75 DEG C, adds the product of preparation in 20g embodiment 1, suspension is remained on 70 DEG C until jelly is formed.Described gel keeps a few minutes with stable gel forming process at 70 DEG C.After being cooled to room temperature, add water to compensate the water loss of potential evaporation in preparation process.
Embodiment 15: gel
The sodium benzoate of 1.5mg/mL is dissolved in pure water, adds 0.2mg/mL saccharin sodium, the 1.0mg/mL malicious correctives of grass and citrate buffer system.After dissolving completely, add 5mg/mL polysorbate 20, subsequently phosphate adsorbent is disperseed by mixing.Form uniform suspension.Finally, under mixing condition, slowly add the hydroxypropyl emthylcellulose of 30mg/mL.
Embodiment 16-20:
Following composition (mg) is dissolved or is suspended in glycerol, mixes and is filled in bar-shaped packaging.
Embodiment 21-22: oral dispersion pancake
Following composition (mg) is mixed.
In description and following claim, unless the context requires otherwise, otherwise word " comprises " or its variant " comprises " group that should be understood to include described entirety or step or entirety or step, but do not get rid of any other entirety or the group of step or entirety or step.
Claims (24)
1. prepare the method for compositions, the method comprises the following steps:
I ferrous sulfate (II) mixes with at least one alkali by (), forming pH is the suspension of 7 to 9, adds rapidly appropriate EDTA;
(ii) logical oxygen, until pH value is about 5.Be separated the precipitation formed;
(iii) precipitation is suspended in aqueous solution;
(iv) one or more carbohydrates and/or humic acid is added, and;
V () is by the prepared product of the dry separating step (iv) of spraying dry or bed spray.
2. method according to claim 1, wherein in step (i), pH is 4 to 9.
3. method according to claim 1, wherein in step (i), pH is 6 to 9.
4., according to the method for aforementioned any one of claim, wherein in step (i), the pH of solution remains the steady state value of 6 to 9, preferably about 8.5.
5. method according to claim 1, wherein in step (i), alkali is selected from sodium carbonate, sodium bicarbonate and sodium hydroxide.
6. method according to claim 5, wherein in step (i), alkali is sodium hydroxide.
7. method according to claim 1, wherein in step (iii), is suspended in precipitation in water, and being formed with the total weight iron content of suspension is the suspension of 3 to 16%.
8. method according to claim 1, wherein in step (iv), compositions contains with the ferrum of the total weight 10-50% of institute's suspendible solid.
9. method according to claim 1, wherein in step (iv), compositions contains with the ferrum of the total weight 15-30% of institute's suspendible solid.
10. method according to claim 1, wherein in step (iv), adds one or more carbohydrates.
11. methods according to claim 10, wherein in step (iv), carbohydrate comprises solubility or insoluble carbohydrate or its mixture.
12. methods according to claim 10, wherein in step (iv), add at least one solubility and the insoluble carbohydrate of at least one.
13. according to the method for claim 11 or 12, and wherein insoluble carbohydrate is starch.
14. according to the method for claim 11 or 12, and wherein soluble-carbohydrate is selected from sucrose, agarose, glucosan, dextrin, glucan derivative, cellulose, cellulose derivative, maltose, lactose, mannitol and composition thereof.
15. methods according to claim 1, wherein carry out at least once washing between step (iii) and (iv).
16. methods according to claim 1, wherein, in step (i), the pH of solution remains the value between 4 to 6, and adds starch in step (i).
17. methods according to claim 1, wherein in step (v), by the prepared product of the dry separating step (iv) of bed spray.
18. methods according to claim 1, wherein the method also comprises following step (vi): optionally granulated by powder under at least one is selected from the existence of the excipient of binding agent and lubricant, obtain the phosphate adsorbent based on δ-FeOOH (multinuclear) as granule.
19. methods according to claim 18, wherein the method also comprises following step (vii): the granule of gained in the powder of gained in step (v) or step (vi) is carried out tabletting, and wherein tableting step optionally carries out under the existence of excipient being selected from filler, binding agent, disintegrating agent, flowable, lubricant and composition thereof.
20. phosphate adsorbents based on ferrum (III) obtained by the method for any one of claim 1-19.
21. are suitable for Orally administered pharmaceutical composition, such as solid or semisolid dosage form, and it contains the phosphate adsorbent of the preparation method ferrum (III) based on the phosphate adsorbent for the preparation of iron content of claim 20.
22. solid dosage formss according to claim 21, it is powder, granule, capsule, tablet (comprising dispersible tablet, chewable tablet, oral cavity disintegration tablet, buccal tablet and slow-release tablet etc.) or film coated tablet.
23. solids or semisolid dosage form, it contains the phosphate adsorbent based on δ-FeOOH (multinuclear) of claim 20.
The phosphate adsorbent based on δ-FeOOH (multinuclear) of 24. claim 20 is preparing the purposes in medicament, and described medicament is used for the treatment of or prevents hyperphosphatemia, hypercalcemia, hyperparathyroidism, minimizing cardiovascular disease incidence and death, renal osteodystrophy, calciphylaxis and soft tissue calcification and associated disease and disorder.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510290939.0A CN105193844A (en) | 2015-05-27 | 2015-05-27 | Method for preparing delta-hydroxyl contained ferric oxide (multinuclear) and medicine compositions of delta-hydroxyl contained ferric oxide, as well as application to field of hyperphosphatemia |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510290939.0A CN105193844A (en) | 2015-05-27 | 2015-05-27 | Method for preparing delta-hydroxyl contained ferric oxide (multinuclear) and medicine compositions of delta-hydroxyl contained ferric oxide, as well as application to field of hyperphosphatemia |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105193844A true CN105193844A (en) | 2015-12-30 |
Family
ID=54942034
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510290939.0A Pending CN105193844A (en) | 2015-05-27 | 2015-05-27 | Method for preparing delta-hydroxyl contained ferric oxide (multinuclear) and medicine compositions of delta-hydroxyl contained ferric oxide, as well as application to field of hyperphosphatemia |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105193844A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107397758A (en) * | 2016-05-19 | 2017-11-28 | 欣凯医药化工中间体（上海）有限公司 | A kind of phosphate binder and preparation method thereof |
| CN107397759A (en) * | 2016-05-19 | 2017-11-28 | 欣凯医药化工中间体（上海）有限公司 | Phosphate binder, its preparation method and its application of the carbohydrate of hydroxide-degraded based on iron |
| CN115175670A (en) * | 2020-01-16 | 2022-10-11 | 威佛费森尤斯医疗肾脏药物有限公司 | Granules of a mixture of iron (III) oxyhydroxide, sucrose and one or more starches, preferably granules of iron (III) oxyhydroxide |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080145410A1 (en) * | 2006-12-14 | 2008-06-19 | Michael Ambuhl | Manufacture process |
| CN102089075A (en) * | 2008-06-13 | 2011-06-08 | 诺瓦提斯公司 | Manufacture process for the preparation of an iron containing phosphate adsorbent |
-
2015
- 2015-05-27 CN CN201510290939.0A patent/CN105193844A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080145410A1 (en) * | 2006-12-14 | 2008-06-19 | Michael Ambuhl | Manufacture process |
| CN102089075A (en) * | 2008-06-13 | 2011-06-08 | 诺瓦提斯公司 | Manufacture process for the preparation of an iron containing phosphate adsorbent |
Non-Patent Citations (2)
| Title |
|---|
| 熊慧欣，等: "不同晶型羟基氧化铁(FeOOH)的形成及其在吸附去除Cr(VI)上的作用", 《岩石矿物学杂志》 * |
| 魏雨，等: "Fe(OH)2悬浮液在EDTA作用下氧气氧化生成δ-FeOOH的机理研究", 《高等学校化学学报》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107397758A (en) * | 2016-05-19 | 2017-11-28 | 欣凯医药化工中间体（上海）有限公司 | A kind of phosphate binder and preparation method thereof |
| CN107397759A (en) * | 2016-05-19 | 2017-11-28 | 欣凯医药化工中间体（上海）有限公司 | Phosphate binder, its preparation method and its application of the carbohydrate of hydroxide-degraded based on iron |
| CN115175670A (en) * | 2020-01-16 | 2022-10-11 | 威佛费森尤斯医疗肾脏药物有限公司 | Granules of a mixture of iron (III) oxyhydroxide, sucrose and one or more starches, preferably granules of iron (III) oxyhydroxide |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102089075B (en) | Manufacture process for the preparation of an iron containing phosphate adsorbent | |
| RU2447933C2 (en) | Phosphate adsorbent based on iron (iii) compounds and carbohydrates | |
| DK2319804T3 (en) | Iron (III) -carbohydrat-based phosphatadsorbens | |
| CA2807621C (en) | Phosphate binder formulation for simple dosing | |
| TWI414297B (en) | Phytosterol nutritional supplements | |
| CN101563295B (en) | Iron (III)-carbohydrate based phosphate adsorbent | |
| JP2016174616A (en) | Disintegrable composition, and easily disintegrable compression molding | |
| JP5537762B2 (en) | Composition for oral intake prepared in dry form and composition for oral intake gel | |
| CN105193844A (en) | Method for preparing delta-hydroxyl contained ferric oxide (multinuclear) and medicine compositions of delta-hydroxyl contained ferric oxide, as well as application to field of hyperphosphatemia | |
| CA3152326C (en) | Preparation of transmucosal psychoactive alkaloid composition | |
| JP2004242509A (en) | Food containing coenzyme q10 and amino acid | |
| CN103816123B (en) | A kind of CEFUROXIME AXETIL composition and method of making the same | |
| CN1935253B (en) | Cerebral proteolysis dispersible tablet and its preparing method | |
| JP2003073262A (en) | Inclusion coating agent for solid preparation, the resultant solid preparation, method for producing the same, and foods |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20151230 |