CN103127042A - Stable and efficient dephosphorization composition - Google Patents
Stable and efficient dephosphorization composition Download PDFInfo
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- CN103127042A CN103127042A CN2013100719759A CN201310071975A CN103127042A CN 103127042 A CN103127042 A CN 103127042A CN 2013100719759 A CN2013100719759 A CN 2013100719759A CN 201310071975 A CN201310071975 A CN 201310071975A CN 103127042 A CN103127042 A CN 103127042A
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Abstract
The invention provides a stable and efficient composition for dephosphorization. The composition comprises lanthanum lactate hydrate and pharmaceutically acceptable proper auxiliary materials, wherein the average value of crystalline water in the lanthanum lactate hydrate is 0.5-6.0. The composition is applied in the form of oral administration, and the clinical daily dosage on the basis of anhydrous lanthanum lactate is 0.05-2.0g. The composition provided by the invention is free of aluminum and calcium, thereby avoiding the side effect of aluminosis, angiosteosis or the like of the patient due to taking of aluminum and calcium. The active component of the composition exists in the form of lanthanum lactate hydrate, so the solubility is high, and thus, the consistent high-level phosphorus combining capacity in vivo and in vitro can be always kept without being dependent on pH. The composition solves the problems of high consumption, high cost, poor mouthfeel and severe adverse reactions, including nausea, emesis and the like, in other lanthanum-containing dephosphorization medicines. The invention also provides a method for preparing the lanthanum lactate hydrate in the composition.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition, what especially relate to a kind of stability and high efficiency falls the phosphorus compositions, belongs to medical technical field.
Background technology
Hyperphosphatemia is that a kind of serium inorganic phosphorus phosphate content surpasses the disease of normal level (the serium inorganic phosphorus normal contents is about 37.2～43.4mg/L), claims again hyperphosphatemia.Phosphate is taken in to increase, to discharge and reduced or the disorder of reallocation aspect all can cause hyperphosphatemia: 1. absorption increases, as oral or intravenous injection excess phosphoric acid salt; 2. discharge and reduce, as the renal failure patient, detection of glomeruli filtration function goes down, and phosphate reduces at the filtrable volume of glomerule, and phosphate is discharged and reduced, and the serium inorganic phosphorus hydrochlorate raises; 3. phosphatic reallocation is disorderly, and when acidosis, disorganization or a large amount of haemolysis, the phosphate reallocation gets muddled.
Clinically, hyperphosphatemia can cause the generation of the serious harm health of people phenomenons such as hyperparathyroidism and osteodystrophy, need to be pointed out that in addition, hyperphosphatemia also easily brings out soft tissue and angiosteosis, for End-stage Renal Disease Patients, it is the key factor that End-stage Renal Disease Patients mortality rate and cardiovascular disease incidence rate increase especially.Therefore, effectively control the serum paraoxonase level and become the Important Action that reduces End-stage Renal Disease Patients mortality rate and cardiovascular disease incidence rate.
At present, the treatment of hyperphosphatemia generally includes the means such as diet limit phosphorus, dialysis treatment, application phosphate binder: 1. diet is limit phosphorus, this is the measure of the most basic control hyperphosphatemia, for patients with chronic renal failure, K-DOQI guide recommendation phosphorus intake every day should be less than 700mg, but have in actual applications larger difficulty, because the intake of phosphorus and protein is proportionate, in diet, phosphorus is taken in restriction and must be caused malnutrition; 2. dialysis treatment, the patient is carried out sufficient hemodialysis, remove the phosphate in blood, thereby reach the purpose that reduces the serium inorganic phosphorus level, but each conventional hemodialysis is removed phosphorus in the 800mg left and right, by 3 dialysis calculating weekly usually, total clearing amount be only 2400mg, and much smaller than the phosphorus intake of 5600～9600mg weekly, so conventional hemodialysis is difficult to effectively control hyperphosphatemia; 3. use phosphate binder, by using phosphate binder, suppress gastrointestinal system to the absorption of phosphorus, and then reduce the serium inorganic phosphorus level, usually adopt oral administration, it is convenient to use, and falls the phosphorus successful, has become the major measure of the current treatment of hyperphosphatemia clinically.
As far back as 20 century 70s, people have developed the first generation and have contained the aluminum phosphate binder, and subsequently, the exploitation of phosphate binder is developed rapidly, and is widely used in clinical.Now, for hyperphosphatemia, usually the phosphate binder of using clinically comprises: 1. contain the aluminum phosphate binder, commonly used is aluminium hydroxide, but, increase because prolonged application makes the absorption of aluminum, produce various syndrome, comprise the unpowered property osteopathia of osteomalacia, non-osteomalacia and dull-witted etc.; 2. contain calcium phosphorus binder, as calcium carbonate, calcium lactate etc., the develop of this type of phosphate binder has solved and has contained in the body that exists in aluminum phosphate binder process of clinical application aluminum and the problem such as accumulate, but, when use contains calcium phosphorus binder, usually be accompanied by serious side effects such as increasing hypercalcemia, metastatic calcification risk, the conversion of inhibition bone; 3. the non-calcium resinae of non-aluminum phosphate binder, the example hydrochloric acid sevelamer is a kind of ion exchange resin, absorb and reduce serium inorganic phosphorus by suppressing intestinal phosphorus-sodium transport body reduction phosphorus, but, its fall the phosphorus effect relatively a little less than, and usually have diarrhoea, feel sick, the insufferable bad problem of patient such as vomiting, mouthfeel are poor.
There are many deficiencies in conventional phosphate binder in process of clinical application, people were both seeking always and can reduce serium inorganic phosphorus for many years, does not cause again in obvious body that aluminum is accumulated, hypercalcemia, clinical be easy to accept safer effective, the phosphate binder of few side effects.In prior art, lanthanum carbonate is the non-calcium non-resin of a kind of non-aluminum class phosphate binder, the approval that successfully obtained U.S. FDA in 2004 is sold, after its oral administration administration, do not absorb in body, the trivalent lanthanum ion of generation has high affinity to phosphoric acid, can be effectively in conjunction with phosphorus, reduce gastrointestinal tract to the absorption of phosphorus, and then control the serium inorganic phosphorus level.Yet lanthanum carbonate is a kind of inorganic salts of its slightly solubility of water electrode, and the dissolubility in water is only 2.38 * 10
-7Mol/L, therefore, after oral administration, as commercially available lanthanum carbonate chewable tablet (trade name: Fosrenol), be difficult in gastrointestinal tract and can spread out fast, further dissociate performance and fall the trivalent lanthanum ion of phosphorus effect, and it falls the also easily impact of the interior pH environmental change of receptor of phosphorus ability, therefore, carbonate form administration with lanthanum, undoubtedly, this intrinsic physicochemical property of lanthanum carbonate has limited giving full play to of the efficient phosphorus binding ability of trivalent lanthanum ion, and this is extremely the be unwilling facts seen of people in clinical practice.
To sum up, for hyperphosphatemia, the development and application of New Phosphorus bonding agent is undoubtedly a kind of effective means, and desirable phosphate binder should have has efficient affinity to phosphorus, the phosphorus binding ability is stable, quick, systemic Absorption is few, has no side effect, can prolonged application, be easy to accept, cheap, but regrettably, still do not have a kind of phosphate binder to satisfy the condition of desirable phosphorus bonding agent at present.Therefore, urgent needs provides a kind of stable, efficient phosphate binder with such comprehensive advantage clinically.
Summary of the invention
What primary and foremost purpose of the present invention was to provide a kind of stability and high efficiency falls the phosphorus compositions, said composition has fast, stablizes, phosphorus binding ability efficiently, can play the good clinical phosphorus effect of falling, consumption is few, cost is low, untoward reaction is few, safe, patient is easy to accept, and is suitable for falling for a long time the application of phosphorus.
The objective of the invention is to be achieved through the following technical solutions, wherein:
It is to be prepared from certain proportioning by the lactic acid lanthanum hydrate that is shown below and pharmaceutically acceptable adjuvant that the phosphorus compositions falls in described stability and high efficiency.
La(Lac)
3·nH
2O[Lac＝CH
3CH(OH)COO
-]
In described lactic acid lanthanum hydrate, the average of n is 0.5～6.0, is preferably 0.5～4.0, further most preferably is 3.0.
Described compositions is applicable to the phosphorus that falls of hyperphosphatemia clinically with oral form administration.
The administration of described compositions oral administration, the odd-numbered day quantity is counted 0.05g～2.0g with anhydrous lactic acid lanthanum, is preferably 0.2g～2.0g.
The preparation of described compositions oral administration administration is to be not more than 80 purpose lactic acid lanthanum hydrates and suitable adjuvant preparation pharmaceutically with particle diameter;
In the preparation of described compositions oral administration administration, lactic acid lanthanum hydrate is 5.0～95.0% of total weight parts, is preferably 10.0～80.0%.
The dosage form of described compositions oral administration administration can be tablet, powder, granule, capsule, oral liquid, is preferably granule.
The granule weight portion of described compositions oral administration administration consists of: lactic acid lanthanum hydrate 10.0～80.0%; Binding agent 0.5～5.0%; Correctives 0.5～2.5%; The filler surplus.
In described granule, binding agent is a kind of in methylcellulose, ethyl cellulose, sodium carboxymethyl cellulose, hypromellose, PVP;
In described granule, correctives is a kind of in citric acid, sodium citrate, ascorbic acid, cyclamate, aspartame, essence;
In described granule, filler is a kind of in dextrin, microcrystalline Cellulose, lactose, starch, pregelatinized Starch.
Described granule particle diameter should account for more than 85% of total particle weight ratio at 10～80 purpose granules, and the grain diameter of preferred particulates agent 90% above weight ratio is at 24～80 orders.
Efficiently fall the phosphorus compositions in order to obtain aforementioned stable, the present invention also provides the wherein following preparation method of lactic acid lanthanum hydrate:
A) take lanthanum carbonate and fully pulverize rear mistake 80 mesh sieves, be dispersed in suitable quantity of water under 65～70 ℃ of conditions;
B) add excessive lactic acid to above-mentioned in a), mix homogeneously under stirring condition, and react completely under 65～70 ℃ of airtight conditions;
C) above-mentioned gained solution evaporation drying under 75～80 ℃ of conditions to constant weight, with filtering after the suitable quantity of water dissolving, is got filtrate and its evaporation drying under 75～85 ℃ of conditions to constant weight, is got lactic acid lanthanum crude product;
D) with above-mentioned gained lactic acid lanthanum crude product, after excessive water washing, concentrated, forced air drying, pulverizing under 90～120 ℃ of conditions the vacuum drying suitable time, get lactic acid lanthanum hydrate;
Described step b) excessive lactic acid, in mole, the lactic acid consumption should be no less than 6 times that add the lanthanum carbonate amount;
Described step c) suitable quantity of water, by weight, the consumption of water should be no less than 8 times that add the lanthanum carbonate amount;
Described steps d) excessive water, by weight, the consumption of water should be no less than 5 times of lanthanum carbonate addition;
Described steps d) suitable time, should be 3.0～15.0h.
Stability and high efficiency of the present invention the phosphorus compositions falls, compared with prior art have following features:
Described compositions is that with suitable pharmaceutically acceptable adjuvant, Uniform Dispersion is prepared from by special process in addition by the lactic acid lanthanum hydrate that contains specific water of crystallization structure that plays pharmacologically active;
Described compositions has stable phosphorus binding ability, and the impact that the performance of the active ability of said composition is not changed by pH further is not subjected to the impact of gastrointestinal system pH variation, can remain the phosphorus binding ability of stable homogeneous at whole gastrointestinal system;
Described compositions, has good solubility property, at gastrointestinal system Uniform Dispersion, stripping capacity active substance trivalent lanthanum ion at once, increased the contact area between trivalent lanthanum and phosphate anion, improved both probability and the speed of combination, so can be fast in body phosphorus be combined, rapid-action in process of clinical application, can reach rapidly with phosphorus and be combined, and then fall the purpose of phosphorus;
Described compositions, strong to the affinity of phosphorus, the comprehensive utilization ratio of lanthanum is high, obtainable phosphate binder relatively clinically, relative lanthanum carbonate particularly, oral lanthanum in equivalent, phosphorus that can affine more volume, reach and more preferably fall the phosphorus purpose, reduced the dose of clinical medicine, further reduced the amount of taking clinically lanthanum, when guaranteeing therapeutic effect, reduced body to the involving in of medicine, thus dialectical raising patient's drug safety;
Described compositions, quantity greatly reduces, particularly reduced the consumption of valuable rare-earth elements of lanthanum, reduced the clinical treatment cost, improved the accessibility of medicine, in addition, when increasing clinical cost-benefit ratio, because having reduced the consumption of rare-earth elements of lanthanum, can further play the effect to rare earth element saving exploitation, scientific and reasonable utilization;
Active substance lactic acid lanthanum hydrate in described compositions, whole body is almost without any absorption, is combined with phosphorus at gastrointestinal system directly to excrete by feces, and toxic and side effects is few, particularly for the clinical patients that needs the prolonged application phosphate binder, the long-term taking compliance is good;
Described compositions adopts oral administration clinically, and is easy to use, and active component lactic acid lanthanum hydrate compares good mouthfeel with the prior art lanthanum carbonate, and the patient takes like a shot, and feels sick, the gastrointestinal side effects such as vomiting, constipation are few;
Described compositions does not contain aluminum, calcium component, all relevant toxic and side effects and untoward reaction of effectively having avoided the patient to cause because taking aluminum, calcium class material;
Description of drawings
Accompanying drawing 1 phosphorus concentration-absorbance standard curve
The impact of accompanying drawing 2pH on the phosphorus binding ability
The phosphorus rate curve falls in accompanying drawing 3 lanthanum carbonates, lactic acid lanthanum trihydrate
Accompanying drawing 4 lanthanum carbonates, lactic acid lanthanum trihydrate pharmacodynamics phosphorus binding ability
The specific embodiment
The phosphorus compositions falls in stability and high efficiency provided by the invention, and wherein, described compositions comprises lactic acid lanthanum hydrate and pharmaceutically acceptable proper auxiliary materials, and described compositions clinical practice has positive beneficial effect, and comprehensive advantage is obvious.
The present inventor finds under study for action, the existing phosphate binder that contains lanthanum, i.e. and commercially available lanthanum carbonate chewable tablet (trade name Fosrenol), wherein the active component lanthanum carbonate is water insoluble active ingredient, in water, solvability is only 2.38 * 10
-7Mol/L, after this intrinsic physicochemical property had determined its oral administration administration, medicine was difficult to rapid dispersion, stripping in vivo.it is to be noted, the dispersion of medicine, stripping is for the medicine of oral administration administration, very crucial as everyone knows, performance to drug effect plays vital effect, especially for lanthanum carbonate, it falls the phosphorus mechanism of action is by through disperseing, the coordination of phosphate radical in gastrointestinal tract of the trivalent lanthanum ion of stripping is combined, form non-absorbent lanthanum orthophosphate, directly send external with feces, the phosphorus effect is fallen thereby finally play by the absorption of phosphorus restriction, therefore, the developer is prepared as chewable tablet, and exhort that the patient takes in process, swallow after medicine fully should being chewed, to improve the dispersion in its body, the stripping behavior, guarantee the therapeutic effect of medicine, but, this mode is extremely limited for the improvement of its phosphorus binding ability efficacy exertion, and a large amount of Clinic Cases show, for this special population of hyperphosphatemia patient, patient's long-term prescription, it is inconvenient fully chewing and taking a large amount of tablets, and, for dysmasesis or the gerontal patient of hyperphosphatemia easily occurs, this is not insoluble, comprehensively, the water-insoluble physicochemical property of lanthanum carbonate exists numerous so and the obstacle that is difficult to go beyond of generation clinically.
In addition, the present inventor is by paying the creative experiments of a large amount of work, find that lanthanum carbonate phosphorus binding ability is subjected to the pH variable effect to a certain extent, it is under low pH environment, as at pH be 3.0 or lower pH condition under, the phosphorus binding ability can keep higher level, under higher pH environment, as at pH be 7.0 or higher pH condition under, the phosphorus binding ability has largely and descends.Therefore, lanthanum carbonate is unsettled to the binding ability of phosphorus to a certain extent, and this treats for clinical application is disadvantageous.Those skilled in the art all know, human gastrointestinal tract environment pH is vicissitudinous, be not to be the homogeneous situation, environment as gastric is meta-acid (pH is about 1.2 left and right), and the environment in intestinal is meta-alkali (pH is about 7.2 left and right), simultaneously, because of individual variation, Different Individual gastronintestinal system pH environment is also different.Therefore, if the medicine of taking can not guarantee stable phosphorus binding ability, will be difficult to guarantee clinical stable curative effect, at this, the present inventor thinks that what be necessary to specify is that human body approximately 70% carries out in the intestinal stage phosphatic absorption, this point is very crucial, the decline of lanthanum carbonate phosphorus binding ability under intestinal stage slight alkali environment is extremely disadvantageous for the clinical phosphorus that falls, and is also the fact that clinician and patient are unwilling to see.
Need to be pointed out that in the lump the present inventor also finds at this, exist in prior art lanthanum carbonate chewable tablet process of clinical application serious feel sick, the untoward reaction such as vomiting, think poor with the mouthfeel of lanthanum carbonate own, dose is large, cause easily that gastronintestinal system is uncomfortable to cause.
The problem that prior art exists is in the urgent need to address, clinically need a kind of desirable phosphorus medicine that falls badly and control hyperphosphatemia patient serium inorganic phosphorus level, stability and high efficiency provided by the present invention falls the phosphorus compositions and has solved the existing problem of prior art, and many beyond thought beneficial effects have been produced, further illustrate the present invention below in conjunction with embodiment, illustrate the technical solution used in the present invention, the technical characterictic that possesses and the beneficial effect that therefore produces, need to prove, the present invention's reagent used, reagent are the commercial goods unless stated otherwise.
Preparation Example 1
The preparation method of the present embodiment explanation lactic acid lanthanum trihydrate of the present invention, concrete steps are as follows:
A) take lanthanum carbonate 1.0kg and fully pulverize rear mistake 80 mesh sieves, be dispersed in suitable quantity of water under 65～70 ℃ of conditions;
B) to the above-mentioned lactic acid that adds 0.9kg in a), mix homogeneously under stirring condition, and react completely under 65～70 ℃ of airtight conditions;
C) above-mentioned gained solution evaporation drying under 75～80 ℃ of conditions to constant weight, with filtering after the 10.0L water dissolution, is got filtrate and its evaporation drying under 75～85 ℃ of conditions to constant weight, is got lactic acid lanthanum crude product;
D) with above-mentioned gained lactic acid lanthanum crude product, after 5.0L water washing, concentrated, forced air drying, pulverizing, vacuum drying 7.5h under 90～100 ℃ of conditions gets lactic acid lanthanum trihydrate, is weighed as 1.72kg;
Preparation Example 2
The present embodiment explanation preparation method that contains different water of crystallization structure lactic acid lanthanum hydrates of the present invention, concrete steps are as follows:
A) take lanthanum carbonate 1.2kg and fully pulverize rear mistake 80 mesh sieves, be dispersed in suitable quantity of water under 65～70 ℃ of conditions;
B) to the above-mentioned lactic acid that adds 1.3kg in a), mix homogeneously under stirring condition, and react completely under 65～70 ℃ of airtight conditions;
C) above-mentioned gained solution evaporation drying under 75～80 ℃ of conditions to constant weight, with filtering after the 12.0L water dissolution, is got filtrate and its evaporation drying under 75～85 ℃ of conditions to constant weight, is got lactic acid lanthanum crude product;
D) with above-mentioned gained lactic acid lanthanum crude product, after 10.0L water washing, concentrated, forced air drying, pulverizing under 100～110 ℃ of conditions vacuum drying 5.5h, get lactic acid lanthanum tetrahydrate, be weighed as 2.36kg;
In addition, the present inventor adopts with above-described embodiment 1 and 2 and is close to same method, by accurate change and control step c) in temperature conditions and time of evaporation drying, other lactic acid lanthanum hydrates have been obtained in work research, as: the inventor adopts the condition of 95～115 ℃, evaporation drying 3.0h successfully obtains lactic acid lanthanum hexahydrate; Adopt the condition of 100～120 ℃, evaporation drying 15.0h prepares lactic acid lanthanum semihydrate.
Need to prove, the present inventor has not only prepared above-mentioned each lactic acid lanthanum hydrate, also all kinds of lactic acid lanthanum hydrates that obtain in above-described embodiment 1, embodiment 2 and research are carried out the identification and analysis of scientific system, concrete grammar is with reference to " Preparation and solubilities of lanthanide lactates " [J, Inorg, Nucl, Chem, 1966, Vol28, PP.913～914] described in a literary composition, qualification result shows that each prepared hydrate is target product.
Simultaneously, it should be explained that the name of lactic acid lanthanum hydrate at this, as structural formula La (Lac)
3NH
2In O, the average of n is 3, this lactic acid lanthanum hydrate called after lactic acid lanthanum trihydrate that will prepare, and the name of other hydrates is carried out according to the average of n in this way.
The clinical practice form of phosphorus compositions is fallen in order to further illustrate stability and high efficiency of the present invention, and mating feature and the preparation technology of the lanthanum of lactic acid described in compositions hydrate, pharmaceutically acceptable adjuvant, the inventor describes in detail in following Preparation Example 3～10, it should be explicitly made clear at this point, in following examples 3～10, described lactic acid lanthanum hydrate is that each corresponding embodiment of the present invention prepares gained:
Preparation Example 3
The preparation of phosphorus composition tablet falls in stability and high efficiency of the present invention:
Prescription forms:
Preparation technology: 1) appropriate lactic acid lanthanum hydrate, microcrystalline Cellulose, lactose, polyvinylpolypyrrolidone, carboxymethyl starch sodium were pulverized 80 mesh sieves after, take recipe quantity standby; 2) the hypromellose solution for standby of preparation 3.0%; 3) with load weighted 1) in each component drop into mix homogeneously in mixer; 4) add recipe quantity 2 in mixture) preparation gained solution soft material processed, efficient wet granulator is granulated, and is dry below 60 ℃; 5) dry gained granule is crossed 16 mesh sieve granulate, adds magnesium stearate, after mix homogeneously on tablet machine tabletting and get final product.
Preparation Example 4
The preparation of phosphorus compositions powder falls in stability and high efficiency of the present invention:
Prescription forms:
Preparation technology: 1) appropriate lactic acid lanthanum trihydrate was pulverized 80 mesh sieves, and took recipe quantity standby; 2) take mannitol, cyclamate, the essence of recipe quantity through pulverizing 65 mesh sieves, mix homogeneously is standby; 3) with 1) with 2) form by prescription and set high in the effect mixer fully mix homogeneously, weighing packing and get final product.
Preparation Example 5
The preparation of phosphorus composition capsule falls in stability and high efficiency of the present invention:
Prescription forms:
Preparation technology: the 1) sodium carboxymethyl cellulose solution of preparation 1.0%, standby; 2) lactic acid lanthanum tetrahydrate, microcrystalline Cellulose, lactose are crossed 80 mesh sieves, standby; 3) in prescription ratio weighing 2) in each component, mix homogeneously; 4) add recipe quantity 1.0% sodium carboxymethyl cellulose solution soft material processed in mixture; 5) with 3) the gained soft material crosses 20 mesh sieves and granulates, and crosses 20 mesh sieve granulate after dry below 60 ℃; 6) add the recipe quantity magnesium stearate, mix homogeneously in the granule after granulate; 7) with 6) the gained mixture is filled in hard capsule case and get final product.
Preparation Example 6
The preparation of phosphorus composition oral liquid falls in stability and high efficiency of the present invention:
Prescription forms:
Preparation technology: 1) take under the refrigerant alcohol, aspartame, essence stirring condition of recipe quantity and be dissolved in appropriate purified water, to forming clear and bright solution; 2) the lactic acid lanthanum hexahydrate with recipe quantity adds to 1) in gained solution, stir; 3) with step 2) gained solution after the membrane filtration of 0.8 μ m, be sub-packed in oral liquid bottle, jump a queue, airtight and get final product.
Preparation Example 7
Prescription forms:
Preparation technology: 1) lactic acid lanthanum hexahydrate, dextrin, lactose were pulverized 120 mesh sieves, standby in prescription ratio mix homogeneously; 2) hypromellose, cyclamate, essence were pulverized 80 mesh sieves after, standby in prescription ratio mix homogeneously; 3) take recipe quantity 1) and 2) mix homogeneously, add purified water to prepare soft material; 4) prepare wet granular with granulator, below 60 ℃, dry rear granulate, pack the gained granule and get final product.
Preparation Example 8
Prescription forms:
Preparation technology: with embodiment 7.
Preparation Example 9
Prescription forms:
Preparation technology: with embodiment 7.
Preparation Example 10
Prescription forms:
Preparation technology: with embodiment 7.
After the granule for preparing embodiment 7～10 each lactic acid lanthanum hydrates, the present inventor adopts the detection method of granule granularity in 2010 editions appendix of Chinese Pharmacopoeia, grain size characteristic to each embodiment gained granule is analyzed, result shows that the preparation that the above embodiment of the present invention 7～10 makes is meeting the requirement while of Chinese Pharmacopoeia to granule, all satisfy the technical characterictic of granule of the present invention, concrete outcome such as following table 1:
Table 1. granule particle size distribution
Below, further illustrate by each Comparative Examples the characteristics that the phosphorus compositions falls in stability and high efficiency of the present invention:
It is to be noted, below in each Comparative Examples, described lactic acid lanthanum hydrate is that each corresponding embodiment of the present invention prepares gained, and described lanthanum carbonate is available from the chemical company limited of A Faaisha (Tianjin), without specifying that other reagent are the commercially available medicinal grade product that is easy to get.
Comparative Examples 1
Dissolubility has important impact for the clinical medicine of oral administration administration, the further dispersion of medicine, stripping behavior play a part crucial to the performance of drug effect, at this, the present inventor is by after the dissolubility of the described lactic acid lanthanum of systematic study hydrate, find the relative lanthanum carbonate of lactic acid lanthanum hydrate of the present invention, have significant advantage.
According to the assay method of dissolubility in Chinese Pharmacopoeia 2010 editions, obtained respectively the dissolubility of each hydrate of lactic acid lanthanum under the condition of different temperatures and lanthanum carbonate, concrete outcome sees the following form 2.
Table 2. lactic acid lanthanum hydrate, lanthanum carbonate dissolubility
By upper table 2 result as can be known, in the water of each hydrate of lactic acid lanthanum under each probe temperature condition, good solubility property is arranged all, be composition soluble in water, and lanthanum carbonate is all water insoluble under each test condition.
Before carrying out following Comparative Examples 2～5, what need here at first to get across is, the content of following phosphorus is to adopt the anti-method of molybdenum antimony to measure, specifically carry out in operational approach and step described in " preparation that lanthanum carbonate is nanocrystalline and phosphorus thereof are in conjunction with the evaluation study of effect " literary composition with reference to Xie Jiaye, Gao Jianping etc., according to the method, at first the present inventor has drawn the standard curve of total phosphorus content to absorbance in solution, concrete outcome such as following table 3, and standard curve is seen accompanying drawing 1.
Table 3. Specification Curve of Increasing phosphorus concentration and absorbance respective value
| Phosphorus concentration (μ g/mL) | 0.2 | 0.4 | 0.6 | 0.7 | 0.9 | 1.0 |
| Absorbance | 0.156 | 0.264 | 0.385 | 0.438 | 0.552 | 0.617 |
Comparative Examples 2
The phosphorus binding ability that contains lanthanum compound, how many available units amount lanthanums can representing in conjunction with the phosphorus amount, the lanthanum of unit quantity can be more in conjunction with the amount of phosphorus, illustrate that this phosphorus binding ability that contains lanthanum compound is stronger, can illustrate that also the lanthanum of using unit quantity can reach more good in conjunction with phosphorus and then fall the purpose of phosphorus.
1) preparation of phosphate solution: take anhydrous potassium dihydrogenphosphate 0.2197g water-soluble, it is moved in the 1000mL volumetric flask, add the 5mL sulfuric acid solution, dilute with water is settled to scale, gets the phosphate solution of phosphorous 50.0 μ g/mL;
2) with the combination of phosphorus: take lanthanum carbonate, lactic acid lanthanum semihydrate, lactic acid lanthanum trihydrate, lactic acid lanthanum tetrahydrate, the lactic acid lanthanum hexahydrate of counting 13.9mg with the amount of lanthanum, be added to respectively 1～No. 6 100mL step 1 be housed) in the beaker of gained phosphate solution, stir and fully was combined with phosphorus 60 minutes down.
3) assay: with 1～No. 6 not add the concentration that contains before lanthanum compound to calculate, be diluted in proportion 5.0 μ g/mL, get 5mL and join in the 25mL volumetric flask, add the dilution of 10mL water, then add the 1mL10% ascorbic acid solution in volumetric flask, mixing, add the 2mL molybdate solution after 30 seconds, fully mixing, place centrifugalize after 15 minutes, get supernatant and adopt the anti-method of molybdenum antimony to measure, further can get remaining phosphorus content in each water sample.
4) experimental result: adopt the total content M that adds phosphorus before lanthanum compound in 1～No. 6 beaker
AlwaysThe actual phosphorus content M that (this Comparative Examples be 50.0 μ g/mL * 100mL=5.0mg) deduct according to step 3) measured
1(for example for lanthanum carbonate M
1=2.78mg), can calculate the compound combination that respectively contains lanthanum and remove the amount of dephosphorization, be M
Always-M
1, further according to adding the amount M (this Comparative Examples is 13.9mg) that respectively contains lanthanum compound, the phosphorus binding ability that can get Unit Weight part lanthanum is (M
Always-M
1)/M, concrete outcome see the following form 4.
Lanthanum carbonate phosphorus binding ability: (M
Always-M
1)/M=(5.0-2.78)/13.9=0.160
Table 4. respectively contains lanthanum compound phosphorus binding ability
| ? | Phosphorus binding ability (mg phosphorus/mg lanthanum) |
| Lanthanum carbonate | 0.160 |
| Lactic acid lanthanum semihydrate | 0.193 |
| Lactic acid lanthanum trihydrate | 0.205 |
| Lactic acid lanthanum tetrahydrate | 0.187 |
| Lactic acid lanthanum hexahydrate | 0.178 |
By upper table 4 result as can be known, the phosphorus binding ability of each lactic acid lanthanum hydrate of the present invention, obviously be better than lanthanum carbonate, simultaneously, the present inventor is unexpected the discovery also, and different hydrates also have slightly difference to the binding ability of phosphorus, special find the strongest with the phosphorus binding ability of lactic acid lanthanum trihydrate, every mg lanthanum can be in conjunction with the phosphorus of much 0.205mg, with the hexahydrated phosphorus binding ability of lactic acid lanthanum relatively a little less than.
Comparative Examples 3
Adopt the assay method described in Comparative Examples 2, the present inventor has studied the impact of pH on lanthanum carbonate, each hydrate phosphorus binding ability of lactic acid lanthanum, investigated respectively the phosphorus binding ability of lanthanum carbonate, each lactic acid lanthanum hydrate under pH=1.0,3.0,7.0 conditions, phosphorus binding ability during wherein take pH=1.0 is 1, and concrete outcome sees the following form 5.
The impact of table 5.pH on lactic acid lanthanum hydrate phosphorus binding ability
Change respectively containing the impact of lanthanum compound phosphorus binding ability in order to present more intuitively pH, accompanying drawing 2 has been drawn and has respectively been contained the curve of lanthanum compound phosphorus binding ability under the condition of different pH.
By upper table 5 result and accompanying drawing 2 as can be known, each hydrate of lactic acid lanthanum is subjected to the impact of pH variation less on the binding ability of phosphorus, all keep higher phosphorus binding ability stability under each pH condition, as lactic acid lanthanum trihydrate at pH in 1.0～7.0 scope, its binding ability maximum to phosphorus has changed (1.061-1.0)/1.0=6.1%, the semihydrate maximum has changed 2.8%, and the tetrahydrate maximum has changed 2.8%, and the hexahydrate maximum has changed 3.5%; And for lanthanum carbonate, it still can keep comparatively stable phosphorus binding ability under low pH, but, when pH is higher, during as pH=7.0, its phosphorus binding ability descends rapidly, the 0.702/1.0=70.2% when only being pH=1.0, descended 29.8%, this is that in process of clinical application, people are unwilling to see.
Not relying on the variation of pH, keep the phosphorus binding ability remain the same from beginning to end stable, is the required satisfied important prerequisite of desirable phosphorus bonding agent clinically, as everyone knows, under normal circumstances, human intake's phosphorus 60～80% absorbs at the small intestinal near-end, then being converted into phosphatic form is present in blood plasma, small intestinal environment meta-alkalescence, pH is slightly larger than 7, with this understanding, the phenomenon that lanthanum carbonate has obvious phosphorus binding ability to descend, and the lactic acid lanthanum under this pH, still has stable phosphorus binding ability; In addition, via this Comparative Examples 3, the discovery that the present inventor is pleasantly surprised, each hydrate of lactic acid lanthanum is keeping not relying on the stable phosphorus binding ability of pH simultaneously, in the Main Stage of human intake's phosphorus, under the approximate pH environment of small intestinal near-end, when being pH=7.0, binding ability to phosphorus has unexpected raising, improves nearly 6.1% level as lactic acid lanthanum trihydrate, and this is very useful for the clinical phosphorus that falls.
Comparative Examples 4
For the hyperphosphatemia patient, falling rapidly phosphorus, to make body serium inorganic phosphorus level reach normal value be very important, therefore, the speed of phosphorus binding ability and fall phosphorus speed and become clinically and to pay close attention to and a very important aspect, the present inventor is unexpected the discovery under study for action, lactic acid lanthanum hydrate, particularly trihydrate obviously are better than lanthanum carbonate aspect phosphorus speed falling, and are embodied in lactic acid lanthanum trihydrate of the present invention and can reach in the short period of time the more gratifying phosphorus effect of falling.
Method described in reference counterpoint example 2, the present inventor has investigated respectively lanthanum carbonate and the fall phosphorus situation of lactic acid lanthanum trihydrate in 60 minutes, by relatively be combined with phosphorus produce 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes the time the phosphorus effect falls, the unexpected discovery, lactic acid lanthanum trihydrate of the present invention can reach rapidly the level of falling phosphorus amount 2.7mg in the time of 20 minutes, reach the 2.7/3.12=86.5% that it always falls the phosphorus ability; And the fall phosphorus amount of lanthanum carbonate in the time of 20 minutes is 0.87mg, always fall the phosphorus amount when extending to 60 minutes and also only be 2.31mg, fall the phosphorus amount in the time of 20 minutes and only reach the 0.87/2.31=37.7% that it always falls the phosphorus ability, lactic acid lanthanum trihydrate is when phosphorus falls in high ability, improved the speed of falling phosphorus with unexpected advantage, concrete outcome is seen accompanying drawing 3.
Comparative Examples 5
For the further practical phosphorus binding ability of research lactic acid lanthanum hydrate, the present inventor is by setting up corresponding animal model, comparative study the phosphorus binding ability of lactic acid lanthanum trihydrate of the present invention and lanthanum carbonate animal pharmacodynamics.
In the animal model of chronic kidney hypofunction, all tested rats (Wistar male rat) are carried out 5/6 the nephrectomy, then be divided at random three groups each 9 of A, B, C.Adopt oral administration, wherein the A group gives lactic acid lanthanum trihydrate, and the B group gives lanthanum carbonate, and dosage is 524mg/kg every day in the amount of lanthanum, and the C group is matched group.Each tested group every rat 24h urine phosphorus total amount when measuring for 0,1,2,3,4,6,8,10 week in research, and get the meansigma methods of respectively organizing rat urine phosphorus total amount, with each treatment time node to the mapping of 24h urine phosphorus total amount, discovery is compared lactic acid lanthanum trihydrate with lanthanum carbonate can reduce urine phosphorus amount faster, greatly, illustrate that thus lactic acid lanthanum trihydrate has stronger, phosphorus binding ability faster, concrete outcome is seen accompanying drawing 4 (ability in conjunction with phosphorus is stronger in vivo to it should be explained that medicine, and the phosphorus that excretes through urine is corresponding also just fewer).
In addition, in a series of researchs, other each lactic acid lanthanum hydrates (Ban Shui, four water, hexahydrate) of the present invention also all have good animal pharmacodynamics and fall the phosphorus ability, can be fast, stronger play in conjunction with phosphorus, fall the effect of phosphorus.
The final purpose of medicine is to be applied to clinically, benefits from clinical patients, and therefore, the final curative effect of medicine and clinical advantage also should embody by the test of clinical efficacy, below each clinical trial example compositions of the present invention is studied in detail:
Clinical trial example 1
This test case is used for estimating the sensory difference that lactic acid lanthanum trihydrate of the present invention is compared with lanthanum carbonate.Concrete method of testing is as follows:
This clinical trial example laboratory sample is for adopting the lactic acid lanthanum hydrate of the corresponding embodiment preparation of commercially available lanthanum carbonate and the present invention, after removing cyclamate and essence according to the prescription of Preparation Example 7, be prepared into corresponding granule with described technique, get respectively lanthanum carbonate granule, lactic acid lanthanum semihydrate granule, lactic acid lanthanum trihydrate granule, lactic acid lanthanum tetrahydrate granule, lactic acid lanthanum hexahydrate granule.
Double blinding, choose 300 healthy volunteers at random, be divided at random 5 groups, every group of 60 people attempt respectively the described corresponding granule of this clinical trial example.The trial method is: get respectively the granule in the amount 1000mg of lanthanum, be uniformly dispersed with the warm water of 100mL and attempt for the respective sets volunteer afterwards, each 25mL, the drug solution of all must not swallowing in cut-and-try process, every volunteer marks by following mouth feel score standard after having attempted.
The mouth feel score standard: mouthfeel evaluation result best result is 5 minutes, minimumly is divided into 1 minute, wherein, shows that mouthfeel was the poorest in 1 minute, increases progressively successively, shows that mouthfeel was best in 5 minutes.
Mouth feel score result: see Table 6.
Table 6. lanthanum carbonate, lactic acid lanthanum hydrate mouthfeel evaluation result
As shown in Table 13: each lactic acid lanthanum hydrate mouthfeel of the present invention all is better than the mouthfeel of lanthanum carbonate, and it is only 3.32 minutes that the evaluation of lanthanum carbonate mouthfeel is divided equally, and each group of lactic acid lanthanum hydrate is estimated and to be divided equally all more than 4.20 minutes, shows good mouthfeel; The most gratifyingly be, each volunteer to corresponding tested material appraisal result without providing 1 minute person, and mainly concentrate on higher 4 minutes and 5 minutes, lactic acid lanthanum semihydrate, trihydrate, tetrahydrate, hexahydrate scoring are respectively (20+30)/60=83.3%, (22+32)/60=90.0%, (17+31)/60=80.0%, (21+30)/60=85.0% in the ratio of 4 minutes and 5 minutes, illustrate that its mouthfeel individual difference is little, different volunteers is all shown good mouthfeel.
Clinical trial example 2
Lactic acid lanthanum trihydrate treatment nephrotic's hyperphosphatemia effectiveness and untoward reaction evaluation:
1) experimenter selects: end stagerenaldisease or the Effect in Chronic Renal Failure Treated by Hemodialysis of selecting age＞18 year old, the patient dialyses weekly 3 times at least, dialysis time＞3 month, serium inorganic phosphorus content＞1.8mmol/L, get rid of suffer from the severe cardiac cerebrovascular system or (with) respiratory system or (with) the digestive system disease person, clinical 315 examples of including in altogether, be divided at random A, B, three groups of each 105 examples of C, wherein, the A group is divided into again A-1 at random, A-2, A-3, A-4, the A-5 group, the B group is divided into B-1, B-2, B-3, B-4, the B-5 group, the C group is divided into C-1, C-2, C-3, C-4, the C-5 group.
2) dosage regimen: according to the characteristics that contain the lanthanum phosphate binder, three groups of A, B, C all take with meal, every day 1 time, clinical taking for 6 weeks; The A group is matched group, takes placebo (pressing the blank granule that the embodiment of the present invention 8 methods prepare except lactic acid lanthanum trihydrate), and dose is with C group granule dosage; The B group is taken commercially available lanthanum carbonate chewable tablet, and the C group is taken the granule of lactic acid lanthanum trihydrate of the present invention, and wherein B, two groups of doses of C all to contain the lanthanum amount, specifically see the following form 7.
The tested B of table 7., C group patient dosage
3) evaluation methodology: the Clinical efficacy of tested A, B, each group of C, adopt each group Δ P to serium inorganic phosphorus reduction amount during treating to estimate, as treated for 6 weeks by detection, in corresponding group, current serium inorganic phosphorus mean concentration is P
6, treatment beginning patient's during front 0 week initial serium inorganic phosphorus mean concentration is P
0, Δ P=P so
0-P
6, the phosphorus effect falls by what size of Δ p value in each corresponding group was relatively estimated tested medicine; Untoward reaction is estimated by calculating each group adverse reaction rate, that untoward reaction comprises is nauseating, vomiting, stomachache, the one that described symptom occurs can be designated as untoward reaction X, if this group sample total is N, and adverse reaction rate=X/N * 100% so.(it is to be noted that respectively organizing corresponding relation is that B-1, C-1 corresponding A-1 a group statistics are first group, B-2, C-2 corresponding A-2 a group statistics are second group, other groups successively correspondence add up respectively into third and fourth, five groups)
4) result of study: each group Clinical efficacy and adverse reaction rate clinical evaluation the results are shown in following table 8～12.
First group of clinical evaluation result of table 8.
Second group of clinical evaluation result of table 9.
The 3rd group of clinical evaluation result of table 10.
The 4th group of clinical evaluation result of table 11.
The 5th group of clinical evaluation result of table 12.
by upper table 8～12 results as can be known, the granule of lactic acid lanthanum trihydrate compositions of the present invention preparation clinically, by to take the amount of lanthanum, all has the good phosphorus ability of falling in consumption 50～2000mg scope, compare with the commercially available lanthanum carbonate chewable tablet of taking in lanthanum amount equivalent, has obvious superiority, show as more that serium inorganic phosphorus concentration is reduced, for example for the 4th group, take B4 group six weeks for the treatment of of lanthanum carbonate chewable tablet, the serium inorganic phosphorus lowering of concentration 14.6mg/L, and the C4 that takes lactic acid lanthanum trihydrate granule organizes the 19.0mg/L that descended, it is 19.0/14.6=1.30 times that the phosphorus ability falls in the lanthanum carbonate chewable tablet, for untoward reaction, by each group adverse reaction rate contrast of above-mentioned table 8～12 as can be known, the granule of lactic acid lanthanum trihydrate compositions preparation of the present invention, adverse reaction rate is far below commercially available lanthanum carbonate chewable tablet clinically, as for the 3rd group, take the B3 group of lanthanum carbonate chewable tablet, adverse reaction rate is 28.6%, the C3 group of taking lactic acid lanthanum trihydrate granule is 14.3%, thereby compositions untoward reaction of the present invention is few, can improve the compliance of clinical patients, embody to a certain extent its Comprehensive Clinical advantage.
In addition, except above-mentioned granule to the preparation of lactic acid lanthanum trihydrate has been done corresponding clinical research, equally lactic acid lanthanum semihydrate, tetrahydrate, hexahydrate have been done detailed clinical research, all obtained gratifying clinical effectiveness, reached the beneficial effect of generation of the present invention, but, comparatively speaking with the tool comprehensive advantage of lactic acid lanthanum trihydrate.
Need to prove: the above is only for the preferred embodiment of the present invention, and is within the spirit and principles in the present invention all not in order to limit the present invention, any modification of doing, is equal to replacement, improvement etc., within all should being included in protection scope of the present invention.
Claims (10)
- A stability and high efficiency the phosphorus compositions falls, it is characterized in that, described compositions comprises: the lactic acid lanthanum hydrate that a) is shown below, b) pharmaceutically acceptable proper auxiliary materials.La(Lac) 3·nH 2O[Lac＝CH 3CH(OH)COO -]。
- 2. compositions according to claim 1, is characterized in that, in described lactic acid lanthanum hydrate, the average of n is 0.5～6.0, is preferably 0.5～4.0, more preferably 3.0.
- 3. compositions according to claim 1 and 2, is characterized in that, the administration of described compositions oral administration is applicable to the phosphorus that falls of hyperphosphatemia clinically.
- 4. compositions according to claim 3, is characterized in that, described compositions odd-numbered day quantity is counted 0.05g～2.0g with anhydrous lactic acid lanthanum, is preferably 0.2～2.0g.
- 5. compositions according to claim 4, is characterized in that, in described compositions, lactic acid lanthanum hydrate is 5.0～95.0% of total weight parts, is preferably 10.0～80.0%.
- 6. according to claim 3～5 described compositionss, is characterized in that, the form of described compositions oral administration administration can be tablet, powder, granule, capsule, oral liquid, is preferably granule.
- 7. compositions according to claim 6, is characterized in that, the granule weight portion of described compositions oral administration administration consists of: lactic acid lanthanum hydrate 10.0～80.0%; Binding agent 0.5～5.0%; Correctives 0.5～2.5%; The filler surplus.
- 8. compositions according to claim 7, is characterized in that, described binding agent is a kind of in methylcellulose, ethyl cellulose, sodium carboxymethyl cellulose, hypromellose, PVP; Described correctives is a kind of in citric acid, sodium citrate, ascorbic acid, cyclamate, aspartame, essence; Described filler is a kind of in dextrin, microcrystalline Cellulose, lactose, starch, pregelatinized Starch.
- 9. according to claim 7 or 8 described compositionss, is characterized in that, described granule particle diameter should account for more than 85% of total particle weight ratio at 10～80 purpose granules, and the grain diameter of preferred 90% above weight ratio is at 24～80 orders.
- 10. prepare the method that the phosphorus compositions falls in the described stability and high efficiency of any one in claim 1～9, it is characterized in that, described method comprises the step that is prepared as follows lactic acid lanthanum hydrate:A) take lanthanum carbonate and fully pulverize rear mistake 80 mesh sieves, be dispersed in suitable quantity of water under 65～70 ℃ of conditions;B) add excessive lactic acid to above-mentioned in a), mix homogeneously under stirring condition, and react completely under 65～70 ℃ of airtight conditions;C) above-mentioned gained solution evaporation drying under 75～80 ℃ of conditions to constant weight, with filtering after the suitable quantity of water dissolving, is got filtrate and its evaporation drying under 75～85 ℃ of conditions to constant weight, is got lactic acid lanthanum crude product;D) with above-mentioned gained lactic acid lanthanum crude product, after excessive water washing, concentrated, forced air drying, pulverizing under 90～120 ℃ of conditions the vacuum drying suitable time, get lactic acid lanthanum hydrate;Wherein, step b) described excessive lactic acid, in mole, the lactic acid consumption should be no less than 6 times that add the lanthanum carbonate amount; Step c) described suitable quantity of water, by weight, the consumption of water should be no less than 8 times that add the lanthanum carbonate amount; Steps d) excessive water described in, by weight, the consumption of water should be no less than 5 times of lanthanum carbonate addition, and described suitable time should be 3.0～15.0h.
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| CN1857302A (en) * | 2006-03-24 | 2006-11-08 | 李诗标 | Medicine for treating hyperphosphatemia and its preparing method |
| CN101304753A (en) * | 2005-11-09 | 2008-11-12 | 夏尔国际许可有限公司 | Treatment of chronic kidney disease (CKD) subjects using lanthanum compounds |
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| CN101304753A (en) * | 2005-11-09 | 2008-11-12 | 夏尔国际许可有限公司 | Treatment of chronic kidney disease (CKD) subjects using lanthanum compounds |
| CN1857302A (en) * | 2006-03-24 | 2006-11-08 | 李诗标 | Medicine for treating hyperphosphatemia and its preparing method |
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| Title |
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| 桑晓云等: "制备醋酸镧的清洁生产循环工艺研究", 《稀土》 * |
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