WO2016051609A1 - Drug comprising lanthanum carbonate hydrate having adjusted particle size - Google Patents
Drug comprising lanthanum carbonate hydrate having adjusted particle size Download PDFInfo
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- WO2016051609A1 WO2016051609A1 PCT/JP2014/080459 JP2014080459W WO2016051609A1 WO 2016051609 A1 WO2016051609 A1 WO 2016051609A1 JP 2014080459 W JP2014080459 W JP 2014080459W WO 2016051609 A1 WO2016051609 A1 WO 2016051609A1
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- A—HUMAN NECESSITIES
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- A61K33/00—Medicinal preparations containing inorganic active ingredients
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- A61K33/244—Lanthanides; Compounds thereof
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- the present invention relates to a medicament comprising a particle size-adjusted lanthanum carbonate hydrate useful as a therapeutic agent for hyperphosphatemia.
- Patent Document 1 discloses lanthanum carbonate 4.4 hydrate, tetrahydrate and 3.8 hydrate, lanthanum carbonate 8.8 hydrate, 1.3 hydrate and 2.2 water.
- An object of the present invention is to provide a medicine using lanthanum carbonate hydrate that can remove phosphate more quickly without the problem of deterioration of product quality due to heat and moisture.
- the present inventor has found that lanthanum carbonate tetrahydrate has decomposition due to heat and moisture absorption, while lanthanum carbonate 7-7 hydrate. Even if it is 7-9 hydrate of lanthanum carbonate, which has been found to be extremely stable, and inferior in ability to remove phosphoric acid in Patent Document 1, phosphoric acid can be reduced by reducing the particle size. It was found that it could be removed almost 100% faster and the present invention was completed. That is, the present invention is as follows.
- [5] Contains lanthanum carbonate hydrate represented by La 2 (CO 3 ) 3 ⁇ xH 2 O (wherein x is a number between 7 and 9), wherein D90 is 70 ⁇ m or less.
- Pharmaceutical composition. [6] The pharmaceutical composition according to [5], wherein D90 is 2 to 65 ⁇ m.
- [7] Expressed by La 2 (CO 3 ) 3 ⁇ xH 2 O (wherein x represents a number between 7 and 9) having a phosphate binding rate constant k 1 of 0.75 min ⁇ 1 or more.
- a pharmaceutical composition containing lanthanum carbonate hydrate [8] The pharmaceutical composition according to any one of [1] to [3] for treating hyperphosphatemia.
- a method for treating hyperphosphatemia by administering the pharmaceutical composition according to any one of [5] to [7] to a patient in need thereof.
- La 2 (CO 3 ) 3 ⁇ xH 2 O (wherein x represents a number between 7 and 9) having a D90 of 70 ⁇ m or less for use in the treatment of hyperphosphatemia.
- the lanthanum carbonate hydrate represented, or a pharmaceutical composition containing it.
- La 2 (CO 3 ) 3 ⁇ xH 2 O (wherein x is 7 to 4 ) having a phosphate binding rate constant k 1 of 0.75 min ⁇ 1 or more for use in the treatment of hyperphosphatemia Lanthanum carbonate hydrate represented by 9) or a pharmaceutical composition containing the same.
- La 2 (CO 3 ) 3 ⁇ xH 2 O (wherein x is 7 to 9), in which 90% integrated diameter (D90) is 70 ⁇ m or less in the manufacture of a medicament used for the treatment of hyperphosphatemia
- D90 is 2 to 65 ⁇ m.
- La 2 (CO 3 ) 3 ⁇ xH 2 O (wherein x is a phosphate binding rate constant k 1 of 0.75 min ⁇ 1 or more in the manufacture of a medicament used for the treatment of hyperphosphatemia) Use of lanthanum carbonate hydrate represented by the number between 7 and 9.).
- Lanthanum carbonate tetrahydrate produced a polymorphic form (II) of lanthanum hydroxide carbonate described in Special Table 2009-536356 in a storage stability test at 40 ° C. and 75% RH. Although there is a change, such decomposition and change are not observed at all in the lanthanum carbonate 7-9 hydrate having a D90 of 70 ⁇ m or less used in the present invention. Further, phosphoric acid can be removed almost 100% faster.
- FIG. 4 is a graph showing changes in phosphoric acid removal rate depending on the particle size distribution in lanthanum carbonate 7.9 hydrate of Examples 1 to 3 and Comparative Example 1. It is a figure which shows a time-dependent change of the powder X-ray-diffraction chart of the lanthanum carbonate 7.9 hydrate of Example 1 preserve
- the lanthanum carbonate hydrate used in the present invention is preferably 7-9 hydrate.
- a commercially available product called an octahydrate can be used as it is, but it can also be produced according to a conventional method, for example, the method described in Patent Document 1.
- the 7-9 hydrate is preferably 7.5-8.5 hydrate.
- the 4.7 hydrate contained in the 3-6 hydrate of lanthanum carbonate described in Patent Document 1 was subjected to a storage stability test at 40 ° C. and 75% RH. As a result, (II) type lanthanum hydroxide carbonate was obtained. As shown in Test Example 3, it was found that was produced and changed to octahydrate.
- lanthanum carbonate 7-9 hydrate was subjected to the same stability test. As a result, no decomposition product was observed, and it was found that the lanthanum carbonate was extremely stable. Therefore, it can be handled stably in the steps of storing the drug substance and formulating, and the active ingredient can be kept stable even in the final drug product.
- the lanthanum carbonate 7-9 hydrate used in the present invention has a 90% cumulative diameter (D90) of 70 ⁇ m or less.
- D90 will be further described.
- the particle diameter is a particle diameter at which the volume cumulative particle size distribution is 90% from the small particle side, and is measured by, for example, a particle size measuring method described later.
- D90 of lanthanum carbonate is preferably 1 to 70 ⁇ m, more preferably 2 to 65 ⁇ m, still more preferably 5 to 65 ⁇ m, particularly preferably 15 to 60 ⁇ m, and most preferably 25 to 55 ⁇ m.
- the lanthanum carbonate hydrate used in the present invention is not inferior in the phosphoric acid removal rate as compared with the lanthanum carbonate tetrahydrate having the same particle size, but the phosphoric acid removal rate is faster.
- D90 is preferably 1 ⁇ m or more, more preferably 2 ⁇ m or more, and further preferably 5 ⁇ m or more.
- the medicament of the present invention can be used as a therapeutic agent for hyperphosphatemia, and further as a therapeutic agent for hyperphosphatemia in patients with chronic kidney disease.
- the medicament of the present invention contains the lanthanum carbonate hydrate used in the present invention as an active ingredient.
- the dose of lanthanum carbonate hydrate varies depending on the patient's condition, body weight, etc., and for example, about 100 mg to 10 g, preferably about 500 mg to 5 g, more preferably about 750 mg to 2.25 g per day for an adult. It is.
- These preparations can be administered 1 to several times a day, preferably 3 times a day.
- the medicament of the present invention can be administered orally to obtain a pharmaceutical preparation suitable for it.
- Examples of the pharmaceutical preparation include orally disintegrating tablets, chewable agents, granules, tablets, capsules and the like.
- Pharmaceutically acceptable carriers used in formulating pharmaceutical preparations include diluents, binders (syrup, gum arabic, gelatin, sorbit, tragacanth, polyvinylpyrrolidone), excipients (lactose, sucrose, corn starch, Potassium phosphate, sorbit, glycine), lubricant (magnesium stearate, talc, polyethylene glycol, silica), disintegrant (potato starch), wetting agent (sodium lauryl sulfate) and coating agent (sucrose, hydroxypropylcellulose, hypromellose) , Ethyl cellulose) and the like.
- This pharmaceutical preparation can be produced by mixing lanthanum carbonate hydrate, a pharmaceutically acceptable carrier and the like according to a conventionally known method.
- the particle size distribution analyzer was measured using Nikkiso Aerotrac LDSA-SPR as a suspension by adding about 5 mg of sample to 6.5 mL of water using water as a dispersion medium under wet conditions.
- the phosphate binding ability test was carried out in the following manners (1) to (7).
- (1) 4.13 g of anhydrous disodium hydrogen phosphate and 2.55 g of sodium chloride were dissolved in 300 mL of deionized water to prepare a stock solution.
- (2) Concentrated hydrochloric acid was added dropwise to 100 mL of the stock solution to adjust to pH 3.
- a 5 mL sample was taken with a syringe and filtered through a 0.02 ⁇ m filter to obtain a time 0 sample.
- (3) 5 mL of the stock solution was added to make the total volume 100 mL again, and concentrated hydrochloric acid was added dropwise to adjust the pH to 3 again.
- hexaammonium heptamolybdate tetrahydrate was dissolved in 40 mL of 2.5N sulfuric acid to prepare a molybdenum test solution.
- Fiske-SubbaRow reducer 2 g was taken and dissolved in 12.6 mL of water to prepare a Fiske-SubbaRow reagent solution.
- (6) Dilute the solution sampled at each time 50 times, add 1 mL of molybdenum test solution and 0.25 mL of Fiske-SubbaRow test solution to 1 mL of this solution, add water to make exactly 25 mL, add the test solution and add 10 mL.
- the lanthanum carbonate 7.9 hydrate of Example 2 was pulverized using a jet mill pulverizer (MC-ONE manufactured by JETPHARMA SOLUTIONS SA) under the conditions of a venturi pressure of 6 MPa, a ring pressure of 3 MPa, and a sample charging speed of 2 g / 10 minutes.
- the title lanthanum carbonate 7.7 hydrate was obtained.
- Test example 1 Phosphate adsorption ability test
- the lanthanum carbonate hydrates of Examples 1 to 3 and Comparative Example 1 were tested for phosphate adsorption ability.
- the results of phosphoric acid removal rate (%) by the phosphate adsorption ability test are shown in Table 2. Moreover, it shows in FIG. 1 as what made it the graph.
- the 7-9 hydrate of lanthanum carbonate significantly improved the phosphate removal rate as the D90 became finer, 99.9 ⁇ m, 64.9 ⁇ m and 29.8 ⁇ m.
- the phosphoric acid removal rate was not further improved and was almost the same.
- the regression line excluding the data near the reaction end point (phosphate removal rate of 98% or more) was a straight line having a multiple correlation coefficient of 0.97 or more.
- Table 3 shows the first-order reaction rate constant k 1 obtained at this time.
- the reaction rate constant measurement k 1 was determined from the numerical values of Table 1 in which the test results of the phosphate removal effect of 8.8 hydrate of Patent Document 1 were described, it was 0.24 min ⁇ 1 , which was lanthanum carbonate of Comparative Example 1 7.9 perfectly matches the k 1 hydrate. Therefore, it can be seen that the lanthanum carbonate 7.9 hydrate of Comparative Example 1 is a lanthanum carbonate having a particle size almost similar to that of the lanthanum carbonate 8.8 hydrate described in Patent Document 1 and exhibiting similar properties. Compared with the hydrate of Comparative Example 1, the hydrate of Example 1 is about 3.5 times, the hydrates of Examples 2 and 3 are about 4 times, and the phosphate removal rate is fast. Therefore, in contrast to 8.8 hydrate of Patent Document 1, the hydrates of Examples 1 to 3 have the same high phosphoric acid removal rate.
- Test example 3 Stability Test The lanthanum carbonate 7.9 hydrate of Example 1 and the lanthanum carbonate 4.7 hydrate of Comparative Example 2 were placed in a brown sample bottle and sealed. This was used as a specimen and stored in a constant temperature and humidity apparatus at 40 ° C. and 75% RH. After 1 month and 3 months, the powder X-ray diffraction of the lanthanum carbonate was measured. The results are shown in FIG. 2 and FIG. As shown in FIG. 2, there was no change in the lanthanum carbonate 7.9 hydrate of Example 1. As shown in FIG.
- a lanthanum carbonate hydrate that does not have a problem of deterioration of product quality due to heat and moisture and that can remove phosphates more quickly and reliably is obtained.
- the medicine to be used can be provided.
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Abstract
This drug comprises a lanthanum carbonate hydrate which has a 90% cumulative diameter (D90) of 70μm or less and which is represented by La2(CO3)3⋅xH2O (in the formula, x represents a number 7-9). The drug does not have the problem of decreased product quality due to heat and moisture, and moreover allows quick and reliable removal of phosphates.
Description
本発明は、高リン酸血症治療剤として有用な粒度調整された炭酸ランタン水和物からなる医薬に関する。
The present invention relates to a medicament comprising a particle size-adjusted lanthanum carbonate hydrate useful as a therapeutic agent for hyperphosphatemia.
慢性腎臓病患者における高リン血症の治療剤として、Ｌａ２（ＣＯ３）３・ｘＨ２Ｏ（ｘ＝主として４）で表される炭酸ランタン水和物を用いた医薬が国内外で販売されている。同医薬品の添付文書には、湿気により製品の品質が影響を受けるので、アルミニウム袋の状態で保存することが、取扱い上の注意として記載されている。
炭酸ランタン水和物を用いる高リン酸塩血症治療剤については、特許３２２４５４４（特許文献１）に記載がなされている。特許文献１には、炭酸ランタンの４．４水和物、４水和物および３．８水和物が、炭酸ランタンの８．８水和物、１．３水和物および２．２水和物よりも、かなり早くリン酸塩に結合することが記載され（第４頁，左欄１～１２行目）、かかる知見に基づいて、Ｌａ２（ＣＯ３）３・ｘＨ２Ｏ（ｘ＝３～６）で表される炭酸ランタンを含む高リン酸塩血症の治療のための医薬組成物が請求項１に記載されている。以上の通り、特許文献１から、当業者は、高リン酸塩血症治療剤に用いるのに適した炭酸ランタンは、３～６水和物であって、８水和物は好ましくないと理解する。また、特許文献１には、用いた炭酸ランタンの粒度については一切記載されていない。 As a therapeutic agent for hyperphosphatemia in patients with chronic kidney disease, a medicine using lanthanum carbonate hydrate represented by La 2 (CO 3 ) 3 xH 2 O (x = mainly 4) is sold in Japan and overseas. ing. In the package insert of the drug, the product quality is affected by moisture, so it is stated as a precaution for handling that the product is stored in an aluminum bag.
A hyperphosphatemia therapeutic agent using lanthanum carbonate hydrate is described in Japanese Patent No. 3224544 (Patent Document 1).Patent Document 1 discloses lanthanum carbonate 4.4 hydrate, tetrahydrate and 3.8 hydrate, lanthanum carbonate 8.8 hydrate, 1.3 hydrate and 2.2 water. It is described that it binds to phosphate much faster than the Japanese product (page 4, left column, lines 1 to 12). Based on this finding, La 2 (CO 3 ) 3 · xH 2 O (x A pharmaceutical composition for the treatment of hyperphosphatemia comprising lanthanum carbonate represented by = 3-6) is described in claim 1. As described above, from Patent Document 1, those skilled in the art understand that lanthanum carbonate suitable for use as a hyperphosphatemia therapeutic agent is 3 to 6 hydrate, and octahydrate is not preferable. To do. Patent Document 1 does not describe any particle size of the lanthanum carbonate used.
炭酸ランタン水和物を用いる高リン酸塩血症治療剤については、特許３２２４５４４（特許文献１）に記載がなされている。特許文献１には、炭酸ランタンの４．４水和物、４水和物および３．８水和物が、炭酸ランタンの８．８水和物、１．３水和物および２．２水和物よりも、かなり早くリン酸塩に結合することが記載され（第４頁，左欄１～１２行目）、かかる知見に基づいて、Ｌａ２（ＣＯ３）３・ｘＨ２Ｏ（ｘ＝３～６）で表される炭酸ランタンを含む高リン酸塩血症の治療のための医薬組成物が請求項１に記載されている。以上の通り、特許文献１から、当業者は、高リン酸塩血症治療剤に用いるのに適した炭酸ランタンは、３～６水和物であって、８水和物は好ましくないと理解する。また、特許文献１には、用いた炭酸ランタンの粒度については一切記載されていない。 As a therapeutic agent for hyperphosphatemia in patients with chronic kidney disease, a medicine using lanthanum carbonate hydrate represented by La 2 (CO 3 ) 3 xH 2 O (x = mainly 4) is sold in Japan and overseas. ing. In the package insert of the drug, the product quality is affected by moisture, so it is stated as a precaution for handling that the product is stored in an aluminum bag.
A hyperphosphatemia therapeutic agent using lanthanum carbonate hydrate is described in Japanese Patent No. 3224544 (Patent Document 1).
本発明の課題は、熱および湿気による製品の品質の低下の問題が無く、リン酸塩をより早く除去できる炭酸ランタン水和物を用いる医薬を提供することにある。
An object of the present invention is to provide a medicine using lanthanum carbonate hydrate that can remove phosphate more quickly without the problem of deterioration of product quality due to heat and moisture.
本発明者は、上記課題を解決すべく、鋭意研究を行った結果、炭酸ランタンの４水和物には熱および吸湿に伴う分解等があるのに対して、炭酸ランタンの７～９水和物は極めて安定であることを見出し、また特許文献１にてリン酸除去能が劣るとされていた炭酸ランタンの７～９水和物であっても、粒度を細かくすることによって、リン酸をより早く、ほぼ１００％除去できることを見出して、本発明を完成した。即ち、本発明は以下の通りである。
［１］ ９０％積算径（Ｄ９０）が７０μｍ以下である、Ｌａ２（ＣＯ３）３・ｘＨ２Ｏ（式中、ｘは７～９の間の数字を示す。）で表される炭酸ランタン水和物からなる医薬。
［２］ Ｄ９０が２～６５μｍである、［１］に記載の医薬。
［３］ ０．７５ｍｉｎ－１以上のリン酸結合速度定数ｋ１を有する、Ｌａ２（ＣＯ３）３・ｘＨ２Ｏ（式中、ｘは７～９の間の数字を示す。）で表される炭酸ランタン水和物からなる医薬。
［４］ 高リン血症を治療するための、［１］～［３］のいずれかに記載の医薬。 As a result of intensive studies to solve the above problems, the present inventor has found that lanthanum carbonate tetrahydrate has decomposition due to heat and moisture absorption, while lanthanum carbonate 7-7 hydrate. Even if it is 7-9 hydrate of lanthanum carbonate, which has been found to be extremely stable, and inferior in ability to remove phosphoric acid inPatent Document 1, phosphoric acid can be reduced by reducing the particle size. It was found that it could be removed almost 100% faster and the present invention was completed. That is, the present invention is as follows.
[1] Lanthanum carbonate represented by La 2 (CO 3 ) 3 · xH 2 O (wherein x is a number between 7 and 9) having a 90% cumulative diameter (D90) of 70 μm or less. A medicine consisting of a hydrate.
[2] The medicament according to [1], wherein D90 is 2 to 65 μm.
[3] La 2 (CO 3 ) 3 · xH 2 O (wherein x represents a number between 7 and 9) having a phosphate binding rate constant k 1 of 0.75 min −1 or more. A pharmaceutical comprising lanthanum carbonate hydrate.
[4] The medicament according to any one of [1] to [3] for treating hyperphosphatemia.
［１］ ９０％積算径（Ｄ９０）が７０μｍ以下である、Ｌａ２（ＣＯ３）３・ｘＨ２Ｏ（式中、ｘは７～９の間の数字を示す。）で表される炭酸ランタン水和物からなる医薬。
［２］ Ｄ９０が２～６５μｍである、［１］に記載の医薬。
［３］ ０．７５ｍｉｎ－１以上のリン酸結合速度定数ｋ１を有する、Ｌａ２（ＣＯ３）３・ｘＨ２Ｏ（式中、ｘは７～９の間の数字を示す。）で表される炭酸ランタン水和物からなる医薬。
［４］ 高リン血症を治療するための、［１］～［３］のいずれかに記載の医薬。 As a result of intensive studies to solve the above problems, the present inventor has found that lanthanum carbonate tetrahydrate has decomposition due to heat and moisture absorption, while lanthanum carbonate 7-7 hydrate. Even if it is 7-9 hydrate of lanthanum carbonate, which has been found to be extremely stable, and inferior in ability to remove phosphoric acid in
[1] Lanthanum carbonate represented by La 2 (CO 3 ) 3 · xH 2 O (wherein x is a number between 7 and 9) having a 90% cumulative diameter (D90) of 70 μm or less. A medicine consisting of a hydrate.
[2] The medicament according to [1], wherein D90 is 2 to 65 μm.
[3] La 2 (CO 3 ) 3 · xH 2 O (wherein x represents a number between 7 and 9) having a phosphate binding rate constant k 1 of 0.75 min −1 or more. A pharmaceutical comprising lanthanum carbonate hydrate.
[4] The medicament according to any one of [1] to [3] for treating hyperphosphatemia.
［５］ Ｄ９０が７０μｍ以下である、Ｌａ２（ＣＯ３）３・ｘＨ２Ｏ（式中、ｘは７～９の間の数字を示す。）で表される炭酸ランタン水和物を含有する医薬組成物。
［６］ Ｄ９０が２～６５μｍである、［５］に記載の医薬組成物。
［７］ ０．７５ｍｉｎ－１以上のリン酸結合速度定数ｋ１を有する、Ｌａ２（ＣＯ３）３・ｘＨ２Ｏ（式中、ｘは７～９の間の数字を示す。）で表される炭酸ランタン水和物を含有する医薬組成物。
［８］ 高リン血症を治療するための、［１］～［３］のいずれかに記載の医薬組成物。
［９］ それを必要とする患者に［５］～［７］のいずれかに記載の医薬組成物を投与することによる、高リン血症を治療する方法。 [5] Contains lanthanum carbonate hydrate represented by La 2 (CO 3 ) 3 · xH 2 O (wherein x is a number between 7 and 9), wherein D90 is 70 μm or less. Pharmaceutical composition.
[6] The pharmaceutical composition according to [5], wherein D90 is 2 to 65 μm.
[7] Expressed by La 2 (CO 3 ) 3 · xH 2 O (wherein x represents a number between 7 and 9) having a phosphate binding rate constant k 1 of 0.75 min −1 or more. A pharmaceutical composition containing lanthanum carbonate hydrate.
[8] The pharmaceutical composition according to any one of [1] to [3] for treating hyperphosphatemia.
[9] A method for treating hyperphosphatemia by administering the pharmaceutical composition according to any one of [5] to [7] to a patient in need thereof.
［６］ Ｄ９０が２～６５μｍである、［５］に記載の医薬組成物。
［７］ ０．７５ｍｉｎ－１以上のリン酸結合速度定数ｋ１を有する、Ｌａ２（ＣＯ３）３・ｘＨ２Ｏ（式中、ｘは７～９の間の数字を示す。）で表される炭酸ランタン水和物を含有する医薬組成物。
［８］ 高リン血症を治療するための、［１］～［３］のいずれかに記載の医薬組成物。
［９］ それを必要とする患者に［５］～［７］のいずれかに記載の医薬組成物を投与することによる、高リン血症を治療する方法。 [5] Contains lanthanum carbonate hydrate represented by La 2 (CO 3 ) 3 · xH 2 O (wherein x is a number between 7 and 9), wherein D90 is 70 μm or less. Pharmaceutical composition.
[6] The pharmaceutical composition according to [5], wherein D90 is 2 to 65 μm.
[7] Expressed by La 2 (CO 3 ) 3 · xH 2 O (wherein x represents a number between 7 and 9) having a phosphate binding rate constant k 1 of 0.75 min −1 or more. A pharmaceutical composition containing lanthanum carbonate hydrate.
[8] The pharmaceutical composition according to any one of [1] to [3] for treating hyperphosphatemia.
[9] A method for treating hyperphosphatemia by administering the pharmaceutical composition according to any one of [5] to [7] to a patient in need thereof.
［１０］ 高リン血症の治療に用いるための、Ｄ９０が７０μｍ以下である、Ｌａ２（ＣＯ３）３・ｘＨ２Ｏ（式中、ｘは７～９の間の数字を示す。）で表される炭酸ランタン水和物、またはそれを含有する医薬組成物。
［１１］ Ｄ９０が２～６５μｍである、［１０］に記載の炭酸ランタン水和物、またはそれを含有する医薬組成物。
［１２］ 高リン血症の治療に用いるための、０．７５ｍｉｎ－１以上のリン酸結合速度定数ｋ１を有する、Ｌａ２（ＣＯ３）３・ｘＨ２Ｏ（式中、ｘは７～９の間の数字を示す。）で表される炭酸ランタン水和物、またはそれを含有する医薬組成物。
［１３］ 高リン血症の治療に用いる医薬の製造における、９０％積算径（Ｄ９０）が７０μｍ以下である、Ｌａ２（ＣＯ３）３・ｘＨ２Ｏ（式中、ｘは７～９の間の数字を示す。）で表される炭酸ランタン水和物の使用。
［１４］ Ｄ９０が２～６５μｍである、［１３］に記載の使用。
［１５］ 高リン血症の治療に用いる医薬の製造における、０．７５ｍｉｎ－１以上のリン酸結合速度定数ｋ１を有する、Ｌａ２（ＣＯ３）３・ｘＨ２Ｏ（式中、ｘは７～９の間の数字を示す。）で表される炭酸ランタン水和物の使用。 [10] La 2 (CO 3 ) 3 · xH 2 O (wherein x represents a number between 7 and 9) having a D90 of 70 μm or less for use in the treatment of hyperphosphatemia. The lanthanum carbonate hydrate represented, or a pharmaceutical composition containing it.
[11] The lanthanum carbonate hydrate according to [10], wherein D90 is 2 to 65 μm, or a pharmaceutical composition containing the same.
[12] La 2 (CO 3 ) 3 · xH 2 O (wherein x is 7 to 4 ) having a phosphate binding rate constant k 1 of 0.75 min −1 or more for use in the treatment of hyperphosphatemia Lanthanum carbonate hydrate represented by 9) or a pharmaceutical composition containing the same.
[13] La 2 (CO 3 ) 3 · xH 2 O (wherein x is 7 to 9), in which 90% integrated diameter (D90) is 70 μm or less in the manufacture of a medicament used for the treatment of hyperphosphatemia Use of lanthanum carbonate hydrate represented by
[14] The use according to [13], wherein D90 is 2 to 65 μm.
[15] La 2 (CO 3 ) 3 · xH 2 O (wherein x is a phosphate binding rate constant k 1 of 0.75 min −1 or more in the manufacture of a medicament used for the treatment of hyperphosphatemia) Use of lanthanum carbonate hydrate represented by the number between 7 and 9.).
［１１］ Ｄ９０が２～６５μｍである、［１０］に記載の炭酸ランタン水和物、またはそれを含有する医薬組成物。
［１２］ 高リン血症の治療に用いるための、０．７５ｍｉｎ－１以上のリン酸結合速度定数ｋ１を有する、Ｌａ２（ＣＯ３）３・ｘＨ２Ｏ（式中、ｘは７～９の間の数字を示す。）で表される炭酸ランタン水和物、またはそれを含有する医薬組成物。
［１３］ 高リン血症の治療に用いる医薬の製造における、９０％積算径（Ｄ９０）が７０μｍ以下である、Ｌａ２（ＣＯ３）３・ｘＨ２Ｏ（式中、ｘは７～９の間の数字を示す。）で表される炭酸ランタン水和物の使用。
［１４］ Ｄ９０が２～６５μｍである、［１３］に記載の使用。
［１５］ 高リン血症の治療に用いる医薬の製造における、０．７５ｍｉｎ－１以上のリン酸結合速度定数ｋ１を有する、Ｌａ２（ＣＯ３）３・ｘＨ２Ｏ（式中、ｘは７～９の間の数字を示す。）で表される炭酸ランタン水和物の使用。 [10] La 2 (CO 3 ) 3 · xH 2 O (wherein x represents a number between 7 and 9) having a D90 of 70 μm or less for use in the treatment of hyperphosphatemia. The lanthanum carbonate hydrate represented, or a pharmaceutical composition containing it.
[11] The lanthanum carbonate hydrate according to [10], wherein D90 is 2 to 65 μm, or a pharmaceutical composition containing the same.
[12] La 2 (CO 3 ) 3 · xH 2 O (wherein x is 7 to 4 ) having a phosphate binding rate constant k 1 of 0.75 min −1 or more for use in the treatment of hyperphosphatemia Lanthanum carbonate hydrate represented by 9) or a pharmaceutical composition containing the same.
[13] La 2 (CO 3 ) 3 · xH 2 O (wherein x is 7 to 9), in which 90% integrated diameter (D90) is 70 μm or less in the manufacture of a medicament used for the treatment of hyperphosphatemia Use of lanthanum carbonate hydrate represented by
[14] The use according to [13], wherein D90 is 2 to 65 μm.
[15] La 2 (CO 3 ) 3 · xH 2 O (wherein x is a phosphate binding rate constant k 1 of 0.75 min −1 or more in the manufacture of a medicament used for the treatment of hyperphosphatemia) Use of lanthanum carbonate hydrate represented by the number between 7 and 9.).
炭酸ランタン４水和物は、４０℃７５％ＲＨの保存安定性試験で、特表２００９－５３６３５６に記載のある水酸化炭酸ランタンの多形体（II）型が生成し、８水和物にも変化するが、本発明で用いられるＤ９０が７０μｍ以下の炭酸ランタンの７～９水和物では、かかる分解・変化は全く観察されない。また、リン酸をより早く、ほぼ１００％除去できる。
Lanthanum carbonate tetrahydrate produced a polymorphic form (II) of lanthanum hydroxide carbonate described in Special Table 2009-536356 in a storage stability test at 40 ° C. and 75% RH. Although there is a change, such decomposition and change are not observed at all in the lanthanum carbonate 7-9 hydrate having a D90 of 70 μm or less used in the present invention. Further, phosphoric acid can be removed almost 100% faster.
１．炭酸ランタン
本発明で用いられる炭酸ランタン水和物は、７～９水和物が好ましく用いられる。７～９水和物としては、８水和物と称される市販のものをそのまま用いることができるが、常法、例えば、特許文献１に記載の方法等に従って製造することもできる。７～９水和物としては、好ましくは７．５～８．５水和物が挙げられる。
特許文献１に記載の炭酸ランタンの３～６水和物に含まれる４．７水和物について、４０℃７５％ＲＨの保存安定性試験を行ったところ、（II）型の水酸化炭酸ランタンが生成し、また８水和物にも変化することが、試験例３に記載の通り、判明した。それに対して、炭酸ランタンの７～９水和物では、同じ安定性試験を行ったところ、分解物が全く観察されず、極めて安定であることが明らかとなった。従って、原体の保存、および製剤化の工程において、安定に取り扱うことができ、さらには最終医薬品においても有効成分を安定に保つことができる。 1. Lanthanum carbonate The lanthanum carbonate hydrate used in the present invention is preferably 7-9 hydrate. As the 7-9 hydrate, a commercially available product called an octahydrate can be used as it is, but it can also be produced according to a conventional method, for example, the method described inPatent Document 1. The 7-9 hydrate is preferably 7.5-8.5 hydrate.
The 4.7 hydrate contained in the 3-6 hydrate of lanthanum carbonate described inPatent Document 1 was subjected to a storage stability test at 40 ° C. and 75% RH. As a result, (II) type lanthanum hydroxide carbonate was obtained. As shown in Test Example 3, it was found that was produced and changed to octahydrate. In contrast, lanthanum carbonate 7-9 hydrate was subjected to the same stability test. As a result, no decomposition product was observed, and it was found that the lanthanum carbonate was extremely stable. Therefore, it can be handled stably in the steps of storing the drug substance and formulating, and the active ingredient can be kept stable even in the final drug product.
本発明で用いられる炭酸ランタン水和物は、７～９水和物が好ましく用いられる。７～９水和物としては、８水和物と称される市販のものをそのまま用いることができるが、常法、例えば、特許文献１に記載の方法等に従って製造することもできる。７～９水和物としては、好ましくは７．５～８．５水和物が挙げられる。
特許文献１に記載の炭酸ランタンの３～６水和物に含まれる４．７水和物について、４０℃７５％ＲＨの保存安定性試験を行ったところ、（II）型の水酸化炭酸ランタンが生成し、また８水和物にも変化することが、試験例３に記載の通り、判明した。それに対して、炭酸ランタンの７～９水和物では、同じ安定性試験を行ったところ、分解物が全く観察されず、極めて安定であることが明らかとなった。従って、原体の保存、および製剤化の工程において、安定に取り扱うことができ、さらには最終医薬品においても有効成分を安定に保つことができる。 1. Lanthanum carbonate The lanthanum carbonate hydrate used in the present invention is preferably 7-9 hydrate. As the 7-9 hydrate, a commercially available product called an octahydrate can be used as it is, but it can also be produced according to a conventional method, for example, the method described in
The 4.7 hydrate contained in the 3-6 hydrate of lanthanum carbonate described in
本発明で用いられる炭酸ランタンの７～９水和物は、９０％積算径（Ｄ９０）が７０μｍ以下である。ここで、Ｄ９０をさらに説明すれば、小粒子側から体積積算粒度分布が９０％となる粒子径を言い、例えば、後述の粒度の測定方法によって、測定される。炭酸ランタンのＤ９０としては、好ましくは１～７０μｍ、より好ましくは２～６５μｍ、さらに好ましくは５～６５μｍ、特に好ましくは１５～６０μｍ、最も好ましくは２５～５５μｍが挙げられる。
試験例１から分かる通り、炭酸ランタンの７～９水和物は、Ｄ９０が９９．９μｍ、６４．９μｍおよび２９．８μｍと細かくなるにつれて、リン酸除去速度が格段に向上する。ただし、Ｄ９０が２９．８μｍよりも小さくなってもリン酸除去速度はさらに向上することはなく、ほぼ同程度である。また、試験例２では、実施例１～３と比較例１について、反応速度定数ｋ１を求めている。特許文献１の８．８水和物と比較例１の炭酸ランタン７．９水和物とは、同じ反応速度定数ｋ１０．２４ｍｉｎ－１を有するため、比較例１の炭酸ランタン７．９水和物は特許文献１の８．８水和物に相当する粒度分布を持つと考えられる。この定数ｋ１によれば、本発明で用いられる炭酸ランタン水和物は、比較例１の水和物に対して３．５倍とはるかに速いリン酸除去速度を持っていることが分かる。従って、特許文献１の８．８水和物に対して、リン酸除去速度が３．５倍程度速いことになる。また、本発明で用いられる炭酸ランタン水和物は、粒度が同程度の炭酸ランタン４水和物に対しても、リン酸除去速度で劣ってはおらず、寧ろリン酸除去速度はより速い。また、炭酸ランタンの７～９水和物の粒度は細かくなり過ぎると、粉体に流動性がなくなり製剤化が困難となる。そこで、Ｄ９０は１μｍ以上が好ましく、より好ましくは２μｍ以上、さらに好ましくは５μｍ以上が挙げられる。 The lanthanum carbonate 7-9 hydrate used in the present invention has a 90% cumulative diameter (D90) of 70 μm or less. Here, D90 will be further described. The particle diameter is a particle diameter at which the volume cumulative particle size distribution is 90% from the small particle side, and is measured by, for example, a particle size measuring method described later. D90 of lanthanum carbonate is preferably 1 to 70 μm, more preferably 2 to 65 μm, still more preferably 5 to 65 μm, particularly preferably 15 to 60 μm, and most preferably 25 to 55 μm.
As can be seen from Test Example 1, in the lanthanum carbonate 7-9 hydrate, as the D90 becomes finer 99.9 μm, 64.9 μm and 29.8 μm, the phosphate removal rate is remarkably improved. However, even if D90 is smaller than 29.8 μm, the phosphoric acid removal rate is not further improved and is approximately the same. In Test Example 2, the reaction rate constant k 1 is obtained for Examples 1 to 3 and Comparative Example 1. Since 8.8 hydrate ofPatent Document 1 and lanthanum carbonate 7.9 hydrate of Comparative Example 1 have the same reaction rate constant k 1 0.24 min −1 , lanthanum carbonate 7.9 of Comparative Example 1 The hydrate is considered to have a particle size distribution corresponding to 8.8 hydrate of Patent Document 1. According to this constant k 1 , it can be seen that the lanthanum carbonate hydrate used in the present invention has a much faster phosphoric acid removal rate of 3.5 times that of the hydrate of Comparative Example 1. Therefore, the phosphate removal rate is about 3.5 times faster than the 8.8 hydrate of Patent Document 1. In addition, the lanthanum carbonate hydrate used in the present invention is not inferior in the phosphoric acid removal rate as compared with the lanthanum carbonate tetrahydrate having the same particle size, but the phosphoric acid removal rate is faster. In addition, if the particle size of lanthanum carbonate 7-9 hydrate becomes too fine, the powder will not be fluid and difficult to formulate. Therefore, D90 is preferably 1 μm or more, more preferably 2 μm or more, and further preferably 5 μm or more.
試験例１から分かる通り、炭酸ランタンの７～９水和物は、Ｄ９０が９９．９μｍ、６４．９μｍおよび２９．８μｍと細かくなるにつれて、リン酸除去速度が格段に向上する。ただし、Ｄ９０が２９．８μｍよりも小さくなってもリン酸除去速度はさらに向上することはなく、ほぼ同程度である。また、試験例２では、実施例１～３と比較例１について、反応速度定数ｋ１を求めている。特許文献１の８．８水和物と比較例１の炭酸ランタン７．９水和物とは、同じ反応速度定数ｋ１０．２４ｍｉｎ－１を有するため、比較例１の炭酸ランタン７．９水和物は特許文献１の８．８水和物に相当する粒度分布を持つと考えられる。この定数ｋ１によれば、本発明で用いられる炭酸ランタン水和物は、比較例１の水和物に対して３．５倍とはるかに速いリン酸除去速度を持っていることが分かる。従って、特許文献１の８．８水和物に対して、リン酸除去速度が３．５倍程度速いことになる。また、本発明で用いられる炭酸ランタン水和物は、粒度が同程度の炭酸ランタン４水和物に対しても、リン酸除去速度で劣ってはおらず、寧ろリン酸除去速度はより速い。また、炭酸ランタンの７～９水和物の粒度は細かくなり過ぎると、粉体に流動性がなくなり製剤化が困難となる。そこで、Ｄ９０は１μｍ以上が好ましく、より好ましくは２μｍ以上、さらに好ましくは５μｍ以上が挙げられる。 The lanthanum carbonate 7-9 hydrate used in the present invention has a 90% cumulative diameter (D90) of 70 μm or less. Here, D90 will be further described. The particle diameter is a particle diameter at which the volume cumulative particle size distribution is 90% from the small particle side, and is measured by, for example, a particle size measuring method described later. D90 of lanthanum carbonate is preferably 1 to 70 μm, more preferably 2 to 65 μm, still more preferably 5 to 65 μm, particularly preferably 15 to 60 μm, and most preferably 25 to 55 μm.
As can be seen from Test Example 1, in the lanthanum carbonate 7-9 hydrate, as the D90 becomes finer 99.9 μm, 64.9 μm and 29.8 μm, the phosphate removal rate is remarkably improved. However, even if D90 is smaller than 29.8 μm, the phosphoric acid removal rate is not further improved and is approximately the same. In Test Example 2, the reaction rate constant k 1 is obtained for Examples 1 to 3 and Comparative Example 1. Since 8.8 hydrate of
２．医薬
本発明の医薬は、高リン酸血症治療剤として、さらには慢性腎臓病患者における高リン血症の治療剤として用いることができる。本発明の医薬は、上記の本発明で用いられる炭酸ランタン水和物を有効成分として含む。炭酸ランタン水和物の投与量としては、患者の状態や体重等によって異なるが、成人１日当たり、例えば、約１００ｍｇ～１０ｇ、好ましくは約５００ｍｇ～５ｇ、より好ましくは約７５０ｍｇ～２．２５ｇが挙げられ。これら製剤は、１日１～数回、好ましくは１日３回に分けて投与することができる。
本発明の医薬は、経口的に投与され、それに適した医薬製剤とすることができる。医薬製剤としては、例えば、口腔内崩壊錠、チュアブル剤、顆粒剤、錠剤、カプセル剤等が挙げられる。医薬製剤に製剤化する際に用いる薬学上許容される担体としては、希釈剤、結合剤（シロップ、アラビアゴム、ゼラチン、ソルビット、トラガカント、ポリビニルピロリドン）、賦形剤（乳糖、ショ糖、コーンスターチ、リン酸カリウム、ソルビット、グリシン）、滑沢剤（ステアリン酸マグネシウム、タルク、ポリエチレングリコール、シリカ）、崩壊剤（バレイショデンプン）、湿潤剤（ラウリル硫酸ナトリウム）およびコーティング剤（白糖、ヒドロキシプロピルセルロース、ヒプロメロース、エチルセルロース）等を挙げることができる。本医薬製剤は、従来公知の方法に従って、炭酸ランタン水和物、薬学上許容される担体等を混合して製造することができる。 2. Medicament The medicament of the present invention can be used as a therapeutic agent for hyperphosphatemia, and further as a therapeutic agent for hyperphosphatemia in patients with chronic kidney disease. The medicament of the present invention contains the lanthanum carbonate hydrate used in the present invention as an active ingredient. The dose of lanthanum carbonate hydrate varies depending on the patient's condition, body weight, etc., and for example, about 100 mg to 10 g, preferably about 500 mg to 5 g, more preferably about 750 mg to 2.25 g per day for an adult. It is. These preparations can be administered 1 to several times a day, preferably 3 times a day.
The medicament of the present invention can be administered orally to obtain a pharmaceutical preparation suitable for it. Examples of the pharmaceutical preparation include orally disintegrating tablets, chewable agents, granules, tablets, capsules and the like. Pharmaceutically acceptable carriers used in formulating pharmaceutical preparations include diluents, binders (syrup, gum arabic, gelatin, sorbit, tragacanth, polyvinylpyrrolidone), excipients (lactose, sucrose, corn starch, Potassium phosphate, sorbit, glycine), lubricant (magnesium stearate, talc, polyethylene glycol, silica), disintegrant (potato starch), wetting agent (sodium lauryl sulfate) and coating agent (sucrose, hydroxypropylcellulose, hypromellose) , Ethyl cellulose) and the like. This pharmaceutical preparation can be produced by mixing lanthanum carbonate hydrate, a pharmaceutically acceptable carrier and the like according to a conventionally known method.
本発明の医薬は、高リン酸血症治療剤として、さらには慢性腎臓病患者における高リン血症の治療剤として用いることができる。本発明の医薬は、上記の本発明で用いられる炭酸ランタン水和物を有効成分として含む。炭酸ランタン水和物の投与量としては、患者の状態や体重等によって異なるが、成人１日当たり、例えば、約１００ｍｇ～１０ｇ、好ましくは約５００ｍｇ～５ｇ、より好ましくは約７５０ｍｇ～２．２５ｇが挙げられ。これら製剤は、１日１～数回、好ましくは１日３回に分けて投与することができる。
本発明の医薬は、経口的に投与され、それに適した医薬製剤とすることができる。医薬製剤としては、例えば、口腔内崩壊錠、チュアブル剤、顆粒剤、錠剤、カプセル剤等が挙げられる。医薬製剤に製剤化する際に用いる薬学上許容される担体としては、希釈剤、結合剤（シロップ、アラビアゴム、ゼラチン、ソルビット、トラガカント、ポリビニルピロリドン）、賦形剤（乳糖、ショ糖、コーンスターチ、リン酸カリウム、ソルビット、グリシン）、滑沢剤（ステアリン酸マグネシウム、タルク、ポリエチレングリコール、シリカ）、崩壊剤（バレイショデンプン）、湿潤剤（ラウリル硫酸ナトリウム）およびコーティング剤（白糖、ヒドロキシプロピルセルロース、ヒプロメロース、エチルセルロース）等を挙げることができる。本医薬製剤は、従来公知の方法に従って、炭酸ランタン水和物、薬学上許容される担体等を混合して製造することができる。 2. Medicament The medicament of the present invention can be used as a therapeutic agent for hyperphosphatemia, and further as a therapeutic agent for hyperphosphatemia in patients with chronic kidney disease. The medicament of the present invention contains the lanthanum carbonate hydrate used in the present invention as an active ingredient. The dose of lanthanum carbonate hydrate varies depending on the patient's condition, body weight, etc., and for example, about 100 mg to 10 g, preferably about 500 mg to 5 g, more preferably about 750 mg to 2.25 g per day for an adult. It is. These preparations can be administered 1 to several times a day, preferably 3 times a day.
The medicament of the present invention can be administered orally to obtain a pharmaceutical preparation suitable for it. Examples of the pharmaceutical preparation include orally disintegrating tablets, chewable agents, granules, tablets, capsules and the like. Pharmaceutically acceptable carriers used in formulating pharmaceutical preparations include diluents, binders (syrup, gum arabic, gelatin, sorbit, tragacanth, polyvinylpyrrolidone), excipients (lactose, sucrose, corn starch, Potassium phosphate, sorbit, glycine), lubricant (magnesium stearate, talc, polyethylene glycol, silica), disintegrant (potato starch), wetting agent (sodium lauryl sulfate) and coating agent (sucrose, hydroxypropylcellulose, hypromellose) , Ethyl cellulose) and the like. This pharmaceutical preparation can be produced by mixing lanthanum carbonate hydrate, a pharmaceutically acceptable carrier and the like according to a conventionally known method.
以下、本発明を実施例、比較例、試験例によりさらに詳細に説明するが、本発明はこれらに何ら限定されるものではない。
本実施例、比較例、試験例では、以下の装置を用いた。
＜測定装置＞
自動滴定装置は、平沼産業製AUTO TITRATOR COM-1700を用いた。
紫外可視分光光度計は、島津製作所製UV1600または、UV1800を用いた。
粉末Ｘ線回折パターンは、CuKα放射線を利用して、フィリップス製X’ Pert PRO PW3040/60(X’ CELERATOI検出器)で測定を行った。
＜粒度の測定方法＞
粒度分布計は、日機装製エアロトラックLDSA-SPRを用い、湿式条件で水を分散媒として、水 6.5mLにサンプル約5mgを加えて懸濁液として測定を行った。 EXAMPLES Hereinafter, although an Example, a comparative example, and a test example demonstrate this invention further in detail, this invention is not limited to these at all.
In the examples, comparative examples, and test examples, the following apparatuses were used.
<Measurement device>
As the automatic titrator, AUTO TITRATOR COM-1700 manufactured by Hiranuma Sangyo was used.
As the UV-visible spectrophotometer, UV1600 or UV1800 manufactured by Shimadzu Corporation was used.
The powder X-ray diffraction pattern was measured with Philips X 'Pert PRO PW3040 / 60 (X' CELERATOI detector) using CuKα radiation.
<Measuring method of particle size>
The particle size distribution analyzer was measured using Nikkiso Aerotrac LDSA-SPR as a suspension by adding about 5 mg of sample to 6.5 mL of water using water as a dispersion medium under wet conditions.
本実施例、比較例、試験例では、以下の装置を用いた。
＜測定装置＞
自動滴定装置は、平沼産業製AUTO TITRATOR COM-1700を用いた。
紫外可視分光光度計は、島津製作所製UV1600または、UV1800を用いた。
粉末Ｘ線回折パターンは、CuKα放射線を利用して、フィリップス製X’ Pert PRO PW3040/60(X’ CELERATOI検出器)で測定を行った。
＜粒度の測定方法＞
粒度分布計は、日機装製エアロトラックLDSA-SPRを用い、湿式条件で水を分散媒として、水 6.5mLにサンプル約5mgを加えて懸濁液として測定を行った。 EXAMPLES Hereinafter, although an Example, a comparative example, and a test example demonstrate this invention further in detail, this invention is not limited to these at all.
In the examples, comparative examples, and test examples, the following apparatuses were used.
<Measurement device>
As the automatic titrator, AUTO TITRATOR COM-1700 manufactured by Hiranuma Sangyo was used.
As the UV-visible spectrophotometer, UV1600 or UV1800 manufactured by Shimadzu Corporation was used.
The powder X-ray diffraction pattern was measured with Philips X 'Pert PRO PW3040 / 60 (X' CELERATOI detector) using CuKα radiation.
<Measuring method of particle size>
The particle size distribution analyzer was measured using Nikkiso Aerotrac LDSA-SPR as a suspension by adding about 5 mg of sample to 6.5 mL of water using water as a dispersion medium under wet conditions.
＜リン酸結合能試験方法＞
リン酸結合能試験は、以下の（１）～（７）の要領で実施した。
（１）無水リン酸水素二ナトリウム4.13g、塩化ナトリウム2.55gを脱イオン水300mLに溶解し、保存溶液を調製した。
（２）保存溶液100mLに濃塩酸を滴下し、pH3に調整した。5mLのサンプルをシリンジによって採取し、0.02μmフィルターを通してろ過し、時刻0サンプルを得た。
（３）保存溶液5mLを加えて再び全量100mLとし、濃塩酸を滴下し、再度pH3に調整した。
（４）リン酸イオンに対してランタンが２当量となるように炭酸ランタン水和物を加えて、室温で攪拌した。反応液を、0.5、1、1.5、2、2.5、3、4、5、10分の時点でサンプリングした。この間、自動滴定装置を用いて濃度1mol/Lの塩酸を滴下し、pH3を維持した。 <Method for testing phosphate binding ability>
The phosphate binding ability test was carried out in the following manners (1) to (7).
(1) 4.13 g of anhydrous disodium hydrogen phosphate and 2.55 g of sodium chloride were dissolved in 300 mL of deionized water to prepare a stock solution.
(2) Concentrated hydrochloric acid was added dropwise to 100 mL of the stock solution to adjust topH 3. A 5 mL sample was taken with a syringe and filtered through a 0.02 μm filter to obtain a time 0 sample.
(3) 5 mL of the stock solution was added to make the total volume 100 mL again, and concentrated hydrochloric acid was added dropwise to adjust the pH to 3 again.
(4) Lanthanum carbonate hydrate was added so that lanthanum was 2 equivalents with respect to phosphate ions, and the mixture was stirred at room temperature. The reaction was sampled at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 10 minutes. During this time, hydrochloric acid having a concentration of 1 mol / L was dropped using an automatic titrator to maintainpH 3.
リン酸結合能試験は、以下の（１）～（７）の要領で実施した。
（１）無水リン酸水素二ナトリウム4.13g、塩化ナトリウム2.55gを脱イオン水300mLに溶解し、保存溶液を調製した。
（２）保存溶液100mLに濃塩酸を滴下し、pH3に調整した。5mLのサンプルをシリンジによって採取し、0.02μmフィルターを通してろ過し、時刻0サンプルを得た。
（３）保存溶液5mLを加えて再び全量100mLとし、濃塩酸を滴下し、再度pH3に調整した。
（４）リン酸イオンに対してランタンが２当量となるように炭酸ランタン水和物を加えて、室温で攪拌した。反応液を、0.5、1、1.5、2、2.5、3、4、5、10分の時点でサンプリングした。この間、自動滴定装置を用いて濃度1mol/Lの塩酸を滴下し、pH3を維持した。 <Method for testing phosphate binding ability>
The phosphate binding ability test was carried out in the following manners (1) to (7).
(1) 4.13 g of anhydrous disodium hydrogen phosphate and 2.55 g of sodium chloride were dissolved in 300 mL of deionized water to prepare a stock solution.
(2) Concentrated hydrochloric acid was added dropwise to 100 mL of the stock solution to adjust to
(3) 5 mL of the stock solution was added to make the total volume 100 mL again, and concentrated hydrochloric acid was added dropwise to adjust the pH to 3 again.
(4) Lanthanum carbonate hydrate was added so that lanthanum was 2 equivalents with respect to phosphate ions, and the mixture was stirred at room temperature. The reaction was sampled at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 10 minutes. During this time, hydrochloric acid having a concentration of 1 mol / L was dropped using an automatic titrator to maintain
（５）七モリブデン酸六アンモニウム四水和物0.5mgを2.5N硫酸40mLに溶解し、モリブデン試液を調製した。Fiske - SubbaRow reducer 2gをとり、水12.6mLに溶解し、Fiske-SubbaRow試液を調製した。
（６）各時刻でサンプリングした液を50倍に希釈し、この液1mLにモリブデン試液1mL、Fiske-SubbaRow試液0.25mLを加え、水を加えて正確に25mLとした液について、試液を加えて10分後の700nmにおける吸光度を、紫外可視分光光度計を用いて測定した。結果から、リン酸の除去率を算出した。
（７）（６）の結果から、以下の式に基づいて、1次反応速度定数ｋ１を導出した。
ｄ［ＰＯ４］／ｄｔ＝－ｋ１［ＰＯ４］ （式１）
［式中、［ＰＯ４］は溶液中のリン酸残存率（％）を表す。
ｔは時間（ｍｉｎ）を表す。
ｋ１は１次反応速度定数（ｍｉｎ－１）を表す。］ (5) 0.5 mg of hexaammonium heptamolybdate tetrahydrate was dissolved in 40 mL of 2.5N sulfuric acid to prepare a molybdenum test solution. Fiske-SubbaRow reducer 2 g was taken and dissolved in 12.6 mL of water to prepare a Fiske-SubbaRow reagent solution.
(6) Dilute the solution sampled at each time 50 times, add 1 mL of molybdenum test solution and 0.25 mL of Fiske-SubbaRow test solution to 1 mL of this solution, add water to make exactly 25 mL, add the test solution and add 10 mL. The absorbance at 700 nm after the minute was measured using an ultraviolet-visible spectrophotometer. From the results, the removal rate of phosphoric acid was calculated.
(7) From the results of (6), a first-order reaction rate constant k 1 was derived based on the following equation.
d [PO 4 ] / dt = −k 1 [PO 4 ] (Formula 1)
[Wherein [PO 4 ] represents the phosphoric acid residual rate (%) in the solution.
t represents time (min).
k 1 represents a first-order reaction rate constant (min −1 ). ]
（６）各時刻でサンプリングした液を50倍に希釈し、この液1mLにモリブデン試液1mL、Fiske-SubbaRow試液0.25mLを加え、水を加えて正確に25mLとした液について、試液を加えて10分後の700nmにおける吸光度を、紫外可視分光光度計を用いて測定した。結果から、リン酸の除去率を算出した。
（７）（６）の結果から、以下の式に基づいて、1次反応速度定数ｋ１を導出した。
ｄ［ＰＯ４］／ｄｔ＝－ｋ１［ＰＯ４］ （式１）
［式中、［ＰＯ４］は溶液中のリン酸残存率（％）を表す。
ｔは時間（ｍｉｎ）を表す。
ｋ１は１次反応速度定数（ｍｉｎ－１）を表す。］ (5) 0.5 mg of hexaammonium heptamolybdate tetrahydrate was dissolved in 40 mL of 2.5N sulfuric acid to prepare a molybdenum test solution. Fiske-SubbaRow reducer 2 g was taken and dissolved in 12.6 mL of water to prepare a Fiske-SubbaRow reagent solution.
(6) Dilute the solution sampled at each time 50 times, add 1 mL of molybdenum test solution and 0.25 mL of Fiske-SubbaRow test solution to 1 mL of this solution, add water to make exactly 25 mL, add the test solution and add 10 mL. The absorbance at 700 nm after the minute was measured using an ultraviolet-visible spectrophotometer. From the results, the removal rate of phosphoric acid was calculated.
(7) From the results of (6), a first-order reaction rate constant k 1 was derived based on the following equation.
d [PO 4 ] / dt = −k 1 [PO 4 ] (Formula 1)
[Wherein [PO 4 ] represents the phosphoric acid residual rate (%) in the solution.
t represents time (min).
k 1 represents a first-order reaction rate constant (min −1 ). ]
実施例１
炭酸ランタン７．９水和物（Ｄ９０＝６４．９μｍ）
市販の上記の炭酸ランタン７．９水和物を購入して、用いた。
実施例２
炭酸ランタン７．９水和物（Ｄ９０＝２９．８μｍ）
実施例１の炭酸ランタン７．９水和物を薬さじ２杯程度、乳鉢に取り、１０～１５分間程度、乳棒ですり潰して粉砕して、掲題の炭酸ランタン７．９水和物を得た。
実施例３
炭酸ランタン７．７水和物（Ｄ９０＝５．３９μｍ）
実施例２の炭酸ランタン７．９水和物をジェットミル粉砕機(ＪＥＴＰＨＡＲＭＡ ＳＯＬＵＴＩＯＮＳ ＳＡ製 ＭＣ－ＯＮＥ)を用い、ベンチュリ圧６ＭＰａ、リング圧３ＭＰａ、サンプル投入速度２ｇ／１０分の条件で粉砕し、掲題の炭酸ランタン７．７水和物を得た。
比較例１
炭酸ランタン７．９水和物（Ｄ９０＝９９．９μｍ）
実施例１の炭酸ランタン７．９水和物１３０ｇ～１７５ｇを３３０メッシュの篩を用いて分級した。篩の上に残った炭酸ランタン７．９水和物４７ｇ～９４ｇを再度分級し、篩の上に残った炭酸ランタンを回収して、掲題の炭酸ランタン７．９水和物を得た。
比較例２
炭酸ランタン４．７水和物（Ｄ９０＝５２．１μｍ）
実施例１の炭酸ランタン７．９水和物を、常圧下、８０℃で４時間、乾燥することで、掲題のＤ９０が５２．１μｍの炭酸ランタン４．７水和物を得た。 Example 1
Lanthanum carbonate 7.9 hydrate (D90 = 64.9 μm)
Commercially available lanthanum carbonate 7.9 hydrate was purchased and used.
Example 2
Lanthanum carbonate 7.9 hydrate (D90 = 29.8 μm)
About 2 tablespoons of lanthanum carbonate 7.9 hydrate of Example 1 were taken into a mortar and ground and crushed for about 10-15 minutes with a pestle to obtain the title lanthanum carbonate 7.9 hydrate. .
Example 3
Lanthanum carbonate 7.7 hydrate (D90 = 5.39 μm)
The lanthanum carbonate 7.9 hydrate of Example 2 was pulverized using a jet mill pulverizer (MC-ONE manufactured by JETPHARMA SOLUTIONS SA) under the conditions of a venturi pressure of 6 MPa, a ring pressure of 3 MPa, and a sample charging speed of 2 g / 10 minutes. The title lanthanum carbonate 7.7 hydrate was obtained.
Comparative Example 1
Lanthanum carbonate 7.9 hydrate (D90 = 99.9 μm)
130 g to 175 g of lanthanum carbonate 7.9 hydrate of Example 1 was classified using a 330 mesh sieve. 47 to 94 g of lanthanum carbonate hydrate remaining on the sieve was classified again, and the lanthanum carbonate remaining on the sieve was recovered to obtain the title lanthanum carbonate 7.9 hydrate.
Comparative Example 2
Lanthanum carbonate 4.7 hydrate (D90 = 52.1 μm)
The lanthanum carbonate 7.9 hydrate of Example 1 was dried under normal pressure at 80 ° C. for 4 hours to obtain the title lanthanum carbonate 4.7 hydrate having a D90 of 52.1 μm.
炭酸ランタン７．９水和物（Ｄ９０＝６４．９μｍ）
市販の上記の炭酸ランタン７．９水和物を購入して、用いた。
実施例２
炭酸ランタン７．９水和物（Ｄ９０＝２９．８μｍ）
実施例１の炭酸ランタン７．９水和物を薬さじ２杯程度、乳鉢に取り、１０～１５分間程度、乳棒ですり潰して粉砕して、掲題の炭酸ランタン７．９水和物を得た。
実施例３
炭酸ランタン７．７水和物（Ｄ９０＝５．３９μｍ）
実施例２の炭酸ランタン７．９水和物をジェットミル粉砕機(ＪＥＴＰＨＡＲＭＡ ＳＯＬＵＴＩＯＮＳ ＳＡ製 ＭＣ－ＯＮＥ)を用い、ベンチュリ圧６ＭＰａ、リング圧３ＭＰａ、サンプル投入速度２ｇ／１０分の条件で粉砕し、掲題の炭酸ランタン７．７水和物を得た。
比較例１
炭酸ランタン７．９水和物（Ｄ９０＝９９．９μｍ）
実施例１の炭酸ランタン７．９水和物１３０ｇ～１７５ｇを３３０メッシュの篩を用いて分級した。篩の上に残った炭酸ランタン７．９水和物４７ｇ～９４ｇを再度分級し、篩の上に残った炭酸ランタンを回収して、掲題の炭酸ランタン７．９水和物を得た。
比較例２
炭酸ランタン４．７水和物（Ｄ９０＝５２．１μｍ）
実施例１の炭酸ランタン７．９水和物を、常圧下、８０℃で４時間、乾燥することで、掲題のＤ９０が５２．１μｍの炭酸ランタン４．７水和物を得た。 Example 1
Lanthanum carbonate 7.9 hydrate (D90 = 64.9 μm)
Commercially available lanthanum carbonate 7.9 hydrate was purchased and used.
Example 2
Lanthanum carbonate 7.9 hydrate (D90 = 29.8 μm)
About 2 tablespoons of lanthanum carbonate 7.9 hydrate of Example 1 were taken into a mortar and ground and crushed for about 10-15 minutes with a pestle to obtain the title lanthanum carbonate 7.9 hydrate. .
Example 3
Lanthanum carbonate 7.7 hydrate (D90 = 5.39 μm)
The lanthanum carbonate 7.9 hydrate of Example 2 was pulverized using a jet mill pulverizer (MC-ONE manufactured by JETPHARMA SOLUTIONS SA) under the conditions of a venturi pressure of 6 MPa, a ring pressure of 3 MPa, and a sample charging speed of 2 g / 10 minutes. The title lanthanum carbonate 7.7 hydrate was obtained.
Comparative Example 1
Lanthanum carbonate 7.9 hydrate (D90 = 99.9 μm)
130 g to 175 g of lanthanum carbonate 7.9 hydrate of Example 1 was classified using a 330 mesh sieve. 47 to 94 g of lanthanum carbonate hydrate remaining on the sieve was classified again, and the lanthanum carbonate remaining on the sieve was recovered to obtain the title lanthanum carbonate 7.9 hydrate.
Comparative Example 2
Lanthanum carbonate 4.7 hydrate (D90 = 52.1 μm)
The lanthanum carbonate 7.9 hydrate of Example 1 was dried under normal pressure at 80 ° C. for 4 hours to obtain the title lanthanum carbonate 4.7 hydrate having a D90 of 52.1 μm.
実施例１～３と比較例１および２の炭酸ランタンの粒度分布の測定
実施例１～３と比較例１および２の炭酸ランタンの粒度分布を測定した結果を、下表に示す。
Measurement of particle size distribution of lanthanum carbonate in Examples 1 to 3 and Comparative Examples 1 and 2 The results of measuring the particle size distribution of lanthanum carbonate in Examples 1 to 3 and Comparative Examples 1 and 2 are shown in the table below.
実施例１～３と比較例１および２の炭酸ランタンの粒度分布を測定した結果を、下表に示す。
試験例１
リン酸吸着能試験
実施例１～３と比較例１の炭酸ランタン水和物についてリン酸吸着能の試験を行った。リン酸吸着能試験によるリン酸除去率（％）の結果を表２に記す。また、それをグラフ化したものとして、図１に示す。
図１から分かる通り、炭酸ランタンの７～９水和物は、Ｄ９０が９９．９μｍ、６４．９μｍおよび２９．８μｍと細かくなるにつれて、リン酸除去速度が格段に向上した。しかし、Ｄ９０が２９．８μｍから５．３９μｍまで小さくなってもリン酸除去速度はさらに向上することはなく、ほぼ同程度であった。
Test example 1
Phosphate adsorption ability test The lanthanum carbonate hydrates of Examples 1 to 3 and Comparative Example 1 were tested for phosphate adsorption ability. The results of phosphoric acid removal rate (%) by the phosphate adsorption ability test are shown in Table 2. Moreover, it shows in FIG. 1 as what made it the graph.
As can be seen from FIG. 1, the 7-9 hydrate of lanthanum carbonate significantly improved the phosphate removal rate as the D90 became finer, 99.9 μm, 64.9 μm and 29.8 μm. However, even when D90 was reduced from 29.8 μm to 5.39 μm, the phosphoric acid removal rate was not further improved and was almost the same.
リン酸吸着能試験
実施例１～３と比較例１の炭酸ランタン水和物についてリン酸吸着能の試験を行った。リン酸吸着能試験によるリン酸除去率（％）の結果を表２に記す。また、それをグラフ化したものとして、図１に示す。
Phosphate adsorption ability test The lanthanum carbonate hydrates of Examples 1 to 3 and Comparative Example 1 were tested for phosphate adsorption ability. The results of phosphoric acid removal rate (%) by the phosphate adsorption ability test are shown in Table 2. Moreover, it shows in FIG. 1 as what made it the graph.
試験例２
反応速度定数測定
これらリン酸吸着能試験の結果を、リン酸残存率（％）＝１００（％）－リン酸除去率（％）として、１次反応の速度式（式１）に代入して解析したところ、反応終点付近（リン酸除去率９８％以上）のデータを除いた回帰直線は、重相関係数0.97以上の直線となった。このとき得られた１次反応速度定数ｋ１を表３に示す。
特許文献１の８．８水和物についてリン酸除去効果の試験結果が記載された表１の数値から反応速度定数測定ｋ１を求めると、０．２４ｍｉｎ－１となり、比較例１の炭酸ランタン７．９水和物のｋ１と完全に一致する。従って、比較例１の炭酸ランタン７．９水和物は、特許文献１に記載の炭酸ランタン８．８水和物と粒度がほぼ近く、同様の性質を示す炭酸ランタンであることが分かる。
比較例１の水和物に対して、実施例１の水和物は３．５倍程度、実施例２および３の水和物は４倍程度、リン酸除去速度が速い。従って、特許文献１の８．８水和物に対して、実施例１～３の水和物は、同様にリン酸除去速度が速いことになる。 Test example 2
Reaction rate constant measurement The results of these phosphate adsorption ability tests were substituted into the rate equation (formula 1) of the primary reaction as phosphoric acid residual rate (%) = 100 (%) − phosphoric acid removal rate (%). As a result of analysis, the regression line excluding the data near the reaction end point (phosphate removal rate of 98% or more) was a straight line having a multiple correlation coefficient of 0.97 or more. Table 3 shows the first-order reaction rate constant k 1 obtained at this time.
When the reaction rate constant measurement k 1 was determined from the numerical values of Table 1 in which the test results of the phosphate removal effect of 8.8 hydrate of Patent Document 1 were described, it was 0.24 min −1 , which was lanthanum carbonate of Comparative Example 1 7.9 perfectly matches the k 1 hydrate. Therefore, it can be seen that the lanthanum carbonate 7.9 hydrate of Comparative Example 1 is a lanthanum carbonate having a particle size almost similar to that of the lanthanum carbonate 8.8 hydrate described in Patent Document 1 and exhibiting similar properties.
Compared with the hydrate of Comparative Example 1, the hydrate of Example 1 is about 3.5 times, the hydrates of Examples 2 and 3 are about 4 times, and the phosphate removal rate is fast. Therefore, in contrast to 8.8 hydrate ofPatent Document 1, the hydrates of Examples 1 to 3 have the same high phosphoric acid removal rate.
反応速度定数測定
これらリン酸吸着能試験の結果を、リン酸残存率（％）＝１００（％）－リン酸除去率（％）として、１次反応の速度式（式１）に代入して解析したところ、反応終点付近（リン酸除去率９８％以上）のデータを除いた回帰直線は、重相関係数0.97以上の直線となった。このとき得られた１次反応速度定数ｋ１を表３に示す。
比較例１の水和物に対して、実施例１の水和物は３．５倍程度、実施例２および３の水和物は４倍程度、リン酸除去速度が速い。従って、特許文献１の８．８水和物に対して、実施例１～３の水和物は、同様にリン酸除去速度が速いことになる。 Test example 2
Reaction rate constant measurement The results of these phosphate adsorption ability tests were substituted into the rate equation (formula 1) of the primary reaction as phosphoric acid residual rate (%) = 100 (%) − phosphoric acid removal rate (%). As a result of analysis, the regression line excluding the data near the reaction end point (phosphate removal rate of 98% or more) was a straight line having a multiple correlation coefficient of 0.97 or more. Table 3 shows the first-order reaction rate constant k 1 obtained at this time.
Compared with the hydrate of Comparative Example 1, the hydrate of Example 1 is about 3.5 times, the hydrates of Examples 2 and 3 are about 4 times, and the phosphate removal rate is fast. Therefore, in contrast to 8.8 hydrate of
試験例３
安定性試験
実施例１の炭酸ランタン７．９水和物および比較例２の炭酸ランタン４．７水和物を褐色のサンプル瓶に取り、密栓した。これを検体とし、４０℃７５％ＲＨの恒温恒湿装置に入庫した。１ヶ月後および３ヶ月後に、上記炭酸ランタンの粉末Ｘ線回折を測定した。その結果を図２および図３に記す。
図２に示す通り、実施例１の炭酸ランタン７．９水和物では、変化はなかった。
図３に示す通り、比較例２の炭酸ランタン４．７水和物では、１ヶ月後に不純物である（II）型の水酸化炭酸ランタンのピーク（▼）が現れ、３ヶ月後にはさらに増加し，炭酸ランタン８水和物のピーク（●）も現れ、不安定であることが分かる。
以上の考察を表４にまとめる。
Test example 3
Stability Test The lanthanum carbonate 7.9 hydrate of Example 1 and the lanthanum carbonate 4.7 hydrate of Comparative Example 2 were placed in a brown sample bottle and sealed. This was used as a specimen and stored in a constant temperature and humidity apparatus at 40 ° C. and 75% RH. After 1 month and 3 months, the powder X-ray diffraction of the lanthanum carbonate was measured. The results are shown in FIG. 2 and FIG.
As shown in FIG. 2, there was no change in the lanthanum carbonate 7.9 hydrate of Example 1.
As shown in FIG. 3, in the lanthanum carbonate 4.7 hydrate of Comparative Example 2, a peak (▼) of (II) type lanthanum hydroxide carbonate, which is an impurity, appears after one month and further increases after three months. , The peak (●) of lanthanum carbonate octahydrate also appears, indicating that it is unstable.
The above considerations are summarized in Table 4.
安定性試験
実施例１の炭酸ランタン７．９水和物および比較例２の炭酸ランタン４．７水和物を褐色のサンプル瓶に取り、密栓した。これを検体とし、４０℃７５％ＲＨの恒温恒湿装置に入庫した。１ヶ月後および３ヶ月後に、上記炭酸ランタンの粉末Ｘ線回折を測定した。その結果を図２および図３に記す。
図２に示す通り、実施例１の炭酸ランタン７．９水和物では、変化はなかった。
図３に示す通り、比較例２の炭酸ランタン４．７水和物では、１ヶ月後に不純物である（II）型の水酸化炭酸ランタンのピーク（▼）が現れ、３ヶ月後にはさらに増加し，炭酸ランタン８水和物のピーク（●）も現れ、不安定であることが分かる。
以上の考察を表４にまとめる。
Stability Test The lanthanum carbonate 7.9 hydrate of Example 1 and the lanthanum carbonate 4.7 hydrate of Comparative Example 2 were placed in a brown sample bottle and sealed. This was used as a specimen and stored in a constant temperature and humidity apparatus at 40 ° C. and 75% RH. After 1 month and 3 months, the powder X-ray diffraction of the lanthanum carbonate was measured. The results are shown in FIG. 2 and FIG.
As shown in FIG. 2, there was no change in the lanthanum carbonate 7.9 hydrate of Example 1.
As shown in FIG. 3, in the lanthanum carbonate 4.7 hydrate of Comparative Example 2, a peak (▼) of (II) type lanthanum hydroxide carbonate, which is an impurity, appears after one month and further increases after three months. , The peak (●) of lanthanum carbonate octahydrate also appears, indicating that it is unstable.
The above considerations are summarized in Table 4.
本発明によって、現在販売されている炭酸ランタン水和物に関する、熱および湿気による製品の品質の低下の問題が無く、しかもリン酸塩をより早く確実に除去することができる炭酸ランタン水和物を用いる医薬を提供することができる。
According to the present invention, a lanthanum carbonate hydrate that does not have a problem of deterioration of product quality due to heat and moisture and that can remove phosphates more quickly and reliably is obtained. The medicine to be used can be provided.
Claims (4)
- ９０％積算径（Ｄ９０）が７０μｍ以下である、Ｌａ２（ＣＯ３）３・ｘＨ２Ｏ（式中、ｘは７～９の間の数字を示す。）で表される炭酸ランタン水和物からなる医薬。 Lanthanum carbonate hydrate represented by La 2 (CO 3 ) 3 · xH 2 O (wherein x is a number between 7 and 9) having a 90% cumulative diameter (D90) of 70 μm or less A medicine consisting of
- Ｄ９０が２～６５μｍである、請求項１に記載の医薬。 The medicament according to claim 1, wherein D90 is 2 to 65 µm.
- ０．７５ｍｉｎ－１以上のリン酸結合速度定数ｋ１を有する、Ｌａ２（ＣＯ３）３・ｘＨ２Ｏ（式中、ｘは７～９の間の数字を示す。）で表される炭酸ランタン水和物からなる医薬。 Carbonic acid represented by La 2 (CO 3 ) 3 · xH 2 O (wherein x is a number between 7 and 9) having a phosphate binding rate constant k 1 of 0.75 min −1 or more. A pharmaceutical consisting of lanthanum hydrate.
- 高リン血症を治療するための、請求項１～３のいずれかに記載の医薬。 The medicament according to any one of claims 1 to 3, for treating hyperphosphatemia.
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| US20110020456A1 (en) * | 2008-03-26 | 2011-01-27 | Nagaraj Amminabavi | Lanthanum composition |
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| JP2012515723A (en) * | 2009-01-21 | 2012-07-12 | マイラン インコーポレイテッド | Disintegrating preparation of lanthanum carbonate |
| US20120219637A1 (en) * | 2009-10-26 | 2012-08-30 | Dhore Aniket | Pharmaceutical compositions of lanthanum carbonate and process for the preparation thereof |
| US20130302383A1 (en) * | 2011-01-19 | 2013-11-14 | Rajesh Jain | Liquid oral composition of lanthanum salts |
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| US20040161474A1 (en) * | 2002-05-24 | 2004-08-19 | Moerck Rudi E. | Rare earth metal compounds methods of making, and methods of using the same |
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| JPH11503119A (en) * | 1995-03-25 | 1999-03-23 | ジョンソン マッセイ パブリック リミティド カンパニー | Pharmaceutical composition containing selected lanthanum carbonate hydrate |
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| JPWO2016051609A1 (en) | 2017-07-13 |
| TW201613560A (en) | 2016-04-16 |
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