JP6225270B2 - Medicament comprising particle size-adjusted lanthanum carbonate hydrate - Google Patents

Description

  The present invention relates to a medicament comprising a particle size-adjusted lanthanum carbonate hydrate useful as a therapeutic agent for hyperphosphatemia.

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), and 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 to 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.

Patent 3224544

  An object of the present invention is to provide a medicament using lanthanum carbonate hydrate that can remove phosphate more quickly without the problem of deterioration of product quality due to heat and moisture.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that lanthanum carbonate tetrahydrate has decomposition due to heat and moisture absorption, while lanthanum carbonate 7-9 hydrate. Even if it is 7-9 hydrate of lanthanum carbonate, which has been found to be extremely stable, and in which phosphoric acid removal ability is inferior in Patent Document 1, phosphoric acid is 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.

[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] 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] 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˜) 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 for use in 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.).

  The lanthanum carbonate tetrahydrate is a storage stability test at 40 ° C. and 75% RH, and a polymorph (II) form of lanthanum hydroxide carbonate described in JP 2009-536356 is produced. Although it changes, 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.

It is a figure which shows the change of the phosphoric acid removal rate by the particle size distribution in the lanthanum carbonate 7.9 hydrate of Examples 1-3 and the comparative example 1. FIG. 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 | saved with the 40 degreeC 75% RH sealing stopper. It is a figure which shows a time-dependent change of the powder X-ray-diffraction chart of the lanthanum carbonate 4.7 hydrate of the comparative example 2 preserve | saved with the 40 degreeC 75% RH sealing stopper.

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 such as 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 shown in Test Example 3, it was found that was produced and changed to octahydrate. On the other hand, in the 7-9 hydrate of lanthanum carbonate, when the same stability test was conducted, no decomposition product was observed, and it was revealed 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 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. The 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 to 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 Patent 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. Moreover, if the particle size of the lanthanum carbonate 7-9 hydrate becomes too fine, the powder will not have fluidity, making formulation difficult. Therefore, D90 is preferably 1 μm or more, more preferably 2 μm or more, and further preferably 5 μm or more.

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., but is 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.

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.

<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 pH 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 maintain pH 3.

(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 ). ]

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 was 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)
The lanthanum carbonate 7.9 hydrate 130g-175g of Example 1 was classified using the 330 mesh sieve. 47 to 94 g of lanthanum carbonate hydrate remaining on the sieve was classified again, and 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.

Measurement of Particle Size Distribution of Lanthanum Carbonate of Examples 1 to 3 and Comparative Examples 1 and 2 The results of measuring the particle size distribution of lanthanum carbonate of Examples 1 to 3 and Comparative Examples 1 and 2 are shown in the table below.

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 lanthanum carbonate 7-9 hydrate significantly improved the phosphate removal rate as the D90 became 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.

Test example 2
Reaction rate constant measurement The results of these phosphate adsorption capacity 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, compared with 8.8 hydrate of patent document 1, the hydrate of Examples 1-3 similarly has a quick 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. 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.

  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)

Lanthanum carbonate hydrate represented by La ₂ (CO ₃ ) ₃ xH ₂ O (wherein x represents a number between 7 and 9), 90% cumulative diameter (D90) is 70 μm or less. A drug for treating hyperphosphatemia (excluding suspensions) .   The medicament according to claim 1, wherein D90 is 2 to 65 µm. Carbonic acid represented 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. The medicament according to claim 1 or 2, comprising lanthanum hydrate. The medicament according to any one of claims 1 to 3, which is an orally disintegrating tablet, chewable agent, granule, tablet or capsule .