WO2016051609A1 - Médicament comprenant un hydrate de carbonate de lanthane ayant une taille de particules ajustée - Google Patents

Médicament comprenant un hydrate de carbonate de lanthane ayant une taille de particules ajustée Download PDF

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Publication number
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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Prior art keywords
hydrate
lanthanum carbonate
lanthanum
particle size
drug
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PCT/JP2014/080459
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English (en)
Japanese (ja)
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佐藤　智則
鈴木　健介
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東和薬品株式会社
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Priority to JP2016551468A priority Critical patent/JP6225270B2/ja
Publication of WO2016051609A1 publication Critical patent/WO2016051609A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/244—Lanthanides; Compounds thereof

Definitions

  • 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.

Abstract

Ce médicament comprend un hydrate de carbonate de lanthane de diamètre cumulé à 90 % (D90) de 70 µm ou moins, et représenté par La2(CO3)3⋅xH2O (dans la formule, x représente un nombre entre 7 et 9). Le médicament ne souffre pas du problème de baisse de qualité du produit lié à la chaleur et à l'humidité, et en outre permet une élimination rapide et fiable des phosphates.
PCT/JP2014/080459 2014-10-02 2014-11-18 Médicament comprenant un hydrate de carbonate de lanthane ayant une taille de particules ajustée WO2016051609A1 (fr)

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Citations (7)

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JPH11503119A (ja) * 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 選択された炭酸ランタン水和物を含有する医薬組成物
US20110020456A1 (en) * 2008-03-26 2011-01-27 Nagaraj Amminabavi Lanthanum composition
CN102432055A (zh) * 2011-09-23 2012-05-02 北京大学 用于治疗高磷血症的碳酸镧纳米颗粒、其制备方法及用途
CN102442692A (zh) * 2011-09-23 2012-05-09 北京大学 碳酸镧水合物、其制备方法以及碳酸镧中是否夹杂碱式碳酸镧的判断方法
JP2012515723A (ja) * 2009-01-21 2012-07-12 マイラン インコーポレイテッド 炭酸ランタンの崩壊製剤
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

Family Cites Families (1)

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Publication number Priority date Publication date Assignee Title
US20040161474A1 (en) * 2002-05-24 2004-08-19 Moerck Rudi E. Rare earth metal compounds methods of making, and methods of using the same

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH11503119A (ja) * 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 選択された炭酸ランタン水和物を含有する医薬組成物
US20110020456A1 (en) * 2008-03-26 2011-01-27 Nagaraj Amminabavi Lanthanum composition
JP2012515723A (ja) * 2009-01-21 2012-07-12 マイラン インコーポレイテッド 炭酸ランタンの崩壊製剤
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
CN102432055A (zh) * 2011-09-23 2012-05-02 北京大学 用于治疗高磷血症的碳酸镧纳米颗粒、其制备方法及用途
CN102442692A (zh) * 2011-09-23 2012-05-09 北京大学 碳酸镧水合物、其制备方法以及碳酸镧中是否夹杂碱式碳酸镧的判断方法

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HE ET AL.: "Preparation and Characterization of Lanthanum Carbonate Octahydrate for the Treatment of Hyperphosphatemia", JOURNAL OF SPECTROSCOPY, vol. 2013, 15 October 2013 (2013-10-15), pages 1 - 6 *
SARBAJNA ET AL.: "Thermogravimetric Method Validation And Study Of Lanthanum Carbonate Octahydrate And Its Degradants", INTERNATIONAL JOURNAL OF CHEMTECH RESEARCH, vol. 5, no. 6, December 2013 (2013-12-01), pages 2810 - 2820 *

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JPWO2016051609A1 (ja) 2017-07-13
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