JP3363143B2 - Phosphate binding polymer particles - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a phosphate-binding polymer, a tablet containing the same and a method for producing the tablet.

[0002]

2. Description of the Related Art Phosphate-binding polymers are non-absorbable polymers having phosphate-adsorbing ability and are useful as therapeutic agents for hyperphosphatemia due to reduced renal function such as chronic renal failure. Phosphate-binding polymers are described, for example, in US Pat.
A crosslinked polymer obtained by crosslinking polyallylamine with a crosslinking agent such as epichlorohydrin as described in JP-A-5-504782, a polycationic polymer compound comprising a primary amine and a secondary amine. Are known compounds.

Phosphate-binding polymer preparations as therapeutic agents for hyperphosphatemia are described in, for example, the above-mentioned US patent, in which various additives including crystalline cellulose can be added to give tablets. The publication does not show any specifically manufactured example, and the inventors actually added various additives to the phosphate-binding polymer obtained by the method described in the publication. , I tried to tablet it by the usual method, but could not tablet it well.

Further, calcium polystyrene sulfonate preparations known as oral adsorbents [Calimate (registered trademark), manufactured by Niken Chemical Co., Ltd.], sodium polystyrene sulfonate preparations (Kyxalate (registered trademark), manufactured by Torii Pharmaceutical Co., Ltd.) , Adsorbed carbon formulation [Kremezin (registered trademark), manufactured by Kureha Chemical Co., Ltd.], cholestyramine formulation [Questran (registered trademark), Bristol-Myers
The dosage forms of Squibb Co., Ltd.], precipitated calcium carbonate preparations (Ebisu Yakuhin Co., Ltd.) are bulk powders, powders or capsules filled with powder, and no tableted examples are found.

[0005]

The phosphate-binding polymer adsorbs phosphorus in food by oral administration and is excreted out of the body along with feces, thereby lowering the absorption of phosphorus from the digestive tract and increasing the blood phosphorus concentration. It has an effect of suppressing the above-mentioned, and a single dose is relatively large as 1 to 2 g. Furthermore, since the phosphoric acid-binding polymer has the property of reacting with water and swelling quickly,
It is hard to take as it is. In addition, the conventional phosphate-binding polymers have insufficient hardness when tablets are molded without using additives, so a considerable amount of crystalline cellulose and / or low-substituted hydroxypropylcellulose is added. It was an essential requirement.

[0006] A dialysis patient, who is a target of administration of a phosphate-binding polymer, which is a therapeutic agent for hyperphosphatemia, often has a limited water intake, and a formulation that can be taken with a small amount of water is desired. It is rare. Promising dosage forms include tablets that can be miniaturized by compression under pressure, preferably coated tablets that are prevented from disintegrating in the mouth and have excellent dosing properties. However, the phosphate-binding polymer alone has low tablet hardness due to pressure compression, and it could not be formulated into tablets as it is. Furthermore, since the phosphoric acid-binding polymer has high hygroscopic and swelling properties, it was not possible to use a method of wet granulation and drying by adding a binder solution containing water or alcohol when formulating. .

[0007] In order to solve these problems, a manufacturing method is desired in which a powdery phosphoric acid-binding polymer is mixed with a powdery additive having excellent moldability and compression is performed. It was necessary to design in consideration of changes in disintegration and dispersibility accompanying it, and further, since a single dose was large, it was necessary to design as a formulation having a high content of the main drug.

The present inventors have studied the tableting of a phosphoric acid-binding polymer using various additives described in US Pat. No. 5,496,545, and found that sufficient hardness, rapid disintegration dispersibility and phosphorus content were obtained. It was not possible to produce excellent phosphoric acid-binding polymer-containing tablets that exhibit acid-binding properties.

[0009]

Therefore, as a result of intensive studies to solve these problems, the present inventors have found that the phosphoric acid-binding polymer itself has specific properties and It is possible to obtain a phosphate-bonding polymer tablet which is substantially composed of only the phosphate-bonding polymer, has sufficient hardness, and exhibits rapid disintegration dispersibility and phosphate-bonding property in the acidic to neutral region without adding Heading, completed the present invention.

The phosphate binding polymers of the present invention preferably have the formula

[0011]

[Chemical 2] [Wherein, the molar ratio of (a + b): c is 45: 1 to 2: 1 and m represents an integer], and 1.18 to
It has a true specific gravity of 1.24.

The tablets of the present invention have a true specific gravity of 1.18 to 1.
24, preferably 1.20 to 1.22, obtained by pulverizing a phosphate-binding polymer, having an average particle size of 400 μm
And a phosphoric acid-binding polymer having a particle size of 500 μm or less of 90% or more and a water content of 1 to 14%, and optionally crystalline cellulose and / or low-substituted hyxypropylcellulose. And a phosphate-binding polymer-containing tablet exhibiting sufficient tablet hardness, rapid disintegration dispersibility, and phosphate binding property.

Furthermore, the present invention comprises a phosphate-binding polymer-containing tablet, which is obtained by adding crystalline cellulose and / or low-substituted oxypropyl cellulose to the above-mentioned phosphate-binding polymer, if necessary, and compression-molding. Manufacturing method.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION The inventors have a true specific gravity of 1.18 to
1.24, preferably 1.20 to 1.22, the average particle size is 400 μm or less, preferably 250 μm or less, and the ratio of the particle size 500 μm or less is 90% or more, preferably 300 μm or less. A phosphoric acid-binding polymer having a ratio of 90% or more and a water content of 1 to 14% is used alone or, if necessary, crystalline cellulose and / or low-substituted hydroxypropyl which is a specific additive. We have found that tablets containing cellulose have excellent properties and completed the present invention. The true specific gravity referred to here is a true specific gravity measuring device (Acupic 1330 type,
This is the value obtained by measurement at Shimadzu Corporation.

The phosphoric acid-binding polymer used in the present invention is, for example, US Pat. No. 5,496,545 (Patent Document 9).
It can be produced by a method similar to the method described in Japanese Patent Publication No. 504782). That is, as a solvent for crosslinking the polymer described in the publication with a predetermined cross-linking agent, instead of water described in the publication, by using a mixed solvent of water and acetonitrile, phosphoric acid having a predetermined true specific gravity A binding polymer can be obtained. The volume mixing ratio of water and acetonitrile in the above mixed medium is usually 10: 90-9.
It is 0:10, preferably 40:60 to 60:40.

The dry phosphoric acid-binding polymer thus obtained has an average particle size of 400 μm or less, preferably 250 μm or less,
Further, the water content is adjusted to 1 to 14 by pulverizing so that the ratio of the particle size of 500 μm or less is 90% or more, preferably the ratio of the particle size of 300 μm or less is 90% or more.
Adjust to be%. Among the phosphate-bonding polymers, a polymer obtained by allowing epichlorohydrin to act on polyallylamine and crosslinking the polyallylamine is particularly preferably used in the present invention. This polymer has the formula

[0017]

[Chemical 3] [In the formula, the molar ratio of (a + b): c is 45: 1 to 2: 1,
Preferably 20: 1 to 4: 1, more preferably about 10 :.
1 to 8: 1, most preferably about 9: 1, and m represents an integer].

Since the phosphoric acid-binding polymer of the present invention is a crosslinked polymer, the above-mentioned m is a large integer indicating the network structure of the crosslinked and extended polymer, and the theoretical maximum number is 1 × 10 17. Is. Since the polymer is network cross-linked, the particles ground into the polymer are essentially one molecule and therefore the molecular weight corresponds to the weight of the individual polymer particles.

If the true specific gravity of the phosphoric acid-binding polymer exceeds 1.24, sufficient hardness cannot be obtained by compression molding alone. Further, those having a true specific gravity of less than 1.18 are not suitable for industrialization. If the average particle size exceeds 400 μm, sufficient hardness necessary for tableting cannot be obtained, which is not preferable. Further, if the water content is less than 1%, sufficient hardness required for tableting cannot be obtained, and the tablet surface is easily worn away, and if the water content is 14% or more, sufficient hardness can be obtained. When tabletted, it becomes plastically deformable and unsuitable as a formulation. In order to make the tablet more excellent in dosage, it is necessary to give the tablet a hardness showing 6 KP or more by a tablet hardness meter and a surface strength showing a weight loss rate of 1% or less in a friability test (100 rotations). And, in order to make tablets that do not show plastic deformability, the water content is 1 to
It may be in the range of 14%. The water content of 1 to 14% as used herein means that the weight loss on drying at 105 ° C. for 16 hours is 1 to 14%, preferably the weight loss on drying is 2 to 14%. In the pulverization process, the phosphoric acid-binding polymer itself absorbs moisture, and the water content is 1 to 14
When it is%, it is not necessary to adjust the water content and the tablet of the present invention can be used as it is.

Here, the apparatus used for pulverizing the phosphate binding polymer is not particularly limited as long as it is a model capable of obtaining a particle size of 500 μm or less and the average particle size as described above, for example, an impact crusher.

In addition, the water content is adjusted by sodium chloride saturated salt aqueous solution (25 ° C., relative humidity 75.3%), calcium chloride saturated salt aqueous solution (25 ° C., relative humidity 84.3%), magnesium nitrate saturated salt aqueous solution (25 ° C., Relative humidity 52.8%)
This can be done by using a humidity control agent such as, or by allowing it to absorb moisture naturally in the air. Further, the phosphoric acid-binding polymer having a desired water content can be obtained by performing the drying step in the production of the phosphoric acid-binding polymer so that the water content is in the range of 1 to 14%.

The crystalline cellulose that can be used in the present invention is not particularly limited, but those having a weight loss on drying at 105 ° C. for 3 hours of 7% or less can be used, and preferably those manufactured by Asahi Kasei Kogyo Co., Ltd. Avicel (registered trademark) P
Commercially available products such as H101, PH102, PH301, PH302, and CEOLUS (registered trademark) KG-801 can be used alone or in combination.

The low degree of substitution of hydroxypropyl cellulose which can be used in the present invention means that the degree of substitution of hydroxypropoxyl group (-OC3H6OH) is 5.0.
˜16.0% by weight, and examples of such a low-substituted hydroxypropyl cellulose include LH-11, LH-21 or LH manufactured by Shin-Etsu Chemical Co., Ltd.
It is preferable to use commercially available products such as -31 alone or in combination.

In the present invention, the amount of crystalline cellulose and / or low-substituted hydroxypropyl cellulose to be added to the phosphate-binding polymer tablet according to need is determined by the dose of the phosphate-binding polymer as an oral preparation and the doseability of the preparation. However, in a preferred embodiment, the average particle size is 250 μm or less, and the ratio of the particle size of 300 μm or less is 90% or more, and the water content is 1 to 1. Crystalline cellulose or low-substituted hydroxypropyl cellulose is 10% by weight or more, preferably 3% with respect to the weight of the phosphoric acid-binding polymer which is 14%.
It is preferably 0% by weight or more. When adding both crystalline cellulose and low-substituted hydroxypropyl cellulose,
The total addition amount of both is 10% by weight or more, preferably 3
It is preferably 0% by weight or more. In consideration of the dosage of the preparation, the upper limit of the addition amount of crystalline cellulose and / or low-substituted hydroxypropylcellulose is 50% by weight to 20% by weight.
The range of 0% by weight is preferable.

Furthermore, since the phosphate binding polymer, crystalline cellulose or low-substituted hydroxypropyl cellulose has a high friction property, when the tableting is continuously carried out, the load on the tableting machine due to the squeak of the punch is applied. Hardened oil may be added to reduce the amount, and as such hardened oil, for example, commercially available products such as Lubri Wax (registered trademark) manufactured by Freund Sangyo Co., Ltd. can be used.

The phosphate-binding polymer tablet of the present invention can be produced by adding, in addition to crystalline cellulose and / or low-substituted hydroxypropylcellulose, excipients such as lactose, sucrose, mannitol, magnesium stearate, polyethylene glycol, etc. Lubricants, other commonly used additives, flavors, colorants and the like may be appropriately added, and the mixture and the tablet may be mixed with the phosphate binding polymer and tableted.

Further, the phosphoric acid-binding polymer tablet of the present invention may be a film tablet whose surface is coated with a film. For the film coating, a water-soluble film base such as hydroxypropylmethyl cellulose or acrylic acid copolymer can be used. In particular, hydroxypropylmethyl cellulose can be preferably used.

[0028]

EXAMPLES The present invention will be described in more detail below with reference to production examples and examples, but the present invention is not limited thereto.

[Production Example 1] Water / acetonitrile (about 5
(0:50 w / w) In a mixed solvent, polychloroamine was added with epichlorohydrin as a cross-linking agent to carry out a cross-linking polymerization reaction, and hydrochloric acid was added at about 40% of primary amine (81.2 mol%) and secondary amine (18.8 mol%). The polycationic phosphate-binding polymer forming a salt was vacuum dried to obtain a dry powder. The phosphoric acid-binding polymer dry powder was crushed using an impact crusher, and the water-containing phosphoric acid-binding polymer (true specific gravity: 1.209 to 1.211, water content: 2.
1 to 2.5%, ratio of particle size 300 μm or less 99.0 to 9
9.6%).

[Production Example 2] Epichlorohydrin as a cross-linking agent was added to polyallylamine in water to carry out a cross-linking polymerization reaction, and hydrochloric acid was added at about 40% of primary amine (81.2 mol%) and secondary amine (18.8 mol%). The polycationic phosphate-binding polymer forming a salt was dried by aeration to obtain a dry powder. The phosphoric acid-binding polymer dry powder was crushed using an impact crusher, and the water-containing phosphoric acid-binding polymer (true specific gravity: 1.253, water content: 3.6 to 3.8).
%, Ratio of particle size of 300 μm or less 99.3 to 99.7%)
Got

Example 1 Production Example 1 (true specific gravity 1.209)
.About.1.211) and Production Example 2 (true specific gravity 1.253), and the water-containing phosphoric acid-bonding polymer was used, and the tablet diameter was 10 mm, the tablet weight was 300 mg / tablet, and the molding pressure was 500 k.
Tablets were obtained by static pressure molding under the conditions of g to 1750 kg. Table 1 shows the results of measuring the hardness of the obtained tablets with a hardness meter (Pharma test).

[0032]

[Table 1] From Table 1, tablets formed by independently molding a phosphate binding polymer having a true specific gravity of 1.253 have sufficient hardness (6
However, the true specific gravity of 1.209-
When the phosphate binding polymer of 1.211 was used, sufficient hardness was obtained at a molding pressure of 1000 kg or more.

Example 2 200 mg of the water-containing phosphoric acid-binding polymer (true specific gravity 1.209) of Production Example 1 was added as an additive to crystalline cellulose (Avicel PH10).
1 Asahi Kasei) is mixed at a ratio of 100 mg, and the tablet diameter is φ1.
0 mm, tablet weight 300 mg / tablet, molding pressure 500 kg,
Tablets were obtained by static pressure molding under the conditions of 750 kg and 1000 kg.

Table 2 shows the results of measuring the hardness of the obtained tablets with a hardness meter and the results (test liquid: water) of the tablets having a molding pressure of 750 kg measured with a disintegration tester (Toyama Sangyo).

[0035]

[Table 2] From Table 2, when crystalline cellulose was added to the phosphate-binding polymer, a tablet hardness of 6 KP or more and a rapid disintegrating property were obtained under a molding pressure of 750 kg or more.

Example 3 767.7 g of the water-containing phosphoric acid-binding polymer (true specific gravity: 1.209) of Production Example 1
On the other hand, 349.5 g of crystalline cellulose, 5.6 g of hardened oil (Labrywax 101 Freund), and 2.2 g of magnesium stearate (Nitto Kasei) as a lubricant were blended. The obtained blended powder was tableted under the conditions of a tablet diameter φ10.5 mm, a tablet weight of 375 mg / tablet and a molding pressure of 1750 kg using a single-punch tableting machine (N-30 type Okada Seiko).
A tablet (plain tablet) containing about 250 mg of a phosphate-binding polymer dried product was obtained.

The obtained tablets were measured by a hardness tester (contester) and showed a tablet hardness of 10.9 KP, and the disintegration time (test liquid: water) was 67 seconds. Furthermore, for a preparation (uncoated tablet) containing 250 mg of a phosphate-binding polymer, hydroxypropylmethylcellulose 2910 (HPMC
TC-5-RW, Shin-Etsu Chemical) 8.25 mg, polyethylene glycol 6000 (NOF Corporation) 1.26 mg, titanium oxide (A-100 Ishihara Sangyo) 1.8 mg, talc 0.69 mg coating machine with a film prescription (Doria coater DRC-500 type Paulec)
To obtain a formulation (film tablet).

About the obtained film tablets, 1 to 30 strokes per minute using a disintegration tester, two test solutions (pH 1.
2: The test was carried out on the Japanese Pharmacopoeia first liquid, water).
The measurement results are shown in FIG.

From FIG. 1, the phosphate-binding polymer preparation showed rapid disintegration in the acidic to neutral range without being affected by the stirring strength (stroke). [Example 4] For 4 tablets (film tablets) containing 250 mg of the phosphate-binding polymer produced in Example 3, sodium chloride 4.7 was used as an evaluation method assuming drug efficacy.
g, N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid 21.3 g, and potassium dihydrogen phosphate 0.544 g are dissolved in water, and the pH is adjusted to 7 to 37 ° C.
Paddle rotation speed 1 using 200 ml of test solution
The phosphate binding capacity was measured under the condition of 00 rpm. The phosphate-binding ability was measured by setting the initial value of the test solution to 1 and the end of adsorption to 0 for the concentration of residual phosphoric acid in the test solution over time due to disintegration of the tablet, dispersion of the phosphate-binding polymer, and adsorption of phosphoric acid. The results are shown in Figure 2.

From FIG. 2, the phosphate-binding polymer preparation showed a rapid phosphate-binding ability.

[0041]

EFFECT OF THE INVENTION The phosphate-binding polymer tablet of the present invention can be formulated alone, or even when an additive is added, the tablet has high hardness, a high content of the active ingredient, and a phosphate-binding property. It has excellent activity and shows rapid disintegration that is not easily affected by stirring strength in the acidic to neutral range, and it is an excellent formulation that can reduce the fluctuation of bioavailability due to motility in the digestive tract and pH. .

[Brief description of drawings]

FIG. 1 is a graph showing the disintegration characteristics (relationship between the number of strokes of a disintegration tester and tablet hardness) of a phosphate-binding polymer preparation in Example 3.

FIG. 2 is a graph showing a phosphate binding profile of a phosphate binding polymer preparation in Example 4.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI A61P 13/12 A61P 13/12 (56) References Special table HEI 9-504782 (JP, A) Special table HEI 10-501842 (JP , A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C08F 8/00-8/50 C08F 26/02 A61K 9/28 A61K 31/785 A61K 47/30 WPI (DIALOG)

Claims (10)

(57) [Claims] 1. The following formula: [Wherein, the molar ratio of (a + b): c is 45: 1 to 2: 1 and m represents an integer], and 1.18 to
Phosphate-binding polymer particles having a true specific gravity of 1.24. Wherein said true specific gravity of the phosphate-binding polymer particles of claim 1 wherein from 1.20 to 1.22. 3. The molar ratio of (a + b): c is 20: 1.
The phosphoric acid-binding polymer particles according to claim 1 or 2 , wherein the ratio is ˜4: 1. Wherein the average particle size is at 400μm or less, and claim 1 ratio of particle diameter equal to or less than 500μm is less than 90%
4. The phosphoric acid-binding polymer particles according to any one of 3 to 3 . 5. The average particle size is at 250μm or less, and claim 1 ratio of particle diameter equal to or less than 300μm is less than 90%
4. The phosphoric acid-binding polymer particles according to any one of items 4 to 4 . 6. is a moisture content of 1-14% claim 1
5. The phosphoric acid-bonding polymer particles according to any one of items 5 to 5 . 7. The phosphate-binding polymer particles, the epichlorohydrin polyallylamine, reacted in a mixed solvent of water and acetonitrile, claim 1 is obtained by crosslinking one Item 5. The phosphoric acid-binding polymer particle according to the item. 8. The phosphate-binding polymer particles, crosslinked after, grinding and / or moisture regulation and is obtained by claim 7 phosphate-binding polymer particles according. 9. A epichlorohydrin polyallylamine, reacted in a mixed solvent of water and acetonitrile, and wherein the obtained by crosslinking, phosphate-binding according to any one of claims 1 to 6 Method for producing polymer particles. 10. The method for producing phosphoric acid-bonding polymer particles according to claim 9 , which is obtained by pulverizing and / or adjusting water content after crosslinking.