JP2002234912A - Phosphate-binding polymer and pharmaceutical preparation using the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a phosphate-binding polymer which, even when used alone or in a high formulation ratio, can form tablets having a high hardness, a high contents of a main medicine and an excellent phosphate-binding capacity, resistance against strong in an acidic to neutral range, rapidly collapsing, and providing an excellent pharmaceutical preparation reducing the motion in a digestive tract or variation in bioavailability due to a pH. SOLUTION: This phosphate-binding polymer is represented by the formula and has a true specific gravity of 1.18-1.24. A pharmaceutical preparation comprising the polymer alone or, if necessary, together with crystalline cellulose and/or low-substitution-degree hydroxypropylcellulose is provided. A production method for the pharmaceutical preparation is also provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] 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 A phosphate-binding polymer is a non-absorbable polymer having a phosphate-adsorbing ability, and is useful as a therapeutic agent for hyperphosphatemia due to a decrease in renal function such as chronic renal failure. Phosphate binding polymers are described, for example, in US Pat.
No. 5 (Japanese Unexamined Patent Publication No. 9-504782) is a crosslinked polymer obtained by crosslinking polyallylamine with a crosslinking agent such as epichlorohydrin, and is a polycationic polymer compound comprising a primary amine and a secondary amine. A known compound known as

[0003] Phosphate-binding polymer preparations as a therapeutic agent for hyperphosphatemia, for example, the above-mentioned US Patent states that various additives including microcrystalline cellulose can be added to tablets to form tablets. The publication does not show specific examples of the production, and the present inventors added various additives to the phosphate-binding polymer actually obtained by the method described in the publication. Tried to make tablets in the usual way, but did not work well.

[0004] Furthermore, calcium polystyrene sulfonate preparations known as oral adsorbents [Calimate (registered trademark), manufactured by Niken Kagaku Co., Ltd.], sodium polystyrene sulfonate preparations (silicalate (registered trademark), manufactured by Torii Pharmaceutical Co., Ltd.) Sorbent preparation [Kremezin (registered trademark), manufactured by Kureha Chemical Co., Ltd.], cholestyramine preparation [Questran (registered trademark), Bristol-Myers
Squibb Co., Ltd.], precipitated calcium carbonate preparations (manufactured by Ebisu Pharmaceutical Co., Ltd.) are capsules filled with raw powders, powders or powders, and no tablets are found.

[0005]

The phosphate-binding polymer adsorbs phosphorus in food by oral administration, and is excreted with feces outside the body, thereby reducing the absorption of phosphorus from the digestive tract to reduce the blood phosphorus concentration. And the dose is relatively large at 1-2 g per dose. Furthermore, since the phosphate-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 polymer, when formed into tablets without using additives, has insufficient tablet hardness, so that a considerable amount of crystalline cellulose and / or low-substituted hydroxypropylcellulose is blended. Was an essential requirement.

[0006] Dialysis patients to whom the phosphate-binding polymer as a therapeutic agent for hyperphosphatemia is administered often have limited water intake, and for such preparations, a dosage form that can be taken with a small amount of water is desired. It is rare. Promising dosage forms include tablets which can be miniaturized by compression under pressure, and preferably coated tablets which are prevented from disintegrating in the mouth and have excellent ingestibility. However, the phosphate-bonding polymer alone has a low tablet hardness due to pressurization alone, and cannot be formulated as a tablet as it is. Furthermore, since the phosphate-binding polymer has high moisture-absorbing and swelling properties, it was not possible to use a manufacturing method in which a binder solution containing water or alcohol was added to perform wet granulation and drying during formulation. .

[0007] In order to solve these problems, a production method in which a powdery phosphoric acid-binding polymer is blended with a powdery additive having excellent moldability and compression is desired. It was necessary to design with attention to the accompanying change in disintegration and dispersibility, and it was necessary to design a preparation with a high content of the active drug because of a large dose per dose.

The present inventors have studied the tableting of a phosphate-binding polymer using various additives described in US Pat. No. 5,496,545, and found that the tablet had sufficient hardness and rapid disintegration and dispersibility. An excellent phosphate-binding polymer-containing tablet exhibiting acid-binding properties could not be produced.

[0009]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies in order to solve these problems, and as a result, the case where the phosphate-binding polymer itself has a specific property, It is possible to obtain a phosphate-binding polymer tablet having sufficient hardness and exhibiting rapid disintegration dispersibility and phosphate-binding property in an acidic to neutral region without substantially adding a phosphate-binding polymer. Heading, the present invention has been completed.

[0010] The phosphate-binding polymer of the present invention preferably has the formula

[0011]

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

The tablet of the present invention has a true specific gravity of 1.18 to 1.
24, preferably obtained by pulverizing a phosphate-binding polymer having a mean particle size of 1.20 to 1.22,
Or less, the proportion of particles having a particle size of 500 μm or less is 90% or more and the water content is 1 to 14%, and if necessary, crystalline cellulose and / or low-substituted hydroxypropylcellulose. And a phosphate-binding polymer-containing tablet exhibiting sufficient tablet hardness, rapid disintegration dispersibility, and phosphate binding properties.

Further, the present invention provides a tablet containing a phosphate-binding polymer, which comprises mixing the above-mentioned phosphate-binding polymer with crystalline cellulose and / or low-substituted hydroxypropylcellulose, if necessary, followed by compression molding. And a method for producing the same.

[0014]

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

The phosphate-binding polymer used in the present invention is described, for example, in US Pat.
-504782) can be produced by a method according to the method described in US Pat. That is, by using a mixed solvent of water and acetonitrile as a solvent for crosslinking the polymer described in the publication with a predetermined crosslinking agent, instead of water described in the publication, phosphoric acid having a predetermined true specific gravity is used. An associative polymer can be obtained. The volume mixing ratio of water and acetonitrile in the above mixed medium is usually 10:90 to 9: 9.
0:10, preferably 40:60 to 60:40.

The obtained dried phosphate-binding polymer has an average particle size of 400 μm or less, preferably 250 μm or less,
In addition, pulverization is performed so that the ratio of particles having a particle size of 500 μm or less is 90% or more, preferably 90% or more of the particles having a particle size of 300 μm or less.
Adjust to be%. Among the phosphoric acid-binding polymers, a polymer obtained by reacting polychloroamine with epichlorohydrin and cross-linking it can be particularly preferably used in the present invention. This polymer has the formula

[0017]

Embedded image [Wherein the molar ratio of (a + b): c is 45: 1 to 2: 1,
Preferably from 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 phosphate-bonding polymer of the present invention is a crosslinked polymer, the above m is a large integer indicating the network structure of the crosslinked and extended polymer, and the maximum theoretical number is 1 × 10 17 It is. Since the polymer is crosslinked in a network, the particles obtained by grinding the polymer are essentially one molecule, and the molecular weight therefore 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 even if it is compression-molded alone. Those having a true specific gravity of less than 1.18 are not suitable for industrialization. If the average particle size is larger than 400 μm, it is not preferable because sufficient hardness required for tableting cannot be obtained. Further, when the water content is less than 1%, sufficient hardness necessary for tableting cannot be obtained, and the tablet surface is easily worn away. When the water content is 14% or more, sufficient hardness is obtained. When formed into tablets, they become plastically deformable and become unsuitable as pharmaceuticals. In order to make the tablet more ingestible, it is necessary to give the tablet a hardness of 6 KP or more on a tablet hardness meter and a surface strength of 1% or less in weight loss rate in a friability test (100 rotations). In order to make a tablet that does not show plastic deformation, the water content is 1 to
Those having a range of 14% are mentioned. Here, the water content of 1 to 14% means 1 to 14% as a loss on drying at 105 ° C. for 16 hours, and preferably 2 to 14% as a loss on drying. During the pulverization process, the phosphate-binding polymer itself absorbs moisture, and the water content is 1 to 14
%, There is no need to adjust the water content, and the tablet can be used as it is in the tablet of the present invention.

Here, the apparatus used for grinding the phosphate-binding polymer is not particularly limited as long as it is a model capable of obtaining a particle diameter of 500 μm or less and the above average particle diameter, for example, an impact-type pulverizer.

The water content is adjusted by adjusting the aqueous solution of a saturated sodium chloride salt (25 ° C., relative humidity 75.3%), the aqueous solution of a saturated salt of calcium chloride (25 ° C., relative humidity 84.3%), and the aqueous solution of a magnesium nitrate saturated salt (25 ° C. (Relative humidity 52.8%)
This can be achieved by using a humectant such as the above, or by naturally absorbing moisture in the air. 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 loss on drying at 105 ° C. for 3 hours of 7% or less can be used, and are preferably manufactured by Asahi Chemical Industry Co., Ltd. Avicel® P
Commercial products such as H101, PH102, PH301, PH302 and CEOLUS (registered trademark) KG-801 can be used alone or in combination.

The low-substituted hydroxypropylcellulose that can be used in the present invention means that the hydroxypropoxyl group (-OC3H6OH) substitution degree is 5.0.
低 16.0% by weight. Examples of such low-substituted hydroxypropylcellulose include LH-11, LH-21 or LH-11 manufactured by Shin-Etsu Chemical Co., Ltd.
It is preferable to use a commercially available product such as -31 alone or as a mixture.

In the present invention, the amount of microcrystalline cellulose and / or low-substituted hydroxypropylcellulose added to the phosphate-binding polymer tablet, if necessary, depends on the dosage of the phosphate-binding polymer as an oral preparation and the ingestibility of the preparation. Can be set arbitrarily in consideration of, for example, in a preferred embodiment, the average particle size is 250 μm or less, and the ratio of the particle size 300 μm or less is 90% or more, and the water content is 1 to 3. 10% by weight or more, preferably 3% by weight, of crystalline cellulose or low-substituted hydroxypropylcellulose, based on the weight of the phosphate-binding polymer being 14%.
0% by weight or more is preferred. When adding both crystalline cellulose and low-substituted hydroxypropyl cellulose,
The total addition amount of both is 10% by weight or more, preferably 3% by weight.
0% by weight or more is preferred. In consideration of the ingestibility of the preparation, the upper limit of the amount of microcrystalline cellulose and / or low-substituted hydroxypropylcellulose is 50% by weight to 20% by weight.
The content is preferably in the range of 0% by weight.

Further, since the phosphate-binding polymer, crystalline cellulose or low-substituted hydroxypropylcellulose has a high friction property, when the tableting is performed continuously, the load on the tableting machine due to the creaking of the punch is reduced. It is preferable to add a hardened oil to reduce the amount of the oil. As such a hardened oil, for example, a commercially available product such as Lubriwax (registered trademark) manufactured by Freund Corporation may be used.

The production of the phosphate-binding polymer tablet of the present invention is carried out by adding excipients such as lactose, sucrose, mannitol, magnesium stearate, polyethylene glycol and the like, in addition to crystalline cellulose and / or low-substituted hydroxypropyl cellulose. Lubricants, other conventional additives, fragrances, coloring agents, and the like can be appropriately added, mixed with a phosphate-binding polymer, and tableted.

Further, the phosphate binding polymer tablet of the present invention can be further made into a film tablet having a surface coated with a film. For the film coating, a water-soluble film base such as hydroxypropylmethylcellulose and an acrylic acid copolymer can be used. Particularly, hydroxypropyl methylcellulose can be preferably used.

[0028]

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

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

[Preparation Example 2] Cross-linking polymerization reaction was carried out by adding epichlorohydrin as a cross-linking agent to polyallylamine in water, and hydrochloric acid was added in about 40% of primary amine (81.2 mol%) and secondary amine (18.8 mol%). The polycationic phosphate-binding polymer forming a salt was air-dried to obtain a dried powder. The phosphoric acid-binding polymer dried powder is pulverized using an impact type pulverizer, and the water-containing phosphoric acid-binding polymer (true specific gravity 1.253, water 3.6 to 3.8)
%, A ratio of particle diameter of 300 μm or less 99.3 to 99.7%)
I got

Example 1 Production Example 1 (true specific gravity 1.209)
1.211) and Production Example 2 (true specific gravity 1.253) were prepared using the water-containing phosphate-binding polymer having a tablet diameter of 10 mm, a tablet weight of 300 mg / tablet, and a molding pressure of 500 k.
The 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, the tablets molded solely with the phosphate binding polymer having a true specific gravity of 1.253 have sufficient hardness (6
KP or more) was not obtained, but the true specific gravity was 1.209 or more.
When the phosphoric acid-binding polymer of 1.211 was used, a sufficient hardness was obtained at a molding pressure of 1000 kg or more.

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

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

[0035]

[Table 2] As shown in Table 2, when crystalline cellulose was added to the phosphate-binding polymer, a tablet having a tablet hardness of 6 KP or more and a rapid disintegration was obtained under a condition of a molding pressure of 750 kg or more.

Example 3 767.7 g of a water-containing phosphate-binding polymer of Production Example 1 (true specific gravity 1.209)
Was mixed at a ratio of 349.5 g of crystalline cellulose, 5.6 g of hardened oil (Lubric wax 101 Freund), and 2.2 g of magnesium stearate (Nitto Kasei) as a lubricant. The obtained blended powder was tableted using a single tableting machine (N-30 type Okada Seiko) under the conditions of a tablet diameter of 10.5 mm, a tablet weight of 375 mg / tablet, and a molding pressure of 1750 kg.
A tablet (uncoated tablet) containing about 250 mg of a dried phosphoric acid-binding polymer was obtained.

As a result of measuring the obtained tablet with a hardness tester (contester), the tablet showed a tablet hardness of 10.9 KP, and the disintegration time (test solution: water) was 67 seconds. Further, for a preparation (uncoated tablet) containing 250 mg of a phosphate-binding polymer, hydroxypropyl methylcellulose 2910 (HPMC
TC-5-RW, Shin-Etsu Chemical) 8.25 mg, polyethylene glycol 6000 (Nippon Yushi) 1.26 mg, titanium oxide (A-100 Ishihara Sangyo) 1.8 mg, talc 0.69 mg (Doria Coater DRC-500 type Powrex)
Was used to obtain a preparation (film tablet).

Using the disintegration tester, 1 to 30 strokes per minute of the obtained film tablets were used for two kinds of test solutions (pH 1.
2: Japanese Pharmacopoeia first liquid, water).
FIG. 1 shows the measurement results.

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

FIG. 2 shows that the phosphate-binding polymer preparation exhibited 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 blended, the tablet has a high hardness, a high content of the main drug, and a high phosphate binding. It is an excellent formulation that exhibits excellent disintegration and rapid disintegration that is not easily affected by stirring intensity in the acidic to neutral range, and can reduce the fluctuation of bioavailability due to gastrointestinal motility and pH. .

[Brief description of the drawings]

FIG. 1 is a graph showing the disintegration properties (the relationship between the number of strokes of a disintegration tester and the 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.

Claims (3)

[Claims] 1. The following formula: Wherein the molar ratio of (a + b): c is from 45: 1 to 2: 1, and m represents an integer.
1. A phosphate binding polymer having a true specific gravity of 1.24. 2. The phosphoric acid-binding polymer according to claim 1, wherein the true specific gravity is 1.20 to 1.22. 3. The molar ratio of (a + b): c is 20: 1.
The phosphate-binding polymer according to claim 1, wherein the ratio is from 4 to 1.