CN108743546B - Sevelamer carbonate dry suspension and preparation method thereof - Google Patents

Abstract

The invention relates to a sevelamer carbonate dry suspension which comprises the following raw material components in parts by weight: 100 parts of sevelamer carbonate, 600 parts of filler 400-containing agent, 50-70 parts of suspending agent and 10-20 parts of flavoring agent. The sevelamer carbonate dry suspension prepared by adopting the formula and the process has the advantages of uniform particle distribution, good stability, good dissolution and good taste; and the blood phosphorus concentration of the patient can be maintained for a long time, the taking times are reduced, and the compliance of the patient is improved.

Description

Sevelamer carbonate dry suspension and preparation method thereof

Technical Field

The invention belongs to the technical synthesis field of pharmaceutical chemicals, and particularly relates to a sevelamer carbonate dry suspension and a preparation method thereof.

Background

Sevelamer carbonate tablet (FDA approved drug product on the market is

Approved for 10 months and 19 days in 2007) as a marketed drug sevelamer hydrochloride tablet (trade name)

Is a new class i drug developed by Gel TexPharmaceuticals inc, 1998, approved by the FDA in the united states for marketing at 10/30.1998), and is also a non-absorbable calcium-free, metal-free phosphate binder, but has a carbonate buffer system that is beneficial to the body. A clinical trial aimed at comparing renivela and Renagel showed that both drugs act equally in controlling serum phosphorus levels within the recommended clinical practice guidelines for KDOQI chronic kidney disease and dialysis. Sevelamer carbonate or sevelamer hydrochloric acidThe salts are all polymeric anion exchange resins. The polymers themselves (active moieties capable of binding to phosphorus) of both compounds are identical, despite the difference in counterions (salts).

Researches show that sevelamer carbonate is insoluble in water, has hydrophilicity, and obviously expands and becomes gel after meeting water. The currently marketed sevelamer carbonate mainly adopts tablets, the tablet size is small, the carrying is convenient, but the compressibility of the sevelamer carbonate raw material is poor, so the auxiliary material proportion is high, the tablet size is large, and great troubles are brought to the administration of patients with dysphagia.

CN107375218A discloses an oral sustained-release dry suspension of sevelamer carbonate, which comprises 30-50% of sevelamer carbonate, 25-35% of a suspending agent, 15-25% of a filler, 5-10% of an adhesive, 2-5% of magnesium stearate, 0.1-1% of sucrose and 0.1-1% of titanium dioxide. Although the dry suspension of the patent has a good slow-release effect, the slow-release effect and the redispersibility of the dry suspension still need to be further improved.

Disclosure of Invention

In order to overcome the problems in the prior art, the invention provides a sevelamer carbonate dry suspension with good slow release effect and redispersibility and a preparation method thereof.

In order to solve the technical problems, the invention adopts the following technical scheme:

the invention aims to provide a sevelamer carbonate dry suspension which comprises the following raw material components in parts by weight: 100 parts of sevelamer carbonate, 600 parts of filler 400-containing agent, 50-70 parts of suspending agent and 10-20 parts of flavoring agent.

Preferably, the feed comprises the following raw material components in parts by weight: 100 parts of sevelamer carbonate, 500 parts of a filling agent, 60 parts of a suspending agent and 15 parts of a flavoring agent.

Preferably, the filler is one or more selected from sucrose, lactose, mannitol, starch, xylitol and maltitol.

Preferably, the suspending agent is selected from one or more of sodium carboxymethylcellulose, sodium alginate and povidone.

Further preferably, the suspending agent is a composition of sodium alginate and povidone, and the mass ratio of the sodium alginate to the povidone is 1-3: 1.

Most preferably, the mass ratio of the sodium alginate to the povidone is 2:1, and the dry suspension prepared by using the sodium alginate and the povidone as the suspending agent has the largest sedimentation volume ratio and the best redispersibility.

Preferably, the flavoring agent is one or more than two of aspartame, orange essence and trisodium citrate.

Further preferably, the flavoring agent is a mixture of aspartame, orange essence and trisodium citrate in a weight ratio of 1-3: 0.5-1.5: 1.

Most preferably, the weight ratio of the aspartame to the orange essence to the trisodium citrate is 2:1:1, and the invention finds that the specific flavoring agent is selected, so that the problem of the taste of the sevelamer carbonate dry suspension can be well solved, and the invention also finds that the dry suspension has quick effect and is beneficial to the stability of the sevelamer carbonate dry suspension.

The invention also aims to provide a preparation method of the sevelamer carbonate dry suspension, which comprises the following steps:

(1) sieving sevelamer carbonate with 100 mesh sieve, and sieving filler, suspending agent and correctant with 80 mesh sieve respectively;

(2) adding water into the sieved sevelamer carbonate, the filling agent, the suspending agent and the flavoring agent, and uniformly mixing to prepare a soft material; granulating with a 25-mesh sieve, and drying to obtain the sevelamer carbonate dry suspension.

Compared with the prior art, the invention has the following advantages:

the sevelamer carbonate dry suspension prepared by adopting the formula and the process has the advantages of uniform particle distribution, good stability, good dissolution and good taste; and the blood phosphorus concentration of the patient can be maintained for a long time, the taking times are reduced, and the compliance of the patient is improved.

Detailed Description

It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

In order to make the technical solutions of the present application more clearly understood by those skilled in the art, the technical solutions of the present application will be described in detail below with reference to specific embodiments.

The test materials used in the examples of the present invention are all conventional in the art and commercially available.

Example 1:

1. the raw material composition is as follows:

100 g of sevelamer carbonate, 500 g of filling agent, 60 g of suspending agent and 15 g of flavoring agent.

Wherein the filler is mannitol, the suspending agent is a composition of sodium alginate and povidone, and the mass ratio of the sodium alginate to the povidone is 2: 1; the corrigent is a mixture of aspartame, orange essence and trisodium citrate in a weight ratio of 2:1: 1.

2. The preparation process comprises the following steps:

(1) sieving sevelamer carbonate with 100 mesh sieve, and sieving filler, suspending agent and correctant with 80 mesh sieve respectively;

(2) adding water into the sieved sevelamer carbonate, the filling agent, the suspending agent and the flavoring agent, and uniformly mixing to prepare a soft material; granulating with a 25-mesh sieve, and drying to obtain the sevelamer carbonate dry suspension.

Example 2:

1. the raw material composition is as follows:

100 g of sevelamer carbonate, 600 g of filling agent, 50 g of suspending agent and 20 g of flavoring agent.

Wherein the filler is lactose, and the suspending agent is sodium carboxymethylcellulose; the corrigent is a mixture of aspartame, orange essence and trisodium citrate in a weight ratio of 2:1: 1.

2. The preparation process comprises the following steps:

the preparation process is the same as in example 1.

Example 3:

1. the raw material composition is as follows:

100 g of sevelamer carbonate, 400 g of filling agent, 70 g of suspending agent and 10 g of flavoring agent.

Wherein the filler is sucrose, and the suspending agent is sodium alginate; the corrigent is a mixture of aspartame, orange essence and trisodium citrate in a weight ratio of 2:1: 1.

2. The preparation process comprises the following steps:

the preparation process is the same as in example 1.

Test example 1: dry suspension settling property and suspension property test

The test was carried out according to the regulations of the Chinese pharmacopoeia 2010 edition on the sedimentation volume ratio of the dry suspension, and the results are shown in Table 1.

TABLE 1

As can be seen from Table 1, the sedimentation volume ratio of the sevelamer carbonate dry suspension is greater than 0.9, the dry suspension conforms to the pharmacopoeia regulations, and the dry suspension prepared from the composition of sodium alginate and povidone as the suspending agent has obviously better redispersibility than the dry suspension prepared from other suspending agents.

Test example 2: rat in vivo test for hyperphosphatemia

9 rats with high blood phosphorus, the weight of which is 190-200 g, and each 3 rats are taken as a group, the dry suspension of the embodiment 1-3 is respectively administrated by gastric lavage, 1ml of venous blood is taken at 0, 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 hours, and the phosphorus content (mmol/L) in the blood is determined, and the result is shown in the table 2.

TABLE 2

	0h	0.5h	1h	2h	4h	6h	8h	10h	12h	24h
											Example 1	4.3	3.4	3.0	2.6	2.6	2.6	2.6	2.6	2.6	2.9
Example 2	4.4	3.5	3.2	2.8	2.8	2.9	3.2	3.2	3.2	3.5
											Example 3	4.3	3.5	3.1	2.9	2.9	2.9	3.1	3.3	3.3	3.6

As can be seen from the table 2, the dry suspension provided by the invention has a good slow release effect, can realize that the phosphorus concentration in the blood of the rat with hyperphosphatemia can be maintained at a relatively stable level within 24h, and the slow release effect of the suspending agent is better when the combination of sodium alginate and povidone is selected as the suspending agent compared with that of a single suspending agent.

The present invention is described in detail in order to make those skilled in the art understand the content and practice the invention, and the invention is not limited to the above embodiments, and all equivalent changes or modifications made according to the spirit of the invention should be covered by the scope of the invention.

Claims (2)

1. The sevelamer carbonate dry suspension is characterized in that: the composite material is prepared from the following raw materials in parts by weight: 100 parts of sevelamer carbonate, 500 parts of a filling agent, 60 parts of a suspending agent and 15 parts of a flavoring agent; the flavoring agent is a mixture of aspartame, orange essence and trisodium citrate in a weight ratio of 2:1: 1; the filler is mannitol; the suspending agent is a composition of sodium alginate and povidone, and the mass ratio of the sodium alginate to the povidone is 2: 1.

2. A method for preparing sevelamer carbonate dry suspension according to claim 1, characterized in that: the method comprises the following steps:

(1) sieving sevelamer carbonate with 100 mesh sieve, and sieving filler, suspending agent and correctant with 80 mesh sieve respectively;

(2) adding water into the sieved sevelamer carbonate, the filling agent, the suspending agent and the flavoring agent, and uniformly mixing to prepare a soft material; granulating with a 25-mesh sieve, and drying to obtain the sevelamer carbonate dry suspension.