KR102281492B1 - A composition of suspension for oral administration comprising sevelamer and the preparation of the same - Google Patents

Abstract

Disclosed are a suspension composition for oral administration containing sevelamer and a method for preparing the same.

Description

A composition of suspension for oral administration comprising sevelamer and the preparation of the same

The present invention relates to a suspension composition for oral administration containing sevelamer carbonate and a method for preparing the same. More specifically, it relates to a stable composition that does not phase-separate in a suspension composition containing sevelamer carbonate as a main component, and does not generate gas or change color, and a method for preparing the same.

Sevelamer carbonate is a polymer represented by the following formula (1):

In the above formula,

a and b are the number of primary amine groups, a+b=9,

c is the number of bridging groups, c=1;

m is an integer representing an extended polymer network.

Sevelamer carbonate is used as a drug to control phosphorus in the serum of patients with chronic kidney disease.

U.S. Patent Nos. 8,808,738 B2, 9,555,056 B2, and 9,895,315 B2, etc. disclose a technique for a method for manufacturing sevelamer carbonate tablets. This tablet has a major component of 800 mg, a total weight exceeding 1,000 mg, a low density of the main component, and a very large size of the tablet, making oral administration difficult.

An attempt has been made to develop a suspension containing sevelamer carbonate in order to solve the problem of taking the sevelamer carbonate tablet formulation and to increase the patient's convenience in taking it. However, when sevelamer carbonate is prepared as a suspension by using a conventional formulation technique, problems occur such as phase separation, color change, and agglomeration of contents. A technique for solving the problems in manufacturing such a suspension has not yet been reported.

U.S. Patent No. 9,095,509 B2 discloses a suspension powder comprising sevelamer carbonate as a main component, propylene glycol alginic acid as a stabilizer, and sodium chloride, a flavor, and a sweetener. This formulation is a powder-type powder that the patient mixes with water or an appropriate solution to form a suspension when taking it. Since this formulation is not a suspension, it is inconvenient to prepare a suspension at the time of taking it, and if the suspension prepared in this way is left without taking it immediately, there is a problem that phase separation occurs as a precipitate and a solution within 3 minutes. there is.

Korean Patent Publication No. 10-1853260 discloses a method for preparing sevelamer carbonate. In this patent, the polyallylamine carbonate content is prepared within the range of 25 to 45%; b) crosslinking the obtained polyallylamine carbonate with epichlorohydrin as a crosslinking agent; and c) a method for preparing sevelamer carbonate by adding an aqueous sodium hydrogen carbonate solution to the reaction solution after the crosslinking reaction has been completed, and also discloses a suspension comprising the thus-prepared sevelamer carbonate. Specifically, the suspension disclosed in this patent contains sevelamer carbonate as a main component, and stabilizers such as microcrystalline cellulose/carboxymethylcellulose sodium and methylcellulose, xanthan gum, and concentrated glycerin are contained therein to prepare a suspension formulation. will do However, such a suspension preparation method cannot be regarded as a preparation method of a suspension agent specialized for the main component of sevelamer carbonate, and the suspension prepared in this way has a problem in that phase separation occurs when left at room temperature for 1 hour. In addition, there is a disadvantage in that the problem of gas generation due to the main component is also maintained as it is.

US Patent No. 8,808,738 B2 US Patent No. 9,555,056 B2 US Patent No. 9,895,315 B2 US Patent No. 9,095,509 B2 Korean Patent Registration No. 10-1853260

The present invention is to provide a suspension composition for oral administration containing sevelamer carbonate and a method for preparing the same.

In order to solve the above problems, in the present invention, by adding a suspending agent, a stabilizer, a solubilizing agent and an antifoaming agent to the sevelamer carbonate, there is no phase separation, no color change, and inhibiting or reducing the formation of bubbles by carbon dioxide gas. A stable suspension could be prepared.

In the sevelamer carbonate-containing suspension composition according to the present invention, phase separation does not occur, the sevelamer carbonate particles are uniformly dispersed in the suspension, there is no color change, and the formation of bubbles by carbon dioxide can be inhibited or reduced. , stable. In addition, it is more convenient to take than tablets containing sevelamer carbonate.

1 is a photograph taken after leaving Examples 1, 4 and 7 (from the left) of the stable suspension composition according to the present invention at room temperature for 4 weeks.
2 is a photograph taken after preparing Comparative Examples 2 and 2 and leaving them at room temperature for 1 hour. In Comparative Example 2, layer separation occurred within 1 hour, and in Example 2, there was no layer separation.

The present invention relates to a suspension composition for oral administration containing sevelamer carbonate. The composition of the present invention includes sevelamer carbonate, a suspending agent, a stabilizing agent, a solubilizing agent and an antifoaming agent as a main component.

In the present invention, suspending agents include xanthan gum, alginic acid, carbomer, guar gum, microcrystalline cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, microcrystalline cellulose · One or more kinds of sodium carboxymethyl cellulose may be selected.

In the present invention, the stabilizing agent may be at least one selected from propylene glycol and glycerol. The stabilizer of the present invention is added for the purpose of preventing phase separation by increasing the viscosity of the medium. However, in the case of a suspension containing sevelamer carbonate as a main component, prevention of phase separation is achieved by adding only one type of stabilizer. doesn't happen Accordingly, the present inventors used one or more dissolution aids among hydrogenated castor oil, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene monoalkyl ethers, lanolin ethers, and lanolin esters together with the above stabilizer together with the above stabilizer. By increasing the non-cohesiveness of the dispersed phase, it was found that phase separation was effectively prevented when sevelamer carbonate was used as a suspending agent. In addition, by using at least one of simethicone, dimethicone and silicone antifoaming agents together with the stabilizer and solubilizing agent, carbon dioxide gas that can be generated from sevelamer carbonate is suppressed, and the sedimentation rate of particles is lowered to make a more stable suspending agent made Sevelamer carbonate is a compound having both a cation and an anion, and when a suspending agent is prepared using a conventional suspending agent or stabilizer, there is a problem in that the color changes, gas is generated, or phase separation occurs. In this case, it is possible to provide a suspension having excellent properties improved from such disadvantages.

In the present invention, the content of the main component may be 0.5 to 20% by weight based on the total weight of the suspension. One dose of the suspension composition of the present invention is preferably 5-50 mL, but is not limited thereto.

The present invention can provide a stable suspension for oral administration without color change and phase separation by reflecting the physical properties of sevelamer carbonate.

Hereinafter, additives that can be used in the suspension composition of the present invention will be described in detail.

suspending agent

As the suspending agent, for example, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, microcrystalline cellulose/sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose derivatives such as cellulose phthalate; natural polymers such as agar, xanthan gum, guar gum, carrageenan, alginic acid, gum arabic, and gelatin; synthetic polymers such as carbomer, polyvinylpyrrolidone, polyvinyl alcohol, and acrylic acid polymer; starches such as corn starch and wheat starch; At least one of propylene glycol alginic acid and the like may be used, but in particular, xanthan gum, alginic acid, carbomer, guar gum, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, Ethyl cellulose, methyl cellulose, microcrystalline cellulose sodium carboxymethyl cellulose, propylene glycol alginic acid, etc. are preferable.

The content of the suspending agent is usually 0.05 to 10% by weight, preferably 0.1 to 5% by weight, more preferably 0.3 to 3% by weight, particularly preferably 0.5 to 3% by weight, based on the total weight of the suspension for oral administration. %am.

The suspending agent composition of the present invention can improve the stability of the suspending agent by uniformly dispersing and maintaining the powder containing the suspending agent sevelamer carbonate. That is, the dispersion of the oral administration suspension is maintained even after the oral administration suspension is stored for a long time. As a result, the distribution of particles containing sevelamercarbonate in the oral administration suspension is maintained homogeneously even without shaking again to disperse the oral administration suspension.

stabilizer

As the stabilizer, at least one selected from propylene glycol, glycerin, polyethylene glycol and the like may be used. In particular, it is preferable to use at least one type of propylene glycol or glycerin.

The content of the stabilizer is usually 0.1 to 20% by weight, preferably 0.2 to 10% by weight, particularly preferably 0.5 to 10% by weight, based on the total weight of the suspension for oral administration.

antifoam

As an antifoaming agent that can be used in the present invention, one or more kinds of myristic acid, palmitic acid, simethicone, dimethicone, silicone antifoaming agent, and the like may be used. Preferably, at least one of simethicone, dimethicone, or silicone antifoaming agent is used. The content of the antifoaming agent may contain 0.005 to 10% by weight based on the total weight of the suspension for oral administration.

solubilizer

The suspension composition of the present invention may include a solubilizing agent. Examples of the solubilizing agent that can be used include hydrogenated castor oil, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene monoalkyl ethers, lanolin ethers, and lanolin esters.

preservative

The suspension composition of the present invention may include a preservative commonly used in liquid formulations. Preservatives that can be used include benzoic acid, sodium benzoate, ethyl paraoxybenzoate, butyl paraoxybenzoate, sorbic acid, potassium sorbate and sodium sorbate.

sweetener

The pharmaceutical composition of the present invention may contain a sweetening agent. As sweeteners, sugar, glucose, maltose, oligosaccharide, galactose, starch syrup, sorbitol, maltitol, invert sugar, xylitol, erythritol, hydrogenated starch syrup, mannitol, trehalose, aspartame, acesulfame salt, sucralose, saccharin salt, licorice extract, stevioside, It may be a sweetener selected from the group consisting of enzyme-treated stevioside, neohesperidin, concentrated glycerin and monelin.

flavoring agent

The pharmaceutical composition of the present invention may contain a fragrance. The fragrance may be a natural fragrance, an artificial fragrance, or a mixture thereof. The natural fragrance may be an extract from a plant leaf, flower, fruit, or the like, an oil of a plant, or the like. Plant oils include spearmint oil, cinnamon oil, peppermint oil (peppermint oil), lemon oil, clove oil, bay oil, thyme oil, cedar leaf oil, nutmeg oil, sage oil and almond oil. In addition, artificial fragrances such as lemon, orange, grape, lime, strawberry, etc. and artificial synthetic fragrances such as vanilla, chocolate, coffee, cocoa, pine needles, ginseng, red ginseng, and citrus may be used as artificial fragrances.

The present invention also relates to a method for preparing a suspension composition containing sevelamer carbonate. Specifically, the method for preparing the sevelamer carbonate-containing suspension composition of the present invention includes adding sevelamer carbonate, a suspending agent, a stabilizing agent, a solubilizing agent and an antifoaming agent to water and stirring.

Hereinafter, the present invention will be described in detail based on examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Examples 1-9: Suspension Preparation

The compositions of the oral suspensions for Examples 1 to 9 are shown in Table 1.

Ingredient name purpose Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Sevelamer carbonate chief ingredient 8000 8000 8000 8000 8000 8000 8000 8000 8000 methyl paraoxybenzoate preservative 10 10 10 10 10 10 10 10 10 propyl paraoxybenzoate preservative 10 10 10 10 10 10 10 10 10 xanthan gum suspending agent 600 800 1000 800 800 800 800 800 800 Microcrystalline Cellulose suspending agent 3000 3000 3000 2000 2500 4000 3000 3000 3000 Carbomer suspending agent 100 100 100 100 100 100 50 150 200 Polyoxyl 40 hydrogenated castor oil solubilizer 3000 3000 3000 3000 3000 3000 3000 3000 3000 propylene glycol stabilizer 40000 40000 40000 40000 40000 40000 40000 40000 40000 Simethicone antifoam 250 250 250 250 250 250 250 250 250 sucralose sweetener 200 200 200 200 200 200 200 200 200 peppermint oil flavoring agent 10 10 10 10 10 10 10 10 10 Purified water solvent qs qs qs qs qs qs qs qs qs Volume (mL) 200 200 200 200 200 200 200 200 200 Viscosity (cps) 348 421 536 301 365 587 ND ND ND Phase separation (room temperature, after 1 day) does not exist does not exist does not exist does not exist does not exist does not exist does not exist does not exist does not exist Phase separation (room temperature, after 4 weeks) does not exist does not exist does not exist does not exist does not exist does not exist does not exist does not exist does not exist Phase separation (refrigerated, after 1 week) does not exist does not exist does not exist does not exist does not exist does not exist does not exist does not exist does not exist Discoloration (room temperature, after 1 week) unchanged unchanged unchanged unchanged unchanged unchanged unchanged unchanged unchanged Discoloration (room temperature, after 4 weeks) unchanged unchanged unchanged unchanged unchanged unchanged unchanged unchanged unchanged Discoloration (refrigerated, after 4 weeks) unchanged unchanged unchanged unchanged unchanged unchanged unchanged unchanged unchanged Gas generation (room temperature, after 4 weeks) does not exist does not exist does not exist does not exist does not exist does not exist does not exist does not exist does not exist Unit: mg or mL

The composition of Example 1 was prepared as follows:

After heating purified water (100 mL) to 80 ± 5℃, add propylene glycol (40 g) and polyoxyl 40 hydrogenated castor oil (3 g), and use a homogenizer (AM-8, Nihonseiki Kaisha Ltd, Tokyo, Japan). Stir well and mix (solution A). Xanthan gum (600 mg) was added to solution A and dissolved while stirring, and microcrystalline cellulose (3 g), carbomer (100 mg), methyl paraoxybenzoate (10 mg), propyl paraoxybenzoate (10 mg), Simethicone (250 mg) and sucralose (200 mg) are added and dissolved while stirring (solution B). After cooling the temperature of solution B to 50 ± 5 °C, sevelamer carbonate (8 g as anhydrous) was added and stirred well to disperse (solution C). After cooling the temperature of solution C to 35 ± 5 ℃, a flavoring agent was added, water was added to make 200 mL, and an oral suspension was prepared.

Examples 2 to 9 and the remaining examples described below were also prepared in a similar manner to Example 1 above. Viscosity and stability were tested for the above-prepared examples in the following manner (viscosity and stability were tested in the same manner for the remaining examples described below).

Viscosity measurement

The viscosity of the prepared suspension was measured with a viscometer (DV2TLVTJ0, BROOKFIELD, Middleboro, USA).

Stability test

Put about 30 mL of the prepared suspension in a 50 mL centrifuge tube, or put it in a suitable container, and store it at room temperature, accelerated conditions (40°C and 75% relative humidity) or refrigerated conditions (4°C the next day, 1 week later, 2 After 4 weeks, check the stability of the suspension.The main test items are color change, phase separation and gas generation.As a result of the experiments of Examples 1 to 9, no phase separation occurs and no color change

Examples 10 to 16

The compositions of the oral suspensions for Examples 10 to 16 are shown in Table 2.

Ingredient name purpose Example 10 Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 Sevelamer carbonate chief ingredient 8000 8000 8000 8000 8000 8000 8000 methyl paraoxybenzoate preservative 10 10 10 10 10 10 10 propyl paraoxybenzoate preservative 10 10 10 10 10 10 10 xanthan gum suspending agent 800 800 800 800 800 800 800 Microcrystalline Cellulose suspending agent 3000 3000 3000 3000 3000 3000 3000 Carbomer suspending agent 100 100 100 100 100 100 100 Polyoxyl 40 hydrogenated castor oil solubilizer 3000 3000 1000 2000 4000 3000 3000 propylene glycol stabilizer 40000 40000 40000 40000 40000 20000 60000 Simethicone antifoam 100 500 250 250 250 250 250 sucralose sweetener 200 200 200 200 200 200 200 peppermint oil flavoring agent 10 10 10 10 10 10 10 Purified water solvent qs qs qs qs qs qs qs Volume (mL) 200 200 200 200 200 200 200 Phase separation (room temperature, after 1 day) does not exist does not exist does not exist does not exist does not exist does not exist does not exist Gas generation (room temperature, after 4 weeks) does not exist does not exist does not exist does not exist does not exist does not exist does not exist

Examples 17-23

The compositions of the oral suspensions for Examples 17 to 23 are shown in Table 3.

Ingredient name purpose Example 17 Example 18 Example 19 Example 20 Example 21 Example 22 Example 23 Sevelamer carbonate chief ingredient 8000 8000 8000 8000 8000 8000 8000 methyl paraoxybenzoate preservative 10 10 10 10 10 10 10 propyl paraoxybenzoate preservative 10 10 10 10 10 10 10 alginic acid suspending agent 4000 4000 4000 2000 1000 1000 400 xanthan gum suspending agent 300 400 500 400 400 - 300 Guar Gum suspending agent - - - - - - 400 Microcrystalline Cellulose and Sodium Carboxymethylcellulose suspending agent - - - - 4000 2000 2000 glycerol stabilizer 4000 3000 4000 4000 4000 4000 4000 Simethicone antifoam 50 50 50 50 50 50 50 peppermint oil flavoring agent 10 10 10 10 10 10 10 Purified water solvent qs qs qs qs qs qs qs Volume (mL) 200 200 200 200 200 200 200 Viscosity (cps) 240 264 272 330 355 640 680 Phase separation (room temperature, after 1 day) does not exist does not exist does not exist does not exist does not exist does not exist does not exist

Examples 24-31

The compositions of the oral suspensions for Examples 24-31 are shown in Table 4.

Ingredient name purpose Example 24 Example 25 Example 26 Example 27 Example 28 Example 29 Example 30 Example 31 Sevelamer carbonate chief ingredient 8000 8000 8000 8000 8000 8000 8000 8000 methyl paraoxybenzoate preservative 10 10 10 10 10 10 10 10 propyl paraoxybenzoate preservative 10 10 10 10 10 10 10 10 alginic acid suspending agent 6000 2000 6000 1000 2000 2000 2000 1000 xanthan gum suspending agent 600 400 400 300 400 400 - - Guar Gum suspending agent - - 600 400 400 500 500 600 Microcrystalline Cellulose and Sodium Carboxymethylcellulose suspending agent - - - - 20000 2000 2000 2000 propylene glycol stabilizer 6000 6000 6000 6000 6000 6000 6000 6000 glycerol stabilizer 4000 3000 4000 4000 4000 4000 4000 4000 Simethicone antifoam 50 50 50 50 50 50 50 50 peppermint oil flavoring agent 10 10 10 10 10 10 10 10 Purified water solvent qs qs qs qs qs qs qs qs Volume (mL) 200 200 200 200 200 200 200 200 Phase separation (room temperature, after 1 day) does not exist does not exist does not exist does not exist does not exist does not exist does not exist does not exist

Examples 32-37

The compositions of the oral suspensions for Examples 32 to 37 are shown in Table 5.

Comparative Example 1 in Table 5 below is a suspension prepared by mixing the suspension powder disclosed in US Patent No. 9,095,509 in purified water, and Comparative Example 2 is a raw material for suspension disclosed in Korean Patent Registration KR 10-1853260 It is manufactured in batches.

Ingredient name purpose Example 32 Example 33 Example 34 Example 35 Example 36 Example 37 Comparative Example 1 Comparative Example 2 Sevelamer carbonate chief ingredient 8000 8000 8000 8000 8000 8000 8000 8000 methyl paraoxybenzoate preservative 10 10 10 10 10 10 10 2.5 propyl paraoxybenzoate preservative 10 10 10 10 10 10 10 0.64 alginic acid suspending agent 4000 4000 4000 4000 - - - - xanthan gum suspending agent - 300 600 500 300 - - 80 Guar Gum suspending agent 400 - - - - - - - Microcrystalline Cellulose and Sodium Carboxymethylcellulose suspending agent - - - - - 2000 - 110 Propylene glycol alginic acid suspending agent - - - - - - 2000 - methyl cellulose suspending agent - - - - - - - 84 propylene glycol stabilizer 6000 6000 6000 8000 8000 8000 - - glycerol stabilizer 4000 4000 3000 4000 4000 4000 - - Simethicone antifoam 50 50 50 50 50 50 - - Stevioside sweetener 85 85 85 85 85 85 - - sucralose sweetener - - - - - - 38 - sodium chloride - - - - - - 94 - citric acid hydrate - - - - - - - 6 sodium citrate hydrate - - - - - - - 6 concentrated glycerin - - - - - - - 500 peppermint oil flavoring agent 16 16 16 16 16 16 - - Purified water solvent qs qs qs qs qs qs qs qs Volume (mL) 200 200 200 200 200 200 200 300 Phase separation (room temperature, 1 hour) does not exist does not exist does not exist does not exist does not exist does not exist detach detach

As a result of the experiments of Examples 1 to 37, there was no phase separation and no color change. However, in Comparative Examples 1 and 2, phase separation occurred within 1 hour. This indicates that when a suspension is prepared with sevelamer carbonate, the use of a stabilizer, a solubilizer and an antifoaming agent achieves an excellent effect of preventing phase separation.

The sevelamer carbonate-containing suspension according to the present invention is stable and has excellent administration convenience.

Claims (13)

Sevelamer carbonate;
benzoic acid, sodium benzoate, ethyl paraoxybenzoate, butyl paraoxybenzoate, sorbic acid, potassium sorbate, and sodium sorbate any one or more preservatives selected from the group consisting of;
Xanthan gum, alginic acid, carbomer, guar gum, microcrystalline cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose and propylene at least one suspending agent selected from the group consisting of glycol alginic acid;
Any one or more stabilizers selected from the group consisting of propylene glycol, glycerin and polyethylene glycol;
hydrogenated castor oil, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene monoalkyl ethers, lanolin ethers, and lanolin esters; and
A suspension composition for oral administration comprising at least one antifoaming agent selected from the group consisting of myristic acid, palmitic acid, simethicone, dimethicone and silicone. delete delete delete delete The suspension composition according to claim 1, wherein the content of the sevelamer carbonate is 0.5 to 20% by weight based on the total weight of the suspension. The suspension composition of claim 1 , wherein a single dose is 5-50 mL. The suspension composition according to claim 1, further comprising at least one selected from the group consisting of a pH adjusting agent, a preservative, a sweetening agent, and a flavoring agent. A method for preparing the suspension composition for oral administration according to claim 1, comprising:
After heating purified water, stirring by adding a stabilizing agent and a solubilizing agent;
adding a suspending agent and an antifoaming agent; and
A method for preparing a suspension composition for oral administration, comprising the step of adding severlamer carbonate. delete delete The method of claim 9, wherein a sweetener is further added in the step of adding a suspending agent and an antifoaming agent. [Claim 10] The method of claim 9, wherein at least one selected from the group consisting of a pH adjuster, a preservative, a sweetener and a flavoring agent is further added.

Images