KR101162682B1 - Pharmaceutical composition containing polystyrene sulfonate metal salt and manufacturing method thereof - Google Patents

Abstract

The present invention relates to a polystyrene sulfonic acid metal salt-containing preparation, which comprises a polystyrene sulfonic acid metal salt and xanthan gum (or polystyrene sulfonic acid metal salt, xanthan gum and magnesium aluminum silicate). The polystyrene sulfonic acid metal salt-containing preparation according to the present invention is easy to carry, easy to suspend in water, the sedimentation is slow when suspended in water, the rough foreign matters are reduced, and the ease of drinking is improved, and the feeling of taking is excellent.

Polystyrene sulfonic acid metal salt, xanthan gum, magnesium aluminum silicate, ethanol granule

Description

Pharmaceutical composition containing polystyrene sulfonate metal salt and manufacturing method

The present invention relates to a polystyrene sulfonate metal salt-containing preparation which is easy to take in suspension in water, does not easily settle when suspended in water, has excellent resuspension, and improves the feeling of taking. The invention also relates to a process for preparing such polystyrenesulfonic acid metal salt containing formulations.

Polystyrene sulfonate metal salts are drugs used for the treatment of hyperkalemia caused by chronic and acute renal failure. Such polystyrenesulfonic acid metal salts are usually suspended in water of about 6 to 10 times. Polystyrene sulfonic acid metal salt is hardly soluble in water and has a unique oral foreign body powder. Since the daily dosage is 5 to 30 g, it leaves a rough feeling in the oral cavity and throat when taking it. not. In addition, polystyrenesulfonic acid metal salts are suspended in water and are easily settled and left in containers when taken, so it is not easy to keep the correct dosage.

In order to remedy these problems associated with feeling and dispersibility, Korean Registered Patent No. 10-0440544 discloses the gelation of carmellose sodium (CMC-Na) and / or when taken with the use of caramelose sodium (CMC-Na) as a gelling agent. Or, by lowering the sedimentation rate of the polystyrene sulfonate metal salt particles by swelling to reduce the rough feeling in the mouth to improve the feeling of taking. However, although the technique has lowered the sedimentation rate to some extent, the discomfort of the rough feeling still remains when taking, and when suspended in water and left for a few minutes for taking, sedimentation occurs and resuspension is difficult in the settled state. The problem remains.

In addition, US Pat. No. 6,703,013 has been prepared in the form of jelly or pudding form by adding a large amount of agar (Agar) to the polystyrene sulfonic acid metal salt to improve the problem to improve the feeling of taking. Such attempts have reduced the rough feeling, but the product is bulky and inconvenient because it has to be stored and carried in the form of jelly or pudding, and this form is thixotropic, which can cause liquefaction and sedimentation when stored at high temperatures. The disadvantage is that care must be taken.

Therefore, the technical problem to be achieved by the present invention is a simple method of preparation, while adding a small amount of a suspending agent such as a gelling agent to reduce the dosage, while suspending in water before taking, easy, polystyrene sulfide improved It is to provide a formulation containing a metal phosphate salt. It is another object of the present invention to provide a formulation which is convenient to use because it is easily dispersed and suspended in water by only a few seconds of stirring before taking, and does not settle for a long time after suspension. Not sedimenting for a long time means that the polystyrene sulfonate metal salt does not sediment in the oral cavity and passes through the oral cavity with the water used for intake, thereby reducing the discomfort of the roughness in the oral cavity. Still another object of the present invention is to provide a patient with a preparation that can be re-dispersed as quickly as possible even if it is shaken lightly even when settled for a long time.

In order to achieve the above technical problem, the present invention provides a polystyrene sulfonate metal salt-containing pharmaceutical composition, characterized in that it contains a polystyrene sulfonate metal salt and xanthan gum as a gelling agent as a suspending agent.

Suspending agents are commonly referred to collectively as ingredients that assist in suspending the active ingredient in water. In the present specification, a component that gels in water to function as a suspending agent is referred to as a 'gelling agent', and a component that helps suspending the active ingredient without gelling in water is intended to be referred to as a 'suspending agent'.

The present invention is based on the findings of the inventors as follows. The polystyrenesulfonic acid metal salts should exhibit low viscosity when suspended in water in order to be easily dispersed in water by stirring for only a few seconds. When a high viscosity is added, the preparation does not easily suspend when the water is added and agitated, causing a long time of stirring, which is inconvenient for the patient to suspend immediately before taking. However, at low viscosity, polystyrenesulfonic acid metal salt, which is a main component, easily settles, making it difficult to take the dose completely easily, and has a disadvantage in that the dose is inferior.

According to the present invention, when xanthan gum, which is a gelling agent, is used as a suspending agent in polystyrene sulfonate metal salts, even when a small amount is used, it is easy to take all the doses because it does not settle, and the taking feeling is excellent, and water is used before taking It is based on the surprising finding that the suspension can be easily prepared in seconds. The use of xanthan gum improves the feeling of taking the polystyrenesulfonic acid metal salts because they do not settle, but it is thought that it is not simply caused by sedimentation.

The content of such xanthan gum is 0.2 to 20% by weight relative to the total weight of the composition, 0.5 to 10% by weight is preferable in terms of the suspension, taking feeling, resuspension, etc., more preferably 0.5 to 5% by weight. desirable.

In the above-mentioned aspect, the polystyrene sulfonate metal salt-containing composition preferably has a viscosity of 50 to 250 cP (25 ° C.), more preferably 50 to 150 cP (25 ° C.) when suspended in 10 times of water.

In the present invention, the polystyrene sulfonate metal salt means polystyrene sulfonate, sodium polystyrene sulfonate, and the like, but is not limited thereto.

The pharmaceutical composition of the present invention is preferably prepared as a powder, granules or dry syrup, the powder, granules or dry syrup according to the present invention may be taken as it is, but is suspended in water before taking as a suspension It is more preferable from the viewpoint of ease of taking, feeling of taking, and the like. Suspensions and jelly-type preparations containing a large amount of water are prepared in advance so that they can be taken immediately without being suspended in water. However, they are bulky and very inconvenient to carry. The relatively high disadvantage is that the use of a preservative is required.

The present invention is also based on the surprising finding that when the pharmaceutical composition further comprises a suspending agent that does not gel in water, not only can the suspension and resuspension be improved before use, but also the feeling of taking can be improved in particular. As the suspending agent that does not gel in water, magnesium aluminum silicate, microcrystalline cellulose, bentonite, magnesium aluminate silicate, aluminum silicate, magnesium silicate, silicon dioxide, kaolin, starch, and the like may be used. The dose was improved even more when (non-gum) was used. Such suspending agent is preferably used 0.1 to 30% by weight, more preferably 1 to 15% by weight relative to the total weight of the composition.

Accordingly, the present invention provides a powder mixed with polystyrene sulfonic acid metal salts and xanthan gum or polystyrene sulfonic acid metal salts, xanthan gum and suspending agent which does not gel in water, and powders, granules or dry syrups obtained by combining and drying these components.

Powders, granules or dry syrups according to the present invention may further include preservatives, sweeteners, pH adjusting agents, flavoring agents, coloring agents, wetting agents, binders, disintegrating agents and the like within the scope of not impairing the object of the present invention. For example, sweeteners include fructose, xylitol, purified white sugar, white sugar, glucose, maltose, D-mannitol, stevioside, glycyrrhetinic acid, glycyrrhetinate, thaumatin, aspartame , Sucralose, saccharin, sodium saccharin, etc. may be used, and the flavoring agent is vanilla, mixed fruit, pineapple, banana, grape, strawberry, orange, raspberry, apricot, lemon, lime fruit, cherry, licorice, spearmint Flavors such as, peppermint, chocolate and coffee can be used.

The polystyrene sulfonate metal salt-containing pharmaceutical composition according to the present invention may be used as a powder by simply mixing the added ingredients. In addition, when used as a powder, granules or dry syrup, the polystyrene sulfonate metal salt-containing composition according to the present invention can be prepared by extrusion granulation, kneading granulation, fluidized bed granulation, rotary stirring fluidized bed granulation.

The present invention also comprises the steps of mixing (S1) polystyrene sulfonate metal salt and xanthan gum; (S2) preparing granules of the mixture of step (S1) with ethanol or an ethanol aqueous solution; And (S3) provides a method for producing a polystyrene sulfonate metal salt-containing powder, granules or dry syrup comprising the step of drying the granules.

Considering the filling process of the composition of the present invention, it is preferable that the product before packaging has some degree of fluidity. Therefore, powders, granules, etc., to which granules are formed to some extent, are more preferable than a powdery powder without granulation process. In general, the solvent used when preparing granules is water, and when a sufficient amount of water is used to prepare granules having sufficient fluidity, polystyrene sulfonate metal salts and xanthan gum are combined to form a strong bond. Suspension may take a relatively long time to loosen the granules, xanthan gum may not be released quickly, may not give the desired viscosity, there is a fear that it is difficult to improve the grip in the mouth due to the presence of particles have. Therefore, when preparing a polystyrene sulfonate metal salt and xanthan gum powder, granules or dry syrup, pure water may be used as a solvent for the association, but ethanol or an aqueous ethanol solution is relatively preferable. In addition, when xanthan gum is added after granulation, the xanthan gum may not be uniformly mixed when suspended in water. However, this reference should not be construed to exclude polystyrene sulfonate metal salts and xanthan gum granules prepared using water in the scope of the present invention.

Preferably in terms of resuspension and taking feeling, more preferably in terms of taking feeling, the present invention further comprises mixing magnesium aluminum silicate in the step (S1), or ethanol of the step (S2) used for coalescing or Provided is a method for producing a powder, granules or dry syrup, characterized in that magnesium aluminum silicate is mixed with an aqueous ethanol solution.

In the production method of the present invention, the ethanol or the ethanol aqueous solution of the step (S2) may contain a binder to facilitate the formation of granules, such a binder is hydroxypropyl cellulose, povidone, hypromellose, polymetha Acrylates and the like can be used. Hydroxypropyl cellulose is more preferable in view of the ease of granule formation, the amount of use, the solvent solubility used and the like.

The polystyrene sulfonate metal salt preparation of the present invention is not only easily suspended in water when taken in suspension, but also has a low viscosity, so that the sedimentation rate can be significantly lowered and maintained in a suspended state for several hours, and is easily resuspended. In addition, the polystyrene sulfonate metal salt preparation of the present invention reduces the rough feeling in the oral cavity which is a problem when taken or taken as it is suspended in water and improves taste and ease of drinking at the same time.

Hereinafter, examples and the like will be described in detail to help understand the present invention. However, embodiments according to the present invention can be modified in many different forms, the scope of the invention should not be construed as limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

<Production of Example 1 and Reference Examples 1 to 5>

As shown in Table 1 below, parts by weight of Examples and Reference Examples were placed in a double cone mixer to prepare a powder by stirring for 10 minutes. The content of Table 1 was an amount manipulated so that the viscosity when the powder prepared in the content for excluding the influence by viscosity was suspended in 10 times of water was about 100cp.

(Unit g) Example 1 Reference Example 1 Reference Example 2 Reference Example 3 Reference Example 4 Reference Example 5 Polystyrene Sulfonate Calcium 300 300 300 300 300 300 Xanthan gum 5.6 - - - - - CMC-Na - 30 - - - - Hydroxymethyl Cellulose - - 18 - - - Hypromellose - - - 12.8 - - Povidone - - - - 51.4 - Gum arabic - - - - - 90

<Evaluation of Example 1 and Reference Examples 1 to 5>

The powder of Example 1 prepared and the powders of Reference Examples 1 to 5 were suspended directly or in 10 times of water, and the sedimentation rate was measured for 24 hours, and the feeling of taking was evaluated. And after leaving for 72 hours, the time required to resuspend was measured. As a control, polystyrenesulfonic acid calcium was evaluated in the same manner by suspending in 10 times the amount of water without additives.

On the other hand, the feeling of taking was better by 10 subjects, compared with the preparation made of calcium polystyrenesulfonate itself (control), that there was no improvement in the feeling of taking, that the slight ease of taking was slightly improved, and that the taking was easy. The ease of evaluation was evaluated in four steps of very good, and the most evaluation result was used for the judgment. The results are shown in Table 2 below.

Sedimentation Speed (mm / hr) Time required for resuspension Taking Control Example 80.96 mm / hr 10 minutes Bad Example 1 No sedimentation No sedimentation good Reference Example 1 4.542 mm / hr 8 minutes Slightly improved Reference Example 2 4.521 mm / hr 8 minutes Slightly improved Reference Example 3 4.583 mm / hr 8 minutes Slightly improved Reference Example 4 4.500 mm / hr 8 minutes Slightly improved Reference Example 5 4.583 mm / hr 8 minutes Slightly improved

As shown in the results of Table 2, although the smallest amount was used, the precipitation rate of the powder obtained in Example 1 using xanthan gum was significantly reduced compared to the powder prepared with the control agent and other gelling agents such as CMC-Na. This means that the use of xanthan gum as a suspending agent in polystyrene sulfonic acid metal salt dry syrup, etc. can significantly improve dispersibility and resuspension. In addition, Example 1 using xanthan gum also improved the feeling of taking compared to the formulation using other gelling agents.

<Manufacture of Examples 2-4 and Reference Examples 6-8>

According to Table 3, a polystyrene sulfonate metal salt-containing powder or granule was prepared. The polystyrene sulfonate calcium and gelling agent xanthan gum, CMC-Na or HPC-H are mixed with a speed mixer with respect to parts by weight of Examples 2 to 4 and Reference Examples 6 to 8, and microcrystalline cellulose or magnesium aluminum silicate is used as a suspending agent. If used, suspending agents were also mixed together. The association was prepared by adding the solution in which the binder HPC-L was dissolved in ethanol while adding it to a speed mixer. The combined product was dried at 60 ° C. for 15 hours, and granulated with an oscillating type granulator to prepare a powder (granule). Reference Example 6 was prepared according to the manufacturing method of Dry Syrup 2 of Korean Patent No. 440544. That is, in Reference Example 6, aspartame and Metros SM-100 were dissolved in 200 g of water / methanol mixed solution (1: 1, w / w) to prepare a coating solution, and the coating solution was prepared using calcium polystyrene sulfonate and CMC-Na. And it was prepared by applying a fluid bed assembly device to the nucleus granules prepared using HPC-M and water. The composition of Table 3 was an amount manipulated so that the viscosity of the powder (granule) prepared in an amount for excluding the influence of the viscosity when suspended in 10 times the amount of water was about 100 cps.

(Unit g) Example 2 Example 3 Example 4 Reference Example 6 Reference Example 7 Reference Example 8 Polystyrene Sulfonate Calcium 300 300 300 300 300 300 Xanthan gum (gelling agent) 5.4 5.4 5.4 - - - Microcrystalline cellulose (suspensioning agent) - 18 - - - - Magnesium aluminum silicate (suspending agent) - - 18 - - 18 HPC-L (Binder) 9 9 9 - 9 9 CMC-Na (gelling agent) - - - 5 - - HPC-M (Binder) - - - 20 - - Aspartame (Sweet) - - - One - - Metros SM-100 (gelling agent) - - - 4.45 - - HPC-H (Gelating Agent) - - - - 18 18

In Table 3, HPC-L is a low viscosity hydroxypropyl cellulose, HPC-M is a medium viscosity hydroxypropyl cellulose, HPC-H means a high viscosity hydroxypropyl cellulose.

<Evaluation of Examples 2-4 and Reference Examples 6-8>

Sedimentation rates of the formulations obtained in Examples 2 to 4 and Reference Examples 6 to 8 were measured for 24 hours on calcium polystyrene sulfonate alone as a control, and the time required for redispersion after standing for 72 hours was also measured. . In addition, the feeling of dose was evaluated using the formulations of Examples 2 to 4 and Reference Examples 6 to 8, and the results are shown in Table 4 below.

Example Sedimentation Speed (mm / hr) Time required for resuspension Taking Control Example 80.96 mm / hr 10 minutes Bad Example 2 No sedimentation No sedimentation good Example 3 No sedimentation No sedimentation good Example 4 No sedimentation No sedimentation Very good Reference Example 6 4.521 mm / hr 8 minutes Slightly improved Reference Example 7 4.583 mm / hr 8 minutes Slightly improved Reference Example 8 4.500 mm / hr 1 minute good

As shown in Table 4, Examples 2 to 4 according to the present invention can be seen that since the sedimentation rate is significantly reduced compared to the Reference Examples 6 to 8 formulations, dispersibility and resuspension are improved. In addition, the preparation of Examples 2 to 4 was improved compared to the preparations of Reference Examples 6 to 7, in particular, a dry syrup prepared by adding xanthan gum, a gelling agent, and magnesium aluminum silicate, a suspending agent, to a polystyrene sulfonate metal salt. In the case of using the xanthan gum only Example 2 was significantly improved feeling.

Example 8 Preparation of Dry Syrup Powder

To prepare a powder for dry syrup as shown in Table 5. 300 g of polystyrene sulfonate, 5.4 g of xanthan gum and 18 g of magnesium aluminum silicate were mixed with a speed mixer, and a mixture prepared by adding 9% HPC-L and 0.24 g of sucralose to 100 g of ethanol was added to the speed mixer. did. The combined product was dried at 60 ° C. for 15 hours, and granulated with an oscillate type granulator, and the powder and the flavoring agent were mixed for 10 minutes using a double cone mixer to prepare a powder for dry syrup.

role Ingredients content chief ingredient Polystyrene Sulfonate Calcium 300 g Gelling agent Xanthan gum 5.4 g Suspending agent Magnesium Silicate 18g Binder HPC-L 9g Flavoring agent Banana flavor 3g Sweetener Sucralose 0.24 g

<Evaluation of Example 8>

Example 8, the sensory test was carried out on 30 subjects using two different dosage methods, in which the polystyrene sulfonate calcium was used as a reference or the reference example 6 using CMC-Na as a gelling agent or suspended in water. Carried out. Each subject took an amount corresponding to 3.3 g of calcium polystyrene sulfonate, and when suspended in water, was suspended in 33 mL of water. The taste and ease of drinking at the time of taking were evaluated in nine stages from -4 to +4 with bad feeling as -4 and good feeling as +4. The results of scoring distribution (number of people) are shown in Table 6 below, and the sensory test results (sum of scoring distributions) are shown in Table 7.

division How to take Evaluation item +4 +3 +2 +1 0 -One -2 -3 -4 Sum Polystyrene Sulfonate Calcium suspension flavor 0 0 One One 7 6 10 2 3 30 Easy to drink 0 One 2 One 8 6 7 4 One 30 as it is flavor 0 0 0 2 10 7 0 9 2 30 Easy to drink 0 One 0 2 5 4 5 6 7 30 Reference Example 6 suspension flavor 0 2 One 15 10 2 0 0 0 30 Easy to drink 0 3 One 5 11 8 One One 0 30 as it is flavor 2 3 13 2 7 2 One 0 0 30 Easy to drink One 2 2 6 6 7 4 3 0 30 Example 8 suspension flavor 9 13 5 2 One 0 0 0 0 30 Easy to drink 7 6 12 3 0 2 0 0 0 30 as it is flavor 14 12 One 2 One 0 0 0 0 30 Easy to drink 5 3 15 3 One 2 0 0 0 30

division How to take flavor Easy to drink Polystyrene Sulfonate Calcium suspension -41 -28 as it is -40 -55 Reference Example 6 suspension 21 3 as it is 41 29 Example 8 suspension 87 71 as it is 104 60

As shown in Table 6 and 7, according to the polystyrene sulfonic acid metal salt-containing dry syrup powder (granule) according to the present invention, both polystyrene sulfonic acid metal salt alone and prior literature in the case of taking as it is or suspended in water Both the taste and the ease of drinking were improved compared to the prepared formulation (Reference Example 6).

Claims (7)

Polystyrene sulfonic acid metal salts; Xanthan gum which is a gelling agent; And a suspending agent that does not gel in water selected from magnesium aluminum silicate or microcrystalline cellulose, Xanthan gum in an amount of 0.2-20% by weight relative to the total weight of the formulation; Suspending agents which do not gel in 1-15% by weight of water relative to the total weight of the formulation; And a residual amount of polystyrene sulfonate metal salt, A pharmaceutical preparation which is suspended and used as a powder, granule or dry syrup containing polystyrenesulfonic acid metal salt. delete delete The pharmaceutical formulation of claim 1 wherein the suspending agent that does not gel in water is magnesium aluminum silicate. (S1) mixing the polystyrene sulfonate metal salt and xanthan gum, (S2) combining the mixture of step (S1) with ethanol or an ethanol aqueous solution to prepare granules, and (S3) comprising the step of drying the granules, In the step (S1) further mixed magnesium aluminum silicate, or (A2) in the ethanol or an aqueous solution of ethanol aluminum magnesium silicate, a binder or a mixture thereof is contained, Xanthan gum in an amount of 0.2-20% by weight relative to the total weight of the formulation; Suspending agents which do not gel in 1-15% by weight of water relative to the total weight of the formulation; And a residual amount of polystyrene sulfonate metal salt, A method for producing a pharmaceutical preparation, which is suspended and used as a polystyrene sulfonate metal salt-containing powder, granule or dry syrup. delete delete