KR101924201B1 - Medicinal adsorbent for oral administration with increased strength - Google Patents

Abstract

TECHNICAL FIELD The present invention relates to an adsorbent for oral administration type medicines, and more particularly to an adsorbent for oral medicines comprising a porous activated carbon having an increased strength. The adsorbent of oral administration type comprising a porous activated carbon having a spherical furan resin as a carbon source according to the present invention can maximize the adsorption ability of indole, which is one of the uremic substances existing in the living body of a patient, And can maximize the selective adsorption rate to the uremic material.

Description

TECHNICAL FIELD [0001] The present invention relates to an adsorbent for oral administration,

TECHNICAL FIELD The present invention relates to an adsorbent for oral administration type medicines, and more particularly to an adsorbent for oral medicines comprising a porous activated carbon having an increased strength.

Patients with defects in renal function or liver function accumulate or produce toxic substances harmful to the body, such as blood, accompanying their organ dysfunction, thus causing encephalopathy such as uremia or consciousness disorder. Since the number of these patients tends to increase year by year, it is an important task to develop a long-term substitute device or therapeutic drug that has the function of removing toxic substances from the body in place of these defective organs. Currently, the artificial kidney is the most popular way to remove toxic substances by hemodialysis. However, such a hemodialysis type artificial kidney requires a specialist in safety management because it uses a special device, and it has drawbacks such as high physical, mental and economic burden of the patient due to extracorporeal blood extraction, no.

As means for solving these drawbacks, an oral adsorbent capable of oral administration and capable of treating dysfunction of the kidney or liver has been developed and used. Surface modified spherical activated carbons generally have a residence time in the upper small intestine of about 3 to 5 hours. Therefore, surface modified spherical activated carbon having a high adsorption ability within about 3 hours after contact with harmful substances and having an excellent initial adsorption performance is preferable.

In addition, it is important to quickly adsorb and remove toxic substances in vivo in a large amount, but it is also important to select adsorption rates that exhibit excellent adsorptivity for toxic substances and adsorption of beneficial ingredients in intestines. Gastrointestinal tract such as stomach and small intestine is an environment in which various substances such as enzymes secreted from the barrier and compounds indispensable for physiological functions such as sugar and protein are mixed. Therefore, there is a need for a medicinally active carbon having a selective adsorption rate which adsorbs a substance causing uremia while inhibiting adsorption of a compound indispensable to physiological function.

Korean Patent Laid-Open No. 10-2004-0032320 discloses an adsorbent for oral administration which has a pore volume of 20 to 15,000 nm in a specific range of 0.04 mL / g or more and less than 0.10 mL / g as an adsorbent for oral administration .

Korean Patent Laid-Open No. 10-2005-0039592 also discloses that the amount of harmful substances adsorbed by the oral adsorbent increases in the range of pore volume of 7.5 to 15000 nm of not less than 0.25 mL / g and does not show a correlation with the increase of the specific surface area .

This is because the adsorbent for oral administration has mainly a petroleum pitch as a carbon source, and according to the invention described in the above literature, it becomes difficult to develop an adsorbent for oral dosage form having a more selective and effective selective adsorption rate.

Particularly, a product conventionally known as an adsorbent for oral administration type medicines is intended to be taken in powder form. In the case of conventional porous activated carbon, since the compressive strength is remarkably low, when it is desired to formulate into a solid unit dosage form, There is a problem that activated carbon is broken in the charging process. That is, as described above, the technology has been developed so far focusing only on the selective adsorption rate and the increase in the adsorption force for a specific uremic material (for example, an indole compound), so that the diameter and the volume , Specific surface area, or refractive index of the spherical activated carbon itself has been studied. Therefore, there has been no attempt to improve the compression strength of the spherical activated carbon itself.

However, when the oral adsorbent is dosed in a dose of about several grams per dose, it often causes discomfort such as vomiting. For this reason, in an actual dosing site, And the like.

Accordingly, there is a great need for a unit solid preparation capable of greatly improving dosage convenience, but as described above, the compressive strength of the activated carbon itself is low, and thus it is considered that nothing has been realized so far.

Accordingly, the inventors of the present invention have found that an adsorbent for oral administration type medicines can be newly developed beyond the conventional limitations and limitations of the prior arts while studying an adsorbent for oral administration type medicines, thereby accomplishing the present invention. Particularly, in the present invention, there is no report on the means that can increase the selective adsorption rate and increase the indole adsorption power, while the prior art focuses only on the increase of the selective adsorption rate or the increase of the indole adsorption power The present invention provides a novel adsorbent for oral administration which can satisfy both of the selective adsorption rate and the indole adsorption power. In addition to the increase of the selective adsorption rate and the increase of the indole adsorption power, the porous activated carbon according to the present invention has a very high strength as compared with conventionally known spherical activated carbon, and thus can be administered as a powder , And can be administered orally by being filled into capsules.

Korean Patent Publication No. 10-2004-0032320 Korean Patent Publication No. 10-2005-0039592

SUMMARY OF THE INVENTION An object of the present invention is to provide an adsorbent for oral administration which comprises a porous activated carbon having an increased strength.

In order to achieve the above object, the present invention provides an adsorbent for oral administration type medical use comprising a porous activated carbon having an increased strength.

According to the present invention, an adsorbent for oral administration type medical use comprising a porous activated carbon having an increased strength can maximize the indole adsorption power and the indole adsorption rate based on a new fact unknown in the prior art, Rate can be maximized. In addition, since it has a strength of 10 N / sphere or more, not only the yield of production is increased but also the shape of the activated carbon is broken during manufacturing and distribution. In addition, by increasing the strength, the prevention of static electricity can be suppressed, and the contamination of the spherical activated carbon due to the foreign matter generated during the manufacturing process can be prevented. In the case of a commercial formulation, the spherical activated carbon sticks due to the generation of static electricity while taking it, which causes inconvenience when taken. On the other hand, the spherical activated carbon of the present invention has the effect of suppressing the generation of static electricity and improving convenience of taking.

Hereinafter, the present invention will be described in detail.

The present invention provides an oral adsorbent for medical use comprising a porous activated carbon having increased strength.

The porous activated carbon having an increased strength according to the present invention preferably has an average particle diameter of 0.1 to 0.5 mm, preferably 0.3 to 0.4 mm.

The porous activated carbon according to the present invention preferably has a pore volume of pore diameter of 7.5 to 15,000 nm of not less than 0.01 mL / g and less than 0.10 mL / g, more preferably not less than 0.03 mL / g and not more than 0.08 mL / g.

On the other hand, the Korean Patent Publication No. 10-2005-0039592 discloses a surface-modified spherical activated carbon having an average particle size of 0.01 to 1 mm and a pore volume of 7.5 to 15,000 nm and a pore volume of 0.25 to 1.0 mL / g. Adsorbent. In this document, it is described that the adsorbing ability of an oral adsorbent, that is, the amount of harmful substances adsorbed by the oral adsorbent increases in the above-mentioned pore volume of 0.25 mL / g or more and does not show a correlation with an increase in specific surface area, It is noted that the adsorption amount of harmful substances is increased rather than the selective adsorption rate.

However, according to the study of the present inventors, unlike the case of the above document, in the case of the adsorbent for oral dosage form comprising the activated carbon having increased strength according to the present invention, the pore volume of pores having a pore diameter of 7.5 to 15,000 nm is 0.01 mL / g or more and less than 0.10 mL / g, and more preferably 0.03 mL / g or more and less than 0.08 mL / g, the indole adsorption power and the indole adsorption rate are increased.

Accordingly, the adsorbent for oral administration of the present invention comprising a porous activated carbon having a spherical furan resin as a carbon source according to the present invention has a pore volume of 7.5 to 15,000 nm in the range of 0.01 mL / g to 0.10 mL / g, The adsorption can be maximized.

The porous activated carbon according to the present invention may have a pore volume of from about 0.005 mL / g to less than 0.04 mL / g, more preferably from 0.01 mL / g to less than 0.03 mL / g, of pore diameter of 20 to 15,000 nm.

On the other hand, Korean Patent Publication No. 10-2004-0032320 discloses a porous spherical carbonaceous material having a pore diameter of 0.01 to 1 mm and a pore diameter of 20 to 15,000 nm of 0.04 mL / g or more and less than 0.10 mL / g An adsorbent for oral administration is disclosed. In this document, the pore volume of the pore diameter of 20 to 15,000 nm is in the range of 0.04 mL / g or more and less than 0.10 mL / g, and the pore volume is within the range of 0.05 mL / g or more and less than 0.10 mL / g And exhibits a more excellent selective adsorption rate.

However, according to an embodiment of the present invention, in the case of an oral adsorbent for oral administration comprising a porous activated carbon having an increased strength according to the present invention, the pore volume of pores having a pore diameter of 20 to 15,000 nm is 0.005 mL / g or more and less than 0.04 mL / g, More preferably 0.01 mL / g or more and less than 0.03 mL / g, and the selective adsorption rate is increased.

That is, unlike the conventional art, the adsorbent for oral administration type medicine comprising the activated carbon of increased strength according to the present invention has a pore volume of not less than 0.01 mL / g and not more than 0.10 mL / g with a pore diameter of 7.5 to 15,000 nm, When the pore volume of 20 to 15,000 nm in diameter satisfies 0.005 mL / g or more and less than 0.04 mL / g, the selective adsorption rate is increased and the indole adsorption power and the adsorption rate are increased at the same time.

In the present invention, a porous activated carbon having an increased strength means a porous activated carbon having a compressive strength of at least 10 N / sphere or more. The strength of the porous activated carbon of the present invention is at least 2 times to 10 times higher than that of the conventional activated carbon. The porous activated carbon of the present invention having increased strength can be produced by using a furan resin as a carbon source.

The activated carbon having increased strength according to the present invention may have a base consumption of 0.1 to 1.0 mmol / g and an acid consumption of 0.3 to 1.0 mmol / g.

In summary, the adsorbent for oral administration type medicament of the present invention has a pore volume of pore diameter of 7.5 to 15,000 nm of not less than 0.01 mL / g and less than 0.10 mL / g, more preferably not less than 0.03 mL / g and not more than 0.08 mL / g, The pore volume of 20 to 15,000 nm in diameter is 0.005 mL / g or more and less than 0.04 mL / g, more preferably 0.01 mL / g or more and less than 0.03 mL / g, and the compression strength is 10 N / .

The adsorbent for oral administration type medicines according to the present invention has a selective adsorption rate of 3.0 or more.

The adsorbent for oral administration type medicines according to the present invention has an initial adsorption rate of indole of 80% or more.

The adsorbent for oral administration of the present invention can be used for the treatment of chronic renal failure, acute renal failure, chronic pyelonephritis, acute pyelonephritis, chronic nephritis, acute nephritic syndrome, acute onset nephritic syndrome, chronic nephritic syndrome, nephrotic syndrome, epileptic nephritis, For the prevention or treatment of one or more diseases selected from the group consisting of diabetic nephropathy, renovascular hypertension, or chronic renal failure before dialysis, chronic hepatitis, alcoholic hepatitis, hepatic encephalopathy, liver cirrhosis, drug allergic liver disorder or primary biliary cirrhosis But it is not limited to the above diseases as long as the disease can be improved or treated due to the adsorption of the uremic substance of the adsorbent for oral administration type medical use.

The respective physical properties, that is, the average particle diameter, specific surface area, pore volume, acid consumption, base consumption, selective adsorption rate and strength, of the surface-modified spherical activated carbon used as the oral administration type adsorbent according to the present invention are measured by the following method .

(1) Average particle size

A particle size based cumulative diagram was created using a laser diffraction particle size distribution analyzer (HELOS Particle Size Analysis, manufactured by Sympatec), and the particle size corresponding to the volume mean diameter (VMD) was taken as the average particle size.

(2) Specific surface area (calculation by BET method)

The gas adsorption amount of spherical activated carbon was measured using a specific surface area meter (ASAP 2420, manufactured by MICROMERITICS CO., LTD.) By gas absorption method, and the specific surface area was calculated by BET equation.

Specifically, spherical activated carbon was filled in a sample tube, dried under reduced pressure at 300 ° C, and then weighed. The sample tube was cooled to -196 캜, nitrogen was introduced, nitrogen was adsorbed on the spherical activated carbon, and the relationship between the nitrogen partial pressure and the adsorption amount (adsorption isotherm) was measured. The sample tube was cooled to room temperature, and the amount of nitrogen released from the spherical activated carbon was measured with a thermal conductivity type detector to determine the gas adsorption amount (v).

The approximate formula derived from the BET equation

Using the obtained v _{m (m} ² / g) by the one-point method (relative pressure x = 0.3) by a nitrogen adsorption at the liquid nitrogen temperature,

Da food

To calculate the specific surface area of the spherical activated carbon. In the above equations, v is a measured gas adsorption amount (m ² / g), and x is a relative pressure.

 (3) Pore volume by mercury porosimetry

The pore volume was measured using a mercury porosimeter (AUTOPORE IV 9500, manufactured by MICROMERITICS). The spherical activated carbon was placed in a sample vessel and degassed for 30 minutes. Mercury was introduced into the sample container and gradually pressurized to press the mercury into the pores of the spherical activated carbon. The pore volume distribution of the spherical activated carbon sample was measured from the relationship between the pressure at this time and the amount of mercury penetration.

Specifically, the volume of mercury injected into spherical activated carbon was measured within a range from a minimum pressure of 0.5 psia to a maximum pressure of 61,000 psia. The calculation of the pore diameter is performed such that, when the mercury is pushed into the cylindrical pores of the diameter (D) by the pressure (P), when the surface tension of the mercury is set to "γ" and the contact angle between the mercury and the pore walls is set to " (D / 2) < ² > P from the balance of the pressure acting on the pore cross section and the pressure acting on the pore cross section. Therefore, D = (-4? Cos?) / P.

The surface tension of mercury was set to 485 dynes / cm, the contact angle of mercury to carbon was set to 130, the pressure P was set to psia, the pore diameter D was set to m, and the pressure P was set to 180.8 / Pore diameter D was obtained.

For example, in the present invention, the pore volume in the pore diameter range of 7.5 to 15000 nm corresponds to the volume of mercury injected from the mercury indentation pressure of 12.05 psia to 24106.6 psia.

(4) Acid consumption

1.0 g of spherical activated carbon was placed in a 100 mL flask, and 50 mL of hydrochloric acid TS for acid consumption was added and the mixture was shaken at 37 占 1 占 폚 for 24 hours with a shaker. After filtering the contents of the flask at room temperature, 20 mL of the solution was taken and used as the sample solution and titrated with 0.1 mol / L potassium hydroxide solution. (Indicator: 2 drops of bromophenol blue TS). The acid consumption was calculated by the following equation.

A: 0.1 mol / L potassium hydroxide consumption of the test solution (mL)

B: 0.1 mol / L potassium hydroxide consumption (mL) of the blank test solution

C: Amount of specimen (g)

f: Factor of 0.1 mol / L potassium hydroxide

(5) Base consumption

1.0 g of spherical activated carbon was placed in a 100 mL flask, and 50 mL of a hydrochloric acid TS for base consumption was added and the mixture was shaken at 37 짹 1 째 C for 24 hours with a shaker. After filtering the contents of the flask at room temperature, 20 mL of the solution was taken and used as the sample solution and titrated with 0.1 mol / L hydrochloric acid. (Indicator: 2 drops of phenolphthalein solution). The base consumption was calculated by the following equation.

A: 0.1 mol / L hydrochloric acid consumption of the test solution (mL)

B: 0.1 mol / L hydrochloric acid consumption (mL) of the blank test solution

C: Amount of specimen (g)

f: Factor of 0.1 mol / L hydrochloric acid

(6) Selective adsorption rate

The selective adsorption rate is calculated as follows.

2.5 g of the porous spherical activated carbon according to the present invention was placed in a 100 mL flask, and 50 mL (stock solution) of pH 7.4 phosphate buffer solution having a concentration of 100 mg / L of DL-? -Aminoisobutyric acid was added thereto. And shaken for 3 hours. The contents of the flask were filtered to prepare a sample solution. Organic carbon was measured according to the Japanese Pharmacopoeia General Test Method Organic Carbon Test, and the residual concentration of DL-? -Aminoisobutyric acid was calculated by the following equation.

T _t : Organic carbon content of the test solution

T _s : Organic carbon amount of standard solution (undiluted solution)

2.5 g of the dried spherical activated carbon was taken in a 100 mL flask, and 50 mL (stock solution) of pH 7.4 phosphate buffer having a concentration of 100 mg / L of α-amylase was added thereto and the mixture was shaken at 37 ± 1 ° C. for 3 hours at 200 rpm. The content of the flask was filtered with a 0.65 탆 membrane filter to prepare a sample solution, and the absorbance at 282 nm was measured according to the extracellular supernatant absorbance measurement method using a pH 7.4 phosphate buffer as a control, and the residual concentration of the? -Amylase was measured Respectively.

A _t : Absorbance of the test solution

A _s : absorbance of the standard solution (stock solution)

(7) Strength measurement

The strength of the porous activated carbon was measured as follows using a compressive strength machine (AFK-500TE manufactured by Digitech).

After placing one sample of the spherical activated carbon to be measured in the middle of the compressive strength type tip, the strength at which the original spherical activated carbon was broken by setting the compressive strength at a rate of 20 mm / min was regarded as the compressive strength value. 22 aliquots of the spherical activated carbon samples were measured in the same manner as above, and the compressive strength values were obtained by taking the values of 20 eggs excluding the maximum value and the minimum value as an average.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1.

100 g of spherical furan resin (manufactured by PURE SPARE CO., LTD.) Was accommodated in a metallic sample container (content 1.5 L) and then carbonized by heating in an electric furnace at a temperature of 500 DEG C under nitrogen gas for 1 hour. Spherical activated carbon was prepared by heating the spherical furan resin carbide using a rotary external heating furnace at a temperature of 900 캜 for 140 minutes under water vapor. The spherical activated carbon was subjected to oxidation treatment at a temperature of 470 ° C for 5 hours under an oxygen-nitrogen mixed gas in which the oxygen concentration was adjusted to 3 vol% using a rotary external heat furnace, and then subjected to reduction treatment at a temperature of 900 ° C for 15 minutes under a nitrogen gas atmosphere To obtain porous spherical activated carbon.

Example 2

The steam activation time in Example 1 was set at 160 minutes, and the other operations were carried out in the same manner as in Example 1.

Example 3

In the same manner as in Example 1 except that the steam activation time was changed to 180 minutes in Example 1.

Example 4

The procedure of Example 1 was repeated except that the steam activation time was 180 minutes and the carbonization temperature was 450 ° C for 1 hour.

Comparative Example 1

100 g of the spherical furan resin was accommodated in a metallic sample container (content 1.5 L) and then carbonized by heating it in an electric furnace at 400 DEG C for 1 hour under nitrogen gas. Spherical activated carbon was prepared by activating spherical furan resin carbide by heating in a rotary external heat furnace at a temperature of 900 캜 for 180 minutes under water vapor. The spherical activated carbon was subjected to oxidation treatment at a temperature of 470 ° C for 5 hours under an oxygen-nitrogen mixed gas in which the oxygen concentration was adjusted to 3 vol% using a rotary external heat furnace, and then subjected to reduction treatment at a temperature of 900 ° C for 15 minutes under a nitrogen gas atmosphere To obtain porous spherical activated carbon.

Comparative Example 2

100 g of the spherical phenol resin was accommodated in a metal sample container (content: 1.5 L), and then carbonized by heating at 450 DEG C for 1 hour under nitrogen gas using an electric furnace. Spherical activated carbon was prepared by heating a spherical phenolic resin carbide using a rotary external heating furnace at a temperature of 900 캜 for 180 minutes under water vapor. The spherical activated carbon was subjected to oxidation treatment at a temperature of 470 ° C for 5 hours under an oxygen-nitrogen mixed gas in which the oxygen concentration was adjusted to 3 vol% using a rotary external heat furnace, and then subjected to reduction treatment at a temperature of 900 ° C for 15 minutes under a nitrogen gas atmosphere To obtain porous spherical activated carbon.

Experimental Example: Selective Adsorption Rate, Indole Adsorption Rate and Indole Adsorption Rate

To evaluate the indole adsorption power of Examples and Comparative Examples, 300 mg of porous spherical activated carbon was added to 900 mL of pH 7.4 phosphate buffer containing indole at a concentration of 1.0 mg / mL, and elution test was performed for 3 hours at a rotation speed of 100 rpm 708-DS). In addition, the selective adsorption rate was calculated by comparing DL-beta-amino isobutyric acid removal and alpha -amylase removal performance. The indole adsorption rate was expressed by the initial adsorption rate (%) of indole determined as follows.

The results of the experiments of the present invention, comparative examples and conventional commercial crmethazine are shown in Table 1 below.

Item Creme Comparative Example
One Comparative Example 2 Example 1 Example 2 Example 3 Example 4 Specific surface area (m ² / g) 1673 1670 1652 1650 1671 1710 1760 Pore volume (mL / g) 20 to 15000 nm 0.063 0.042 0.081 0.007 0.018 0.025 0.033 7.5-15000 nm 0.125 0.104 0.112 0.026 0.047 0.064 0.078 Average particle diameter (mm) 0.349 0.353 0.331 0.355 0.363 0.356 0.361 Base consumption (mmol / g) 0.48 0.11 0.42 0.44 0.41 0.40 0.43 Acid consumption (mmol / g) 0.56 0.66 0.6 0.71 0.62 0.53 0.61 Remaining concentration of? -amylase (mg / L) 88.2 88.3 90 95.4 93.2 96.7 93.5 Residual concentration of DL- [beta] -aminoisobutyric acid (mg / L) 69.8 73.2 87.5 69.3 70.7 70.8 71.1 Select adsorption rate 2.56 2.29 1.25 6.67 4.31 8.84 4.45 Indole adsorption (mg / g) 720 717 705 725 730 755 760 Initial adsorption rate (%) of indole 75.28 75.07 76.31 82.15 82.74 83.84 85.70 Compressive strength (N / sphere) 2.7 8.7 1.5 15.2 14.1 12.3 11.6

As can be seen from the above table, it can be seen that the crèmezine and the comparative examples 1 and 2 which do not satisfy the pore volume requirement of the present invention do not satisfy both the selective adsorption rate and the indole adsorption power at the same time. In addition, it was found that the compression strength of the porous activated carbon was significantly lowered in Comparative Example 2, in which the pitch was regarded as a carbon source and the carbon source was a carbon source, and thus it was difficult to fill the solid unit dosage form, for example, capsules.

Claims (6)

An adsorbent for oral administration comprising a porous activated carbon, wherein the porous activated carbon has a pore volume of pore diameter of 7.5 to 15,000 nm of not less than 0.01 mL / g and less than 0.10 mL / g, a pore volume of pore diameter of 20 to 15,000 nm of not less than 0.005 mL / 0.04 mL / g. ≪ / RTI > delete The porous activated carbon according to claim 1, wherein the pore volume of the porous activated carbon having a pore diameter of 7.5 to 15,000 nm is 0.03 mL / g or more and less than 0.08 mL / g, and the pore volume of the pore diameter is 20 to 15000 nm is less than 0.03 mL / g Or a pharmaceutically acceptable salt thereof. The adsorbent for oral administration type medicament according to any one of claims 1 to 3, wherein the selective adsorption ratio of the porous activated carbon is 3.0 or more. The adsorbent for oral administration type medicament according to any one of claims 1 to 3, wherein the initial adsorption rate of indole in the porous activated carbon is 80% or more. The adsorbent for oral administration according to claim 1 or 3, wherein the porous activated carbon has a pore volume of 10 N / sphere or more.