WO2015119352A1

WO2015119352A1 - Orally administered medical adsorbent with increased strength

Info

Publication number: WO2015119352A1
Application number: PCT/KR2014/009103
Authority: WO
Inventors: 강세연; 성은진; 송세현; 손세일; 이홍우; 박찬수; 남우근; 이진구
Original assignee: 대원제약주식회사; 주식회사 퓨어스피어
Priority date: 2014-02-07
Filing date: 2014-09-29
Publication date: 2015-08-13
Also published as: CN106029218A; JP6386571B2; KR20150093907A; CN106029218B; JP2017507126A; KR101924201B1

Abstract

The present invention relates to an orally administered medical adsorbent, and more specifically, to an orally administered medical adsorbent with increased strength, comprising porous activated carbon. An orally administered medical adsorbent comprising porous activated carbon by using a spherical furan resin as a carbon source, according to the present invention, can maximize the adsorption of indole, which is one among uremic toxins present in the body of a patient, and can maximize the selective adsorption for uremic toxins, on the basis of a new fact which has not been hitherto known in the relevant art.

Description

Oral dosage medicinal adsorbents with increased strength

The present invention relates to an oral dosage form pharmaceutical adsorbent, and more particularly, to an oral dosage form pharmaceutical adsorbent composed of porous activated carbon with increased strength.

Patients with renal or hepatic impairment accumulate or produce harmful toxic substances in the blood, etc. in association with their organ dysfunction, causing encephalopathy such as uremia or consciousness disorder. Since the number of these patients tends to increase year by year, the development of long-term substitute devices or therapeutic drugs having the function of removing toxic substances in vitro in place of these defect organs has become an important task. Currently, the artificial kidney is the most popular method of removing toxic substances by hemodialysis. However, such hemodialysis artificial kidneys require specialized technicians for safety management because they use special devices, and they have drawbacks such as high physical, mental and economic burden of the patient by extracorporeal extraction of blood. no.

As a means of resolving these drawbacks, oral administration is possible, and oral adsorbents that can treat kidney or liver dysfunction have been developed and used. Oral adsorbents of surface-modified spherical activated carbon generally have a residence time in the upper small intestine of about 3 to 5 hours. Therefore, a surface modified spherical activated carbon having a high adsorption capacity and excellent initial adsorption performance within about 3 hours after contact with harmful substances is preferable.

In addition, it is also important to quickly adsorb and remove large quantities of toxic substances in living organisms, but it also shows excellent adsorption to toxic substances, and the selective adsorption rate of intestinal beneficial components is also important. The gastrointestinal tract such as the small intestine is an environment in which various substances such as sugars and proteins are essential for physiological functions and enzymes secreted from the barrier. Therefore, there has been a demand for a medicinal activated carbon having a selective adsorption rate for adsorbing the causative agent of uremia, while suppressing the adsorption of compounds essential for physiological function.

Korean Patent Laid-Open No. 10-2004-0032320 discloses an oral adsorbent for oral administration, wherein an oral adsorbent having a high selective adsorption rate in a specific range of from 0.04 mL / g or more and less than 0.10 mL / g has a pore volume of 20 to 15000 nm. It is described.

In addition, Korean Patent Publication No. 10-2005-0039592 discloses that the amount of harmful substances adsorbed by the oral adsorbent increases in the area of 0.25 mL / g or more in the volume of 7.5-15000 nm and does not correlate with the increase in the specific surface area. It is described.

This is because the adsorbent for oral administration mainly uses a petroleum pitch as a carbon source, and according to the invention described in the prior document, it is difficult to develop an oral dosage form pharmaceutical adsorbent having a more detailed and effective selective adsorption rate.

In particular, products known as oral dosage medicinal adsorbents are conventionally to be taken as a powder. In the case of conventional porous activated carbon, since the compressive strength is significantly low, when formulated into a solid unit dosage form, for example, a capsule In the case of charging to, there was a problem that the activated carbon is broken during the charging process. That is, until now, as described above, since the technology development has been focused only on the increase in the selective adsorption rate and the adsorption force for a specific toxic substance (for example, an indole compound), the diameter and volume of the activated carbon micropores are mainly used. However, only studies on the specific surface area, or the refractive index have been made, and there has been no attempt to improve the present invention due to the fact that the compressive strength of the spherical activated carbon itself is significantly lowered.

However, since the oral adsorbent is close to several g at a single dose, it is often caused by discomfort such as vomiting when taking it as a powder. Therefore, in practice, the oral adsorbent uses an auxiliary means such as Orlite. Administration is made.

Therefore, although there is a great need for a unit solid preparation that can greatly enhance the convenience of dosing, as described above, it is thought that nothing has been realized until now because the compressive strength of the activated carbon itself is low.

Accordingly, the inventors of the present invention, while studying the oral dosage form pharmaceutical adsorbent, have found that the oral dosage form pharmaceutical adsorbent can be newly developed beyond the common sense and limitations of the prior art, thereby achieving the present invention. In particular, the present invention focuses only on increasing the selective adsorption rate or increasing the indole adsorption force in the prior art, and there is no report on the means for increasing the indole adsorption force while increasing the selective adsorption rate. In view of the above, there is provided a novel oral dosage form pharmaceutical adsorbent that can satisfy both selective adsorption and indole adsorption. In addition, as well as the increase in selective adsorption rate and indole adsorption capacity, the porous activated carbon according to the present invention has a very high strength compared to the spherical activated carbon known in the art, and thus can be administered as a powder There is an advantage that can be administered orally by filling in a capsule.

It is an object of the present invention to provide an oral dosage form medicinal adsorbent composed of porous activated carbon having increased strength.

In order to achieve the above object, the present invention provides an oral dosage form pharmaceutical adsorbent composed of porous activated carbon with increased strength.

According to the present invention, the oral dosage form medicinal adsorbent composed of porous activated carbon with increased strength can maximize indole adsorption and indole adsorption rate on the basis of new facts that are not known in the art, and at the same time, selective adsorption for toxic substances. The rate can be maximized. In addition, since the strength of 10N / sphere or more, not only the production yield is increased, but also solves the problem that the shape of the activated carbon during the manufacturing and distribution process is broken. In addition, by increasing the strength, antistatic prevention can be suppressed, and contamination of spherical activated carbon due to foreign matters generated during the manufacturing process can be prevented. In the case of commercially available formulations, spherical activated carbon adheres due to the generation of static electricity when taking, which causes inconvenience when taking, whereas the spherical activated carbon of the present invention has the effect of suppressing the generation of static electricity to enhance the convenience of taking.

Hereinafter, the present invention will be described in detail.

The present invention provides an oral dosage form medicinal adsorbent composed of porous activated carbon having increased strength.

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

Porous activated carbon with increased strength according to the present invention has a pore volume of from about 7.5 mL to about 15000 nm in pore volume of 0.01 mL / g or more and less than 0.10 mL / g, more preferably 0.03 mL / g or more and less than 0.08 mL / g.

In contrast, Korean Patent Publication No. 10-2005-0039592 discloses oral administration, characterized in that the surface of the modified spherical activated carbon having an average particle diameter of 0.01 to 1 mm, a pore volume of 7.5 to 15000 nm, 0.25 to 1.0 mL / g. Solvent adsorbent is disclosed. The document states that the adsorption capacity of the oral adsorbent, ie the amount of harmful substances adsorbed by the oral adsorbent, increases in the above pore volume area of 0.25 mL / g and does not correlate with the increase in specific surface area. It is noted that the adsorption of harmful substances is increased rather than the selective adsorption rate.

However, according to the study of the present inventors, in contrast to the above-mentioned document, in the case of the oral dosage form medicinal adsorbent composed of porous activated carbon having increased strength according to the present invention, the pore volume of the pore diameter of 7.5 ~ 15000nm is 0.01mL / It has been found that the indole adsorption capacity and the indole adsorption rate increase at more than g and less than 0.10 mL / g, more preferably at least 0.03 mL / g and less than 0.08 mL / g.

Therefore, the oral dosage form pharmaceutical adsorbent composed of porous activated carbon having a spherical furan resin according to the present invention as a carbon source has an indole which is a urea substance in a pore volume of 0.01 mL / g or more and 0.10 mL / g in a pore diameter of 7.5 to 15000 nm. Adsorption can be maximized.

The porous activated carbon having increased strength according to the present invention has a pore volume of 20 to 15000 nm and a pore volume of 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.

On the other hand, Korean Patent Publication No. 10-2004-0032320 is characterized in that the porous spherical carbonaceous material having a diameter of 0.01 to 1mm, the pore volume of the pore diameter 20 ~ 15000nm of 0.04mL / g or more and less than 0.10mL / g. An adsorbent for oral administration is disclosed. In this document, the selective adsorption rate is excellent within the range of pore volume of 20 to 15000 nm and the pore volume of 0.04 mL / g or more and less than 0.10 mL / g, and the pore volume of 0.05 mL / g or more and less than 0.10 mL / g. It is described that it shows an excellent selective adsorption rate.

However, according to one embodiment of the present invention, in the case of the oral dosage form medicinal adsorbent composed of the porous activated carbon with increased strength according to the present invention, the pore volume of the pore diameter of 20 ~ 15000nm 0.005mL / g or more, less than 0.04mL / g, More preferably, the selective adsorption rate increases from 0.01 mL / g or more and less than 0.03 mL / g.

That is, the oral dosage form pharmaceutical adsorbent composed of porous activated carbon having increased strength of the present invention, unlike conventional technical knowledge, has a pore volume of 0.01 mL / g or more and 0.10 mL / g, with a pore diameter of 7.5 to 15000 nm. When the pore volume with a diameter of 20 to 15000 nm satisfies 0.005 mL / g or more and less than 0.04 mL / g, a new fact that the selective adsorption rate increases, the indole adsorption force and the adsorption rate also increase simultaneously was confirmed and the present invention was reached.

In the present invention, porous activated carbon having increased strength means porous activated carbon having a compressive strength of at least 10 N / sphere. The strength of the porous activated carbon of the present invention has a strength of at least 2 times up to 10 times compared to the strength of the conventional activated carbon. Porous activated carbon having increased strength of the present invention can be prepared using furan resin as a carbon source.

Porous activated carbon with increased strength according to the present invention has a base consumption of 0.1 to 1.0 mmol / g, and an oxygen ratio of 0.3 to 1.0 mmol / g.

In summary, the oral dosage form pharmaceutical adsorbent of the present invention has a pore volume of from 0.01 mL / g to less than 0.10 mL / g, more preferably from 0.03 mL / g to less than 0.08 mL / g, with pores having a pore diameter of 7.5 to 15000 nm. When the pore volume with a diameter of 20 to 15000 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 compressive strength is 10 N / sphere or more, the optimal urea removal ability will be exhibited. Can be.

The oral dosage form pharmaceutical adsorbent according to the present invention has a selective adsorption rate of 3.0 or more.

The oral dosage form pharmaceutical adsorbent according to the present invention has an indole initial adsorption rate of 80% or more.

Oral dosage form medicinal adsorbents of the present invention are chronic renal failure, acute renal failure, chronic pyelonephritis, acute pyelonephritis, chronic nephritis, acute nephrotic syndrome, acute progressive nephrotic syndrome, chronic nephritis syndrome, neproje syndrome, interstitial nephritis, lipoid neprogeze, For the prevention or treatment of one or more diseases selected from the group consisting of diabetic nephropathy, neovascular hypertension, or mild renal failure prior to dialysis, chronic hepatitis, alcoholic hepatitis, hepatic cirrhosis, cirrhosis, drug allergic liver failure or primary biliary cirrhosis Although it can be used as a disease that can be improved or treated due to the adsorption of the toxic substance of the oral dosage form pharmaceutical adsorbent is not particularly limited to the disease.

The physical property values of the surface modified spherical activated carbon used as the oral dosage form adsorbent according to the present invention, that is, the average particle diameter, specific surface area, pore volume, oxygen ratio, base consumption amount, selective adsorption rate and strength are measured by the following method. .

(1) average particle diameter

A particle diffraction diagram based on volume was prepared using a laser diffraction particle size distribution device (HELOS Particle Size Analysis, manufactured by Sympatec), and the mean particle size corresponding to the volume mean diameter (VMD) was used.

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

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

Specifically, the spherical activated carbon was filled into a sample tube, and dried under reduced pressure at 300 ° C., and the weight thereof was measured. The sample tube was cooled to -196 ° C, nitrogen was introduced to adsorb nitrogen to the spherical activated carbon, and the relationship between the nitrogen partial pressure and the adsorption amount (adsorption isotherm) was measured. The sample tube was brought to room temperature, and the amount of nitrogen released from the spherical activated carbon was measured by a thermal conductivity detector to obtain a gas adsorption amount (v).

Approximation derived from BET equation

vm = 1 / {v × (1-x)}

V _m (m ² / g) was obtained by the one-point method (relative pressure x = 0.3) by nitrogen adsorption at liquid nitrogen temperature using

Formula

Specific surface area = 4.35 × vm

The specific surface area of the spherical activated carbon was calculated by. In each of the above formulas, v is the amount of gas adsorption measured (m ² / g), and x is the relative pressure.

(3) Pore volume by mercury porosimetry

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

Specifically, the volume of mercury intruded into the spherical activated carbon in the range of 0.5 psia minimum pressure to 61,000 psia maximum was measured. The pore diameter is calculated by injecting mercury into the cylindrical pores of diameter D at a pressure P. If the surface tension of mercury is γ and the contact angle between mercury and the pore wall is θ, the surface tension is From the balance of the pressure acting on the pore cross section, the following equation -πDγcosθ = π (D / 2) ² × P is established. Therefore, D = (-4γcosθ) / P.

The surface tension of mercury is 485 dynes / cm, the contact angle of mercury and carbon is 130 °, the pressure P is psia, the pore diameter D is expressed in μm, and the pressure P and P are expressed by the following equation D = 180.8 / P. The relationship between pore diameter D was obtained.

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

(4) oxygen ratio

1.0 g of spherical activated carbon was taken into a 100 mL flask, and 50 mL of hydrochloric acid solution for oxygen ratio was added thereto, followed by shaking with a shaker at 37 ± 1 ° C for 24 hours. After the contents of the flask were filtered at room temperature, 20 mL of the above solution was taken as a sample solution, and titrated with 0.1 mol / L potassium hydroxide solution. (Indicator: 2 drops of bromine phenol blue solution) It was corrected by a blank test in the same manner. Oxygen ratio was calculated by the following equation.

A: 0.1 mol / L potassium hydroxide consumption (mL)

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

C: amount of sample (g)

f: factor of 0.1 mol / L potassium hydroxide

(5) Base consumption

1.0 g of spherical activated carbon was taken into a 100 mL flask, and 50 mL of hydrochloric acid solution for basic consumption was added thereto, followed by shaking with a shaker at 37 ± 1 ° C for 24 hours. After the contents of the flask were filtered at room temperature, 20 mL of the above solution was taken as a sample solution and titrated with 0.1 mol / L hydrochloric acid. (Indicator: 2 drops of phenolphthalein solution) Corrected by a blank test in the same manner. Base consumption was calculated by the following equation.

A: 0.1 mol / L hydrochloric acid consumption of the sample liquid (mL)

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

C: amount of sample (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 taken in a 100 mL flask, and then 50 mL (stock solution) of pH 7.4 phosphate buffer solution at a concentration of 100 mg / L of DL-β-aminoisobutyl acid was added thereto. Shake 3 hours. The contents of the flask were filtered and then sampled. After measuring the organic carbon according to the Japanese Pharmacopoeia General Test Method Organic Carbon Test Method, the residual concentration of DL-β-aminoisobutyl acid was calculated by the following equation.

T _t : amount of organic carbon in the sample solution

T _s : amount of organic carbon in standard solution (stock solution)

2.5 g of dried spherical activated carbon was taken in a 100 mL flask, and then 50 mL of a pH 7.4 phosphate buffer solution (stock solution) at a concentration of 100 mg / L of α-amylase was added thereto, followed by shaking at 37 ± 1 ° C. at 200 rpm for 3 hours. The contents of the flask were filtered with a membrane filter of 0.65 µm to prepare a sample solution. The pH 7.4 phosphate buffer solution was used as a control, and the absorbance at wavelength 282 nm was measured according to the UV-visible absorbance method. The residual concentration of α-amylase was determined by the following equation. Calculated.

A _t : absorbance of the sample solution

A _s : absorbance of standard solution (stock solution)

(7) strength measurement

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

One spherical activated carbon sample to be measured was placed in the middle of the compressive strength tip, and the compressive strength was lowered at a speed of 20 mm / min to determine the compressive strength value. 22 spherical activated carbon samples were measured in the same manner as described above, and the compressive strength values were determined by taking the average of 20 tablets except the maximum and minimum values.

Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited by an Example.

Example 1.

100 g of spherical furan resin (manufactured by Pure Sphere Co., Ltd.) was housed in a metal sample container (1.5 L content), and carbonized by heating at 500 ° C. under nitrogen gas for 1 hour using an electric furnace. Spherical activated carbon was prepared by heating spherical furan resin carbide by heating at a temperature of 900 ° C. for 140 minutes using a rotary external heat furnace. Spherical activated carbon was oxidized at a temperature of 470 ° C for 5 hours under oxygen-nitrogen mixture gas of which oxygen concentration was adjusted to 3 vol% using a rotary external furnace, followed by reduction for 15 minutes at 900 ° C under nitrogen gas. It progressed and obtained porous spherical activated carbon.

Example 2

The steam activation time in Example 1 was performed to 160 minutes, and the others were prepared in the same manner as in Example 1.

Example 3

In Example 1, the steam activation time was performed to 180 minutes, and the others were prepared in the same manner as in Example 1.

Example 4

In Example 1, it was prepared in the same manner as in Example 1 except that the steam activation time was 180 minutes and the carbonization temperature was performed at 450 ° C. for 1 hour.

Comparative Example 1

100 g of a spherical furan resin was accommodated in a metal sample container (1.5 L content), and carbonized by heating at 400 ° C. under nitrogen gas for 1 hour using an electric furnace. Spherical activated carbon was prepared by heating spherical furan resin carbide by heating at a temperature of 900 ° C. for 180 minutes using a rotary external heat furnace. Spherical activated carbon was oxidized at a temperature of 470 ° C for 5 hours under oxygen-nitrogen mixture gas of which oxygen concentration was adjusted to 3 vol% using a rotary external furnace, followed by reduction for 15 minutes at 900 ° C under nitrogen gas. It progressed and obtained porous spherical activated carbon.

Comparative Example 2

100 g of a spherical phenolic resin was accommodated in a metal sample container (1.5 L content), and then carbonized by heating at a temperature of 450 ° C. under nitrogen gas for 1 hour using an electric furnace. Spherical activated carbon was prepared by heating spherical phenolic resin carbide by heating for 180 minutes at a temperature of 900 ° C. under steam using a rotary external heat furnace. Spherical activated carbon was oxidized at a temperature of 470 ° C for 5 hours under oxygen-nitrogen mixture gas of which oxygen concentration was adjusted to 3 vol% using a rotary external furnace, followed by reduction for 15 minutes at 900 ° C under nitrogen gas. It progressed and obtained porous spherical activated carbon.

Experimental Example: Selective adsorption rate, indole adsorption capacity and indole adsorption rate

In order to evaluate the indole adsorption capacity of the Examples and Comparative Examples, 300 mg of porous spherical activated carbon was added to 900 mL of pH 7.4 phosphate buffer solution containing indole 1.0 mg / mL, and the dissolution test was performed at 100 rpm for 3 hours (eluator Agilent). 708-DS) was carried out. In addition, the selective adsorption rate was calculated by comparing DL-β-aminoisobutyl acid removal and α-amylase removal ability. The indole adsorption rate was expressed by the indole initial adsorption rate (%) obtained as follows.

Experimental results for the examples, comparative examples and the commercially available cremezin of the present invention are shown in Table 1 below.

Table 1

Item		Cremezine	Comparative Example 1	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)	20-15000nm	0.063	0.042	0.081	0.007	0.018	0.025	0.033
Pore volume (mL / g)	7.5-15000nm	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
Oxygen Ratio (mmol / g)		0.56	0.66	0.6	0.71	0.62	0.53	0.61
Residual Concentration of α-amylase (mg / L)		88.2	88.3	90	95.4	93.2	96.7	93.5
Residual Concentration of DL-β-Aminoisobutyl Acid (mg / L)		69.8	73.2	87.5	69.3	70.7	70.8	71.1
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
Indole initial adsorption rate (%)		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 in the above table, it was found that the cremezine and Comparative Examples 1 and 2 that do not satisfy the pore volume requirements of the present invention do not satisfy both the selective adsorption rate and the indole adsorption force at the same time. In addition, it was found that the comparative example 2 using the cremezin and the phenol resin using the pitch as the carbon source had a significant decrease in the compressive strength of the porous activated carbon, so that it was difficult to fill the solid unit formulation, for example, a capsule.

Claims

Oral dosage form pharmaceutical adsorbent consisting of porous activated carbon with increased strength.
The method of claim 1, wherein the pore volume of the porous activated carbon having an increased strength of 7.5 to 15000 nm has a pore volume of 0.01 mL / g or more and less than 0.10 mL / g, and a pore volume of 20-15000 nm of pore diameter of 0.005 mL / g or more 0.04. Oral dosage form pharmaceutical adsorbent, characterized in that less than mL / g.
The method of claim 1, wherein the pore volume of the porous activated carbon having an increased strength of 7.5-15000 nm has a pore volume of 0.03 mL / g or more and less than 0.08 mL / g, and a pore volume of pore diameter of 20-15000 nm of 0.01 mL / g or more 0.03. Oral dosage form pharmaceutical adsorbent, characterized in that less than mL / g.
The oral dosage form medicinal adsorbent according to any one of claims 1 to 3, wherein the selective adsorption rate of the porous activated carbon with increased strength is 3.0 or more.
The oral dosage form pharmaceutical adsorbent according to any one of claims 1 to 3, wherein the indole initial adsorption rate of the porous activated carbon having increased strength is 80% or more.
4. The oral dosage form medicinal adsorbent according to any one of claims 1 to 3, wherein the porous activated carbon having increased strength is 10 N / sphere or more.