Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/44—Elemental carbon, e.g. charcoal, carbon black
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/02—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material
  • B01J20/20—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising free carbon; comprising carbon obtained by carbonising processes
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
  • B01J20/28002—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their physical properties
  • B01J20/28011—Other properties, e.g. density, crush strength
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
  • B01J20/28054—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their surface properties or porosity
  • B01J20/28069—Pore volume, e.g. total pore volume, mesopore volume, micropore volume
  • B01J20/28071—Pore volume, e.g. total pore volume, mesopore volume, micropore volume being less than 0.5 ml/g
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
  • B01J20/28054—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their surface properties or porosity
  • B01J20/28078—Pore diameter
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
  • B01J20/28054—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their surface properties or porosity
  • B01J20/28078—Pore diameter
  • B01J20/28083—Pore diameter being in the range 2-50 nm, i.e. mesopores
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
  • B01J20/28054—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their surface properties or porosity
  • B01J20/28078—Pore diameter
  • B01J20/28085—Pore diameter being more than 50 nm, i.e. macropores

Definitions

• 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.
• 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.
• 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.
• 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.
• 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.
• the oral adsorbent 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.
• 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.
• 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.
• a novel oral dosage form pharmaceutical adsorbent that can satisfy both selective adsorption and indole adsorption.
• 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.
• the present invention provides an oral dosage form pharmaceutical adsorbent composed of porous activated carbon with increased strength.
• 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.
• 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.
• antistatic prevention can be suppressed, and contamination of spherical activated carbon due to foreign matters generated during the manufacturing process can be prevented.
• 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.
• 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 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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 has a base consumption of 0.1 to 1.0 mmol / g, and an oxygen ratio of 0.3 to 1.0 mmol / g.
• 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.
• 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,
• 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
• 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. .
• 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.
• HELOS Particle Size Analysis manufactured by Sympatec
• 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.
• ASAP 2420 manufactured by MICROMERITICS
• 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).
• v is the amount of gas adsorption measured (m 2 / g)
• x is the relative pressure
• 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.
• 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 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 ⁇ m
• the relationship between pore diameter D was obtained.
• 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.
• the selective adsorption rate is calculated as follows.
• T s amount of organic carbon in standard solution (stock solution)
• 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.
• spherical furan resin manufactured by Pure Sphere Co., Ltd.
• a metal sample container 1.5 L content
• 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 1 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 1 the steam activation time was performed to 180 minutes, and the others were prepared in the same manner as in Example 1.
• 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.
• a spherical furan resin 100 g 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.
• a spherical phenolic resin 100 g 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.
• indole adsorption capacity 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.
• the selective adsorption rate was calculated by comparing DL- ⁇ -aminoisobutyl acid removal and ⁇ -amylase removal ability.
• the indole adsorption rate was expressed by the indole initial adsorption rate (%) obtained as follows.
• 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 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 ⁇ -amylase (mg / L) 88.2 88.3 90 95.4 93.2 96.7 93.5 Residual Concentration of DL- ⁇ -Aminoisobutyl Acid (mg / L)

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• 2014
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