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Title:  Adsorbent for oral administration

United States Patent:  6,830,753

Issued:  December 14, 2004

Inventors:  Sonobe; Naohiro (Fukushima, JP); Ise; Michihito (Tokyo, JP); Morimoto; Susumu (Tokyo, JP); Yamato; Hideyuki (Tokyo, JP); Mitsuhashi; Satoshi (Saitama, JP); Hayashi; Haruhisa (Tokyo, JP)

Assignee:  Kureha Chemical Industry Co., Ltd. (Tokyo, JP)

Appl. No.:  267795

Filed:  October 10, 2002

Abstract

An adsorbent for an oral administration, comprising a porous spherical carbonaceous substance wherein a diameter is 0.01 to 1 mm, a specific surface area determined by a BET method is 700 m2 /g or more, a volume of pores having a pore diameter of 20 to 15000 nm is from not less than 0.04 mL/g to less than 0.10 mL/g, a total amount of acidic groups is 0.30 to 1.20 meq/g, and a total amount of basic groups is 0.20 to 1.00 meq/g, is disclosed.

Description of the Invention

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to an adsorbent for an oral administration, and a pharmaceutical composition comprising the adsorbent for an oral administration. The adsorbent for an oral administration, according to the present invention, comprises a porous spherical carbonaceous substance having a pore volume within a specific scope, and exhibits an excellent adsorbability of harmful toxins in gastrointestinal tracts, despite a low adsorbability of useful components such as digestive enzymes in a body, when orally administered. Further, when the present adsorbent is administered to patients suffering from liver or renal diseases, a remarkable curative effect can be obtained.

2. Description of the Related Art

In patients with a lack of a renal function or a liver function, harmful toxic substances are accumulated or formed in bodies, such as blood, with a progress of a disorder of the organ functions, and thus, an encephalopathia occurs such as a disturbance of consciousness or uremia. There is a growing number of such patients from year to year, and therefore, a development of an organ-substitute apparatus or medicament having a function to remove toxic substances from bodies, in place of such defective organs, has become a serious problem. A method for removing toxic substances by a hemodialysis is prevalent as an artificial kidney at present. Nevertheless, the hemodialysis-based artificial kidney requires a special apparatus, and thus, a skilled specialist is required from a safely operating standpoint of view. Further, blood must be taken from a patient's body, and thus, there are disadvantages in that patients must bear high physical, mental and economic burdens. Accordingly, hemodialysis is not satisfactory.

Recently, as a means of remedying the above disadvantages, an oral adsorbent which can be orally administered and cure a disorder of renal and liver functions has received considerable attention. Specifically, an adsorbent disclosed in Japanese Examined Patent Publication (Kokoku) No. 62-11611 [=U.S. Pat. No. 4,681,764] comprises a porous spherical carbonaceous substance having particular functional groups; has a high safety factor and is stable to a body; and has a useful selective adsorbability, that is, an excellent adsorbability of harmful substances in the presence of a bile acid in an intestine, and a low adsorbability of useful substances such as digestive enzymes in the intestine. For these reasons, the oral adsorbent is widely and clinically used for a patient suffering from a disorder of a liver or renal function, as an adsorbent having few side effects such as constipation.

SUMMARY OF THE INVENTION

The inventors of the present invention engaged in intensive research to develop an oral adsorbent having a more excellent selective adsorbability than the above-mentioned oral adsorbent comprising the porous spherical carbonaceous substance, and surprisingly found that a porous spherical carbonaceous substance having a pore volume within a special scope exhibits an excellent selective adsorbability, that is, an excellent adsorbability of .beta.-aminoisobutyric acid, which is a toxic substance in a renal disease, despite a low adsorbability of useful substances, for example, digestive enzymes, such as .alpha.-amylase, less than that of the adsorbent disclosed in Japanese Examined Patent Publication (Kokoku) No. 62-11611. Further, the present inventors also found that the newly found porous spherical carbonaceous substance has few side effects such as constipation, and exhibits an excellent function as an oral medicament for treating a liver or renal disease.

The present invention is based on the above findings.

Accordingly, the object of the present invention is to provide an oral adsorbent exhibiting an excellent selective adsorbability.

Other objects and advantages of the present invention will be apparent from the following description.

In accordance with the present invention, there is provided an adsorbent for an oral administration, comprising a porous spherical carbonaceous substance wherein a diameter is 0.01 to 1 mm, a specific surface area determined by a BET method is 700 m2 /g or more, a volume of pores having a pore diameter of 20 to 15000 nm is from not less than 0.04 mL/g to less than 0.10 mL/g, a total amount of acidic groups is 0.30 to 1.20 meq/g, and a total amount of basic groups is 0.20 to 1.00 meq/g.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The porous spherical carbonaceous substance used as the adsorbent for an oral administration according to the present invention has a pore volume within a specific scope. That is, a volume of pores having a diameter of 20 to 15000 nm ranges from not less than 0.04 mL/g to less than 0.10 mL/g. On the other hand, the above-mentioned Japanese Examined Patent Publication (Kokoku) No. 62-11611 discloses an adsorbent comprising a porous spherical carbonaceous substance wherein a volume of voids having a pore radius of 100 to 75000 angstrom, that is, a volume of pores having a diameter of 20 to 15000 nm, is 0.1 to 1 mL/g. Further, the Japanese Publication mentions that the adsorbent exhibits excellent adsorbability of octopamine and .alpha.-aminobutyric acid, which is a substance causing a hepatic encephalopathy, dimethylamine, .beta.-aminoisobutyric acid, or aspartic acid, which is a toxic substance or a precursor thereof in a renal disease, or a water-soluble basic or amphoteric substance, such as arginine, in the presence of a bile acid, despite a low adsorbability of useful substances, for example, digestive enzymes. In Examples 1 to 3 of the above-mentioned Japanese Examined Patent Publication (Kokoku) No. 62-11611, adsorbents wherein a volume of voids having a pore radius of 37.5 to 75000 angstrom is 0.20 to 0.23 mL/g were actually prepared, and an excellent adsorbability of .beta.-aminoisobutyric acid, .gamma.-amino-n-butyric acid, dimethylamine, and octopamine was actually confirmed.

On the contrary, the inventors of the present invention found that, as shown in the working Examples of the present specification, when the volume of pores having a pore diameter of 20 to 15000 nm is adjusted to range from not less than 0.04 mL/g to less than 0.10 mL/g, an adsorbability of .alpha.-amylase that is a useful substance, is significantly lowered, while maintaining a high adsorbability of .beta.-aminoisobutyric acid, that is a toxic substance. When the volume of pores having a pore diameter of 20 to 15000 nm is increased, the useful substances such as digestive enzymes are more easily adsorbed. Therefore, a smaller volume of pores having a pore diameter of 20 to 15000 nm is preferable from a viewpoint that an adsorption of useful substances is reduced. On the other hand, if the volume of pores having such a pore diameter becomes too small, the adsorption of harmful substances is lowered.

Therefore, in the adsorbent for an oral administration, a ratio (T/U) of an adsorption amount (T) of toxic substances to an adsorption amount (U) of useful substances, that is, a selective adsorption rate, is important. For example, the selective adsorption rate of the porous spherical carbonaceous substance can be evaluated by the ratio (Tb/Ua) of an adsorption amount (Tb) of DL-.beta.-aminoisobutyric acid (toxic substance) to an adsorption amount (Ua) of .alpha.-amylase (useful substance). More particularly, the selective adsorption rate can be evaluated by, for example, an equation:

A=Tb/Ua

wherein A denotes a selective adsorption rate, Tb denotes an adsorption amount of DL-.beta.-aminoisobutyric acid, and Ua denotes an adsorption amount of .alpha.-amylase.

The porous spherical carbonaceous adsorbent of the present invention exhibits an excellent selective adsorption rate when the volume of pores having a pore diameter of 20 to 15000 nm ranges from not less than 0.04 mL/g to less than 0.10 mL/g, and a more excellent selective adsorption rate when the volume of pores having a pore diameter of 20 to 15000 nm ranges from not less than 0.05 mL/g to less than 0.10 mL/g.

The porous spherical carbonaceous substance used as the adsorbent for an oral administration according to the present invention has a diameter of 0.01 to 1 mm. When the diameter of the porous spherical carbonaceous substance becomes less than 0.01 mm, an exterior surface area of the porous spherical carbonaceous substance is increased, and useful substances such as digestive enzymes are easily adsorbed. When the diameter is more than 1 mm, a diffusion distance of toxic substances into the inside of the porous spherical carbonaceous substance is increased, and an adsorption rate is lowered. The diameter is preferably 0.02 to 0.8 mm. The expression that "a diameter is Dl to Du" as used herein means that a screen passing percentage (%) in a range of a screen opening Dl to Du is 90% or more in a particle-sizes accumulating standard curve prepared in accordance with JIS K 1474 as mentioned below in relation with a method for determining an average particle diameter.

The porous spherical carbonaceous substance used as the adsorbent for an oral administration according to the present invention has a specific surface area (referred to as "SSA" hereinafter) determined by a BET method of 700 m2 /g or more. When the porous spherical carbonaceous substance has the SSA of less than 700 m2 /g, an adsorbability of toxic substances is lowered. The SSA is preferably 800 m2 /g or more. The upper limit of the SSA is not particularly limited, but the SSA is preferably 2500 m2 /g or less in view of a bulk density and strength.

The porous spherical carbonaceous substance used as the adsorbent for an oral administration according to the present invention has a special constitution of functional groups, that is, a total amount of acidic groups is 0.30 to 1.20 meq/g, and a total amount of basic groups is 0.20 to 1.00 meq/g. When the porous spherical carbonaceous substance does not satisfy the functional-groups requirement, that the total amount of acidic groups is 0.30 to 1.20 meq/g, and the total amount of basic groups is 0.20 to 1.00 meq/g, the adsorbability of the harmful substances is lowered. In the functional-groups requirement, the total amount of acidic groups is preferably 0.30 to 1.00 meq/g and the total amount of basic groups is preferably 0.30 to 0.60 meq/g. When the adsorbent for an oral administration according to the present invention is used as a medicament for treating a liver or renal disease, a preferable functional-groups constitution is that the total amount of acidic groups is 0.30 to 1.20 meq/g, the total amount of basic groups is 0.20 to 1.00 meq/g, a phenolic hydroxyl group is 0.20 to 0.70 meq/g, and a carboxyl group is 0.15 meq/g or less, and a ratio (a/b) of the total amount of acidic groups (a) to the total amount of basic groups (b) is 0.40 to 2.5, and a relation [(b+c)-d] between the total amount of basic groups (b), the phenolic hydroxyl group (c), and the carboxyl group (d) is 0.60 or more.

The porous spherical carbonaceous substance used as the adsorbent for an oral administration according to the present invention may be prepared by, for example, the following methods.

First, a dicyclic or tricyclic aromatic compound or a mixture thereof having a boiling point of 200oC. or more is added as an additive to a pitch such as a petroleum pitch or a coal pitch. The whole is heated and mixed, and then shaped to obtain a shaped pitch. The porous spherical carbonaceous substance is for an oral administration, and the raw material must have a sufficient purity from a safety standpoint, and have stable properties.

Thereafter, the shaped pitch is dispersed and granulated in hot water at 70 to 180oC., with stirring, to obtain a microspherical shaped pitch. Further, the additive is extracted and removed from the shaped pitch by a solvent having a low solubility to the pitch but a high solubility to the additive. The resulting porous pitch is oxidized by an oxidizing agent to obtain a porous pitch having an infusibility to a heat. The resulting infusible porous pitch is treated at 800 to 1000oC. in a gas flow such as steam or carbon dioxide gas reactive with carbon to obtain a porous carbonaceous substance.

Then, the resulting porous carbonaceous substance is oxidized in a temperature range of 300 to 800oC., preferably 320 to 600oC. in an atmosphere containing 0.1 to 50% by volume, preferably 1 to 30% by volume, particularly preferably 3 to 20% by volume of oxygen, and thereafter reduced in a temperature range of 800 to 1200oC., preferably 800 to 1000oC., in an atmosphere of a non-oxidizable gas to obtain the porous spherical carbonaceous substance used as the adsorbent for an oral administration according to the present invention.

In the above method, the atmosphere containing oxygen in the particular amount may be pure oxygen, or nitrogen oxides or air as the oxygen source. As the atmosphere inert against carbon, for example, nitrogen, argon or helium may be used alone or in the form of a mixture thereof.

The purposes of the addition of the aromatic compound to the raw pitch are that a flowability of the raw pitch is enhanced by lowering a softening point of the raw pitch whereby the granulation thereof is made easier, and the porous pitch is produced by extracting and removing the additive from the shaped pitch, whereby a structure control and a calcination of the carbonaceous material by oxidization in the subsequent steps is made easier. As the additive, for example, naphthalene, methylnaphthalene, phenyl-naphthalene, benzyl-naphthalene, methylanthracene, phenanthrene, or biphenyl may be used alone or in a mixture thereof. An amount of the additive added to the pitch is preferably 10 to 50 parts by weight of the aromatic compound with respect to 100 parts by weight of the pitch.

It is preferable that the pitch and the additive are mixed under a melted condition with heating, to achieve a homogeneous mixing. Further, it is preferable that the mixture of the pitch and the additive is shaped to form particles having a particle size of about 0.01 to 1 mm, to control the particle size (diameter) of the resulting porous spherical carbonaceous adsorbent. The shaping may be conducted during the melted condition, or by grinding the mixture after it has cooled.

A preferable solvent used to extract and remove the additive from the mixture of the pitch and the additive may be, for example, an aliphatic hydrocarbon, such as butane, pentane, hexane, or heptane, a mixture comprising an aliphatic hydrocarbon as a main component, such as naphtha or kerosene, or an aliphatic alcohol, such as methanol, ethanol, propanol, or butanol.

The additive may be removed from the shaped mixture by extracting the additive with the solvent from the shaped mixture of the pitch and the additive, while maintaining the shape. It is assumed that, upon the extraction, through-holes of the additive are formed in the shaped product, and a shaped pitch having a uniform porosity can be obtained. In this connection, the size of through-holes of the additive (i.e., pore volume) may be controlled by a conventional method, for example, by controlling an amount of the additive, or a precipitating temperature (cooling temperature) of the additive in the granulating step of the shaped pitch. Further, when the resulting shaped pitch is crosslinked by oxidation, the pore volume generated by extracting the additive is affected by a condition of the treatment. For example, if it is strongly crosslinked by oxidation, a heat contraction caused by a heat treatment is small, and thus the pores obtained by extracting the additive tend to be maintained.

Then, the resulting porous shaped pitch is crosslinked by oxidation, that is, the resulting porous shaped pitch is oxidized by an oxidizing agent, preferably at room temperature to 300oC. to obtain the porous infusible shaped pitch having a non-fusibility to heat. As the oxidizing agent, for example, oxygen gas (O2), or a gas mixture prepared by diluting oxygen gas (O2) with air or nitrogen may be used.

Properties of the porous spherical carbonaceous substance used as the adsorbent for an oral administration according to the present invention, namely, the average particle diameter, the specific surface area, the pore volume, the total amount of acidic groups, and the total amount of basic groups are measured by the following methods.

(1) An Average Particle Diameter

A particle-sizes accumulating standard curve is prepared in accordance with JIS K 1474 for the porous spherical carbonaceous substance. The average particle diameter is determined from a screen opening (mm) at an intersection point with a line that is horizontal to an abscissa axis and starts from an intersection point in the particle-sizes accumulating standard curve with a perpendicular line from a 50% point of the abscissa axis.

(2) A Specific Surface Area

An amount of gas adsorbed is measured by a specific surface area measuring apparatus (for example, Flow Sorb II 2300 manufactured by MICROMERITICS) in accordance with a gas adsorbing method of a continuous flow for the porous spherical carbonaceous substance sample, and a specific surface area can be calculated by a BET equation. More particularly, the porous spherical carbonaceous substance is charged as a sample in a sample tube. A helium gas stream containing 30% by volume of nitrogen is passed through the sample tube, and an amount of nitrogen adsorbed to the porous spherical carbonaceous substance sample is measured by the following procedures. Specifically, the sample tube is cooled to -196oC., whereby nitrogen is adsorbed to the porous spherical carbonaceous substance sample, and then the temperature of the sample tube is raised to room temperature. During the raising the temperature, nitrogen is emitted from the porous spherical carbonaceous substance sample. The amount of the emitted nitrogen is measured by a heat conductivity type detector as an amount (v) of gas adsorbed.

A value vm is calculated in accordance with a one-point method (relative pressure x=0.3) by a nitrogen adsorption at a temperature of liquid nitrogen, using an approximate equation:

vm =1/(v.multidot.(1-x))

derived from the BET equation. Then, a specific surface area of the sample is calculated by an equation:

specific surface area=4.35xvm (m2 /g).

In the above equations, vm is an adsorption amount (cm3 /g) necessary to form a monomolecular layer on a surface of the sample, v is an adsorption amount (cm3 /g) actually found, and x is a relative pressure.

(3) A Pore Volume by a Mercury Injection Method

The pore volume can be measured by a mercury porosimeter (for example, AUTOPORE 9200 manufactured by MICROMERITICS). The porous spherical carbonaceous substance is charged as a sample in a sample vessel, and degassed under a pressure of 2.67 Pa or less for 30 minutes. Then, mercury is introduced into the sample vessel, a pressure applied is gradually increased (maximum pressure=414 MPa) to force the mercury into the micropores in the porous spherical carbonaceous substance sample. A pore volume distribution of the porous spherical carbonaceous substance sample is measured from a relationship between the pressure and an amount of forced mercury by equations as mentioned below. Specifically, a volume of mercury inserted into the porous spherical carbonaceous substance sample while a pressure is applied is increased from a pressure (0.07 MPa) corresponding to a pore diameter of 15 .mu.m to the maximum pressure (414 Mpa) corresponding to a pore diameter of 3 nm. A pore diameter can be calculated as follows. When mercury is forced into a cylindrical micropore having a diameter (D) by applying a pressure (P), a surface tension (.gamma.) of mercury is balanced with a pressure acting on a section of the micropore, and thus, a following equation is held:

-.pi.D.gamma. cos .theta.=.pi.(D/2)2.multidot.P

wherein .theta. is a contact angle of mercury and a wall of the micropore. Therefore, a following equation:

D=(-4.gamma. cos .theta.)/P

is held.

In the present specification, the relationship between the pressure (P) and the pore diameter (D) is calculated by an equation:

D=1.27/P

given that a surface tension of mercury is 484 dyne/cm, a contact angle of mercury and carbon is 130o, a unit of the pressure P is Mpa, and a unit of the pore diameter D is .mu.m. The volume of pores having a pore diameter of 20 to 15000 nm in the present invention corresponds to a volume of mercury inserted by applying a pressure increasing from 0.07 Mpa to 63.5 Mpa.

(4) Total Amount of Acidic Groups

The total amount of acidic groups is an amount of NaOH consumed, which may be determined by adding 1 g of the porous spherical carbonaceous substance sample, after being crushed to form particles having a size of less than 200 mesh, to 50 mL of a 0.05N NaOH solution; shaking the mixture for 48 hours; then filtering out the porous spherical carbonaceous substance sample; and titrating until neutralization.

(5) Total Amount of Basic Groups

The total amount of basic groups is an amount of HCl consumed, which may be determined by adding 1 g of the porous spherical carbonaceous substance sample after being crushed to form particles having a less than 200 mesh size, to 50 mL of a 0.05N HCl solution; shaking the mixture for 24 hours; then filtering out the porous spherical carbonaceous substance sample; and titrating until neutralization.

The porous spherical carbonaceous substance used as the adsorbent for an oral administration according to the present invention contains both ionic groups, that is, acidic groups and basic groups, as above, and exhibits an excellent selective adsorbability of toxic substances under an intestinal condition. Therefore, the porous spherical carbonaceous substance may be used as an adsorbent for an oral administration for treating or preventing a renal disease or a liver disease.

As the renal disease, there may be mentioned, for example, chronic renal failure, acute renal failure, chronic pyelonephritis, acute pyelonephritis, chronic nephritis, acute nephritic syndrome, acute progressive nephritic syndrome, chronic nephritic syndrome, nephrotic syndrome, nephrosclerosis, interstitial nephritis, tubulopathy, lipoid nephrosis, diabetic nephropathy, renovascular hypertension, or hypertension syndrome, or secondary renal diseases caused by these primary diseases, or a light renal failure before a dialysis therapy, and may be used in an improvement of a light renal failure before a dialysis therapy or a disease condition for a patient during a dialysis therapy (see "Clinical Nephrology", Asakura-shoten, Nishio Honda, Kenkichi Koiso, and Kiyoshi Kurokawa, 1990; and "Nephrology" Igaku-shoin, Teruo Omae and Sei Fujimi, ed., 1981).

As the liver disease, there may be mentioned, for example, fulminant hepatitis, chronic hepatitis, viral hepatitis, alcoholic hepatitis, hepatic fibrosis, liver cirrhosis, hepatic cancer, autoimmune hepatitis, drug allergic hepatopathy, primary biliary cirrhosis, tremor, encephalopathia, dysbolism, or dysfunction. Further, the porous spherical carbonaceous substance can be used in a treatment of a disease caused by toxic substances in a body, such as psychosis.

When the adsorbent for an oral administration according to the present invention is used as a medicament for a treatment of a liver or renal disease, a dosage thereof depends on the subject (human or other animal), age, individual differences, disease conditions, and so on. Therefore, in some cases, a dosage outside of the following dosage may be appropriate, but in general, the oral dosage in the case of a human is usually 1 to 20 g of the adsorbent per day, wherein the daily dosage may be divided into three to four portions. The dosage may appropriately vary with the disease conditions. The formulation may be administered in any form, such as powders, granules, tablets, sugar-coated tablets, capsules, suspensions, sticks, divided packages, or emulsions. In the case of capsules, the usual gelatin capsules, or if necessary, enteric capsules may be used. In the case of tablets, the formulations must be broken into the original fine particles inside the body. The adsorbent may be used as a mixture with an electrolyte-controlling agent, such as an aluminum gel or KAYEXALATE.RTM. (Windrop Lab, U.S.A.) or other agents.

Claim 1 of 11 Claims

What is claimed is:

1. An adsorbent for an oral administration, comprising a porous spherical carbonaceous substance wherein a diameter is 0.01 to 1 mm, a specific surface area determined by a BET method is 700 m2 /g or more, a volume of pores having a pore diameter of 20 to 15000 nm is from not less than 0.04 mL/g to less than 0.10 mL/g, a total amount of acidic groups is 0.30 to 1.20 meq/g, and a total amount of basic groups is 0.20 to 1.00 meq/g.


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