CN108883130A - Contain the tablet and its manufacturing method that spherical adsorbent charcoal is administered orally - Google Patents

Contain the tablet and its manufacturing method that spherical adsorbent charcoal is administered orally Download PDF

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Publication number
CN108883130A
CN108883130A CN201780019680.3A CN201780019680A CN108883130A CN 108883130 A CN108883130 A CN 108883130A CN 201780019680 A CN201780019680 A CN 201780019680A CN 108883130 A CN108883130 A CN 108883130A
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tablet
additive
volume fraction
gum
cladding product
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CN108883130B (en
Inventor
町佳树
神谷洋平
小野佐市
小西麻由
嶋田紘尚
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Kureha Corp
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Kureha Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/06—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of pills, lozenges or dragees
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin

Abstract

The purpose of the present invention is to provide a kind of yield height that spherical adsorbent charcoal is administered orally, spherical adsorbent charcoal is administered orally and bonds the tablet and its manufacturing method high with the uniformity of additive.Described problem can be solved by tablet with the following characteristics：Every 1mm of defined five prisms3The ratio between the maxima and minima of additive volume fraction be 100 or less；The relative standard deviation of the volume fraction of the cube of defined three dividing bodies is 5% or less；Alternatively, every 1mm of defined five prisms3The ratio between the maxima and minima of additive volume fraction for 100 hereinafter, the relative standard deviation of the volume fraction of the cube of defined three dividing bodies is 5% or less.

Description

Contain the tablet and its manufacturing method that spherical adsorbent charcoal is administered orally
Technical field
Contain tablet and its manufacturing method that spherical adsorbent charcoal is administered orally the present invention relates to a kind of.According to the present invention, It can provide the manufacturing method for showing the tablet of excellent yield.
Background technique
Absorbent for oral administration can be adsorbed with harmful substance by being taken in alimentary canal, as a result, can be to kidney Dirty, liver dysfunction is treated (patent document 1).It is harmful in order to make the spherical adsorbent charcoal of the oral administration play absorption Pharmacological action as substance, it is important that maintain the spherical shape that spherical adsorbent charcoal is administered orally, and maintain its pore knot Structure.The oral administration use spherical adsorbent charcoal for example as trade name " KREMEZIN (registered trademark) capsule 200mg " and " KREMEZIN (registered trademark) particulate subpackage 2g " (hereinafter referred to as " KREMEZIN ") is sold.
KREMEZIN is 6g for every 1 day dosage of Patients With Kidney Diseases, its point 3 times are taken, therefore each time Dose is 2g.The volume of the granula subtilis 2g of KREMEZIN is about 4cm3, the volume taken will not lack.Taking 4cm as a result,3 Granula subtilis in the case where, since spheric active carbon is not dissolved in water, gritty sense can be remained in oral cavity, there is also entertain Detest the patient of sense.
On the other hand, in the case where the capsule of KREMEZIN, intraoral gritty sense will not occur.But in glue The dead volume (dead volume) other than spheric active carbon can be generated in wafer, therefore compared with the volume of granula subtilis, capsule Volume increase to about 1.5 times of (about 6cm3).Specifically, volume is about 0.613cm3Capsule must once take ten Capsule, there is also the patients more than complaint dose.
In addition, in order to eliminate the gritty sense of granula subtilis, or since the dose of capsule is more, there is also when many differences The patient of granula subtilis, capsule can not be taken by taking a large amount of water just.In Patients With Kidney Diseases or patients with renal failure, there is limit The patient of moisture intake processed, these patients are when taking granula subtilis or capsule etc., it is desirable that while taking as a small amount of as possible Water, thus for for needing the patient by a large amount of water, meeting is with very big pain originally.
Existing technical literature
Patent document
Patent document 1：Japanese Patent Publication 62-11611 bulletin
Patent document 2：Japanese Unexamined Patent Publication 2006-8602 bulletin
Patent document 3：No. 2012/121202 bulletin of International Publication
Summary of the invention
Problems to be solved by the invention
In order to solve described problem, consider oral administration tablet is made with spherical adsorbent charcoal.But ball is used in oral administration Shape adsorbent charcoal is different from general drug, can not carry out compression molding (patent document 2) by compression etc..That is, same as glass Ground, oral administration with spherical adsorbent charcoal have it is stone, lack morphotropism, frangible property, if therefore progress compression molding, Oral administration is destroyed with spherical adsorbent charcoal and is unable to maintain that spherical shape.
The inventors of the present invention have found following fact：By using the particle preparation additive for showing film Forming ability Kneading method, can produce be available for it is practical containing the tablet (patent document 3) that spherical adsorbent charcoal is administered orally.But Using kneading method to manufacture tablet, the low yield of spheric active carbon.In addition, the mouth of the tablet obtained by kneading method The uniformity for taking the spherical adsorbent charcoal of administrable and bonding additive is low.It should be noted that with granule or capsule phase Than the adsorbance of the DL- B-AIB of the tablet obtained by kneading method reduces sometimes.
Therefore, the purpose of the present invention is to provide a kind of yield height that spherical adsorbent charcoal is administered orally, oral administration is used The uniformity of spherical adsorbent charcoal and bonding additive high tablet and its manufacturing method.
Technical solution
The present inventor is high to the yield of the spherical adsorbent charcoal of oral administrable, spherical adsorbent charcoal is administered orally and bonding is used The high tablet of the uniformity of additive and its manufacturing method conduct in-depth research, as a result, being surprised to find following thing It is real：Solution by that will contain bonding additive is spraying or is added dropwise in spherical adsorbent charcoal is administered orally, by compression forming methods Tablet is manufactured, improves the yield that spherical adsorbent charcoal is administered orally by leaps and bounds, and then has obtained the spherical suction of oral administration The uniformity of attached charcoal and bonding additive also leaps the tablet of raising.
The present invention is completed based on this opinion.
Therefore, the present invention relates to following tablet and its manufacturing methods：
[1] a kind of tablet, which is characterized in that containing additive and spherical adsorbent charcoal is administered orally,
In in the case where passing through X ray CT microscope to from the tablet from upper surface from upper surface to lower surface Center portion and positioned at the end of the straight line extended from center to four directions, from upper surface to lower surface be on one side five of 1mm In the case that the volume fraction of the additive of prism is parsed, every 1mm of five prisms3Additive volume fraction maximum value with The ratio between minimum value is 100 or less；
[2] a kind of tablet, which is characterized in that containing additive and oral administration use adsorbent charcoal,
In each dividing body that the length in the flat direction of the tablet is divided into trisection, aobvious by X ray CT Micro mirror is to the center of the length for being located at flat direction and is located at the center of tablet from upper surface and is formed by one side 2mm In the case that the volume fraction of cube is parsed, the relative standard deviation of the volume fraction of the cube of three dividing bodies is 5% Below；
[3] a kind of tablet, which is characterized in that containing additive and oral administration use adsorbent charcoal,
In in the case where passing through X ray CT microscope to from the tablet from upper surface from upper surface to lower surface Center portion and positioned at the end of the straight line extended from center to four directions, from upper surface to lower surface be on one side five of 1mm In the case that the volume fraction of the additive of prism is parsed, every 1mm of five prisms3Additive volume fraction maximum value with The ratio between minimum value is 100 hereinafter, in each dividing body that the length in the flat direction of the tablet is divided into trisection, is being led to X ray CT microscope is crossed to the center for the length for being located at flat direction and positioned at the center of the tablet from upper surface by one In the case that the volume fraction for the cube that side 2mm is formed is parsed, the opposite mark of the volume fraction of the cube of three dividing bodies Quasi- deviation is 5% or less；
[4] tablet according to any one of [1]~[3], wherein
The additive is selected from by sodium alginate, propylene glycol alginate, carboxymethyl cellulose, carboxymethyl cellulose Calcium, ghatti gum, carragheen, carboxyl vinyl polymer, sodium carboxymethylcellulose, xanthan gum, guar gum, Wen Quince seed glue, Portugal Mannosan, copolyvidone, gellan gum, gelatin, tamarind gum, tara gum, dextrin, cornstarch, bassora gum, hyaluronic acid Sodium, hydroxypropul starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pulullan polysaccharide, povidone, gathers hydroxyethyl cellulose Ethylene oxide, polyvinyl alcohol, polyvinyl alcohol-acryl acid-methyl methacrylate copolymer, Macrogol 6000, ethyl cellulose Element, methylcellulose, phosphoric acid crosslinked starch, locust bean gum, agar, cold plum powder, complete pre-gelatinized starch, avicel cellulose carboxylic first What base sodium cellulosate, oxidized starch, low degree of substitution hydroxypropyl cellulose, part pre-gelatinized starch, carbohydrate and glycitols were constituted Bonding additive in group；
[5] tablet according to any one of [1]~[4], wherein
The oral administration is spheric active carbon with spherical adsorbent charcoal；
[6] tablet according to [5], wherein
The average grain diameter of the spheric active carbon is 0.02~1mm；
[7] a kind of manufacturing method of tablet, it includes following process：
It (1) will be containing selected from by sodium alginate, propylene glycol alginate, carboxymethyl cellulose, calcium carboxymethylcellulose, print It is poly- to spend natural gum, carragheen, carboxyl vinyl polymer, sodium carboxymethylcellulose, xanthan gum, guar gum, Wen Quince seed glue, Portugal's sweet dew Sugar, copolyvidone, gellan gum, gelatin, tamarind gum, tara gum, dextrin, cornstarch, bassora gum, Sodium Hyaluronate, hydroxyl second Base cellulose, hydroxypropul starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pulullan polysaccharide, povidone, polycyclic oxygen second Alkane, polyvinyl alcohol, polyvinyl alcohol-acryl acid-methyl methacrylate copolymer, Macrogol 6000, ethyl cellulose, methyl Cellulose, phosphoric acid crosslinked starch, locust bean gum, agar, cold plum powder, complete pre-gelatinized starch, avicel cellulose carboxymethyl cellulose In the group that plain sodium, oxidized starch, low degree of substitution hydroxypropyl cellulose, part pre-gelatinized starch, carbohydrate and glycitols are constituted The solution of bonding additive is spraying or is added dropwise in spherical adsorbent charcoal is administered orally, by bonding with additive to oral administrable Spherical adsorbent charcoal is coated；
(2) compression forming process, by the way that solvent is made an addition to the spherical adsorbent charcoal of oral administration being wrapped by, then Compression forming is carried out, formed body is obtained；And
(3) obtained formed body is dried.
Beneficial effect
The manufacturing method of tablet according to the present invention containing oral administration spherical adsorbent charcoal (such as spheric active carbon), The yield of spherical adsorbent charcoal is administered orally used in can improving.In addition, being contained by what the manufacturing method of the present invention obtained Oral administration prevents from being administered orally being locally present with spherical adsorbent charcoal and bonding additive with the tablet of spherical adsorbent charcoal, The uniformity that spherical adsorbent charcoal and bonding additive is administered orally is improved.Therefore, the hardness of the tablet obtained obtains To improve.It should be noted that above-mentioned tablet can embody the adsorption capacity of excellent DL- B-AIB.That is, according to this hair The manufacturing method of bright tablet, compared with the kneading method described in the patent document 3, can improve in the manufacturing method of tablet take orally to The yield of medicinal spherical adsorbent charcoal, can also improve hardness, also it can be expected that improving the adsorption capacity of DL- B-AIB.
Tablet according to the present invention, compared with capsule, it is possible to provide volume, the tablet that taking is improved can be reduced. That is, volume is about 0.613cm in the case where capsule3Capsule must once take ten capsules, there is also complain take Patient more than dosage, in contrast, 65% of the volume in the case that tablet of the invention can be reduced volume to capsule (about 4cm3), taking is improved.In addition, tablet according to the present invention, compared with granula subtilis, it is possible to provide one kind improves gritty The tablet of the shortcomings that takings such as sense.A kind of tablet according to the present invention, it is possible to provide spherical shape that spherical adsorbent charcoal is administered orally It is maintained, pore structure will not be destroyed, and can give full play to the tablet of the function of absorbent for oral administration.
Detailed description of the invention
Fig. 1 is that the volume fraction that tablet is parsed in tablet of the invention is schematically shown from upper surface (A) and side (B) Three cubes position figure.
Fig. 2 is to indicate the tablet (A) obtained by the manufacturing method of the present invention and the tablet obtained by previous kneading method (B) the parsing image for the X ray CT microscope (nano3DX) of the additive in being locally present.
Fig. 3 is that the volume that additive is parsed in tablet of the invention is schematically shown from upper surface (A) and side (B) The figure of the position of five prisms of rate.
Fig. 4 is to indicate from upper surface to lower surface through X ray CT microscope to the additive in tablet of the invention Volume fraction parsed in the case where variation curve graph.
Fig. 5 is to indicate that the spheric active carbon (A) obtained by kneading method remains on stirring granulating machine and (B) is attached to molding The photo of mold.
Fig. 6 is to indicate to carry out based on 256 grades of lightness information to by volume fraction of the analysis software ImageJ to additive The curve graph and photo that in the case where calculating, additive and spheric active carbon are divided.
Specific embodiment
(1) containing the tablet that spherical adsorbent charcoal is administered orally
Of the invention contains bonding additive with the tablet of spherical adsorbent charcoal containing oral administration.Bonding addition Agent is preferably from by sodium alginate, propylene glycol alginate, carboxymethyl cellulose, calcium carboxymethylcellulose, ghatti gum (ghattigum), carragheen (carrageenan), carboxyl vinyl polymer, sodium carboxymethylcellulose, xanthan gum, Guar Jiao, Wen Quince seed glue, glucomannans (glucomannan), copolyvidone, gellan gum, gelatin, tamarind gum, tara gum, paste Essence, cornstarch, bassora gum, Sodium Hyaluronate, hydroxyethyl cellulose, hydroxypropul starch, hydroxypropyl cellulose, hydroxypropyl methyl Cellulose, pulullan polysaccharide (Pullulan), povidone, polyethylene oxide, polyvinyl alcohol, polyvinyl alcohol-acrylic acid-methyl-prop E pioic acid methyl ester copolymer, Macrogol 6000, ethyl cellulose, methylcellulose, phosphoric acid crosslinked starch, locust bean gum, agar, Cold plum powder, complete pre-gelatinized starch, avicel cellulose sodium carboxymethylcellulose, oxidized starch, low degree of substitution hydroxypropyl cellulose, It is selected in the group that part pre-gelatinized starch, carbohydrate and glycitols are constituted.In addition, the oral administration is excellent with spherical adsorbent charcoal It is selected as spheric active carbon.
《Spherical adsorbent charcoal is administered orally》
As long as the spherical adsorbent charcoal of oral administration can be administered orally with spherical adsorbent charcoal used in medical application, It is just not particularly limited, preferably oral administration spheric active carbon, that is, the spherical activity used can be taken orally in medical application Charcoal.It should be noted that in the present specification, as the example that spherical adsorbent charcoal is administered orally, using spherical activity sometimes Charcoal is illustrated.
For example, the average grain diameter for the spheric active carbon that tablet of the invention is included is not particularly limited, preferably 0.02 ~1mm, more preferably 0.03~0.90mm, further preferably 0.05~0.80mm.In addition, the partial size of the spheric active carbon (diameter) ranges preferably from 0.01~2mm, more preferably 0.02~1.5mm, further preferably 0.03~1mm.
" spheric active carbon " means that BET specific surface area is 100m2The active carbon of/g or more, spherical work used in the present invention The BET specific surface area of property charcoal is preferably 500m2/ g or more, more preferably 700m2/ g or more, further preferably 1300m2/ g with On, particularly preferably 1650m2/ g or more.
In order to maintain its pore structure, play pharmacological action as absorption harmful substance, what tablet was included take orally to The form of medicinal spherical adsorbent charcoal (such as spheric active carbon) is preferably the spherical shape for maintaining to be administered orally spherical adsorbent charcoal.That is, The adsorption capacity of toxicant, such as selection adsorption rate will receive diameter, average grain diameter, specific surface area and specific pore Pore volume in diameter range etc. influences, it is therefore desirable that maintaining not make oral administration damaged with spherical adsorbent charcoal and shadow The spherical shape of diameter or average grain diameter is rung, the pore structure for influencing specific surface area, pore volume is maintained.In turn, by remaining spherical, Prevented also from side effects such as constipation.
《Additive》
Additive used in tablet of the invention contains bonding additive.By containing bonding additive, can obtain High and excellent strength the tablet to uniformity.
Although tablet of the invention is characterized in that containing the bonding uses additive as additive, can also contain There is the additive (hereinafter sometimes referred to " other additives ") other than bonding additive.That is, tablet of the invention can be containing viscous Knot uses additive and other additives as additive, can also only contain bonding and use additive as additive.In other words, originally Additive used in inventing can be formed by bonding with additive and other additives, can also be formed by bonding with additive. (content of additive)
As long as effect of the invention can be obtained, oral administration spherical adsorbent charcoal (such as spheric active carbon) and additive Weight ratio is just not particularly limited, such as additive is preferably 1~35 weight %, more preferably 1.5~35 weight %, further Preferably 2~35 weight %.If oral administration, in the range, can be obtained with the weight ratio of spherical adsorbent charcoal and additive The high tablet of even property.In the case where the amount of additive is very few, it is difficult to form tablet sometimes.In addition, having if additive is excessive When tablet volume become larger, tablet to take quantitative change more.
《The uniformity of the volume fraction of tablet》
Volume fraction in tablet of the invention is uniform.That is, with using general compound as the tablet of effective component In the case where comparing, tablet of the invention contain oral administration use spherical adsorbent charcoal (such as spheric active carbon) as effectively at Point, thus according to Fig. 1 etc. it will be apparent that, be administered orally spherical adsorbent charcoal between there are gaps.It considers：If it exists should The coarse part in the intensive part in gap and gap, then hardness or wear intensity of tablet etc. reduce.In other words, it is contemplated that：If Exist in tablet by the uneven of the volume fraction formed with spherical adsorbent charcoal and additive is administered orally, then the hardness of tablet Or wear intensity etc. reduces.That is, the volume fraction of tablet is uniformly, hardness and wear intensity of tablet etc. to can be improved as a result,.
Such as it can be by the following method come the uniformity of the volume fraction of specific tablet of the invention.That is, can be in following feelings Determine that the uniformity of tablet is high under condition：In each dividing body that the length in the flat direction of tablet is divided into trisection, logical X ray CT microscope is crossed to the center for the length for being located at flat direction and positioned at the center of the tablet from upper surface by one In the case that the volume fraction for the cube that side 2mm is formed is parsed, the opposite mark of the volume fraction of the cube of three dividing bodies Quasi- deviation is 5% or less.
As shown in Figure 1, tablet other than the pill of spherical shape, has flat shape.Fig. 1 (A) is indicated from upper surface The flat tablet of observation, and Fig. 1 (B) indicates the flat tablet from side.In the feelings of the tablet from upper surface Under condition, tablet is in the shapes such as round or ellipse, quadrangle or rectangle as Fig. 1 (A) mostly, but tablet usually has There is symmetrical form, it can specific " cube at the center of the tablet from upper surface as shown in the dotted line of the square of Fig. 1 (A) Body ".In addition, can be set as shown in Fig. 1 (B) in the case where tablet flat from side by the length in flat direction Be divided into the dividing body of trisection, in respective dividing body, can shown in dotted line like that specific " the length positioned at flat direction Center cube ".Therefore, can it is specific " positioned at the length in flat direction center and be located at tablet from upper surface Center three cubes formed by one side 2mm ".It should be noted that in the case where tablet is the pill of spherical shape, Flat direction can be set as to arbitrary direction, specific " center of the length in flat direction " and " tablet from upper surface " center " etc..
For three cubes, can be parsed by X ray CT microscope to calculate the body of each cube Product rate.Moreover, calculating the relative standard deviation of the volume fraction of three obtained cube, it is in relative standard deviation In 5% situation below, it is determined as that the uniformity of tablet is high.
It should be noted that the length in the flat direction of tablet be less than 6mm in the case where, formed by one side 2mm three A cube is locally overlapped sometimes.But even if in the case where three cubes are overlapped, it still can be to cube of three dividing bodies The relative standard deviation of the volume fraction of body is calculated, they relative standard deviation be 5% situation below under, can determine that It is high for the uniformity of tablet.
The relative standard deviation of the volume fraction is preferably 4.7% hereinafter, further preferably 4.5% or less.Opposite mark Quasi- deviation is smaller, then uniformity more improves, and can more improve hardness or wear intensity of tablet etc..Therefore, the volume fraction is opposite The lower limit of standard deviation is most preferably 0% or more, can be 0.1% or more in practical, can also be 0.3% or more, can also be 0.4% or more.The range of the relative standard deviation of the volume fraction may be, for example, 0.1~5%, can also be 0.3~4.7%, It can be 0.4~4.5%.《The uniformity of additive being locally present》
The distribution of additive in tablet of the invention is uniform, that is, with the previous tablet containing spheric active carbon It compares, the excellent in uniformity of the volume fraction of the additive of tablet of the invention.For example, being pinched as shown in Fig. 2 (B) by previous In the legal obtained tablet containing spheric active carbon, additive is offset to the part close to the surface on tablet top (by white Indicate additive), the uniformity of additive is low.It considers：In the case where additive biasing, hardness or wear intensity of tablet etc. It reduces.In other words, it is contemplated that：If there are the uneven of the volume fraction of additive, the hardness or wear intensity of tablet in tablet Deng reduction.That is, the volume fraction of additive is uniformly, hardness and wear intensity of tablet etc. to can be improved as a result,.
Such as it can be by the following method come the uniformity of the volume fraction of specific additive of the invention.In following situation Under, it can determine that the uniformity of the distribution of additive is high：Passing through X ray CT microscope from upper surface to lower surface to from upper surface Observe tablet in the case where central part and positioned at the end of the straight line extended from center to four directions, from upper surface under Surface on one side for 1mm five prisms additive volume fraction parsed in the case where, every 1mm of five prisms3's The ratio between maxima and minima of additive volume fraction is 100 or less.That is, being added in five prisms in tablet of the invention The ratio between maxima and minima of agent volume fraction is 100 or less.On the other hand, it in previous tablet, is added in five prisms The ratio between maxima and minima of agent volume fraction is more than 100, therefore the hardness of tablet or wear intensity etc. reduce.
As shown in figure 3, tablet other than the pill of spherical shape, has flat shape.Fig. 3 (A) is indicated from upper surface The flat tablet of observation, and Fig. 3 (B) indicates the flat tablet from side.In the feelings of the tablet from upper surface Under condition, tablet is in the shapes such as round or ellipse, quadrangle or rectangle as Fig. 3 (A) mostly, but tablet usually has There is symmetrical form, it can be specific " the central part in the case where from upper surface as shown in the dotted line of the C square of Fig. 3 (A) Prism ".In addition, specific " can be located at from center to four directions and extend shown in the dotted line of N, E, S and W square of Fig. 3 (A) Straight line end prism ".In addition, in the case where tablet flat from side, it is described as shown in the dotted line of Fig. 3 (B) Prism is located at the position from upper surface to lower surface in the flat direction of tablet.It therefore, can specific " the case where from upper surface Under central part prism " and " positioned at the center from tablet to four directions extend straight line end prism ".
For five prisms, can be parsed from upper surface to lower surface by X ray CT microscope to calculate The volume fraction of the additive of each prism.Moreover, every 1mm can be calculated in the arbitrary position of prism3Additive volume fraction, ask Every 1mm out3Additive volume fraction maximum value and minimum value.
In the present invention, in every 1mm3The ratio between the maxima and minima of additive volume fraction be 100 or less situation Under, it can determine that the uniformity of the distribution for additive is high, but the ratio between described maxima and minima is preferably 99 hereinafter, more preferably For 98 hereinafter, further preferably 96 or less.The ratio between maxima and minima is smaller, then the uniformity of additive more improves, more Hardness or the wear intensity etc. of tablet can be improved.Therefore, the lower limit of the ratio between maxima and minima is most preferably 1 or more, practical On, it can be 2 or more, can also be 4 or more, can also be 6 or more.The range of the ratio between maxima and minima may be, for example, 1~100, It can also be 2~99, can also be 4~98, can also be 6~96.
It should be noted that according to the shape of tablet, compared with the prism of location of C, the prism of the position N, E, S and W Height is lower sometimes, in this case, can measure every 1mm by finding out3Additive volume fraction, from upper surface to lower surface Additive volume fraction, " the ratio between the maxima and minima of additive volume fraction " can be calculated.
(X ray CT microscope)
The X ray CT microscope parsed to the volume fraction of tablet and the volume fraction of additive in the present invention is such as Lower device：It can be carried out with inside of the high-resolution of submicron order to samples such as materials or tablet plane (2D) or three-dimensional (3D) Observation.It can be parsed with fine structure of the high-resolution to material or tablet etc..For example, as described in the embodiment that Sample can parse the volume fraction of the tablet formed by spheric active carbon and additive, or can also be only to the body of additive Product rate is parsed.
As X ray CT microscope, it is possible to use commercially available " nano3DX (high resolution 3 d X-ray microscope：Strain formula meeting Society is of science " and " three-dimensional measurement X ray CT device TDM series：Big and scientific Co., Ltd. ".Described device has 1 μm or less High-resolution, can be used attached software or image processing software ImageJ of device etc. to the volume fraction or additive of tablet Volume fraction is calculated.
(bonding additive)
Bonding used in tablet of the invention includes with additive：Sodium alginate, propylene glycol alginate, carboxymethyl are fine Tie up element, calcium carboxymethylcellulose, ghatti gum, carragheen, carboxyl vinyl polymer, sodium carboxymethylcellulose, xanthan gum, melon Your Jiao, Wen Quince seed glue, glucomannans, copolyvidone, gellan gum, gelatin, tamarind gum, tara gum, dextrin, cornstarch, Bassora gum, Sodium Hyaluronate, hydroxyethyl cellulose, hydroxypropul starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, Pu Lu Blue polysaccharide, povidone, polyethylene oxide, polyvinyl alcohol, polyvinyl alcohol-acryl acid-methyl methacrylate copolymer, poly- second two Alcohol 6000, ethyl cellulose, methylcellulose, phosphoric acid crosslinked starch, locust bean gum, agar, cold plum powder, complete pre-gelatinized are formed sediment Powder, avicel cellulose sodium carboxymethylcellulose, oxidized starch, low degree of substitution hydroxypropyl cellulose, part pre-gelatinized starch, sugar Class, sugar alcohol or their combination.Bonding is coated on additive and spherical adsorbent charcoal is administered orally, which makes respectively The tablet of the invention that the spherical adsorbent charcoal of a oral administration combines has the hardness of 105N or more.
(other additives)
Hereinafter, to can be used as bonding with the additive (other additives) other than additive carry out using additive carry out Explanation.
In general, additive used in pharmaceuticals is recorded in " pharmaceuticals additive topical reference book 2016 ", such as can enumerate： Excipient, lubricant, disintegrating agent, surfactant and binder etc..Excipient, lubricant, disintegrating agent and binder Function is not necessarily single, such as the avicel cellulose for being classified as excipient also has function as disintegrating agent in most instances Can, in addition, also there is the function as the binder for improving mouldability in direct compression method.Therefore, sometimes excipient, profit Lubrication prescription, disintegrating agent and the respective function of binder can repeat.It is following to list excipient, lubricant, disintegrating agent and bonding The additive for not being classified as these additives also can be used as other additives in the example of agent.
Excipient is mainly used for increment (incremental agent) or dilutes the additive of (diluent), specifically, can enumerate：It forms sediment Powder, calcium monohydrogen phosphate, synthetic aluminium silicate or magnesium trisilicate etc..
In addition, binder is for providing cohesive force to main ingredient, incremental agent and carrying out molding additive, it is for maintaining Dosage form, prevent packaging process, conveying when breakage, and improve mechanical strength additive.Specifically, can enumerate：Crystallization Cellulose, low degree of substitution hydroxypropyl cellulose, sodium carboxymethylcellulose, cellulose powder, hydroxypropyl methyl cellulose, methyl are fine Tie up element, hydroxypropyl cellulose, starch, complete pre-gelatinized starch, part pre-gelatinized starch, dextrin, Arabic gum, sodium alginate, Bassora gum, purification gelatin, polyvinyl alcohol or povidone etc..
In turn, disintegrating agent is so that preparation is disintegrated and is dispersed for moistening in alimentary canal in the case where taking tablet At the additive of particle.Specifically, can enumerate：Carboxymethyl cellulose, calcium carboxymethylcellulose, low substitution degree hydroxy-propyl fiber Element, hydroxypropyl methyl cellulose, cellulose powder, starch, carboxymethyl starch sodium or hydroxypropul starch etc..
Lubricant is that have the various property such as mobility, fillibility, adhesion and the mouldability for improving powder in tabletting The additive of the function of matter is the additive of the quality and manufacture efficiency for improving tablet.Specifically, can enumerate：Sucrose Aliphatic ester, talcum, magnesium stearate or stearic acid etc..
Surfactant can be enumerated：Polyoxyethylene base Aethoxy Sklerol, higher alcohol hydrosulphate, N- cocounut oil acyl-L-arginine second Ester DL- pyrrolidone carboxylic acid salt, N- cocounut oil acyl-N- methylaminoethyl sodium sulfonate, cholesterol, self-emulsifying type glycerol monostearate Ester, sucrose fatty ester, saualane, stearyl alcohol, 40 stearate of polyethylene glycol (polyoxyl 40stearate), cetanol, Cetomacrogol 1000, diethyl sebacate, sorbitan fatty acid ester, Span-83, detergent alkylate Sodium sulfonate, sorbitan trioleate, nonylphenoxypolyoxyethylenes ethane sulfuric ester ammonium liquid, polyoxyethylene octylphenyl Ether, Crodaret 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl base ether, gathers oleyl amine polyoxyethylene Ethylene oxide cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitol beeswax, ethylene nonyl Phenyl ether, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (124) polyoxypropylene (39) glycol, polyoxyethylene (160) polyoxypropylene (30) Glycol, polyoxyethylene (2E.O.) sodium laureth sulfate (70%), gathers polyoxyethylene (10) polyoxypropylene (4) cetyl ether 35 castor oil of ethylene oxide, polysorbate 20, polysorbate 60, polyoxyethylene sorbitan monoleate, polyethylene glycol 400, sorbitan list oleic acid Ester, glycerin monostearate, sorbitan monostearate, Span-20, N- coco-nut oil fatty acid acyl Base L-arginine ethyl ester DL- pyrrolidone carboxylic acid salt, lauryl dimethyl amine oxide liquid, Lauryl pyrolidone, laurel Base sodium sulphate, lauric acid diethyl amide, sodium N-lauroyl sarcosinate, Lauromacrogol (Lauromacrogol), polyoxyethylene laural Base ether phosphoric acid sodium or polyoxyethylene oleyl ether phosphate (8MOL) etc..
(content that bonding uses additive)
As long as effect of the invention can be obtained, oral administration with spherical adsorbent charcoal (such as spheric active carbon) with bond with adding Add the weight ratio of agent to be just not particularly limited, the content of the additive of the bonding in tablet of the invention be preferably 1 weight % with On, more preferably 1.5 weight % or more, further preferably 2 weight % or more.In the very few situation of the amount of bonding additive Under, the hardness of the tablet obtained sometimes reduces.The upper limit of bonding additive does not limit, and bonding is preferably 35 weights with additive % is measured hereinafter, more preferably 30 weight % are hereinafter, further preferably 25 weight % or less.If bonding additive is excessive, Sometimes the volume of tablet becomes larger, tablet to take quantitative change more.It is easy to become the viewpoint of 105N or more from the hardness of obtained tablet Consider, 1~35 weight % that ranges preferably from of the content of the bonding additive in tablet of the invention (or can be 1~30 Weight % or 1~25 weight), more preferably 1.5~30 weight % (or can be 1.5~25 weight % or 1.5~20 weights Measure %), it is still more preferably 2~25 weight % (or can be 2~20 weight % or 2~17 weight %).
In addition, tablet of the invention can also contain other additives as additive, as long as effect of the invention can be obtained, Bonding is also not particularly limited with the weight ratio of additive and other additives, it is preferred that relative to bonding additive 100 Parts by weight, other additives are preferably 10000 parts by weight hereinafter, more preferably 1000 parts by weight are hereinafter, further preferably 100 Parts by weight are hereinafter, below most preferably 50 parts by weight.If the amount of other additives is excessive, the hardness of the tablet obtained sometimes drops It is low.It should be noted that the lower limit of above-mentioned weight ratio is not particularly limited, relative to bonding 100 parts by weight of additive, other The content of additive may be, for example, 0.1 parts by weight or more, can also be 1 parts by weight or more, can also be to be more than 10 parts by weight.
(2) manufacturing method of tablet
The manufacturing method of tablet of the invention includes following process：It (1) will be containing selected from by sodium alginate, alginic acid the third two Alcohol ester, carboxymethyl cellulose, calcium carboxymethylcellulose, ghatti gum, carragheen, carboxyl vinyl polymer, carboxymethyl cellulose Plain sodium, xanthan gum, guar gum, Wen Quince seed glue, glucomannans, copolyvidone, gellan gum, gelatin, tamarind gum, tara gum, Dextrin, cornstarch, bassora gum, Sodium Hyaluronate, hydroxyethyl cellulose, hydroxypropul starch, hydroxypropyl cellulose, hydroxypropyl first Base cellulose, pulullan polysaccharide, povidone, polyethylene oxide, polyvinyl alcohol, polyvinyl alcohol-acrylic acid-methacrylic acid methyl esters Copolymer, Macrogol 6000, ethyl cellulose, methylcellulose, phosphoric acid crosslinked starch, locust bean gum, agar, cold plum powder, Complete pre-gelatinized starch, avicel cellulose sodium carboxymethylcellulose, oxidized starch, low degree of substitution hydroxypropyl cellulose, part are pre- The solution for the bonding additive in group that gelatinized starch, carbohydrate and glycitols are constituted is spraying or is added dropwise in oral administration use Spherical adsorbent charcoal (such as spheric active carbon) coats the spherical adsorbent charcoal of oral administrable with additive by bonding；(2) it presses Then contracting molding procedure carries out compression forming by the way that solvent is made an addition to the spherical adsorbent charcoal of oral administration being wrapped by, Obtain formed body；And obtained formed body is dried in (3).
" bonding additive " used in the manufacturing method of tablet of the invention can be used it is described " (1) contain take orally to Bonding additive described in the tablet of a medicinal spherical adsorbent charcoal " column.
《It coats process (1)》
Method for coating (1)：It will be containing selected from fine by sodium alginate, propylene glycol alginate, carboxymethyl cellulose, carboxymethyl Tie up plain calcium, ghatti gum, carragheen, carboxyl vinyl polymer, sodium carboxymethylcellulose, xanthan gum, guar gum, Wen Quince seed It is glue, glucomannans, copolyvidone, gellan gum, gelatin, tamarind gum, tara gum, dextrin, cornstarch, bassora gum, transparent Matter acid sodium, hydroxyethyl cellulose, hydroxypropul starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pulullan polysaccharide, poly- dimension Ketone, polyethylene oxide, polyvinyl alcohol, polyvinyl alcohol-acryl acid-methyl methacrylate copolymer, Macrogol 6000, ethyl Cellulose, methylcellulose, phosphoric acid crosslinked starch, locust bean gum, agar, cold plum powder, complete pre-gelatinized starch, avicel cellulose Sodium carboxymethylcellulose, oxidized starch, low degree of substitution hydroxypropyl cellulose, part pre-gelatinized starch, carbohydrate and glycitols structure At group in the solution of bonding additive sparge oral administration with spherical adsorbent charcoal (such as spheric active carbon), by bonding The spherical adsorbent charcoal of oral administrable is coated with additive.As method for coating, spray-on process is used.It, can as spray-on process It enumerates：Top-spray mode, tangent line spray pattern, bottom spray mode or side spray pattern etc..
For example, bonding additive and other additives are dissolved in solvent in the case where top-spray mode, make Standby spray liquid.Then, for example, oral administration is put into rotational flow applying device or fluidized bed granulation dress with spherical adsorbent charcoal It sets, goes out spray liquid by spraying from top.
It as solvent used in spray liquid, being not particularly limited, be had using can be used as all of pharmaceuticals additive Solvent, such as can enumerate：Water, acetic acid, acetone, methyl phenyl ethers anisole, n-butyl alcohol, 2- butanol, n-butyl acetate, t-butyl methyl ether, Cumene, dimethyl sulfoxide, ethyl alcohol, ethyl acetate, diethyl ether, Ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate Ester, methyl acetate, 3- methyl-1-butanol, methyl ethyl ketone, 2- methyl-1-propyl alcohol, pentane, 1- amylalcohol, 1- propyl alcohol, 2- propyl alcohol, Propyl acetate, tetrahydrofuran, acetonitrile, chlorobenzene, chloroform, hexamethylene, 1,2- dichloroethylene, methylene chloride, N, N- dimethylacetamide Amine, N,N-dimethylformamide, 1,4- dioxane, cellosolvo, ethylene glycol, formamide, hexane, methanol, 2- methoxyl group Ethyl alcohol, methyl butyl ketone, hexahydrotoluene, N-Methyl pyrrolidone, nitromethane, pyridine, sulfolane, tetrahydronaphthalene, toluene, 1,1,2- trichloro ethylene or dimethylbenzene etc..In addition, surfactant is not particularly limited, can enumerate：Polyoxyethylene base Aethoxy Sklerol, Higher alcohol hydrosulphate, N- cocounut oil acyl-L-arginine ethyl ester DL- pyrrolidone carboxylic acid salt, N- cocounut oil acyl-N- methylaminoethyl Sodium sulfonate, cholesterol, self-emulsifying type glycerin monostearate, sucrose fatty ester, saualane, stearyl alcohol, polyethylene glycol 40 are hard Resin acid ester, cetanol, cetomacrogol 1000, diethyl sebacate, sorbitan fatty acid ester, sorbitan sesquialter oleic acid Ester, neopelex, sorbitan trioleate, nonylphenoxypolyoxyethylenes ethane sulfuric ester ammonium liquid, polyoxy Ethylene octyl phenyl ether, oleyl amine polyoxyethylene, Crodaret 20, polyoxyethylene hydrogenated castor oil 60, polyoxy second Alkene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitol bee Wax, ethylene nonyl phenyl ether, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene (105) polyoxypropylene (5) two Alcohol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (124) polyoxypropylene (39) glycol, polyoxyethylene (160) Polyoxypropylene (30) glycol, polyoxyethylene (10) polyoxypropylene (4) cetyl ether, polyoxyethylene (2E.O.) lauryl ether sulphur Sour sodium (70%), Emulsifier EL-35, polysorbate 20, polysorbate 60, polyoxyethylene sorbitan monoleate, polyethylene glycol 400, sorb Sugar alcohol acid anhydride monoleate, glycerin monostearate, sorbitan monostearate, Span-20, N- coconut palm Seed oil fatty acid acyl L-arginine ethyl ester DL- pyrrolidone carboxylic acid salt, lauryl dimethyl amine oxide liquid, lauryl pyrrole Pyrrolidone, NaLS, lauric acid diethyl amide, sodium N-lauroyl sarcosinate, Lauromacrogol (Lauromacrogol), Polyoxyethylene lauryl ether sodium phosphate or polyoxyethylene oleyl ether phosphate (8MOL) etc..
As long as bonding is substantially homogeneously coated on oral administration with additive with spherical adsorbent charcoal (such as spheric active carbon), Amount of the bonding with additive relative to quantity of solvent is just not particularly limited, and relative to solvent, bonding is preferably 0.01 with additive ~100w/v%, more preferably 0.1~50w/v%, further preferably 1~15w/v%.
《Compression forming process (2)》
It is (such as spherical with spherical adsorbent charcoal that solvent is made an addition to the oral administration being wrapped by by compression forming process (2) Active carbon), then carry out compression forming.For example, solvent to be made an addition to the spherical adsorbent charcoal of oral administration being wrapped by, pressed It after shortening type into, is dried, the tablet that intensity is 105N or more can be obtained as a result,.
As solvent, organic solvent, water or their mixed liquor can be enumerated.Having in the mixed liquor of organic solvent and water The capacity of solvent and water ratio is not particularly limited, and preferably 5:95~95:5, more preferably 15:85~85:15, it is further excellent It is selected as 30:70~70:30.By the way that for the range, the bonding that can make water penetration that spherical adsorbent charcoal be administered orally to cladding is used Additive.
(organic solvent)
As long as effect of the invention can be obtained, organic solvent workable for the manufacturing method is not particularly limited, example It can such as enumerate：Acetic acid, acetone, methyl phenyl ethers anisole, n-butyl alcohol, 2- butanol, n-butyl acetate, t-butyl methyl ether, cumene, dimethyl are sub- Sulfone, ethyl alcohol, ethyl acetate, diethyl ether, Ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3- Methyl-1-butanol, methyl ethyl ketone, 2- methyl-1-propyl alcohol, pentane, 1- amylalcohol, 1- propyl alcohol, 2- propyl alcohol, propyl acetate, tetrahydro Furans, acetonitrile, chlorobenzene, chloroform, hexamethylene, 1,2- dichloroethylene, methylene chloride, DMAC N,N' dimethyl acetamide, N, N- dimethyl Formamide, 1,4- dioxane, cellosolvo, ethylene glycol, formamide, hexane, methanol, 2-methyl cellosolve, methyl butyl Ketone, hexahydrotoluene, N-Methyl pyrrolidone, nitromethane, pyridine, sulfolane, tetrahydronaphthalene, toluene, tri- chloroethene of 1,1,2- Alkene or dimethylbenzene etc..《Drying process (3)》
In the manufacturing method of tablet of the invention, obtained formed body is dried.As long as drying means makes to form There is no limit for the solvent evaporation of body, such as can enumerate：It is freeze-dried, be dried under reduced pressure, blow it is dry, spontaneously dry or heating It is dry.
For example, heating temperature is not particularly limited in the case where heat drying, such as preferably 50~200 DEG C, preferably It is 80~180 DEG C.Heating time is also not particularly limited, and preferably 10 minutes~3 hours, more preferably 30 minutes~2 hours.
But in the case where heating temperature height, heating time can be shortened, those skilled in the art can suitably determine to add Hot temperature and heating time.
In addition, the moisture content of the tablet obtained by drying process (3) is not particularly limited, preferably 0.01~20 weight Measure %, more preferably 0.1~10 weight %.
Embodiment
Hereinafter, the present invention is specifically described by embodiment, but the scope of the present invention is not limited to these implementations Example.
《Production Example 1：The manufacture of the spherical carbonaceous material of porosity》
It is same with the method described in embodiment 1 of Japanese Patent No. No. 3522708 (Japanese Unexamined Patent Publication 2002-308785 bulletins) Obtain to sample the spherical carbonaceous material of porosity.Concrete operations are as follows.
By petroleum pitch (softening point=210 DEG C；Quinoline non-soluble ingredient=1 weight % or less；Atomic ratio=0.63 H/C) 68kg and naphthalene 32kg charging is in the pressure vessel of the internal volume 300L with stirring blade, after 180 DEG C of progress melting mixings, It is cooled to 80~90 DEG C to be squeezed out, obtains band-like formed body.It then, should in such a way that diameter and length ratio are about 1~2 Band-like formed body is broken.
It is dissolving the polyvinyl alcohol (saponification degree=88%) of 0.23 weight % and is being heated in 93 DEG C of aqueous solution, putting into institute Fragment is stated, after being dispersed with stirring progress spheroidizing, the polyvinyl alcohol water solution is replaced with water, is thus cooled down, 20 DEG C cooling 3 hours, carry out the solidification of pitch and the precipitation of naphthalene crystal, obtain pelletted pitch formed body slurry.
After filtering removes most water, by the n-hexane of about 6 times of weight of pelletted pitch formed body by asphalt moulding Naphthalene in body extracts removal.Using fluidized bed, import heat air while, the porosity pelletted pitch liter that will as above obtain Temperature keeps being aoxidized for 1 hour to 235 DEG C, then at 235 DEG C, obtains the spherical oxidized asphalt of porosity of hot infusibility.
Then, spherical to porosity at 900 DEG C in the nitrogen atmosphere containing 50vol% water vapour using fluidized bed Oxidized asphalt be activated within 170 minutes, porosity spheric active carbon is obtained, and then it is used fluidized bed, in oxygen concentration Under the nitrogen of 18.5vol% and the mixed-gas atmosphere of oxygen, in 470 DEG C of progress, 15 minutes 3 hours oxidation processes, then with stream Change bed in a nitrogen atmosphere, in 900 DEG C of progress reduction treatment in 17 minutes, obtain the spherical carbonaceous material of porosity.It will obtain in this way The spherical carbonaceous material of porosity use in pharmacological test example below as spheric active carbon.
The key property of obtained carbonaceous material is as described below.
Specific surface area=1300m2/ g (BET method)；
Pore volume=0.08mL/g
(passing through the pore volume for pore diameter 20~15000nm range that mercury injection method is found out)
Average grain diameter=350 μm；
Acidic groups=0.67meq/g；
Total alkaline base=0.54meq/g；
Compression strength=31.2MPa；And
Apply deformation rate=0.7% when 2MPa pressure.
《Production Example 2：The manufacture of the spherical carbonaceous material of porosity》
Porosity Spherical Carbon is got similarly with the method described in embodiment 1 of Japanese Unexamined Patent Publication 2005-314416 bulletin Metallic substance (the modified spheric active carbon in surface).Concrete operations are as follows.
Deionization exchanged water 220g and methylcellulose 58g is added to the detachable flask of 1L, is properly added thereto Divinylbenzene (57% divinylbenzene and 43% vinyl xylene, ethyl vinyl benzene) 184g, 2 of styrene 105g, purity 57%, 2 '-azos bis- (2,4- methyl pentane nitrile) 1.68g and n-butyl alcohol 63g as pore-foaming agent, then in nitrogen displacement system The two-phase system stirs with 200rpm in portion, after being heated to 55 DEG C, is kept for 20 hours in this state.Obtained resin is filtered, After being dried with rotary evaporator, n-butyl alcohol is removed from resin by distillation with pressure Reduction Dryer, is then subtracted at 90 DEG C It press dry dry 12 hours, obtains 180 μm of average grain diameter of spherical porous synthetic resins.The specific surface area of porous synthetic resins is about For 90m2/g。
Obtained spherical porous synthetic resins 100g is fitted into the reaction tube with porous plate, with vertical tube furnace into Row cure treatment.Non-fusible condition is to make dry air from reaction tube lower part towards upper flow with 3L/min, with 5 DEG C/h liter Temperature is kept for 4 hours at 260 DEG C to after 260 DEG C, thus obtains spherical porosity resene.In nitrogen atmosphere, at 600 DEG C After carrying out heat treatment in 1 hour to spherical porosity resene, using fluidized bed, in the nitrogen gas of the water vapour containing 64.5vol% It carries out being activated for 10 hours in atmosphere, at 820 DEG C, has obtained spheric active carbon.In turn, the spherical activity that will be obtained with fluidized bed Charcoal under the nitrogen of oxygen concentration 18.5vol% and the mixed-gas atmosphere of oxygen, at 470 DEG C of progress oxidation in 15 minutes in 3 hours Reason, then with fluidized bed in a nitrogen atmosphere, carries out reduction treatment in 17 minutes at 900 DEG C, obtained the spherical activity of surface modification Charcoal.
The key property of the modified spheric active carbon in obtained surface is as follows.
Specific surface area=1763m2/ g (BET method)；
Pore volume=0.05mL/g
(passing through the pore volume for pore diameter 20~15000nm range that mercury injection method is found out)
Average grain diameter=111 μm (Dv50)；
Acidic groups=0.59meq/g；
Total alkaline base=0.61meq/g；
Bulk density=0.50g/cm3；
Compression strength=436.5MPa；And
Apply deformation rate=0.2% when 2MPa pressure.
It should be noted that in the present specification, being come although not recording using spheric active carbon obtained in Production Example 2 The embodiment of tablet is made, but tablet of the invention can be got similarly with spheric active carbon obtained in Production Example 1.
《Embodiment 1》
The spheric active carbon 500g obtained by Production Example 1 is put into rotational flow applying device (MP-01), it is spraying such as table The spray liquid of formula shown in 1.Then it is dried, has obtained cladding product 535.5g.Using low pressure molding machine, relative to packet It covers the ratio that product 1g is 1.2mL and adds ethanol/water mixed liquor (6:4) after, obtained cladding product is formed, are dried, thus The tablet of diameter 15mm is obtained.
The rate of recovery of the expression cladding product of table 2.Cladding product are calculated by obtained cladding product amount/cladding product theoretical amount × 100 The rate of recovery (%).The above-mentioned rate of recovery is higher, then oral administration is more improved with the yield of spherical adsorbent charcoal.
Obtained tablet is parsed by X ray CT microscope, obtained the volume fraction of tablet shown in table 54 with And the result of tablet inner additive volume fraction shown in table 55.
[table 1]
Ingredient name Use level
Pulullan polysaccharide 30g
NaLS 4.5g
Purified Water 500mL
[table 2]
The theoretical amount (g) of cladding product Obtained cladding product amount (g) The rate of recovery (%) of cladding product
534.5 535.5 100.2
《Embodiment 2》
The spheric active carbon 500g obtained by Production Example 1 is put into rotational flow applying device (MP-01), it is spraying such as table The spray liquid of formula shown in 3.Then it is dried, has obtained cladding product 751.78g.Using low pressure molding machine, with relative to The ratio that cladding product 1g is 1.2mL adds ethanol/water mixed liquor (6:4) after, obtained cladding product is formed, are dried, by This has obtained the tablet of diameter 12mm.
The rate of recovery of the expression cladding product of table 4.Obtained tablet is parsed by X ray CT microscope, has obtained table The result of tablet inner additive volume fraction shown in the volume fraction and table 55 of tablet shown in 54.
[table 3]
[table 4]
The theoretical amount (g) of cladding product Obtained cladding product amount (g) The rate of recovery (%) of cladding product
769.23 751.78 97.7
《Embodiment 3》
The spheric active carbon 500g obtained by Production Example 1 is put into rotational flow applying device (MP-01), it is spraying such as table The spray liquid of formula shown in 5.Then it is dried, has obtained cladding product 512.5g.Obtained cladding product are filled in Teflon The molding die (diameter 12mm, depth 10.2mm, R16mm) of grand (Teflon) (registered trademark) system, relative to cladding product 1g For 0.9mL ratio add water after, by be installed on the moulding stick of blender to top gently compress come to tablet surface into Row finishing, is dried, results in the tablet of diameter 12mm.
The rate of recovery of the expression cladding product of table 6.Obtained tablet is parsed by X ray CT microscope, has obtained table The result of tablet inner additive volume fraction shown in the volume fraction and table 55 of tablet shown in 54.
[table 5]
Ingredient name Use level
Pulullan polysaccharide 30g
Purified Water 500mL
[table 6]
The theoretical amount (g) of cladding product Obtained cladding product amount (g) The rate of recovery (%) of cladding product
530.0 512.5 96.7
《Embodiment 4》
The spheric active carbon 500g obtained by Production Example 1 is put into rotational flow applying device (MP-01), it is spraying such as table The spray liquid of formula shown in 7.Then it is dried, has obtained cladding product 500.0g.Using low pressure molding machine, relative to packet It covers the ratio that product 1g is 1.9mL and adds ethanol/water mixed liquor (4:6) after, obtained cladding product is formed, are dried, thus The tablet of diameter 12mm is obtained.
The rate of recovery of the expression cladding product of table 8.Obtained tablet is parsed by X ray CT microscope, has obtained table The result of tablet inner additive volume fraction shown in the volume fraction and table 55 of tablet shown in 54.
[table 7]
Ingredient name Use level
Sodium alginate 30g
Purified Water 1000mL
[table 8]
The theoretical amount (g) of cladding product Obtained cladding product amount (g) The rate of recovery (%) of cladding product
530.0 500.0 94.3
《Embodiment 5》
The spheric active carbon 500g obtained by Production Example 1 is put into rotational flow applying device (MP-01), it is spraying such as table The spray liquid of formula shown in 9.Then it is dried, has obtained cladding product 506.8g.Using low pressure molding machine, relative to packet It covers the ratio that product 1g is 1.4mL and adds ethanol/water mixed liquor (5:5) after, obtained cladding product is formed, are dried, thus The tablet of diameter 12mm is obtained.
The rate of recovery of the expression cladding product of table 10.Obtained tablet is parsed by X ray CT microscope, has obtained table The result of tablet inner additive volume fraction shown in the volume fraction and table 55 of tablet shown in 54.
[table 9]
Ingredient name Use level
Propylene glycol alginate 30g
Purified Water 1100mL
[table 10]
The theoretical amount (g) of cladding product Obtained cladding product amount (g) The rate of recovery (%) of cladding product
530.0 506.8 95.6
《Embodiment 6》
The spheric active carbon 500g obtained by Production Example 1 is put into rotational flow applying device (MP-01), it is spraying such as table The spray liquid of formula shown in 11.Then it is dried, has obtained cladding product 564.4g.Using low pressure molding machine, with relative to The ratio that cladding product 1g is 1.1mL adds ethanol/water mixed liquor (6:4) after, obtained cladding product is formed, are dried, by This has obtained the tablet of diameter 12mm.
The rate of recovery of the expression cladding product of table 12.Obtained tablet is parsed by X ray CT microscope, has obtained table The result of tablet inner additive volume fraction shown in the volume fraction and table 55 of tablet shown in 54.
[table 11]
Ingredient name Use level
Ghatti gum 100g
Purified Water 1000mL
[table 12]
The theoretical amount (g) of cladding product Obtained cladding product amount (g) The rate of recovery (%) of cladding product
600.0 564.4 94.1
《Embodiment 7》
The spheric active carbon 500g obtained by Production Example 1 is put into rotational flow applying device (MP-01), it is spraying such as table The spray liquid of formula shown in 13.Then it is dried, has obtained cladding product 530.8g.Using low pressure molding machine, with relative to The ratio that cladding product 1g is 1.2mL adds ethanol/water mixed liquor (2:8) after, obtained cladding product is formed, are dried, by This has obtained the tablet of diameter 12mm.
The rate of recovery of the expression cladding product of table 14.Obtained tablet is parsed by X ray CT microscope, has obtained table The result of tablet inner additive volume fraction shown in the volume fraction and table 55 of tablet shown in 54.
[table 13]
Ingredient name Use level
Carboxyl vinyl polymer 45g
Purified Water 3000mL
[table 14]
The theoretical amount (g) of cladding product Obtained cladding product amount (g) The rate of recovery (%) of cladding product
545.0 530.8 97.4
《Embodiment 8》
The spheric active carbon 500g obtained by Production Example 1 is put into rotational flow applying device (MP-01), it is spraying such as table The spray liquid of formula shown in 15.Then it is dried, has obtained cladding product 497.8g.Using low pressure molding machine, with relative to The ratio that cladding product 1g is 1.1mL adds ethanol/water mixed liquor (5:5) after, obtained cladding product is formed, are dried, by This has obtained the tablet of diameter 12mm.
The rate of recovery of the expression cladding product of table 16.Obtained tablet is parsed by X ray CT microscope, has obtained table The result of tablet inner additive volume fraction shown in the volume fraction and table 55 of tablet shown in 54.
[table 15]
Ingredient name Use level
Sodium carboxymethylcellulose 30g
Purified Water 600mL
[table 16]
The theoretical amount (g) of cladding product Obtained cladding product amount (g) The rate of recovery (%) of cladding product
530.0 497.8 93.9
《Embodiment 9》
The spheric active carbon 500g obtained by Production Example 1 is put into rotational flow applying device (MP-01), it is spraying such as table The spray liquid of formula shown in 17.Then it is dried, has obtained cladding product 518.1g.Using low pressure molding machine, with relative to The ratio that cladding product 1g is 1.0mL adds ethanol/water mixed liquor (4:6) after, obtained cladding product is formed, are dried, by This has obtained the tablet of diameter 12mm.
The rate of recovery of the expression cladding product of table 18.Obtained tablet is parsed by X ray CT microscope, has obtained table The result of tablet inner additive volume fraction shown in the volume fraction and table 55 of tablet shown in 54.
[table 17]
Ingredient name Use level
Xanthan gum 45g
Purified Water 3000mL
[table 18]
The theoretical amount (g) of cladding product Obtained cladding product amount (g) The rate of recovery (%) of cladding product
545.0 518.1 95.1
《Embodiment 10》
The spheric active carbon 500g obtained by Production Example 1 is put into rotational flow applying device (MP-01), it is spraying such as table The spray liquid of formula shown in 19.Then it is dried, has obtained cladding product 537.3g.Using low pressure molding machine, with relative to The ratio that cladding product 1g is 1.4mL adds ethanol/water mixed liquor (1:9) after, obtained cladding product is formed, are dried, by This has obtained the tablet of diameter 12mm.
The rate of recovery of the expression cladding product of table 20.Obtained tablet is parsed by X ray CT microscope, has obtained table The result of tablet inner additive volume fraction shown in the volume fraction and table 55 of tablet shown in 54.
[table 19]
Ingredient name Use level
Guar gum 60g
Purified Water 4000mL
[table 20]
The theoretical amount (g) of cladding product Obtained cladding product amount (g) The rate of recovery (%) of cladding product
560.0 537.3 95.9
《Embodiment 11》
The spheric active carbon 500g obtained by Production Example 1 is put into rotational flow applying device (MP-01), it is spraying such as table The spray liquid of formula shown in 21.Then it is dried, has obtained cladding product 525.2g.Using low pressure molding machine, with relative to The ratio that cladding product 1g is 1.3mL adds ethanol/water mixed liquor (1:9) after, obtained cladding product is formed, are dried, by This has obtained the tablet of diameter 12mm.
The rate of recovery of the expression cladding product of table 22.Obtained tablet is parsed by X ray CT microscope, has obtained table The result of tablet inner additive volume fraction shown in the volume fraction and table 55 of tablet shown in 54.
[table 21]
Ingredient name Use level
Glucomannans 45g
Purified Water 3000mL
[table 22]
The theoretical amount (g) of cladding product Obtained cladding product amount (g) The rate of recovery (%) of cladding product
545.0 525.2 96.4
《Embodiment 12》
The spheric active carbon 500g obtained by Production Example 1 is put into rotational flow applying device (MP-01), it is spraying such as table The spray liquid of formula shown in 23.Then it is dried, has obtained cladding product 622.6g.Using low pressure molding machine, with relative to The ratio that cladding product 1g is 0.6mL adds ethanol/water mixed liquor (1:9) after, obtained cladding product is formed, are dried, by This has obtained the tablet of diameter 12mm.
The rate of recovery of the expression cladding product of table 24.Obtained tablet is parsed by X ray CT microscope, has obtained table The result of tablet inner additive volume fraction shown in the volume fraction and table 55 of tablet shown in 54.
[table 23]
Ingredient name Use level
Copolyvidone 225g
Purified Water 1200mL
[table 24]
The theoretical amount (g) of cladding product Obtained cladding product amount (g) The rate of recovery (%) of cladding product
725.0 622.6 85.9
《Embodiment 13》
The spheric active carbon 500g obtained by Production Example 1 is put into rotational flow applying device (MP-01), it is spraying such as table The spray liquid of formula shown in 25.Then it is dried, has obtained cladding product 548.3g.Using low pressure molding machine, with relative to The ratio that cladding product 1g is 1.2mL adds ethanol/water mixed liquor (1:9) after, obtained cladding product is formed, are dried, by This has obtained the tablet of diameter 12mm.
The rate of recovery of the expression cladding product of table 26.Obtained tablet is parsed by X ray CT microscope, has obtained table The result of tablet inner additive volume fraction shown in the volume fraction and table 55 of tablet shown in 54.
[table 25]
Ingredient name Use level
Tara gum 75g
Purified Water 6000mL
[table 26]
The theoretical amount (g) of cladding product Obtained cladding product amount (g) The rate of recovery (%) of cladding product
575.0 548.3 95.4
《Embodiment 14》
The spheric active carbon 500g obtained by Production Example 1 is put into rotational flow applying device (MP-01), it is spraying such as table The spray liquid of formula shown in 27.Then it is dried, has obtained cladding product 524.0g.Using low pressure molding machine, with relative to The ratio that cladding product 1g is 1.1mL adds ethanol/water mixed liquor (1:9) after, obtained cladding product is formed, are dried, by This has obtained the tablet of diameter 12mm.
The rate of recovery of the expression cladding product of table 28.Obtained tablet is parsed by X ray CT microscope, has obtained table The result of tablet inner additive volume fraction shown in the volume fraction and table 55 of tablet shown in 54.
[table 27]
Ingredient name Use level
Bassora gum 45g
Purified Water 3000mL
[table 28]
The theoretical amount (g) of cladding product Obtained cladding product amount (g) The rate of recovery (%) of cladding product
545.0 524.0 96.1
《Embodiment 15》
The spheric active carbon 500g obtained by Production Example 1 is put into rotational flow applying device (MP-01), it is spraying such as table The spray liquid of formula shown in 29.Then it is dried, has obtained cladding product 543.5g.Using low pressure molding machine, with relative to The ratio that cladding product 1g is 1.1mL adds ethanol/water mixed liquor (4:6) after, obtained cladding product is formed, are dried, by This has obtained the tablet of diameter 12mm.
The rate of recovery of the expression cladding product of table 30.Obtained tablet is parsed by X ray CT microscope, has obtained table The result of tablet inner additive volume fraction shown in the volume fraction and table 55 of tablet shown in 54.
[table 29]
Ingredient name Use level
Sodium Hyaluronate 60g
Purified Water 3500mL
[table 30]
The theoretical amount (g) of cladding product Obtained cladding product amount (g) The rate of recovery (%) of cladding product
560.0 543.5 97.1
《Embodiment 16》
The spheric active carbon 500g obtained by Production Example 1 is put into rotational flow applying device (MP-01), it is spraying such as table The spray liquid of formula shown in 31.Then it is dried, has obtained cladding product 531.9g.Using low pressure molding machine, with relative to The ratio that cladding product 1g is 1.2mL adds ethanol/water mixed liquor (5:5) after, obtained cladding product is formed, are dried, by This has obtained the tablet of diameter 12mm.
The rate of recovery of the expression cladding product of table 32.Obtained tablet is parsed by X ray CT microscope, has obtained table The result of tablet inner additive volume fraction shown in the volume fraction and table 55 of tablet shown in 54.
[table 31]
Ingredient name Use level
Hydroxyethyl cellulose 60g
Purified Water 2000mL
[table 32]
The theoretical amount (g) of cladding product Obtained cladding product amount (g) The rate of recovery (%) of cladding product
560.0 531.9 95.0
《Embodiment 17》
The spheric active carbon 500g obtained by Production Example 1 is put into rotational flow applying device (MP-01), it is spraying such as table The spray liquid of formula shown in 33.Then it is dried, has obtained cladding product 543.3g.Using low pressure molding machine, with relative to The ratio that cladding product 1g is 1.2mL adds ethanol/water mixed liquor (4:6) after, obtained cladding product is formed, are dried, by This has obtained the tablet of diameter 12mm.
The rate of recovery of the expression cladding product of table 34.Obtained tablet is parsed by X ray CT microscope, has obtained table The result of tablet inner additive volume fraction shown in the volume fraction and table 55 of tablet shown in 54.
[table 33]
Ingredient name Use level
Hydroxypropyl cellulose 75g
Purified Water 600mL
[table 34]
The theoretical amount (g) of cladding product Obtained cladding product amount (g) The rate of recovery (%) of cladding product
575.0 543.3 94.5
《Embodiment 18》
The spheric active carbon 500g obtained by Production Example 1 is put into rotational flow applying device (MP-01), it is spraying such as table The spray liquid of formula shown in 35.Then it is dried, has obtained cladding product 502.9g.Using low pressure molding machine, with relative to The ratio that cladding product 1g is 1.4mL adds ethanol/water mixed liquor (6:4) after, obtained cladding product is formed, are dried, by This has obtained the tablet of diameter 12mm.
The rate of recovery of the expression cladding product of table 36.Obtained tablet is parsed by X ray CT microscope, has obtained table The result of tablet inner additive volume fraction shown in the volume fraction and table 55 of tablet shown in 54.
[table 35]
Ingredient name Use level
Hydroxypropyl methyl cellulose 36g
Purified Water 600mL
[table 36]
The theoretical amount (g) of cladding product Obtained cladding product amount (g) The rate of recovery (%) of cladding product
536.0 502.9 93.8
《Embodiment 19》
The spheric active carbon 500g obtained by Production Example 1 is put into rotational flow applying device (MP-01), it is spraying such as table The spray liquid of formula shown in 37.Then it is dried, has obtained cladding product 515.4g.Using low pressure molding machine, with relative to The ratio that cladding product 1g is 1.2mL adds ethanol/water mixed liquor (6:4) after, obtained cladding product is formed, are dried, by This has obtained the tablet of diameter 12mm.
The rate of recovery of the expression cladding product of table 38.Obtained tablet is parsed by X ray CT microscope, has obtained table The result of tablet inner additive volume fraction shown in the volume fraction and table 55 of tablet shown in 54.
[table 37]
Ingredient name Use level
Methylcellulose 75g
Purified Water 600mL
[table 38]
The theoretical amount (g) of cladding product Obtained cladding product amount (g) The rate of recovery (%) of cladding product
575.0 515.4 89.6
《Embodiment 20》
The spheric active carbon 500g obtained by Production Example 1 is put into rotational flow applying device (MP-01), it is spraying such as table The spray liquid of formula shown in 39.Then it is dried, has obtained cladding product 530.8g.Using low pressure molding machine, with relative to The ratio that cladding product 1g is 1.4mL adds ethanol/water mixed liquor (6:4) after, obtained cladding product is formed, are dried, by This has obtained the tablet of diameter 12mm.
The rate of recovery of the expression cladding product of table 40.Obtained tablet is parsed by X ray CT microscope, has obtained table The result of tablet inner additive volume fraction shown in the volume fraction and table 55 of tablet shown in 54.
[table 39]
Ingredient name Use level
Phosphoric acid crosslinked starch 50g
The Purified Water of heating 600mL
[table 40]
The theoretical amount (g) of cladding product Obtained cladding product amount (g) The rate of recovery (%) of cladding product
550.0 530.8 96.5
《Embodiment 21》
The spheric active carbon 500g obtained by Production Example 1 is put into rotational flow applying device (MP-01), it is spraying such as table The spray liquid of formula shown in 41.Then it is dried, has obtained cladding product 552.0g.Using low pressure molding machine, with relative to The ratio that cladding product 1g is 1.1mL adds ethanol/water mixed liquor (1:9) after, obtained cladding product is formed, are dried, by This has obtained the tablet of diameter 12mm.
The rate of recovery of the expression cladding product of table 42.Obtained tablet is parsed by X ray CT microscope, has obtained table The result of tablet inner additive volume fraction shown in the volume fraction and table 55 of tablet shown in 54.
[table 41]
Ingredient name Use level
Locust bean gum 75g
Purified Water 3000mL
[table 42]
The theoretical amount (g) of cladding product Obtained cladding product amount (g) The rate of recovery (%) of cladding product
575.0 552.0 96.0
《Embodiment 22》
The spheric active carbon 500g obtained by Production Example 1 is put into rotational flow applying device (MP-01), it is spraying such as table The spray liquid of formula shown in 43.Then it is dried, has obtained cladding product 490.6g.Using low pressure molding machine, with relative to The ratio that cladding product 1g is 1.1mL adds ethanol/water mixed liquor (6:4) after, obtained cladding product is formed, are dried, by This has obtained the tablet of diameter 12mm.
The rate of recovery of the expression cladding product of table 44.Obtained tablet is parsed by X ray CT microscope, has obtained table The result of tablet inner additive volume fraction shown in the volume fraction and table 55 of tablet shown in 54.
[table 43]
Ingredient name Use level
Agar 15g
The Purified Water of heating 600mL
[table 44]
The theoretical amount (g) of cladding product Obtained cladding product amount (g) The rate of recovery (%) of cladding product
515.0 490.6 95.3
《Embodiment 23》
The spheric active carbon 500g obtained by Production Example 1 is put into rotational flow applying device (MP-01), it is spraying such as table The spray liquid of formula shown in 45.Then it is dried, has obtained cladding product 545.5g.Using low pressure molding machine, with relative to The ratio that cladding product 1g is 1.1mL adds ethanol/water mixed liquor (6:4) after, obtained cladding product is formed, are dried, by This has obtained the tablet of diameter 12mm.
The rate of recovery of the expression cladding product of table 46.Obtained tablet is parsed by X ray CT microscope, has obtained table The result of tablet inner additive volume fraction shown in the volume fraction and table 55 of tablet shown in 54.
[table 45]
Ingredient name Use level
Cold plum powder 70g
Purified Water 600mL
[table 46]
The theoretical amount (g) of cladding product Obtained cladding product amount (g) The rate of recovery (%) of cladding product
570.0 545.5 95.7
《Embodiment 24》
The spheric active carbon 500g obtained by Production Example 1 is put into rotational flow applying device (MP-01), it is spraying such as table The spray liquid of formula shown in 47.Then it is dried, has obtained cladding product 516.4g.Using low pressure molding machine, with relative to The ratio that cladding product 1g is 1.0mL adds ethanol/water mixed liquor (1:9) after, obtained cladding product is formed, are dried, by This has obtained the tablet of diameter 12mm.
The rate of recovery of the expression cladding product of table 48.Obtained tablet is parsed by X ray CT microscope, has obtained table The result of tablet inner additive volume fraction shown in the volume fraction and table 55 of tablet shown in 54.
[table 47]
Ingredient name Use level
Complete pre-gelatinized starch 35g
Purified Water 1100mL
[table 48]
The theoretical amount (g) of cladding product Obtained cladding product amount (g) The rate of recovery (%) of cladding product
535.0 516.4 96.5
《Embodiment 25》
The spheric active carbon 500g obtained by Production Example 1 is put into rotational flow applying device (MP-01), it is spraying such as table The spray liquid of formula shown in 49.Then it is dried, has obtained cladding product 533.3g.Using low pressure molding machine, with relative to The ratio that cladding product 1g is 1.4mL adds ethanol/water mixed liquor (6:4) after, obtained cladding product is formed, are dried, by This has obtained the tablet of diameter 12mm.
The rate of recovery of the expression cladding product of table 50.Obtained tablet is parsed by X ray CT microscope, has obtained table The result of tablet inner additive volume fraction shown in the volume fraction and table 55 of tablet shown in 54.
[table 49]
Ingredient name Use level
Oxidized starch 60g
The Purified Water of heating 600mL
[table 50]
The theoretical amount (g) of cladding product Obtained cladding product amount (g) The rate of recovery (%) of cladding product
560.0 533.3 95.2
《Embodiment 26》
The spheric active carbon 500g obtained by Production Example 1 is put into rotational flow applying device (MP-01), it is spraying such as table The spray liquid of formula shown in 51.Then it is dried, has obtained cladding product 520.7g.Using low pressure molding machine, with relative to The ratio that cladding product 1g is 0.9mL adds ethanol/water mixed liquor (2:8) after, obtained cladding product is formed, are dried, by This has obtained the tablet of diameter 12mm.
The rate of recovery of the expression cladding product of table 52.Obtained tablet is parsed by X ray CT microscope, has obtained table The result of tablet inner additive volume fraction shown in the volume fraction and table 55 of tablet shown in 54.
[table 51]
Ingredient name Use level
Part pre-gelatinized starch 50g
Purified Water 600mL
[table 52]
The theoretical amount (g) of cladding product Obtained cladding product amount (g) The rate of recovery (%) of cladding product
550.0 520.7 94.7
《Comparative example 1》
The spheric active carbon 500g obtained by Production Example 1 is added to stirring granulating machine (VG-01), is added while stirring Add and be dissolved in pulullan polysaccharide 25g solution 5 minutes of Purified Water 600mL, then carry out mediating for 10 minutes, has recycled kneading Object.The rate of recovery of the expression kneaded material of table 53.
《Comparative example 2》
The spheric active carbon 20g obtained by Production Example 1, pulullan polysaccharide 1.2g and NaLS 0.18g is equal It is distributed in beaker evenly, further adds Purified Water 24mL.In a manner of the cohesion agglomerate (after powder) for not forming additive, make Obtained mixture is mediated with spatula (spatula).The kneaded material (slurry) of preparation is filled in molding die (diameter 12mm, depth 10.2mm), it is ground with spatula, the moulding stick by being installed on blender carries out gently compression to top come to tablet It is modified on surface.By the way that each molding die is dried, tablet has been obtained.By X ray CT microscope to obtaining Tablet is parsed, and the knot of tablet inner additive volume fraction shown in the volume fraction and table 55 of tablet shown in table 54 has been obtained Fruit.
《Comparative example 3》
The spheric active carbon 20g obtained by Production Example 1, pulullan polysaccharide 9.36g and NaLS 1.40g is equal It is distributed in beaker evenly, further adds Purified Water 28mL.In a manner of the cohesion agglomerate (after powder) for not forming additive, make Obtained mixture is mediated with spatula (spatula).The kneaded material (slurry) of preparation is filled in molding die (diameter 12mm, depth 10.2mm), it is ground with spatula, the moulding stick by being installed on blender carries out gently compression to top come to tablet It is modified on surface.By the way that each molding die is dried, tablet has been obtained.By X ray CT microscope to obtaining Tablet is parsed, and the result of tablet inner additive volume fraction shown in table 55 has been obtained.
[table 53]
The yield (%) of spheric active carbon
Embodiment 1 (1) 100.2
Comparative example 1 (1) 87.8
In the kneading method of comparative example 1, as shown in figure 5, spheric active carbon remains on mixing machine, or it is attached to shaping mould Tool, therefore yield is 87.8%, but in the manufacturing method of the present invention of embodiment 1, the yield of spheric active carbon changes by leaps and bounds It is apt to be 100.2%.
《Use the parsing of the volume fraction of the microscopical tablet of X ray CT》
For the two batch tablets obtained by embodiment 1 and the three batch tablets obtained by comparative example 2, X-ray is used CT microscope nano3DX (Co., Ltd. Neo-Confucianism) under the following conditions parses tablet inside.
Line source：Mo
Voltage：50kV
Electric current：24mA
Pixel size：8.64μm/voxel
Shoot number：1200
Shooting time：About 3 hours
Using attached analysis software, find out in the top, middle part and lower part for being divided into the tablet of three parts on one side The volume fraction of the cube of 2mm.The relative standard of the volume fraction of three cubes of the three batch tablets obtained by comparative example 2 is inclined Poor (RSD) is up to 5.5%, 7.1% and 5.3%.On the other hand, three cubes of the two batch tablets obtained by embodiment 1 The RSD of the volume fraction of body is 1.0% and 2.4%, and tablet of the invention has high uniformity (table 54).
For each batch tablet obtained by embodiment 2~26, X ray CT microscope TDM1000H-II (2K) is used (big and scientific Co., Ltd.) under the following conditions parses tablet inside.
Line source：W
Voltage：50kV (embodiment 2~26)
Electric current：0.080mA (embodiment 2), 0.085mA (embodiment 3~26)
Pixel size：17.5 μm/voxel (embodiment 2), 12.7 μm/voxel (embodiment 3~26)
Shoot number：700~1500 (arbitrarily being set according to the thickness of tablet)
Shooting time：20 minutes (embodiment 2), 10 minutes (embodiment 3~26)
Using analysis software ImageJ, find out in the top, middle part and lower part for being divided into the tablet of three parts on one side The volume fraction of the cube of 2mm.Based on 256 grades of lightness information in obtained image, by according to big saliva method carry out from Dynamic threshold calculations distinguish spheric active carbon and additive with gap, which is equivalent to the number of 2mm thickness The ratio of the pixel number of spheric active carbon and additive when amount carries out integrating is set as volume fraction (table 54).
[table 54]
《Use the parsing of the additive volume fraction of the microscopical tablet of X ray CT》
It is micro- using X ray CT for the tablet obtained by Examples 1 to 26 and the tablet obtained by comparative example 2,3 Mirror TDM1000H-II (2K) (big and scientific Co., Ltd.) under the following conditions parses tablet inside.
Line source：W
Voltage：40kV (embodiment 1, comparative example 2), 50kV (embodiment 2~26, comparative example 3)
Electric current：0.095mA (embodiment 1, comparative example 2), 0.080mA (embodiment 2, comparative example 3), 0.085mA (embodiment 3~26)
Pixel size：15.9 μm/voxel (embodiment 1), 14.4 μm/voxel (comparative example 2), 17.5 μm/voxel (realities Apply example 2, comparative example 3), 12.7 μm/voxel (embodiment 3~26)
Shoot number：700~1500 (arbitrarily being set according to the thickness of tablet)
Shooting time：(implement within 30 minutes (embodiment 1, comparative example 2), 20 minutes (embodiment 2, comparative example 3), 10 minutes Example 3~26)
Tablet for the tablet of embodiment 1, the tablet of embodiment 3~26 and comparative example 2 is respectively one, for implementation The tablet of example 2 and comparative example 3 is respectively three, in this regard, by analysis software ImageJ to the five of C, N, E, S and W of Fig. 3 The volume fraction of the additive of a prism is calculated.Due to the information based on 256 grades of lightness in obtained image, it is equivalent to The distribution of the pixel number of the lightness of spheric active carbon is in normal distribution, therefore by the average value of the lightness plus standard deviation The part of lightness more than 2.5 times of resulting numerical value is defined as additive, and the ratio of the pixel number is set as additive the area ratio, The image is set as additive body with the ratio for being equivalent to the pixel number of the additive when quantity of defined thickness carries out integrating Product rate (Fig. 6).By the maximum in the numerical value of the maxima and minima of the additive volume fraction in each prism and five prisms The ratio between value and minimum value are shown in table 55.In addition, by the position C of comparative example 2 additive the area ratio and volume fraction from upper The variation of surface to lower surface is shown in Fig. 4.
As shown in figure 4, the additive volume fraction of the tablet obtained by previous kneading method is from the upper surface of tablet to following table It is significantly changed between face.
[table 55]

Claims (7)

1. a kind of tablet, which is characterized in that containing additive and spherical adsorbent charcoal is administered orally,
From upper surface to lower surface by X ray CT microscope to the tablet from upper surface in the case where center Portion and positioned at the end of the straight line extended from center to four directions, from upper surface to lower surface on one side be 1mm five ribs In the case that the volume fraction of the additive of column is parsed, every 1mm of five prisms3Additive volume fraction maximum value with most The ratio between small value is 100 or less.
2. a kind of tablet, which is characterized in that containing additive and oral administration use adsorbent charcoal,
In each dividing body that the length in the flat direction of the tablet is divided into trisection, passing through X ray CT microscope Center to the length for being located at flat direction and cube formed by one side 2mm positioned at the center of the tablet from upper surface In the case that the volume fraction of body is parsed, the relative standard deviation of the volume fraction of the cube of three dividing bodies is 5% or less.
3. a kind of tablet, which is characterized in that containing additive and spherical adsorbent charcoal is administered orally,
From upper surface to lower surface by X ray CT microscope to the tablet from upper surface in the case where center Portion and positioned at the end of the straight line extended from center to four directions, from upper surface to lower surface on one side be 1mm five ribs In the case that the volume fraction of the additive of column is parsed, every 1mm of five prisms3Additive volume fraction maximum value with most It is small value the ratio between be 100 hereinafter,
In each dividing body that the length in the flat direction of the tablet is divided into trisection, passing through X ray CT microscope Center to the length for being located at flat direction and cube formed by one side 2mm positioned at the center of the tablet from upper surface In the case that the volume fraction of body is parsed, the relative standard deviation of the volume fraction of the cube of three dividing bodies is 5% or less.
4. tablet described in any one of claim 1 to 3, wherein
The additive is selected from by sodium alginate, propylene glycol alginate, carboxymethyl cellulose, calcium carboxymethylcellulose, print It is poly- to spend natural gum, carragheen, carboxyl vinyl polymer, sodium carboxymethylcellulose, xanthan gum, guar gum, Wen Quince seed glue, Portugal's sweet dew Sugar, copolyvidone, gellan gum, gelatin, tamarind gum, tara gum, dextrin, cornstarch, bassora gum, Sodium Hyaluronate, hydroxyl second Base cellulose, hydroxypropul starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pulullan polysaccharide, povidone, polycyclic oxygen second Alkane, polyvinyl alcohol, polyvinyl alcohol-acryl acid-methyl methacrylate copolymer, Macrogol 6000, ethyl cellulose, methyl Cellulose, phosphoric acid crosslinked starch, locust bean gum, agar, cold plum powder, complete pre-gelatinized starch, avicel cellulose carboxymethyl cellulose In the group that plain sodium, oxidized starch, low degree of substitution hydroxypropyl cellulose, part pre-gelatinized starch, carbohydrate and glycitols are constituted Bonding uses additive.
5. tablet according to any one of claims 1 to 4, wherein
The oral administration is spheric active carbon with spherical adsorbent charcoal.
6. tablet according to claim 5, wherein
The average grain diameter of the spheric active carbon is 0.02~1mm.
7. a kind of manufacturing method of tablet, it includes following process：
It (1) will be containing selected from by sodium alginate, propylene glycol alginate, carboxymethyl cellulose, calcium carboxymethylcellulose, India tree Glue, carragheen, carboxyl vinyl polymer, sodium carboxymethylcellulose, xanthan gum, guar gum, Wen Quince seed glue, glucomannans, Copolyvidone, gellan gum, gelatin, tamarind gum, tara gum, dextrin, cornstarch, bassora gum, Sodium Hyaluronate, ethoxy are fine It ties up element, hydroxypropul starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pulullan polysaccharide, povidone, polyethylene oxide, gather Vinyl alcohol, polyvinyl alcohol-acryl acid-methyl methacrylate copolymer, Macrogol 6000, ethyl cellulose, Methyl cellulose Element, phosphoric acid crosslinked starch, locust bean gum, agar, cold plum powder, complete pre-gelatinized starch, avicel cellulose sodium carboxymethylcellulose, The bonding in group that oxidized starch, low degree of substitution hydroxypropyl cellulose, part pre-gelatinized starch, carbohydrate and glycitols are constituted It is sprayed or is added dropwise with the solution of additive in the spherical adsorbent charcoal of oral administration, it is spherical to oral administrable with additive by bonding Adsorbent charcoal is coated；
(2) then compression forming process is carried out by the way that solvent is made an addition to the spherical adsorbent charcoal of oral administration being wrapped by Compression forming obtains formed body；And
(3) obtained formed body is dried.
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