CN107213126A - A kind of method that 3D printing technique prepares the oral quick disintegrating tablet for the treatment of hyperphosphatemia - Google Patents

A kind of method that 3D printing technique prepares the oral quick disintegrating tablet for the treatment of hyperphosphatemia Download PDF

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CN107213126A
CN107213126A CN201710349211.XA CN201710349211A CN107213126A CN 107213126 A CN107213126 A CN 107213126A CN 201710349211 A CN201710349211 A CN 201710349211A CN 107213126 A CN107213126 A CN 107213126A
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copolyvidone
adhesive
powder
polysorbate
tablet
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CN107213126B (en
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卜昕
王鑫桐
鲁再丰
赵伟
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Xi'an Di Plus Biological Technology Co Ltd
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Xi'an Di Plus Biological Technology Co Ltd
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Priority to PCT/CN2018/086323 priority patent/WO2018210177A1/en
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/24Heavy metals; Compounds thereof
    • A61K33/244Lanthanides; Compounds thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0002Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0053Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, 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
    • A61K9/2077Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B33ADDITIVE MANUFACTURING TECHNOLOGY
    • B33YADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y80/00Products made by additive manufacturing

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Inorganic Chemistry (AREA)
  • Zoology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Manufacturing & Machinery (AREA)
  • Materials Engineering (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention provides a kind of method that 3D printing technique prepares the oral quick disintegrating tablet for the treatment of hyperphosphatemia:The former powder of lanthanum carbonate pharmaceutical grade and auxiliary material are fully mixed, tablet is made using powder liquid 3D printing technique with ethanol water, glycerine, polysorbate, copolyvidone S 630 mixed solution.Tablet drugloading rate prepared by the present invention is big, easy disintegrating, can improve patient compliance, it is adaptable to the accurate dosage treatment hyperphosphatemia of patients of chronic renal failure.

Description

A kind of method that 3D printing technique prepares the oral quick disintegrating tablet for the treatment of hyperphosphatemia
Technical field
The invention belongs to field of medicaments, and in particular to a kind of oral rapidly disintegrating for the treatment of hyperphosphatemia prepared by 3D printing technique Piece and preparation method thereof.
Background technology
The U.S. in 3D printing 19 end of the centurys of earliest origin, but just developed to 1980s.3D printing technique is most Just applied to fields such as manufacturing industry, Aero-Space and industrial designs, development and maturation with 3D printing technique, this is emerging Science and technology initially enters field of medicaments, and in medical model manufacturing, tissue and organ regeneration, clinical repair treatment and medicament research and development experiment In terms of achieve a series of achievement in research.On July 31st, 2015, food and medicine Surveillance Authority of the U.S. have approved Aprecia drugmakers first using 3D printing technique prepare Spritam (Levetiracetam) rapidly dissolving tablet listing, for Office's hair property of other antiepileptic therapeutic alliance adults or child patient is broken out, myoclonic seizure and primary whole body are insane Epilepsy is broken out.This means 3D printing technique is further strided forward after after printing human organ to pharmaceutical field.
3D printing technique pharmacy is printed using layer-transferred powdering, and obtained tablet reticulates structure;This method uses water Property fluid combination multiple layer powder mixture, to produce porous water-soluble base, make it have well disintegration effect, be patient Solve and swallow difficult problem.Spritam is prepared into loose structure using 3D printing technique, and powder glues in the case of no compression Knot is formed, and major ingredient powder accounting is improved well.
U.S. FDA approval lanthanum carbonate is used to treat hyperphosphatemia within 2004.Lanthanum carbonate is the research and development of Shire drugmakers of Britain Phosphate binder of a new generation without aluminium and calcium.The listing of lanthanum carbonate provides more effective treatment side for End Stage Renal Disease patient Method.At present, the lanthanum carbonate medicine clinically used is main based on chewable tablets, but it has poor taste, is difficult to swallow, makes work The shortcomings of skill is cumbersome, exists for some trouble and takes difficulty.
Though the document report and commercial prod that have had different 3D printings to prepare tablet at present emerge, treatment is high The lanthanum carbonate 3D printing pharmaceutical formulation and printing technology of phosphoremia are not reported.Develop the carbon of the accurate dosage treatment of individuation Sour lanthanum 3D tablets are current urgent problems to be solved.
The content of the invention
An object of the present invention is the oral quick disintegrating tablet for providing treatment hyperphosphatemia prepared by a kind of 3D printing technique, With drugloading rate is big, hardness is high and oral cavity easy disintegrating feature;The second object of the present invention is the system for providing the oral quick disintegrating tablet Preparation Method.
To reach above-mentioned purpose, present invention employs following technical scheme:
A kind of oral quick disintegrating tablet for the treatment of hyperphosphatemia prepared by 3D printing technique, it is former that the oral quick disintegrating tablet includes pharmaceutical grade Powder component and adhesive, the former powder component of the pharmaceutical grade is by mass percentage by 30~75% lanthanum carbonate, 5~30% Disintegrant, 2~40% filler, 0~20% diluent, 0~25% sweetener, 1~25% binder, 0.3 ~3% lubricant and 0.05~2% flavouring composition;The consumption of adhesive is the former powder component weight of pharmaceutical grade in tablet 0.01~0.1 times of amount;
The disintegrant is selected from microcrystalline cellulose, dried starch or alginic acid;
The filler is selected from starch, dextrin, mannitol or sorbierite;
The diluent is selected from lactose;
The sweetener is selected from sucrose;
The binder is selected from PVP, copolyvidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or ethyl cellulose Element;
The lubricant is selected from magnesium stearate, superfine silica gel powder or talcum powder;
The flavouring is selected from Sucralose or Icing Sugar;
Described adhesive is selected from ethanol water, starch solution or added with PVP, copolyvidone, glycerine, poly- sorb The ethanol water of at least one of ester, hydroxypropyl cellulose, hydroxypropyl methyl cellulose;In ethanol water, the body of ethanol Product percentage is 5~60%.
It is preferred that, the disintegrant is selected from microcrystalline cellulose;Filler is selected from mannitol;Binder is selected from copolyvidone; Lubricant is selected from superfine silica gel powder;Flavouring is selected from Sucralose;Adhesive, which is selected from, is added with glycerine, polysorbate and copolyvidone Ethanol water, glycerine, polysorbate, the final concentration of copolyvidone be followed successively by 0.2~4%, 0.1 in terms of mass fraction~ 2%th, 1~5%.
It is preferred that, the copolyvidone is selected from Plasdone S-630, and disintegrant is selected from microcrystalline cellulose PH101, carbonic acid Lanthanum is selected from the lanthanum carbonate of micronizing, and polysorbate is selected from polyoxyethylene sorbitan monoleate.
The piece weight of the oral quick disintegrating tablet is 1~2.5g, and wherein lanthanum carbonate accounting is 40~70%.
The oral quick disintegrating tablet is made using the former powder of pharmaceutical grade and adhesive of powder liquid 3D printing method, is had Body is as follows:
A kind of 3D printing technique prepares the oral quick disintegrating tablet method for the treatment of hyperphosphatemia, comprises the following steps:
1) by mass fraction by 30~75% lanthanum carbonate, 5~30% disintegrant, 2~40% filler, 0~ 20% diluent, 0~25% sweetener, 1~25% binder, 0.3~3% lubricant and 0.05~2% Flavouring is well mixed, and obtains printing powder used;
2) adhesive is prepared, wherein, adhesive is selected from ethanol water, starch solution or tieed up added with PVP, copolymerization The ethanol water of at least one of ketone, glycerine, polysorbate, hydroxypropyl cellulose, hydroxypropyl methyl cellulose;Ethanol is water-soluble In liquid, the percentage by volume of ethanol is 5~60%;
3) Software for Design of 3 D-printing tablet:Pass through computer CAD software or Magics Software for Design cylindrical mouths Cavity disintegrating tablet size (such as Tablet diameter in the range of 15~22mm it is adjustable) and quantity parameter, be translated into 3D printing The file of the recognizable STL forms of machine (LTY-200 types), is imported in 3D printer software systems;
4) powder liquid 3D printing method is used, three-dimensional structure tablet is made using adhesive in the powder successively laid, wherein Relevant parameter is as follows:Powdering floor height is 0.1~0.6mm, and the powdering number of plies is 10~77 layers, and adhesive individual layer hydrojet number of times is 1 or 2 Secondary, the consumption of adhesive is 0.01~0.1 times of powder weight for needed for single tablet;
5) tablet is hung 15~60 minutes naturally;It is subsequently placed in 30~70 DEG C of baking ovens and dries 1~2.5h, obtains medical treatment The oral quick disintegrating tablet of hypopotassaemia.
It is preferred that, the preparation method of described adhesive is:, will using the ethanol water of mass fraction 5~60% as solvent Glycerine, polysorbate and copolyvidone are dissolved in the ethanol water, glycerine in adhesive, polysorbate, copolyvidone Mass fraction is followed successively by 0.2~4%, 0.1~2%, 1~5%.
It is preferred that, lanthanum carbonate is placed in by the lanthanum carbonate and mannitol before crossing 100~200 mesh sieves, and sieving before combination Dried 5~40 minutes in 30~70 DEG C of baking ovens.
Beneficial effects of the present invention are embodied in:
Oral quick disintegrating tablet formulation content proportioning of the present invention is effectively controlled the drugloading rate and hardness of medicine and collapsed Solution, wherein the flavouring added, makes medicine have good mouthfeel when taking.The oral quick disintegrating tablet uses 3D printing technique system Into compared with traditional tablet forming technique, preparation technology is simple, monolithic dosage is high, and tablet has porous water-soluble base, in water In can quickly dissolve, disintegration time limited meets pharmacopoeial requirements, and disintegration time 2~60 seconds is that patient brings new oral body Test.Through experiment, the hardness of oral quick disintegrating tablet of the present invention reaches as high as 10kg or so, while with compared with high drug load, Hardness is effectively guaranteed, and is laid a good foundation for the accurate medication of individuation, with high market application foreground.
Brief description of the drawings
Fig. 1 is lanthanum carbonate 3D printing tablet just (a), anti-(b) face schematic diagram.
Embodiment
The invention will be further described with reference to the accompanying drawings and examples, and described is only explanation of the invention, without It is to limit.
Embodiment 1:
(1) prescription (tablet)
Note:± 0.1g of each component addition based on existing amount in prescription.
(2) 3D printing technique:
1) lanthanum carbonate bulk drug (the lanthanum carbonate raw material of micronizing) and mannitol cross 150 mesh sieves before weighing, and viscosity is larger Powder (referring mainly to lanthanum carbonate) be put into 50 DEG C of baking ovens and dry 15 minutes before sieving, be easy to the larger powder of viscosity to mix;
2) powder prepared is mixed, is sufficiently stirred for mixing, obtains drug powder, ready-to-print;
3) adhesive (spray solution) is prepared:10% ethanol+(1.0% glycerine, 0.5% polyoxyethylene sorbitan monoleate)+2% Plasdone S-630 are used as adhesive;That is adhesive by glycerine, gathers using the ethanol water of percentage by volume 10% as solvent Sorb ester 80, Plasdone S-630 dissolve wherein, glycerine, polyoxyethylene sorbitan monoleate, Plasdone S-630 quality in adhesive Fraction is followed successively by 1.0%, 0.5%, 2%;
4) Software for Design of 3 D-printing tablet:
Size and number by computer CAD software or Magics Software for Design cylindrical mouth cavity disintegrating tablets etc. is joined Number, is translated into the file of the recognizable STL forms of 3D printer (LTY-200 types), imports in 3D printer software systems;
5) adhesive is added in hydrojet print cartridge, using 3D printing technique, printing in layer manufactures three-dimensional structure medicine Piece (i.e. successively powdering, adhesive is sprayed in interlayer film-making position), floor height 0.13mm, individual layer hydrojet 2 times, 42 layers of the number of plies;Monolithic medicine The consumption of adhesive described in piece is 0.01~0.1 times of drug powder weight;
6) tablet that printing is formed is hung 30 minutes;50 DEG C of baking ovens are subsequently placed in, drying time is 1.5~2h;
7) packed after tablet drying;Referring to Fig. 1, the following structural features of tablet:
Front:Surface is smooth (due to having sprayed adhesive after last time powdering), non-breakable.
Reverse side:Porous matrix bottom, overall tablet is network structure;When being put into a small amount of water, capillarity, medicine are utilized Piece can fater disintegration.
Through examining:Piece weight 0.98g (close to 1g), uses the hardness-testing devices of YD- II to measure tablet hardness for 0.78kg, uses ZB-1C intelligent disintegration testers measurement disintegration time limited be:4~10 seconds.
Embodiment 2:
(1) prescription (tablet)
Note:± 0.1g of each component addition based on existing amount in prescription.
(2) 3D printing technique
Condition is same as Example 1;
Through examining:Piece weight 1.08g, hardness 3.48kg, disintegration time limited is:3~7 seconds.
Embodiment 3:
(1) prescription (tablet)
Note:± 0.1g of each component addition based on existing amount in prescription.
(2) 3D printing technique
In addition to following condition, other are same as Example 1:
1. individual layer hydrojet 2 times, 61 layers of the number of plies;
Through examining:Piece weight 1.62g, hardness 4.71kg, disintegration time limited is:4~5 seconds.
Embodiment 4:
(1) prescription (tablet)
Note:± 0.1g of each component addition based on existing amount in prescription.
(2) 3D printing technique
It is same as Example 1 outside condition;
Through examining:Piece weight 1.16g, hardness 2.36kg, disintegration time limited is:4~7 seconds.
Embodiment 5:
(1) prescription (tablet)
Note:± 0.1g of each component addition based on existing amount in prescription.
(2) 3D printing technique
In addition to following condition, other are same as Example 1:
1. the number of plies is 61 layers, individual layer hydrojet 2 times;
Through examining:Piece weight 1.56g, hardness 3.32kg, disintegration time limited is:7~9 seconds.
Lanthanum carbonate 3D printing tablet usage of the present invention is:Orally.
Experiment shows, lanthanum carbonate 3D printing tablet of the present invention has big (the lanthanum carbonate major ingredient in single tablet of drugloading rate Accounting is 40~70%), the features such as easy disintegrating, hardness are high and convenient to take, mouthfeel is preferably good, under high dose load Fast disintegration property can be kept, can be disintegrated completely in 60 seconds, it meets《Chinese Pharmacopoeia》Disintegration time limited require (middle traditional Chinese medicines Allusion quotation》Measurement standard:All it is disintegrated in 15 minutes).It is applied to the treatment of patients of chronic renal failure hyperphosphatemia.

Claims (10)

1. a kind of oral quick disintegrating tablet for the treatment of hyperphosphatemia prepared by 3D printing technique, it is characterised in that:The oral quick disintegrating tablet bag Include the former powder component of pharmaceutical grade and adhesive, the former powder component of the pharmaceutical grade by mass percentage by 30~75% carbonic acid Lanthanum, 5~30% disintegrant, 2~40% filler, 0~20% diluent, 0~25% sweetener, 1~25% Binder, 0.3~3% lubricant and 0.05~2% flavouring composition;The consumption of adhesive is that pharmaceutical grade is former in tablet 0.01~0.1 times of powder composition weight;
The disintegrant is selected from microcrystalline cellulose, dried starch or alginic acid;
The filler is selected from starch, dextrin, mannitol or sorbierite;
The diluent is selected from lactose;
The sweetener is selected from sucrose;
The binder is selected from PVP, copolyvidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or ethyl cellulose;
The lubricant is selected from magnesium stearate, superfine silica gel powder or talcum powder;
The flavouring is selected from Sucralose or Icing Sugar;
Described adhesive is selected from ethanol water, starch solution or added with PVP, copolyvidone, glycerine, polysorbate, hydroxyl The ethanol water of at least one of propyl cellulose, hydroxypropyl methyl cellulose;In ethanol water, the volume basis of ethanol Number is 5~60%.
2. oral quick disintegrating tablet according to claim 1, it is characterised in that:The disintegrant is selected from microcrystalline cellulose;Filling Agent is selected from mannitol;Binder is selected from copolyvidone;Lubricant is selected from superfine silica gel powder;Flavouring is selected from Sucralose;Adhesive Selected from the ethanol water added with glycerine, polysorbate and copolyvidone, glycerine, polysorbate, the final concentration of copolyvidone 0.2~4%, 0.1~2%, 1~5% is followed successively by terms of mass fraction.
3. oral quick disintegrating tablet according to claim 1, it is characterised in that:The copolyvidone is selected from Plasdone S- 630, disintegrant is selected from microcrystalline cellulose PH101, and lanthanum carbonate is selected from the lanthanum carbonate of micronizing, and polysorbate is selected from polysorbate 80。
4. oral quick disintegrating tablet according to claim 3, it is characterised in that:The piece weight of the oral quick disintegrating tablet is 1~2.5g, Wherein lanthanum carbonate accounting is 40~70%.
5. oral quick disintegrating tablet according to claim 1, it is characterised in that:The oral quick disintegrating tablet is to utilize the former powder of pharmaceutical grade What material and adhesive were made of powder liquid 3D printing method.
6. a kind of 3D printing technique prepares the oral quick disintegrating tablet method for the treatment of hyperphosphatemia, it is characterised in that:Comprise the following steps:
1) by mass fraction by 30~75% lanthanum carbonate, 5~30% disintegrant, 2~40% filler, 0~20% Diluent, 0~25% sweetener, 1~25% binder, 0.3~3% lubricant and 0.05~2% flavouring It is well mixed, obtain printing powder used;
2) adhesive is prepared, wherein, adhesive is selected from ethanol water, starch solution or added with PVP, copolyvidone, sweet The ethanol water of at least one of oil, polysorbate, hydroxypropyl cellulose, hydroxypropyl methyl cellulose;In ethanol water, The percentage by volume of ethanol is 5~60%;
3) powder liquid 3D printing method is used, three-dimensional structure tablet is made using adhesive in the powder successively laid, wherein related Parameter is as follows:Powdering floor height is 0.1~0.6mm, and the powdering number of plies is 10~77 layers, and adhesive individual layer hydrojet number of times is 1 or 2 time, The consumption of adhesive is 0.01~0.1 times of powder weight for needed for single tablet;
4) tablet is hung 15~60 minutes naturally;It is subsequently placed in 30~70 DEG C of baking ovens and dries 1~2.5h, obtains medical treatment low potassium The oral quick disintegrating tablet of mass formed by blood stasis.
7. method according to claim 6, it is characterised in that:The disintegrant is selected from microcrystalline cellulose, dried starch or sea Alginic acid;Filler is selected from starch, dextrin, mannitol or sorbierite;Diluent is selected from lactose;Sweetener is selected from sucrose;Binder Selected from PVP, copolyvidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or ethyl cellulose;Lubricant is selected from tristearin Sour magnesium, superfine silica gel powder or talcum powder;Flavouring is selected from Sucralose or Icing Sugar;Adhesive, which is selected from, is added with glycerine, polysorbate And the ethanol water of copolyvidone, glycerine, polysorbate, the final concentration of copolyvidone be followed successively by 0.2 in terms of mass fraction~ 4%th, 0.1~2%, 1~5%.
8. the method according to claim 6 or 7, it is characterised in that:The preparation method of described adhesive is:With mass fraction 5~60% ethanol water is solvent, and glycerine, polysorbate and copolyvidone are dissolved in the ethanol water, is bonded Glycerine, polysorbate, the mass fraction of copolyvidone are followed successively by 0.2~4%, 0.1~2%, 1~5% in agent.
9. method according to claim 7, it is characterised in that:The lanthanum carbonate and mannitol cross 100~200 before combination Lanthanum carbonate is placed in 30~70 DEG C of baking ovens before mesh sieve, and sieving and dried 5~40 minutes.
10. method according to claim 7, it is characterised in that:The copolyvidone is selected from Plasdone S-630, crystallite Cellulose is selected from microcrystalline cellulose PH101, and lanthanum carbonate is selected from the lanthanum carbonate of micronizing, and polysorbate is selected from polyoxyethylene sorbitan monoleate.
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CN113350300B (en) * 2021-05-06 2022-12-02 广东药科大学 3D printing traditional Chinese medicine effervescent tablet and preparation method thereof

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Publication number Priority date Publication date Assignee Title
WO2018210177A1 (en) * 2017-05-17 2018-11-22 西安棣加生物科技有限公司 Rapidly disintegrating oral tablet for treating hyperphosphatemia prepared by 3d printing technology, and preparation method therefor
CN108969497A (en) * 2018-10-12 2018-12-11 沈阳华泰药物研究有限公司 A kind of lanthanum carbonate tablet composition and preparation method thereof
CN113018313A (en) * 2019-12-25 2021-06-25 远大生命科学(辽宁)有限公司 A pharmaceutical composition for treating phosphorus metabolism disorder
CN113018313B (en) * 2019-12-25 2023-05-02 远大生命科学(辽宁)有限公司 Pharmaceutical composition for treating phosphorus metabolic disorder

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