WO2002049621A1 - Formulations medicamenteuses a enrobage enterique et leur fabrication - Google Patents

Formulations medicamenteuses a enrobage enterique et leur fabrication Download PDF

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Publication number
WO2002049621A1
WO2002049621A1 PCT/FI2001/001103 FI0101103W WO0249621A1 WO 2002049621 A1 WO2002049621 A1 WO 2002049621A1 FI 0101103 W FI0101103 W FI 0101103W WO 0249621 A1 WO0249621 A1 WO 0249621A1
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WO
WIPO (PCT)
Prior art keywords
enteric
amylopectin
pellets
coated
pellet
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PCT/FI2001/001103
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English (en)
Inventor
Hongxia Guo
Jyrki HEINÄMÄKI
Jouko Yliruusi
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Licentia Oy
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Publication date
Application filed by Licentia Oy filed Critical Licentia Oy
Priority to AU2002219249A priority Critical patent/AU2002219249A1/en
Publication of WO2002049621A1 publication Critical patent/WO2002049621A1/fr

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Classifications

    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • 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

Definitions

  • the present invention relates to enteric pellet drug formulations comprising amylopectin, microcrystalline cellulose (MCC) and at least one therapeuticaUy active agent.
  • Enteric-coated drug products are widely used in modern drug therapy.
  • Enteric- coated dosage forms are designed to resist the acidic environment of the stomach and to disintegrate (i.e. rapidly release therapeutically active agent) in the higher-pH environment of the intestinal fluid.
  • Some of the most important reasons for enteric coating are (1) to protect acid-labile active agents from the gastric fluid, (2) to prevent gastric distress or nausea due to irritation from an active agent, (3) to deliver active agents intended for local action in the intestines, and (4) to deliver therapeutically active agents that are optimally absorbed in the small intestine to their primary absorption site.
  • Therapeutically active agents generally formulated to enteric-coated dosage forms include for example acetylsalicylic acid, non-steroidal anti-inflammatory drugs, omeprazole, erythromycin and replacing pancreatic enzymes.
  • enteric materials used in drug products today are pH-sensitive films.
  • Enteric films that are pH-sensitive consist of a long-chain polymer with ionizable carboxyl groups and a pKa between 4 and 6. These films are therefore insoluble in the low-pH environment of the gastric fluid, but as pH exceeds the pKa value, as in the intestine, they will rapidly dissolve.
  • the most commonly used pH- sensitive film materials include cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP), and methacrylic acid copolymers (Chambliss, Pharm. Technol., 9: 124-140, 1983).
  • Enteric polymers can be applied to granules, pellets (i.e. small spherical granules) or tablets from organic solvent solutions, aqueous solutions of alkali salts or from aqueous latex or pseudolatex dispersions.
  • Interest in the use of aqueous-based enteric film coating systems has increased owing to well-documented drawbacks (uneconomic, unsafe and toxic causing health and environmental risks) associated with organic-solvent-based coating systems.
  • aqueous latex and pseudolatex systems of CAP and HPMCP have been widely used since early 1980's.
  • a common problem associated with enteric-coated formulations made of aqueous disperse systems or solutions is the lack of gastric protection.
  • enteric films prepared from organic-solvent- based solutions showed considerably lower permeability to a basic drug, theophylline, compared with films prepared from aqueous latex and pseudolatex dispersions, and ammoniated aqueous polymer solutions.
  • Heinamaki et al. Int. J. Pharm., 109: 9-16, 1994, reported that the diffusion of a water-soluble active agent through the films prepared from ammoniated aqueous solutions is more rapid than that through the films prepared from organic-solvent-based (acetone) solution.
  • aging under stress conditions can change the permeability and mechanical properties of ammoniated aqueous enteric films based on cellulose acetate phthalate (CAP) or cellulose acetate trimellitate (CAT).
  • CAP cellulose acetate phthalate
  • CAT cellulose acetate trimellitate
  • the therapeutically active agents are highly water-soluble, they may easily diffuse through the film coat or dissolve in the spray mist during the coating operation, resulting in active agents being included in the film. Suitable method to completely prevent this phenomenon has not been found yet.
  • a fairly effective method is to keep the particle size of the spray mist small and use a low spray rate (Nagai, in Aqueous polymeric coatings for pharmaceutical dosage forms, McGinity (ed.), 177- 225, 1997).
  • starches or their constituent amylopectin is known in the pharmaceutical industry. They have been used as fillers for improving the process of manufacture of solid dosage forms and also as disintegrating agent.
  • amylopectin when used as a co-filler or sub-coat in a drug formulation for enteric drug delivery consisting of a pellet subsequently film-coated with an aqueous enteric latex or pseudolatex dispersion or solution of pH-sensitive polymers, improves considerably acid resistance properties of the pellet and thus of the drug formulation.
  • the pellet containing amylopectin as a co-filler provides considerably low premature permeability even to a highly water- soluble active agent in an acidic environment of the simulated gastric fluid. Reliable and effective drug release is occurred in the higher-pH environment of the simulated intestinal fluid.
  • Amylopectin used as a sub-coating material in enteric- coated pellets also improves acid resistance properties of the pellets in the simulated gastric fluid.
  • pellet as used herein is intended to include all small-sized drag dose forms, such as pellets, granules, pills, small tablets and the like, which are used to deliver therapeutically active agent(s). These dosage forms pass easily the pylorus and reach quickly the intestine, thus the start of the effect is not postponed.
  • the drug formulation of the present invention is characterized by what is defined in the characterizing parts of the independent claims.
  • the pellet of the enteric pellet drug formulation according to the invention is film- coated with an aqueous enteric latex or pseudolatex dispersion or solution of pH- sensitive polymers and the amylopectin forms a sub-coat or is used as a co-filler.
  • the ingredients of the pellet may be thoroughly mixed together.
  • the pellet consists of a core containing microcrystalline cellulose and at least one therapeutically active agent and of an amylopectin sub-coat applied on the core.
  • the pellet may additionally contain an other filler, for example lactose, especially when amylopectin is used for sub-coating the pellet.
  • lactose especially when amylopectin is used for sub-coating the pellet.
  • amylopectin used is preferably natural amylopectin, such as corn starch amylopectin.
  • starch consists of essentially linear amylose and branched amylopectin.
  • Amylose is a polymer of ⁇ -l,4-bound glycosyl units (500-6000).
  • amylopectin short linear ⁇ -l,4-glucan chains are bound to each other by ⁇ -1,6 bonds.
  • Amylopectin is very large in size (molecular weight 10-1000- 10 ⁇ g/mol). Waxy corn starch contains almost entirely amylopectin, with no amylose.
  • the drug formulation of the invention is well adapted for use with a therapeutically active agent, which is water-soluble and even highly water-soluble, such as riboflavin sodium phosphate. It may also be used in connection with other kinds of therapeutically active agents, such as proteins and peptides.
  • a therapeutically active agent which is water-soluble and even highly water-soluble, such as riboflavin sodium phosphate. It may also be used in connection with other kinds of therapeutically active agents, such as proteins and peptides.
  • the pellet of the invention may be prepared by using extrusion-spheronization, r c.nommpnaarc.rtiinonn n orr c ceennttririffuuggaall t teecchrinniirq ⁇ uieess
  • the pellet thus obtained is subsequently film-coated with an aqueous enteric latex or pseudolatex dispersion or ammoniated solution of pH-sensitive polymers in order to obtain a drug formulation, which is intended for small intestine or colonic drug delivery.
  • Aqueous enteric coatings can be successfully applied to controlled-release (site-specific) granules and pellets (i.e. small spherical granules) in an air- suspension process.
  • Sub-coating with amylopectin according to the invention is also advantageous for the subsequent enteric-coating.
  • Sub-coating improves the bonding of the enteric- coating on the pellet core. If the amylopectin is placed in the core itself, sub-coating may be done by any method known in the art.
  • a water-soluble drug and excipient i.e. lactose
  • a water-soluble drug and excipient i.e. lactose
  • Amylopectin used as a co-filler in the pellet cores or as an aqueous sub-coat according to the invention prevents efficiently drug migration from the core into the enteric film coat layer. Even very highly water-soluble agents can be retained in the core until the pellets reach the intestine.
  • FIG 7. Fluorescence intensity of riboflavin sodium phosphate in the enteric film coat applied onto the amylopectin and lactose containing pellets.
  • Pellet cores for subsequent enteric-coating procedure were prepared by using riboflavin sodium phosphate as a model drug for highly water-soluble active agent.
  • the composition of pellet cores was as follows (in %):
  • Pellet cores were prepared by extrusion-spheronization technique (NICA M6L mixer/granulator; Nica E170 extruder; Nica S320 spheronizer; Nica System AB, M ⁇ lndal, Sweden). The speed of the powder feeder was 35 rpm, and that of liquid input pump and spheronization time were 195 rpm and 6 minutes, respectively. Pellet cores were dried for 24 hours in a drying oven at 32°C. The dried pellet cores were sieved manually, and those in diameter of 0.71-1.0 mm were selected for film coating.
  • the in vitro release tests for pellet cores were performed using the USP apparatus (basket method).
  • the dissolution medium was 500 ml of 0. IN hydrochlori.de acid, at 37 ⁇ 0.5°C.
  • the basket rotation speed was kept at 100 rpm. Samples were filtered through a filter and assayed by UV spectrophotometiy at 444 nm for riboflavin sodium phosphate.
  • the surface and internal structure of the pellets cores were studied with confocal laser microscope, CLSM (Bio-Rad Lasersharp MRC-1024, Bio-Rad, U.K.) attached to an Axiovert 135M inverted microscope using a Zeiss Plan-Neofluar 10 x /0.30 N.A. air lens.
  • CLSM Bio-Rad Lasersharp MRC-1024, Bio-Rad, U.K.
  • Axiovert 135M inverted microscope using a Zeiss Plan-Neofluar 10 x /0.30 N.A. air lens.
  • the 488 nm line of an Krypton-Argon laser and the laser power of 0.15 mW were used.
  • the iris, black gain control and all other settings were kept constant during the experiments.
  • Kalman filter was applied per picture. Images were recorded with intervals of 5 ⁇ m in the Z- direction.
  • the spherical granules (pellets) for oral administration containing at least one freely water-soluble active agent and mixture of microcrystalline cellulose (MCC) and amylopectin can be prepared by using extrasion-spheronization or centrifugal techniques.
  • the CLSM images shown in Figures 1 and 2 demonstrate that there seem to be differences between amylopectin and lactose containing pellet cores. Amylopectin pellets appeared to have even smoother surface without any pores than respective lactose pellets. On the contrary, CLSM images showed relatively large non-fluorescence areas in the lactose pellets. By using a larger magnification for CLSM, the surface morphology of the pellet cores and the original shape of the excipients were better distinguished.
  • Riboflavin sodium phosphate was shown to be in a dissolved form in the pellets.
  • the SEM scanning electron microscope
  • results on the pellet cores and enteric-coated pellets were consistent with the CLSM results.
  • the pellet cores containing amylopectin as a co-filler had a smoother surface compared to that of lactose containing pellets.
  • Aqueous enteric coatings were applied to pellets in an air-suspension process.
  • the composition of aqueous enteric pseudolatex dispersion was as follows (in grams):
  • the pellet cores were coated using Aeromatic air-suspension equipment (Aeromatic Strea-1, Aeromatic AG, Muttenz, Switzerland).
  • the coating batches comprised of 300 g pellet cores. Time for pre-heating of the pellet cores was 10 minutes.
  • the inlet temperature was adjusted to 40 ⁇ 2°C, and outlet air temperature was 30 ⁇ 2°C for Aquateric ® (FMC Corporation, Philadelphia, USA) coating.
  • the pneumatic spraying pressure was 1.6 bar, and the air flow rate 100 m h. Pump rate of the coating solution was 3.4 g/min at start. Application of 2% coating by weight was run at this rate, and subsequently at a rate of 6.8 g/min was proceeded to complete the coating run.
  • enteric-coated pellets were then cured in an oven at 60 ⁇ 2°C for two hours.
  • the theoretical amounts of coating were 20% and 30% of the total weight of the pellets.
  • Figure 6 shows the CLSM images of amylopectin and lactose pellets after 30% theoretical weight increase of Aquateric ® enteric fihn coating, h the film-coated amylopectin pellets, appreciable coalescence of the polymeric spheres was formed in the pellet surface (dark network areas). With amylopectin containing pellets, no riboflavin sodium phosphate (i.e. drug migration) could be seen around the pellet core. In the film-coated lactose pellets, the film was not formed by well-defined and discrete polymeric beads (Figure 6). Furthermore, some riboflavin sodium phosphate was found to have migrated to the film-coat of the pellets. The large non- fluorescence areas in lactose containing pellets can be seen even after film coating.
  • a significant amount of drug may dissolve in the coating formulation and reduce the surface tension of the liquid, which is essential for the development of the capillary pressure needed for the deformation of the polymeric spheres.
  • the film deposited on the substrate may become less continuous, and eventually lead to relatively fast release rates.
  • Drug molecules may also interpose themselves between adjacent polymer spheres and dissolve during dissolution to generate a porous and more permeable coating material that subsequently releases the drag at fast rates.
  • irregular lactose pellets can form uneven film after coating. This may also result in rapid release rate as shown in the dissolution test.
  • pellet cores lactose as a co-filler
  • enteric film coating as described in examples 1 and 2, respectively, were used.
  • the pellet cores were sub-coated with an aqueous amylopectin, and subsequently film-coated with an aqueous enteric pseudolatex dispersion of pH-sensitive polymer, CAP.
  • Aqueous sub-coating solution of amylopectin was prepared by exposing the starch dispersion to high thermal and pressure conditions using a reactor equipped with a blade mixer (VTT Automation, Espoo, Finland). Amylopectin was first dispersed in cold water. Solution of 5% (w/w) was made. Once loaded into the reactor, the starch dispersion solution was gradually heated to 157°C and the pressure in the vessel reached 3.0 bar. The starch solution was cooled down to approximately 95°C. The temperature of the solution was maintained above 60°C for film coating. As a sub- coating reference, 5% aqueous hydroxypropyl methylcellulose (HPMC) solution was used.
  • HPMC aqueous hydroxypropyl methylcellulose
  • the pellets were coated using an Aeromatic air-suspension film coater (Areomatic Strea-1, Aeromatic AG, Muttenz, Switzerland). Each coating batch comprised 300 g pellets. Pellet cores were pre-heated for 10 minutes. The inlet air temperature was adjusted to 78 ⁇ 2°C and 60 ⁇ 2°C, the outlet air temperature to 50 ⁇ 2°C and 42 ⁇ 2°C for amylopectin and HPMC sub-coating, respectively. Pneumatic spraying pressure was 1.4 bar, and the air flow rate was 100 m /h. Pump rate of the coating solution was 2.0 ⁇ 0.2 g/min until a 2% theoretical increase in coating weight was obtained.
  • composition (% w/w) of aqueous enteric coating dispersion was as follows: Aquateric ® 11.0, triacetin 3.9, Tween 0.1 and water 85.0. After sub-coating, the nozzle and spraying-tube were carefully washed and subsequent enteric coating was started. The pneumatic spraying pressure and air flow rate were as in sub-coating. Pump rate of the coating solution was 3.2 ⁇ 0.2 g/min until a 2% increase in coating weight was obtained, then proceeding at a pump rate of 6.4 + 0.2 g/min to complete the coating run. After spraying, the inlet air temperature 68 °C and outlet air temperature 56°C was maintained for an additional 2 hours in the drying phase. The pellets were then cured in an oven at 60°C for two hours. The theoretical amounts of coating were 30% (w/w) and 35% (w/w) of the total weight of the pellets.
  • aqueous amylopectin as a sub-coat clearly improved the gastric resistance capacity of the present film-coated pellets.
  • the present invention provides formulation for preparing enteric-coated pellets for highly water-soluble active ingredients since the premature release of the active ingredient in the stomach (an acidic environment) is blocked by the effective sub-coat.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne des formulations médicamenteuses pour administration entérique comprenant une pastille enrobée dans un film avec une dispersion entérique aqueuse de latex ou de pseudolatex, ou bien une solution de polymères sensibles au pH. Ces granules sphériques (pastilles) à enrobage entérique sont de préférence préparées à partir d'un mélange en poudre granuleuse humide de cellulose microcristalline et d'amylopectine tirée de l'amidon de maïs. La pastille qui renferme de l'amylopectine comme co-excipient présente une perméabilité prématurée extrêmement faible, même à un agent actif fortement hydrosoluble dans le milieu acide du suc gastrique simulé. Une libération sure et efficace du médicament se produit dans l'environnement à pH élevé du fluide intestinal simulé. Utilisée comme matériau de sous-couche dans les pastilles à enrobage entérique, l'amylopectine améliore également les propriétés de résistance aux acides desdites pastilles dans le suc gastrique simulé.
PCT/FI2001/001103 2000-12-18 2001-12-17 Formulations medicamenteuses a enrobage enterique et leur fabrication WO2002049621A1 (fr)

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AU2002219249A AU2002219249A1 (en) 2000-12-18 2001-12-17 Enteric-coated drug formulations and their manufacture

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FI20002768 2000-12-18
FI20002768A FI20002768A (fi) 2000-12-18 2000-12-18 Enteropäällysteisiä lääkekoostumuksia ja niiden valmistus

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2088154A1 (fr) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Procédés et compositions pour le traitement de troubles gastro-intestinaux
WO2010059836A1 (fr) 2008-11-20 2010-05-27 Decode Genetics Ehf Composés bicycliques substitués à pont aza pour maladie cardiovasculaire et du système nerveux central
WO2010084499A2 (fr) 2009-01-26 2010-07-29 Israel Institute For Biological Research Composés spiro hétérocycliques bicycliques
EP2476680A1 (fr) 2008-01-11 2012-07-18 Albany Molecular Research, Inc. Pyridoindoles à substitution (1-azinone)
EP2628727A2 (fr) 2007-11-21 2013-08-21 Decode Genetics EHF Inhibiteurs de PDE4 biaryle pour le traitement de troubles pulmonaires et cardiovasculaires
US8957202B2 (en) 2011-12-15 2015-02-17 Industrial Technology Research Institute Enterosoluble and intestinal-enzyme-biodegradable materials and method for preparing the same
WO2019183245A1 (fr) 2018-03-20 2019-09-26 Icahn School Of Medicine At Mount Sinai Composés inhibiteurs de kinase, compositions et procédés d'utilisation
WO2020142485A1 (fr) 2018-12-31 2020-07-09 Icahn School Of Medicine At Mount Sinai Composés inhibiteurs de kinase, compositions et procédés d'utilisation
WO2021105040A1 (fr) * 2019-11-27 2021-06-03 Dsm Ip Assets B.V. Comprimé de système de pastilles à unités multiples comprenant de la riboflavine
WO2021105041A1 (fr) * 2019-11-27 2021-06-03 Dsm Ip Assets B.V. Comprimé mups comprenant de la riboflavine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991007949A1 (fr) * 1989-11-24 1991-06-13 British Technology Group Ltd. Compositions a liberation retardee
WO1995005807A1 (fr) * 1993-08-20 1995-03-02 Novo Nordisk A/S Nouveau produit pharmaceutique destine a etre administre par voie orale et comprenant de la progesterone, un polyethylene glycol ainsi qu'un excipient
EP1005864A1 (fr) * 1998-11-30 2000-06-07 Tecnimede-Sociedade Tecnico-Medicinal, S.A. Compositions pharmaceutiques stables dépourvues d'antioxidant contenant des dérivés thiènopyridine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991007949A1 (fr) * 1989-11-24 1991-06-13 British Technology Group Ltd. Compositions a liberation retardee
WO1995005807A1 (fr) * 1993-08-20 1995-03-02 Novo Nordisk A/S Nouveau produit pharmaceutique destine a etre administre par voie orale et comprenant de la progesterone, un polyethylene glycol ainsi qu'un excipient
EP1005864A1 (fr) * 1998-11-30 2000-06-07 Tecnimede-Sociedade Tecnico-Medicinal, S.A. Compositions pharmaceutiques stables dépourvues d'antioxidant contenant des dérivés thiènopyridine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RIITTA JUNNILA ET AL.: "Waxy corn starch: A potent cofiller in pellets produced by extrusion- spheronization", PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY, vol. 5, no. 1, 2000, pages 67 - 76, XP002909932 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2088154A1 (fr) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Procédés et compositions pour le traitement de troubles gastro-intestinaux
EP2628727A2 (fr) 2007-11-21 2013-08-21 Decode Genetics EHF Inhibiteurs de PDE4 biaryle pour le traitement de troubles pulmonaires et cardiovasculaires
EP2674417A2 (fr) 2007-11-21 2013-12-18 Decode Genetics EHF Inhibiteurs de PDE4 biaryle pour le traitement de l'inflammation
EP2476680A1 (fr) 2008-01-11 2012-07-18 Albany Molecular Research, Inc. Pyridoindoles à substitution (1-azinone)
WO2010059836A1 (fr) 2008-11-20 2010-05-27 Decode Genetics Ehf Composés bicycliques substitués à pont aza pour maladie cardiovasculaire et du système nerveux central
WO2010084499A2 (fr) 2009-01-26 2010-07-29 Israel Institute For Biological Research Composés spiro hétérocycliques bicycliques
US8957202B2 (en) 2011-12-15 2015-02-17 Industrial Technology Research Institute Enterosoluble and intestinal-enzyme-biodegradable materials and method for preparing the same
WO2019183245A1 (fr) 2018-03-20 2019-09-26 Icahn School Of Medicine At Mount Sinai Composés inhibiteurs de kinase, compositions et procédés d'utilisation
WO2020142485A1 (fr) 2018-12-31 2020-07-09 Icahn School Of Medicine At Mount Sinai Composés inhibiteurs de kinase, compositions et procédés d'utilisation
WO2021105040A1 (fr) * 2019-11-27 2021-06-03 Dsm Ip Assets B.V. Comprimé de système de pastilles à unités multiples comprenant de la riboflavine
WO2021105041A1 (fr) * 2019-11-27 2021-06-03 Dsm Ip Assets B.V. Comprimé mups comprenant de la riboflavine
CN114760992A (zh) * 2019-11-27 2022-07-15 帝斯曼知识产权资产管理有限公司 包含核黄素的mups片剂

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AU2002219249A1 (en) 2002-07-01
FI20002768A (fi) 2002-06-19

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