WO2000067747A1 - Gelules contenant du docusate - Google Patents

Gelules contenant du docusate Download PDF

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Publication number
WO2000067747A1
WO2000067747A1 PCT/US2000/006200 US0006200W WO0067747A1 WO 2000067747 A1 WO2000067747 A1 WO 2000067747A1 US 0006200 W US0006200 W US 0006200W WO 0067747 A1 WO0067747 A1 WO 0067747A1
Authority
WO
WIPO (PCT)
Prior art keywords
formulation
liquid
ethylhexyl
sulfosuccinate
bis
Prior art date
Application number
PCT/US2000/006200
Other languages
English (en)
Inventor
Robert Anthony Scott
Ewart Thomas Cole
Geoff Rowley
Philippa Walters
Zhao-Ping Zhong
Original Assignee
Warner-Lambert Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Warner-Lambert Company filed Critical Warner-Lambert Company
Priority to AU38734/00A priority Critical patent/AU3873400A/en
Publication of WO2000067747A1 publication Critical patent/WO2000067747A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives

Definitions

  • the present invention relates to a formulation comprising bis (2-ethylhexyl) sulfosuccinate, which can be readily filled into hard capsules, and liquid-filled hard capsules containing said formulation.
  • Hard capsules have traditionally been used as a container for particulate solids that are usually in the form of powders or pellets.
  • particulate solids that are usually in the form of powders or pellets.
  • drugs either dissolved or suspended in a liquid vehicle for a long time the only available oral unit dosage form was the soft capsule.
  • formulating drug substances such as liquids for filling into hard capsules offers various benefits.
  • the filling of liquids into capsule 1 - presents no dust hazard and the possibility of cross-contamination via airborne particles can also be eliminated.
  • the excipient used provides protection against moisture and oxygen by totally surrounding the drug particles thus improving the formulation of oxygen-sensitive or moisture-sensitive drugs and extending their shelf life.
  • the excipients to be used for formulations of liquid fill hard capsules may be classified according to rheological properties during the filling stage.
  • Liquid- filled formulations can be (a) mobile Newtonian liquids, (b) thixotropic gels both tillable at ambient temperature and (c) thermosoftening systems which are either Newtonian or non- Newtonian at elevated filling temperatures, e.g. 70°C, but solid at ambient temperature.
  • the present invention provides a formulation comprising bis (2-ethylhexyl) sulfosuccinate and an excipient selected from the group consisting of glyceride derivatives, polyethylene glycols and mixtures thereof, which formulation forms a solution at least at the maximum acceptable liquid-filling temperature for hard capsules.
  • a method for preparing such a formulation by mixing bis (2- ethylhexyl) sulfosuccinate and an excipient selected from the group consisting of glyceride derivatives, polyethylene glycols and mixtures thereof, with stirring, and optionally heating the mixture at elevated temperatures in order to form a formulation which forms a solution at least at the maximum acceptable liquid-filling temperature for hard capsules.
  • liquid- filled hard capsules comprising such a formulation.
  • the empty hard capsule is composed of shell material, water and, optionally, colouring and/or opacifying agents.
  • the shell material may be selected from gelatin, cellulose ethers, starch or polyvinylalcohol or mixtures thereof.
  • Gelatin may be of animal or non-animal origin or of modified gelatins like succinylated gelatin.
  • Suitable cellulose ethers are alkyl- and/or hydroxyalkyl substituted cellulose ether with 1 to 4 carbon atoms in the alkyl chains, preferably methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethylmethyl cellulose, hydroxyethylethyl cellulose, hydroxypropylmethyl cellulose or the like.
  • Starch may be e.g. corn starch or modified starches such as starch ethers and oxidized starch, more particularly hydroxpropylated starch and hydroxyethylated starch.
  • the empty hard capsule is a container of stable dimensions.
  • the capsule shells can be standard articles available on the market from industrial suppliers, for example, the Capsugel Division of the Warner-Lambert Company, the European Hard Capsule Division of R.P. Scherer, or Shionogi Company.
  • Empty capsules are robust and show good stability on storage in a wide range of conditions . When stored in their original containers at for example 15 to 20°C and 35 to 65% relative humidity, they form a suitable delivery route for many drug formulations. Because of their stability, according to the present invention hard capsules can be successfully filled and used in all countries with climates rating from arctic to tropical .
  • One essential component of the formulations according to the present invention is bis (2-ethylhexyl) sulfosuccinate (which is often also called “docusate”) , more preferred bis (2- ethylhexyl) sulfosuccinate sodium, bis (2- ethylhexyl) sulfosuccinate potassium or bis (2- ethylhexyl) sulfosuccinate calcium, most preferred bis (2- ethylhexyl) sulfosuccinate sodium.
  • Bis (2-ethylhexyl) sulfosuccinate (“docusate”) is widely used in pharmaceutical formulations as an anionic surfactant, wetting agent as well as laxative and fecal softener. Therefore, the formulations according to the present invention could be used in several different ways, for example as a laxative composition or as a basic formulation of hard capsules, which offers the possibility to produce formulations containing other active ingredients which formulations remain in a stable and clear state over a prolonged period of time .
  • the content of bis (2- ethylhexyl) sulfosuccinate based on the total weight of the liquid fill is usually in a range of from 0.01 to 99,99 % w/w, preferably in a range of from 0,1 to 90 % w/w, more preferably in a range of from 1 to 80 % w/w and most preferably in a range of 5 to 50 % w/w.
  • the excipients used are selected from glyceride derivatives, polyethylene glycols and mixtures thereof.
  • the excipient selected is a thermosoftening excipient selected from the above-mentioned group .
  • the polyethylene glycols used according to the present invention have melting ranges from 40 to 70°C and are available in a wide range of viscosity grades.
  • the polyethylene gly-cols especially polyethylene glycols, usually have a weight average molecular weight in a range of from 1000 to 20000, preferably in a range of from 2000 to 10000, more preferably in a range of from 3000 to 6000 and most preferably have a weight average molecular weight of 6000.
  • polyethylenglycol/polypropylengly-col copolymers which are often also called poloxamers .
  • Polyethylene glycols having average molecular weight grades below 1000 for example are hygroscopic so they tend to dehydrate and crack capsule shells. Viscosity grades above 20000 tend to produce matrices that sometimes craze on cooling, and thus, may give a less elegant matrix appearance and unexpectedly high matrix viscosities in the process.
  • Glyceride derivatives include semi-synthetic glycerides and chemical glycerides and are preferably characterized by melting-point ranges of 30 to 60°C and by varying degrees of hydrophilicity (HLB values between 2 and 20) . These materials may be selected according to the melting range and HLB value to provide a wide range of release-rate characteristics .
  • Usable semi-synthetic glycerides comprise medium-chain partial glycerides with varying melting ranges and HLB values according to their content of mono-diglycerides and the chain length of the specific fatty acid concerned.
  • Usable chemical glycerides are excipients derived from vegetable oils, preferably hydrogenated vegetable oils. These compounds are defined as saturated poly(glycol) glycerides and contain varying blends of glycerides (mono- ,di- and tri) and their mono- and di-esters, plus polyethylene glycols and low-molecular weight polyethylene glycols.
  • the excipient used should have physical characteristics which enable the fill material to be satisfactorily dosed, without stringing, between room temperature and about 70°C.
  • the upper limit of 70°C is the maximum acceptable temperature for the shell capsule.
  • the excipient used should have a viscosity ranging from 0.1 Pa s to 27 Pa s at room temperature.
  • excipients to be used according to the present invention are excipients derived from hydrogenated fat and oils with controlled hydrophilic properties, such as excipients available under the trademark Gelucire, polyethylene glycols having weight average molecular weight ranges of 3000 to 6000, available as PEG-3000 to PEG-6000, myristic acid triglycerides, available under the trademark Dynasan, other suitable vegetable oil excipients such as Miglyol 812 N, Miglyol 829, arachis (peanut) , sesame, corn and cottonseed oil; and polyethylene glycol/polypropylene glycol-copolymers, usually designated as poloxamers.
  • excipients available under the trademark Gelucire polyethylene glycols having weight average molecular weight ranges of 3000 to 6000, available as PEG-3000 to PEG-6000, myristic acid triglycerides, available under the trademark Dynasan, other suitable vegetable oil excipients such as Miglyol 8
  • liquid fill formulations may contain other components which are usually included into liquid-filled formulations.
  • these components comprise adjuvants, colouring agents, viscosity changing components, softening agents, thickening agents, diluents, opacifying agents and other components .
  • Preferred additives are thickening agents such as silicon dioxides, partial glycerides, for example mixtures of mono- and diglycerides, glycol stearates, waxy ester materials, glyceryl stearates, cetyl palmitate, polyoxyalkylene glycerol monostearate waxes, fatty acid mixtures, glycerine monostearates, hydrated castor oil, mixtures of mono diglycerides of higher saturated fatty acids, mixtures of fatty alcohols, waxes and oils, mixtures of mono- and diglycerides of pal itinic and stearic acid, and fatty alcohol ether sulfates.
  • Such additives are available on the market for example under the trademark Aerosil from Degussa,
  • silicon dioxide is used as a preferred thickening agent.
  • dispersion of silicon dioxide in formulations containing an oil excipient selected from the group consisting of glyceride derivatives, polyethylene glycols and mixtures thereof, preferably glyceride derivatives, especially vegetable oils, to produce a clear and stable gel having an increased viscosity can be simplified if the formulation also includes bis (2-ethylhexyl) sulfosuccinate.
  • bis (2-ethylhexyl) sulfosuccinate and the excipient as well as one or more additives mentioned above are combined to form a mixture. If the excipient is a liquid at ambient temperature, bis (2-ethylhexyl) sulfo-succinate can be dissolved or dispersed in the excipient. If a suspension is to be produced at room temperature, the particle size of the drug must not exceed 100 ⁇ m and the consistency of the vehicle must be sufficient to prevent sedimentation.
  • Solvents such as glycerol, propylene glycol and sorbitol which are commonly used in syrups and soft shell capsules, are hygroscopic and are unsuitable as excipients for filling into hard capsules. This also applies to PEGs having a molecular weight of less than 1000. These PEGs are too hygroscopic and therefore not recommended for filling into hard capsules at high concentrations.
  • thermosoftened materials are used as the excipients.
  • thermosoftening material selected is non- toxic, pharmacologically inert and the melting point is low enough so that thermal damage to the capsule body or degradation of bis (2-ethylhexyl) sulfosuccinate is avoided. Furthermore, it is preferred that the melting point is high enough to prevent melting during transportation and storage.
  • bis (2-ethylhexyl) sulfosuccinate can be formulated with an excipient used according to the present invention either at room temperature or at elevated temperatures to form a fluid.
  • the manufacturing process comprises liquefying an excipient (this means a melting step if thermosoftening excipients are used, or a simple stirring step when using liquids), adding bis (2-ethylhexyl) sulfosuccinate into the liquefied excipient, and optionally heating the resulting mixture to obtain a composition which forms a solution at least at the maximum acceptable liquid-filling temperature for hard shell .
  • thermosoftening excipients are selected according to narrow melting ranges within the region of 30 to 60°C and also so as to match the requirements on viscosity to ensure good filling control.
  • Increasing the viscosity of the filling composition can be achieved by adding a thickening agent, for example one of the additives mentioned above, especially silicon dioxide.
  • a method for preparing a formulation suitable for liquid-filling into hard capsules by mixing bis (2-ethylhexyl) sulfosuccinate and an excipient selected from the group consisting of glyceride derivatives, polyethylene glycols and mixtures thereof, with stirring, and optionally heating the mixture at elevated temperatures in order to form a formulation which forms a solution at least at the maximum acceptable liquid-filling temperature for hard capsules.
  • the excipients used are preferably middle chain length vegetable fatty acid esters, such as Miglyol ® oils, polyethylene glycols, such as PEG 6000, and poloxamers such as polyoxamers of the Synperonic ® series .
  • the formulation comprising bis (2-ethylhexyl) sulfosuccinate and an excipient as defined above, also includes silicon dioxide as a thickening agent in order to increase viscosity and to maintain clarity of the gel produced.
  • silicon dioxide can be added to the mixture of bis (2- ethylhexyl) sulfosuccinate and the excipient used according to the present invention.
  • the mixture can be subjected to a mechanical mixing for example by using a magnetic stirring device, for example a paddle mixer, or by sonification, such as an ultrasonic method.
  • a magnetic stirring device for example a paddle mixer
  • sonification such as an ultrasonic method.
  • an ultrasonic method decreases the time for dissolution or dispersion.
  • mechanical stirring is the preferred measure to improve the dissolution or dispersion of the active ingredient .
  • bis (2-ethylhexyl) sulfosuccinate is a waxy solid which is difficult to disperse or even to dissolve in liquids or molten excipients because of its cohesive texture.
  • poloxamers are more effective dispersion vehicles in the molten state for bis (2-ethylhexyl) sulfosucci-nate than polyethylene glycols.
  • solution of bis (2- ethylhexyl) sulfosuccinate in a liquid excipient. This can be achieved by using one of the glycerides defined above at room temperature or at elevated temperature (for example 30 to 50°C) depending on the oil properties and mixing conditions.
  • the temperature for dissolution could preferably be in a range of 30 to 50°C in case of vegetable oil excipients optionally by using magnetic stirring, in a range of 80 to 110 °C (especially 100°C) optionally by using magnetic stirring, if PEG, for example PEG 6000, is used, in a range of 50 to 70 °C in case of a semi-solid or solid poloxamer is used and at room temperature to 40°C, preferably in a range of from 30 to 40°C optionally by using magnetic stirring, if a liquid poloxamer excipient is used.
  • a further important factor is the size of bis (2- ethylhexyl) sulfosuccinate used during mixing.
  • the size of bis (2-ethylhexyl) sulfosuccinate could be reduced for example by grating, in order to facilita e mixing, dispersion and/or dissolution.
  • the capsule body is filled with the liquid mixture, for example in a highspeed machinery, which involves pumping of the formulation through precision pumps to ensure good filling weight uniformity throughout processing.
  • a highspeed machinery which involves pumping of the formulation through precision pumps to ensure good filling weight uniformity throughout processing.
  • proportion of solids content and processing temperature have to be considered.
  • Thermosoftening excipients used must be able to withstand prolonged high temperature exposure without significant physical or chemical change .
  • capsule filling machines most modern capsule filling machines can be modified to allow hard gelatin capsules to be filled with liquid in either a cold or hot state.
  • liquid- filling machines there are five recommended requirements for liquid- filling machines. Firstly, they should maintain the product at a constant temperature of up to about 70°C. Secondly, they should maintain a homogenous suspension in a product hopper. Thirdly, the machine should accurately dose volumes of liquid from 0.001 to 10 ml. Fourthly, they should eject a filled capsule body when the cap is missing. Fifthly, they should interrupt dosing when a capsule body is absent .
  • the capsule body is closed by a cap. If capsules are filled with materials that remain fluid, these capsules require sealing to prevent leakage. Sealing also prevents ingress of oxygen and can improve stability.
  • a process can be used which involves passing the capsule over a wheel that revolves in a gelatin bath. A quantity of gelatin is picked up by the wheel and deposited on the junction between the body and the cap. The gelatin band is dried by passing the capsule through a drying chamber.
  • a method of sealing a hard gelatin capsule may be mentioned, wherein a gelatin band is applied to the junction between the body and cap of the capsule.
  • Bis (2-ethylhexyl) sulfosuccinate which is also called docusate, can be used as a laxative to provide stimulant and softening properties.
  • the docusate used is usually docusate sodium, however also docusate calcium and docusate potassium could be used according to the present invention.
  • capsules are further provided containing a formulation as defined above. These capsules can be used to orally administer bis (2-ethylhexyl) sulfosuccinate in a very safe manner. Furthermore, the capsules prepared show a very high stability of the formulation contained.
  • a method of treating subjects including human beings suffering from obstruction by orally administering liquid fill hard gelatin capsules containing bis (2-ethylhexyl) sulfosuccinate.
  • the ultrasonic method decreased the time for dissolution of DS in the oil excipients, however, the increase in water temperature due to ultrasonic vibration, was not controllable and therefore considered not totally suitable for manufacture.
  • the time for dissolution of the same concentration of DS in the formulation decreased considerably at 45°C in comparison with 37°C using magnetic stirring.
  • DS/Miglyol 812N and DS/Miglyol 829 in the three concentrations were all clear and stable, whereas the only clear solution of DS with cottonseed oil when stored at room temperature was 100mgDS/500mg Cottonseed.
  • the remaining DS solutions prepared with the other vegetable oil excipients showed evidence of crystallization of DS after 24 hours at room temperature so that heating was necessary to obtain clear solutions.
  • Solution of DS in Miglyol 812N can also be achieved at room temperature with overnight storage .
  • 100mgDS/350mgMiglyol 812N and 100mgDS/350mgMiglyol 829 were selected to produce the 500g batch for the compatibility test .
  • Cutina HR was suggested as an additive agent for changing the viscosity of DS formulation with Miglyol 812N. Previous investigations had used silicon dioxide to change the viscosity and maintain clarity of the gel.
  • a normal oral dose of DS is a lOOmg/capsule and thus a formulation containing 20% w/w DS in polymer was investigated (capsule fill weight of 500 mg) . From the thermal characteristics it was assumed that this formulation could be filled on the second heating cycle at the normal capsule filling temperature of 70°C. However, the first heating cycle for the preparation of the drug formulation with PEG 6000 required investigation using three different physical thermal mixing methods in order to determine the best conditions for drug dispersion in the molten polymer prior to filling. The best dispersion of DS in PEG 6000 was achieved by dispersing solid DS in melted PEG 6000 in an oven at 100°C with mixing by a magnetic stirrer. Recent results with poloxamer PE/F68 indicate much easier dissolution of DS than with PEG 6000.
  • DS was successfully dissolved in Synperonic PE/L61, PE/L81, PE/F68, PE/F87 and PE/F108.
  • concentrations of DS with poloxamer chosen for a size 1 capsule were lOOmg DS/350mg Synperonic PE/L- and lOOmg DS/400mg Synperonic PE/F- .

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (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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  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Emergency Medicine (AREA)
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Abstract

L'invention concerne une préparation comprenant du bis (2-éthylhexyle) sulfosuccinate et un excipient choisi parmi le groupe des dérivés de glycéride, des polyéthylèneglycols et des mélanges associés. Cette préparation constitue une solution au moins à une température maximum acceptable de remplissage de gélules. L'invention concerne également un autre mode de réalisation d'une telle préparation consistant à mélanger du bis (2-éthylhexyle) sulfosuccinate et un excipient choisi parmi le groupe des dérivés de glycéride, des polyéthylèneglycols et des mélanges associés, puis à agiter et, éventuellement, à chauffer le mélange à des températures élevées de manière à former une préparation qui constitue une solution au moins à une température maximum acceptable de remplissage de gélules. L'invention concerne également des gélules contenant une telle préparation.
PCT/US2000/006200 1999-05-06 2000-03-10 Gelules contenant du docusate WO2000067747A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU38734/00A AU3873400A (en) 1999-05-06 2000-03-10 Docusate hard gelatin capsules

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US30604799A 1999-05-06 1999-05-06
US09/306,047 1999-05-06

Publications (1)

Publication Number Publication Date
WO2000067747A1 true WO2000067747A1 (fr) 2000-11-16

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PCT/US2000/006200 WO2000067747A1 (fr) 1999-05-06 2000-03-10 Gelules contenant du docusate

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AU (1) AU3873400A (fr)
WO (1) WO2000067747A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002096394A2 (fr) * 2001-05-30 2002-12-05 Euro-Celtique S.A. Composition pharmaceutique
CN103070846A (zh) * 2013-01-17 2013-05-01 安士制药（中山）有限公司 一种多库酯钠软胶囊

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2347041A1 (fr) * 1976-04-05 1977-11-04 American Cyanamid Co Compositions renfermant du dioctylsulfosuccinate de calcium et leur utilisation comme amollissants des selles
WO1995006463A1 (fr) * 1993-09-01 1995-03-09 Pfizer Inc. Compositions pharmaceutiques contenant des tensio-actifs anioniques
EP0642786A1 (fr) * 1993-09-14 1995-03-15 Euro-Celtique S.A. Méthode pour la préparation d'une composition laxative
WO1995017201A1 (fr) * 1993-12-20 1995-06-29 The Procter & Gamble Company Compositions laxatives contenant des fibres mucilagineuses et du sulfosuccinate de dioctyle
EP0815864A1 (fr) * 1996-06-28 1998-01-07 McNEIL-PPC, INC. Composition pharmaceutique semi-solide contenant un médicament antiflatulent

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2347041A1 (fr) * 1976-04-05 1977-11-04 American Cyanamid Co Compositions renfermant du dioctylsulfosuccinate de calcium et leur utilisation comme amollissants des selles
WO1995006463A1 (fr) * 1993-09-01 1995-03-09 Pfizer Inc. Compositions pharmaceutiques contenant des tensio-actifs anioniques
EP0642786A1 (fr) * 1993-09-14 1995-03-15 Euro-Celtique S.A. Méthode pour la préparation d'une composition laxative
WO1995017201A1 (fr) * 1993-12-20 1995-06-29 The Procter & Gamble Company Compositions laxatives contenant des fibres mucilagineuses et du sulfosuccinate de dioctyle
EP0815864A1 (fr) * 1996-06-28 1998-01-07 McNEIL-PPC, INC. Composition pharmaceutique semi-solide contenant un médicament antiflatulent

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002096394A2 (fr) * 2001-05-30 2002-12-05 Euro-Celtique S.A. Composition pharmaceutique
WO2002096394A3 (fr) * 2001-05-30 2003-01-16 Euro Celtique Sa Composition pharmaceutique
US7704948B2 (en) 2001-05-30 2010-04-27 Euro-Celtique S.A. Pharmaceutical composition
CN103070846A (zh) * 2013-01-17 2013-05-01 安士制药（中山）有限公司 一种多库酯钠软胶囊

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