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WO1998034598A2 - Formulations homogenes sous forme de granules destinees a la technologie d'aspiration des doses - Google Patents

Formulations homogenes sous forme de granules destinees a la technologie d'aspiration des doses Download PDF

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Publication number
WO1998034598A2
WO1998034598A2 PCT/EP1998/000797 EP9800797W WO9834598A2 WO 1998034598 A2 WO1998034598 A2 WO 1998034598A2 EP 9800797 W EP9800797 W EP 9800797W WO 9834598 A2 WO9834598 A2 WO 9834598A2
Authority
WO
WIPO (PCT)
Prior art keywords
formulations
excipients
formulations according
pharmaceutically active
dry
Prior art date
Application number
PCT/EP1998/000797
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English (en)
Other versions
WO1998034598A3 (fr
Inventor
Jan Willem Groenendaal
Original Assignee
Gist-Brocades B.V.
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 Gist-Brocades B.V. filed Critical Gist-Brocades B.V.
Priority to AU64964/98A priority Critical patent/AU6496498A/en
Publication of WO1998034598A2 publication Critical patent/WO1998034598A2/fr
Publication of WO1998034598A3 publication Critical patent/WO1998034598A3/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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules

Definitions

  • the present invention relates to homogeneous granulated formulations and to a process to prepare the same, suitable for a Dose Sipping device.
  • New dosage forms are developed to meet this challenge, in particular homogeneous granulated formulations are manufactured to be used together with a Dose Sipping device, meet various requirements necessary for a working composition of a granulate, the granulate must possess appropriate physico-chemical properties relating to hardness, stability, friability, disintegration time and so on.
  • a pharmaceutically active material is preferably a dry pharmaceutical dosage form such as
  • a tabletting mixture consists of an active ingredient and several or one of the following excipients : - diluents, to dilute the concentration of the active material ,
  • the hard gelatin capsules are filled with pure active ingre-hens or mixtures, granulates of active material and excipients particles as mentioned above under tablet mixture.
  • Solid mixtures of particles consist of mixtures of active material and excipients particles like those mentioned above under tablet mixture, excluding dry binders and lubricants.
  • the solid mixtures can consist of granules or partly of granules and powder excipients.
  • a good flowability is required because they are used for filling with the aid of specifically designed filling equipment in small bottles for multiple dose applications or small bags for single dose. Because tabletting, capsule filling and in most cases solid mixture filling are high speed processes, the requirements for mixtures concerning flowability and low dust amount are high.
  • the flowability of mixtures can be increased by the use of granulates . These granulates are made before the actual tabletting, capsule or solid mixture filling by means of specific techniques called dry or wet granulation.
  • Dry granulation is the formation of agglomerates without the use of a liquid, the agglomerates are made by dry compaction of the ingredients, followed by breaking the large compacts and finally by sieving out the required particle size.
  • Wet granulation is the formation of agglomerates according to the successive steps: mixing of the ingredients; adding a granulating fluid; drying the wet mass during which the actual agglomeration takes place and finally sieving out the required particle size.
  • a way to ensure a proper release of the pharmaceutically active material from the Dose Sipping device by ALZA, indica- ted as above, or a similar device described in for instance the American patents US 4,792,333 or US 4,981, 468, is to avoid blocking of the straw and to avoid entry of the dry medicine in the oral cavity of the patient.
  • granu- lation formulations have been developed which meet amongst others the requirements set .
  • patent application W091/16893 a granule, containing ⁇ -lactam as an active material, combined with an effervescent adjuvant used for aqueous suspensions has been described.
  • patent application W092/19227 also discloses a tablet, consisting of a medicament and optional intra- and extra-granular disintegrants .
  • a ⁇ -lactam tablet which comprises thermal infusion granules obtained using hydrophobic wax, has been described.
  • the resulting tablet is bi-layered, coated with a hydrophobic wax.
  • patent application W095/28927 describes a tablet formulation, comprising amoxycillin trihydrate and clavulanate coated by polymers.
  • Microcrystalline cellulose is used as a disintegrant.
  • sustained-release tablets containing ⁇ -lactam and a ⁇ -lacta- raase inhibitor have been described.
  • patent application WO96/04908 describes a tablet consisting of two layers with different compositions inclusive a film coating. The granulates of the patents mentioned above are not homogeneous and they are further processed by coating or tabletting. Also disintegrants are used frequently.
  • a new granulate composition of homogeneous granulated formulations for oral delivery preferably by means of a Dose Sipping device has been provided for.
  • These granules are homogeneous, with a particle size of 125 to 1000 ⁇ m, permitting the formulations to be wetted and admix or dissolve after contact with a fluid.
  • the size of the particles is from 125 to 750 ⁇ m, whereby each particle comprises a blend of pharmaceutically active materials and one or more excipients allowing the granulates to be wetted and admix better with a fluid.
  • the pharmaceutically active materials should already be wetted, in admix or dissolved before entering the oral cavity of the patient, avoiding a gritty feeling, bad taste and inhalation.
  • the pharmaceutically active material comprises the group of antibacterial antibiotics which are co-formulated with a number of excipients into a homogeneous blend. Suitable for this purpose is an anti- infective agent selected from any of the groups of antibacterial antibiotics consisting of Cephalosporins or related ⁇ -lactams.
  • the ⁇ -lactams are for instance penicillin V potassium salt or acid, amoxycillin trihydrate, ampicillin trihydrate and for instance Cloxacillin Sodium, Flucloxacil- lin Sodium and Dicloxacillin Sodium, and Cephalosporins are for instance Cephalosporin, Cephalexin, Cefaclor and Cefa- droxil .
  • the pharmaceutically active material comprises Tetracyclines, for instance Tetracycline, Oxytetracycline, Doxycycline, Minocycline, Chlortetracycline and Demeclocycline or any acid salt, for instance a chloric salt, thereof and also Macrolides, for instance Erythromycin, Clarithromycin, Roxithromycin and Azithromycin, or any stearate and/or any estolate thereof. All antibiotics are optionally combined with ⁇ -lactamse inhibitors, such as sulbactam or clavulanic acid.
  • the excipients used for coformulation are mannitol and/or sorbitol which are cool sweeteners and dry binders, rice starch and Emcompress ® (Edward Mendell Co Inc) as dry binders. Furthermore magnesium stearate and Lubritab ® (Edward Mendell Co Inc) are used as lubrificants for the compressing tools. Aerosil ® was used as a flowing aid. The resulting granules compositions have a good flowability and the right disintegrating characteristics to admix, dissolve without either blocking the straw or allowing dry material to enter the oral cavity of the patient.
  • the invention provides for homogeneous granulated formulations of pharmaceutically active materials, characterized by the preparation of a blend of pharmaceutically active material and one or more excipients, wherein the granulates comprising said blend have a particle size from 125 to 1000 ⁇ m, preferably a particle size of 125 to 750 ⁇ m, permitting the formulations to be wetted and admix with a fluid, preferably by means of a Dose Sipping device, suitable for oral delivery.
  • This device has been described in the patent appli- cation WO 97/03634.
  • the Dose Sipping device is often referred to as a straw.
  • a pharmaceutically active material used for oral delivery is preferably formulated as a dry pharmaceutical dosage form such as
  • the manufacture of the oral tablets is done by compacting mixtures of particles.
  • the particles can be of primary form like crystals or can be agglomerated to clusters of primary particles. These agglomerates are often called granules or granulates.
  • a tabletting mixture consists of an active in- gredient and several or one of the following excipients; diluents, to dilute the concentration of the active material, such as calcium carbonate, calcium sulphate, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, lactose, magnesium carbonate, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, powdered cellulose, pregelatinized starch, sorbitol, rice starch, sucrose, tribasic calcium phosphate, - (dry) binders, which increase the plastic deformation of the mixture, such as acacia, alginic acid
  • - flowing agents or glidants which increase the flowability of the mixture, such as colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, rice starch, talc, tri basic calcium phosphate,
  • - lubricants to lubricate the metallic parts of the tabletting tools used, such as calcium stearate, glyceryl mono- stearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulphate, sodium stearyl fumerate, stearic acid, talc, zinc stearate,
  • the tabletting tools used such as calcium stearate, glyceryl mono- stearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulphate, sodium stearyl fumerate, stearic acid, talc, zinc stearate,
  • flavouring agents are: maltol, ethyl maltol, ethyl vanillin, fumaric acid, malic acid, menthol, vanillin, a number of concentrated and purified flavours from vegetable origin are microencapsulated powders, sweeteners such as compressible sugar, confectioner's sugar, dextrose, glycerin, lactose, liquid glucose, maltitol solution, mannitol,
  • solubilizing agents which helps to wet the particles and let fluids penetrate into the agglomerate of particles, such as cyclodextrins, lecithin, sucrose, mannitol, sorbitol.
  • the hard gelatin capsules are filled with pure active ingredients or mixtures, granulates of active material and excipients particles as mentioned above under tablet mixture.
  • Solid mixtures of particles consist of mixtures of active material and excipients particles like those mentioned above under tablet mixture, excluding dry binders and lubricants.
  • the solid mixtures can consist of granules or partly of granules and powder excipients. For solid mixtures a good flowability is required because they are used for filling with the aid of specifically designed filling equipment in small bottles for multiple dose applications or small bags for single dose.
  • Wet granulation is the formation of agglomerates according to the successive steps: mixing of the ingredients; adding a granulating fluid, containing a dissolved binder like cellulose derivatives; screening and drying the wet mass during which the actual agglomeration takes place and finally a second screening by sieving out the required particle size to discard lumps.
  • Compositions of granulates manufactured as described, containing both active material and any excipients to be used, and/or part of the excipients can be added afterwards as separate granules and mixed later.
  • Some of the excipients to be used are commercially available as granulates and can be mixed with separately manufactured granules containing the active material.
  • the granulated formulations manufactured for this invention are homogeneous granules with a particle size of 125 to 1000 ⁇ m, permitting the formulations to be wetted and admix after contacting with a fluid.
  • the particle size is from 125 to 750 ⁇ m allowing the granulates to be wetted and admix better with a fluid.
  • the pharmaceutically active materials are already in admix or dissolved before entering the oral cavity of the patient, avoiding a gritty feeling, bad taste and inhalation.
  • the manufacture of the before mentioned granulated formulations is characterised by dry granulation such as slugging and/or dry roller compaction of said blend, or wet granulation and further sieving of said blend.
  • dry granulation procedure is described as follows. An anti-infective is mixed with a liquid containing a dissolved binder like cellulose derivatives. The wet mass is screened and dried after which as second screening is performed to discard lumps.
  • slugging and more preferably dry roller compaction are used.
  • the pharmaceutically active material as used in the Dose Sipping device mentioned above comprises the group of antibacterial antibiotics wherein the pharmaceutically active materials are co-formu- lated with a number of excipients into a homogeneous blend.-
  • the materials were weighed and mixed by hand using a spatula and a small glass beaker, the Aerosil ® and magnesium stearate were shortly mixed as last additives.
  • the slugging was done by any known means, for instance with a Korsch EK-0 excenter tabletting press equipped with flat punches of 16 mm diameter. Tablets were pressed by hand by turning the hand wheel of the press.
  • the weight of the tablets was about 550 mg and the thickness 2 mm, the hardness was about 40 N.
  • the slugging was followed by breaking the tablets by hand and carefully crumbling in a mortar with the aid of a pestle.
  • the crumbled material was sieved out in order to obtain a granulate with a particle size, from 125 ⁇ m to 1000 ⁇ m, preferably from 125 to 750 ⁇ m, recycling the particles > 750 ⁇ m to the mortar and discarding the powder ⁇ 125 ⁇ m.
  • Dry roller compaction was done, using a IR 520 roller compactor, equipped with a Fitzmill hammer mill.
  • the capacity is 30 to 150 kg per hour.
  • 100 kg material was used, mixed thoroughly to homogeneity.
  • 38 kg of Amoxycillin trihydrate was mixed with 30 kg of mannitol, 30 kg of dibasic calcium phosphate and 2 kg of magnesium stearate.
  • 38 kg of amoxycillin trihydrate was mixed with 60 kg of mannitol and 2 kg of hydrogenated vegetable oil .
  • the mixture was fed to the roller compactor, the compacts were milled with a Fitzmill after which a sieve fraction between 125 and 1000 ⁇ m was obtained.
  • the compressibility index was measured by means of the following procedure. A measuring cylinder is filled with a weight amount of granulate and the volume is measured. A standardized tapping procedure is performed and again the volume is measured.
  • the pharmaceutically active material used is an anti- infective agent selected from any of the groups of antibacterial antibiotics consisting of Cephalosporins or related ⁇ -lactams.
  • the ⁇ -lactams are for instance penicillin V potassium salt or acid, amoxycillin trihydrate, ampicillin trihydrate and for instance Cloxacillin Sodium, Flucloxacil- lin Sodium and Dicloxacillin Sodium, and Cephalosporins are for instance Cephalosporin, Cephalexin, Cefaclor and Cefa- droxil .
  • Tetracyclines for instance Tetracycline, Oxytetracycline, Doxycycline, Minocycline, Chlortetracycline and Demeclocycline or any acid salt, for instance cloric acid salt, thereof and also Macrolides, for instance Erythromycin, Clarithromycin, Roxithromycin and Azithromycin, or any stearate and/or any estolate thereof can be used to prepare the granulates of the invention.
  • excipients used in co-formulation with the pharmaceutically active materials mentioned above were selected from a group consisting of dry binders, lubricants, flow aids, taste improvers and disintegrants. A blend of several different combinations of the pharmaceutically active material and excipients was used.
  • Friability was monitored during filling process, trans- port and storage of the filled straw.
  • the attrition was simulated in a so called friabilator where the granules fell over a fixed length in a flat cylinder during 100 revolutions.
  • the weight of the granules before and after the test was determined.
  • the colour of the granules, for instance with amoxycillin is of some significant importance because of the used granulation process, in this case dry roller compaction. It is an indication for decomposition and loss of stability of amoxycillin during storage.
  • the requirements for colour of the amoxycillin powder and the granulated product will be maintained throughout the process .
  • the parameter is the so called 'colour Hunter b' ⁇ 5.0 determined with a spectrocolo- rimeter .
  • Granulates manufactured with microcrystalline cellulose such as Avicel PH102 ® from FMC were used, but when they come into contact with a fluid they swell. When sipping starts fluid enters the lower part of the particle batch in the straw.
  • a lubricant preferably magnesium stearate and/or a hydrogenated vegetable oil such as Lubritab ® , which is a brand name from Edward Mendell Co Inc.
  • Lubritab ® a brand name from Edward Mendell Co Inc.
  • the granulates manufactured with this lubricant were not too hydrophobic and did not block the straw.
  • Lubricants are used to facilitate the release of the slugged or dry roller compacted formulations from the seal-press or disks.
  • a flow aid preferably Aero- sil ® 200.
  • Flow aids are used to ensure an optimal flow of the powder, during the filling process, containing the pharmaceutically active agents and excipients.
  • the optimal flowability is tested by means of an angle of repose (from: The Theory and Practice of Industrial Pharmacy, published by Lea & Febiger, 1986) .
  • a funnel is placed 2 cm above a plain surface, the granulate is carefully added into the funnel, adding of the granulate is stopped after the formed heap touched the funnel .
  • a disintegrant excipient preferably rice starch was selected. Or rice starch co- formulated with mannitol or sorbitol together with a pharmaceutically active material .
  • the thus manufactured granulate is homogeneous, all excipients are thoroughly mixed before the process of granulation is started. No post granulation preparations such as addition of wax or other coatings are necessary. However filling the straw with a mixture of different complete granulates is considered, i.e. several antibacterial antibiotics combined or an additional flavour granulate added. The straws were filled with 3 cm of granules which gave an amount of 625 to 690 mg of granules, depending on their composition and physical structure.
  • Mannitol granulate (Pearlitol ® SD 200, from Roquette)
  • Aerosil ® 200 (Degussa, colloidal silicon dioxide)
  • DC-Sorbitol granulate (Neosorb P 20/60 ® , from Roquette)
  • Emcompress ® dibasic calcium phosphate anhydrous, from Edward Mendell Co Inc
  • Lubritab ® (Edward Mendell Co Inc)
  • Avicel ® is a dry binder and a weak disintegrant.
  • Explotab ® is a strong disintegrant .
  • Mannitol is a cool sweetener and a dry binder.
  • Magnesium stearate and Lubritab ® are lubrificants for the compressing tools.
  • Aerosil ® is a flowing aid.
  • Sorbitol is a cool sweetener and a dry binder.
  • Rice starch is a dry binder.
  • Emcompress ® is a dry binder.
  • mannitol granulate and sorbitol granulate were used. II Dry granulation process
  • a Sipping Simulator is a device, designed by ALZA, to simulate the suction on the straw filled with formulations when placed in a fluid.
  • the apparatus consists of a commercial available hand vacuum pump from Equus Products Inc. (to be used as a brake bleeding kit for cars) , a plateau fastened to the same and a tube with a valve .
  • the tube was connected to the upper end of the straw, vacuum till 10 cm Hg was applied by hand, the valve was opened and simulated sipping started. The flow characteristics of the granulate and the fluid was visually observed.
  • the ALZA Sipping Simulator has been designed to simulate the action of drawing fluid through a straw into the mouth. The purpose is to test the functionality of Dose Sipping devices.
  • the Sipping Simulator consists of three main pieces:
  • the upper part of the straw was attached to the tube of the Sipping Simulator which was preset on a pressure of 10 cm Hg and the lower part in distilled water.
  • the straws were filled with 3 cm of granules which gave an amount of 625 to 690 mg of granules, depending on their composition.
  • compositions of granulates made by slugging are shown below
  • compositions of granulates made by slugging are shown below
  • A3 flows slowly ( ⁇ 0.5 - 1 second)
  • T3 flows slowly ( ⁇ 2 -3 seconds)
  • Pen-VK sieved fraction of flows slowly ( ⁇ 0.5 second) 250 to 1000 ⁇ m
  • Pen-VK The solubility of Pen-VK was good and the granules dissolved when the sucking experiment took place. When tested with the mouth Pen-VK gave a very bitter taste and suspension and/or solution in the mouth, so dry granulate entering the mouth must be avoided.
  • Formulations with sorbitol stuck much less on the punch than formulations with mannitol.
  • a disadvantage of sorbitol is that it is hygroscopic, mannitol is not.

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  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On a élaboré un certain nombre de formulations homogènes sous forme de granulés destinées à la technologie d'aspiration des doses, qu'on utilise pour administrer une matière pharmaceutiquement active telle que par exemple des agents anti-infectieux comme des antibiotiques antibactériens qui sont co-formulés avec un certain nombre d'excipients.
PCT/EP1998/000797 1997-02-07 1998-02-06 Formulations homogenes sous forme de granules destinees a la technologie d'aspiration des doses WO1998034598A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU64964/98A AU6496498A (en) 1997-02-07 1998-02-06 Homogeneous granulated formulations for dose sipping technology

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP97200327.1 1997-02-07
EP97200327 1997-02-07

Publications (2)

Publication Number Publication Date
WO1998034598A2 true WO1998034598A2 (fr) 1998-08-13
WO1998034598A3 WO1998034598A3 (fr) 1998-11-19

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Application Number Title Priority Date Filing Date
PCT/EP1998/000797 WO1998034598A2 (fr) 1997-02-07 1998-02-06 Formulations homogenes sous forme de granules destinees a la technologie d'aspiration des doses

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AU (1) AU6496498A (fr)
WO (1) WO1998034598A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6858596B2 (en) 2000-08-05 2005-02-22 Smithkline Beecham Corporation Formulation containing anti-inflammatory androstane derivative
DE102006007830A1 (de) * 2006-02-17 2007-08-30 Grünenthal GmbH Lagerstabile orale Darreichungsform von Amoxicillin und Clavulansäure
US8956653B2 (en) 2010-01-29 2015-02-17 Mahmut Bilgic Preparations for effervescent formulations comprising cephalosporin and uses thereof
WO2020021111A1 (fr) * 2018-07-27 2020-01-30 Sisteks D.O.O. Paille pour administration orale de formulation pharmaceutique

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2251250C3 (de) * 1972-10-19 1981-06-25 Hoechst Ag, 6230 Frankfurt Verfahren zur Herstellung hochdosierter Antibiotica-Tabletten
US4792333A (en) * 1986-11-04 1988-12-20 Strawdose, Inc. Unit dose drug package and administering device
EP0281200B1 (fr) * 1987-03-02 1994-01-19 Yamanouchi Europe B.V. Composition pharmaceutique, granulé pharmaceutique et leur procédé de fabrication
US4981468A (en) * 1989-02-17 1991-01-01 Eli Lilly And Company Delivery device for orally administered therapeutic agents
GB9009473D0 (en) * 1990-04-27 1990-06-20 Beecham Group Plc Pharmaceutical formulation
GB9109862D0 (en) * 1991-05-08 1991-07-03 Beecham Lab Sa Pharmaceutical formulations
GB9408117D0 (en) * 1994-04-23 1994-06-15 Smithkline Beecham Corp Pharmaceutical formulations
DK0840591T3 (da) * 1995-07-21 2001-04-17 Alza Corp System til oral afgivelse af diskrete enheder

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6858596B2 (en) 2000-08-05 2005-02-22 Smithkline Beecham Corporation Formulation containing anti-inflammatory androstane derivative
DE102006007830A1 (de) * 2006-02-17 2007-08-30 Grünenthal GmbH Lagerstabile orale Darreichungsform von Amoxicillin und Clavulansäure
US8956653B2 (en) 2010-01-29 2015-02-17 Mahmut Bilgic Preparations for effervescent formulations comprising cephalosporin and uses thereof
US9603794B2 (en) 2010-01-29 2017-03-28 Mahmut Bilgic Preparations of effervescent formulations comprising cephalosporin and uses thereof
WO2020021111A1 (fr) * 2018-07-27 2020-01-30 Sisteks D.O.O. Paille pour administration orale de formulation pharmaceutique

Also Published As

Publication number Publication date
WO1998034598A3 (fr) 1998-11-19
AU6496498A (en) 1998-08-26

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