US20020001598A1 - Pharmaceutical microspheres containing valproic acid for oral administration - Google Patents

Pharmaceutical microspheres containing valproic acid for oral administration Download PDF

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Publication number
US20020001598A1
US20020001598A1 US09/147,788 US14778899A US2002001598A1 US 20020001598 A1 US20020001598 A1 US 20020001598A1 US 14778899 A US14778899 A US 14778899A US 2002001598 A1 US2002001598 A1 US 2002001598A1
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United States
Prior art keywords
pharmaceutical
microspheres according
valproic acid
weight
microspheres
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Legal status (The legal status 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 status listed.)
Abandoned
Application number
US09/147,788
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English (en)
Inventor
Christian Langlois
Jean-Yves Lanne
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi Aventis France
Original Assignee
Sanofi SA
Sanofi Synthelabo SA
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Filing date
Publication date
Application filed by Sanofi SA, Sanofi Synthelabo SA filed Critical Sanofi SA
Assigned to SANOFI reassignment SANOFI ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LANGLOIS, CHRISTIAN, LANNE, JEAN-YVES
Assigned to SANOFI-SYNTHELABO reassignment SANOFI-SYNTHELABO MERGER (SEE DOCUMENT FOR DETAILS). Assignors: SANOFI
Publication of US20020001598A1 publication Critical patent/US20020001598A1/en
Priority to US10/270,159 priority Critical patent/US20030157177A1/en
Assigned to SANOFI-AVENTIS reassignment SANOFI-AVENTIS CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: SANOFI-SYNTHELABO
Priority to US11/357,426 priority patent/US8535721B2/en
Abandoned legal-status Critical Current

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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

  • the present invention generally relates to new pharmaceutical microspheres for oral administration.
  • the invention relates to new phamaceutical microspheres for oral administration containing valproic acid of formula:
  • alkali metal such as sodium or potassium
  • alkaline-earth metal such as calcium or magnesium
  • Sodium valproate is an anti-epileptic medicament widely sold at the current time, in particular in the form of tablets assaying 500 mg per administration unit.
  • sodium valproate has a rather unpleasant, bitter taste. It will consequently prove to be necessary to take into account this disadvantage in administration forms suitable for children, for example syrup forms or solutions to be taken orally, by masking this taste using various expedients.
  • administration forms such as syrups do not allow children to benefit from the advantages resulting in some cases from the gastroresistance and the prolonged release of the active ingredient.
  • microsphere pharmaceutical form lends itself poorly to sustained release of the active ingredient. This is because, for equal masses, the surface area developed by these spheres will increase as their diameter becomes smaller, the consequence of which will be that these microspheres dissolve faster.
  • the spherical particle formed by dispersion solidify as microspheres.
  • the mean concentration of valproic acid in these microspheres does not exceed 17%, these microspheres having a certain concentration of the surfactant used, namely a mixture of ethoxylated or non-ethoxylated polysorbates.
  • Another technique for forming pharmaceutical microspheres resorts to the prilling technique.
  • This process has been applied, for example, to pharmaceutical ingredients with an undefined crystallization point which melt in the excipient, as described in Patent EP 438,350.
  • This excipient can be, for example, a fatty alcohol, such as stearyl alcohol, a fatty acid, such as stearic acid, a glycerol ester, a hydrogenated oil, a fatty acid salt, a polyol, a wax, a polyoxyethylene glycol or an esterified polyoxyethylene.
  • stearic acid is exemplified therein as excipient.
  • ketoprofen fatty acids and their salts, glycerol esters, hydrogenated oils, waxes or esterified polyoxyethylenes alone can be used.
  • microspheres In the majority of cases, these microspheres have additionally turned out to be suitable for sustained release of the active ingredient, without requiring them to be provided with a specific coating for this purpose.
  • a first subject of the invention relates to pharmaceutical microspheres containing, as active principle, a mixture of valproic acid and of one of its pharmaceutically acceptable salts, such as the sodium salt, in combination with a matrix vehicle selected from glycerol esters, hydrogenated oils, esterified polyethylene glycols, waxes and their mixtures.
  • a matrix vehicle selected from glycerol esters, hydrogenated oils, esterified polyethylene glycols, waxes and their mixtures.
  • Another subject of the invention relates to a process for the preparation of microspheres containing a mixture of valproic acid and of a pharmaceutically acceptable salt of this acid, in combination with a matrix vehicle.
  • the invention relates to a pharmaceutical form for oral administration containing microspheres according to the invention.
  • active principle will denote the mixture of valproic acid and of pharmaceutically acceptable salt of this acid used in the context of the present invention.
  • microspheres of the invention can be obtained according to the prilling process mentioned above, which consists:
  • a fluidized bed can be added to this prilling tower, which bed makes it possible to keep the not yet completely solidified microspheres constantly fluidized.
  • the mixture used in the prilling can be obtained by heating the matrix vehicle to its melting temperature, then, when the mass is completely molten, by adding valproic acid and then a pharmaceutically acceptable salt of this acid, and by maintaining the combined mixture with stirring until a clear fluid is obtained.
  • microspheres of the invention contain, as active principle, a mixture in all proportions of valproic acid and of one of its pharmaceutically acceptable salts.
  • This salt is generally an alkali metal salt, preferably the sodium salt, or an alkaline-earth metal salt, such as the calcium or magnesium salt.
  • the active principle is composed of mixtures of 15% to 60% by weight of valproic acid and of 40% to 85% by weight of pharmaceutically acceptable salt of this acid.
  • Mixtures containing from 25% to 35% by weight of valproic acid and from 65% to 75% by weight of the salt in question represent mixtures which are particularly preferred for the purposes of the invention.
  • the viscosity of the composition formed by the pharmaceutical ingredient and the matrix excipient is a limiting factor in making use of the prilling process suited to the preparation of pharmaceutical microspheres.
  • the microspheres of the invention will contain at most 35% by weight of active principle, as described above, preferably from 30% to 35% by weight.
  • This matrix vehicle which is composed of one or of several excipients of the class of glycerol esters, hydrogenated oils, esterified polyethylene glycols, or waxes, is selected such that its melting point is between 50° C. and 120° C., generally between 70° C. and 90° C.
  • This matrix vehicle does not contain any additional contribution of surface-active agents, such as those of the ethoxylated or non-ethoxylated polysorbate type.
  • Excipients capable of melting at a temperature of the order of 80° C. are preferably selected. Moreover, an excessively high temperature would require an excessively high drop height for the microspheres in order to achieve complete solidification, with the risk of causing the active principle to degrade.
  • the excipients in question can be selected from:
  • saturated or unsaturated fatty acid glycerides in particular glycerides containing up to 80 carbon atoms, such as, for example, glyceryl tribehenate, glyceryl palmitate/stearate, glyceryl monostearate, glyceryl monooleate or caprylic/capric glycerides, such as glyceryl tricaprylate/caprate
  • saturated polyglycolysed glycerides such as mixtures of glycerol monoesters, diesters and triesters and of polyethylene glycol mono- and diesters
  • hydrogenated oils such as hydrogenated castor oil
  • a wax such as natural beeswax or synthetic beeswax.
  • matrix excipients capable of forming microspheres according to the invention can be selected from:
  • glyceryl tribehenate such as sold under the trademark Compritol® 888
  • glyceryl palmitate/stearate such as sold under the trademark Precirol® ATO5
  • glyceryl monostearate such as sold under the trademark Monomuls® 90/25
  • glyceryl monooleate such as sold under the trademark Myverol® 18/99
  • glyceryl tricaprylate/caprate such as sold under the trademark Labrafac® lipophile
  • saturated polyglycolysed glycerides such as sold under the trademarks Gelucire® 50-02 or Labrafil® 2130CS
  • excipients used in the context of the invention will furthermore be selected while taking into account the hydrophilic, lipophilic (or hydrophobic) or amphiphilic nature which they may possess and according to the kinetics desired for the release of the active principle.
  • mixtures of excipients of the type either glyceryl tribehenate (Compritol® 888)/surfactant (Labrafil® 2130CS) or glyceryl tribehenate (Compritol® 888)/glyceryl monooleate (Myverol® 18/99) or synthetic beeswax (Cutina® BW)/hydrogenated castor oil (Cutina® HR)/glyceryl monostearate (Monomuls® 90/25) have proved to be suitable for fairly immediate release of the active principle.
  • Microspheres comprising from 55% to 60% by weight of product Compritol® 888 or of product Precirol® ATO5, from 30% to 35% by weight of active principle (valproic acid/sodium valproate) and from 10% to 15% by weight of surfactant Labrafil® 2130CS were used for this purpose.
  • hydrophobic substances such as hydrogenated castor oil (Cutina® HR), beeswax, paraffin, the product Gelucire® 50-02 or the product Labrafac® lipophile, has furthermore made it possible to accentuate the delayed release of the active principle.
  • Cutina® HR hydrogenated castor oil
  • beeswax paraffin
  • paraffin the product Gelucire® 50-02
  • microspheres containing from 65 to 70% by weight of the product Compritol® 888 and from 30% to 35% by weight of active principle have revealed, during dissolution tests, a slow dissolution profile.
  • Analogous results were recorded from microspheres comprising from 55% to 60% by weight of the product Compritol® 888, 10% to 15% by weight of the product Cutina® HR, beeswax, paraffin, the product Gelucire® 50-02 or the product Labrafac® lipophile and 30% to 35 by weight of active principle.
  • the active principle used in the present invention is composed of a hydrophobic component, namely valproic acid, and of a hydrophilic component, that is to say a pharmaceutically acceptable salt of this acid, it seems that the most suitable matrix excipients should be amphiphilic substances, in order, by their hydrophobic part, to provide for the delayed release of the active principle and, by their hydrophilic part, to provide for the regulation of the rate of release of this active principle from the excipient.
  • composition A microspheres formed of 68.37 g of natural beeswax as matrix vehicle and of 31.63 g of active principle, namely 9.63 g of valproic acid and 22 g of sodium valproate, hereinafter denoted “Composition A microspheres”.
  • the active principle consequently corresponds to a 30.45%/69.55% by weight valproic acid/sodium valproate mixture.
  • a divisible retard tablet formulated with 478 mg of a valproic acid/sodium valproate mixture, namely 145 mg of acid and 333 mg of salt, this tablet comprising in particular methacrylic acid polymers as excipient.
  • the active ingredients of this commercial tablet-consequently correspond to a 30.33%/69.67% by weight valproic acid/sodium valproate mixture or to 500 mg of active ingredient expressed as sodium valproate.
  • microspheres represents the percentages of dissolution of the valproate anion as a function of the time from the above Composition
  • a divisible retard tablet such as above so that each subject receives a dose of active ingredient (valproic acid/sodium valproate) equivalent to 500 mg expressed as sodium valproate.
  • composition A/water represents the mean blood concentration obtained with the Composition A microspheres in water
  • composition A/yoghurt represents the mean blood concentration obtained with the Composition A microspheres in yoghurt
  • microspheres containing from 30% to 35% of active principle in combination with a matrix vehicle entirely composed of beeswax represent microspheres of vital importance.
  • microspheres of this type in which the active principle is formed of 25% to 35% of valproic acid and of 65% to 75% of a pharmaceutically acceptable salt of this acid, such as sodium valproate, are particularly preferred for the purposes of the invention.
  • prilling makes it possible to obtain a so-called monodisperse particle size distribution with the advantage of producing spheres which are regular in size. Consequently, during the administration of the medicament containing them, the amount of such microspheres received by the patient will be constant.
  • the pharmaceutical microspheres of the invention possess this advantage, in that they exhibit such a regular spherical shape, with a diameter of between 250 ⁇ m and 500 ⁇ m, generally of the order of 400 ⁇ m.
  • these microspheres can be covered with a film-forming agent, so as to form, for example, a gastroresistant film.
  • Such pharmaceutical forms can be, for example, a tablet, including a divisible tablet, a capsule, including a hard gelatin capsule, or a powder packaged, for example, in a chartula or in a system for dispensing unit doses, in particular a dispensing/measuring bottle or a container furnished with an adjustable-volume measuring spoon, for example for adjusting doses to the weight of the patient.
  • the microspheres in question can receive agents which facilitate flow, as well as lubricants, inorganic fillers, such as silicas, talc or aluminium oxide, or alternatively sweeteners, such as aspartame.
  • These pharmaceutical forms can advantageously comprise, per administration unit, from 50 to 500 mg of active principle in the form of microspheres according to the invention, in particular from 50 to 250 mg.
  • Microspheres with the following composition are prepared: % by weight White beeswax 68.424 Valproic acid 9.576 Sodium valproate 22 100.00
  • 68.424 g of white beeswax are introduced into the jacketed vessel of a melting device thermostatically adjusted to 95° C. and then the wax is melted at a temperature of 90° C. to 93° C. while monitoring that the product has completely melted.
  • the mixture is then prilled, at a temperature of 90° C., through 200 ⁇ m injectors maintained at a temperature of 87° C. to 91° C. and under a pressure of 0.5 bar.
  • the frequency of the vibrator of the device (5.75 ⁇ 10 3 to 6.70 ⁇ 10 3 Hz) is adjusted, so as to individualize the droplets formed, under stroboscopic monitoring at a frequency of 25,000 Hz.
  • Microspheres solidified by cooling during their fall in air (drop height: approximately 2.5 m) refrigerated by a countercurrent of cold air or by a liquid nitrogen bath are thus collected at the base of the device. These microspheres have a mean diameter of 400 ⁇ m.
  • Microspheres were prepared in the same way, but by using other matrix excipients, from the following formulations, which all proved to be clear after dissolution of the active principle (rig appearance Of crystals):
  • Example 1 756.7 mg of microspheres as prepared in Example 1 are introduced into a chartula, so as to form an oral administration unit containing 238.96 mg of active principle composed of 30.4%/ 69 . 6 % by weight valproic acid/sodium valproate, which corresponds to 250 mg of active principle expressed as sodium valproate.
  • microspheres prepared in Example 1 i.e. 8 g of active principle per packaged unit, are introduced into a bottle with a working volume of approximately 45 ml which allows unit doses to be dispensed.
  • This bottle makes it possible to dispense approximately 50 unit doses containing 150 mg of active principle composed of 30.4%/69.6% by weight valproic acid/sodium valproate.

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US09/147,788 1996-10-07 1997-10-03 Pharmaceutical microspheres containing valproic acid for oral administration Abandoned US20020001598A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US10/270,159 US20030157177A1 (en) 1996-10-07 2002-10-15 Pharmaceutical microspheres containing valproic acid for oral administration
US11/357,426 US8535721B2 (en) 1996-10-07 2006-02-21 Pharmaceutical microspheres containing valproic acid for oral administration

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR9612201A FR2754177B1 (fr) 1996-10-07 1996-10-07 Microspheres pharmaceutiques d'acide valproique pour administration orale
FR96/12201 1996-10-07

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US (3) US20020001598A1 (de)
EP (1) EP0956010B1 (de)
JP (1) JP3523270B2 (de)
KR (1) KR100334687B1 (de)
CN (1) CN100367945C (de)
AR (1) AR013613A1 (de)
AT (1) ATE216228T1 (de)
AU (1) AU731235B2 (de)
BR (1) BR9712268A (de)
CA (1) CA2267096C (de)
CO (1) CO4900080A1 (de)
CZ (1) CZ288876B6 (de)
DE (1) DE69712100T2 (de)
DK (1) DK0956010T3 (de)
DZ (1) DZ2316A1 (de)
EE (1) EE03744B1 (de)
EG (1) EG24070A (de)
ES (1) ES2174293T3 (de)
FR (1) FR2754177B1 (de)
HK (1) HK1021939A1 (de)
HR (1) HRP970537B1 (de)
HU (1) HU225103B1 (de)
ID (1) ID24596A (de)
IL (1) IL128745A (de)
IS (1) IS1985B (de)
ME (1) ME00664B (de)
MY (1) MY120521A (de)
NO (1) NO325723B1 (de)
NZ (1) NZ334399A (de)
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PT (1) PT956010E (de)
RS (1) RS49602B (de)
RU (1) RU2177315C2 (de)
SI (1) SI0956010T1 (de)
SK (1) SK282113B6 (de)
TR (1) TR199900789T2 (de)
TW (1) TW508251B (de)
UY (1) UY24738A1 (de)
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060252831A1 (en) * 2005-05-06 2006-11-09 Christopher Offen Method for the treatment of magnesium and potassium deficiencies
US20060252830A1 (en) * 2005-05-06 2006-11-09 Brandon Stephen F Method for the treatment of magnesium and potassium deficiencies

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE300285T1 (de) 1999-06-07 2005-08-15 Altana Pharma Ag Neue zubereitung und darreichungsform enthaltend einen säurelabilen protonenpumpeninhibitor
AU2003289782A1 (en) * 2002-12-16 2004-07-09 The University Of British Columbia Valproic acid analogues and pharmaceutical compositions thereof
TWI428271B (zh) * 2004-06-09 2014-03-01 Smithkline Beecham Corp 生產藥物之裝置及方法
KR20070100686A (ko) * 2004-09-07 2007-10-11 오르펀 메디칼, 인크. 개선된 ｇｈｂ 조성물
US9149433B2 (en) * 2004-11-30 2015-10-06 Basf Corporation Method for formation of micro-prilled polymers
US8992422B2 (en) 2006-03-23 2015-03-31 Ethicon Endo-Surgery, Inc. Robotically-controlled endoscopic accessory channel
CN101543631B (zh) * 2008-03-28 2012-01-11 沈阳兴齐制药有限公司 含蜂蜡的微球基质、含有它的药物组合物及其用途
CN102421428B (zh) * 2009-05-12 2014-01-29 株式会社爱茉莉太平洋 用于防止脱发或促进毛发生长的组合物
NZ720512A (en) * 2013-11-13 2018-01-26 Tillotts Pharma Ag Multi-particulate drug delivery system
CN104013596A (zh) * 2014-05-16 2014-09-03 安士制药（中山）有限公司 一种丙戊酸软胶囊及其制备方法
CN105456217A (zh) * 2014-08-27 2016-04-06 捷思英达医药技术（上海）有限公司 一种双丙戊酸钠缓释剂组合物及其制备方法
WO2019039346A1 (ja) 2017-08-24 2019-02-28 三井化学株式会社 電池用非水電解液及びリチウム二次電池
JPWO2019039345A1 (ja) 2017-08-24 2020-03-26 三井化学株式会社 リチウム二次電池及び非水電解液
FR3087445B1 (fr) * 2018-10-19 2021-12-17 Soc Dexploitation De Produits Pour Les Industries Chimiques Seppic Composition lipidique pour l'encapsulation d'une substance active et permettant le controle de la vitesse de liberation de ladite substance active
CN111012753A (zh) * 2020-01-07 2020-04-17 仁和堂药业有限公司 一种提高丙戊酸钠片剂稳定性的方法
CN112274499A (zh) * 2020-11-16 2021-01-29 仁和堂药业有限公司 一种提高丙戊酸钠片剂稳定性的方法

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2293974A1 (fr) * 1973-03-02 1976-07-09 Kaltenbach Roger Procede et dispositif pour la granulation reguliere de divers produits
US5212326A (en) * 1979-08-20 1993-05-18 Abbott Laboratories Sodium hydrogen divalproate oligomer
DK150008C (da) * 1981-11-20 1987-05-25 Benzon As Alfred Fremgangsmaade til fremstilling af et farmaceutisk oralt polydepotpraeparat
IL72381A (en) * 1983-07-20 1988-03-31 Sanofi Sa Pharmaceutical composition based on valproic acid
US5185159A (en) * 1983-07-20 1993-02-09 Sanofi Pharmaceutical composition based on valproic acid and a process for preparing it
US4913906B1 (en) * 1985-02-28 2000-06-06 Yissum Res Dev Co Controlled release dosage form of valproic acid
JP2893191B2 (ja) * 1988-11-08 1999-05-17 武田薬品工業株式会社 放出制御性マトリックス剤
EP0418596A3 (en) * 1989-09-21 1991-10-23 American Cyanamid Company Controlled release pharmaceutical compositions from spherical granules in tabletted oral dosage unit form
FR2657257B1 (fr) * 1990-01-19 1994-09-02 Rhone Poulenc Sante Procede de preparation de medicaments sous forme de perles.
TW209174B (de) * 1991-04-19 1993-07-11 Takeda Pharm Industry Co Ltd
ES2073301T3 (es) * 1991-05-20 1995-08-01 Marion Laboratories Inc Composicion multi-capa de liberacion controlada.
FR2682677A1 (fr) * 1991-10-17 1993-04-23 Sanofi Elf Complexe forme de l'acide propyl-2 pentene-2 ouique (e) et de son sel de sodium, sa preparation et compositions pharmaceutiques le contenant.
US6287598B1 (en) * 1993-05-28 2001-09-11 Alza Corporation Method for providing sustained antiepileptic therapy
US5690959A (en) * 1993-05-29 1997-11-25 Smithkline Beecham Corporation Pharmaceutical thermal infusion process
AUPN969796A0 (en) * 1996-05-07 1996-05-30 F.H. Faulding & Co. Limited Taste masked liquid suspensions
US5916910A (en) * 1997-06-04 1999-06-29 Medinox, Inc. Conjugates of dithiocarbamates with pharmacologically active agents and uses therefore
US6248363B1 (en) * 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
UA80393C2 (uk) * 2000-12-07 2007-09-25 Алтана Фарма Аг Фармацевтична композиція, яка містить інгібітор фде 4, диспергований в матриці

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060252831A1 (en) * 2005-05-06 2006-11-09 Christopher Offen Method for the treatment of magnesium and potassium deficiencies
US20060252830A1 (en) * 2005-05-06 2006-11-09 Brandon Stephen F Method for the treatment of magnesium and potassium deficiencies

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IL128745A0 (en) 2000-01-31
US8535721B2 (en) 2013-09-17
ME00664B (me) 2007-06-04
ZA978954B (en) 1999-04-07
KR20000048828A (ko) 2000-07-25
JP3523270B2 (ja) 2004-04-26
WO1998015268A1 (fr) 1998-04-16
ID24596A (id) 2000-07-27
CN100367945C (zh) 2008-02-13
FR2754177A1 (fr) 1998-04-10
HK1021939A1 (en) 2000-07-21
CZ288876B6 (cs) 2001-09-12
SK36499A3 (en) 2000-12-11
BR9712268A (pt) 1999-08-31
NZ334399A (en) 2000-05-26
CA2267096A1 (fr) 1998-04-16
US20060263437A1 (en) 2006-11-23
RS49602B (sr) 2007-06-04
PL190105B1 (pl) 2005-10-31
EE03744B1 (et) 2002-06-17
AU731235B2 (en) 2001-03-29
EE9900140A (et) 1999-12-15
DE69712100D1 (de) 2002-05-23
TW508251B (en) 2002-11-01
SK282113B6 (sk) 2001-11-06
ES2174293T3 (es) 2002-11-01
EP0956010B1 (de) 2002-04-17
IL128745A (en) 2004-05-12
HUP9903855A3 (en) 2000-06-28
PT956010E (pt) 2002-08-30
SI0956010T1 (en) 2002-10-31
HUP9903855A2 (hu) 2000-05-28
IS4996A (is) 1999-03-11
DZ2316A1 (fr) 2002-12-28
EG24070A (en) 2008-05-11
US20030157177A1 (en) 2003-08-21
IS1985B (is) 2005-02-15
CZ121199A3 (cs) 1999-08-11
UY24738A1 (es) 2001-05-31
KR100334687B1 (ko) 2002-04-27
NO991613L (no) 1999-04-06
HRP970537A2 (en) 1998-08-31
HRP970537B1 (en) 2002-08-31
AR013613A1 (es) 2001-01-10
CA2267096C (fr) 2003-09-16
FR2754177B1 (fr) 1999-08-06
CN1232391A (zh) 1999-10-20
HU225103B1 (en) 2006-06-28
ATE216228T1 (de) 2002-05-15
MY120521A (en) 2005-11-30
NO325723B1 (no) 2008-07-07
YU17899A (sh) 2000-03-21
JP2000504038A (ja) 2000-04-04
TR199900789T2 (xx) 1999-07-21
AU4560297A (en) 1998-05-05
NO991613D0 (no) 1999-04-06
DE69712100T2 (de) 2002-11-28
PL332249A1 (en) 1999-08-30
RU2177315C2 (ru) 2001-12-27
CO4900080A1 (es) 2000-03-27
DK0956010T3 (da) 2002-08-12
EP0956010A1 (de) 1999-11-17

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