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WO2004062692A1 - Formulation de substances actives a faible hydrosolubilite - Google Patents

Formulation de substances actives a faible hydrosolubilite Download PDF

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Publication number
WO2004062692A1
WO2004062692A1 PCT/EP2004/050012 EP2004050012W WO2004062692A1 WO 2004062692 A1 WO2004062692 A1 WO 2004062692A1 EP 2004050012 W EP2004050012 W EP 2004050012W WO 2004062692 A1 WO2004062692 A1 WO 2004062692A1
Authority
WO
WIPO (PCT)
Prior art keywords
formulation
formulation according
active substance
alkyl
ionic hydrophilic
Prior art date
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.)
Ceased
Application number
PCT/EP2004/050012
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English (en)
Inventor
Maria A.E. Van Der Heijden-Van Beek
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.)
Abbott Healthcare Products BV
Original Assignee
Solvay Pharmaceuticals BV
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 Solvay Pharmaceuticals BV filed Critical Solvay Pharmaceuticals BV
Publication of WO2004062692A1 publication Critical patent/WO2004062692A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin

Definitions

  • the present invention relates to formulations of benzazepin -, benzoxazepin- and benzothiazepin- N -acetic acid compounds, a method for the preparation of said formulations and the use thereof in the prevention and/or treatment of diseases
  • EP 0733642 is related to these compounds and their physiologically acceptable salts as such and to the use of the compound in heart insufficiency
  • EP 0830863, WO00/48601 and WO01/03699 are related to the use of the above compounds in the improvement of gastrointestinal blood flow, in the treatment of hypertension and in the treatment and prophylaxis of cardiac damages indu ced by ad ⁇ amycin and comparable anti-cancer drugs, respectively
  • Ri is a selected from the group consisting of (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl which may be substituted by a (CrC B )alkoxy, phenyl-(C C 6 )-alkyl and phenyloxy-(C r
  • R 4 is a biolabile ester forming group; or a pharmaceutically acceptable salt thereof; characterised in that said formulation is consisting of a) said substance or a pharmaceutically acceptable salt thereof in an amount of up to 20% of the total weight of the formulation, and b) a non-ionic hydrophilic surfactant ingredient, which is in the liquid form between 15° and 30 °C, selected from the group consisting of polyoxyethylene glycol sorbitan fatty acid esters (polysorbates) and non hydrogenated polyoxyethylene castor oil derivatives, said non -ionic hydrophilic surfactants having a hydrophilic-lipophilic balance (HLB) value of between 14 and 16.
  • Preferred pharmaceutically active salts of the active substances according to the present invention are bivalent metal salts. Even more preferred are calcium salts.
  • the most preferred active substances according to the present invention are 3-[1- ⁇ 2'- (ethoxycarbonyl) ⁇ -4'-phenylbutyl]cyclopentan-1-carbonylamino]-2,3,4,5-tetrahydro-2- oxo-1 H-1 -benzazepin -1 -acetic acid, preferably in its 3S,2'R form and 3-[1- ⁇ 2'- (ethoxycarbonyl) ⁇ -4'-naphtylbutyl]cyclopentan-1-carbonylamino]-2,3,4,5-tetrahydro-2- oxo-1 H-1 -benzazepin-1 -acetic acid, also preferably in its 3S,2'R form.
  • Thermodynamically stable refers to the absence of significant physical or chemical changes of the product that might affect the quality of the product during storage .
  • poorly water-soluble is meant that the aqueous solubility of the active substance is less than 1 in 1000.
  • non-ionic hydrophilic surfactant refers to those amphiphilic substances that are soluble in water (they have higher HLB values), posses surface activity and are not ionised in aqueous solutions (H.
  • HLB value is meant a value on a scale from 0 to 20, that is assigned to each surfactant based on the relative proportions of the hydrophilic and hydrophobic part of the molecule. Oil soluble surfactants have low HLB values, whereas water soluble surfactants have higher HLB values. The HLB value is calculated as:
  • semi-solid means a system that behaves as a solid material at ambient conditions, but will change to a system that behaves as a liquid due to a change in the physical conditions of the system, e.g. the application of stress on the material or a rise in temperature.
  • Semi-solids just as normal solids, retain their shape as long as no outside forces are applied, but unlike normal solids they are easily deformed on application of outside forces.
  • semi -solid is related to the mixture of the active substance and the the non -ionic hydrophilic surfactant ingredient, as this mixture may be liquid but often is in a semi -solid form.
  • thermodynamically stable liquid or semi-solid solution With the term derived from a thermodynamically stable liquid or semi-solid solution is meant that the formulation no longer comprises the stable liquid or semi -solid solution in its original state, but that due to further steps, e.g. absorption on a carrier or dissolution in a diluent, the original liquid or semi -solid solution state is lost.
  • the non-ionic hydrophilic surfactant ingredient is selected from the group consisting of polyoxyethylene glycol sorbitan fatty acid esters (polysorbates) and non hydrogenated polyoxyethylene castor oil derivatives, said surfactants having a hydrophilic-lipophilic balance (HLB) value of between 14 and 16.
  • polyoxyethylene glycol polysorbates are commercially available from ICI Inc., and are known under the trademark Tween®.
  • Non hydrogenated polyoxyethylene castor oil derivatives are commercially available from the BASF Corporation under the trademark Cremophor®.
  • Cremophor® EL The most preferred compound for the present invention is Cremophor® EL.
  • the above combination of active substances and non-ionic hydrophilic surfactant leads to a very stable formulation at a low ratio between the non-ionic hydrophilic surfactant and the active substance, compared with the prior art.
  • the formulation also has a high solubility in gastro -intestinal fluids, remaining soluble even in the highly acidic gastric environment, and a high bioavailibility.
  • the ratio between the active substance in the formulation and the non -ionic hydrophilic surfactant is between 1 : 1 and 1 : 8 by weight, preferably between 1 : 3 and 1 : 6 and most preferred is 1 : 5.
  • the active substance can be used in an amount between about 0.01 and 50% by weight, more preferably in an amount between 0.1 and 30% by weight, even more preferably in an amount between 1 and 25% and most preferred in an amount between about 10 and 25% of the total weight of the formulation .
  • the active substance may be formulated in its acid form or in the form of a pharmaceutically acceptable salt.
  • Bivalent metal salts such as magnesium, calcium, zinc or iron salts are preferred.
  • the most preferred salt is a calcium salt.
  • the present invention can be used in two main classes of embodiments. In the first class of embodiments the formulated product in a concentrate d form is filled into a soft or hard gelatin capsule, or, after having been absorbed on a carrier, into a hard gelatin capsule.
  • the formulation is diluted further with a diluent to form a drop formulation or a drinkable solution.
  • both embodiments of the formulation according to the present invention may also comprise auxiliary materials that are needed to obtain a good formulation.
  • auxiliary materials that can be used are coloring agents, preservatives such as methylparahydroxybenzoate and propylparahydroxybenzoate , a suitable aroma or an artificial sweetener.
  • suitable coloring agents, aromas and sweeteners are well known in the art.
  • the formulation may contain, apart from the active substance and the non -ionic hydrophilic surfactant ingredient, a fatty or oily diluent or a mixture of these diluents.
  • Said diluent or mixture of diluents is preferably selected from the group consisting of polyethylene glycol 200 (PEG 200), polyethylene glycol 400 (PEG 400), polyethylene 600 (PEG 600), Labrasol R (mixture of caprylocaproyl Macrogol-8 glycerides) oleic acid, peanut oil, sesam oil, soy bean oil, ethyloleate, isopropylmyristate and Miglyol 812.
  • the diluent or mixture of diluents may be used in such art amount that the desired weight of the formulation to fill into the capsule is reached.
  • the formulation When the formulation is absorbed on a carrier the following carriers may be used: Cab-O-Sil, Accurel Powder and Avicel, si licified Avicel, Kollidon CL and all other acceptable pharmaceutical fillers and desintegrants.
  • the diluent or mixture of diluents used in the second class of embodiments are miscible with water and are suitable for oral purposes. Therefore the diluent or mixture of diluents is preferably selected from the group consisting of ethanol, glycerol, propylene glycol, PEG 200, PEG 400, PEG 600, and water. The most preferred diluent is water.
  • the amount of diluent or mixture of diluents may be used in such an amount that the desired weight of the formulation that is needed for a drinkable or drop formulation is reached. Preferably the amount is between 20% and 98% of the total weight of the formulation.
  • the solution normally wi II be diluted till a preferred final concentration of between 5 and 100 g active substance per liter.
  • the solution will have a most preferred concentration of between 1 and 50 g active substance per liter.
  • the present invention is also related to a method of preparing the formulations according to the present invention.
  • a method is used that is characterized in that a) the non-ionic hydrophilic surfactant ingredient is mixed with the active substance with the general formula I as defined above, at between 50-80°C to dissolve the active substance and b) the resulting mixture is optionally mixed with a diluent and/or auxiliary materials.
  • the mixing of the non-ionic hydrophilic surfactant and the active substance preferably takes place at a temperature of between 70 and 75 C C, and the resulting mixture is optionally mixed with the diluent at a preferred temperature of between 60 and 80°C.
  • the resulting mixture can be filled into a soft or hard gelatine capsule.
  • the carrier-absorbed formulation When the carrier-absorbed formulation has to be prepared the resulting mixture is first absorbed on the carrier, e.g. by spraying of the mixture on the carrier, followed by filling of the carrier -absorbed formulation into the hard gelatine capsule.
  • a method is used that is characterized in that a) the non-ionic hydrophilic surfactant ingredient is mixed with the active substance with the general formula I as defined above, at between 50-80°C and b) the resulting mixture is mixed with a diluent and optionally with the auxiliary materials .
  • the mixing and dissolving of the non-ionic hydrophilic surfactant and the active substance preferably takes place at a temperature of between 70 and 75°C, and the resulting mixture is mixed with the diluent at a preferred temperature of between 60 and 80 °C followed by cooling to ambient temperature while stirring. In this way a drinkable solution or a drop formulation is obtained.
  • a quantity of a surfactant together with the poorly water soluble active substance is composed.
  • the compositions are given in Table 1 for liquid filled capsules which contain 50 mg active substance. The effect of the amount and the effect of type of surfactant on the release of the active substance from the liquid filled capsule determines the bioavailability of the drug.
  • the non-ionic hydrophilic surfactant, Tween® 80 or Cremophor® EL is heated to a temperature between 60 °C and 70 °C.
  • the active substance is added and dissolved at said temperature.
  • the resulti ng solution is filled into capsule size 1.
  • Dissolution testing of the liquid/ semi-solid filled capsules is performed in artificial gastro-intestinal fluid of 37 °C using USP II apparatus using a paddle speed of 75 rpm.
  • the dissolution is tested in a sequential range of increasing pH of the medium starting with 400 ml pH 2, prepared from 400 ml 0.01 N hydrochloric acid.
  • One hour after starting the dissolution 15 ml of the medium is withdrawn and the pH of the buffer is changed into pH 4.5 by adding 88.5 ml 0.05 N glacial acetic acid and 211.5 ml 0.05 N sodium acetate solution.
  • the concentration of the surfactants in the dissolution medium affects the UV absorption, so the absorption of placebo compositions of the said formulations are simultaneously detected at 240 nm and 267 nm using an optical path length of 2 mm.
  • the amount of drug substance released from the liquid filled capsules is calculated from equation 1 in which A is the UV absorption, V is the volume of the dissolution
  • a l % medium expressed in ml, ' »» is the absorption coefficient of a 1 % w/w solution of the said active substance in the dissolution medium recorded through a optical path length of 1 cm, d is the dose or label claim expressed in mg and I is the optical path length in cm.
  • the values for V andA ,' " are given in Table 2. The tolerance in the measurement is about 10%.
  • a formulation of a surfactant together with the poorly water soluble active compound is composed.
  • the compositions for a batch size of 100 gram are given in Table 3 for an oral solution containing 10 mg/ml, calculated as acid.
  • the amount and type of surfactant determines the release of the active substance from the liquid filled capsule, or the release of the active substance into the oral solution and prevents precipitation of the drug in an acidic environment.
  • Table 3 Composition of an oral solution
  • the required quantity of purified water is heated to 70-75°C. Separately the active substance and the non-ionic surfactant are also heated to 70-75 Q C while stirring, until complete dissolution of the active substance.
  • the heated purified water is slowly (in approximately 10 minutes) added under stirring, normally resulting in a clear solution. When the solution is not clear after completion of the addition of water, it is stirred for an additional 10 minutes while heating at 70°C.
  • the resulting solution is cooled down slowly in one hour to a temperature of 30 °C, while stirring and is ready for use.
  • Figure 1 clearly shows that the active substance remains dissolved in pH 2 (data from 0 up to 60 minutes), in pH 4.5 (the next 30 minutes) and pH 6.8 (data until end of test). That means that even in gastric environment the active substance will not precipitate.

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

Abstract

L'invention concerne une formulation à biodisponibilité améliorée comprenant une solution liquide ou semi-solide stable sur le plan thermodynamique de la substance active sur le plan biologique, à faible hydrosolubilité de formule générale (I) dans laquelle: R1 est sélectionné dans le groupe renfermant (C1-C6)alcoxy(C1-C6)alkyle pouvant être substitué par un alcoxy en (C1-C6), un phényl-(C1-C6)-alkyle et un phényloxy-(C1- C6)-alkyle, le groupe phényle pouvant être substitué par un alkyle en (C1-C6), un alcoxy ou halogène en (C1-C6) et un naphtyl-(C1-C6)-alkyle, R2 et R3 désignent de manière indépendante un hydrogène ou un halogène, R4 représente un groupe formant un ester biolabile; ou un sel acceptable sur le plan pharmaceutique de celui-ci; caractérisée en ce que la formulation comprend a) la substance ou un sel acceptable sur le plan pharmaceutique de celle-ci dans une quantité allant jusqu'à 50 % du poids total de la formulation, et b) un ingrédient tensioactif hydrophile non ionique, sous forme liquide entre 15° et 30 °C, sélectionné dans le groupe renfermant des esters d'acide gras de polyoxyéthyélène glycol sorbitan (polysorbates) et des dérivés d'huile de ricin de polyoxyéthylène non hydrogénés, le tensioactif hydrophile non ionique possédant une valeur d'équilibre hydrophile-lipophile (HLB) comprise entre 14 et 16 . L'invention concerne également un procédé de préparation de la formulation et l'utilisation de celle-ci dans la prévention et/ou le traitement de maladies.
PCT/EP2004/050012 2003-01-13 2004-01-12 Formulation de substances actives a faible hydrosolubilite Ceased WO2004062692A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP03100043 2003-01-13
EP03100043.3 2003-01-13
US44002403P 2003-01-15 2003-01-15
US60/440,024 2003-01-15

Publications (1)

Publication Number Publication Date
WO2004062692A1 true WO2004062692A1 (fr) 2004-07-29

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006067150A1 (fr) * 2004-12-23 2006-06-29 Solvay Pharmaceuticals B.V. Formulation orale a liberation instantanee d'une substance active peu hydrosoluble
WO2007144418A1 (fr) * 2006-06-16 2007-12-21 Solvay Pharmaceuticals B.V. Composition pharmaceutique orale d'une substance active peu soluble dans l'eau
WO2007147873A1 (fr) * 2006-06-22 2007-12-27 Solvay Pharmaceuticals B.V. Composition pharmaceutique à administration par voie orale contenant un principe actif peu soluble dans l'eau
US20090263479A1 (en) * 2008-04-22 2009-10-22 Solvay Phamaceuticals Gmbh Formulations for poorly permeable active pharmaceutical ingredients
WO2010144865A2 (fr) 2009-06-12 2010-12-16 Meritage Pharma, Inc. Procédés de traitement de troubles gastro-intestinaux
US10293052B2 (en) 2007-11-13 2019-05-21 Meritage Pharma, Inc. Compositions for the treatment of gastrointestinal inflammation
WO2019151882A1 (fr) 2018-01-31 2019-08-08 FORTY-FOUR PHARMACEUTICALS Sp. z o.o. Inhibiteurs d'endopeptidase neutre (nep) et d'endopeptidase humaine soluble (hsep) destinés à la prophylaxie et au traitement de maladies oculaires
US11413296B2 (en) 2005-11-12 2022-08-16 The Regents Of The University Of California Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract
US12337001B2 (en) 2018-01-31 2025-06-24 Christopher Turski Neutral endopeptidase (NEP) and human soluble endopeptidase (hSEP) inhibitors to reduce detrimental effects of perfusion deficiency of parenchymal organs

Citations (10)

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Publication number Priority date Publication date Assignee Title
EP0292050A1 (fr) * 1987-05-18 1988-11-23 Janssen Pharmaceutica N.V. Compositions contenant de la flunarizine
EP0517412A1 (fr) * 1991-06-03 1992-12-09 MERCK SHARP & DOHME LTD. Formulations pharmaceutiques d'une benzodiazepine
US5260301A (en) * 1990-03-01 1993-11-09 Fujisawa Pharmaceutical Co., Ltd. Pharmaceutical solution containing FK-506
WO2000000179A1 (fr) * 1998-06-27 2000-01-06 Won Jin Biopharma Co., Ltd. Preparation a dispersion solide d'un medicament faiblement hydrosoluble contenant de l'huile, un acide gras ou leurs melanges
US6096338A (en) * 1994-03-16 2000-08-01 R. P. Scherer Corporation Delivery systems for hydrophobic drugs
WO2000048601A1 (fr) * 1999-02-16 2000-08-24 Solvay Pharmaceuticals Gmbh Medicament pour le traitement de l'hypertension arterielle
WO2001078686A1 (fr) * 2000-04-17 2001-10-25 Yamanouchi Pharmaceutical Co., Ltd. Compositions solides enrobees a liberation decalee dans le temps
US6352718B1 (en) * 1999-09-27 2002-03-05 American Cyanamid Company Vasopressin antagonist formulation and process
EP1236476A1 (fr) * 1999-12-10 2002-09-04 Takeda Chemical Industries, Ltd. Compositions medicinales a usage par voie orale
WO2003068266A1 (fr) * 2002-02-14 2003-08-21 Solvay Pharmaceuticals B.V. Formulation de solution solide orale d'une substance active faiblement hydrosoluble

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0292050A1 (fr) * 1987-05-18 1988-11-23 Janssen Pharmaceutica N.V. Compositions contenant de la flunarizine
US5260301A (en) * 1990-03-01 1993-11-09 Fujisawa Pharmaceutical Co., Ltd. Pharmaceutical solution containing FK-506
EP0517412A1 (fr) * 1991-06-03 1992-12-09 MERCK SHARP & DOHME LTD. Formulations pharmaceutiques d'une benzodiazepine
US6096338A (en) * 1994-03-16 2000-08-01 R. P. Scherer Corporation Delivery systems for hydrophobic drugs
WO2000000179A1 (fr) * 1998-06-27 2000-01-06 Won Jin Biopharma Co., Ltd. Preparation a dispersion solide d'un medicament faiblement hydrosoluble contenant de l'huile, un acide gras ou leurs melanges
WO2000048601A1 (fr) * 1999-02-16 2000-08-24 Solvay Pharmaceuticals Gmbh Medicament pour le traitement de l'hypertension arterielle
US6352718B1 (en) * 1999-09-27 2002-03-05 American Cyanamid Company Vasopressin antagonist formulation and process
EP1236476A1 (fr) * 1999-12-10 2002-09-04 Takeda Chemical Industries, Ltd. Compositions medicinales a usage par voie orale
WO2001078686A1 (fr) * 2000-04-17 2001-10-25 Yamanouchi Pharmaceutical Co., Ltd. Compositions solides enrobees a liberation decalee dans le temps
WO2003068266A1 (fr) * 2002-02-14 2003-08-21 Solvay Pharmaceuticals B.V. Formulation de solution solide orale d'une substance active faiblement hydrosoluble

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DATABASE WPI Section Ch Week 200203, Derwent World Patents Index; Class B07, AN 2002-025949, XP002278632 *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2005318199B2 (en) * 2004-12-23 2011-04-28 Panacea Biotec Ltd. Oral immediate release formulation of a poorly watersoluble active substance
WO2006067150A1 (fr) * 2004-12-23 2006-06-29 Solvay Pharmaceuticals B.V. Formulation orale a liberation instantanee d'une substance active peu hydrosoluble
RU2382649C2 (ru) * 2004-12-23 2010-02-27 Солвей Фармасьютикалс Б.В. Пероральная лекарственная форма с немедленным высвобождением малорастворимого активного вещества
US11413296B2 (en) 2005-11-12 2022-08-16 The Regents Of The University Of California Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract
EA014898B1 (ru) * 2006-06-16 2011-02-28 Солвей Фармасьютикалс Б.В. Пероральная фармацевтическая композиция из активного вещества, плохо растворимого в воде
WO2007144418A1 (fr) * 2006-06-16 2007-12-21 Solvay Pharmaceuticals B.V. Composition pharmaceutique orale d'une substance active peu soluble dans l'eau
WO2007147873A1 (fr) * 2006-06-22 2007-12-27 Solvay Pharmaceuticals B.V. Composition pharmaceutique à administration par voie orale contenant un principe actif peu soluble dans l'eau
US10293052B2 (en) 2007-11-13 2019-05-21 Meritage Pharma, Inc. Compositions for the treatment of gastrointestinal inflammation
US11357859B2 (en) 2007-11-13 2022-06-14 Viropharma Biologics Llc Compositions for the treatment of gastrointestinal inflammation
JP2011518208A (ja) * 2008-04-22 2011-06-23 アボツト・プロダクツ・ゲゼルシヤフト・ミツト・ベシユレンクテル・ハフツング 難透過性医薬品活性成分のための改善された製剤
WO2009130204A3 (fr) * 2008-04-22 2010-08-05 Abbott Products Gmbh Formulations améliorées pour des ingrédients pharmaceutiques actifs faiblement perméables
EA032766B1 (ru) * 2008-04-22 2019-07-31 Эбботт Продактс Гмбх Улучшенные композиции для активных фармацевтических компонентов с плохой проницаемостью
US20090263479A1 (en) * 2008-04-22 2009-10-22 Solvay Phamaceuticals Gmbh Formulations for poorly permeable active pharmaceutical ingredients
WO2010144865A2 (fr) 2009-06-12 2010-12-16 Meritage Pharma, Inc. Procédés de traitement de troubles gastro-intestinaux
WO2019151882A1 (fr) 2018-01-31 2019-08-08 FORTY-FOUR PHARMACEUTICALS Sp. z o.o. Inhibiteurs d'endopeptidase neutre (nep) et d'endopeptidase humaine soluble (hsep) destinés à la prophylaxie et au traitement de maladies oculaires
US12337001B2 (en) 2018-01-31 2025-06-24 Christopher Turski Neutral endopeptidase (NEP) and human soluble endopeptidase (hSEP) inhibitors to reduce detrimental effects of perfusion deficiency of parenchymal organs

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