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WO1999032089A1 - Compositions pharmacutiques comprenant des micelles qui comprennent un gluocorticosteroide lipophile et un tensio-actif unique - Google Patents

Compositions pharmacutiques comprenant des micelles qui comprennent un gluocorticosteroide lipophile et un tensio-actif unique Download PDF

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Publication number
WO1999032089A1
WO1999032089A1 PCT/SE1998/002426 SE9802426W WO9932089A1 WO 1999032089 A1 WO1999032089 A1 WO 1999032089A1 SE 9802426 W SE9802426 W SE 9802426W WO 9932089 A1 WO9932089 A1 WO 9932089A1
Authority
WO
WIPO (PCT)
Prior art keywords
surfactant
glucocorticosteroid
micelles
composition
pharmaceutically acceptable
Prior art date
Application number
PCT/SE1998/002426
Other languages
English (en)
Inventor
Gabrielle Sjöquist
Original Assignee
Astrazeneca Ab
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
Priority to NZ505073A priority Critical patent/NZ505073A/xx
Priority to EEP200000388A priority patent/EE200000388A/xx
Priority to BR9813811-1A priority patent/BR9813811A/pt
Priority to JP2000525082A priority patent/JP2001526210A/ja
Priority to IL13688098A priority patent/IL136880A0/xx
Priority to KR1020007006879A priority patent/KR20010024789A/ko
Priority to HU0102365A priority patent/HUP0102365A3/hu
Priority to PL98341361A priority patent/PL341361A1/xx
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to AU19935/99A priority patent/AU1993599A/en
Priority to SK953-2000A priority patent/SK9532000A3/sk
Priority to CA002315782A priority patent/CA2315782A1/fr
Priority to EP98964662A priority patent/EP1043973A1/fr
Publication of WO1999032089A1 publication Critical patent/WO1999032089A1/fr
Priority to NO20003220A priority patent/NO20003220L/no

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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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising micelles in an aqueous medium, wherein the micelles comprise a lipophilic glucocorticosteroid and one and only one pharmaceutically acceptable surfactant
  • the invention further relates to a process for the preparation of the pharmaceutical composition and use of the pharmaceutical composition for the manufacture of a medicament for treating allergic and/or infla - matory diseases in the respiratory tract or for treating intestinal diseases and methods for treatment of the diseases in a mammal, including man.
  • Rhinitis and asthma are today effectively treated by the use of glucocorticosteroids such as e.g. mometasone furoate, budesonide, and fluticasone propionate.
  • glucocorticosteroids such as e.g. mometasone furoate, budesonide, and fluticasone propionate.
  • Patent applications that can be mentioned in this context are WO 92/13873 and WO 96/19199 both to Astra AB of Sweden.
  • the glucocorticosteroid compositions are used in the form of powders in dry powder inhalers, as solutions or suspensions in pressurized metered dose inhalers (pMDIs).
  • pMDIs pressurized metered dose inhalers
  • a suspension in water is a user-friendly form of administration as the solution is easily accepted by the mucosa.
  • the glucocorticosteroid crystals are in contact with the water which can affect the stability of the glucocorticosteroid.
  • a glucocorticosteroid ester may be chemically degraded for example by ester hydrolysis when using such a compound.
  • the compositions in the form of suspensions may be less stable than solutions e.g.
  • compositions for trans- mucosal membrane administration of protein or peptide drugs wherein the compositions comprise the drug in mixtures with at least one bile salt or fusidate or a derivative thereof and at least one non-ionic detergent of the formula RO(CHR'CH 2 O) n R, wherein one R is H and the other R represents the radical of a saturated or unsaturated cyclic or acyclic organic alcohol of 6-40 carbons.
  • EP 0179583 Al to Merck & Co. Inc. discloses a system for enhancing the water dissolution rate and solubility of poorly soluble drugs.
  • the compositions of EP 0179583 Al involve combining the poorly water-soluble drug with the surfactant in appropriate ratios and by an appropriate method that results in the formation of an anhydrous product.
  • the examples are directed to anhydrous compositions of the antiparasitic agents ivermectin or abamectin and a surfactant.
  • IBD inflammatory bowel diseases
  • a pharmaceutical composition comprising micelles in an aqueous medium, wherein the micelles comprise a lipophilic glucocortico- steroid and one and only one pharmaceutically acceptable surfactant.
  • the composition comprises one and only one non- ionic surfactant.
  • composition is used for treating allergic and/or inflammatory diseases in the respiratory tract.
  • composition is used for treating intestinal diseases.
  • a process for the preparation of a pharmaceutical composition comprising micelles in an aqueous medium, wherein the micelles comprise a lipophilic glucocorticosteroid and one and only one pharmaceutically acceptable surfactant, the process comprising the steps of: a) dissolving the glucocorticosteroid in the surfactant; b) adding an aqueous medium to the solution from step a) and stirring the solution.
  • composition comprising micelles in an aqueous medium, wherein the micelles comprise a lipophilic glucocorticosteroid and one and only one pharmaceutically acceptable surfactant, for the manufacture of a medicament for treating allergic and inflammatory diseases in the respiratory tract is obtained.
  • composition comprising micelles in an aqueous medium, wherein the micelles comprise a lipophilic glucocorticosteroid and one and only one pharmaceutically acceptable surfactant for the manufacture of a medicament for treating intestinal diseases is obtained.
  • Another aspect of the invention is a method for treatment of allergic and/or inflammatory diseases in the respiratory tract of a mammal, including man.
  • the method is characterized by administration to the mammal in need of such treatment of an therapeutically effective amount of a pharmaceutical composition comprising micelles in an aqueous medium, wherein the micelles comprise a lipophilic glucocorticosteroid and one and only one pharmaceutically acceptable surfactant.
  • a last aspect of the invention is a method for treatment of intestinal diseases in a mammal, including man.
  • the method is characterized by administration to the mammal in need of such treatment of an therapeutically effective amount of a pharmaceutical composition comprising micelles in an aqueous medium, wherein the micelles comprise a lipophilic glucocorticosteroid and one and only one pharmaceutically acceptable surfactant.
  • lipophilic glucocorticosteroids and their esters can be incorporated in micelles formed by a surfactant, especially a non-ionic surfactant, in an aqueous medium.
  • a surfactant especially a non-ionic surfactant
  • micelles are molecular aggregates formed in the solution of a surfactant.
  • Surfactants in a dilute aqueous solution exist primarily as monomers, but at higher concentrations a number of surfactant molecules aggregate to form micelles. Thereby a stable formulation is obtained in which the lipophilic glucocorticosteroid/glucocorticosteroid ester is protected and is possible to be absorbed.
  • the micelles will act as non-aqueous reservoirs for the lipophilic glucocorticosteroid and will positively affect the pharmacokinetic and deposition of the glucocorticosteroid molecule.
  • the glucocorticosteroid will also be more easy to dose accurately as well as for the patient to administer accurately.
  • lipophilic reference can be made to the above mentioned reference where on p. 155 it is stated that "lipophilic drugs may be wetted by oils and semipolar liquids.”
  • compositions comprising the lipophilic glucocorticosteroids used in the invention in an aqueous medium are very difficult to dissolve in water and then to obtain a stable composition. It was found in the present invention that by dissolving the lipophilic glucocorticosteroid in a surfactant, preferably a non-ionic surfactant, stable compositions can be obtained with the glucocorticosteroid in micellar form.
  • a surfactant preferably a non-ionic surfactant
  • the inventor of the present invention has further found that use of the stable compositions comprising e.g. rofleponide palmitate incorporated in micelles formed by a surfactant, causes less irritation in the lung after oral inhalation by human patients, than is experienced after oral inhalation of the same surfactant on its own.
  • the present compositions comprise one and only one surfactant.
  • the surfactant used in the present compositions can be non-ionic, zwitterionic, anionic or cationic. It is, however, preferred, to use a non-ionic surfactant, since this normally reduces the risk of side-effects after administration. Examples of non-ionic, zwitterionic, anionic or cationic surfactants which may be used in the present invention can be found in Wade and Weller, Handbook of Pharmaceutical Excipients, 1994, The Pharmaceutical Press, London.
  • the non-ionic surfactants used according to the present invention are suitably selected from poloxamers, e.g. poloxamer 188; polyoxyethylene alkyl ethers, e.g.poloxyl 10 stearyl ether, poloxyl 20 stearyl ether; polyoxyethylene stearates, e.g. polyoxyl 8 stearate, poloxyl 12 stearate; polyoxyethyleneglycolhydroxystearates, e.g. polyoxyethyleneglycol 12- hydroxystearates, and polyoxyethylene sorbitan fatty acid esters.
  • a preferred group of non- ionic surfactants is polyoxyethylene sorbitan fatty acid esters, e.g.
  • polyoxyethylene 20 sorbitan monolaurate, monopalmitate, monostearate or monooleate also known as poly- sorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80, respectively
  • suitable commercial polysorbates are Tween 20, Tween 40, Tween 60 and Tween 80.
  • a further preferred group of non-ionic surfactants is polyoxyethyleneglycol 12-hydroxy- stearates and an especially preferred compound is polyoxyethyleneglycol 660 12-hydroxy- stearate.
  • lipophilic glucocorticosteroids relate to lipophilic glucocorticosteroids per se, as well as their pharmaceutically acceptable solvates, esters, acetals and salts, and solvates of any of these.
  • glucocorticosteroids examples include betamethasone, fluticasone (e.g. as propionate), budesonide, tipredane, dexamethasone, beclomethasone (e.g. as dipropionate), prednisolone, fluocinolone (e.g. as acetonide), triamcinolone (e.g. as acetonide), mometasone (e.g. as furoate), rofleponide (e.g.
  • mometasone furoate beclomethasone dipropionate or fluticasone propionate or glucocorticosteroids with an asymmetric acetal structure, e.g. comprising 16 ⁇ ,17 ⁇ -butylidenedioxy group, such as budesonide or rofleponide or pharmaceutically acceptable solvates, esters, acetals or salts, or where applicable, solvates thereof.
  • the most preferred lipophilic glucocorticosteroid ester is rofleponide palmitate.
  • the amount of surfactant used in the composition should be less than 5 % (w/w) of the total composition weight.
  • the amount of surfactant is less than 3 % (w/w) and most preferably less than 1 % (w/w) of the total composition weight.
  • the concentration of the surfactant must, however, be higher than the critical micellar concentration (CMC), being the lowest concentration at which micelles are formed in an aqueous medium.
  • CMC critical micellar concentration
  • the CMC value depends primarily upon the temperature and the concentration of possible additives. It lies within the competence of the skilled person to determine the CMC for each indivi-dual composition and thus prepare suitable micelles according to the present invention.
  • the amount of the glucocorticosteroid used depends on the field of use. If the glucocorticosteroid is used for treating diseases in the respiratory tract by inhalation a suitable daily dose is from 10 to 2400 ⁇ g, preferably from 10 to 1600 ⁇ g. If the glucocorticosteroid is used for treating intestinal diseases a suitable daily dose is from 400 to 4000 ⁇ g, preferably from 800 to 3000 ⁇ g.
  • composition according to the invention may also contain one or more pharmaceutically acceptable additives such as buffers and other pH modifiers, antioxidants, complexing agents to further increase the stability, viscosity regulating agents andisotonicity modifying agents.
  • pharmaceutically acceptable additives such as buffers and other pH modifiers, antioxidants, complexing agents to further increase the stability, viscosity regulating agents andisotonicity modifying agents.
  • Compounds used as such agents are compounds generally used in drug formulations e.g. EDTA for complexing and carboxymethyl cellulose (CMC) for regulating viscosity.
  • substances for adjusting the isotonicity can be mentioned glucose, mannitol, salts, glycerol and propylene-glycol.
  • alkaline buffers are used such that the pH of the composition is from 4 to 7. It is, however, preferred to use one or more antioxidants), which may be water-soluble to a smaller or larger degree.
  • antioxidants include, without limitation, tocopherols, especially ⁇ -tocopherol, and preferably racemic ⁇ -tocopherol, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT) and ascorbic acid.
  • BHA butylhydroxyanisole
  • BHT butylhydroxytoluene
  • ascorbic acid ascorbic acid
  • the aqueous medium is added to the glucocorticosteroid- surfactant solution and the mixture is stirred, preferably intensely stirred, to obtain a stable and homogeneous solution.
  • the aqueous medium is of the same temperature as the one of the glucocorticosteroid-surfactant solution before it is added to the solution. If other pharmaceutically acceptable additives are used they are suitably added to the aqueous medium before mixing with the glucocorticosteroid-surfactant solution if they are water soluble. Otherwise they are added to the surfactant solution.
  • glucose is dissolved in the aqueous medium in an isotonic amount.
  • the surfactant used can be a solid compound at ambient temperature or a more or less fluid compound. If a solid surfactant is used it should be heated in order to melt it in a first step of the process. The glucocorticosteroid is then dissolved in the melted surfactant. This is a preferred embodiment of the invention.
  • the glucocorticosteroid can be dissolved directly in the surfactant at ambient temperature or it may be suitable to increase the temperature of the surfactant to more readily dissolve the glucocorticosteroid. Then the water is added.
  • a further possibility is to dissolve the surfactant in a conventional organic solvent, e.g. ethanol, and then to dissolve the glucocorticosteroid in this solution or vice versa.
  • the organic solvent then has to be evaporated before the aqueous medium is added. It is impor- tant that the organic solvent is removed from the composition otherwise the composition will have a stinging effect in the nose of the patient if the composition is used for the manufacture of a medicament for treating allergic and/or inflammatory diseases in the respiratory tract.
  • the composition according to the invention can be made sterile in a conventional manner, e.g. by using dry heat, steam or irradiation.
  • the composition according to the invention is used for the manufacture of a medicament for treating allergic and/or inflammatory diseases in the respiratory tract.
  • the composition can then be administered via the upper and lower respiratory tract, including nasal or oral inhalation.
  • the composition according to the invention can be used in common devices for aqueous solutions for nasal and oral inhalation e.g. in a spray pump or in a nebulizer.
  • nebulisation reference is made to "Medication Nebulizer Performance", Chest 1 10(2), (1996), pp. 498-505.
  • the composition according to the invention is also used for the manufacture of a medicament for treating intestinal diseases such as inflammatory bowel diseases (IBD), ulcerative colitis and Crohn's disease.
  • the compositions can then be administered by rectal administration.
  • the invention also relates to a method for treatment of allergic and/or inflammatory diseases in the respiratory tract of a mammal, including man.
  • the composition according to the invention is administered in a therapeutically effective amount to the mammal in need of such a treatment, preferably by nasal or oral inhalation.
  • the invention also relates to a method of treatment of intestinal diseases in a mammal, including man.
  • the composition according to the invention is administered in a therapeutically effective amount to the mammal in need of such a treatment, preferably by rectal administration.
  • Solutol® HS 15 polyethyleneglycol 660 12-hydroxystearate manufactured by BASF of Germany is melted in a beaker at 35°C-40°C. 100 mg rofleponide palmitate is added to the melt and dissolved.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Organic Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une composition pharmaceutique comprenant des micelles dans un milieu aqueux, les micelles comprenant un glucocorticostéroïde lipophile et un et un seul tensioactif acceptable du point de vue pharmaceutique. L'invention concerne également un procédé de préparation de la composition pharmaceutique et l'utilisation de la composition pharmaceutique dans la fabrication d'un médicament destiné au traitement de troubles allergiques et/ou inflammatoires dans l'appareil respiratoire ou au traitement d'affections intestinales, ainsi que des méthodes de traitement de ces affections chez un mammalien, y compris l'homme.
PCT/SE1998/002426 1997-12-22 1998-12-22 Compositions pharmacutiques comprenant des micelles qui comprennent un gluocorticosteroide lipophile et un tensio-actif unique WO1999032089A1 (fr)

Priority Applications (13)

Application Number Priority Date Filing Date Title
HU0102365A HUP0102365A3 (en) 1997-12-22 1998-12-22 Pharmaceutical compositions comprising micelles comprising lipophilic glucocorticosteroid and only one surfactant and process for their preparation
BR9813811-1A BR9813811A (pt) 1997-12-22 1998-12-22 "composições farmacêuticas compreendendo micelas que compreendem glicocorticosteróide lipofìlico e apenas um único tensoativo"
JP2000525082A JP2001526210A (ja) 1997-12-22 1998-12-22 親油性糖質副腎皮質ステロイドおよび界面活性剤を１つだけ含有するミセルを含んでなる医薬組成物
IL13688098A IL136880A0 (en) 1997-12-22 1998-12-22 Pharmaceutical compositions comprising micelles comprising lipophilic glucocorticosteroid and only one surfactant
KR1020007006879A KR20010024789A (ko) 1997-12-22 1998-12-22 친지성 글루코코르티코스테로이드와 1종의 계면활성제의미셀을 포함하는 제약 조성물
NZ505073A NZ505073A (en) 1997-12-22 1998-12-22 Pharmaceutical compositions comprising micelles comprising lipophilic glucocorticosteroid and only one surfactant, useful for treating allergic, inflammatory and intestinal diseases
SK953-2000A SK9532000A3 (en) 1997-12-22 1998-12-22 Pharmaceutical compositions comprising micelles comprising lipophilic glucocorticosteroid and only one surfactant
PL98341361A PL341361A1 (en) 1997-12-22 1998-12-22 Pharmacological compositions comprising micelles containing a lypophilic glucocorticosteroid and only one surfactant
AU19935/99A AU1993599A (en) 1997-12-22 1998-12-22 Pharmaceutical compositions comprising micelles comprising lipophilic glucocorticosteroid and only one surfactant
EEP200000388A EE200000388A (et) 1997-12-22 1998-12-22 Ravimkoostis, mis sisaldab mitselle, mis sisaldavad lipofiilset glükokortikosteroidi ja ainult üht pindaktiivset ainet
CA002315782A CA2315782A1 (fr) 1997-12-22 1998-12-22 Compositions pharmacutiques comprenant des micelles qui comprennent un gluocorticosteroide lipophile et un tensio-actif unique
EP98964662A EP1043973A1 (fr) 1997-12-22 1998-12-22 Compositions pharmacutiques comprenant des micelles qui comprennent un gluocorticosteroide lipophile et un tensio-actif unique
NO20003220A NO20003220L (no) 1997-12-22 2000-06-21 Farmasøytiske preparater omfattende miceller innbefattende lipofilt glukokortikosteroid og kun ett overflateaktivt middel

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9704833A SE9704833D0 (sv) 1997-12-22 1997-12-22 New formulation
SE9704833-4 1997-12-22

Publications (1)

Publication Number Publication Date
WO1999032089A1 true WO1999032089A1 (fr) 1999-07-01

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Application Number Title Priority Date Filing Date
PCT/SE1998/002426 WO1999032089A1 (fr) 1997-12-22 1998-12-22 Compositions pharmacutiques comprenant des micelles qui comprennent un gluocorticosteroide lipophile et un tensio-actif unique

Country Status (20)

Country Link
EP (1) EP1043973A1 (fr)
JP (1) JP2001526210A (fr)
KR (1) KR20010024789A (fr)
CN (1) CN1283106A (fr)
AR (1) AR017220A1 (fr)
AU (1) AU1993599A (fr)
BR (1) BR9813811A (fr)
CA (1) CA2315782A1 (fr)
EE (1) EE200000388A (fr)
HU (1) HUP0102365A3 (fr)
ID (1) ID26945A (fr)
IL (1) IL136880A0 (fr)
NO (1) NO20003220L (fr)
NZ (1) NZ505073A (fr)
PL (1) PL341361A1 (fr)
SE (1) SE9704833D0 (fr)
SK (1) SK9532000A3 (fr)
TR (1) TR200001977T2 (fr)
WO (1) WO1999032089A1 (fr)
ZA (1) ZA9811461B (fr)

Cited By (23)

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WO2001003703A1 (fr) * 1999-07-12 2001-01-18 Astrazeneca Ab Composition orale comportant en tant que premier principe actif un rofleponide et en tant que second ingredient un antibiotique, destinee a traiter des troubles intestinaux tels que la maladie de crohn
WO2001056578A1 (fr) * 2000-01-31 2001-08-09 Astrazeneca Ab Utilisation de rofleponide pour le traitement du syndrome du colon irritable
WO2002074282A1 (fr) * 2001-03-15 2002-09-26 Astrazeneca Ab Nouvelle composition
US6750210B2 (en) 2000-08-05 2004-06-15 Smithkline Beecham Corporation Formulation containing novel anti-inflammatory androstane derivative
US6759398B2 (en) 2000-08-05 2004-07-06 Smithkline Beecham Corporation Anti-inflammatory androstane derivative
US6777400B2 (en) 2000-08-05 2004-08-17 Smithkline Beecham Corporation Anti-inflammatory androstane derivative compositions
US6777399B2 (en) 2000-08-05 2004-08-17 Smithkline Beecham Corporation Anti-inflammatory androstane derivative compositions
US6787532B2 (en) * 2000-08-05 2004-09-07 Smithkline Beecham Corporation Formulation containing anti-inflammatory androstane derivatives
US6858596B2 (en) 2000-08-05 2005-02-22 Smithkline Beecham Corporation Formulation containing anti-inflammatory androstane derivative
US6858593B2 (en) 2000-08-05 2005-02-22 Smithkline Beecham Corporation Anti-inflammatory androstane derivative compositions
US6878698B2 (en) 2001-04-07 2005-04-12 Glaxo Group Limited Anti-inflammatory androstane derivatives
EP1661556A1 (fr) * 2003-08-20 2006-05-31 Ajinomoto Co., Inc. Preparation medicinale ayant des proprietes de dissolution ameliorees
US7125985B2 (en) 2000-08-05 2006-10-24 Glaxo Group Limited Compounds useful in the manufacture of an anti-inflammatory androstane derivative
US7291608B2 (en) 2001-04-30 2007-11-06 Glaxo Group Limited Anti-inflammatory 17.β.-carbothioate ester derivatives of androstane with a cyclic ester group in position 17.α
US7498321B2 (en) 2000-08-05 2009-03-03 Glaxo Group Limited 17β-carbothioate 17α-arylcarbonyloxyloxy androstane derivative as anti-inflammatory agents
WO2010029374A1 (fr) * 2008-09-12 2010-03-18 Critical Pharmaceuticals Limited Améliorations apportées à l’absorption d’agents thérapeutiques à travers des membranes de muqueuses ou à travers la peau
US8933060B2 (en) 2002-06-14 2015-01-13 Cipla Limited Combination of azelastine and ciclesonide for nasal administration
US20160158152A1 (en) * 2013-07-17 2016-06-09 Council Of Scientific & Industrial Research Pharmaceutical composition for the treatment of diminution of bone tissue
US9931349B2 (en) 2016-04-01 2018-04-03 Therapeuticsmd, Inc. Steroid hormone pharmaceutical composition
US10286077B2 (en) 2016-04-01 2019-05-14 Therapeuticsmd, Inc. Steroid hormone compositions in medium chain oils
US10328087B2 (en) 2015-07-23 2019-06-25 Therapeuticsmd, Inc. Formulations for solubilizing hormones
EP2736485B1 (fr) * 2011-07-29 2019-08-28 Universität Regensburg Solutions aqueuses de substances lipophiles, en particulier de solutions médicamenteuses
WO2021049742A1 (fr) * 2019-09-09 2021-03-18 한국콜마주식회사 Composition cosmétique ayant une excellente absorption percutanée

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US8497258B2 (en) 2005-11-12 2013-07-30 The Regents Of The University Of California Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract
CN100579510C (zh) * 2006-04-13 2010-01-13 新疆维吾尔自治区包虫病临床研究所 新型前体胶束制剂及其生产方法
CA2704957A1 (fr) * 2007-11-13 2009-05-22 Meritage Pharma, Inc. Compositions pour le traitement de l'inflammation gastro-intestinale
US20090131386A1 (en) 2007-11-13 2009-05-21 Meritage Pharma, Inc. Compositions for the treatment of inflammation of the gastrointestinal tract
CN101982168B (zh) * 2010-11-02 2012-05-23 山东大学 一种槲皮素纳米胶束制剂及其制备方法
CN102793678B (zh) * 2011-05-26 2017-06-30 邓世明 一种不含吐温的多烯紫杉醇注射剂的制备方法
JP5456802B2 (ja) * 2012-01-23 2014-04-02 株式会社Ｃａｃ 細胞遊走促進剤及び創傷治療用の経皮吸収剤

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WO2001003703A1 (fr) * 1999-07-12 2001-01-18 Astrazeneca Ab Composition orale comportant en tant que premier principe actif un rofleponide et en tant que second ingredient un antibiotique, destinee a traiter des troubles intestinaux tels que la maladie de crohn
WO2001056578A1 (fr) * 2000-01-31 2001-08-09 Astrazeneca Ab Utilisation de rofleponide pour le traitement du syndrome du colon irritable
US7541350B2 (en) 2000-08-05 2009-06-02 Glaxo Group Limited Formulation containing anti-inflammatory androstane derivative
US6787532B2 (en) * 2000-08-05 2004-09-07 Smithkline Beecham Corporation Formulation containing anti-inflammatory androstane derivatives
US6759398B2 (en) 2000-08-05 2004-07-06 Smithkline Beecham Corporation Anti-inflammatory androstane derivative
US6777400B2 (en) 2000-08-05 2004-08-17 Smithkline Beecham Corporation Anti-inflammatory androstane derivative compositions
US6777399B2 (en) 2000-08-05 2004-08-17 Smithkline Beecham Corporation Anti-inflammatory androstane derivative compositions
US7629335B2 (en) 2000-08-05 2009-12-08 Glaxo Group Limited Anti-inflammatory androstane derivative
US6858596B2 (en) 2000-08-05 2005-02-22 Smithkline Beecham Corporation Formulation containing anti-inflammatory androstane derivative
US6858593B2 (en) 2000-08-05 2005-02-22 Smithkline Beecham Corporation Anti-inflammatory androstane derivative compositions
US7531528B2 (en) 2000-08-05 2009-05-12 Glaxo Group Limited Formulation containing anti-inflammatory androstane derivatives
US6750210B2 (en) 2000-08-05 2004-06-15 Smithkline Beecham Corporation Formulation containing novel anti-inflammatory androstane derivative
US7125985B2 (en) 2000-08-05 2006-10-24 Glaxo Group Limited Compounds useful in the manufacture of an anti-inflammatory androstane derivative
US7132532B2 (en) 2000-08-05 2006-11-07 Glaxo Group Limited Compounds useful in the manufacture of an anti-inflammatory androstane derivative
US7144845B2 (en) 2000-08-05 2006-12-05 Glaxo Group Limited Compounds useful in the manufacture of an anti-inflammatory androstane derivative
US7498321B2 (en) 2000-08-05 2009-03-03 Glaxo Group Limited 17β-carbothioate 17α-arylcarbonyloxyloxy androstane derivative as anti-inflammatory agents
WO2002074282A1 (fr) * 2001-03-15 2002-09-26 Astrazeneca Ab Nouvelle composition
US6878698B2 (en) 2001-04-07 2005-04-12 Glaxo Group Limited Anti-inflammatory androstane derivatives
US7291608B2 (en) 2001-04-30 2007-11-06 Glaxo Group Limited Anti-inflammatory 17.β.-carbothioate ester derivatives of androstane with a cyclic ester group in position 17.α
US7592329B2 (en) 2002-02-04 2009-09-22 Glaxo Group Limited Crystalline complexes of fluticasone-2-furoate
US9901585B2 (en) 2002-06-14 2018-02-27 Cipla Limited Combination of azelastine and fluticasone for nasal administration
US8933060B2 (en) 2002-06-14 2015-01-13 Cipla Limited Combination of azelastine and ciclesonide for nasal administration
US8937057B2 (en) 2002-06-14 2015-01-20 Cipla Limited Combination of azelastine and mometasone for nasal administration
US9259428B2 (en) 2002-06-14 2016-02-16 Cipla Limited Combination of azelastine and fluticasone for nasal administration
EP1661556A1 (fr) * 2003-08-20 2006-05-31 Ajinomoto Co., Inc. Preparation medicinale ayant des proprietes de dissolution ameliorees
EP1661556A4 (fr) * 2003-08-20 2010-05-19 Ajinomoto Kk Preparation medicinale ayant des proprietes de dissolution ameliorees
US20110171140A1 (en) * 2008-09-12 2011-07-14 Critical Pharmaceuticals Limited Absorption of therapeutic agents across mucosal membranes or the skin
US8795634B2 (en) 2008-09-12 2014-08-05 Critical Pharmaceuticals Limited Absorption of therapeutic agents across mucosal membranes or the skin
AU2009290656B2 (en) * 2008-09-12 2015-05-07 Critical Pharmaceuticals Limited Improvements in the absorption of therapeutic agents across mucosal membranes or the skin
WO2010029374A1 (fr) * 2008-09-12 2010-03-18 Critical Pharmaceuticals Limited Améliorations apportées à l’absorption d’agents thérapeutiques à travers des membranes de muqueuses ou à travers la peau
EP2736485B1 (fr) * 2011-07-29 2019-08-28 Universität Regensburg Solutions aqueuses de substances lipophiles, en particulier de solutions médicamenteuses
US20160158152A1 (en) * 2013-07-17 2016-06-09 Council Of Scientific & Industrial Research Pharmaceutical composition for the treatment of diminution of bone tissue
US10596115B2 (en) * 2013-07-17 2020-03-24 Council Of Scientific & Industrial Research Pharmaceutical composition for the treatment of diminution of bone tissue
US10328087B2 (en) 2015-07-23 2019-06-25 Therapeuticsmd, Inc. Formulations for solubilizing hormones
US10912783B2 (en) 2015-07-23 2021-02-09 Therapeuticsmd, Inc. Formulations for solubilizing hormones
US10286077B2 (en) 2016-04-01 2019-05-14 Therapeuticsmd, Inc. Steroid hormone compositions in medium chain oils
US9931349B2 (en) 2016-04-01 2018-04-03 Therapeuticsmd, Inc. Steroid hormone pharmaceutical composition
US10532059B2 (en) 2016-04-01 2020-01-14 Therapeuticsmd, Inc. Steroid hormone pharmaceutical composition
WO2021049742A1 (fr) * 2019-09-09 2021-03-18 한국콜마주식회사 Composition cosmétique ayant une excellente absorption percutanée

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SE9704833D0 (sv) 1997-12-22
ZA9811461B (en) 1999-06-22
CN1283106A (zh) 2001-02-07
EE200000388A (et) 2002-02-15
EP1043973A1 (fr) 2000-10-18
NO20003220L (no) 2000-08-22
AU1993599A (en) 1999-07-12
NZ505073A (en) 2002-09-27
HUP0102365A2 (hu) 2001-11-28
BR9813811A (pt) 2000-10-03
TR200001977T2 (tr) 2000-12-21
AR017220A1 (es) 2001-08-22
IL136880A0 (en) 2001-06-14
HUP0102365A3 (en) 2002-01-28
NO20003220D0 (no) 2000-06-21
PL341361A1 (en) 2001-04-09
SK9532000A3 (en) 2000-11-07
ID26945A (id) 2001-02-22
KR20010024789A (ko) 2001-03-26
JP2001526210A (ja) 2001-12-18
CA2315782A1 (fr) 1999-07-01

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