WO1992011016A1 - Composition pharmaceutique contenant de l'uridine-5'-triphosphate et destinee au traitement de la mucoviscidose - Google Patents

Composition pharmaceutique contenant de l'uridine-5'-triphosphate et destinee au traitement de la mucoviscidose Download PDF

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Publication number
WO1992011016A1
WO1992011016A1 PCT/GB1991/002299 GB9102299W WO9211016A1 WO 1992011016 A1 WO1992011016 A1 WO 1992011016A1 GB 9102299 W GB9102299 W GB 9102299W WO 9211016 A1 WO9211016 A1 WO 9211016A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
utp
acceptable salt
cystic fibrosis
composition
Prior art date
Application number
PCT/GB1991/002299
Other languages
English (en)
Inventor
Christopher Ernest Pollard
Dale Michael Jackson
Original Assignee
Fisons Plc
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 Fisons Plc filed Critical Fisons Plc
Publication of WO1992011016A1 publication Critical patent/WO1992011016A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof

Definitions

  • This invention relates to a new method of symptomatic treatment of cystic fibrosis using a known compound, and to pharmaceutical compositions containing that compound.
  • cystic fibrosis A major symptom of cystic fibrosis is the accumulation of thick mucus in the airways, particularly the lungs, which is difficult for a patient to expectorate. This thick mucus is readily colonized by bacteria, for example Pseudomonas aeruginosa, leading to chronic infection and scarring of the lung tissue. The resulting impairment of lung function is the usual cause of death, and the majority of patients die before reaching 20 years of age.
  • Uridine 5'-triphosphate (hereinafter referred to as UTP) has been indicated in the treatment of neuralgia and related disorders, and is present in a lyophilized powder sold under the name 'Mionevrasi Forte' in Italy. In use, the powder is dissolved and injected intramuscularly.
  • a pharmaceutical composition adapted for inhalation to the lungs comprising UTP, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the composition may be adapted for inhalation to the lungs to the exclusion of all other modes of administration.
  • Pharmaceutically acceptable salts of UTP include alkali and alkaline earth metal salts, for example sodium, calcium, and ammonium salts.
  • a specific salt which may be mentioned is the trisodium salt, particularly its dihydrate.
  • compositions according to the invention include solutions for nebulization, non-pressurized powders and pressurized aerosols.
  • solutions for nebulization are aqueous solutions, more preferably isotonic aqueous solutions.
  • the pH of such a solution is preferably in the range 6-8, for example 7.
  • Preferred concentrations of UTP, or a pharmaceutically acceptable salt thereof, in a solution for nebulization are in the range 5x10 " * to 5xl0 "5 M, for example lxlO ⁇ M.
  • UTP In non-pressurized powder and pressurized aerosol compositions UTP, or a pharmaceutically acceptable salt thereof, preferably has a mass median diameter in the range l-10 ⁇ m, more preferably 2-4 ⁇ m. Such fine particles are able to penetrate deeply into the lungs, allowing a lower dosage of drug to be administered for an equivalent and longer lasting effect. Particles of UTP, or a pharmaceutically acceptable salt thereof, within the above range of mass median diameters form a second aspect of the invention.
  • Particles according to the second aspect of the invention may be prepared by grinding or milling using conventional methods, and are preferably dried thoroughly before being incorporated into an inhalation composition.
  • 'mass median diameter is meant the diameter such that half the particulate mass is in particles of lesser diameter and half in particles of greater diameter.
  • the mass median diameter is essentially a Stokes diameter and may be determined using a Joyce Loebl sedimentation disc centrifuge either in a two-layer or line start photometric mode (J Bagness and A Ottaway, Proc Soc Analyt Chem, Part 4, Vol 9, 1972, pages 83-86).
  • Non-pressurized powder compositions preferably contain a pharmaceutically acceptable carrier having a mass median diameter of up to 400 ⁇ m.
  • a preferred carrier is lactose, for example crystalline lactose.
  • Non-pressurised powder compositions preferably contain from 2 to 50% by weight, more preferably from 5 to 25% by weight, and particularly from 10 to 15% by weight of the active ingredient, and from 50 to 98% by weight, more especially from 75 to 95% by weight of the carrier.
  • Pressurized aerosol compositions will generally contain a pharmaceutically acceptable aerosol propellant, which may be a compressed gas such as nitrogen, or a liquefied gas propellant.
  • a pharmaceutically acceptable aerosol propellant which may be a compressed gas such as nitrogen, or a liquefied gas propellant.
  • pressurized aerosol compositions contain from 0.5 to 5%, for example from 1 to 3.5% by weight, of finely divided active ingredient.
  • Liquefied gas propellant media are preferably such that the active ingredient does not dissolve therein to a substantial extent.
  • Suitable liquefied gas propellants which may be employed are dimethyl ether and alkanes containing up to five carbon atoms, for example butane or pentane, or a lower alkyl chloride, eg methyl, ethyl or propyl chlorides.
  • the most suitable liquefied gas propellants are the fluorinated and fluorochlorinated lower alkanes such as are sold under the Registered Trade Mark 'Freon'.
  • the use of the latter type of propellants is a matter of current concern, and they may be replaced by a suitable substitute when such is available. Mixtures of the above mentioned propellants may suitably be employed.
  • the composition may also contain a surface active agent.
  • the surface active agent may be a liquid or solid non-ionic surface active agent or may be a solid anionic surface active agent. It is preferred to use the solid anionic surface active agent in the form of the sodium salt.
  • a preferred solid anionic surface active agent is sodium dioctyl-sulphosuccinate.
  • the liquid non-ionic surface-active agent to comprise from 0.1 to 2%, and more preferably from 0.2 to 1%, by weight of the total composition. Such compositions tend to be more physically stable on storage.
  • Pressurized aerosol compositions may be prepared by mixing the various components at a temperature and pressure at which the propellant is in the liquid phase and the active ingredient is in the solid phase, and then filled into aerosol canisters by conventional methods.
  • a method of symptomatic treatment of cystic fibrosis which comprises administering a therapeutically effective amount of UTP, or a pharmaceutically acceptable salt thereof, to a patient suffering from such a condition.
  • the preferred mode of administration is by inhalation to the lung.
  • a suitable dose for administration by inhalation is in the range 1 to lOmg per day, for example 5mg per day.
  • the efficacy of UTP, or a pharmaceutically acceptable salt thereof, in the symptomatic treatment of cystic fibrosis may be enhanced by using in conjunction with drugs having a sodium ion channel blocking effect.
  • a sodium ion channel blocker which may be mentioned is amiloride.
  • the sorbitan ester is dispersed in up to half the propellant 12 at -40°C while stirring with a high dispersion mixer.
  • the active ingredient is added to the resulting dispersion and disperses in it.
  • the balance of the propellant 12 is then added at -50°C, followed by the 5 propellant 114 also cooled to -50°C.
  • the resulting mixtures are then filled into vials onto which valves, eg metering valves, are subsequently crimped.
  • a portion of rabbit tracheal epithelium was mounted in an Ussing chamber.
  • the chamber was connected via electrodes to a voltage clamp system, which allows the 'short circuit current' to be measured.
  • This short circuit current is equal to the sum of all active ion transport processes taking place in the tissue.
  • the 0 dominant ion transport processes are chloride ion secretion and sodium ion absorption.
  • amiloride a sodium ion channel blocker
  • the short circuit current was measured at a variety of ATP and UTP concentrations, 5 and a dose response curve then constructed, allowing ED 50 values (the concentration at which 50% of the maximum response is observed) to be calculated.
  • ED S0 values of ATP and UTP were found to be 2x10 ⁇ and 2xlO '7 M respectively. This suggests that UTP will be substantially more efficacious in thinning mucus in cystic o fibrosis patients than ATP.

Abstract

L'uridine-5'-triphosphate, ou un sel pharmaceutiquement acceptable de celle-ci, est utile au traitement symptomatique de la mucoviscidose lorsqu'on l'aspire dans les poumons. Des compositions pharmaceutiques adaptées à ce traitement sont, par exemple, les solutions à nébuliser, les poudres non pressurisées et les aérosols sous pression.
PCT/GB1991/002299 1990-12-22 1991-12-20 Composition pharmaceutique contenant de l'uridine-5'-triphosphate et destinee au traitement de la mucoviscidose WO1992011016A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB90/27968.8 1990-12-22
GB909027968A GB9027968D0 (en) 1990-12-22 1990-12-22 Method of treatment

Publications (1)

Publication Number Publication Date
WO1992011016A1 true WO1992011016A1 (fr) 1992-07-09

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1991/002299 WO1992011016A1 (fr) 1990-12-22 1991-12-20 Composition pharmaceutique contenant de l'uridine-5'-triphosphate et destinee au traitement de la mucoviscidose

Country Status (3)

Country Link
GB (1) GB9027968D0 (fr)
IE (1) IE914498A1 (fr)
WO (1) WO1992011016A1 (fr)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5420116A (en) * 1991-06-05 1995-05-30 Synthelabo Pharmaceutical compositions for the treatment of disorders of the respiratory tract
EP0663830A1 (fr) * 1991-06-19 1995-07-26 The University Of North Carolina At Chapel Hill Methode de traitement de maladie pulmonaire a l'aide d'uridine-triphosphates
DE4425255A1 (de) * 1994-07-16 1996-01-18 Asta Medica Ag Formulierung zur inhalativen Applikation
US5596088A (en) * 1993-10-15 1997-01-21 The University Of North Carolina At Chapel Hill DNA Encoding the human P2U receptor and null cells expressing P2U receptors
WO1998003182A2 (fr) * 1996-07-23 1998-01-29 Inspire Pharmaceuticals, Inc. Utilisation d'uridine triphosphates et de composes apparentes pour prevenir et traiter la pneumonie chez des patients immobilises
US5726160A (en) * 1995-04-13 1998-03-10 Milkhaus Laboratories, Inc. Methods for treating respiratory disease
WO1998019685A1 (fr) * 1996-11-07 1998-05-14 Inspire Pharmaceuticals, Inc. Traitement de la bronchite avec des uridine triphosphates et composes associes
EP0841900A1 (fr) * 1995-07-31 1998-05-20 The University Of North Carolina At Chapel Hill Procede pour diagnostiquer des maladies pulmonaires
US5789391A (en) * 1996-07-03 1998-08-04 Inspire Pharmaceuticals, Inc. Method of treating sinusitis with uridine triphosphates and related compounds
WO1999001138A1 (fr) * 1996-07-03 1999-01-14 Inspire Pharmaceuticals, Inc. Formulation pharmaceutique d'uridine triphosphate pouvant etre administree en faible volume
WO1999009998A1 (fr) * 1997-08-29 1999-03-04 The University Of North Carolina At Chapel Hill Utilisation d'uridine 5'-diphosphate et d'analogues de ces derniers pour le traitement de maladies pulmonaires
WO1999032085A2 (fr) * 1997-12-23 1999-07-01 Inspire Pharmaceuticals, Inc. Nouvelles compositions pharmaceutiques d'uridine triphosphate
US5948768A (en) * 1995-04-13 1999-09-07 Milkhaus Laboratory Treatment of otitis media by sublingual administration of DNA
US6096721A (en) * 1995-04-13 2000-08-01 Milkhaus Laboratory, Inc. Method for treating mucositis by sublingual administration of DNA
US6423694B1 (en) * 1996-02-21 2002-07-23 Inspire Pharmaceuticals, Inc. Method of treating otitis media with uridine triphosphates and related compounds
US6998121B2 (en) 2003-01-23 2006-02-14 Milkhaus Laboratory, Inc. Method of treatment of connective tissue disorders by administration of streptolysin O
US7629312B2 (en) 2003-01-23 2009-12-08 Milkhaus Laboratory, Inc. Method of treatment of tendonitis by administration of streptolysin O

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE699421A (fr) * 1966-06-03 1967-12-04

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE699421A (fr) * 1966-06-03 1967-12-04

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
"The Merck Index", 1989, 11th edition, pages 1554-1555, Merck & Co., Inc., Rayway, NJ, US, see article: "Uridine 5'-triphosphate" *
British Journal of Pharmacology, vol. 103, no. 3, July 1991, S.J. MASON et al.: "Regulation of transepithelial ion transport and intracellular calcium by extracellular ATP in human normal and cystic fibrosis airway epithelium", pages 1649-1656, see the whole article *
J.E.F. REYNOLDS: "Martindale - The extra pharmacopoeia", 29th edition, 1989, page 1627, The Pharmaceutical Press, London, GB, see article: "Uridine triphosphate" *
Nature, vol. 322, 31 July 1986, M.J. WELSH et al.: "Chloride and potassium channels in cystic fibrosis airway epithelia", pages 467-470, see the whole article *
New England Journal of Medicine, vol. 325, no. 8, 22 August 1991, M.R. KNOWLES et al.: "Activation by extracellular nucleotides of chloride secretion in the airway epithelia of patients with cystic fibrosis", pages 533-538, see the whole article *
P.H. LIST et al.: "Hagers Handbuch der pharmazeutischen Praxis", 1971, vol. 7, part A: "Arzneiformen", pages 339-341, Springer-Verlag, Berlin, DE, see pages 339-341 *
Pediatr. Pulmonol., supp. 5, 1990, L.L. CLARKE et al.: "Activation of an apical Cl conductance by exogenous ATP in cystic fibrosis airway epithelium", page 216, see the whole article *
Science, vol. 233, no. 4763, 1 August 1986, R.A. FRIZZELL et al.: "Altered regulation of airway epithelial cell chloride channels in cystic fibrosis", pages 558-560, see the whole article *

Cited By (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5420116A (en) * 1991-06-05 1995-05-30 Synthelabo Pharmaceutical compositions for the treatment of disorders of the respiratory tract
EP0663830A1 (fr) * 1991-06-19 1995-07-26 The University Of North Carolina At Chapel Hill Methode de traitement de maladie pulmonaire a l'aide d'uridine-triphosphates
EP0663830A4 (fr) * 1991-06-19 1996-01-24 Univ North Carolina Methode de traitement de maladie pulmonaire a l'aide d'uridine-triphosphates.
US5596088A (en) * 1993-10-15 1997-01-21 The University Of North Carolina At Chapel Hill DNA Encoding the human P2U receptor and null cells expressing P2U receptors
US5607836A (en) * 1993-10-15 1997-03-04 The Curators Of The University Of Missouri Methods of detecting compounds which bind to the P2U receptor
US5691156A (en) * 1993-10-15 1997-11-25 The University Of North Carolina At Chapel Hill Method of inhibiting cell growth with the P2U receptor
US6284287B1 (en) 1994-07-16 2001-09-04 Asta Medica Ag Particulate formulation for administration by inhalation
DE4425255A1 (de) * 1994-07-16 1996-01-18 Asta Medica Ag Formulierung zur inhalativen Applikation
US6100244A (en) * 1995-04-13 2000-08-08 Milkhaus Laboratory, Inc. Method for treating respiratory distress by sublingual administration of DNA
US5726160A (en) * 1995-04-13 1998-03-10 Milkhaus Laboratories, Inc. Methods for treating respiratory disease
US5955442A (en) * 1995-04-13 1999-09-21 Milkhaus Laboratory, Inc. Methods for treating respiratory disease
US5948768A (en) * 1995-04-13 1999-09-07 Milkhaus Laboratory Treatment of otitis media by sublingual administration of DNA
US6096721A (en) * 1995-04-13 2000-08-01 Milkhaus Laboratory, Inc. Method for treating mucositis by sublingual administration of DNA
EP0841900A4 (fr) * 1995-07-31 1998-06-10
US6133247A (en) * 1995-07-31 2000-10-17 University Of North Carolina At Chapel Hill Method of detecting lung disease
US5902567A (en) * 1995-07-31 1999-05-11 The University Of North Carolina At Chapel Hill Method of detecting lung disease
US6214536B1 (en) 1995-07-31 2001-04-10 The University Of North Carolina At Chapel Hill Method of detecting lung disease
EP0841900A1 (fr) * 1995-07-31 1998-05-20 The University Of North Carolina At Chapel Hill Procede pour diagnostiquer des maladies pulmonaires
US6423694B1 (en) * 1996-02-21 2002-07-23 Inspire Pharmaceuticals, Inc. Method of treating otitis media with uridine triphosphates and related compounds
US5789391A (en) * 1996-07-03 1998-08-04 Inspire Pharmaceuticals, Inc. Method of treating sinusitis with uridine triphosphates and related compounds
WO1999001138A1 (fr) * 1996-07-03 1999-01-14 Inspire Pharmaceuticals, Inc. Formulation pharmaceutique d'uridine triphosphate pouvant etre administree en faible volume
US5981506A (en) * 1996-07-03 1999-11-09 Inspire Pharmaceuticals, Inc. Method for treating sinusitis with uridine triphosphates and related compounds
US5958897A (en) * 1996-07-03 1999-09-28 Inspire Pharmaceuticals, Inc. Method of treating sinusitis with uridine triphosphates and related compounds
US5968913A (en) * 1996-07-03 1999-10-19 Inspire Pharmaceuticals, Inc. Pharmaceutical compositions of uridine triphosphate
US5972904A (en) * 1996-07-03 1999-10-26 Inspire Pharmaceuticals, Inc. Method of treating sinusitis with uridine triphosphates and related compounds
WO1998003182A3 (fr) * 1996-07-23 1998-05-14 Inspire Pharmaceuticals Inc Utilisation d'uridine triphosphates et de composes apparentes pour prevenir et traiter la pneumonie chez des patients immobilises
AU727790B2 (en) * 1996-07-23 2000-12-21 Inspire Pharmaceuticals, Inc. Use of uridine triphosphates and related compounds for the prevention and treatment of pneumonia in immobilized patients
US6703376B2 (en) 1996-07-23 2004-03-09 Inspire Pharmaceuticals, Inc. Use of uridine triphosphates and related compounds for the prevention and treatment of pneumonia in immobilized patients
WO1998003182A2 (fr) * 1996-07-23 1998-01-29 Inspire Pharmaceuticals, Inc. Utilisation d'uridine triphosphates et de composes apparentes pour prevenir et traiter la pneumonie chez des patients immobilises
US5763447A (en) * 1996-07-23 1998-06-09 Inspire Pharmaceuticals Method of preventing or treating pneumonia in immobilized patients with uridine triphosphates and related compounds
WO1998019685A1 (fr) * 1996-11-07 1998-05-14 Inspire Pharmaceuticals, Inc. Traitement de la bronchite avec des uridine triphosphates et composes associes
US6159952A (en) * 1996-11-07 2000-12-12 Inspire Pharmaceuticals, Inc. Method of treating bronchitis with uridine triphosphate and related compounds
AU744981B2 (en) * 1996-11-07 2002-03-07 Merck Sharp & Dohme Corp. Method of treating bronchitis with uridine triphosphates and related compounds
US6143279A (en) * 1997-08-29 2000-11-07 The University Of North Carolina At Chapel Hill Uridine 5'-diphosphate and analogs useful for treating lung diseases
WO1999009998A1 (fr) * 1997-08-29 1999-03-04 The University Of North Carolina At Chapel Hill Utilisation d'uridine 5'-diphosphate et d'analogues de ces derniers pour le traitement de maladies pulmonaires
US6022527A (en) * 1997-08-29 2000-02-08 The University Of North Carolina At Chapel Hill Method of treating lung diseases with uridine 5'-diphosphate and analogs thereof
AU747350B2 (en) * 1997-12-23 2002-05-16 Inspire Pharmaceuticals, Inc. Novel pharmaceutical compositions of uridine triphosphate
WO1999032085A2 (fr) * 1997-12-23 1999-07-01 Inspire Pharmaceuticals, Inc. Nouvelles compositions pharmaceutiques d'uridine triphosphate
WO1999032085A3 (fr) * 1997-12-23 1999-09-02 Inspire Pharmaceuticals Inc Nouvelles compositions pharmaceutiques d'uridine triphosphate
US6998121B2 (en) 2003-01-23 2006-02-14 Milkhaus Laboratory, Inc. Method of treatment of connective tissue disorders by administration of streptolysin O
US7196058B2 (en) 2003-01-23 2007-03-27 Milkhaus Laboratory, Inc. Method of treatment of conditions by administration of streptolysin O
US7629312B2 (en) 2003-01-23 2009-12-08 Milkhaus Laboratory, Inc. Method of treatment of tendonitis by administration of streptolysin O

Also Published As

Publication number Publication date
IE914498A1 (en) 1992-07-01
GB9027968D0 (en) 1991-02-13

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