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WO1987001586A1 - Aerosol - Google Patents

Aerosol Download PDF

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Publication number
WO1987001586A1
WO1987001586A1 PCT/GB1986/000549 GB8600549W WO8701586A1 WO 1987001586 A1 WO1987001586 A1 WO 1987001586A1 GB 8600549 W GB8600549 W GB 8600549W WO 8701586 A1 WO8701586 A1 WO 8701586A1
Authority
WO
WIPO (PCT)
Prior art keywords
aerosol
agent
liposomes
liposome formulation
formulation according
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/GB1986/000549
Other languages
English (en)
Inventor
James Arthur Hayward
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 Vascular Devices Ltd
Original Assignee
Biocompatibles Ltd
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 Biocompatibles Ltd filed Critical Biocompatibles Ltd
Publication of WO1987001586A1 publication Critical patent/WO1987001586A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • 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
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant

Definitions

  • This invention relates to an aerosol comprising liposomes.
  • Aerosols have achieved wide application in clinical respiratory science (cf. Clarke and Pavia, 1984). Therapeutic aerosols have been used for centuries 5 in the treatment of asthma and are still used increasingly in the treatment of chronic obstructive airway diseases. Ventilation-imaging by inhalation of radioaerosols is commonly used in clinical diagnoses.
  • Aerosol deposition is affected by the aerodynamic properties of the inhaled solutes and by the physiology and anatomy of the airway. Particles more
  • _- Drug absorption in the lung may be by diffusion-limited processes or by
  • Phospholipids have been identified in the secretions of every division of the respiratory system (Lopez-Vidriero, 1984).
  • the film facing the alveolar space is rich in highly surface active phospholipids.
  • Pulmonary surfactant is composed of 90 % lipid, most (75 % ⁇ of which is phosphatidylcholine (PC).
  • PC phosphatidylcholine
  • This phospholipid class is present in sufficient quantity to form a monomolecular film over the entire alveolar surface.
  • the surfactant properties of PC lower the surface tension at the air-alveolar interface; the hydrocarbon chains form a hydrophobic surface which acts as a water repellant and helps to keep the alveolar surface dry.
  • Liposomes have been utilised in a variety of parenteral and topical delivery routes, but have not been utilised to prolong solute delivery to the lung.
  • the present invention concerns liposome aerosols especially those containing entrapped drugs and/or imaging agents with the explicit purpose of localising and prolonging delivery to the lung by imposing an additional, natural barrier to the diffusion of free solutes.
  • a previous study (Geiger et al., 1975) has examined the fate of nebulised liposomes of PC as a therapeutic replacement for surfactant deficiency in RDS.
  • the present invention provides an aerosol comprising a carrier fluid and suspended therein liposomes comprising a phospholipid, a therapeutic or diagnostic agent for inhalation being entrapped in the liposome.
  • the phospholipid is a phosphatidyl choline derivative, e.g. distearoyl, dipal itoyl or dimyristoylphosphatidyl choline.
  • the carrier fluid is typically an aqueous medium in the form of droplets containing a number of liposomes, the droplets being suspended in a propellant gas suitable for inhalation, preferably compressed air.
  • a propellant gas suitable for inhalation preferably compressed air.
  • the invention also provides a liposomal formulation for administration by inhalation as an aerosol, the liposomes comprising a phospholipid and a therapeutic or diagnostic agent having activity in or being capable of absorption from the respiratory tract.
  • the invention further provides a process for producing aerosolised liposomal formulations which comprises dispersing liposomes, comprising a phospholipid, a therapeutic or diagnostic agent for inhalation being entrapped in the liposomes, in a carrier fluid.
  • aerosolised liposomes as vehicles for delivery of therapeutic and diagnostic agents in respiratory medicine. This invention is contingent upon the demonstration of liposomal integrity and latency during the nebulisation process. In support of our invention, we provide below evidence for solute entrapment within nebulised, liposomal microcapsules.
  • Aerosolised liposomes according to the invention may be used for diagnostic and therapeutic applications.
  • the nature of the entrapped solute and the lipid composition of the liposomes being varied according to the intended use.
  • an advantage of aerosolised liposomes is the therapeutic value of the carrier itself: phospholipid surfactants have an obligatory role in respiratory function.
  • diagnostic applications for aerosolised liposomes are imaging, functional assessment and provocation or challenge testing.
  • the inclusion of gamma-emitting radionuclides (such as TC ) or radiopacifiers within their enclosed volume is useful for ventilation imaging.
  • Site-directed liposomes may be prepared by attachment of a tissue-specific molecule, such as a monoclonal antibody, to the external face of the liposomes; this technique can be used, for instance, in targetting neoplastic foci. Rates of mucociliary clearance may be determined with non-targeted liposomes which, because of their small size, have access to small airways. Provocation tests, in which the patient is challenged with a suspected allergen, may be enhanced by the use of liposomal carriers. The antigenicity of many allergens is increased by incorporation in liposomes, thereby permitting lower challenge doses of the antigen.
  • a tissue-specific molecule such as a monoclonal antibody
  • Aerosolised liposomes may be used therapeutically in those cases where either the drug itself exhibits toxic effects after clearance from the lung or the efficacy of the drug is diminished by a too-rapid clearance.
  • the systemic effects of such drugs include a number of undesirable side-effects such as suppression of the hypothalamic-pituitary-adrenal axis and the development of Cushingoid features, but these and similar side-effects may be limited by the prolonged confinement of an aerosolised drug within the lung as is afforded by entrapment of the steroid within liposomes.
  • therapeutic aerosolrsed liposomes may be used to deliver prophylactic agents (such as sodium cromoglycate) , mucolytics (such as ri-acetylcysteine) , antibiotics, prostaglandins, vaccines, local and general anaesthetics, bronchodilators, bronchoconstrictors and methyl xanthines.
  • prophylactic agents such as sodium cromoglycate
  • mucolytics such as ri-acetylcysteine
  • antibiotics such as ri-acetylcysteine
  • prostaglandins such as ri-acetylcysteine
  • vaccines such as ri-acetylcysteine
  • local and general anaesthetics such as bronchodilators, bronchoconstrictors and methyl xanthines.
  • Rates of therapeutic or diagnostic agent delivery may be controlled by the lipid composition.
  • a new development in this field is the inclusion of diacetylenic, butadienic, vinylic, acryloylic and methacryloylic moieties into the fatty acyl chains of synthetic lipids forming the liposome.
  • Therapeutic and diagnostic agent delivery from such liposomes may be regulated by controlling the extent of polymerisation of the polymerisable lipids.
  • Distearoylphosphatidylcholine (DSPC) and cholesterol (1:1, moleimole) were dried from chloroform solution onto the walls of a glass tube under a steady stream of Ng.
  • the dried film was dispersed in 8 mis (10 H final lipid concentra tion) of Tris-buffered saline (TBS; 0.06 M Tris, 0.09 M NaCl, pH 7.5) containing 250 mM of the sodium salt of carboxyfluorescein (CF) at 60°C with vigorous vortexing.
  • TBS Tris-buffered saline
  • CF carboxyfluorescein
  • Extravesicular CF was removed by five-times centrifugation (5 minutes/room temperature/15, 000 X g) and washing in TBS. The final pellet was redispersed in 10 ml TBS to yield 8 mM total lipid.
  • DMPC dimyristoylphosphatidyl choline
  • _1 (Medic Aid, Ltd.) operated at 61 min (compressed air), although other methods of nebulisation may be employed.
  • This nebuliser is such that greater than 99.9% of the aerosol is returned to the reservoir via a system of baffles.
  • the integrity of aerosolised liposomes could be assessed by sampling the nebuliser reservoir as a function of time.
  • the integrity of nebulised liposomes was assessed by electron microscopy of negatively stained samples.
  • the extent of entrapment of CF was determined by relief of self-quenching according to the method of Senior and Gregoriadis (1984). Vesicle stability is reflected by the X Latency which is defined as:
  • Table I %CF latency as a function of nebulisation time. The date presented in Table I indicate that there is essentially no effect of nebulisation on liposome stability over a period of 5 minutes. Neither did nebulisation affect the appearance of the liposomes as revealed by electron microscopy.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Otolaryngology (AREA)
  • Pulmonology (AREA)
  • Medicinal Preparation (AREA)

Abstract

Aérosol comprenant un fluide porteur et des liposomes en suspension dans ledit fluide et contenant un phospholipide, un agent thérapeutique ou diagnostique destinés à être inhalés étant enfermés dans lesdits liposomes.
PCT/GB1986/000549 1985-09-17 1986-09-17 Aerosol Ceased WO1987001586A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8522964 1985-09-17
GB858522964A GB8522964D0 (en) 1985-09-17 1985-09-17 Aerosol

Publications (1)

Publication Number Publication Date
WO1987001586A1 true WO1987001586A1 (fr) 1987-03-26

Family

ID=10585297

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1986/000549 Ceased WO1987001586A1 (fr) 1985-09-17 1986-09-17 Aerosol

Country Status (4)

Country Link
EP (1) EP0240511A1 (fr)
JP (1) JPS63501014A (fr)
GB (1) GB8522964D0 (fr)
WO (1) WO1987001586A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0223831A4 (fr) * 1985-05-22 1987-10-12 Liposome Technology Inc Procede et systeme d'inhalation de liposomes.
EP0267050A3 (en) * 1986-11-06 1988-10-26 Clayton Foundation For Research Small particle aerosol liposome and liposome-drug combinations for medical use
EP0410848A1 (fr) * 1989-07-27 1991-01-30 Laboratoire Des Stallergenes Procédé pour combiner un mélange de substances hétérogènes à des liposomes
US5006343A (en) * 1988-12-29 1991-04-09 Benson Bradley J Pulmonary administration of pharmaceutically active substances
US5141674A (en) * 1984-03-08 1992-08-25 Phares Pharmaceutical Research N.V. Methods of preparing pro-liposome dispersions and aerosols
EP0450991A3 (en) * 1990-02-20 1992-12-16 Synthelabo Use of phospholipids in the treatment of obstructive airway diseases
RU2174390C2 (ru) * 1996-10-16 2001-10-10 Рисерч Дивелопмент Фаундейшн Высокодозированные липосомные аэрозольные фармацевтические композиции
US6656497B2 (en) * 1997-06-11 2003-12-02 Lipogel Liposomal vector for active-principle
WO2012016044A1 (fr) 2010-07-28 2012-02-02 Life Technologies Corporation Composés antiviraux contenant un azide
WO2012016048A1 (fr) 2010-07-28 2012-02-02 Life Technologies Corporation Composés antiviraux contenant un azide
WO2013112780A1 (fr) 2012-01-26 2013-08-01 Life Technologies Corporation Méthodes pour augmenter la capacité d'infection des virus
US9980959B2 (en) 2004-05-11 2018-05-29 Biolipox Ab Method and composition for treating rhinitis

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2003225689B2 (en) * 2002-03-05 2009-03-26 Transave, Inc. Methods for entrapment of bioactive agent in a liposome or lipid complex

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1055465A (en) * 1962-09-27 1967-01-18 Vantorex Ltd Allergenic aerosol compositions
EP0087993A1 (fr) * 1982-02-17 1983-09-07 Parfums Christian Dior Mélange pulvérulent de constituants lipidiques et de constituants hydrophobes, procédé pour le préparer, phases lamellaires lipidiques hydratées et procédé de fabrication, compositions pharmaceutiques ou cosmetiques comportant des phases lamellaires lipidiques hydratées
FR2550706A1 (fr) * 1983-08-17 1985-02-22 Sterwin Ag
EP0136812A2 (fr) * 1983-08-25 1985-04-10 Technicare Corporation Réactifs pour l'augmentation du contraste dans la formation d'images par résonance magnétique nucléaire
WO1986001714A1 (fr) * 1984-09-17 1986-03-27 Riker Laboratories, Inc. Systeme d'administration aerosol de liposomes pour la liberation entretenue de medicaments
EP0158441B1 (fr) * 1984-03-08 1992-05-06 Phares Pharmaceutical Holland B.V. Composition formatrice de liposomes

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1055465A (en) * 1962-09-27 1967-01-18 Vantorex Ltd Allergenic aerosol compositions
EP0087993A1 (fr) * 1982-02-17 1983-09-07 Parfums Christian Dior Mélange pulvérulent de constituants lipidiques et de constituants hydrophobes, procédé pour le préparer, phases lamellaires lipidiques hydratées et procédé de fabrication, compositions pharmaceutiques ou cosmetiques comportant des phases lamellaires lipidiques hydratées
FR2550706A1 (fr) * 1983-08-17 1985-02-22 Sterwin Ag
EP0136812A2 (fr) * 1983-08-25 1985-04-10 Technicare Corporation Réactifs pour l'augmentation du contraste dans la formation d'images par résonance magnétique nucléaire
EP0158441B1 (fr) * 1984-03-08 1992-05-06 Phares Pharmaceutical Holland B.V. Composition formatrice de liposomes
WO1986001714A1 (fr) * 1984-09-17 1986-03-27 Riker Laboratories, Inc. Systeme d'administration aerosol de liposomes pour la liberation entretenue de medicaments

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 97, No. 10, September 1982 (Columbus, Ohio, US) W.D. SEUFERT et al.: "Dipalmitoryl-Phosphatidylcholine Dissolved in Ethanol Forms Highly Elastic Monolayers", see page 414, Abstract No. 78826w, & Can. J. Physiol. Pharmacol. 1982, 60(6), 862-4 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5141674A (en) * 1984-03-08 1992-08-25 Phares Pharmaceutical Research N.V. Methods of preparing pro-liposome dispersions and aerosols
EP0223831A4 (fr) * 1985-05-22 1987-10-12 Liposome Technology Inc Procede et systeme d'inhalation de liposomes.
EP0267050A3 (en) * 1986-11-06 1988-10-26 Clayton Foundation For Research Small particle aerosol liposome and liposome-drug combinations for medical use
AU600766B2 (en) * 1986-11-06 1990-08-23 Research Development Foundation Small particle aerosol liposome and liposome-drug combinations for medical use
US5006343A (en) * 1988-12-29 1991-04-09 Benson Bradley J Pulmonary administration of pharmaceutically active substances
EP0451215A4 (en) * 1988-12-29 1991-11-13 Bradley J Benson Pulmonary administration of pharmaceutically active substances
EP0410848A1 (fr) * 1989-07-27 1991-01-30 Laboratoire Des Stallergenes Procédé pour combiner un mélange de substances hétérogènes à des liposomes
EP0450991A3 (en) * 1990-02-20 1992-12-16 Synthelabo Use of phospholipids in the treatment of obstructive airway diseases
RU2174390C2 (ru) * 1996-10-16 2001-10-10 Рисерч Дивелопмент Фаундейшн Высокодозированные липосомные аэрозольные фармацевтические композиции
US6656497B2 (en) * 1997-06-11 2003-12-02 Lipogel Liposomal vector for active-principle
US9980959B2 (en) 2004-05-11 2018-05-29 Biolipox Ab Method and composition for treating rhinitis
WO2012016044A1 (fr) 2010-07-28 2012-02-02 Life Technologies Corporation Composés antiviraux contenant un azide
WO2012016048A1 (fr) 2010-07-28 2012-02-02 Life Technologies Corporation Composés antiviraux contenant un azide
US9144575B2 (en) 2010-07-28 2015-09-29 Life Technologies Corporation Anti-viral azide containing compounds
US9855287B2 (en) 2010-07-28 2018-01-02 Life Technologies Corporation Anti-viral azide containing compounds
US10179143B2 (en) 2010-07-28 2019-01-15 Life Technologies Corporation Anti-viral azide containing compounds
US10632133B2 (en) 2010-07-28 2020-04-28 The Johns Hopkins University Anti-viral azide containing compounds
WO2013112780A1 (fr) 2012-01-26 2013-08-01 Life Technologies Corporation Méthodes pour augmenter la capacité d'infection des virus

Also Published As

Publication number Publication date
GB8522964D0 (en) 1985-10-23
EP0240511A1 (fr) 1987-10-14
JPS63501014A (ja) 1988-04-14

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