WO2004004685A1 - Systemes modeles d'aerosol pour suspension medicinale - Google Patents

Systemes modeles d'aerosol pour suspension medicinale Download PDF

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Publication number
WO2004004685A1
WO2004004685A1 PCT/US2003/018529 US0318529W WO2004004685A1 WO 2004004685 A1 WO2004004685 A1 WO 2004004685A1 US 0318529 W US0318529 W US 0318529W WO 2004004685 A1 WO2004004685 A1 WO 2004004685A1
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WO
WIPO (PCT)
Prior art keywords
pigment
medicinal aerosol
model system
aerosol model
propellant
Prior art date
Application number
PCT/US2003/018529
Other languages
English (en)
Inventor
Philip A. Jinks
Original Assignee
3M Innovative Properties Company
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 3M Innovative Properties Company filed Critical 3M Innovative Properties Company
Priority to AU2003243522A priority Critical patent/AU2003243522A1/en
Publication of WO2004004685A1 publication Critical patent/WO2004004685A1/fr

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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
    • A61K9/0012—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
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]

Definitions

  • the present invention relates to medicinal suspension aerosol model systems and their use, in particular for experimental studies and/or screening relating to formulations and/or hardware systems performance in medicinal aerosol dispensing systems, in particular metered dose medicinal aerosol dispensers, such as pressurized metered dose inhalers.
  • Such aerosol formulations generally comprise medicament, one or more propellants, (e.g. chlorofluorocarbons and more recently hydrogen-containing fluorocarbons, such as propellant 134a (CF 3 CH 2 F) and propellant 227 (CF 3 CHFCF 3 )), as well as any additional excipients or components.
  • propellants e.g. chlorofluorocarbons and more recently hydrogen-containing fluorocarbons, such as propellant 134a (CF 3 CH 2 F) and propellant 227 (CF 3 CHFCF 3 )
  • the medicament may be in solution or more often the medicament may be in particulate form dispersed in the propel! ant(s).
  • a model medicinal suspension aerosol system can be provided, which has similar properties to or can mimic medicinal suspension aerosol formulations and can be thus advantageously used for experimental studies and/or screenings of formulation and/or hardware system technology.
  • a medicinal aerosol model system comprising a composition comprising particles of a pigment dispersed in a propellant.
  • compositions comprising particles of a pigment dispersed in a propellant as a medicinal aerosol model system for experimental studies and/or screenings of formulations and/or hardware systems for medicinal aerosol dispensers.
  • Such model medicinal aerosol systems are advantageous, in that a number of studies and/or screenings can be performed without the necessary use of the medicament. This is especially beneficial during initial stages of development projects in which substantial number of preliminary testing is performed and/or when the medicament under investigation is expensive, available in limited quantities, sensitive, or extremely potent.
  • Such model medicinal aerosol systems are particular advantageous for rapid screenings, for example visual assessment of dispersion properties including e.g. properties relating to uniformity of particle dispersion, sedimentation, creaming, particle-particle interactions, and in case of dispersion of two or more compounds, co-flocculation, dispersion homogeneity, etc.
  • the pigment can be similarly assayed like the medicament, with the additional advantage that the pigment can often be assayed by
  • the pigment in particular colored or black pigment, allows for a supplemental visual assessment of the test-system in conjunction with assay-type testing.
  • the use of model aerosol systems according to the invention can greatly facilitate the identification of the underlying problem by allowing an easy, quick visual assessment of the system under test.
  • Medicinal aerosol model systems comprise a composition comprising particles of a pigment dispersed in a propellant.
  • pigment here is understood to include inorganic or organic colored, white or black coloring agents, dyes as well as pigments.
  • the pigment is a colored or a black pigment, i.e. a non-white pigment.
  • the pigment is an organic pigment.
  • the pigment is non-toxic, more desirably a food grade pigment.
  • Suitable pigments include for example Methylene Blue, Amaranth, Ponceau 3R, Ponceau SX as well as a number of food grade pigments, such as Brilliant Blue FCF, Fast Green FCF, Allura Red AC, Indigo-Carmine (Indigotine), Erythrosine, Tartrazine, Sunset Yellow
  • FCF Citrus Red 2, Orange B, Annatto, Canthaxanthin, Carmine (Cochineal Extract), Curcumin, Quinoline Yellow and Brilliant Black BN.
  • the pigment has low solubility (50 ⁇ g/g or lower), more desirably is substantially insoluble (10 ⁇ g/g or lower) or most desirably completely insoluble, in the liquefied propellant(s) or if applicable the liquefied propellant system (i.e. propellant(s) including any excipients, such as co-solvent (e.g. ethanol) or surfactant).
  • propellant(s) including any excipients, such as co-solvent (e.g. ethanol) or surfactant).
  • the propellant is a propellant typically used in medicinal aerosol formulations, such as chlorofluorocarbons, such as CFC 11 (CC1 3 F), CFC 12 (CC1 2 F 2 ) and CFC 114 (CC1F 2 CC1F 2 ) and more particularly, hydrofluoroalkanes such as propellant 134a (CF CH 2 F) and propellant 227 (CF 3 CHFCF 3 ).
  • chlorofluorocarbons such as CFC 11 (CC1 3 F), CFC 12 (CC1 2 F 2 ) and CFC 114 (CC1F 2 CC1F 2 ) and more particularly, hydrofluoroalkanes such as propellant 134a (CF CH 2 F) and propellant 227 (CF 3 CHFCF 3 ).
  • the pigment is soluble in an organic solvent, such as methanol, suitable for use with such assaying technique.
  • Assay-type testing can be further facilitated by selecting a pigment, which is water-soluble.
  • a pigment which is water-soluble.
  • a number of the pigments listed above are water-soluble, including but not limited to Methylene Blue, Amaranth, Ponceau 3R, Ponceau SX, Brilliant Blue FCF, Fast Green FCF, Allura Red AC, Indigo-Carmine, Erythrosine, Tartrazine, Sunset Yellow FCF, Carmine and Quinoline Yellow.
  • An aqueous solution such as 0.01 M HC1 acid or 0.01 M ⁇ aOH solution, may also be use as a solvent for the pigment in assay-type testing.
  • the pigment is in form of a solid, which can be readily processed in a similar manner as medicament, e.g. ball milled, fluid energy milled.
  • the particle size of pigment generally corresponds to the particle size of medicament in suspension aerosol to be modeled.
  • the particles of pigment are generally micronized particles or particles processed by other methods, preferably having a mass median diameter equal to or less than 10 micron, more particularly from 1 to 10 micron, even more particularly from 1 to 5 micron.
  • Mass median diameter can be determined using any conventional particle size measurement method known to those skilled in the art, such as laser diffraction.
  • pigment particles having a mass median diameter of less than one micron, more particularly nano-sized particles may also be applicable.
  • the density of the pigment is similar to that of medicaments used in aerosol formulations.
  • the density preferably ranges from 1.00 to 1.50 g/cm 3 at 20°C, more preferably 1.05 to 1.40 g/cm 3 .
  • Density can be determined by any conventional method known to those skilled in the art, such as helium pycnometry.
  • the density of the pigment may be selected to match or closely match (e.g. ⁇ up to 0.05 g/cm 3 ) the density of the specific drug being modeled.
  • the density may be appropriately selected as to represent an average or middle value, for example from about 1.20 to about 1.37 g/cm 3 .
  • Methylene Blue and Brilliant Blue have been found to be desirably suitable in regard to density (both approximately 1.33 g/cm 3 ), particle processing, and solubility characteristics (in propellant such as 134a and/or 227 as well as in water) as well as color contrast (on white or metal surfaces) for ease in visual observations and adsorption characteristics for spectrophotometry or colorimetry, and thus particularly suitable for general modeling of medicinal suspension formulations.
  • model medicinal aerosol suspension systems according to the invention can be advantageously used in a wide range of experimental studies, testing or screenings relating to formulation and/or dispensing hardware technology for medicinal aerosol administration.
  • model medicinal aerosol systems can be used in visual assessment of dispersion properties or dynamics of suspension formulations including e.g. properties relating to uniformity of particle dispersion, sedimentation, creaming, particle-particle interactions as well as particle-surface interactions.
  • Their use is particular advantageous for visual assessment of dispersion characteristics of medicinal suspension formulations comprising two (or more) dispersed particulate components, e.g. two suspended drugs or a drug dispersed together with a particulate bulking agent.
  • modeling compositions are used in which one of the particulate components is replaced with an appropriate selected particulate pigment, preferentially a colored or black pigment. Due to the presence of two colors (e.g. a blue pigment versus a (typically) white drug), co-flocculation and dispersion homogeneity of the two components can be readily visually observed and assessed.
  • model medicinal aerosol systems can be effectively used for assay-type studies or testing, such as deposition, loss of dose, uniformity of content, through life drug delivery, simulated patient use and aerodynamic spray characterization (using for example an Andersen Cascade Impactor or a Twin Stage Impinger).
  • assay-type testing can be desirably supplemented with a visual analysis or assessment of the system under testing.
  • a visual analysis or assessment of the system under testing For example, in typical medicament deposition studies, after a determined period of storage of the medicinal aerosol formulation in a particular dispenser, the formulation is dispensed from the dispenser and the hardware components of dispenser are worked up with organic solvent to dissolve any medicament, which deposited or accumulated. After assaying with HPLC, the loss of medicament from the formulation due to deposition, accumulation, etc. can be quantified. Such determination of loss due to deposition, etc.
  • model systems according to the invention can be applied to support development projects (as initial testing models) or alternatively to aid in problem detection when the results of testing of the medicament formulation are anomalous or indicate poor performance.
  • model systems can aid in differentiating between variability, which may be caused by analytical methods or may be inherent in the system being tested.
  • model systems according to the invention can be used to analyze deposition patterns on components of the dispensing system.
  • the model systems can be advantageously applied in development work and/or trouble shooting for valves, in particular metering valves, e.g. for studying flow paths including filling or leaking pathways, for example either by visual tracking or deposition patterns.
  • the model systems are particularly advantageous for testing metered dose medicinal aerosol dispensers, more particularly pressurized metered dose inhalers, which typically have a metering volume of 100 ⁇ l or less.
  • the model formulations with Brilliant Blue allow a visual assessment of the co-flocculation process for a two component suspension system and show that, despite differences in density between lactose and Brilliant Blue, the co-flocculation remains stable.
  • model formulations of the same composition were prepared in which Brilliant Blue was used rather than the drug.
  • Brilliant Blue was used rather than the drug.
  • metered dose inhalers containing the model formulation also showed high doses, again near end of life, demonstrating that the Brilliant Blue composition behaves similar to the experimental drug formulation and can act as a model system thereof.
  • a visual examination of the components of the inhalers used in the testing showed clearly a build-up of the blue pigment in a region of dead volume within the deep drawn metal valve stem of the dispenser valve. The visual detection of such a deposition or accumulation when using drug containing formulations was difficult if not impossible, due to the difficulty of recognizing white on the surface of a metal component.

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

Abstract

L'invention concerne la fabrication et l'utilisation de systèmes modèles d'aérosol pour suspension médicinale comprenant une composition contenant des particules d'un pigment dispersé dans un gaz propulseur, pour des études expérimentales et/ou des criblages de préparations. L'invention concerne également un système matériel permettant l'administration d'un aérosol médicinal.
PCT/US2003/018529 2002-07-09 2003-06-12 Systemes modeles d'aerosol pour suspension medicinale WO2004004685A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003243522A AU2003243522A1 (en) 2002-07-09 2003-06-12 Medicinal suspension aerosol model systems

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0215749.3 2002-07-09
GB0215749A GB0215749D0 (en) 2002-07-09 2002-07-09 Medicinal suspension aerosol model systems

Publications (1)

Publication Number Publication Date
WO2004004685A1 true WO2004004685A1 (fr) 2004-01-15

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2003/018529 WO2004004685A1 (fr) 2002-07-09 2003-06-12 Systemes modeles d'aerosol pour suspension medicinale

Country Status (3)

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AU (1) AU2003243522A1 (fr)
GB (1) GB0215749D0 (fr)
WO (1) WO2004004685A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2410637A1 (de) * 1974-03-06 1975-09-11 Rudolf Dr Med Drumm Mittel zur rachenpflege
EP0175671A1 (fr) * 1984-08-23 1986-03-26 Kuhlemann & Co. Préparation pharmaceutique et procédé pour l'administration de cette préparation pharmaceutique
GB2184654A (en) * 1985-12-18 1987-07-01 Bayer Ag Dihydropyridine spray

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2410637A1 (de) * 1974-03-06 1975-09-11 Rudolf Dr Med Drumm Mittel zur rachenpflege
EP0175671A1 (fr) * 1984-08-23 1986-03-26 Kuhlemann & Co. Préparation pharmaceutique et procédé pour l'administration de cette préparation pharmaceutique
GB2184654A (en) * 1985-12-18 1987-07-01 Bayer Ag Dihydropyridine spray

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SHALLAJA, SOMARAJU; ET AL.: "Semiautomated Spray Pattern Testing of Nasal Sprays", PHARMACEUTICAL TECHNOLOGY, vol. 21, no. 5, 1997, pages 58,60,62,64, XP008022846 *
W. H. FINLAY; ET AL.: "Predicting regional lung dosages of a nebulized suspension: Pulmicort (budesonide).", PARTICULATE SCIENCE AND TECHNOLOGY, vol. 15, no. 3-4, 1998, pages 243 - 251, XP008022857 *

Also Published As

Publication number Publication date
AU2003243522A1 (en) 2004-01-23
GB0215749D0 (en) 2002-08-14

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