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WO2003002111A1 - Particules a inhaler - Google Patents

Particules a inhaler Download PDF

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Publication number
WO2003002111A1
WO2003002111A1 PCT/FI2002/000573 FI0200573W WO03002111A1 WO 2003002111 A1 WO2003002111 A1 WO 2003002111A1 FI 0200573 W FI0200573 W FI 0200573W WO 03002111 A1 WO03002111 A1 WO 03002111A1
Authority
WO
WIPO (PCT)
Prior art keywords
particles
inhalation
orazipone
liquid feed
feed stock
Prior art date
Application number
PCT/FI2002/000573
Other languages
English (en)
Inventor
Wiwik Watanabe
Petri Ahonen
Esko Kauppinen
David Brown
Jorma Jokiniemi
Esa Muttonen
Original Assignee
Orion Corporation
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 Orion Corporation filed Critical Orion Corporation
Publication of WO2003002111A1 publication Critical patent/WO2003002111A1/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
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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
    • A61K31/12—Ketones
    • 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
    • A61P11/06—Antiasthmatics

Definitions

  • the present invention relates to inhalation particles of orazipone and inhalation compositions of orazipone suitable for pulmonary drug delivery and to methods for the preparation thereof.
  • the compositions are particularly useful to treat asthma, COPD and other respiratory diseases.
  • Orazipone or 3-[(4-methylsulfonylphenyl)-methylene]-2,4-pentanedione is a locally acting anti-inflammatory agent that has anti-inflammatory properties complimentary to those of corticosteroids.
  • Orazipone is useful e.g. in the treatment of asthma, COPD and other respiratory diseases.
  • a method for preparing orazipone is described in European Patent No. 440324 B 1.
  • Inhalation has become the primary route of administration in the treatment of pulmonary and other diseases. This is because, besides providing direct access to the lungs, medication delivered through the respiratory tract provides rapid and predictable onset of action and requires lower dosages when compared to the oral route. To ensure an accurate delivery deeply into the lungs the particles of the active ingredient should be micron-sized, preferably with the aerodynamic particle size from about 1 to 5 ⁇ m.
  • a powdered inhalation composition containing conventionally micronized (i.e. milled) orazipone particles is disclosed in US 6,201,027.
  • the particles provide more controlled delivery of orazipone by inhalation and exhibit improved dispersibility, as well as good stability as a result of their crystalline nature.
  • the particles have a narrow aerodynamic particle size distribution, typically between 1-5 ⁇ m that is especially suitable for the preparation of compositions for pulmonary delivery via inhalation.
  • the particles have curved, preferably substantially spherical, and rough, porous surface, significantly less force is required to remove a particle from a surface, to break-up aggregates of particles or detach particles from a coarse carrier material.
  • the present invention provides inhalation particles incorporating orazipone, wherein said particles have a curved surface and are in crystalline form.
  • the particles are substantially spherical.
  • the particles are polycrystalline with rough surface.
  • the mean mass aerodynamic diameter of the particles is typically between about 0.5 - 10 ⁇ m, more typically between about 1 - 5 ⁇ m.
  • the aerodynamic particle size distribution of said particles is typically between about 0.5 - 10 ⁇ m, more typically between 1-5 ⁇ m.
  • the present invention provides an inhalation composition
  • an inhalation composition comprising particles incorporating orazipone, wherein said particles have a curved surface and are in crystalline form.
  • the particles may be formulated into an inhalation composition together with one or more pharmaceutically acceptable additives, diluents or carriers.
  • the composition can be in the form of dry inhalation powder for delivery by a dry powder inhaler (DPI).
  • DPI dry powder inhaler
  • composition can be in the form of suspension for delivery by other means such as pressurized metered dose inhaler (pMDI) or a nebulizer.
  • pMDI pressurized metered dose inhaler
  • nebulizer a nebulizer
  • the composition is provided in the form of dry inhalation powder.
  • the present invention provides a method for preparing orazipone particles, comprising the steps of: providing liquid feed stock comprising orazipone; atomising said liquid feed stock to create droplets; suspending said droplets in a carrier gas; passing said carrier gas and droplets suspended therein through a heated tube flow reactor under predetermined residence time and temperature history; and collecting the orazipone particles produced.
  • Figures la and lb show scanning electron microscopy images of the orazipone particles produced by a conventional milling process.
  • FIGS 2a and 2b are schematic diagrams showing parts of the apparatus used in the method of the invention.
  • Figure 3 is a schematic diagram of the electrostatic precipitator.
  • Figure 4 shows the XRD pattern of orazipone powder of the invention.
  • Figure 5 depicts a scanning electron microscopy image of the orazipone particle of the invention produced at reactor temperature of 50°C.
  • Figures 6 shows a scanning electron microscopy image of the orazipone particle of the invention produced at reactor temperature of 100°C.
  • the particles of the present invention are preferably prepared using an aerosol flow reactor method (aerosol synthesis method). It is a one-step continuous process that can directly produce particles in a desirable particle size range.
  • aerosol synthesis method is a one-step continuous process that can directly produce particles in a desirable particle size range.
  • the method has been used to produce various materials, e.g. ceramic powder (US 5,061,682) or zirconia powder (US 4,999,182), at high operation temperatures. However, the method has not been used to produce pharmaceutical materials, which require a significantly lower synthesis temperature (less than 300 °C).
  • the aerosol flow reactor method comprises generally the following steps:
  • the droplets are already suspended in the carrier gas before they are fed into the tubular flow reactor that is placed in an oven and maintained at a constant temperature.
  • the carrier gas flows evenly in the tubular reactor with a constant rate, controlled temperature field and non-circulating flow. Therefore, the temperature history and the residence time of each droplet and product particle can be properly controlled and the excellent uniformity of the particles can be ensured. Accordingly, the method provides better control of the droplet size distribution (and thus the particle size distribution) such that particles with optimal aerodynamic particle size distribution, typically between about 1-5 ⁇ m, can be obtained.
  • the method allows essentially complete crystallization of the particles.
  • the method is able to produce consistent and controlled particle properties, including particle size and size distribution, shape, crystallinity, polymorphic phase, surface roughness and chemical purity.
  • the liquid feed stock of step (a) may be prepared by mixing one or several active ingredients with a suitable solvent to form a solution, suspension, dispersion, gel, emulsion, slurry or the like, and is preferably homogenous to ensure uniform distribution of the components in the mixture.
  • the liquid feed stock in the form of a solution is preferred.
  • solvents maybe employed in the preparation of the a liquid feed stock, including but not limited to, water, hydrocarbons, halogenated hydrocarbons, alchohols, ketones and the like.
  • suitable solvents include methyl ethyl ketone, acetone, isopropyl alcohol, and combinations thereof.
  • the active ingredients should be sufficiently soluble in the solvent of the solution so as to obtain, from the atomized droplets of the liquid feed stock, uniform particles with the desired particle size, size distribution and drug ratio.
  • the total solids dissolved may be present in wide range of concentrations, typically from about 0.1 % to about 30 % by weight, for example from about 1 % to about 10 % by weight.
  • a liquid feed stock containing a relatively low concentration of solids results in particles having a relatively small diameter. The finding of suitable liquid feed stock concentrations for each active agent/solvent combinations is considered to be a routine to one skilled in the art.
  • the liquid feed stock concentration is firstly chosen at its maximum solubility so as to obtain the largest particle size with the atomizer and atomizer conditions used. From the results, a better approximation of the liquid feed stock concentration needed to obtain the desired particle size range with the atomizer and the atomizer conditions used can be easily achieved.
  • the liquid feed stock is atomized to create droplets in a suitable atomizer, which are well known in the art, such as a spray nozzle (e.g. a two fluid nozzle), an ultrasonic or air assisted nebuliser or a spinning disc, an ultrasonic nebulizer being preferred.
  • a spray nozzle e.g. a two fluid nozzle
  • an ultrasonic or air assisted nebuliser or a spinning disc an ultrasonic nebulizer being preferred.
  • the devices used in this process include ultrasonic generators sold under trademarks Omron NE-U12 and RBI Pyrosol 7901. While there are no special restrictions placed on the atomisers used in the process, it is recommended to use an atomiser that can produce uniform droplets of constant composition and in a specific size range. Such devices are suitable to produce particles with controlled chemical and physical properties suitable for delivery by inhalation.
  • the droplets of the liquid feed stock are suspended in a carrier gas before passing through a heated tube flow reactor.
  • the carrier gas can be any kind of gas and is preferably inert with respect to the drug molecules and the solvent. It is recommended to use nitrogen gas or other inert gases.
  • the temperature of the carrier gas is typically ambient. To maintain a uniform solution concentration in the droplets in the suspending phase, it is preferred to bubble the carrier gas through a bottle containing the same solvent as the liquid feed stock before entering the atomizer.
  • the temperature history and residence time of each droplet and product particle can be better cont- rolled than in the conventional spray-drying method. Therefore, excellent uniformity of the resulted particles and a narrow particle size distribution can be ensured.
  • the droplets suspended in the carrier gas are passed through a tubular flow reactor that is maintained at a constant temperature. The temperature and the flow rate of the carrier gas are adjusted to evaporate the solvent and to allow the crystallisation process to occur. The particles formed are then collected using an electrostatic precipitator, a cyclone, a planar filter (e.g. nylon) or other particle collecting devices.
  • the particle size may be controlled to any expected particle size ranges by selection of the atomizer and its operation conditions, and concentration of the liquid feed stock. It is also possible to employ a droplet size modification apparatus (e.g. impactor or virtual impactor, or using size selective collection of particles, e.g. a cyclone) downstream of the flow reactor. Normally, however, this is not required if the atomizer can already produce a sufficient narrow size distribution.
  • a droplet size modification apparatus e.g. impactor or virtual impactor, or using size selective collection of particles, e.g. a cyclone
  • the reactor tube is preferably placed inside an oven to maintain a uniform reactor wall temperature during the process.
  • the oven can be of any kind that has sufficient temperature control (i.e. ⁇ 1 °C or less) at low temperatures (less than 300 °C). The temperature of the oven is set such that the materials being processed do not decompose.
  • the selected oven temperature is within the range of about 30 to 300 °C.
  • the range of oven temperature used for the particle production may vary between 20 to 120 °C, preferably between 30 to 100 °C.
  • the particle collection system and the line from the flow reactor outlet to the particle collection system are preferably heated to a temperature above the boiling point of the solution to prevent the re-condensation process to occur.
  • the tempera- ture should not be too high so as to cause material degradation.
  • dry carrier gas may be introduced to the particle collection system. The carrier gas is preferably heated at a temperature the same as that of reactor.
  • the aerosol flow reactor conditions are selected such that crystalline substantially spherical particles of homogeneous constituents having a narrow particle size distribution and rough surfaces are formed.
  • the particle size of the resulting orazipone powder is such that the mean mass aerodynamic diameter of said particles is between about 0.5 - 10 ⁇ m, more typically between about 1 - 5 ⁇ m. Particularly it is preferred that more than 98 % of the mass is in particles having a diameter of 5 ⁇ m or less, and less than about 5 % of the mass being in particles having a diameter of 0.5 ⁇ m or less. It is particularly preferred that the aerodynamic particle size distribution of said particles is between about 0.5 - 10 ⁇ m, more preferably between about 1 - 5 ⁇ m.
  • the orazipone particle of the invention is in a crystalline form, i.e. has a relative degree of crystallinity preferably 90 % or higher, more preferably 95 % or higher, most preferably 99 % or higher.
  • the aerosol flow reactor conditions are selected such that the resulting particles are in a crystalline form.
  • the relative degree of crystallinity can be determined based on the x-ray powder diffraction patterns. The value of the relative degree of crystallinity can be estimated by a known method of broadening of the diffraction maxima (FWHM- values).
  • the particles are typically polycrystalline, i.e. an individual particle consists of a plurality of smaller crystallites.
  • the orazipone particles of the invention have curved surface.
  • the term "particle with curved surface” means herein a regular shaped particle with rounded, dragee-like, nearly spherical or substantially spherical form such form being consistent and apparent when examined under a scanning electron microscope.
  • the majority of the particles are as rounded as possible and substantially devoid of sharp or broken edges or flat faceted surfaces.
  • the particles are substantially spherical.
  • the curved surface reduces the contact areas between particles and thereby improves aerosolization and deagglomeration of the particles upon inhalation.
  • the surface of the particles of the invention is rough, i.e.
  • the roughness is consistent over the entire surface of the particle, apparent when examined under the scanning electron microscope, and the ratio of the maximum and minimum diameter of the particle is between 1.01 - 1.5, preferably between 1.02 - 1.3, more preferably between 1.03 - 1.2.
  • the rough surface of the particles appears typically as porous, filled consistently with dimples and cavities. A rough surface is advantageous since it increases the effective separation distance of the particles, and thus improves aerosolization and deagglomeration properties of the particles.
  • the surface roughness can be controlled by controlling the primary crystallite size of the partic- les.
  • additives known in the art maybe additionally incorporated in the particles together with the active ingredient or ingredients.
  • additives include e.g. diluents such as lactose, carriers and stabilizers and the like, hi such a case the additives are included in the liquid feed stock of the process together with the active ingredients.
  • additives incorporated in the particle are preferably in crystalline form. It is particularly preferred that at least about 90 w-% of the total weight of the particle is in crystalline form.
  • the active ingredients constitute at least 90 w-%, preferably at least 95 w-%, more preferably at least 99 w- %, of the total weight of particles. Most preferably the particles are free from other material than the active ingredients.
  • the particles of the invention may be formulated into an inhalation composition together with one or more pharmaceutically acceptable additives, diluents or carriers.
  • suitable solid diluents or carriers comprise lactose, dextran, mannitol and glucose, lactose being preferred.
  • aerosol carriers include non-chlorofluorocarbon-based carriers such as HFA (hydrofluoroalkane).
  • HFA hydrofluoroalkane
  • Typical additives include solubilizers, stabilizers, flavouring agents, colorizing agents and preserving agents.
  • the particles of the invention are preferably administered in the form of a dry powder composition.
  • the particles obtained are generally in the form of individual (unagglomerated) particles which are well suited for pulmonary drug delivery by inhalation as such, e.g. they can be filled directly into capsules, cartridges, blister packs or reservoirs of dry powder inhalers.
  • the particles maybe adapted to form loose agglomerates of several individual particles, said agglomerates breaking into individual particles upon dispersion in the inhaled air stream.
  • the particles may also be combined with pharmaceutically acceptable carrier materials or excipients typically used in dry inhalation powders. Such carriers may be used simp- ly as bulking agents or to improve the flowability of the powder.
  • the particles may be used in admixture with carrier particles, e.g. lactose, having larger particle size than the active ingredients, typically in the range of 5 to 100 ⁇ m.
  • carrier particles e.g. lactose
  • the total amount of the active ingredients is typically about 0.1 - 50 % (w/w), preferably about 1 - 10 % (w/w), based on total weight of the composition.
  • Such compositions can be prepared by methods known in the art.
  • the particles of the invention can be also administered in the form of pressurized metered dose inhalation suspension, where the particles are suspended in pressurized aerosol carrier and delivered using pressurized metered dose inhaler (pMDI).
  • the particles can be administered in the form of a suspension used in the delivery via a nebulizer.
  • Example 1 (Reference). SEM images ofmicronized orazipone particles
  • Figure la to lb show scanning electron microscopy (SEM) images of orazipone particles micronized by conventional high energy milling. It can be seen that the particles are irregular in shape, have flat faceted surfaces and have large crystallites, which neck strongly together forming large aggregates.
  • SEM scanning electron microscopy
  • Example 2 Inhalation particles incorporating orazipone
  • the orazipone liquid feed stock was prepared by dissolving 1 g of orazipone powder in 50 ml of methyl ethyl ketone at room temperature. Aerosol Synthesis
  • FIG. 2a shows the experimental set-up of the particle synthesis
  • Fig. 2b show optional configuration used for particle analysis.
  • the liquid feed stock described above was atomised using an ultrasonic atomizer (2), sold under trade mark RBI Pyrosol 7901.
  • the resulted droplets, which were suspended into a carrier gas, were then passed through a heated tube flow reactor (4).
  • Nitrogen gas was used as a carrier gas, with a constant flow rate of 1.5 1/min.
  • the carrier gas was bubbled through methyl ethyl ketone in a saturation bottle (1) before entering the atomizer.
  • a vertical tube which was inserted into an oven (3), was used to evaporate the solvent from the droplets.
  • the oven used was a WTB Binder FD/FED 400 that has temperature variations of ⁇ 1 and + 2°C for temperature at 70 and 150°C, respectively.
  • the tube was made of stainless steel, with an inner diameter and a heated length of 30 and 800 mm, respectively.
  • the oven temperature was set at 50 °C.
  • the minimum particle residence time in the heated zone under the selected process conditions was approximately 3.3 seconds. From the CFD calculation, it is shown that temperature field is uniform and the velocity is fully developed and non-circulating in the heated zone.
  • FIG. 3 shows the schematic diagram of ESP having inlet (16) and exit for exhaust gas (19).
  • the ESP was made of a tubular stainless steel collection plate (20) with inside diameter and length of 47 and 300 mm, respectively.
  • a 0.05 mm diameter tungsten wire was placed on the center axis of the collection plate and a high voltage (18) was applied between the wire and the plate.
  • the high electric field formed a corona discharge (17) on the wire and charged the gas molecules.
  • the gas ions were then formed. These ions migrated across the space between the wire and the plate under the influence of the applied electric field.
  • the particle size distribution was measured by an electrical low pressure impactor (12) (ELPI) connected to a vacuum (13).
  • ELPI electrical low pressure impactor
  • the particles exiting the tubular tube were passed into two diluters (10a and 10b), with a dilution ratio of 1 : 10, before entering the ELPI.
  • the first diluter (10a) was heated at 50°C and the nitrogen gas entering the first diluter is also heated at the same temperature.
  • Some particles exiting from the first diluter were sampled directly into a TEM grid (11) via a combination electrostatic precipitator connected to a vacuum, for morphology analysis.
  • the diluter, the line to the diluter and the gas line into the diluter were layered with heating elements that were kept also at 50°C.
  • the gravimetric measurement shows that a narrow particle size distribution within the range of aerodynamic size of interest, i.e. at around 1-5 ⁇ m, was obtained.
  • Crystallinity of the sample was studied by X-ray powder diffraction (Diffractometer D500, Siemens GmbH, Düsseldorf, Germany).
  • a copper target X-ray (wavelength 0.1541nm) tube was operated with the power of 40 kV x 40 mA.
  • the relative degree crystallinity of the powder was determined based on the x-ray powder diffraction patterns shown in Figure 4. The estimation was based on the broadening of the diffraction maxima (FWHM-values) positioned at 2 ⁇ range 3- 53°. It is noticed that the powder was well crystallised. The maximum intensities were sharp and well above background intensities. iii. Particle shape and surface structure
  • the product purity was analysed using Hewlett-Packard HP 1090 Liquid Chromatograph equipped with diode array detector (wavelength 277).
  • the column used was a Hewlett-Packard Hypersil ODS, 5 ⁇ m, 100x2.1 mm.
  • the quantitative analyses were carried using the external standard method (four different standard concentrations).
  • 15 mM phosphate buffer (pH 2 with H 3 PO 4 ) methanol at the ratio of 60:40 (v/v) was used as a mobile phase.
  • the powder samples were first dissolved into methanol and diluted with a 15 mM phosphate buffer (pH 2 with H 3 PO 4 ) : methanol (50:50).
  • the liquid samples were then diluted with a 15 mM phosphate buffer (pH 2 with H 3 PO 4 ) : methanol (50:50).
  • the analysis results showed that the purity of resulted powder is 100%
  • Example 3 Inhalation particles comprising Orazipone with controlled primary crystallite size
  • the liquid feed preparation and aerosol synthesis process are the same as example 2 except that the process temperatures are set at 100°C.
  • the minimum particle residence time in the heated zone under the selected process conditions was approximately 3.8 seconds.
  • the particle size distribution is the same as that of example 2 but the primary crystallite sizes are smaller, as shown in Figure 6. Thus, it is possible to control primary crystallite size, and thus particle surface roughness, by varying the process conditions.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pulmonology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Otolaryngology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des particules cristallines d'orazipone présentant une surface incurvée à rugosité contrôlée. Ces particules sont par exemple utilisées pour traiter l'asthme, la broncho-pneumopathie chronique obstructive et d'autres maladies respiratoires. Lesdites particules présentent une distribution étroite des tailles particulaires, des surfaces rugueuses et une stabilité améliorée. Les particules à inhaler selon cette invention sont notamment utilisées pour administrer un médicament par inhalation.
PCT/FI2002/000573 2001-06-28 2002-06-28 Particules a inhaler WO2003002111A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FI20011386A FI20011386A0 (fi) 2001-06-28 2001-06-28 Inhalaatiopartikkeleja
FI20011386 2001-06-28

Publications (1)

Publication Number Publication Date
WO2003002111A1 true WO2003002111A1 (fr) 2003-01-09

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PCT/FI2002/000573 WO2003002111A1 (fr) 2001-06-28 2002-06-28 Particules a inhaler

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WO (1) WO2003002111A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003061637A1 (fr) * 2002-01-23 2003-07-31 Orion Corporation Compositions destinees a une administration pulmonaire

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000001667A1 (fr) * 1998-07-01 2000-01-13 Orion Corporation β-DICETONES SUBSTITUEES ET LEURS UTILISATIONS
US6051257A (en) * 1997-02-24 2000-04-18 Superior Micropowders, Llc Powder batch of pharmaceutically-active particles and methods for making same
WO2001049263A1 (fr) * 1999-12-30 2001-07-12 Orion Corporation Particules pour inhalation
WO2002028378A1 (fr) * 2000-10-06 2002-04-11 Orion Corporation Particules associees pour le traitement de l'asthme
WO2002028377A1 (fr) * 2000-10-06 2002-04-11 Orion Corporation Particules d'inhalation comprenant une combinaison d'au moins deux principes actifs

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6051257A (en) * 1997-02-24 2000-04-18 Superior Micropowders, Llc Powder batch of pharmaceutically-active particles and methods for making same
WO2000001667A1 (fr) * 1998-07-01 2000-01-13 Orion Corporation β-DICETONES SUBSTITUEES ET LEURS UTILISATIONS
WO2001049263A1 (fr) * 1999-12-30 2001-07-12 Orion Corporation Particules pour inhalation
WO2002028378A1 (fr) * 2000-10-06 2002-04-11 Orion Corporation Particules associees pour le traitement de l'asthme
WO2002028377A1 (fr) * 2000-10-06 2002-04-11 Orion Corporation Particules d'inhalation comprenant une combinaison d'au moins deux principes actifs

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003061637A1 (fr) * 2002-01-23 2003-07-31 Orion Corporation Compositions destinees a une administration pulmonaire

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Publication number Publication date
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