WO1997044012A1 - Formulation comprising microparticles, for inhalation - Google Patents

Formulation comprising microparticles, for inhalation Download PDF

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Publication number
WO1997044012A1
WO1997044012A1 PCT/GB1997/001309 GB9701309W WO9744012A1 WO 1997044012 A1 WO1997044012 A1 WO 1997044012A1 GB 9701309 W GB9701309 W GB 9701309W WO 9744012 A1 WO9744012 A1 WO 9744012A1
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Prior art keywords
microparticles
surfactant
drug
formulation
propellant
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Application number
PCT/GB1997/001309
Other languages
French (fr)
Inventor
Ian Joseph Smith
Cheryl Vanessa Rogerson
Original Assignee
Andaris Limited
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Publication date
Application filed by Andaris Limited filed Critical Andaris Limited
Priority to CA002253478A priority Critical patent/CA2253478A1/en
Priority to JP09541766A priority patent/JP2000512268A/en
Priority to AU27838/97A priority patent/AU2783897A/en
Publication of WO1997044012A1 publication Critical patent/WO1997044012A1/en
Priority to NO985341A priority patent/NO985341D0/en

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    • 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]
    • 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
    • A61K9/12—Aerosols; Foams
    • 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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds

Definitions

  • This invention relates to a formulation of a drug, in the form of microparticles, suitable for administration by means of a metered dose inhaler.
  • Drugs to be administered to the airways may be formulated dry, for use in a dry powder inhaler, or in a solution or suspension, to be delivered by means of a pressurised metered dose inhaler (pMDI) .
  • pMDI pressurised metered dose inhaler
  • Suspensions/ formulations of pMDIs typically comprise the drug, micronised to a respirable particle size, surfactant such as oleic acid, lecithin or Span®85, and a propellant.
  • the propellant has been a chlorofluorocarbon (CFC) such as Pll, P12 or P114.
  • CFCs are good solvents for surfactants, but their use involves major environmental concerns.
  • Suitable replacement propellants include the hydrofluoroalkanes HFA134a and HFA227, but the solubility of surfactants in HFAs is poor, and this is reflected in the resulting suspension characteristics.
  • the solubility of the surfactant in HFAs has been increased by the use of saturated hydrocarbons and alcohols, e.g. ethanol, as disclosed in EP-A-0372777.
  • the surfactant may be adsorbed onto the drug particle surface.
  • the surfactant may have limited solubility in the propellant and, in the case of suspension metered dose inhalers, it is then difficult to achieve sufficient adsorption of surfactant onto the drug particle surface to facilitate a controlled flocculation system which is stable.
  • An object behind the present invention is to avoid the disadvantages of poor surfactant solubility and consequent drug suspension instability described above. Summary of the Invention It has now been realised that spray-drying is useful as a means to produce novel drug particles of respirable size range, containing surfactant. This can provide high local concentrations of surfactant on the surface of the particle, to create the appropriate repulsive forces between particles. More particularly, by balancing the repulsive forces through formulation (i.e. quantity and type of surfactant, pH, etc) , when particles are attracted by Van der Waals forces, they are unable to move close together because of electrostatic, steric and entropic repulsive forces. In these circumstances, floccules are formed. The sediment will have a large volume and, because the balancing attractive force is relatively weak, the floccules are easily dispersed.
  • formulation i.e. quantity and type of surfactant, pH, etc
  • Microparticles according to this invention comprise a therapeutic agent and a surfactant.
  • the use of spray- drying can provide a product in which , the surfactant is uniformly distributed through the matrix of drug and, if necessary or desired, a wall-forming excipient.
  • the microparticles can be formulated with a propellant, e.g. a HFA, for use in a metered dose inhaler.
  • a propellant e.g. a HFA
  • the components used in this invention may all be conventional.
  • Drugs for use in therapy, administered by inhalers are exemplified in WO-A-9608914.
  • Suitable surfactants include oleic acid, lecithin and sorbitan trioleate as are used in conventional metered dose inhalers.
  • EP-A-0372777 which also describes relevant drugs.
  • Spray-drying techniques and wall-forming materials are described fully in WO-A-9218164 and WO-A-9608914.
  • the materials may be water-soluble, and will generally be predominantly water-soluble, but this may not be essential.
  • These techniques and materials, and the characteristics of the resultant microparticles described therein, are suitable for use in this invention.
  • the microparticles may be up to 50 ⁇ m, e.g. at least 1 ⁇ m, and preferably 0.5 to 5 ⁇ m in size. They can have a narrow size range, e.g. more than 90% by mass within the desired range.
  • a surfactant is the additional component in known microcapsules.
  • the amount of surfactant that is used will be chosen with primary regard to the successful formulation of the microparticles in propellant, and all the necessary parameters can be chosen by the skilled man without undue experimentation. Typically, the amount of surfactant will be 0.01 to 15%, preferably at least 0.05%, usually no more than 10%, preferably no more than 5%, and most preferably up to 2.5%, the percentages being by weight based on the weight of the drug. If too little or too much surfactant is present, formulation may be more difficult.
  • the amount of drug in the microcapsules will be chosen with regard to ease of formulation and production, and can readily be determined by one of ordinary skill in the art. The amount of drug in the formulation for inhalation will normally be the same as has previously been used for the desired effect, e.g. up to 250 ⁇ g (or more) per actuation of a pMDI.
  • Salbutamol sulphate was chosen as a model drug substance, and microparticles were formed using three surfactants commonly used in pMDIs, i.e. lecithin, oleic acid and sorbitan trioleate.
  • the range of surfactant to drug was from 0.05 to 5% w/w.
  • Samples of 125 ⁇ g product with HFA134a propellant and oleic acid were also examined for priming behaviour, single shot drug delivery, fine particle dose, and expiry dosing behaviour.
  • the total solids content of the spray-drying solution ranged from 24.1-25.1% w/v, depending upon the surfactant level.
  • ethanol was added to the spray-dry feedstock as a cosolvent.
  • An inlet temperature of 140°C and a solution feed rate of 4 g per minute was employed for all batches.
  • the feedstock was kept under nitrogen.
  • microcapsules were examined microscopically. From photomicrographs, the microcapsules appeared of similar size for all batches. The microcapsules were also sized using a Coulter LS, after suspension in acetone and sonication.
  • the mean volume median diameter of the microcapsules was 4.3 ⁇ m (range 3.8-4.8). If a smaller sized microparticle is desired, for pMDI formulation, the total solids content of the spray-dry feedstock should be reduced.
  • Pressurised metered dose inhalers were prepared in plastic-coated glass bottles, closed with Bespak BK357 valves, of 50 ⁇ l nominal metering volume.
  • the appropriate weight of microcapsules was placed in the bottle (5, 25 or 50 mg for 25, 125 and 250 ⁇ g per actuation, respectively) and 12 g HFA134a or 14.1 g HFA227 added. This gave a nominal 200 actuations per bottle.
  • the actuator used in these tests was supplied by Bespak and had a jet orifice diameter of 0.53 mm.
  • Figure 1 is a plot of salbutamol ex-actuator (0-400 ⁇ g) against shot number (1 to 8).
  • ⁇ represents 0.05%
  • ⁇ represents 0.5%
  • ⁇ represents 1.25%
  • x represents 2.5%
  • * represents 5%.
  • the first actuation for each sample gave a low shot weight and corresponding low ex-actuator drug content.
  • the drug content per actuation has been examined for individual actuations 1 to 8 and 96 to 100. These data can be used as a measure of dose uniformity.
  • the actuator deposition across the samples ranged from 6.4 to 34.9 ⁇ g, i.e. 5-28% of the target dose, after exclusion of actuations 1 to 3 as priming shots.
  • the variability of the total dose was believed to be a better comparator.
  • Figure 2 is a graph of % coefficient of variation (0-
  • Figure 3 is a graph of the range of salbutamol per actuation (0-400 ⁇ g) against % oleic acid (0.05-5). The 0.5% formulation, having the highest turbidity score, gave uniform dosing.
  • the size distribution of the drug emitted from the pMDI was assessed using an Astra Draco multi-stage impinger.
  • the four stages of the impinger have cut-off diameters of 1.7, 3.1, 6.8 and 13.4 ⁇ m at 60 litre per minute air flow.
  • the size distribution was assessed at the beginning of the pack (actuations 11 to 20) and towards the end of the pack (actuations 150 to 159). For the 0.05, 0.5, 1.25% w/w oleic acid samples, the distributions are similar at the beginning and end of the pack.
  • the drug per actuation for the 5.0% w/w oleic acid formulation is markedly different between the beginning and end of the pack (286 ⁇ g and 88 ⁇ g, respectively) .
  • the shape of the distributions also differs, suggesting that the drug discharged at the end of the pack is of larger size than that discharged at the start of the pack.
  • Figures 4 to 8 are each graphs, respectively for 0.05, 0.5, 1.25, 2.5 and 5% oleic acid, of salbutamol ex-actuator ( ⁇ g) against shot number.
  • ⁇ represents ex-actuator and ⁇ represents shot weight, in each case.

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  • 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)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Dispersion Chemistry (AREA)
  • Otolaryngology (AREA)
  • Pulmonology (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Microparticles, up to 50 νm in size, comprising a therapeutic agent and a surfactant. They can be homogeneously formulated with a HFC propellant.

Description

FORMULATION COMPRISING MICROPARTICLES. FOR INHALATION Field of the Invention
This invention relates to a formulation of a drug, in the form of microparticles, suitable for administration by means of a metered dose inhaler. Background of the Invention
Drugs to be administered to the airways may be formulated dry, for use in a dry powder inhaler, or in a solution or suspension, to be delivered by means of a pressurised metered dose inhaler (pMDI) . Suspensions/ formulations of pMDIs typically comprise the drug, micronised to a respirable particle size, surfactant such as oleic acid, lecithin or Span®85, and a propellant. In the past, the propellant has been a chlorofluorocarbon (CFC) such as Pll, P12 or P114. CFCs are good solvents for surfactants, but their use involves major environmental concerns. Suitable replacement propellants include the hydrofluoroalkanes HFA134a and HFA227, but the solubility of surfactants in HFAs is poor, and this is reflected in the resulting suspension characteristics.
The solubility of the surfactant in HFAs has been increased by the use of saturated hydrocarbons and alcohols, e.g. ethanol, as disclosed in EP-A-0372777. Alternatively, the surfactant may be adsorbed onto the drug particle surface. However, the surfactant may have limited solubility in the propellant and, in the case of suspension metered dose inhalers, it is then difficult to achieve sufficient adsorption of surfactant onto the drug particle surface to facilitate a controlled flocculation system which is stable.
An object behind the present invention is to avoid the disadvantages of poor surfactant solubility and consequent drug suspension instability described above. Summary of the Invention It has now been realised that spray-drying is useful as a means to produce novel drug particles of respirable size range, containing surfactant. This can provide high local concentrations of surfactant on the surface of the particle, to create the appropriate repulsive forces between particles. More particularly, by balancing the repulsive forces through formulation (i.e. quantity and type of surfactant, pH, etc) , when particles are attracted by Van der Waals forces, they are unable to move close together because of electrostatic, steric and entropic repulsive forces. In these circumstances, floccules are formed. The sediment will have a large volume and, because the balancing attractive force is relatively weak, the floccules are easily dispersed.
Microparticles according to this invention comprise a therapeutic agent and a surfactant. The use of spray- drying can provide a product in which, the surfactant is uniformly distributed through the matrix of drug and, if necessary or desired, a wall-forming excipient. The microparticles can be formulated with a propellant, e.g. a HFA, for use in a metered dose inhaler. Description of the Invention The components used in this invention may all be conventional. Drugs for use in therapy, administered by inhalers, are exemplified in WO-A-9608914. Suitable surfactants include oleic acid, lecithin and sorbitan trioleate as are used in conventional metered dose inhalers. A fuller list of types and examples of suitable surfactants is given in EP-A-0372777, which also describes relevant drugs.
Spray-drying techniques and wall-forming materials (of which HSA, viz . human serum albumin, is one example) are described fully in WO-A-9218164 and WO-A-9608914. The materials may be water-soluble, and will generally be predominantly water-soluble, but this may not be essential. These techniques and materials, and the characteristics of the resultant microparticles described therein, are suitable for use in this invention. Thus, for example, the microparticles may be up to 50 μm, e.g. at least 1 μm, and preferably 0.5 to 5 μm in size. They can have a narrow size range, e.g. more than 90% by mass within the desired range.
In essence, therefore, a surfactant is the additional component in known microcapsules. The amount of surfactant that is used will be chosen with primary regard to the successful formulation of the microparticles in propellant, and all the necessary parameters can be chosen by the skilled man without undue experimentation. Typically, the amount of surfactant will be 0.01 to 15%, preferably at least 0.05%, usually no more than 10%, preferably no more than 5%, and most preferably up to 2.5%, the percentages being by weight based on the weight of the drug. If too little or too much surfactant is present, formulation may be more difficult. The amount of drug in the microcapsules will be chosen with regard to ease of formulation and production, and can readily be determined by one of ordinary skill in the art. The amount of drug in the formulation for inhalation will normally be the same as has previously been used for the desired effect, e.g. up to 250 μg (or more) per actuation of a pMDI.
The following Examples illustrate the invention. Examples
Salbutamol sulphate was chosen as a model drug substance, and microparticles were formed using three surfactants commonly used in pMDIs, i.e. lecithin, oleic acid and sorbitan trioleate. The range of surfactant to drug was from 0.05 to 5% w/w.
The current marketed pMDIs of salbutamol contain 100 μg salbutamol base equivalent per actuation. However, a typical range of dose per actuation across pMDI products covers 25-250 μg per actuation, although this can be much more. In this study, formulations were therefore prepared at 25, 125 and 250 μg per actuation, in plastic coated bottles, with HFA134a or HFA227. These were assessed by visual examination on initial preparation and after six months storage at 20°C. In particular, differential flocculation behaviour between differing levels of surfactant, and signs of headspace and wall drug deposition after storage, were examined.
Samples of 125 μg product with HFA134a propellant and oleic acid were also examined for priming behaviour, single shot drug delivery, fine particle dose, and expiry dosing behaviour.
Batches of microcapsules were prepared in a minispray drier. The key process parameters are given in Tables Al (using oleic acid) , A2 (using sorbitan trioleate) and A3 (lecithin) . Table Al
Figure imgf000006_0001
Table A2
Figure imgf000006_0002
Table A3
Figure imgf000007_0001
The total solids content of the spray-drying solution ranged from 24.1-25.1% w/v, depending upon the surfactant level. To achieve solution of the higher levels of surfactant, ethanol was added to the spray-dry feedstock as a cosolvent. An inlet temperature of 140°C and a solution feed rate of 4 g per minute was employed for all batches. The feedstock was kept under nitrogen.
The prepared microcapsules were examined microscopically. From photomicrographs, the microcapsules appeared of similar size for all batches. The microcapsules were also sized using a Coulter LS, after suspension in acetone and sonication.
The mean volume median diameter of the microcapsules was 4.3 μm (range 3.8-4.8). If a smaller sized microparticle is desired, for pMDI formulation, the total solids content of the spray-dry feedstock should be reduced.
Pressurised metered dose inhalers were prepared in plastic-coated glass bottles, closed with Bespak BK357 valves, of 50 μl nominal metering volume. The appropriate weight of microcapsules was placed in the bottle (5, 25 or 50 mg for 25, 125 and 250 μg per actuation, respectively) and 12 g HFA134a or 14.1 g HFA227 added. This gave a nominal 200 actuations per bottle.
One week after manufacture each series of bottles was shaken, then placed against a black background and allowed to settle. Photographs were taken immediately and also 1 minute, 10 minutes, 30 minutes, 20 hours and 1 week after shaking. Tables Bl and B2 give the turbidity scores after 30 minutes settling for HFA134a and HFA227, respectively. The turbidity of the samples was scored on a 0 to +++++ scale, where 0 represents a completely clear supernatant and +++++ the most turbid supernatant. The HFA134a suspensions gave a greater degree of differential settling behaviour across the series compared to HFA227 suspensions.
Table Bl
Figure imgf000008_0001
Table B2
Figure imgf000008_0002
To have particles remaining in suspension after 30 min. is indicative of good physical stability in such systems. Turbid solutions will generally perform better. The 125 μg salbutamol/oleic acid formulations containing 0.05, 0.5, 1.25, 2.5 and 5% w/w surfactant were examined according to the following regime:
Figure imgf000009_0001
The actuator used in these tests was supplied by Bespak and had a jet orifice diameter of 0.53 mm.
The drug actuation and shot weight results for actuations 1 to 8 are shown in Figure 1, which is a plot of salbutamol ex-actuator (0-400 μg) against shot number (1 to 8). On the graph, ♦ represents 0.05%, ■ represents 0.5%, ▲ represents 1.25%, x represents 2.5%, and * represents 5%. As would be expected, the first actuation for each sample gave a low shot weight and corresponding low ex-actuator drug content. The samples which had shown the most turbid supernatants on visual examination (0.05% and 2.5%) displayed the most consistent dosing near to target.
The drug content per actuation has been examined for individual actuations 1 to 8 and 96 to 100. These data can be used as a measure of dose uniformity. The actuator deposition across the samples ranged from 6.4 to 34.9 μg, i.e. 5-28% of the target dose, after exclusion of actuations 1 to 3 as priming shots. As the main aim of this study was to compare different formulations, the variability of the total dose was believed to be a better comparator.
Figure 2 is a graph of % coefficient of variation (0-
60) against % oleic acid (0.05-5). Figure 3 is a graph of the range of salbutamol per actuation (0-400 μg) against % oleic acid (0.05-5). The 0.5% formulation, having the highest turbidity score, gave uniform dosing.
The size distribution of the drug emitted from the pMDI was assessed using an Astra Draco multi-stage impinger. The four stages of the impinger have cut-off diameters of 1.7, 3.1, 6.8 and 13.4 μm at 60 litre per minute air flow. The size distribution was assessed at the beginning of the pack (actuations 11 to 20) and towards the end of the pack (actuations 150 to 159). For the 0.05, 0.5, 1.25% w/w oleic acid samples, the distributions are similar at the beginning and end of the pack.
The drug per actuation for the 5.0% w/w oleic acid formulation is markedly different between the beginning and end of the pack (286 μg and 88 μg, respectively) . The shape of the distributions also differs, suggesting that the drug discharged at the end of the pack is of larger size than that discharged at the start of the pack.
In a study of doses to exhaustion, the fall in shot weight was followed from actuation 160 and, after a 10% fall in shot weight was observed, the drug per actuation was determined. The results for drug per actuation through the use of the pack are shown in Figures 4 to 8.
Figures 4 to 8 are each graphs, respectively for 0.05, 0.5, 1.25, 2.5 and 5% oleic acid, of salbutamol ex-actuator (μg) against shot number. ♦ represents ex-actuator and ■ represents shot weight, in each case.

Claims

1. Microparticles, up to 50 μm in size, comprising a therapeutic agent and a surfactant.
2. Microparticles according to claim 1, comprising also a wall-forming material.
3. Microparticles according to claim 1 or claim 2, whose components are at least predominantly water-soluble.
4. Microparticles according to any preceding claim, 0.5 to 10 μm in size.
5. Microparticles according to any preceding claim, obtainable by spray-drying.
6. A homogeneous formulation of microparticles according to any preceding claim and a propellant.
7. A formulation according to claim 6, wherein the propellant is a hydrofluorocarbon.
8. A metered dose inhaler comprising a formulation according to claim 6 or claim 7.
PCT/GB1997/001309 1996-05-17 1997-05-14 Formulation comprising microparticles, for inhalation WO1997044012A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002253478A CA2253478A1 (en) 1996-05-17 1997-05-14 Formulation comprising microparticles, for inhalation
JP09541766A JP2000512268A (en) 1996-05-17 1997-05-14 Formulation containing fine particles for inhalation
AU27838/97A AU2783897A (en) 1996-05-17 1997-05-14 Formulation comprising microparticles, for inhalation
NO985341A NO985341D0 (en) 1996-05-17 1998-11-16 Formulation comprising microparticles for inhalation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9610341.1 1996-05-17
GBGB9610341.1A GB9610341D0 (en) 1996-05-17 1996-05-17 Formulation for inhalation

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AR (1) AR007178A1 (en)
AU (1) AU2783897A (en)
CA (1) CA2253478A1 (en)
GB (1) GB9610341D0 (en)
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WO1999038493A1 (en) * 1998-01-30 1999-08-05 Rtp Pharma Inc. Microparticle inhalation formulations
WO2000010541A1 (en) * 1998-08-25 2000-03-02 Advanced Inhalation Research, Inc. Stable spray-dried protein formulations
EP1767195A2 (en) * 1998-08-25 2007-03-28 Advanced Inhalation Research, Inc. Stable spray-dried protein formulations
US7566445B1 (en) 1996-08-01 2009-07-28 Norton Healthcare Limited Medicinal aerosols and methods of delivery thereof
US8877162B2 (en) 2000-05-10 2014-11-04 Novartis Ag Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery
US9421166B2 (en) 2001-12-19 2016-08-23 Novartis Ag Pulmonary delivery of aminoglycoside
US9554993B2 (en) 1997-09-29 2017-01-31 Novartis Ag Pulmonary delivery particles comprising an active agent

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WO1992018164A1 (en) * 1991-04-10 1992-10-29 Delta Biotechnology Limited Preparation of diagnostic agents
WO1995027476A1 (en) * 1994-04-11 1995-10-19 The Center For Innovative Technology Hydrofluorocarbon propellant containing medicinal aerosols
WO1995031964A1 (en) * 1994-05-21 1995-11-30 Glaxo Wellcome Australia Limited Fluticasone propionate formulations
WO1996009814A1 (en) * 1994-09-29 1996-04-04 Andaris Limited Spray-dried microparticles as therapeutic vehicles

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0372777A2 (en) * 1988-12-06 1990-06-13 Riker Laboratories, Inc. Medicinal aerosol formulations
WO1992018164A1 (en) * 1991-04-10 1992-10-29 Delta Biotechnology Limited Preparation of diagnostic agents
EP0681843A2 (en) * 1991-04-10 1995-11-15 Andaris Limited Preparation of diagnostic agents
WO1995027476A1 (en) * 1994-04-11 1995-10-19 The Center For Innovative Technology Hydrofluorocarbon propellant containing medicinal aerosols
WO1995031964A1 (en) * 1994-05-21 1995-11-30 Glaxo Wellcome Australia Limited Fluticasone propionate formulations
WO1996009814A1 (en) * 1994-09-29 1996-04-04 Andaris Limited Spray-dried microparticles as therapeutic vehicles

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7566445B1 (en) 1996-08-01 2009-07-28 Norton Healthcare Limited Medicinal aerosols and methods of delivery thereof
US9650203B2 (en) 1996-08-01 2017-05-16 Norton Healthcare Limited Medicinal aerosols and methods of delivery thereof
US8834849B2 (en) 1996-08-01 2014-09-16 Norton Healthcare Limited Medicinal aerosols and methods of delivery thereof
US9554993B2 (en) 1997-09-29 2017-01-31 Novartis Ag Pulmonary delivery particles comprising an active agent
JP2002501885A (en) * 1998-01-30 2002-01-22 アールティーピー・ファーマ・インコーポレーテッド Formulation for inhalation of fine particles
JP2010248206A (en) * 1998-01-30 2010-11-04 Oban Energy Ltd Microparticle inhalation formulations
WO1999038493A1 (en) * 1998-01-30 1999-08-05 Rtp Pharma Inc. Microparticle inhalation formulations
US6086376A (en) * 1998-01-30 2000-07-11 Rtp Pharma Inc. Dry aerosol suspension of phospholipid-stabilized drug microparticles in a hydrofluoroalkane propellant
EP1767195A3 (en) * 1998-08-25 2007-04-04 Advanced Inhalation Research, Inc. Stable spray-dried protein formulations
EP1767195A2 (en) * 1998-08-25 2007-03-28 Advanced Inhalation Research, Inc. Stable spray-dried protein formulations
WO2000010541A1 (en) * 1998-08-25 2000-03-02 Advanced Inhalation Research, Inc. Stable spray-dried protein formulations
US8877162B2 (en) 2000-05-10 2014-11-04 Novartis Ag Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery
US9439862B2 (en) 2000-05-10 2016-09-13 Novartis Ag Phospholipid-based powders for drug delivery
US9421166B2 (en) 2001-12-19 2016-08-23 Novartis Ag Pulmonary delivery of aminoglycoside

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NO985341L (en) 1998-11-16
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KR20000011020A (en) 2000-02-25
ZA974328B (en) 1998-05-19
JP2000512268A (en) 2000-09-19
GB9610341D0 (en) 1996-07-24
CA2253478A1 (en) 1997-11-27
AR007178A1 (en) 1999-10-13

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