WO1997044012A1 - Formulation destinee a l'inhalation et comprenant des microparticules - Google Patents

Formulation destinee a l'inhalation et comprenant des microparticules 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
Authority
WO
WIPO (PCT)
Prior art keywords
microparticles
surfactant
drug
formulation
propellant
Prior art date
Application number
PCT/GB1997/001309
Other languages
English (en)
Inventor
Ian Joseph Smith
Cheryl Vanessa Rogerson
Original Assignee
Andaris Limited
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 Andaris Limited filed Critical Andaris Limited
Priority to AU27838/97A priority Critical patent/AU2783897A/en
Priority to CA002253478A priority patent/CA2253478A1/fr
Priority to JP09541766A priority patent/JP2000512268A/ja
Publication of WO1997044012A1 publication Critical patent/WO1997044012A1/fr
Priority to NO985341A priority patent/NO985341L/no

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

Abstract

On décrit des microparticules d'une taille maximale de 50 νm qui comprennent un agent thérapeutique et un tensio-actif. On peut les formuler de manière homogène avec un agent propulseur HFC.
PCT/GB1997/001309 1996-05-17 1997-05-14 Formulation destinee a l'inhalation et comprenant des microparticules WO1997044012A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU27838/97A AU2783897A (en) 1996-05-17 1997-05-14 Formulation comprising microparticles, for inhalation
CA002253478A CA2253478A1 (fr) 1996-05-17 1997-05-14 Formulation destinee a l'inhalation et comprenant des microparticules
JP09541766A JP2000512268A (ja) 1996-05-17 1997-05-14 吸入用微粒子含有配合物
NO985341A NO985341L (no) 1996-05-17 1998-11-16 Formulering omfattende mikropartikler for inhalering

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

Publications (1)

Publication Number Publication Date
WO1997044012A1 true WO1997044012A1 (fr) 1997-11-27

Family

ID=10793869

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1997/001309 WO1997044012A1 (fr) 1996-05-17 1997-05-14 Formulation destinee a l'inhalation et comprenant des microparticules

Country Status (9)

Country Link
JP (1) JP2000512268A (fr)
KR (1) KR20000011020A (fr)
AR (1) AR007178A1 (fr)
AU (1) AU2783897A (fr)
CA (1) CA2253478A1 (fr)
GB (1) GB9610341D0 (fr)
NO (1) NO985341L (fr)
WO (1) WO1997044012A1 (fr)
ZA (1) ZA974328B (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999038493A1 (fr) * 1998-01-30 1999-08-05 Rtp Pharma Inc. Formulations d'inhalation de microparticules
WO2000010541A1 (fr) * 1998-08-25 2000-03-02 Advanced Inhalation Research, Inc. Formulations proteiques atomisees stables
EP1767195A2 (fr) * 1998-08-25 2007-03-28 Advanced Inhalation Research, Inc. Formulations de protéines stables séchées par pulvérisation
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

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0372777A2 (fr) * 1988-12-06 1990-06-13 Riker Laboratories, Inc. Formulations d'aérosols à usage médical
WO1992018164A1 (fr) * 1991-04-10 1992-10-29 Delta Biotechnology Limited Preparation d'agents diagnostiques
WO1995027476A1 (fr) * 1994-04-11 1995-10-19 The Center For Innovative Technology Aerosols medicamenteux contenant un gaz propulseur a base d'hydrofluorocarbones
WO1995031964A1 (fr) * 1994-05-21 1995-11-30 Glaxo Wellcome Australia Limited Formulations a base de propionate de fluticasone
WO1996009814A1 (fr) * 1994-09-29 1996-04-04 Andaris Limited Microparticules sechees par pulverisation utilisees comme excipient therapeutique

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0372777A2 (fr) * 1988-12-06 1990-06-13 Riker Laboratories, Inc. Formulations d'aérosols à usage médical
WO1992018164A1 (fr) * 1991-04-10 1992-10-29 Delta Biotechnology Limited Preparation d'agents diagnostiques
EP0681843A2 (fr) * 1991-04-10 1995-11-15 Andaris Limited Préparation d'agents diagnostiques
WO1995027476A1 (fr) * 1994-04-11 1995-10-19 The Center For Innovative Technology Aerosols medicamenteux contenant un gaz propulseur a base d'hydrofluorocarbones
WO1995031964A1 (fr) * 1994-05-21 1995-11-30 Glaxo Wellcome Australia Limited Formulations a base de propionate de fluticasone
WO1996009814A1 (fr) * 1994-09-29 1996-04-04 Andaris Limited Microparticules sechees par pulverisation utilisees comme excipient therapeutique

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 (ja) * 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 微粒子吸入用製剤
JP2010248206A (ja) * 1998-01-30 2010-11-04 Oban Energy Ltd 微粒子吸入用製剤
WO1999038493A1 (fr) * 1998-01-30 1999-08-05 Rtp Pharma Inc. Formulations d'inhalation de microparticules
US6086376A (en) * 1998-01-30 2000-07-11 Rtp Pharma Inc. Dry aerosol suspension of phospholipid-stabilized drug microparticles in a hydrofluoroalkane propellant
EP1767195A3 (fr) * 1998-08-25 2007-04-04 Advanced Inhalation Research, Inc. Formulations de protéines stables séchées par pulvérisation
EP1767195A2 (fr) * 1998-08-25 2007-03-28 Advanced Inhalation Research, Inc. Formulations de protéines stables séchées par pulvérisation
WO2000010541A1 (fr) * 1998-08-25 2000-03-02 Advanced Inhalation Research, Inc. Formulations proteiques atomisees stables
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

Also Published As

Publication number Publication date
NO985341D0 (no) 1998-11-16
ZA974328B (en) 1998-05-19
NO985341L (no) 1998-11-16
AU2783897A (en) 1997-12-09
KR20000011020A (ko) 2000-02-25
CA2253478A1 (fr) 1997-11-27
AR007178A1 (es) 1999-10-13
JP2000512268A (ja) 2000-09-19
GB9610341D0 (en) 1996-07-24

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