WO2002007705A1 - Carrier material for dry powder inhalation - Google Patents

Carrier material for dry powder inhalation Download PDF

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Publication number
WO2002007705A1
WO2002007705A1 PCT/EP2001/008395 EP0108395W WO0207705A1 WO 2002007705 A1 WO2002007705 A1 WO 2002007705A1 EP 0108395 W EP0108395 W EP 0108395W WO 0207705 A1 WO0207705 A1 WO 0207705A1
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Prior art keywords
carrier
dry powder
powder inhalation
carrier material
produced
Prior art date
Application number
PCT/EP2001/008395
Other languages
French (fr)
Inventor
Klass Daniel Kussendrager
Mark Jason Heath Ellison
Original Assignee
Campina B.V.
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 Campina B.V. filed Critical Campina B.V.
Priority to AU2001279771A priority Critical patent/AU2001279771A1/en
Publication of WO2002007705A1 publication Critical patent/WO2002007705A1/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
    • A61K9/0075—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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

Definitions

  • the present invention relates to a carrier material for use in dry powder inhalation formulations, to the process for manufacture of these carrier materials and to dry powder inhalation formulations using the carrier materials.
  • Dry powder inhalers have been in existence since the late 1960 's. Interest in this technique for delivering pharmacological active components to the lungs was initially limited due to the popularity of pressurized metered dose inhalers (pMDI's). However, since the decision to eliminate CFC's from pMDI's due to environmental issues, dry powder inhalers are becoming more popular.
  • pMDI's pressurized metered dose inhalers
  • formulations for dry powder inhalation comprise a pharmacologically active component and an inert carrier material, being in most cases ⁇ -lactose monohydrate crystals.
  • the active component is usually micronised with a particle size less than 5 ⁇ m, to enable deposition in the lower levels of the lungs.
  • the purpose of the inert carrier is to aid flow and to prevent the formation of agglomerates of the active component which agglomerates can not be dispersed, thus preventing deposition at the site of action.
  • ⁇ -lactose does not have an optimal flow, which may lead to problems, such as clogging, in the inhaler.
  • ⁇ -lactose monohydrate does not always lead to a 100% drug delivery.
  • the carrier hits the throat, after which the drug, which is in loose association with the carrier, detaches therefrom and is transported to the lungs where it has its effect. In case the drug does not end up in the right location, i.e. the lung, there may arise problems for the patient.
  • spray-dried carrier material consists of spherical particles, which show excellent flow characteristics, but that spray dried products may contain amorphous material which can undergo crystallisation in the presence of moisture.
  • the active ingredient such as a drug
  • a crystallisation step should be incorporated into the manufacture of the carrier material .
  • the purpose of the crystallisation step is to remove substantially all, and preferably all the amorphous material present.
  • the present invention thus relates to a carrier material, comprising carrier particles that are spherical in nature and contain substantially no or no amorphous material.
  • carrier material is for example obtainable by a method comprising the steps of: a) providing a carrier base material consisting of spherical carrier particles; and b) crystallising the carrier base material in order to remove amorphous material present in the particles to obtain the carrier material.
  • the provision of the spherical carrier base material can be achieved by spray drying a starting material to obtain a powder that consists of substantially spherical particles of the carrier material that still contain amorphous material.
  • a suitable method for obtaining such carrier base material is described in EP-239 172, which is incorporated herein by reference.
  • the method described therein comprises feeding a slurry of crystalline ⁇ -lactose hydrate in a saturated lactose solution to a spray drier and drying the same, wherein the selection of the ratio between the amounts of crystalline material and dissolved lactose in the slurry determines the ratio between the amounts of crystalline and amorphous lactose in the spray dried product.
  • the person skilled in the art of spray drying can modify the process conditions to obtain a suitable spray dried product based on his common general knowledge of spray drying.
  • the present invention thus provides a spray dried product with substantially no or no amorphous material, by virtue of which it has excellent flow properties and is stable with regard to air moisture.
  • Preferred carrier materials are those known to be useful for dry powder inhalation formulations.
  • monosaccharides such as glucose, fructose, mannose etc. and the polyols derived therefrom like sorbitol, mannitol etc.
  • disaccharides such as lactose, maltose, sucrose and their derivatives such as lactitol, maltitol, and oligo- and polysaccharides such as dextrins and starches.
  • the carrier base material for the spray drying process can be one of the above mentioned materials or combinations of these.
  • the carrier base material is a crystalline carrier base material, in particular a crystalline sugar such as glucose, fructose, sucrose or mannitol and most preferably the carrier base material is lactose.
  • the amorphous content of the spray dried product (base powder) is generally within the range 0.5% to 50%.
  • the amorphous material present in the spray dried powder particles can then be crystallised by any suitable method.
  • a particularly preferred method yielding good results is the use of a fluid bed dryer using suitable conditions with regard to temperature and relative humidity which allow the amorphous material to crystallise.
  • Suitable temperature conditions are a temperature of 20 to 100°C, preferably 30 to 90°C, more preferably 40 to 80 °C, even more preferably 50 to 70 °C, most preferably 60°C in combination with a suitable relative humidity of 80% to 10%, preferably 70 to 15%, more preferably 60 to 20%, even more preferably 50 to 25%, further more preferably 40 to 30%, most preferably 35%.
  • the carrier material of the invention produced for the purpose of dry powder inhalation has a particle size typically between 1 ⁇ m and 400 ⁇ m. Preferably, the particle size is between 40 ⁇ m and 300 ⁇ m. Typically, at least 90% of the particles are within this latter range.
  • the present invention furthermore relates to a dry powder inhalation formulation which contains a carrier material of the invention and at least one pharmacologically active component.
  • the active component may be selected from the group consisting of steroids, sympathomimetics, mucolytics, proteins, peptides, sodium cromoglycate or from the group consisting of hypnotics, sedatives, analgesics, ani-inflammatory agents, anti-histamines, anticonvulscents, muscle relaxants, anti-spasmodics, anti-bacterials, antibiotics, cardiovascular agents and hypoglycaemic agents.
  • the active component is budesonide or alternatively sodium cromoglycate.
  • ⁇ -lactose monohydrate is commonly used in dry powder inhalation formulations. It has generally a good performance, but over time the problems described in the specification, i.e. crystallisation upon contact with air humidity and thus decreased stability and performance, may occur.
  • ⁇ -lactose monohydrate standard crystal form of lactose
  • non-pretreated ⁇ -lactose monohydrate and a selected size fraction of the carrier material of the invention were used in an inhalation formulation.
  • a second control standard spray dried lactose was used as a second control standard spray dried lactose was used.
  • a suspension of a fine milled ⁇ -lactose monohydrate powder in an aqueous lactose solution was spray dried, resulting in a spray dried powder with approximately 20% amorphous lactose. This represents the standard spray dried lactose.
  • the amorphous lactose in the spray dried powder obtained above was then crystallised by a treatment in a fluid bed dryer at a temperature of 60 °C and a relative humidity of 35 % to obtain a powder having 90% of the particles in the particle size range from 40- 300 ⁇ m.
  • ⁇ -Lactose monohydrate was obtained from DMV International, Veghel, the Netherlands.
  • Budesonide was used as the active component, with an active ingredient to carrier ratio of 1:62.5.
  • the formulations were prepared using a tumble mixer.
  • the budesonide concentrations were determined by UV spectroscopy.
  • the performance of the formulations was assessed in vitro using the multi-stage liquid i pinger, with the method described in the USP24.
  • the device used was a multidose inhaler, utilising a reservoir system. The results obtained are shown in table 1 as a percentage (%) of the nominal dose.
  • the fraction "Stage 3 + 4 + filter" is considered as the fraction reaching the lungs

Abstract

The present invention relates to a carrier material for use in dry powder inhalation formulations, comprising carrier particles that are spherical in nature and contain no amorphous material. In addition the invention provides a method for the preparation of a carrier material for use in dry powder inhalation formulations, comprising the steps of providing a carrier base material consisting of sperical carrier particles; and crystallising the carrier base material in order to remove amorphous material present in the particles to obtain the carrier material.

Description

CARRIER MATERIAL FOR DRY POWDER INHALATION
The present invention relates to a carrier material for use in dry powder inhalation formulations, to the process for manufacture of these carrier materials and to dry powder inhalation formulations using the carrier materials.
Dry powder inhalers have been in existence since the late 1960 's. Interest in this technique for delivering pharmacological active components to the lungs was initially limited due to the popularity of pressurized metered dose inhalers (pMDI's). However, since the decision to eliminate CFC's from pMDI's due to environmental issues, dry powder inhalers are becoming more popular.
Traditionally, formulations for dry powder inhalation comprise a pharmacologically active component and an inert carrier material, being in most cases α-lactose monohydrate crystals. The active component is usually micronised with a particle size less than 5 μm, to enable deposition in the lower levels of the lungs. The purpose of the inert carrier is to aid flow and to prevent the formation of agglomerates of the active component which agglomerates can not be dispersed, thus preventing deposition at the site of action.
It was however found that over time α-lactose does not have an optimal flow, which may lead to problems, such as clogging, in the inhaler. In addition, it was found that α-lactose monohydrate does not always lead to a 100% drug delivery. Ideally, upon inhalation of a dry powder inhalation formulation, the carrier hits the throat, after which the drug, which is in loose association with the carrier, detaches therefrom and is transported to the lungs where it has its effect. In case the drug does not end up in the right location, i.e. the lung, there may arise problems for the patient.
Due to the increased interest in dry powder inhalation formulations, other concepts have been investigated include the use of anhydrous β-lactose as a carrier or agglomerates of the active component without carrier. These concepts have not led to satisfactory results either. It is therefore the object of the present invention to provide an improved carrier material for dry powder inhalation formulations.
In the research that led to the present invention it was found that spray-dried carrier material consists of spherical particles, which show excellent flow characteristics, but that spray dried products may contain amorphous material which can undergo crystallisation in the presence of moisture. When this crystallisation occurs in the presence of the active ingredient, such as a drug, it may become bound and will not detach upon inhalation. The presence of amorphous material can therefore potentially affect stability and performance of the inhalation formulation, if moisture uptake occurs within the dry powder inhaler. It was found that in order to improve the functionality of spray dried products in dry powder inhalation formulations a crystallisation step should be incorporated into the manufacture of the carrier material . The purpose of the crystallisation step is to remove substantially all, and preferably all the amorphous material present.
The present invention thus relates to a carrier material, comprising carrier particles that are spherical in nature and contain substantially no or no amorphous material. Such carrier material is for example obtainable by a method comprising the steps of: a) providing a carrier base material consisting of spherical carrier particles; and b) crystallising the carrier base material in order to remove amorphous material present in the particles to obtain the carrier material.
The provision of the spherical carrier base material can be achieved by spray drying a starting material to obtain a powder that consists of substantially spherical particles of the carrier material that still contain amorphous material. A suitable method for obtaining such carrier base material is described in EP-239 172, which is incorporated herein by reference. In summary, the method described therein comprises feeding a slurry of crystalline α-lactose hydrate in a saturated lactose solution to a spray drier and drying the same, wherein the selection of the ratio between the amounts of crystalline material and dissolved lactose in the slurry determines the ratio between the amounts of crystalline and amorphous lactose in the spray dried product. The person skilled in the art of spray drying can modify the process conditions to obtain a suitable spray dried product based on his common general knowledge of spray drying.
The present invention thus provides a spray dried product with substantially no or no amorphous material, by virtue of which it has excellent flow properties and is stable with regard to air moisture.
Preferred carrier materials are those known to be useful for dry powder inhalation formulations. In particular these are monosaccharides such as glucose, fructose, mannose etc. and the polyols derived therefrom like sorbitol, mannitol etc. , disaccharides such as lactose, maltose, sucrose and their derivatives such as lactitol, maltitol, and oligo- and polysaccharides such as dextrins and starches.
The carrier base material for the spray drying process can be one of the above mentioned materials or combinations of these. Preferably, the carrier base material is a crystalline carrier base material, in particular a crystalline sugar such as glucose, fructose, sucrose or mannitol and most preferably the carrier base material is lactose.
The amorphous content of the spray dried product (base powder) is generally within the range 0.5% to 50%. The amorphous material present in the spray dried powder particles can then be crystallised by any suitable method. A particularly preferred method yielding good results is the use of a fluid bed dryer using suitable conditions with regard to temperature and relative humidity which allow the amorphous material to crystallise. Suitable temperature conditions are a temperature of 20 to 100°C, preferably 30 to 90°C, more preferably 40 to 80 °C, even more preferably 50 to 70 °C, most preferably 60°C in combination with a suitable relative humidity of 80% to 10%, preferably 70 to 15%, more preferably 60 to 20%, even more preferably 50 to 25%, further more preferably 40 to 30%, most preferably 35%.
The carrier material of the invention produced for the purpose of dry powder inhalation has a particle size typically between 1 μm and 400 μm. Preferably, the particle size is between 40 μm and 300 μm. Typically, at least 90% of the particles are within this latter range. The present invention furthermore relates to a dry powder inhalation formulation which contains a carrier material of the invention and at least one pharmacologically active component. The active component may be selected from the group consisting of steroids, sympathomimetics, mucolytics, proteins, peptides, sodium cromoglycate or from the group consisting of hypnotics, sedatives, analgesics, ani-inflammatory agents, anti-histamines, anticonvulscents, muscle relaxants, anti-spasmodics, anti-bacterials, antibiotics, cardiovascular agents and hypoglycaemic agents. Preferably the active component is budesonide or alternatively sodium cromoglycate.
The performance of carrier material of the present invention is demonstrated in the following examples that are given for illustration purposes only. EXAMPLES EXAMPLE 1
Comparison to α-lactose monohydrate α-Lactose monohydrate is commonly used in dry powder inhalation formulations. It has generally a good performance, but over time the problems described in the specification, i.e. crystallisation upon contact with air humidity and thus decreased stability and performance, may occur. To demonstrate the performance of the invention in comparison to α-lactose monohydrate (standard crystal form of lactose) , non-pretreated α-lactose monohydrate and a selected size fraction of the carrier material of the invention were used in an inhalation formulation. As a second control standard spray dried lactose was used. A suspension of a fine milled α-lactose monohydrate powder in an aqueous lactose solution was spray dried, resulting in a spray dried powder with approximately 20% amorphous lactose. This represents the standard spray dried lactose.
To prepare the carrier material of the invention, the amorphous lactose in the spray dried powder obtained above was then crystallised by a treatment in a fluid bed dryer at a temperature of 60 °C and a relative humidity of 35 % to obtain a powder having 90% of the particles in the particle size range from 40- 300 μm. α-Lactose monohydrate was obtained from DMV International, Veghel, the Netherlands. Budesonide was used as the active component, with an active ingredient to carrier ratio of 1:62.5. The formulations were prepared using a tumble mixer. The budesonide concentrations were determined by UV spectroscopy. The performance of the formulations was assessed in vitro using the multi-stage liquid i pinger, with the method described in the USP24. The device used was a multidose inhaler, utilising a reservoir system. The results obtained are shown in table 1 as a percentage (%) of the nominal dose. The fraction "Stage 3 + 4 + filter" is considered as the fraction reaching the lungs.
Table 1
Figure imgf000007_0001
EXAMPLE 2
Comparison between carrier material of the invention and standard spray dried material
Analogous to the method described in Example 1, two inhalation preparations of sodium cromoglycate using carrier material of the invention and standard spray dried material were prepared and tested. Table 2 shows the results.
Table 2
Figure imgf000007_0002
Figure imgf000008_0001
EXAMPLE 3
Comparison between carrier material of the invention and standard spray dried material Two inhalation preparations of budesonide were prepared using carrier material of the invention and standard spray dried material, wherein the carrier material of the invention was prepared at varying spray drying conditions. The preparation and testing of these formulations was as described in Example 1. The deposition values given in Table 3 are the average of two determinations .
Table 3
Figure imgf000008_0002

Claims

1. Carrier material for use in dry powder inhalation formulations, comprising carrier particles that are spherical in nature and contain no amorphous material .
2. Method for the preparation of a carrier material for use in dry powder inhalation formulations, comprising the steps of: a) providing a carrier base material consisting of spherical carrier particles; and b) crystallising the carrier base material in order to remove amorphous material present in the particles to obtain the carrier material.
3. Method as claimed in claim 2 , wherein the provision of the spherical carrier base material is achieved by spray drying a starting material under conditions that lead to a powder that consists of substantially spherical particles of the carrier material that still contain amorphous material.
4. Method as claimed in claim 2 and 3, wherein the spherical carrier base material is produced by feeding a slurry of crystalline α-lactose hydrate in a saturated lactose solution to a spray drier and drying the same.
5. Method as claimed in claims 2-4, wherein step b) is performed at a temperature between 20 and 100 "C, preferably between 30 and 90 °C, more preferably between 40 and 80 °C, even more preferably between 50 and 70 °C, most preferably at 60 °C in combination with a relative humidity of 80% to 10%, preferably 70 to 15%, more preferably 60 to 20%, even more preferably 50 to 25%, further more preferably 40 to 30%, most preferably 35%.
6. Method according to claims 1-5, wherein the carrier material is produced of a monosaccharide, in particular glucose, fructose, mannose, or of the polyols derived therefrom, in particular sorbitol, mannitol.
7. Method according to claims 1-5, wherein the carrier material is produced of a disaccharide, in particular lactose, maltose, sucrose, or their polyols, in particular lactitol, mannitol.
8. Method according to claims 1-5, wherein the carrier material is produced of oligosaccharides or polysaccharides, in particular dextrins and starches.
9. Method according to claims 1-7, where the material is produced of a crystalline sugar, in particular glucose, fructose, mannitol, or sucrose.
10. Method according to claims 1-7, wherein the material is produced of lactose.
11. Carrier material for use in dry powder inhalation formulations obtainable by a method as claimed in claims 2-10.
12. A carrier material according to claim 11, wherein the particle size of the material is between 1 μm and 400 μm.
13. A carrier material according to claim 12 , wherein the particle size of the material is between 40 μm and 300 μm.
14. A dry powder inhalation formulation which contains a carrier material according to claims 1 or Ills and at least one pharmacologically active component.
15. A dry powder inhalation formulation according to claim 14, in which the active component is selected from the group consisting of steroids, sympathomimetics , mucolytics, proteins, peptides, sodium cromoglycate .
16. A dry powder inhalation formulation according to claim 14 , in which the active component is selected from the group consisting of hypnotics, sedatives, analgesics, ani-inflammatory agents, anti-histamines, anticonvulscents, muscle relaxants, anti-spasmodics, anti-bacterials, antibiotics, cardiovascular agents and hypoglycaemic agents.
17. A dry powder inhalation formulation according to claim 14, wherein the active component is budesonide.
18. A dry powder inhalation formulation according to claim 14, wherein the active component is sodium cromoglycate.
PCT/EP2001/008395 2000-07-20 2001-07-19 Carrier material for dry powder inhalation WO2002007705A1 (en)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003082253A1 (en) * 2002-03-28 2003-10-09 Lab Pharma Oy A method for treating carrier particles and its use
WO2003070908A3 (en) * 2002-02-19 2004-10-28 Dow Agrosciences Llc Novel spinosyn-producing polyketide synthases
WO2006037736A1 (en) * 2004-10-01 2006-04-13 Boehringer Ingelheim International Gmbh Novel powder inhalation preparations based on modified lactose blends that are used as adjuvants
WO2006037738A1 (en) * 2004-10-01 2006-04-13 Boehringer Ingelheim International Gmbh Modifying surfaces of lactose serving as an auxiliary agent to be used for powder inhalants
WO2008058691A2 (en) * 2006-11-15 2008-05-22 Jagotec Ag Powder formulation for inhalation
US8414867B2 (en) 2003-11-14 2013-04-09 Jagotec Ag Dry powder formulations
US8877251B2 (en) 2005-12-12 2014-11-04 Jagotec Ag Powder compositions for inhalation
CN111643487A (en) * 2020-06-12 2020-09-11 苏州大学 Lactose microsphere and preparation method thereof

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EP0239172A2 (en) * 1986-03-21 1987-09-30 Dmv-Campina B.V. Improved spray dried lactose and process for preparing the same
US5254330A (en) * 1990-01-24 1993-10-19 British Technology Group Ltd. Aerosol carriers
US5376386A (en) * 1990-01-24 1994-12-27 British Technology Group Limited Aerosol carriers
WO1998031346A1 (en) * 1997-01-16 1998-07-23 Massachusetts Institute Of Technology Preparation of particles for inhalation
US5874063A (en) * 1991-04-11 1999-02-23 Astra Aktiebolag Pharmaceutical formulation

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EP0239172A2 (en) * 1986-03-21 1987-09-30 Dmv-Campina B.V. Improved spray dried lactose and process for preparing the same
US5254330A (en) * 1990-01-24 1993-10-19 British Technology Group Ltd. Aerosol carriers
US5376386A (en) * 1990-01-24 1994-12-27 British Technology Group Limited Aerosol carriers
US5874063A (en) * 1991-04-11 1999-02-23 Astra Aktiebolag Pharmaceutical formulation
WO1998031346A1 (en) * 1997-01-16 1998-07-23 Massachusetts Institute Of Technology Preparation of particles for inhalation

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003070908A3 (en) * 2002-02-19 2004-10-28 Dow Agrosciences Llc Novel spinosyn-producing polyketide synthases
WO2003082253A1 (en) * 2002-03-28 2003-10-09 Lab Pharma Oy A method for treating carrier particles and its use
US8414867B2 (en) 2003-11-14 2013-04-09 Jagotec Ag Dry powder formulations
US7736628B2 (en) 2004-10-01 2010-06-15 Boehringer Ingelheim International Gmbh Powdered inhalants based on modified lactose mixtures as excipient
WO2006037736A1 (en) * 2004-10-01 2006-04-13 Boehringer Ingelheim International Gmbh Novel powder inhalation preparations based on modified lactose blends that are used as adjuvants
WO2006037738A1 (en) * 2004-10-01 2006-04-13 Boehringer Ingelheim International Gmbh Modifying surfaces of lactose serving as an auxiliary agent to be used for powder inhalants
JP2008514675A (en) * 2004-10-01 2008-05-08 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Surface modification of lactose that functions as an aid used for powder inhalers
JP2008514674A (en) * 2004-10-01 2008-05-08 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Novel powder inhalation formulations based on modified lactose blends used as adjuvants
US7658949B2 (en) 2004-10-01 2010-02-09 Boehringer Ingelheim International Gmbh Surface modification of lactose excipient for use in powders for inhalation
US8877251B2 (en) 2005-12-12 2014-11-04 Jagotec Ag Powder compositions for inhalation
WO2008058691A2 (en) * 2006-11-15 2008-05-22 Jagotec Ag Powder formulation for inhalation
JP2010509384A (en) * 2006-11-15 2010-03-25 ヤゴテック アーゲー Improvements in or related to organic compounds
AU2007321385B2 (en) * 2006-11-15 2013-08-22 Jagotec Ag Powder formulation for inhalation
WO2008058691A3 (en) * 2006-11-15 2008-10-23 Jagotec Ag Powder formulation for inhalation
CN111643487A (en) * 2020-06-12 2020-09-11 苏州大学 Lactose microsphere and preparation method thereof

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