WO1999061003A1 - Drug delivery system comprising a tightly compacted solid medicament stock - Google Patents

Drug delivery system comprising a tightly compacted solid medicament stock Download PDF

Info

Publication number
WO1999061003A1
WO1999061003A1 PCT/EP1999/003680 EP9903680W WO9961003A1 WO 1999061003 A1 WO1999061003 A1 WO 1999061003A1 EP 9903680 W EP9903680 W EP 9903680W WO 9961003 A1 WO9961003 A1 WO 9961003A1
Authority
WO
WIPO (PCT)
Prior art keywords
delivery system
drug delivery
tightly compacted
medicament stock
liposomes
Prior art date
Application number
PCT/EP1999/003680
Other languages
French (fr)
Inventor
Wolfgang Fleischer
Karen Reimer
Original Assignee
Euroceltique S.A.
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 Euroceltique S.A. filed Critical Euroceltique S.A.
Priority to JP2000550463A priority Critical patent/JP2002516269A/en
Priority to EP99953285A priority patent/EP1083886B1/en
Priority to CA002332369A priority patent/CA2332369A1/en
Priority to AU42667/99A priority patent/AU747877B2/en
Priority to IL13922999A priority patent/IL139229A0/en
Priority to DE69906518T priority patent/DE69906518D1/en
Priority to DE29923848U priority patent/DE29923848U1/en
Priority to DE29923847U priority patent/DE29923847U1/en
Priority to BR9911070-9A priority patent/BR9911070A/en
Priority to HU0102892A priority patent/HUP0102892A3/en
Priority to KR1020007013258A priority patent/KR20010043820A/en
Priority to AT99953285T priority patent/ATE235895T1/en
Publication of WO1999061003A1 publication Critical patent/WO1999061003A1/en

Links

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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • 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
    • 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
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • A61P11/04—Drugs for disorders of the respiratory system for throat disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Drug delivery system comprising a tightly compacted solid medicament stock
  • This invention is concerned with a drug delivery system comprising a tightly compacted solid medicament stock, a method for the preparation of the medicament stock as well as the use of the solid medicament stock of the invention.
  • Pulmonary application by way of inhalation or insufflation of drug substances has e.g. been achieved by administration of the respective drug as an aerosol or by powder inhalation. Since aerosols are often based on fluorohydrocarbons or other hydrocarbons, it is generally desirable to substitute aerosols by powder inhalation.
  • EP 0 407 028 discloses a device for administering drugs by inhalation in powdered form.
  • the drawback of the device and the medicament disclosed is that the solid reservoir cannot be handled safely since only low pressures are applied for compactation.
  • the compacted body is brittle and may fall apart when not handled carefully.
  • WO 94/14490 and WO 93/29165 are concerned with a system for application of powder or fine particles via inhalation.
  • the device according to WO 93/24165 allows generation of particles from a compacted tablet which has an isotropic substructure.
  • the compacted medicament according to WO 94/14490 is manufactured by applying pressures of up to 500 MPa, thus some orders of magnitude higher than those applied in EP 0 407 028.
  • the compacted body according to WO 94/14490 is advantageous as compared to the compacted body according to EP 0 407 028. It allows e.g. easy handling since caused by its tightness it does not fall apart. Furthermore, it does not tend to absorb water as compared to the less compacted body according to EP 0 407 028.
  • Liposomes are well known carriers of pharmaceutical compositions. Advantages of application of medicaments via liposomes have been subject of several reviews. Pulmonary application of liposomes has permitted major advances in the treatment of infectious diseases and asthma (compare e.g. H. Schreier, Pulmonary adjations of liposomes, in "Medical applications of liposomes", Paphadjopoulos & Lasic (eds.), Elsevier, 1997; RJ Gonzalez-Rothi & H. Schreier, Pulmonary delivery of liposome encapsulated drugs in asthma therapy, Clin. Immunother. 4, 331 - 337, 1995; H. Schreier, RJ. Gonzalez-Rothi, A. A.
  • aerosolized antimicrobiols e.g. aminoglycosides for the management of cystic fibrosis, ribavirin for respiratory syncytial virus infections in infants and pentamidine for the treatment of pulmonary Pneumocystis carinii infections in immuno-compromised patients have only recently been introduced (WO 96/27393, H. Schreier, K.J. McNicol, M. Ausborn, D.W. Soucy, H. Derendorf, A.A.
  • particulate carriers are generally prepared as known in the art.
  • microspheres which are used to deliver a very wide range of therapeutic or cosmetic agents, are made as described for example in WO 95/15118.
  • Nanoparticles may in some cases be used, provided that they can be loaded with a sufficient amount of active agent and can be administered to the lower respiratory tract according to this invention. They can be prepared according to the methods known in the art, as e.g. described by Heyder (GSF Mtinchen) in "Drugs delivered to the lung", Abstracts IV, Hilton Head Island Converence, May 1998.
  • PLD pulse laser deposition
  • a further suitable delivery system employs Large Porous Particles as disclosed by David A. Edwards et al. in " Large Porous Particles for Pulmonary Drug Delivery” (Science, 20. June 1997, Vol. 276, p. 1868-1871).
  • liposomes may be operated using suitable such alternative particulate carriers combined with, or instead of, liposomes.
  • Pulmonary delivery of drugs is complicated by (i) the need for training patients to coordinate breathing and inhaling of aerosols, (ii) rapid absorption of most drugs, necessitating frequent dosing which often is responsible for systemic side effects, (iii) poor aqueous solubility of drugs which may cause local irritation and inflammation in the airways or prevent the use of aerosols entirely, and (iv) poor cytosolic penetration of drug to treat intracellular pathogens.
  • Particulate carriers especially liposomes alleviate some of the problems encountered in conventional aerosol delivery, due to their ability to (i) serve as a solubilization matrix for poorly soluble agents; (ii) act as a pulmonary sustained release reservoirs, and (iii) facilitate intracellular delivery of drugs, specifically to alveolar macrophages. Consequently, liposomes may provide a means to (i) prevent local irritation of lung tissue and reduce pulmonary toxicity, (ii) prolong local therapeutic drug levels, and (iii) generate high intracellular drug concentrations, e.g. in infected alveolar macrophages.
  • Drugs that have been considered for pulmonary delivery via liposomes include anticancer drugs (antimicrobials, peptides, enzymes, antiasthmatic and antiallergic compounds as well as cromolyn sodium). Also immunomodulators, immunosuppressive agents, antiviral and antimycobacterial agents as well as gene constructs have been considered.
  • the drug delivery system of the present invention comprises a tightly compacted solid medicament stock having an essentially isotropic solid state structure comprising an active agent and which stock is suitable for the generation of inhalable particles containing said active agents, wherein the tightly compacted solid medicament stock comprises at least one active agent which is associated with the particulate carrier, such as liposomes.
  • the present invention is inter alia based on the unexpected finding that liposomes can withstand the high pressures which must be applied to form the tightly compacted solid medicament stock containing the liposomes. It is further surprising that the carriers, especially liposomes, which were loaded with an active agent or associated with an active agent, are not emptied or fully destroyed, when a powder containing e.g.
  • liposomes is generated by, for example, abrading methods performed with a device as disclosed in WO 93/24165 (which is incorporated by reference) from this tightly compacted medicament stock.
  • pressures up to 500 MPa are applied according to WO 94/14490 (which is also incorporated by reference).
  • the agent-associating liposomes survive both the compacting process (as in WO 97/14490) and the abrasion process (as in WO 93/24165) quite intact and apparently unchanged.
  • the active agent which is associated with the carriers is arranged in and/or arranged on said carrier.
  • the active agent is e.g. incorporated in liposomes or liposomes are loaded with the active agent, i.e. the active agent is encapsulated by the liposomes.
  • the active agent is also incorporated in the outer membrane enclosing the liposome, or even on the outer surface of the liposome membrane, so that the active agent is in this case not only released from the inner part of the liposome, but also from the membrane or shell of the liposome.
  • the nature of the particulate carrier, especially the liposomes is basically not critical for the drug delivery system of the present invention. All kinds of liposomes including negatively charged, neutral and cationic liposomes and lipid complexes as described in WO 96/27393 can be pressed to a tightly compacted medicament stock of the invention. Liposomes as described in our earlier application, now EP 0 639 373, can be employed in practising this invention.
  • the liposomes which are associated with at least one active agent are combined with at least one auxiliary material, such as a filler material.
  • the auxiliary material is a pharmaceutically acceptable filler material e.g. selected from physiologically acceptable sugars or salts. Particularly preferred are auxiliary materials selected from lactose, trehalose, glucose, mannit, sodium chloride and combinations thereof. It is preferred to use lactose as the auxiliary material in a ratio of at least one hundred parts by weight lactose to one part by weight liposome.
  • the medicament stock of the drug delivery system of the invention is compacted by isostatic pressing with pressures of from 50 to 500 MPa.
  • the at least one active agent can basically be any agent which shows pharmaceutical or biological effects, ranging from for example, small molecules to artificial human chromosomes, as long as they can be loaded or associated with liposomes.
  • the at least one active agent is selected from the group comprising ⁇ 2 -sympathomimetics having a short duration of effect such as salbutamol, terbutalin, fenoterol, bambuterol, ⁇ 2 -sympathomimetics having a long duration of effect such as salmeterol, formoterol, corticosteroids for inhalative purposes such as budesonide, beclomethason, fluticasone, anti-cholinergic agents such as ipatropium bromide, oxitropium bromide, - nonsteroidal anti-allergic agents such as DSCG, nedocromile, anti-inflammatory, especially antibiotic and/or antiseptic agents, such as povidone-iodine and combinations thereof.
  • the at least one active agent in the medicament stock of the drug delivery system of the present invention may be selected from ⁇ -lactam antibiotics such as penicillins, cephalosporines, imipinem; aminoglycosides such as tobramycin, gentamycin; inhibitors of gyrase such as ofloxacin, ciprofloxacin, - anti- viral agents such as ganciclovir, azidothymidin, anti-mycotic agents such as polyeme, azole, vaccines against measles, German measles, diphtheria, pertussis, polio and the like, vaccines consisting essentially of viral or bacterial components, - vaccines containing DNA coding for the generation of specific antigens, opioids for alleviation and therapy of pain such as morphine, oxycodone, hydromorphone, buprenorphine, fentanyl, alfentanyl, sulfentanyl and the like, anti-infective agents such as oli
  • the invention may be less suitable for hygroscopic agents, agents which are easily oxidized, and some agents unstable when exposed to light.
  • suitable protective substances to the liposome membrane forming amphiphilics, to the interior substances of the liposome, and/or to the auxiliary or carrier substances, to sufficiently protect and stabilize even such sensitive agents for use with this invention.
  • any suitable method for generation powder from a solid precursor may be employed. Particularly preferred are methods such as micronization or abrading methods especially those disclosed in EP 0 407 028 (incorporated by reference) as well as WO 94/14490 (incorporated by reference).
  • the particles which are generated from the tightly compacted medicament stock preferably have particle sizes of from 0.1 to 50 ⁇ m, more preferred of from 1 to 8 ⁇ m when used in pulmonar applications.
  • the respective particle sizes are preferably from 1 to 15 ⁇ m when used for nasal applications.
  • the method for the preparation of the medicament stock to be used in the drug delivery system according to the invention comprises to steps of preparation of the particulate carrier, especially the liposomes, and loading in a per se known manner.
  • the loaded carrier particles are mixed with at least one auxiliary material and are subsequently formed to a shaped body by isostatic pressing.
  • the pressure applied is in the range of from 50 to 500 MPa.
  • the shaped body is preferably shaped to be used with the device as disclosed in WO 93/24165. This is especially a ring tablet as disclosed in WO 94/14490.
  • the carrier is a liposome material
  • a dried lipid film for example, of phosphatidylcholine and phosphatidylglycerol may e.g. be dispersed in an aqueous solution, preferably in a physiological solution.
  • the respective active agent is present in the same solution, as is (optionally) the auxiliary material.
  • the dispersion is treated by intimately mixing the ingredients, for example, by shaking. Then the dispersion undergoes one or more freeze-thaw cycles and is emulsified, preferably by extrusion through a membrane.
  • the freeze-thaw and emulsification cycles are repeated several times.
  • methods for separation of liposomes and active drug are employed. These methods are known to the skilled person and are selected depending on the size of the active agent to be encapsulated. If, for example, a low molecular weight active agent has to be separated from the liposome dispersion this may be performed by dialyzing the mixture.
  • the final dispersion is further processed, for example, subsequently by freezing and freeze-drying.
  • the solid material preferably prepared by lyophilization is titurated to give a coarse liposome granulate. This granulate is mixed with the auxiliary material and subsequently compressed at pressures between 50 and 500 MPa. Solid, non-brittle tablets having a smooth surface are obtained by such procedures.
  • the tightly compacted solid medicament stock to be used in the drug delivery system of the invention is useful for the generation of particles which can be administered by insufflation and/or inhalation.
  • the tightly compacted solid medicament can be used in conventional therapy of diseases and disorders of the respiratory tract as well as diseases and disorders of organs.
  • the medicament stock of the invention can also be used in gene therapy and/or vaccination.
  • Gene therapy is emerging as a clinically viable therapeutic regimen for genetic, neoplastic and infectious deseases.
  • a prominent example is cystic fibrosis, a genetic disease resulting from immunization of the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
  • CTR cystic fibrosis transmembrane conductance regulator
  • vaccination can be effected by delivery of respective structures or substances with the drug delivery system of the present invention.
  • the conventional vehicles for inducing an immunoresponse can be administered by carriers such as liposomes which are present in a tightly compacted medicament stock of the invention.
  • PBS phosphate-buffered saline
  • FITC-dextran fluorescein isothiocyanate-dextran
  • alpha-lactose alpha-lactose
  • the freeze-thaw and extrusion cycle was repeated three times.
  • the liposome dispersion was dialyzed against a lactose solution (1,800 grams of alpha- lactose/ 10 L PBS) using a hollow-fiber cartridge with a molecular weight cutoff of 18,000 at a flow rate of 8 - 10 ml min.
  • the fluorescence concentration remained constant at approximately 50% of the original concentration as measured with a Hitachi F-2000 fluorescence spectrophotometer.
  • the final dispersion was frozen in a mixture of dry ice and ethanol and thransf erred to a lyophilizer (Edwars Supermodulyo).
  • the frozen preparation was freeze-dried at -40°C and 0.07 mbar for 48 hrs. followed by secondary drying at 25°C for 4 hrs.. The vacuum was replaced with dry nitrogen. The yield was 41.7 grams.
  • the lyophilized cake was triturated to give a free flowing, coarse liposome granulate. This granulate was mixed at a 1:10 Ratio w/w with lactose as compressed isostatically at 150 MPa for approximately 60 sec.
  • Solid, non-brittle tablets with a smooth surface were produced, mounted onto the plastic holder of the device according to WO 93/24165 and stored at room temperature in a plastic container. Tablets were actuated 20 times. The total mass shaved from the tablet surface per actuation and the FITC-dextran content per actuation were determined. A total delivered mass of 9.66 +/- 0.99 mg was found, containing 208 -+7-63 F.U. of FITC-dextran.
  • the PVP iodine solution was then added to the lipid film in the flask and the mixture was shaken until the film dissolved. This produced liposome formation from the hydrated lipids in the flask.
  • the product was centrifuged and the supernatant liquid was discarded.
  • the saccarose solution was added ad 12 ml and the product was again centrifuged. Afterwards the supernatant liquid was again discarded.
  • a further washing step using the saccharose solution or the sodium chloride buffer solution could be used.
  • sodium chloride buffer solution was added ad 12 ml, and the liposomes were homogenously distributed therein.
  • the product was then distributed into vials each containing 2 ml liposome dispersion, and the vials were then subjected to a freeze- drying step.
  • each vial comprised about 40 mg solids.
  • the ring tablets were used with the abrading device of WO 93/24165 and delivered a total of approximately 10 mg of powder upon each actuation.
  • the PVP-iodine content in the powder corresponded to the theoretical (calculated) value, within the experimental error margin.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Epidemiology (AREA)
  • Dispersion Chemistry (AREA)
  • Otolaryngology (AREA)
  • Dermatology (AREA)
  • Virology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Anesthesiology (AREA)
  • Molecular Biology (AREA)
  • AIDS & HIV (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Materials For Medical Uses (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

A drug delivery system comprising a tightly compacted solid medicament stock having an essentially isotropic solid state structure comprising an active agent and which stock is suitable for the generation of inhalable particles containing said active agent, wherein the tightly compacted solid medicament stock comprises at least one active agent which is associated with a particulate carrier material, especially comprising liposomes.

Description

Drug delivery system comprising a tightly compacted solid medicament stock
This invention is concerned with a drug delivery system comprising a tightly compacted solid medicament stock, a method for the preparation of the medicament stock as well as the use of the solid medicament stock of the invention.
Pulmonary application by way of inhalation or insufflation of drug substances has e.g. been achieved by administration of the respective drug as an aerosol or by powder inhalation. Since aerosols are often based on fluorohydrocarbons or other hydrocarbons, it is generally desirable to substitute aerosols by powder inhalation.
EP 0 407 028 discloses a device for administering drugs by inhalation in powdered form. The drawback of the device and the medicament disclosed is that the solid reservoir cannot be handled safely since only low pressures are applied for compactation. The compacted body is brittle and may fall apart when not handled carefully.
WO 94/14490 and WO 93/29165 are concerned with a system for application of powder or fine particles via inhalation. The device according to WO 93/24165 allows generation of particles from a compacted tablet which has an isotropic substructure. The compacted medicament according to WO 94/14490 is manufactured by applying pressures of up to 500 MPa, thus some orders of magnitude higher than those applied in EP 0 407 028. The compacted body according to WO 94/14490 is advantageous as compared to the compacted body according to EP 0 407 028. It allows e.g. easy handling since caused by its tightness it does not fall apart. Furthermore, it does not tend to absorb water as compared to the less compacted body according to EP 0 407 028.
Liposomes are well known carriers of pharmaceutical compositions. Advantages of application of medicaments via liposomes have been subject of several reviews. Pulmonary application of liposomes has permitted major advances in the treatment of infectious diseases and asthma (compare e.g. H. Schreier, Pulmonary aplications of liposomes, in "Medical applications of liposomes", Paphadjopoulos & Lasic (eds.), Elsevier, 1997; RJ Gonzalez-Rothi & H. Schreier, Pulmonary delivery of liposome encapsulated drugs in asthma therapy, Clin. Immunother. 4, 331 - 337, 1995; H. Schreier, RJ. Gonzalez-Rothi, A. A. Stecenko, Pulmonary delivery of liposomes, J. Controlled Release 24, 209 - 223, 1993). The diseased lung is particularly accessible to topical therapy by inhalation of drug aerosols (H. Schreier and S. M. Sawyer, Liposomal DNA vectors for cystic fibrosis gene therapy, Current applications, limitations, and future directions, Adv. Drug. Del. Rev. 19, 73 - 87, 1996; L. Gagne & H. Schreier, Aerosohzation of plasmid DNA, Protective effects of solute condensing agents, and liposome carriers, Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 1997). While antiasthmatic and antiallergic agents delivered by metered dose inhalers (MDI's) are widely used, aerosolized antimicrobiols e.g. aminoglycosides for the management of cystic fibrosis, ribavirin for respiratory syncytial virus infections in infants and pentamidine for the treatment of pulmonary Pneumocystis carinii infections in immuno-compromised patients have only recently been introduced (WO 96/27393, H. Schreier, K.J. McNicol, M. Ausborn, D.W. Soucy, H. Derendorf, A.A.
Stecenko, RJ. Gonzalez-Rothi, Pulmonary delivery of amikacin liposomes and acute liposome toxicity in the sheep, Int. J. Pharmaceut. 87, 183 - 193, 1992). Other particulate carriers have been described in the art, which are comparable to liposomes. These include microspheres, nanoparticles, Large Porous Particles, pulse laser polymer coated molecules, artificial virus envelopes etc.
Where alternative particulate carriers are used, they are generally prepared as known in the art. Thus, microspheres which are used to deliver a very wide range of therapeutic or cosmetic agents, are made as described for example in WO 95/15118.
Nanoparticles may in some cases be used, provided that they can be loaded with a sufficient amount of active agent and can be administered to the lower respiratory tract according to this invention. They can be prepared according to the methods known in the art, as e.g. described by Heyder (GSF Mtinchen) in "Drugs delivered to the lung", Abstracts IV, Hilton Head Island Converence, May 1998.
Methods using a pulse laser deposition (PLD) apparatus and a polymeric target to apply coatings to drug powders in a short non-aqueous process are also suitable for the formation of particulate preparations according to this invention. These have e.g. been described by Talton et al., "Novel Coating Method for Improved Dry Delivery", Univ. of Florida UF 1887 (1998).
A further suitable delivery system employs Large Porous Particles as disclosed by David A. Edwards et al. in " Large Porous Particles for Pulmonary Drug Delivery" (Science, 20. June 1997, Vol. 276, p. 1868-1871).
Where hereinafter reference is made to liposomes, it should be understood that the invention may be operated using suitable such alternative particulate carriers combined with, or instead of, liposomes. Pulmonary delivery of drugs is complicated by (i) the need for training patients to coordinate breathing and inhaling of aerosols, (ii) rapid absorption of most drugs, necessitating frequent dosing which often is responsible for systemic side effects, (iii) poor aqueous solubility of drugs which may cause local irritation and inflammation in the airways or prevent the use of aerosols entirely, and (iv) poor cytosolic penetration of drug to treat intracellular pathogens. Illustrative of such problems is the controversial use of ribavirin aerosols which requires excessive aerosohzation ("aerosol tent"), frequent monitoring of valves, tubing changes, and endotracheal tube suctioning to prevent precipitation of drug, while the clinical result is modest at best. Another therapeutically undesirable aspect of pulmonary drug delivery is rapid absorption of most drugs from the lung, necessitating frequent dosing, e.g. of bronchodilators and corticosteroids. Particulate carriers, especially liposomes alleviate some of the problems encountered in conventional aerosol delivery, due to their ability to (i) serve as a solubilization matrix for poorly soluble agents; (ii) act as a pulmonary sustained release reservoirs, and (iii) facilitate intracellular delivery of drugs, specifically to alveolar macrophages. Consequently, liposomes may provide a means to (i) prevent local irritation of lung tissue and reduce pulmonary toxicity, (ii) prolong local therapeutic drug levels, and (iii) generate high intracellular drug concentrations, e.g. in infected alveolar macrophages. Drugs that have been considered for pulmonary delivery via liposomes include anticancer drugs (antimicrobials, peptides, enzymes, antiasthmatic and antiallergic compounds as well as cromolyn sodium). Also immunomodulators, immunosuppressive agents, antiviral and antimycobacterial agents as well as gene constructs have been considered.
It is an object of the present invention to provide a drug delivery system for pulmonary delivery of active agents associated with liposomes or other such particulate carriers. Another object of the invention is to provide a tightly compacted solid medicament stock which is suitable for the generation of inhalable particles containing active agents.
The drug delivery system of the present invention comprises a tightly compacted solid medicament stock having an essentially isotropic solid state structure comprising an active agent and which stock is suitable for the generation of inhalable particles containing said active agents, wherein the tightly compacted solid medicament stock comprises at least one active agent which is associated with the particulate carrier, such as liposomes. The present invention is inter alia based on the unexpected finding that liposomes can withstand the high pressures which must be applied to form the tightly compacted solid medicament stock containing the liposomes. It is further surprising that the carriers, especially liposomes, which were loaded with an active agent or associated with an active agent, are not emptied or fully destroyed, when a powder containing e.g. liposomes is generated by, for example, abrading methods performed with a device as disclosed in WO 93/24165 (which is incorporated by reference) from this tightly compacted medicament stock. Preferably, pressures up to 500 MPa are applied according to WO 94/14490 (which is also incorporated by reference).
Surprisingly, the agent-associating liposomes survive both the compacting process (as in WO 97/14490) and the abrasion process (as in WO 93/24165) quite intact and apparently unchanged.
According to the invention it is preferred that the active agent which is associated with the carriers is arranged in and/or arranged on said carrier. Preferably the active agent is e.g. incorporated in liposomes or liposomes are loaded with the active agent, i.e. the active agent is encapsulated by the liposomes. However, in loading processes it may well occur that the active agent is also incorporated in the outer membrane enclosing the liposome, or even on the outer surface of the liposome membrane, so that the active agent is in this case not only released from the inner part of the liposome, but also from the membrane or shell of the liposome.
The nature of the particulate carrier, especially the liposomes is basically not critical for the drug delivery system of the present invention. All kinds of liposomes including negatively charged, neutral and cationic liposomes and lipid complexes as described in WO 96/27393 can be pressed to a tightly compacted medicament stock of the invention. Liposomes as described in our earlier application, now EP 0 639 373, can be employed in practising this invention.
Preferably, the liposomes which are associated with at least one active agent, are combined with at least one auxiliary material, such as a filler material. Preferably, the auxiliary material is a pharmaceutically acceptable filler material e.g. selected from physiologically acceptable sugars or salts. Particularly preferred are auxiliary materials selected from lactose, trehalose, glucose, mannit, sodium chloride and combinations thereof. It is preferred to use lactose as the auxiliary material in a ratio of at least one hundred parts by weight lactose to one part by weight liposome. In a preferred embodiment, the medicament stock of the drug delivery system of the invention is compacted by isostatic pressing with pressures of from 50 to 500 MPa.
The at least one active agent can basically be any agent which shows pharmaceutical or biological effects, ranging from for example, small molecules to artificial human chromosomes, as long as they can be loaded or associated with liposomes. In particular the at least one active agent is selected from the group comprising β2-sympathomimetics having a short duration of effect such as salbutamol, terbutalin, fenoterol, bambuterol, β2-sympathomimetics having a long duration of effect such as salmeterol, formoterol, corticosteroids for inhalative purposes such as budesonide, beclomethason, fluticasone, anti-cholinergic agents such as ipatropium bromide, oxitropium bromide, - nonsteroidal anti-allergic agents such as DSCG, nedocromile, anti-inflammatory, especially antibiotic and/or antiseptic agents, such as povidone-iodine and combinations thereof.
Furthermore, the at least one active agent in the medicament stock of the drug delivery system of the present invention may be selected from β-lactam antibiotics such as penicillins, cephalosporines, imipinem; aminoglycosides such as tobramycin, gentamycin; inhibitors of gyrase such as ofloxacin, ciprofloxacin, - anti- viral agents such as ganciclovir, azidothymidin, anti-mycotic agents such as polyeme, azole, vaccines against measles, German measles, diphtheria, pertussis, polio and the like, vaccines consisting essentially of viral or bacterial components, - vaccines containing DNA coding for the generation of specific antigens, opioids for alleviation and therapy of pain such as morphine, oxycodone, hydromorphone, buprenorphine, fentanyl, alfentanyl, sulfentanyl and the like, anti-infective agents such as oligo/polyribo- and/or oligo/polydesoxy- ribonucleic acids, peptides, polypeptides such as insulin, low and high molecular heparin, hormones such as growth factors, hormones of the thyroid gland, sex hormones, calcitonin, and combinations thereof. Unless extra precautions are taken, the invention may be less suitable for hygroscopic agents, agents which are easily oxidized, and some agents unstable when exposed to light. However, it is often possible to add suitable protective substances to the liposome membrane forming amphiphilics, to the interior substances of the liposome, and/or to the auxiliary or carrier substances, to sufficiently protect and stabilize even such sensitive agents for use with this invention.
In order to generate the particulate material from the tightly compacted medicament stock of the invention, any suitable method for generation powder from a solid precursor may be employed. Particularly preferred are methods such as micronization or abrading methods especially those disclosed in EP 0 407 028 (incorporated by reference) as well as WO 94/14490 (incorporated by reference).
The particles which are generated from the tightly compacted medicament stock preferably have particle sizes of from 0.1 to 50 μm, more preferred of from 1 to 8 μm when used in pulmonar applications. The respective particle sizes are preferably from 1 to 15 μm when used for nasal applications.
The method for the preparation of the medicament stock to be used in the drug delivery system according to the invention comprises to steps of preparation of the particulate carrier, especially the liposomes, and loading in a per se known manner. Optionally, the loaded carrier particles are mixed with at least one auxiliary material and are subsequently formed to a shaped body by isostatic pressing. Preferably, the pressure applied is in the range of from 50 to 500 MPa.
The shaped body is preferably shaped to be used with the device as disclosed in WO 93/24165. This is especially a ring tablet as disclosed in WO 94/14490. Where the carrier is a liposome material, a dried lipid film, for example, of phosphatidylcholine and phosphatidylglycerol may e.g. be dispersed in an aqueous solution, preferably in a physiological solution. The respective active agent is present in the same solution, as is (optionally) the auxiliary material. The dispersion is treated by intimately mixing the ingredients, for example, by shaking. Then the dispersion undergoes one or more freeze-thaw cycles and is emulsified, preferably by extrusion through a membrane. The freeze-thaw and emulsification cycles are repeated several times. In order to remove unencapsulated active agent, methods for separation of liposomes and active drug are employed. These methods are known to the skilled person and are selected depending on the size of the active agent to be encapsulated. If, for example, a low molecular weight active agent has to be separated from the liposome dispersion this may be performed by dialyzing the mixture. The final dispersion is further processed, for example, subsequently by freezing and freeze-drying. The solid material, preferably prepared by lyophilization is titurated to give a coarse liposome granulate. This granulate is mixed with the auxiliary material and subsequently compressed at pressures between 50 and 500 MPa. Solid, non-brittle tablets having a smooth surface are obtained by such procedures.
The tightly compacted solid medicament stock to be used in the drug delivery system of the invention is useful for the generation of particles which can be administered by insufflation and/or inhalation. The tightly compacted solid medicament can be used in conventional therapy of diseases and disorders of the respiratory tract as well as diseases and disorders of organs. The medicament stock of the invention can also be used in gene therapy and/or vaccination.
Gene therapy is emerging as a clinically viable therapeutic regimen for genetic, neoplastic and infectious deseases. A prominent example is cystic fibrosis, a genetic disease resulting from immunization of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Because of this pulmonary delivery of liposomal carriers of gene constructs has received much attention recently. However, it has been shown experimentally, that repeated cycling of DNA with or without liposomes, through a conventional nebulizer is detrimental for DNA and leads to complete degradation within minutes from the onset of nebulization. In addition to these, and in view of other general liposome-related stability considerations, gene therapy requires relatively concentrated doses of DNA complexes or encapsulated within liposomes to be delivered. Concentrated solutions of DNA/lipid complexes tend, however, to aggregate and precipitate, thus making nebulization of aqueous dispersions impractical. The drug delivery system of the present invention using the tightly compacted medicament stock of the invention, however, is able to overcome the drawbacks of other DNA liposome administration methods as known in the prior art. Other gene therapy objectives may be the curing of factor IX and αj-antitrypsin gene deficiencies as well as treatment of hemophilia which is related to deficiencies of factor VIII production or production of other important proteins in the blood clotting cascade. Of course, it is to be understood that the above-mentioned gene therapy targets are only mentioned for illustrative purposes. They are not intended to limit the scope of the invention.
Also vaccination can be effected by delivery of respective structures or substances with the drug delivery system of the present invention. In this case the conventional vehicles for inducing an immunoresponse can be administered by carriers such as liposomes which are present in a tightly compacted medicament stock of the invention.
The following examples are intended to explain the invention in more detail and are not intended to restrict or limit the scope of the invention. Example I
A dry lipid film consisting of 5.76 grams of phosphatidylcholine and 0.64 grams of phosphatidylglycerol was dispersed in 160 ml of phosphate-buffered saline (PBS) containing 3.8 grams of fluorescein isothiocyanate-dextran (FITC-dextran) and 28.8 grams of alpha-lactose. The dispersion was shaken manually for 2 hours, then underwent for freeze-thaw cycles and was emulsified by extrusion through 100 nm pore-size membranes (Poretic) for 10 min at no more than 3,000 psi using an EmulsiFex-C5 (Avestin) homogenizer. The freeze-thaw and extrusion cycle was repeated three times. In order to remove unencapsulated FITC-dextran, the liposome dispersion was dialyzed against a lactose solution (1,800 grams of alpha- lactose/ 10 L PBS) using a hollow-fiber cartridge with a molecular weight cutoff of 18,000 at a flow rate of 8 - 10 ml min. After three dialysis cycles, the fluorescence concentration remained constant at approximately 50% of the original concentration as measured with a Hitachi F-2000 fluorescence spectrophotometer.
The final dispersion was frozen in a mixture of dry ice and ethanol and thransf erred to a lyophilizer (Edwars Supermodulyo). The frozen preparation was freeze-dried at -40°C and 0.07 mbar for 48 hrs. followed by secondary drying at 25°C for 4 hrs.. The vacuum was replaced with dry nitrogen. The yield was 41.7 grams. The lyophilized cake was triturated to give a free flowing, coarse liposome granulate. This granulate was mixed at a 1:10 Ratio w/w with lactose as compressed isostatically at 150 MPa for approximately 60 sec. Solid, non-brittle tablets with a smooth surface were produced, mounted onto the plastic holder of the device according to WO 93/24165 and stored at room temperature in a plastic container. Tablets were actuated 20 times. The total mass shaved from the tablet surface per actuation and the FITC-dextran content per actuation were determined. A total delivered mass of 9.66 +/- 0.99 mg was found, containing 208 -+7-63 F.U. of FITC-dextran. Example II
The above procedure was repeated using liposomes made in accordance with EP 0 639 373, as follows:
In a 1000 ml glass flask, provided with glass beads for increased surface, 51.9 mg cholesterol and 213 mg hydrogenated soy bean lecithine were dissolved in a sufficient amount of a mixture of methanol and chloroform in a 2:1 ratio. The solvent was then evaporated under a vacuum until a film was formed on the inner surface of the flask and on the glass beads.
2.4 g PNP iodine (containing about 10% available iodine) were separately dissolved in 12 ml water.
Again in a separate vessel, 8.77 g sodium chloride and 1.78 g Νa2HPO4-2H2O were dissolved in 400 ml water. Further water was added up to a total volume of 980 ml, and then, approximately 12 ml IN hydrochloric acid were added to adjust pH to 7.4. This solution was then topped up with water to exactly 1000 ml.
In a fourth vessel, 900 mg saccharose and 57 mg disodium succinate were dissolved in 12 ml water.
The PVP iodine solution was then added to the lipid film in the flask and the mixture was shaken until the film dissolved. This produced liposome formation from the hydrated lipids in the flask. The product was centrifuged and the supernatant liquid was discarded. The saccarose solution was added ad 12 ml and the product was again centrifuged. Afterwards the supernatant liquid was again discarded. At this stage, a further washing step, using the saccharose solution or the sodium chloride buffer solution could be used. After the last centrifugation step and discarding of the supernatant, sodium chloride buffer solution was added ad 12 ml, and the liposomes were homogenously distributed therein. The product was then distributed into vials each containing 2 ml liposome dispersion, and the vials were then subjected to a freeze- drying step.
After the freeze-drying, each vial comprised about 40 mg solids.
The solid liposomes were then compacted, with lactose, as described in Example I.
The ring tablets were used with the abrading device of WO 93/24165 and delivered a total of approximately 10 mg of powder upon each actuation. The PVP-iodine content in the powder corresponded to the theoretical (calculated) value, within the experimental error margin.

Claims

C l a i m s
1. A drug delivery system comprising a tightly compacted solid medicament stock having an essentially isotropic solid state structure comprising an active agent and which stock is suitable for the generation of inhalable particles containing said active agent, wherein the tightly compacted solid medicament stock comprises at least one active agent which is associated with liposomes or a similar particulate carrier.
2. The drug delivery system of claim 1, wherein the at least one active agent comprised in the tightly compacted medicament stock is encapsulated in and/or associated with the membranes of said liposomes.
3. The drug delivery system of claim 1 and/or 2, wherein said tightly compacted solid medicament stock contains said liposomes together with auxiliary material such as filler materials.
4. The drug delivery system of any one of the claims 1 to 3, wherein said at least one active agent comprised in the tightly compacted solid medicament stock is selected from the group comprising ╬▓2-sympathomimetics having a short duration of effect such as salbutamol, terbutalin, fenoterol, bambuterol, ╬▓2-sympathomimetics having along duration of effect such as salmeterol, formoterol, corticosteroids for inhalative purposes such as budesonide, beclomethason, fluticasone, anti-cholinergic agents such as ipatropium bromide, oxitropium bromide, nonsteroidal anti-allergic agents such as DSCG, nedocromile, anti-inflammatory, especially antiobiotic and/or antiseptic agents such as povidone-iodine and combinations thereof.
5. The drug delivery system of any one of the claims 1 to 3, wherein said at least one active agent comprised in the tightly compacted solid medicament stock is selected from the group comprising ╬▓-lactam antibiotics such as penicillins, cephalosporines, imipinem; aminoglycosides such as tobramycin, gentamycin; inhibitors of gyrase such as ofloxacin, ciprofloxacin, anti-viral agents such as ganciclovir, azidothymidin, anti-mycotic agents such as polyeme, azole, vaccines against measles, German measles, diphtheria, pertussis, polio and the like, - vaccines consisting essentially of viral or bacterial components, vaccines containing DNA coding for the generation of specific antigens, opioids for alleviation and therapy of pain such as morphine, oxycodone, hydromorphone, buprenorphine, fentanyl, alfentanyl, sulfentanyl and the like, - anti-infective agents such as oligo/polyribo- and/or oligo/polydesoxy- ribonucleic acids, peptides, polypeptides such as insulin, low and high molecular heparin, hormones such as growth factors, hormones of the thyroid gland, sex hormones, calcitonin, and combinations thereof.
6. The drug delivery system of any one of the claims 1 to 5, wherein the tightly compacted solid medicament stock has been compacted by isostatic pressing with pressures of from 50 to 500 MPa.
7. The drug delivery system of any one of the claims 1 to 6, wherein the auxiliary material in the tightly compacted solid medicament stock is selected from lactose, threhalose, glucose, mannit sodium chloride and combinations thereof.
8. The drug delivery system of any one of the claims 1 to 7, wherein the liposomes are mixed with lactose in a ratio of at least 100 parts by weight lactose to 1 part by weight liposome.
9. The drug delivery system of any one of the claims 1 to 5, wherein the tightly compacted medicament stock is subjected to suitable processes to generate particles such as by micronisation or abrading.
10. The drug delivery system of claim 9, wherein the generated particles have particle sizes ranging from 0.1 to 50 ╬╝m, in particular from 1 to 8 ╬╝m when used in pulmonal applications, and from 1 to 15 ╬╝m when used for nasal applications.
11. The drug delivery system of claim 1 wherein the particulate carrier is selected from microspheres, nanoparticles, Large Porous Particles, artificial virus envelopes and similar pharmaceutically acceptable materials.
12. A method for the preparation of the tightly compacted solid medicament stock of the drug delivery system of any one of the claims 1 to 11, wherein the liposomes are prepared or loaded in a known manner, are optionally mixed with at least one auxiliary material, and are subsequently formed to a shaped body by isostatic pressing.
13. The method of claim 12, wherein the isostatic pressing is performed with pressures of from 50 to 500 MPa.
14. Use of a tightly compacted solid medicament stock in a drug delivery system of any one of the claims 1 to 11 for the generation of particles which can be administered by insufflation and/or inhalation, in the therapy of diseases and disorders of the respiratory tract as well as diseases and disorders of organs, gene therapy and/or vaccination.
PCT/EP1999/003680 1998-05-27 1999-05-27 Drug delivery system comprising a tightly compacted solid medicament stock WO1999061003A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
JP2000550463A JP2002516269A (en) 1998-05-27 1999-05-27 Drug Delivery System Including Strongly Compressed Solid Drug Materials
EP99953285A EP1083886B1 (en) 1998-05-27 1999-05-27 Drug delivery system comprising a tightly compacted solid medicament stock
CA002332369A CA2332369A1 (en) 1998-05-27 1999-05-27 Drug delivery system comprising a tightly compacted solid medicament stock
AU42667/99A AU747877B2 (en) 1998-05-27 1999-05-27 Drug delivery system comprising a tightly compacted solid medicament stock
IL13922999A IL139229A0 (en) 1998-05-27 1999-05-27 Drug delivery system comprising a tightly compacted solid medicament stock
DE69906518T DE69906518D1 (en) 1998-05-27 1999-05-27 DRUG DISPENSING SYSTEM CONTAINS A SOLID, SOLID, DRY-BASED BASIS
DE29923848U DE29923848U1 (en) 1998-05-27 1999-05-27 Preparations for the use of anti-inflammatory, in particular antiseptic active substances and / or active substances promoting wound healing in the upper respiratory tract and / or the ear
DE29923847U DE29923847U1 (en) 1998-05-27 1999-05-27 Preparations for the use of anti-inflammatory, in particular antiseptic agents and / or agents promoting wound healing in the lower respiratory tract
BR9911070-9A BR9911070A (en) 1998-05-27 1999-05-27 Drug delivery system comprising a sharply compacted solid drug raw material
HU0102892A HUP0102892A3 (en) 1998-05-27 1999-05-27 Drug delivery system comprising a tightly compacted solid medicament stock, process for its preparation and for its use
KR1020007013258A KR20010043820A (en) 1998-05-27 1999-05-27 Drug delivery system comprising a tightly compacted solid medicament stock
AT99953285T ATE235895T1 (en) 1998-05-27 1999-05-27 DRUG DELIVERY SYSTEM CONTAINING A HARD-PACKED, SOLID DRUG BASE

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US8689598P 1998-05-27 1998-05-27
US60/086,895 1998-05-27

Publications (1)

Publication Number Publication Date
WO1999061003A1 true WO1999061003A1 (en) 1999-12-02

Family

ID=22201600

Family Applications (3)

Application Number Title Priority Date Filing Date
PCT/EP1999/003677 WO1999060998A1 (en) 1998-05-27 1999-05-27 Preparations for the application of anti-inflammatory, especially antiseptic agents and/or agents promoting the healing of wounds, to the upper respiratory tract and/or the ear
PCT/EP1999/003681 WO1999060999A1 (en) 1998-05-27 1999-05-27 Preparations for the application of anti-inflammatory, especially antiseptic agents and/or agents promoting the healing of wounds, to the lower respiratory tract
PCT/EP1999/003680 WO1999061003A1 (en) 1998-05-27 1999-05-27 Drug delivery system comprising a tightly compacted solid medicament stock

Family Applications Before (2)

Application Number Title Priority Date Filing Date
PCT/EP1999/003677 WO1999060998A1 (en) 1998-05-27 1999-05-27 Preparations for the application of anti-inflammatory, especially antiseptic agents and/or agents promoting the healing of wounds, to the upper respiratory tract and/or the ear
PCT/EP1999/003681 WO1999060999A1 (en) 1998-05-27 1999-05-27 Preparations for the application of anti-inflammatory, especially antiseptic agents and/or agents promoting the healing of wounds, to the lower respiratory tract

Country Status (19)

Country Link
US (2) US20080038330A1 (en)
EP (3) EP1083886B1 (en)
JP (3) JP2002516269A (en)
KR (3) KR100613706B1 (en)
CN (3) CN1303271A (en)
AT (3) ATE319427T1 (en)
AU (3) AU747877B2 (en)
BR (3) BR9911072A (en)
CA (3) CA2332369A1 (en)
CY (1) CY1105834T1 (en)
DE (6) DE29923766U1 (en)
DK (2) DK1079806T3 (en)
ES (2) ES2260915T3 (en)
HK (2) HK1035335A1 (en)
HU (3) HUP0102892A3 (en)
IL (4) IL139230A0 (en)
PT (2) PT1079807E (en)
RU (3) RU2212884C2 (en)
WO (3) WO1999060998A1 (en)

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10125731A1 (en) * 2001-05-17 2003-03-06 A I D Autoimmun Diagnostika Gm Dosage form of immunological agents
US6667344B2 (en) 2001-04-17 2003-12-23 Dey, L.P. Bronchodilating compositions and methods
US7297344B1 (en) 1999-05-27 2007-11-20 Euro-Celtique, S.A. Preparations for the promotion of wound healing in the upper respiratory tract and/or ear
US7300667B1 (en) 1999-05-27 2007-11-27 Euro-Celtique, S.A. Preparations for the application of anti-inflammatory, especially antiseptic agents and/or agents promoting the healing of wounds, to the lower respiratory tract
US7348362B2 (en) 2003-07-10 2008-03-25 Dey, L.P. Bronchodilating β-agonist compositions and methods
US7468194B1 (en) 1999-05-27 2008-12-23 Euro-Celtique, S.A. Preparations for the application of anti-inflammatory agents
US7473433B2 (en) 2000-12-21 2009-01-06 Nektar Therapeutics Pulmonary delivery of polyene antifungal agents
US8158133B2 (en) 2004-12-02 2012-04-17 Vetoquinol Pharmaceutical composition useful for vaccines
JP2012176993A (en) * 2000-02-08 2012-09-13 Euro-Celtique Sa Controlled-release composition containing opioid agonist and antagonist
US8623851B2 (en) 2001-04-17 2014-01-07 Mylan Specialty L.P. Formoterol/steroid bronchodilating compositions and methods of use thereof
US9114081B2 (en) 2007-05-07 2015-08-25 Insmed Incorporated Methods of treating pulmonary disorders with liposomal amikacin formulations
US9119783B2 (en) 2007-05-07 2015-09-01 Insmed Incorporated Method of treating pulmonary disorders with liposomal amikacin formulations
US9333214B2 (en) 2007-05-07 2016-05-10 Insmed Incorporated Method for treating pulmonary disorders with liposomal amikacin formulations
US9402845B2 (en) 2005-12-08 2016-08-02 Insmed Incorporated Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof
US9566234B2 (en) 2012-05-21 2017-02-14 Insmed Incorporated Systems for treating pulmonary infections
US9827317B2 (en) 2002-10-29 2017-11-28 Insmed Incorporated Sustained release of antiinfectives
US9895385B2 (en) 2014-05-15 2018-02-20 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US9925251B2 (en) 2011-10-19 2018-03-27 President And Fellows Of Harvard College Treatments for Mycobacterium tuberculosis
US9925205B2 (en) 2007-05-04 2018-03-27 Insmed Incorporated Compositions of multicationic drugs for reducing interactions with polyanionic biomolecules and methods of use thereof
US10124066B2 (en) 2012-11-29 2018-11-13 Insmed Incorporated Stabilized vancomycin formulations
WO2019202400A1 (en) * 2018-04-17 2019-10-24 Universite De Caen Normandie Bambuterol for the treatment of alzheimer's disease
EP3621596B1 (en) 2017-05-10 2022-02-23 Université de Bordeaux Tablets comprising nucleic acid vectors
US11571386B2 (en) 2018-03-30 2023-02-07 Insmed Incorporated Methods for continuous manufacture of liposomal drug products

Families Citing this family (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2341532T3 (en) * 1999-05-27 2010-06-22 Euro-Celtique S.A. PREPARATION WITH POVIDONA YODADA FOR THE TREATMENT OF WOUNDS.
US6989157B2 (en) * 2000-07-27 2006-01-24 Nucryst Pharmaceuticals Corp. Dry powders of metal-containing compounds
DE10141650C1 (en) * 2001-08-24 2002-11-28 Lohmann Therapie Syst Lts Safe transdermal therapeutic system for administration of fentanyl or analogous analgesics, having matrix layer of carboxy group-free polyacrylate adhesive providing high permeation rate
KR20040093155A (en) * 2002-03-18 2004-11-04 야마노우치세이야쿠 가부시키가이샤 Powdery medicinal compositions for inhalation and process for producing the same
JP4391948B2 (en) * 2002-11-11 2009-12-24 興和株式会社 Composition for repairing damaged skin
AU2003301077B2 (en) * 2002-12-18 2009-12-24 Hough Ear Institute Otologic nanotechnology
EP1449520A1 (en) * 2003-02-24 2004-08-25 Euro-Celtique S.A. Use of PVP-Iodine liposomes for treatment of herpes
DE60315955T2 (en) * 2003-05-19 2008-06-05 Euro-Celtique S.A. Dry liposomal PVP-iodine preparations
US7723311B2 (en) 2003-06-18 2010-05-25 Nanobiomagnetics, Inc. Delivery of bioactive substances to target cells
US7344491B1 (en) 2003-11-26 2008-03-18 Nanobiomagnetics, Inc. Method and apparatus for improving hearing
US8651113B2 (en) 2003-06-18 2014-02-18 Swr&D Inc. Magnetically responsive nanoparticle therapeutic constructs and methods of making and using
US20050058673A1 (en) 2003-09-09 2005-03-17 3M Innovative Properties Company Antimicrobial compositions and methods
US9028852B2 (en) 2004-09-07 2015-05-12 3M Innovative Properties Company Cationic antiseptic compositions and methods of use
BRPI0608690B8 (en) 2005-03-10 2021-05-25 3M Innovative Properties Co use of an antimicrobial composition
AU2006223136A1 (en) 2005-03-10 2006-09-21 3M Innovative Properties Company Antimicrobial compositions comprising esters of hydroxycarboxylic acids
DE102006011314A1 (en) 2006-03-11 2007-10-18 Peter Dr. Engels Cosmetic preparations containing an additive from the baobab plant
US20080057129A1 (en) * 2006-04-03 2008-03-06 Lerner E I Drug microparticles
RU2315593C1 (en) * 2006-08-02 2008-01-27 Открытое Акционерное Общество Завод Экологической Техники И Экопитания "Диод" Antioxidant liposomal composition fir inhalation in lung and upper respiratory tract diseases
US8268347B1 (en) * 2006-10-24 2012-09-18 Aradigm Corporation Dual action, inhaled formulations providing both an immediate and sustained release profile
US8119156B2 (en) * 2006-10-24 2012-02-21 Aradigm Corporation Dual action, inhaled formulations providing both an immediate and sustained release profile
US8071127B2 (en) 2006-10-24 2011-12-06 Aradigm Corporation Dual action, inhaled formulations providing both an immediate and sustained release profile
JP5551442B2 (en) 2006-10-27 2014-07-16 スリーエム イノベイティブ プロパティズ カンパニー Antibacterial composition
WO2009067067A1 (en) * 2007-11-23 2009-05-28 Pharmalundensis Ab Method and means for obtaining bronchorelaxation
WO2009085651A1 (en) 2007-12-20 2009-07-09 Nucryst Pharmaceuticals Corp. Metal carbonate particles for use in medicine and methods of making thereof
KR20100048751A (en) * 2008-10-31 2010-05-11 주식회사 동성바이오레인 Capsulated functional dual core aerosol composition and the method for their manufacture
NL2002442C2 (en) 2009-01-22 2010-07-26 Weezenbeek Specialties B V Van Process for rejuvenating a composition containing a compound.
EP2226073A1 (en) 2009-03-02 2010-09-08 Euro-Celtique S.A. Topical pharmaceutical composition comprising an antiseptic and arginine for wound healing
US20110086084A1 (en) * 2009-10-13 2011-04-14 David William Koenig Active Agent Containing Polymer Network Delivery Composition and Articles Using the Same
SI2722053T1 (en) 2010-12-30 2018-02-28 Aktsionernoye Obshchestvo "Nauchnyi Tsentr Protivoninfektsionnyh Preparatov" Antibacterial agent for treating infectious diseases of bacterial origin
KR101860485B1 (en) * 2011-11-03 2018-07-02 (주)아모레퍼시픽 Tissue for skin with nano-emulsion, method for manufacturing the same and method for using the same
RU2538433C1 (en) * 2013-06-11 2015-01-10 Закрытое акционерное общество "ФИРН М" (ЗАО ФИРН М") Pharmaceutical composition for preventing and treating infectious-inflammatory diseases of various origins by oromucosal administration
US9987227B2 (en) 2013-10-22 2018-06-05 Aradigm Corporation Inhaled surfactant-modified liposomal formulations providing both an immediate and sustained release profile
RU2550932C1 (en) * 2014-03-18 2015-05-20 Александр Александрович Кролевец Method for producing cephalosporin nanocapsules in xanthum gum
US20160120806A1 (en) * 2014-04-08 2016-05-05 Aradigm Corporation Nanocrystals formed in a microenvironment
WO2015157038A1 (en) 2014-04-08 2015-10-15 Aradigm Corporation Liposomal ciprofloxacin formulations with activity against non-tuberculous mycobacteria
CN106456551A (en) * 2014-04-08 2017-02-22 阿拉迪姆公司 Liposomes that form drug nanocrystals after freeze-thaw
US11000542B2 (en) 2014-07-23 2021-05-11 Firebrick Pharma Limited Treatment and prevention of the common cold using povidone-iodine
KR102086150B1 (en) 2017-04-10 2020-03-06 부산대학교 산학협력단 in situ Hydrogel Forming Powder Composition for Wound Healing, and Method for Preparing thereof
WO2019009630A1 (en) * 2017-07-04 2019-01-10 김대황 Solid composition comprising iodine agent and sodium chloride having improved water solubility, and antiviral and antimicrobial composition for eye, oral cavity, nasal cavity or inhalation containing aqueous solution thereof
KR101935250B1 (en) * 2017-07-04 2019-01-04 김대황 Antiviral and antibacterial composition comprising iodide and osmotic tastant for eye, oral cavity, nasal cavity or inhalation
US20200289552A1 (en) * 2017-07-04 2020-09-17 Fluchem Ltd Solid composition comprising iodine agent and sodium chloride having improved water solubility, and antiviral and antimicrobial composition for eye, oral cavity, nasal cavity or inhalation containing aqueous solution thereof
KR102026805B1 (en) 2017-12-12 2019-11-04 주식회사 크로파세 A anti-inflammation cosmetic composition
RU2730834C1 (en) * 2020-01-17 2020-08-26 Александр Александрович Кролевец Method of producing thymol nanocapsules
AU2020389480A1 (en) * 2020-03-30 2021-10-14 Hyundaibioscience Co.,Ltd. Ethosomal composition including ethosomes encapsulating vitamin and dexpanthenol and method for preparing the same
CN111700883B (en) * 2020-07-23 2021-04-06 深圳大佛药业股份有限公司 Salbutamol sulfate sustained-release inhalation preparation and production process thereof
JP2022151426A (en) * 2021-03-26 2022-10-07 均 石井 Agents for treating upper respiratory inflammation
JP2022151438A (en) * 2021-03-26 2022-10-07 均 石井 Agents for treating conchitis and tympanitis

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0260241A1 (en) * 1986-09-12 1988-03-16 Aktiebolaget Draco A new system for administration of liposomes to mammals
EP0407028A2 (en) * 1989-05-31 1991-01-09 FISONS plc Medicament inhalation device and formulation
WO1994014490A1 (en) * 1992-12-23 1994-07-07 Bernhard Hugemann Compacted drug body for use in the mechanical generation of inhalable active-substance particles
WO1994028876A1 (en) * 1993-06-07 1994-12-22 Advanced Therapies, Inc. Liposome powders

Family Cites Families (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE615889A (en) * 1952-04-15 1900-01-01
US4113857A (en) * 1977-05-16 1978-09-12 The Purdue Frederick Company Process for the preparation of iodophor compounds and methods for stabilizing iodophor pharmaceutical compositions containing the same
US4675009A (en) * 1977-11-07 1987-06-23 Lec Tec Corporation Drug dispensing device for transdermal delivery of medicaments
US4235871A (en) * 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
FR2536278A1 (en) * 1982-11-18 1984-05-25 Dupont Michele NOVEL THERAPEUTIC COMPOSITION USEFUL IN PARTICULAR FOR WOUND HEALING
US4704383A (en) * 1983-12-29 1987-11-03 The Research Foundation Of State University Of New York Non-antibacterial tetracycline compositions possessing anti-collagenolytic properties and methods of preparing and using same
FR2581542B1 (en) * 1985-05-07 1988-02-19 Oreal TOPICAL COMPOSITIONS FOR THE TREATMENT OF SKIN BASED ON SALICYLIC ACID DERIVATIVES
FR2591105B1 (en) * 1985-12-11 1989-03-24 Moet Hennessy Rech PHARMACEUTICAL COMPOSITION, IN PARTICULAR DERMATOLOGICAL, OR COSMETIC, BASED ON HYDRATED LIPID LAMELLAR PHASES OR LIPOSOMES CONTAINING A RETINOIDE OR A STRUCTURAL ANALOG OF SUCH A RETINOID AS A CAROTENOID.
US5049388A (en) * 1986-11-06 1991-09-17 Research Development Foundation Small particle aerosol liposome and liposome-drug combinations for medical use
US4938965A (en) * 1987-07-22 1990-07-03 Her Majesty The Queen In Right Of Canada, As Represented By The Minister Of National Defence Of Her Majesty's Canadian Government Ocular delivery of prophylactic agents
US5246708A (en) * 1987-10-28 1993-09-21 Pro-Neuron, Inc. Methods for promoting wound healing with deoxyribonucleosides
DE3826946C1 (en) * 1988-08-09 1990-03-15 A. Nattermann & Cie Gmbh, 5000 Koeln, De
US4906476A (en) * 1988-12-14 1990-03-06 Liposome Technology, Inc. Novel liposome composition for sustained release of steroidal drugs in lungs
US5006343A (en) * 1988-12-29 1991-04-09 Benson Bradley J Pulmonary administration of pharmaceutically active substances
US5232692A (en) * 1989-04-28 1993-08-03 Research And Education Institute, Inc. Povidone-iodine neonatal ophthalmic antimicrobial prophylactic agent
US5089389A (en) * 1989-08-25 1992-02-18 Eastman Kodak Company Buffered composition, coated article test device and a method for their use
US5128139A (en) * 1991-02-15 1992-07-07 Nu Skin International, Inc. Composition containing liposome-entrapped grapefruit seed extract and method for making
DE4111982C2 (en) * 1991-04-12 1998-12-24 Merz & Co Gmbh & Co Stable small particulate liposome preparations, their preparation and use
EP0580860B2 (en) * 1991-04-16 2004-12-15 Nippon Shinyaku Company, Limited Method of manufacturing solid dispersion
WO1992019244A2 (en) * 1991-05-01 1992-11-12 Henry M. Jackson Foundation For The Advancement Of Military Medicine A method for treating infectious respiratory diseases
US5552158A (en) * 1993-02-23 1996-09-03 Norac Technologies Inc. Skin care composition
DE4306475A1 (en) * 1993-03-02 1994-09-08 Ensenat Pedro Gonzalez Liposomes containing chlorhexidine diacetate or chlorhexidine digluconate
US5512269A (en) * 1993-06-09 1996-04-30 Burroughs Wellcome, Co. Method of treating retained pulmonary secretions
US5456904A (en) * 1993-06-28 1995-10-10 The Procter & Gamble Company Photoprotection compositions comprising certain chelating agents
DE9312509U1 (en) * 1993-08-20 1993-10-28 Euro-Celtique S.A., Luxemburg/Luxembourg Preparations for external administration of antiseptic and / or wound healing promoting agents
US5863556A (en) * 1993-08-20 1999-01-26 Euro-Celtique, S.A. Preparations for the external application of antiseptic agents and/or agents promoting the healing of wounds
US5942245A (en) * 1994-11-04 1999-08-24 Polymun Scientific Immunbiologische Forschung Gmbh Application of SOD in liposomes
US5744457A (en) * 1995-03-31 1998-04-28 Hamilton Civic Hospitals Research Development Inc. Compositions and methods for inhibiting thrombogenesis
JPH08301774A (en) * 1995-05-08 1996-11-19 Kowa Co Throat disinfectant
WO1998055104A1 (en) * 1997-06-06 1998-12-10 Shionogi & Co., Ltd. Improvement in medicament administration system
US7300667B1 (en) * 1999-05-27 2007-11-27 Euro-Celtique, S.A. Preparations for the application of anti-inflammatory, especially antiseptic agents and/or agents promoting the healing of wounds, to the lower respiratory tract
ES2341532T3 (en) * 1999-05-27 2010-06-22 Euro-Celtique S.A. PREPARATION WITH POVIDONA YODADA FOR THE TREATMENT OF WOUNDS.
US7297344B1 (en) * 1999-05-27 2007-11-20 Euro-Celtique, S.A. Preparations for the promotion of wound healing in the upper respiratory tract and/or ear
CA2368192A1 (en) * 1999-05-27 2000-12-07 Wolfgang Fleischer Preparations for the application of antiseptic agents to the interior of the human or animal body
US6497896B2 (en) * 2001-02-12 2002-12-24 Supergen, Inc. Method for administering camptothecins via injection of a pharmaceutical composition comprising microdroplets containing a camptothecin
DE60315955T2 (en) * 2003-05-19 2008-06-05 Euro-Celtique S.A. Dry liposomal PVP-iodine preparations
US8435261B2 (en) * 2009-07-15 2013-05-07 Regents Of The University Of Minnesota Treatment and placement device for sinusitis applications

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0260241A1 (en) * 1986-09-12 1988-03-16 Aktiebolaget Draco A new system for administration of liposomes to mammals
EP0407028A2 (en) * 1989-05-31 1991-01-09 FISONS plc Medicament inhalation device and formulation
WO1994014490A1 (en) * 1992-12-23 1994-07-07 Bernhard Hugemann Compacted drug body for use in the mechanical generation of inhalable active-substance particles
WO1994028876A1 (en) * 1993-06-07 1994-12-22 Advanced Therapies, Inc. Liposome powders

Cited By (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7297344B1 (en) 1999-05-27 2007-11-20 Euro-Celtique, S.A. Preparations for the promotion of wound healing in the upper respiratory tract and/or ear
US7300667B1 (en) 1999-05-27 2007-11-27 Euro-Celtique, S.A. Preparations for the application of anti-inflammatory, especially antiseptic agents and/or agents promoting the healing of wounds, to the lower respiratory tract
US7468194B1 (en) 1999-05-27 2008-12-23 Euro-Celtique, S.A. Preparations for the application of anti-inflammatory agents
JP2012176993A (en) * 2000-02-08 2012-09-13 Euro-Celtique Sa Controlled-release composition containing opioid agonist and antagonist
JP2014169306A (en) * 2000-02-08 2014-09-18 Euro-Celtique Sa Controlled-release composition containing opioid agonist and antagonist
US7473433B2 (en) 2000-12-21 2009-01-06 Nektar Therapeutics Pulmonary delivery of polyene antifungal agents
US6667344B2 (en) 2001-04-17 2003-12-23 Dey, L.P. Bronchodilating compositions and methods
US9597396B2 (en) 2001-04-17 2017-03-21 Mylan Specialty Lp Formoterol/steroid bronchodilating compositions and methods of use thereof
US8623851B2 (en) 2001-04-17 2014-01-07 Mylan Specialty L.P. Formoterol/steroid bronchodilating compositions and methods of use thereof
DE10125731A1 (en) * 2001-05-17 2003-03-06 A I D Autoimmun Diagnostika Gm Dosage form of immunological agents
US9827317B2 (en) 2002-10-29 2017-11-28 Insmed Incorporated Sustained release of antiinfectives
US7465756B2 (en) 2003-07-10 2008-12-16 Jpmorgan Chase Bank, N.A. Bronchodilating beta-agonist compositions and methods
US7541385B2 (en) 2003-07-10 2009-06-02 Chaudry Imtiaz A Bronchodilating β-agonist compositions and methods
US7473710B2 (en) 2003-07-10 2009-01-06 Jpmorgan Chase Bank, N.A. Bronchodilating beta-agonist compositions and methods
US7462645B2 (en) 2003-07-10 2008-12-09 Jpmorgan Chase Bank, N.A. Bronchodilating beta-agonist compositions and methods
US9730890B2 (en) 2003-07-10 2017-08-15 Mylan Pharmaceuticals, Inc. Bronchodilating beta-agonist compositions and methods
US7348362B2 (en) 2003-07-10 2008-03-25 Dey, L.P. Bronchodilating β-agonist compositions and methods
US8158133B2 (en) 2004-12-02 2012-04-17 Vetoquinol Pharmaceutical composition useful for vaccines
US10328071B2 (en) 2005-12-08 2019-06-25 Insmed Incorporated Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof
US9402845B2 (en) 2005-12-08 2016-08-02 Insmed Incorporated Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof
US9511082B2 (en) 2005-12-08 2016-12-06 Insmed Incorporated Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof
US9549925B2 (en) 2005-12-08 2017-01-24 Insmed Incorporated Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof
US9549939B2 (en) 2005-12-08 2017-01-24 Insmed Incorporated Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof
US9925205B2 (en) 2007-05-04 2018-03-27 Insmed Incorporated Compositions of multicationic drugs for reducing interactions with polyanionic biomolecules and methods of use thereof
US9724301B2 (en) 2007-05-07 2017-08-08 Insmed Incorporated Methods of treating pulmonary disorders with liposomal amikacin formulations
US9114081B2 (en) 2007-05-07 2015-08-25 Insmed Incorporated Methods of treating pulmonary disorders with liposomal amikacin formulations
US9737555B2 (en) 2007-05-07 2017-08-22 Insmed Incorporated Method of treating pulmonary disorders with liposomal amikacin formulations
US9333214B2 (en) 2007-05-07 2016-05-10 Insmed Incorporated Method for treating pulmonary disorders with liposomal amikacin formulations
US9119783B2 (en) 2007-05-07 2015-09-01 Insmed Incorporated Method of treating pulmonary disorders with liposomal amikacin formulations
US10064882B2 (en) 2007-05-07 2018-09-04 Insmed Incorporated Methods of treating pulmonary disorders with liposomal amikacin formulations
US9925251B2 (en) 2011-10-19 2018-03-27 President And Fellows Of Harvard College Treatments for Mycobacterium tuberculosis
US9566234B2 (en) 2012-05-21 2017-02-14 Insmed Incorporated Systems for treating pulmonary infections
US10124066B2 (en) 2012-11-29 2018-11-13 Insmed Incorporated Stabilized vancomycin formulations
US10471149B2 (en) 2012-11-29 2019-11-12 Insmed Incorporated Stabilized vancomycin formulations
US10238675B2 (en) 2014-05-15 2019-03-26 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US10251900B2 (en) 2014-05-15 2019-04-09 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US10398719B2 (en) 2014-05-15 2019-09-03 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US12016873B2 (en) 2014-05-15 2024-06-25 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US11395830B2 (en) 2014-05-15 2022-07-26 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US10588918B2 (en) 2014-05-15 2020-03-17 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US10751355B2 (en) 2014-05-15 2020-08-25 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US10828314B2 (en) 2014-05-15 2020-11-10 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US11446318B2 (en) 2014-05-15 2022-09-20 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
US9895385B2 (en) 2014-05-15 2018-02-20 Insmed Incorporated Methods for treating pulmonary non-tuberculous mycobacterial infections
EP3621596B1 (en) 2017-05-10 2022-02-23 Université de Bordeaux Tablets comprising nucleic acid vectors
US12115257B2 (en) 2017-05-10 2024-10-15 Université De Bordeaux Nucleic acid vector tablets
US11571386B2 (en) 2018-03-30 2023-02-07 Insmed Incorporated Methods for continuous manufacture of liposomal drug products
US20210121432A1 (en) * 2018-04-17 2021-04-29 Université De Caen Normandie Bambuterol for the Treatment of Alzheimer's Disease
WO2019202400A1 (en) * 2018-04-17 2019-10-24 Universite De Caen Normandie Bambuterol for the treatment of alzheimer's disease

Also Published As

Publication number Publication date
RU2202340C2 (en) 2003-04-20
BR9911071A (en) 2001-02-06
DE69933208T2 (en) 2007-08-30
CN1303276A (en) 2001-07-11
CA2332369A1 (en) 1999-12-02
HUP0102892A3 (en) 2002-12-28
BR9911070A (en) 2001-02-06
KR100613706B1 (en) 2006-08-21
HUP0102337A3 (en) 2002-12-28
CN1303271A (en) 2001-07-11
JP2002516266A (en) 2002-06-04
ATE235895T1 (en) 2003-04-15
RU2212884C2 (en) 2003-09-27
US20120009253A1 (en) 2012-01-12
EP1083886A1 (en) 2001-03-21
EP1083886B1 (en) 2003-04-02
KR20010043819A (en) 2001-05-25
CN1303272A (en) 2001-07-11
ES2273493T3 (en) 2007-05-01
ES2260915T3 (en) 2006-11-01
KR100445146B1 (en) 2004-08-18
WO1999060999A1 (en) 1999-12-02
AU4370499A (en) 1999-12-13
HUP0102899A3 (en) 2002-12-28
HUP0102337A2 (en) 2002-03-28
JP4741726B2 (en) 2011-08-10
DK1079807T3 (en) 2007-01-22
HK1035335A1 (en) 2001-11-23
HUP0102892A2 (en) 2002-03-28
AU4266799A (en) 1999-12-13
WO1999060998A1 (en) 1999-12-02
IL139231A0 (en) 2001-11-25
KR20010043821A (en) 2001-05-25
CA2332389C (en) 2008-09-09
JP4741727B2 (en) 2011-08-10
DE69906518D1 (en) 2003-05-08
DE69930259D1 (en) 2006-05-04
AU747877B2 (en) 2002-05-30
AU752018B2 (en) 2002-09-05
BR9911072A (en) 2001-02-06
DE29923847U1 (en) 2001-04-12
AU759264B2 (en) 2003-04-10
CY1105834T1 (en) 2011-02-02
AU4370699A (en) 1999-12-13
CA2332371A1 (en) 1999-12-02
PT1079807E (en) 2007-01-31
ATE339187T1 (en) 2006-10-15
JP2002516269A (en) 2002-06-04
JP2002516265A (en) 2002-06-04
HU226710B1 (en) 2009-07-28
AU752018C (en) 2003-10-09
PT1079806E (en) 2006-06-30
HK1035336A1 (en) 2001-11-23
IL139229A0 (en) 2001-11-25
DE29923766U1 (en) 2001-06-07
IL139230A0 (en) 2001-11-25
DK1079806T3 (en) 2006-07-17
KR20010043820A (en) 2001-05-25
US20080038330A1 (en) 2008-02-14
EP1079806B1 (en) 2006-03-08
RU2211693C2 (en) 2003-09-10
ATE319427T1 (en) 2006-03-15
HU226729B1 (en) 2009-08-28
IL139230A (en) 2007-07-24
EP1079807B1 (en) 2006-09-13
DE69933208D1 (en) 2006-10-26
EP1079807A1 (en) 2001-03-07
DE69930259T2 (en) 2006-11-23
HUP0102899A2 (en) 2002-03-28
CA2332389A1 (en) 1999-12-02
DE29923848U1 (en) 2001-04-12
EP1079806A1 (en) 2001-03-07

Similar Documents

Publication Publication Date Title
EP1083886B1 (en) Drug delivery system comprising a tightly compacted solid medicament stock
AU2018319592B2 (en) Dry powder compositions for intranasal delivery
Courrier et al. Pulmonary drug delivery systems: recent developments and prospects
Muralidharan et al. Inhalable nanoparticulate powders for respiratory delivery
ES2359298T3 (en) AEROSOLS THAT INCLUDE DRUGS IN NANOPARTICLES.
CA2464250C (en) Kit for the preparation of a pharmaceutical composition
Vanbever et al. Sustained release of insulin from insoluble inhaled particles
RU2000131695A (en) DRUG DELIVERY SYSTEM
JPS63500175A (en) Liposome inhalation method and inhalation system
UA43886C2 (en) A pharmaceutical composition comprising PROLIPOSOMNYY powder method of producing said composition, method of production PROLIPOSOMNOHO powder TREATMENT METHOD patients requiring therapy and powder inhaler
AU2002350622A1 (en) Kit for the preparation of a pharmaceutical composition
CA2803672C (en) Liposomes for pulmonary administration
Gaspar et al. Inhaled liposomes–current strategies and future challenges
WO2006066367A1 (en) Solid lipidic particles as pharmaceutically acceptable fillers or carriers for inhalation
US20220241271A1 (en) Inhalable dry powders
JP2006511617A (en) Pharmaceutical porous particles
Bi et al. Liposomes as a carrier for pulmonary delivery of peptides and proteins
MXPA00011650A (en) Drug delivery system comprising a tightly compacted solid medicament stock
Dhahir et al. Dry powder inhalers: main characteristics, classifications and novel drug delivery systems review
PR et al. Nano Aerogels an Aerosolised Gel Therapy
CN118576558A (en) Preparation method and application of inhalable dry powder of lipid nano-carrier
Wu Inhalable Nanoparticulate Powders for Respiratory Delivery. Invited Review.

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 99806648.6

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 139229

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 1999953285

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: IN/PCT/2000/00303/DE

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 42667/99

Country of ref document: AU

ENP Entry into the national phase

Ref document number: 2332369

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 1020007013258

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: PA/a/2000/011650

Country of ref document: MX

Ref document number: 09701218

Country of ref document: US

WWP Wipo information: published in national office

Ref document number: 1999953285

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 1020007013258

Country of ref document: KR

NENP Non-entry into the national phase

Ref country code: CA

WWG Wipo information: grant in national office

Ref document number: 42667/99

Country of ref document: AU

WWG Wipo information: grant in national office

Ref document number: 1999953285

Country of ref document: EP

WWR Wipo information: refused in national office

Ref document number: 1020007013258

Country of ref document: KR