Pharmaceutical compositions comprising cyclosporin
Inventors
Keller, Manfred • Akkar, Aslihan • Mehrwald, Ralf
Assignees
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Publication Number
US-9724382-B2
Publication Date
2017-08-08
Expiration Date
Abstract
The invention relates to liquid pharmaceutical compositions containing: a) a therapeutically effective dose of a cyclosporin; b) an aqueous carrier liquid; c) a first solubilizing substance selected among the group of phospholipids; and d) a second solubilizing substance selected among the group of non-ionic surfactants. Preferably, the cyclosporin is liposome solubilized. The inventive composition is suitable for oral, parenteral, nasal, mucosal, topical, and particularly pulmonary application in the form of an aerosol.
Core Innovation
The invention relates to liquid aqueous pharmaceutical compositions comprising a cyclosporin in a liposomally solubilised form. The composition includes an aqueous carrier liquid and solubility enhancing substances comprising a first solubility enhancing substance selected from the group of phospholipids and a second solubility enhancing substance selected from the group of nonionic surfactants, wherein the phospholipid is a mixture of natural phospholipids.
The described composition is administered as an aerosol for pulmonary or nasal application using a therapeutically effective dose of cyclosporin. The administration volume is less than 4 ml and the cyclosporin is provided in a liposomally solubilised form, without organic solvents and preferably using unilamellar liposomes.
The invention addresses pulmonary delivery by specifying aerosol-related formulation aspects including liposome size distribution and properties related to nebulization and aerosol performance. It is supported with experimental evidence including calu-3 TEER tolerability and aerosol characterization, and it includes in vivo gamma-scintigraphy in lung transplant patients showing substantial lung deposition and tolerability without premedication.
Claims Coverage
The provided content includes one independent claim and dependent refinements. The inventive coverage centers on a cyclosporin liposomally solubilised aqueous composition and aerosol administration for pulmonary or nasal use, with further features directed to deposition performance, droplet size distribution, nebuliser residue, nebuliser type, and premedication conditions.
Cyclosporin in liposomally solubilised form with defined solubility enhancers
Providing a composition comprising a cyclosporin in liposomally solubilised form, an aqueous carrier liquid, a first solubility enhancing substance selected from the group of phospholipids and a second solubility enhancing substance selected from the group of nonionic surfactants, wherein the phospholipid is a mixture of natural phospholipids.
Aerosol pulmonary or nasal administration with volume under 4 ml
Administering a volume of less than 4 ml of the composition to the subject as an aerosol for pulmonary or nasal application, wherein the volume comprises a therapeutically effective dose of the cyclosporin.
Treatment for specified respiratory and transplant-related conditions
Applying the method to a subject suffering from or susceptible to asthma, refractory asthma, chronic obstructive bronchitis, parenchymal fibrotic or interstitial lung disease and/or inflammation, lung cancer, acute or chronic lung transplant rejection, undesired reaction after lung, stem cell, or bone marrow transplantation and the diseases resulting therefrom.
Pulmonary deposition performance and central-to-peripheral ratio targets
Requiring pulmonary deposition of at least 30% and a central-to-peripheral deposition ratio between 30:70 and 70:30.
Droplet size distribution constraints for aerosol
Specifying that the aerosol droplet size distribution has 50% to 98% of droplets smaller than 5 µm and a geometric standard deviation less than 2.2.
Nebuliser residue limitation for active agent
Requiring that the residue of active agent remaining in the nebuliser is less than 20%.
Electronic vibrating membrane nebuliser administration
Administering the composition as an aerosol produced using an electronic vibrating membrane nebuliser.
No premedication prior to administration
Performing administration without premedication.
The inventive concept centers on a cyclosporin liposomally solubilised aqueous composition using phospholipids and nonionic surfactants, administered as an aerosol for pulmonary or nasal use at a volume under 4 ml, with additional claim features narrowing aerosol deposition performance, droplet size distribution, nebuliser residue, nebuliser type, and premedication conditions.
Stated Advantages
Limited or reversible integrity impact compared with propylene glycol, as shown by calu-3 TEER tolerability.
Substantial lung deposition in lung transplant patients.
Tolerability in lung transplant patients without premedication.
Reduced systemic exposure, with a reported short pharmacokinetic half-life.
Documented Applications
Pulmonary or nasal treatment of asthma, including refractory asthma, chronic obstructive bronchitis, parenchymal fibrotic or interstitial lung disease and/or inflammation, and lung cancer.
Treatment of acute or chronic lung transplant rejection and undesired reaction after lung, stem cell, or bone marrow transplantation and diseases resulting therefrom.
Pulmonary delivery as an aerosol via nebulizers, including electronic vibrating membrane devices, supported by gamma-scintigraphy in lung transplant patients.
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