An aerosol delivery device includes an aerosol generator for generating an aerosol in the aerosol delivery device with a membrane and a vibrator which is configured to vibrate a fluid and to aerosolise the fluid by the membrane. The aerosol delivery device further includes a fluid reservoir for receiving the fluid to be aerosolised, the fluid reservoir being arranged in fluid communication with the membrane, a controller which is configured to sequentially operate the vibrator at a plurality of different vibration frequencies, a sensor which is configured to detect at least one electrical parameter of the vibrator for each of the plurality of different vibration frequencies, and a detector which is configured to detect the presence of fluid in contact with the membrane and/or in the fluid reservoir on the basis of the dependence of the detected values of the at least one electrical parameter on the vibration frequency.

The present invention discloses bis(pentahydroxyhexyl)amino substituted 2-{[(3-amino-pyrazin-2-yl)formamido]methyl}-1H-1,3-benzodiazol-3-ium derivatives of formula (I) as inhibitors of ENaC and are of use in the treatment of respiratory diseases and conditions, skin conditions or ocular conditions, wherein the respiratory disease or condition is e.g. cystic fibrosis, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, bronchiectasis, including non-cystic fibrosis bronchiectasis, and asthma; the skin condition is e.g. psoriasis, atopic dermatitis and ichthyosis; and the ocular condition is e.g. dry eye disease.

##STR00001##

Some embodiments of the invention include methods for treating an animal for cystic fibrosis comprising one or more administrations of one or more compositions comprising saracatinib. Other embodiments of the invention include treating an animal for cystic fibrosis comprising one or more administrations of one or more compositions comprising saracatinib, optionally a corrector of F508 CFTR, and optionally a potentiator of F508 CFTR. Still other embodiments of the invention include methods for treating a human with cystic fibrosis caused by the F508 deletion mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), comprising one or more administrations of one or more compositions comprising saracatinib, and optionally VX770, VX809, or both. Additional embodiments of the invention are also discussed herein.

The present specification provides a compound of formula (I):

##STR00001##

or a pharmaceutically acceptable salt thereof; a process for preparing such a compound; and to the use of such a compound in the treatment of an ROR and/or RORt mediated disease state.

The present invention concerns a method of treatment of cystic fibrosis in a patient in need thereof, the method comprising administering an effective amount of a compound of formula I

##STR00001##

Wherein R1, X. Y and Z are as defined in the description.

Cystic fibrosis is developed through mutation of Cystic Fibrosis Transmembrane conductance Regulator (CFTR), which is one type of chloride channel. An object of the present invention is to provide compounds effective in the treatment of cystic fibrosis that open a chloride channel different from CFTR, which is the cause of the disease, and do not depend on CFTR.

Compounds of the present invention are compounds or pharmaceutically acceptable salts thereof that open calcium dependent chloride channels (CaCCs) via G-protein coupled receptor 39 (GPR39) agonism to have strong chloride ion-secretory action, and are represented by the following general formula (I):

General formula (I):

##STR00001##

wherein, X represents a carboxyl group or a tetrazolyl group; Q represents a C.sub.1-C.sub.3 alkylene group, an oxygen atom, a sulfur atom, etc.; G represents a phenyl group where the phenyl group may have 1 to 3 substituents independently selected from the group consisting of a halogen atom, a cyano group, a C.sub.1-C.sub.6 alkyl group, etc.; R.sup.1 represents a C.sub.1-C.sub.6 alkyl group, etc.; R.sup.2 represents a C.sub.1-C.sub.6 alkyl group that may have 1 to 3 substituents independently selected from the following group A, or a group selected from the following group B: Group A: a phenyl group and a pyridyl group, wherein the phenyl group and the pyridyl group may have 1 to 3 substituents independently selected from the following group D; Group B: OH, O-M, SH, S-M, NH.sub.2, NH-M, and N-M.sub.2, wherein M is a C.sub.1-C.sub.6 alkyl group that may have 1 or 2 substituents independently selected from the following group C, or a C.sub.3-C.sub.6 cycloalkyl group that may have 1 or 2 substituents independently selected from the following group C; Group C: a halogen atom, a cyano group, a phenyl group, a pyridyl group, etc., wherein the phenyl group and the pyridyl group may have 1 to 3 substituents independently selected from the following group D; and Group D: a halogen atom, a cyano group, a C.sub.1-C.sub.6 alkyl group, etc.

Cystic fibrosis is developed through mutation of Cystic Fibrosis Transmembrane conductance Regulator (CFTR), which is one type of chloride channel. An object of the present invention is to provide compounds effective in the treatment of cystic fibrosis that open a chloride channel different from CFTR, which is the cause of the disease, and do not depend on CFTR.

Compounds of the present invention are compounds or pharmaceutically acceptable salts thereof that open calcium dependent chloride channels (CaCCs) via G-protein coupled receptor 39 (GPR39) agonism to have strong chloride ion-secretory action, and are represented by the following general formula (I):

General formula (I):

##STR00001##

wherein, X represents a carboxyl group or a tetrazolyl group; Q represents a C.sub.1-C.sub.3 alkylene group, an oxygen atom, a sulfur atom, etc.; G represents a phenyl group where the phenyl group may have 1 to 3 substituents independently selected from the group consisting of a halogen atom, a cyano group, a C.sub.1-C.sub.6 alkyl group, etc.; R.sup.1 represents a C.sub.1-C.sub.6 alkyl group, etc.; R.sup.2 represents a C.sub.1-C.sub.6 alkyl group that may have 1 to 3 substituents independently selected from the following group A, or a group selected from the following group B: Group A: a phenyl group and a pyridyl group, wherein the phenyl group and the pyridyl group may have 1 to 3 substituents independently selected from the following group D; Group B: OH, O-M, SH, S-M, NH.sub.2, NH-M, and N-M.sub.2, wherein M is a C.sub.1-C.sub.6 alkyl group that may have 1 or 2 substituents independently selected from the following group C, or a C.sub.3-C.sub.6 cycloalkyl group that may have 1 or 2 substituents independently selected from the following group C; Group C: a halogen atom, a cyano group, a phenyl group, a pyridyl group, etc., wherein the phenyl group and the pyridyl group may have 1 to 3 substituents independently selected from the following group D; and Group D: a halogen atom, a cyano group, a C.sub.1-C.sub.6 alkyl group, etc.

Provided herein are methods, compounds, and compositions for modulating expression of at least one member of the Notch signaling pathway in a cell or individual. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate a respiratory disorder associated with excessive mucus production in an individual.

Provided herein are methods, compounds, and compositions for modulating expression of at least one member of the Notch signaling pathway in a cell or individual. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate a respiratory disorder associated with excessive mucus production in an individual.

The present invention provides, among other things, compositions and methods of formulating nucleic acid-containing nanoparticles comprising no more than three distinct lipids components, one distinct lipid component being a sterol-based cationic lipid. In some embodiments, the present invention provides compositions and methods in which the lipid nanoparticles further comprise helper lipids and PEG-modified lipids. The resulting formulation comprises a high encapsulation percentage for nucleic acids.