Patent Abstract:
the present invention relates to a pharmaceutical , preferably inhalable , porous , free flowing particle to be used in therapeutical application , optionally comprising a therapeutically active compound or substance , whereby the particle consists of one or more network forming compounds , which in diluted solutions self associates to large three dimensional structures having a density of & lt ; 0 . 5 g / cm 3 .

Detailed Description:
impacters such as , for example , the 5 - stage multistage liquid impinger ( msli ) or the 8 - stage andersen cascade impacter ( aci ), which are described in chapter 601 of the united states pharmacopoeia ( usp ) or in the inhalants monograph of the european pharmacopoeia ( ph . eur . ), are suitable for testing the particles of the present invention . particles according to the present invention have been tested in an andersen impacter . the andersen impacter is a standard instrument for the testing of inhalation products . the andersen impacter is an apparatus in which one determines the aerodynamic size of an aerosol . the principle is that one increases the speed of an air flow comprising particles in several steps . in each step the air flow is diverted which makes particles having a large aerodynamic diameter will not accompany the air flow but will impact onto a disc present on each step . the particles can then be collected from each disc and be analysed with respect to density , aerodynamic size and geometric diameter . in the case of phospholipids , water and oil the amount of water is critical for the formation of large three dimensional network structures in a solution . the amount of water needed to form large structures has an upper and a lower limit depending on the system , i . e ., type of oil and type of lipid and other components . the amount is in the range of 1 to 20 moles of water per mole of lipid . a suitable amount of water for use in a particular formulation may be determined by standard methods such as cryo - tem . a solution consisting of 7 g of dppc , dipalmitoylphosphatidylcholine , ( cas nr : 63 - 89 - 8 ) and 3 g of dmpc , dimyristoylphosphatidylcholine ( cas nr : 18194 - 24 - 6 ) was mixed with 630 μl of water ( milli - q ) and 1000 ml of n - hexane ( cas 110 - 54 - 3 ). the total solution was mixed while stirred and was heated ( 50 ° c .) until a viscous solution was obtained . the solution was dried in a spray drier of the mark mobile minor ™ från gea niro a / s , having a mass flow of 4 . 9 kg / hr , a solution temperature of 50 ° c . and using nitrogen ( n 2 ) as a drying gas . ingoing temperature was thus 50 ° c ., while outgoing temperature was 36 ° c . the product obtained consisted of porous low density particles having a large three dimensional network having an aerodynamic diameter of 5 μm a geometric diameter of 50 μm and a density ≈ 0 . 01 g / cm 3 . in the accompanying photographs , sem , particles are shown which have attached to step 4 , 2 particles , ( fig1 - 2 ), and step 6 , 2 particles ( fig3 - 4 ) in an andersen impactor . the test conditions were thus such that on step 4 particles having a aerodynamic diameter of 1 , 4 - 2 , 3 μm and on step 6 particles having the aerodynamic diameter 0 . 5 - 0 . 8 μm are attached . the particles on the photographs have a geometrical diameter that is 10 times or more , larger than the aerodynamic diameter that normally get caught on theses steps . the particles are , as evident from the pictures , no perfect spheres , so a part of the explanation that they attach to these steps can be explained by the form factor , but the dominating reason why so large particles attach so far down in the impactor is that they have a considerably lower density . the theoretical relationship between the aerodynamic diameter ( d a ) and the geometrical diameter ( d g ), as mentioned above , is given by the following relationship : andersen test conditions were : suction time 4 s ; flow 60 l / min , and temperature 23 ° c ., at 30 % rh . the solution which was dried contained about 1 % dry matter . at a maintained volume after drying , this results in particles having a density of about 0 . 01 g / cm 3 . this means , that at equal aerodynamic diameters , these particles are about ten times larger than particles having the density 1 g / cm 3 . this in turn leads to the fact that it is possible to manufacture inhalable particles ( d a = 0 . 5 - 5 μm ) which also will become free flowing ( normally & gt ; 40 μm ). this example shows a manufacture essentially as in example 1 but in a smaller scale and using a smaller spray drier . a solution of 0 . 3505 g of dppc , dipalmitoylphosphatidylcholine , ( cas nr : 63 - 89 - 8 ) was mixed with 0 . 1501 g of dmpc , dimyristoylphosphatidylcholine ( cas nr : 18194 - 24 - 6 ), and 32 . 5 μl of water ( milli - q ). 50 ml of n - hexane ( cas 110 - 54 - 3 ) were added . the solution was mixed while being stirred and heated ( 52 ° c .) until a viscous solution was obtained . the solution was dried using a spray drier of the mark sdmicro ™ of gea niro a / s , using a mass flow of 400 g / hr , a solution temperature of 52 ° c . and nitrogen ( n2 ) as drying gas , whereby the ingoing temperature was 52 ° c ., and outgoing temperature was 37 ° c . the product obtained consisted of porous low density particles having a large three dimensional network having an aerodynamic diameter of 5 μm a geometric diameter of 50 μm and a density ≈ 0 . 01 g / cm 3 . a solution consisting of 2 g of dmpc ( cas nr : 18194 - 24 - 6 ) and 1 g dppc ( cas nr : 63 - 89 - 8 ) was mixed with 180 μl of water ( milli - q ) and 300 ml n - hexane ( cas nr : 110 - 54 - 3 ). the solution was mixed while stirred and heated ( 55 ° c .) until viscous solution was obtained . the solution was dried in a spray drier of the mark sdmicro ™ of gea niro a / s , using a mass flow of 1000 g / h , a solution temperature of 600 ° c . and nitrogen as drying gas , whereby the ingoing temperature was 50 ° c ., and the outgoing was 39 ° c . the particles was tested in a standard impactor ( 5 - step mli , multistage liquid impinger ). at the test condition ( 30 l / min ) the cut - off values for step 3 and 4 is 4 . 38 μm and 2 . 40 μm . the two first steps ( 1 and 2 ) contained water ( 20 ml ) to avoid particle bouncing . in the accompanying photographs , sem , particles are shown which have attached to step 4 ( fig5 ). the particles on the photographs have a geometrical diameter that is about 10 - times or more , larger than the aerodynamic diameter that normally get caught on this step ( 2 , 4 μm ). a solution consisting of 0 . 9 g of natural surfactant extract of porcine origin was mixed with 550 μl of water ( milli - q ) and 90 ml n - hexane ( cas nr : 110 - 54 - 3 ). the solution was dried in a spray drier of the mark sdmicro ™ of gea niro a / s , using a mass flow of 900 g / h , a solution temperature of 60 ° c . and nitrogen as drying gas , whereby the ingoing temperature was 50 ° c ., and the outgoing was 40 ° c . the particles was tested in a standard impactor ( 5 - step ml , multistage liquid impinger ). at the test condition ( 30 l / min ) the cut - off values for step 3 and 4 is 4 . 38 μm and 2 . 40 μm . the two first steps ( 1 and 2 ) contained water ( 20 ml ) to avoid particle bouncing . in the accompanying photographs , sem , particles are shown which have attached to step 4 ( fig7 - 8 ). the particles on the photographs have a geometrical diameter that is 10 times or more , larger than the aerodynamic diameter that normally get caught on theses steps ( 2 . 4 μm ). the powder from example 3 was mixed with dry latex particles to test the lipid particles as carrier particles . latex spheres 7 μm , density 1 . 05 g / cm 3 , dc - 07 from duke scientific corporation . lipid powder ( 0 . 0114 g ) and latex spheres ( 0 . 0099 g ) was mixed in a vial using a vortex genie 2 from scientific industries . the powder was tested in a standard impactor ( 5 - step mli , multistage liquid impinger ). at the test condition ( 30 l / min ) the cut - off values for step 3 and 4 is 4 . 38 μm and 2 . 40 μm . the two first steps ( 1 and 2 ) contained water ( 20 ml ) to avoid particle bouncing . in the accompanying photographs , sem , particles are shown which have attached to step 3 ( fig9 ). the large lipid particle on the photograph have a geometrical diameter that is 10 times or more , larger than the aerodynamic diameter that normally get caught on this step . the smaller latex particles attached on the surface have a geometrical diameter that is 2 times or more , larger than the aerodynamic diameter that normally get caught on this step ( 4 . 38 μm ). this shows that these particles may serve as vehicle for non - inhalable particles . a solution consisting of 1 g of natural lung surfactant extracts ( curosurf ®) mixed with 200 μl of water ( milli - q ) and 100 ml n - hexane ( cas nr : 110 - 54 - 3 ). the solution was mixed while stirred and heated ( 55 ° c .) until a viscous solution was obtained . the solution was dried in a spray drier ( of the mark sdmicro ™ of gea niro a / s , using a mass flow of 1000 g / h , a solution temperature of 60 ° c . and nitrogen as drying gas , whereby the ingoing temperature was 50 ° c ., and the outgoing was 39 ° c . fine particle fraction ( fpf ) determined by mli , multistage liquid impinger and chemical analysis . a solution consisting of 3 g dppc ( cas nr : 63 - 89 - 8 ) and 0 . 15 g cholesterol ( cas nr : 57 - 88 - 5 ) was mixed with 180 μl of water ( milli - q ) and 300 ml n - hexane ( cas nr : 110 - 54 - 3 ). the solution was mixed while stirred and heated ( 55 ° c .) until a viscous solution was obtained . fine particle fraction ( fpf ) determined by mli , multistage liquid impinger and chemical analysis . a solution consisting of 1 g sphingomyelin ( cas nr : 85187 - 10 - 6 ) was mixed with 60 μl of water ( milli - q ) and 100 ml n - hexane ( cas nr : 110 - 54 - 3 ). the solution was mixed while stirred and heated until a viscous solution was obtained . fine particle fraction ( fpf ) determined by mli , multistage liquid impinger and chemical analysis . a solution consisting of 0 . 8 g of glycerol dioleat gdo ( cas nr : 25637 - 87 - 7 ) and 0 . 2 g dppc ( cas nr : 63 - 89 - 8 ) was mixed with 60 μl of water ( mili - q ) and 100 ml n - hexane ( cas nr : 110 - 54 - 3 ). the solution was mixed while stirred and heated until a viscous solution was obtained . fine particle fraction ( fpf ) determined by mli , multistage liquid impinger and chemical analysis . a solution consisting of 1 g of monogalactocyidiacylglycerol ( mgdg ) was mixed with 60 μl of water ( milil - q ) and 100 ml n - hexane ( cas nr : 110 - 543 ). the solution was mixed while stirred and heated until a viscous solution was obtained . fine particle fraction ( fpf ) determined by mli , multistage liquid impinger and chemical analysis . a solution consisting of 1 g of digalactocyldiacylglycerol ( dgdg ) was mixed with 60 μl of water ( milli - q ) and 100 ml n - hexane ( cas nr : 110 - 543 ). the solution was mixed while stirred and heated until a viscous solution was obtained . fine particle fraction ( fpf ) determined by mli , multistage liquid impinger and chemical analysis . a solution consisting of 2 g of dmpc ( cas nr : 18194 - 24 - 6 ), 1 g dppc ( cas nr : 63 - 89 - 8 ) and 0 . 3 g cyclosporine ( cas nr 79217 - 60 - 0 ) was mixed with 180 μl of water ( milli - q ) and 300 ml n - hexane ( cas nr : 110 - 54 - 3 ). the solution was mixed while stirred and heated ( 55 ° c .) until a viscous solution was obtained . fine particle fraction ( fpf ) determined by mli , multistage liquid impinger and chemical analysis . a solution consisting of 2 g of dmpc ( cas nr : 18194 - 24 - 6 ), 1 g dppc ( cas nr : 63 - 89 - 8 ) and 0 . 015 g calcitonin was mixed with 180 μl of water ( milli - q ) and 300 ml n - hexane ( cas nr : 110 - 54 - 3 ). the solution was mixed while stirred and heated ( 55 ° c .) until a viscous solution was obtained . fine particle fraction ( fpf ) determined by mli , multistage liquid impinger and chemical analysis . a solution consisting of 2 g of dmpc ( cas nr : 18194 - 24 - 6 ), 1 g dppc ( cas nr : 63 - 89 - 8 ) and 0 . 015 g formoterol ( cas nr : 73573 - 87 - 2 ) was mixed with 180 μl of water ( milli - q ) and 300 ml n - hexane ( cas nr : 110 - 54 - 3 ). the solution was mixed while stirred and heated ( 55 ° c .) until a viscous solution was obtained . fine particle fraction ( fpf ) determined by mli , multistage liquid impinger and chemical analysis . powder made according to example 3 was mixed with dry particles of formoterol ( cas nr : 73573 - 87 - 2 ). lipid powder ( 0 . 01 g ) and formoterol particles ( 0 . 005 g ) was mixed in a vial using a vortex genie 2 from scientific industries . fine particle fraction ( fpf ) determined by mli , multistage liquid impinger and chemical analysis . powder made according to example 3 was mixed with dry particles of budesonide ( cas nr : 51333 - 22 - 3 ). lipid powder ( 0 . 01 g ) and budesonide particles ( 0 . 01 g ) was mixed in a vial using a vortex genie 2 from scientific industries . fine particle fraction ( fpf ) determined by mli , multistage liquid impinger and chemical analysis . powder made according to example 3 was mixed with dry particles of cyclosporin ( cas nr 79217 - 60 - 0 ). lipid powder ( 0 . 01 g ) and cyclosporin ( 0 . 005 g ) was mixed in a vial using a vortex genie 2 from scientific industries . fine particle fraction ( fpf ) determined by mli , multistage liquid impinger and chemical analysis . powder made according to example 3 was mixed with dry particles of calcitonin . lipid powder ( 0 . 01 g ) and calcitonin ( 0 . 01 g ) was mixed in a vial using a vortex genie 2 from scientific industries . fine particle fraction ( fpf ) determined by mli , multistage liquid impinger and chemical analysis . bhat , m . g ., g . w . cuff , et al . 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