Title of Invention	METERED ELECTRO-DOSE
Abstract	An electro-dose constituting a medicament powder for use in a dry powder inhaler, characterised in that the electro-dose is prepared from an electro-powder constituting an active powder substance or a dry powder medicament formulation, with or without one or more excipients, which is metered onto a device member forming a dose carrier, giving a fine particle fraction (FPF) presenting of the order 50% or more of its content with a particle size between 0.5 and 5 μm, the dose further presenting an optimized porosity of 75 to 99.9 %.

Title of Invention

METERED ELECTRO-DOSE

Abstract

An electro-dose constituting a medicament powder for use in a dry powder inhaler, characterised in that the electro-dose is prepared from an electro-powder constituting an active powder substance or a dry powder medicament formulation, with or without one or more excipients, which is metered onto a device member forming a dose carrier, giving a fine particle fraction (FPF) presenting of the order 50% or more of its content with a particle size between 0.5 and 5 μm, the dose further presenting an optimized porosity of 75 to 99.9 %.

Full Text	FORM 2 THE PATENTS ACT 1970 [39 OF 1970] 8 THE PATENTS RULES, 2003 COMPLETE SPECIFICATION [See Section 10; rule 13] "METERED ELECTRO-DOSE" MEDERIO AG, of P.O. Box 138, CH-6052 Hergiswil NW, Switzerland, The following specification particularly describes the invention and the manner in which it is to be performed: ORIGINAL 127/MUMNP/2003 GRANTED 22-5-2006 Metered electro-dose TECHNICAL FIELD The present invention relates to electrostatic dosing and more particularly to an electro-dose using electro-powder as well as a process and a method for preparation of a metered electro-dose for inhalation into the deep or upper lungs by means of an inhaler device. BACKGROUND The dosing of drugs is carried out in a number of different ways in the medicament service today. Within health care more and more is focused on the possibility of dosing medicament drugs as a powder directly to the airways and lungs of a patient by means of an inhaler in order to obtain an effective, quick and patient-friendly administration of such substances. A dry powder inhaler, DPI, represents a device intended for administration of powder into the deep or upper lung airways by oral inhalation. With deep lung should be understood the peripheral lung and alveoli, where direct transport of active substance to the blood can take place. Particle sizes, to reach into the deep lung, should be in a range 0.5-3 μm and for a local lung delivery in the range 3-5 μm. A larger grain size will easily stick in the mouth and throat, and a smaller grain size may accompany the expiration air out again. To succeed with systemic delivery of medicament powders to the deep lung by inhalation there are some criteria, which have to be fulfilled. The most important is a very high degree of de-agglomeration of the medicament powder but also an exact dose is of great importance. This is not possible with dry powder inhalers of today without special arrangements as for example a so called spacer. By means of a spacer the small grains are evenly distributed in a container from which the inhalation can take place. Upon inhalation from the spacer the fine powder floating free in the air will effectively reach the alveoli of the lung. This method in principle has two drawbacks, firstly difficulties to control the amount of medicine emitted to the lung as an uncontrolled amount of powder sticks to the walls of the spacer and secondly difficulties in handling the relatively space demanding apparatus. Powders for inhalers have a tendency of agglomerating, in other word to clod or to form small or larger lumps, which then have to be de-agglomerated. De-agglomeration is defined as breaking up agglomerated powder by introducing electrical, mechanical, or aerodynamic energy. Usually de-agglomeration is performed as a stage one during dosing and as a final stage two during the patient's inspiration through the DPI. Inhaler devices normally use the force exerted by the patient's more or less normal inspiration effort for de-agglomerating the medicament substance administered when inhaling in an effort to bring as much as possible of the active substance into the lungs. This often leads to inhaler designs using high pressure drops, which will put the patient's lungpower to the test. One major problem with some of the techniques described above is to also obtain a low relative standard deviation (RSD) between doses with this type of technique due to lack of in line control possibilities in production making it hard to be in compliance with regulatory demands. As already noted for an optimum amount of substance to reach the alveoli, an administered powder dose should preferably have a grain size between 0.5 and 3μm. Besides, the inspiration must take place in a calm way to decrease air speed and thereby reduce deposition in the upper respiratory tracts. Technologies to de-agglomerate today include advanced mechanical and aerodynamic systems and combinations between electrical and mechanical filling systems that can be seen in for instance in U.S. Patent No. 5,826,633. Further there are systems disclosed for dispersing aerosolized doses of medicaments, e.g. U.S. Patent No. 5,775,320, U.S. Patent No. 5,785,049, and U.S. Patent No. 5,740,794. Furthermore, in our International Publications WO 00/06236 and WO 00/06235 principles for de-agglomeration and classification are disclosed. 5 The term electro-powder refers to a micronized medicament powder presenting controlled electrostatic properties to be suitable for electrostatic administration in an inhaler device. Such an electro-powder provides possibilities for a better dosing from electrostatically operating equipment such as disclosed in our U.S. Patent No. 6,089,227 as well as our Swedish Patents No. 9802648-7 and 9802649-5, which present excellent inhalation dosing performance. The state of the art also discloses a number of solutions for depositing powder for dosing. U.S. Patent No. 6,063,194 discloses a powder deposition apparatus for depositing grains on a substrate using an electrostatic chuck having one or more collection zones and using an optical detection for quantifying the amount of grains deposited. U.S. Patent No. 5,714,007 and U.S. patent No. 6,007,630 disclose an apparatuses for electrostatically depositing a medicament powder upon predefined regions of a substrate, the substrates being used to fabricate suppositories, inhalants, tablet capsules and the like. In U.S. Patent No. 5,699,649 and U.S. Patent No. 5,960,609 are presented metering and packaging methods and devices for pharmaceuticals and drugs, the methods using electrostatic phototechnology to package microgram quantities of fine powders in discrete capsule and tablet form. Often, devices of prior art technology do not reach a sufficiently high degree of de-agglomeration and an exact dose is not well developed and leaves much to be desired when it comes to dosage conformity and lung deposition effectiveness of the medicament substance. Therefore, there is still a demand of pre-fabricated high accuracy pre-metered doses to be loaded into an inhaler device, which then will ensure repeated exact doses to be given. The active dry powder then must possess a fine particle fraction, which arantees its administration to a position within the lung of a patient where it will exert its expected effect. SUMMARY An electro-dose and a method and a process for obtaining an electro-dose are disclosed. The electro-dose constitutes a pre-metered medicament powder intended for use in a dry powder inhaler and is formed from an electro-powder constituting an active powder substance or a dry powder medicament formulation with or without one or more excipients, the electro-dose being loaded onto a device member forming a dose carrier. The electro-dose prepared from an electro-powder presenting a fine particle fraction (FPF) having of the order 50 % or more of its content with a particle size between 0.5 and 5 μm. The electro-powder of such a pre-metered electro-dose further provides electrostatic properties regarding absolute specific charge per mass after charging of the order 0.1 to 25 μC/g and presents a charge decay rate constant Q50 of more than 0.1 sec with a tap density of less than 0.8 g/ml and a water activity aw of less than 0.5. The electro-dose porosity is adjusted by means of a mechanical and/or electrical vibration of the dose receiving device member during the electro-dose build-up operation to obtain an optimized porosity value of 75 to 99.9% calculated as 100 - 100x(Densityelectro-dose/Densityeletro-powder). A number of parameters must be kept under strict control during the processing in order to obtain the desired electro-dose for utilization in a dry powder inhaler. An electro-dose according to the present invention is set forth by the independent claim 1 and the dependent claims 2 to 6. Furthermore a method for obtaining an electro-dose is set forth by the independent claim 7 and further embodiments of the method are set forth by the dependent claims 8 to 23. Also a process for the manufacturing of an electro-dose is set forth by the independent claim 24 and the dependent claims 25 to 33. SHORT DESCRIPTION OF THE ADRAWINGS The invention, together with further objects and advantages thereof, may best be understood by making reference to the following description taken together with the accompanying drawings, in which: FIG. 1 is a simplified flow chart for creating an electro-dose from an electro-powder; FIG. 2 is a flow chart illustrating the powder dose analysis when preparing the electro-dose; FIG. 3 is a summary flow chart illustrating preparation of the electro-dose; FIG. 4 illustrates a cross section of a dose carrier provided with a conducting or dissipative sheet for the preparation of an electro-dose by electric field technique methods; FIG. 5 illustrates a cross section of a dose carrier made from a conductive or dissipative material for the preparation of an electro-dose by electric field technique methods; FIG. 6 illustrates a cross section of a dose carrier containing a buried conductive material sheet inside an isolative material for the preparation of an electro-dose by means of electric field technique methods; FIG. 7 illustrates a cross section of a dose carrier containing several separate buried conductive material sheets for the preparation of an electro-dose by electric field technique methods; FIG. 8 illustrates transfer of electro-powder to a carrier by means of electric field techniques; FIG. 9 illustrates transfer of electro-powder to the carrier by means of an electric field and a focusing means; FIG. 10 illustrates a control circuitry utilized in the transfer of powder according to FIG. 9; FIG. 11 illustrates an applied alternating electric field as function of time in transferring powder particles to the carrier; FIG. 12 illustrates displacement of carrier surface in micrometers as a function of time; FIG 13 illustrates a "tree" structure in an enlarged view initial positioning of de-agglomerated particles at the carrier surface; FIG. 14 illustrates a "sponge" structure in an enlarged view of particles positioned at the carrier surface after a compaction operation; FIG. 15 illustrates in an enlarged view of a "velvet" structure of the particles at the carrier surface; FIG. 16 is graph representing dose porosity and de-agglomeration for particles of sizes 3 and 5 micrometers; FIG. 17 is a graph representing calculation of de-agglomeration for particles up to 3 micrometers from an initial electro-powder particle size; FIG. 18 is a graph representing calculation of de-agglomeration for particles up to 5 micrometers from an initial electro-powder particle size; and FIG. 19 shows a measurement set-up used for a measurement of size distribution and mass and further calculation of deagglomeration and flow rate. DESCRIPTION In a starting step 100 of Figure 1 an electrostatically dosed electro-powder is brought into a powder dose analysis step 110. Dosing parameters are then determined in a step 120 to finally result in an electro-dose in a step 160. Electro-powder here is defined as a prepared active substance with or without one or more excipients meeting a set of electrical specifications for optimum electrostatic dosing properties. Specific charge is expressed in Coulomb per mass unit in this context as μC/g after charging. Such an electro-powder should present an absolute specific charge, after charging by induction, corona, or tribo-charging, of the order of 0.1 to 25 μC/g (0.1x10-6 - 25x10-6 Coulomb/gram of negative or positive charge) and a discharge rate constant Q50 > 0.1 sec. Q50 is defined as the time until 50% of the electrostatic charge is discharged, (for instance after a corona charging in an Electrical Low Pressure Impactor (ELPI) model 3935 from DEKATI LTD): Furthermore the electro-powder should constitute a powder with more than 50 % of fine particle fraction with a particle size less than 5μm and have a water content of less than 4 % together with a water activity aw Water content is defined as the amount of weakly bound water. It's calculated as the difference between the total water content, determined e g by Karl-Fischer titration, and the amount of strongly bound water, e.g. crystal water, characteristic for the substance. Water activity aw is a dimensionless quantity, which may, for instance, be measured with an AquaLab model series 3 TE. Tap density is, for instance, measured by using a Dual Autotap from Quantachrome® Corporation according to British Pharmacopoeia for Apparent Volume method. Both water activity and tap density are quantities well know to a person skilled in the field of chemistry analysis. All measurements are performed at room temperature defined as in a range of 18 - 25°C in air or nitrogen atmosphere with a relative humidity less than 5 %. The absolute specific charge is the charge the electro-powder presents after an electrostatic charging being performed and subsequently measured in μ/g with an electrometer, e.g. a Keithley Electrometer 6512 or an Electrical Low Pressure Impactor (ELPI) model 3935 from DEKATI LTD. The electro-dose is then defined as an electrostatically dosed electro-powder possessing the following specification: Porosity defined as Dpelectro-dose= 100 -100( densitye electro-dose/ densityelectro-powder) > 75 % and having a optimized de-agglomeration of > 25 % and more preferable being more than 50 % and most preferable more than 75 % and meeting a dosage uniformity according to USP 24-NF 19 Supplement 601 Aerosols/Physical Tests pages 2674 -2688, which will hereafter be referred to as USP, and also possessing a de-agglomeration difference measured according to USP compared with the de-agglomeration at a flow representing a pressure drop over the inhaler device reduced to 1 kPa (1 - (de-agglomeration(Q1kpa)/de-agglomeration(Q)) x 100) Particles intended for the deep lung, here defined as the peripheral lung and alveoli, where direct transport of an active substance to the blood can take place, should have a particle size in the range 0.5 - 3 μm, For treatment in the local lung, defined as upper parts of the lung, where treatment normally takes place for instance in asthma treatment, the particle size should be in the range 3-5 μm. All particle sizes are defined as the size of the particles measured with for instance a laser diffraction instrument e.g. a Malvern Mastersizer for physical size classification or an Andersen Impactor for an aerodynamic size classification and if not stated otherwise always referred to as aerodynamic particle size. The active substance is a pharmacologically active chemical or biological substance, with or without one or more excipients intended for administration into the deep or upper lung airways by oral inhalation from a dry powder inhaler device (DPI), where inhaled macromolecules could be from the following therapeutic areas: Insulin rapid intermediate and slow acting and diabetes peptides, interferons, interleukins and antagonists, antibodies, peptides for immune suppression, nerve growth factors, vaccines, gene therapies, genetically modified virons and/or bacterias, parathyroid hormone, osteoporosis peptides, antiobesity peptides, luteinizing hormone releasing hormone (LHRH) and LHRH analogs, somatostatin analogs, human calcitonin, colony stimulating factor, erythropoietins, growth hormones, erectile dysfunction, anti-pregnancy hormones. The active substance also could be selected from the pharmacologically active chemical and biological substances vasopressin, a vasopressin analogue, desmopressin, glucagon, corticotropin, gonadotropin, calcitonin, C-peptide of insulin, parathyroid hormone, human growth hormone, growth hormone, growth hormone releasing hormone, oxytocin, corticotropin releasing hormone, a somatostatin analogue, a gonadotropin agonist analogue, atrial natriuretic peptide, thyroxine releasing hormone, follicle stimulating hormone, prolactin, an interleukin, a growth factor, a polypeptide vaccine, an enzyme, an endorphin, a glycoprotein, a lipoprotein kinas, intra-cellular receptors, transcription factors, gene transcription activators/repressors, neurotransmitters (natural or synthetic), proteo¬glycans, a polypeptide involved in the blood coagulation cascade, that exerts its pharmacological effect systemically or any other polypeptide that has a molecular weight (Daltons) of up to 50 kDa or from the group consisting of proteins, polysaccharides, lipids, nucleic acids and combinations thereof or from the group consisting of leuprolide and albuterol or is among opiates or nicotine and nicotine derivates or scopolamin, morphine, apomorphine analoges or equivalent active substances or pharmacologically active chemicals for asthma treatment, e.g. budesonid, salbutamol, terbutalin .sulphate, salmeterol, flutikason, formoterol or salts thereof. The first step 110 of the powder dose analysis includes a series of at least five powder doses to be analyzed in a step 210 illustrated in Figure 2. Standard settings of the input parameters are then used, which are well spread over an interval to have a possibility to in a sequence of steps 220 to 270 determine the most important specifications regarding height, area, mass, porosity and dose de-agglomeration at flow rate Q according to USP and Q1kPa. Very important is to determine if a porosity adjustment is necessary to be performed by active use of mechanical and/or electrical methods in the preparation of the electro-powder into an electro-dose by adjusting the dose porosity to an optimum giving an optimum inhalation performance regarding de-agglomeration. The porosity of the electro-dose is then defined as Dp = 100- 100(densityeiectro-dose/'densityelectro-powder) producing a measure in percent. Dose height is then measured in step 220 for the powder doses of step 210 using for instance a Laser displacement sensor from Keyence LK-031 with electronics LK-2001 and cables LK-C2 giving the height of the powder bed in μm. The electro-powder doses tested in step 210 are then brought to step 230 for dose area investigation, wherein the projected size of the powder dose onto the device member is measured with, e.g., a stereo microscope from Olympus and noted down in millimeters with a resolution of 100 μm. A machine script is a program to control a sequence of operations inside a feeding device 45 in Figure 8, which is a device that in a controlled way is feeding electrostatically charged electro-powder into an electrical field allowing selected electro-powder particles with the right particle size to be transported to the device member and having a set of parameters added to the script to control the flexible settings of a powder dose. This electrostatic dosing device 45 is also performing a check of the absolute specific charge and all other essential parameters, e.g. feeding rate of de-agglomerated electro-powder by the machine script. The dose de-agglomeration step 240 is defined as breaking up agglomerated electro-powder by introducing electrical, mechanical, or aerodynamic energy. Usually de-agglomeration is performed as a stage one during dosing of the electro-powder and as a final stage two during the patient's inspiration of the electro-dose through the DPI. De-agglomeration is measured, e.g. using a Malvern Mastersizer as an example of a laser diffraction instrument used to measure particle size distribution both in aerosols and in liquids for physical size classification or an Andersen Impactor for an aerodynamic size classification as described in USP. Table I Dosing Vibration Frequency Electrical Filter Machine Time KHz; μm ti;t2;E1;E2 field E Potential Script (s) s ; V V/mm vf 8 0;0 0.5;0.01;250;-50 250 600 Test QC 1 8 0;0 0.5;0.01;250;-50 250 600 Test QC 1 8 0;0 0.5;0.01;250;-50 250 600 Test QC 1 8 0;0 0.5;0.01;250;-50 250 600 Test QC 1 8 0;0 0.5;0.01;250;-50 250 600 Test QC 1 8 0;0 0.5;0.01;300;-50 300 650 Test QC 1 8 0;0 0.5;0.01;350;-50 350 700 Test QC 1 8 0;0 0.5;0.01;400;-50 400 750 Test QC 1 8 0;0 0.5;0.01;500;-50 500 800 Test QC 1 8 0;0 0.5;0.01;1000;-50 1000 1000 Test QC 1 The electro-powder de-agglomeration is performed in the electrostatic feeding device 45 where de-agglomeration and classifying of the electro-powder is performed then resulting in obtaining a majority of the powder particles being in the correct size range 0.5-5 μm for being dosed onto the device member. This de-agglomeration operation is referred to as de-agglomeration # 1 or electro-powder de-agglomeration. The electro-dose de-agglomeration or de-agglomeration #2 takes place when sucking off the electro-dose from the device member accompanied with a de-agglomeration of the dose in the mouthpiece. De-agglomeration #2 is measured as two different airflow values, whereby the first airflow Q is according to USP and the second airflow QlkPa is at a pressure drop over the inhaler device of 1 kPa. The two different airflow values are for determining if an increase in inhalation energy has a major effect on the de-agglomeration #2. It is important to minimize the effect of the inhalation energy by adjusting the de-agglomeration #2 and the dosing properties and de-agglomeration # 1 to meet the electro-dose specification. The electro-dose de-agglomeration is measured using a mouthpiece with a nozzle in the procedure which is identical to the construction and settings inside the DPI intended to be used and with a same device member as is to be used with the DPI. The portion at the end of the mouthpiece towards the device member has to be aerodynamically correctly constructed to minimize retention. The de-agglomeration is then calculated using the electro-powder particle size specification as input material and the High Performance Liquid Chromatography HPLC analysis regarding particle size distribution after a standard sucking off from the device member as the output result. The de-agglomeration of the electro-dose is then calculated as percent of de-agglomerated electro-dose at 3 μ.m, DD3μm, and 5 \tm.t DD5μm, compared to the amount of powder less than 3 p,m and 5 pm in the original electro-powder. The de-agglomeration must be more than 25 % to meet the electro-dose specification. Figure 17 and Figure 18 present calculations of de-agglomeration at 3 pm and 5 pxn, respectively, in a graphical representation marking the areas under the particle size distribution curves for the initial and resulting distributions respectively. The curves plotted with dots representing initial electro-powder size distribution and the curves plotted with squares representing resulting electro-dose size distribution. She dose mass in step 250 is possible to be measured in two different ways. First option is to use a Malvern Mastersizer, where the powder is collected on a filter after analysis through the instrument. The filter is then possible to analyze either using a balance, e.g. a Mettler Toledo UMT5 Ultra Microbalance or by chemical analyzes, e.g. a HPLC SpectraSYSTEM with a UV 6000 detector or any other suitable detector. A second option and also most preferable is to determine the powder mass using an Andersen Impactor and analyze both the aerodynamic particle size distribution and the total mass using for instance the HPLC SpectraSYSTEM with a UV 6000 detector in accordance with USP. To meet the electro-dose specification the mass must conform to the uniformity of dose stipulated in the USP and more preferably be between 95 % Results from the above analysis: dose height in step 220, dose area in step 230, dose de-agglomeration in step 240 and dose mass in step 250 is noted down for calculations. Dose density is calculated from dose mass in micrograms from step 250 divided by dose height in millimeters from step 220 and divided by dose area in mm2 from step 230 and noted down as dose density in μg/ mm3 in step 260 Dose porosity in step 265 is here defined in percent as Dp = 100 -100x(density electro-dose/density electro-powder) with the electro-powder density in this example being 1,4 kg/dm3. Dose mass per dose area is calculated in step 270 as dose mass in μg from step 250 divided by dose area from step 230 and noted as μg/mm2. The results are then combined with the settings presented in Table I and are presented with the results in Table II below. Thus, all analytical results are noted down together with input data in an analytical report as step 280 forming a decision material for the step 120 of Figure 1 determining dosing parameters. The result of this calculated example illustrates that, in order to obtain a high quality dose with respect to de-agglomeration in step 240, the dose porosity obtained at step 265 should be to approximately 98 % . Table II Test Dose Dose Dose de-aggl. Dose Dose Dose Dose height 220 area 230 240 mass 250 density 260 Porosity 265 mass/area 270 3 μm 5μm μm mm2 % % μg μg/mm3 % μag/mm2 1 196 40 80 82 77 9 99.4 1.9 2 92 40 81 84 73 20 98.6 1.8 3 76 40 81 85 75 25 98.2 1.9 4 64 40 84 87 78 30 97.9 2.0 5 69 40 83 89 77 28 98.0 1.9 6 124 40 77 84 173 35 97.5 4.3 7 137 40 74 81 214 39 97.2 5.4 8 148 40 66 73 365 62 95.6 9.1 9 135 40 63 68 415 77 94.5 10.4 10 124 40 58 64 520 105 92.5 13.0 The decision in step 120 determining dosing parameters is then used to make, several powder dosages in a step 130 for tests and to verify that the chosen settings are correct and verified in a step 140 according to a repeated step of powder dose analysis. If the result of this powder dose analysis proves to be according to set specification for an electro-dose the settings is noted down for the continued manufacturing process. On the other hand, if powder dosing according to step 130 results are not within set specification for an electro-dose, the result is in a step 145 returned to the step 120 of determining dosing and parameters for a new optimized parameter settings. The determining preparation of electro-dose as a step 310 in Figure 3 is then taking into account the specification of the electro-powder in step 300 and dosing parameters in step 320 to have a new set of tests for the preparation of the electro-dose. A very useful tool to optimize the electro-dose is to use a statistical planning method for the tests to reduce the total amount of tests needed and fast finding the optimum preparation scheme for a desired electro-dose. Figure 4 shows an illustrative cross section a device member with a dissipative or conductive carrier area 14 as a dose receiver for the electro-dose and an isolative material 10, e.g. plastic, having a surface resistance greater than 1011 Ω. Figure 5 illustrates a cross section with another material as walls where the dissipative or conductive material 11 has a potential defined through an applied voltage 12 and where a conductive material is a material with a surface resistance Figure 6 shows in an illustrative cross section a device member with a dissipative or conductive material area 24 located under or behind a thin layer approximately 10-3000 μm of isolative material 10 and where the dissipative or conductive material is having a set potential through an applied voltage 12. Figure 7 shows an illustrative cross section of a device member with two separate dissipative or conductive materials 22 and 24 and a isolative material 10, where the dissipative or conductive material 24 forms the dose receiver of the electro-dose through an applied voltage 12 attracting the electrostatically charged electro-powder and the conductive material 22 is a conductive or dissipative material for applying a second electrical field'to guide the powder to the correct position through a second applied voltage 18 In a further illustrative embodiment similar to Figure 5 the device member material forming the dose carrier may be chosen from an isolative plastic material, which is processed before dosing by ionized air to remove electrostatic charges from its surface. In another embodiment an isolative plastic material is processed before dosing by introducing the device member . into humid air to remove electrostatic charge from its surface. In a third embodiment the device member isolative plastic material is processed before dosing by combination of ionized air and humid air to remove electrostatic charges from its surface. In still a further embodiment the device member is temporarily given a dissipative surface by applying a thin solvent layer onto its surface, e.g. water, carbon dioxide or other non-toxic and FDA approved solvent. Such a solvent layer is then applied with appropriate electrical properties by using a temperature difference or a high humidity chamber and after dosing removing the solvent from the device member. Figure 8 shows in an illustrative example a dosing and metering set-up where a feeding device 45 for electrostatically charged electro-powder is subject to an electrical field 48 created by a separate applied potential 46 measured in V/mm and intended for transporting the electrostatically charged powder in a controlled way for dosing, metering or measuring purposes. A total field acts between the device member and the electro-powder feeder 45 through two different adjusted potentials 12 and 46. Between the feeder 45 and the device member is situated a filter 44 to shield part of the device member not to be subject to dosing until the device member is in the correct position and then having a transportation of electrostatically charged electro-powder particles 49 metered onto the carrier portion of the device member. Figure 9 shows an illustrative example of a dosing and metering set-up with a device member 11 made from a dissipative material at which powder is dosed by an applied electrical field between the feeder of electrostatically Charged electro-powder 45 and the device member utilizing an electrical filter 52 with a applied make-up potential to guide the powder to the correct position onto the carrier portion of the device member. The filter potential also serves as a possibility to control depositing on and off in a simple way by switching the applied voltage to the filter between normal potential and a much lower potential compared to the potential applied to the device member in this example. The guiding of electrostatically charged electro-powder particles 49 is then a function of applied voltage of the feeder of electrostatically charged electro-powder 49 and the voltage applied to the device member 12 and the potential of the filter 52. The filter 52 is supported by an isolative filter holding material 44. Figure 10 shows in an illustrative example a dosing and metering set-up with a device member 11 in a dissipative material dosed onto by an applied electrical field between the feeder 45 of electrostatically charged electro-powder and the device member utilizing an electrical filter 52 with an applied make-up potential 59 to guide the powder to the correct position at the carrier portion of the device member 11. The filter potential also serves as a possibility to control deposition on and off in a simple way by changing the potential of the filter 52. The guiding of electrostatically charged electro-powder particles 49 is then a function of applied voltage to the feeder 45 of electrostatically charged electro-powder and the applied voltage to the device member 11 and the potential of the filter 52. The filter 52 is supported by an isolative filter holding material 44. The dose is possible to measure during the dosing and metering operation by using the electrometer €6 and switching the voltage 65 in front of a high voltage generator 67. During the dosing and metering operation it is also possible to control the density of the electro-dose by utilizing a mechanical vibration 64 or an electrical frequency utilizing, e.g. the switching box 65 resulting in a possibility to control the electrical field and the mechanical movement according to Figures 11 and 12. figure 11 shows an example of electrical fields E1 and E2 applied as alternating fields at a pre-selected frequency to have the electro-powder to "dance" at the device member 11 to thereby achieve an optimum porosity for • an optimum of de-agglomeration according to Figure 16. Figure 11 shows how the total dosing time period T is divided up in periods t1 when the electrical field is at a maximum value of Ei and other time periods t2 when the electrical field is at a minimum value of E2, whereby the time periods t1 and t2 are in the range lO6 Figure 12 illustrates an example of a set up with a mechanical vibration having a total dosing time period T and a maximum displacement of D1 during t1 and no displacement during the time period t2 to make the dosed electro-powder particles to "dance" at the device member 11 and thereby, by means of a control of the applied field, having a controlled adjustment of the porosity to an optimum situation for an optimized de-agglomeration according to Figure 16, whereby the time periods t1 and t2 are in the range 10-6 Figure 13 shows a "tree" structure of powder particles at the device member 11 showing the ordering of particles of an electro-dose not being subject to adjustment of dose porosity disclosing chains of powder rising from the device member. The electro-powder particles 72 are forming "trees" of particles resulting in an extremely high porosity. The porosity of an electro-dose is calculated using the width and height of the "tree" structure together with the length to calculate the volume and then dividing the mass of the electro-dose with the volume to obtain the density of the electro-dose. The porosity is then calculated as Dp = 100 - 100-100(densityelectro-dose /density electro-powder) in percent, where the density of the electro-powder in this example is 1.4kg/dm3. It should be noted that in the preferred process the carrier is turned with its receiving surface facing downwards as illustrated in Figures 13 to 15 when picking up the charged particles 72, 82 or 92. However, the process may also be performed as indicated by Figures 6 to 10. Figure 14 shows an electro-dose on the device member 11 with a "sponge" structure defined as an intermediate structure of the electro-dose, where some of the "tree" structures 82 have collapsed and are connected top to top forming a matrix with a medium to low density and less porosity through a adjusted density by electrical frequency or mechanical vibration during the dosing and metering operation thereby obtaining a lower porosity compared to the "tree" structure of Figure 13. Figure 15 shows an electro-dose at a device member 11 presenting a velvet structure 92 after being porosity adjusted with the proper electrical frequency or mechanical vibration thereby obtaining a look like a smooth velvet cloth which shows much less porosity than the "sponge" structure. Figure 16 illustrates the effect of a dose porosity adjustment in which the de-agglomeration of the electro-dose is measured at different porosities showing an optimum de-agglomeration both for particles less than 5 μm and for particles less than 3 μm having a porosity in the range marked as A also indicating that the electro-dose is independent of the flow at porosities inside the range A. In the range marked B the de-agglomeration is in a transition area and showing medium flow dependence and a lower grade of de-agglomeration. In range C the porosity is lower and the powder much harder to de-agglomerate in dose de-agglomeration and also showing a strong dependence of the flow i.e. the energy level of the de-agglomeration #2 and are not suitable as an dose for inhalation and subject to optimization. DD5μm is the dose de-agglomeration at 5 μm and at a differential pressure according to USP and DD1kPa is also according to USP but at a pressure drop over the inhaler of lkPa. Measurement of de-agglomeration is performed, e.g., according to Figure 19, using an Andersen Inpactor together with a mouthpiece and a device member in a set-up identical with the intended DPI for the electro-dose or instead of the Andersen Tmpactor using a Malvern Master Sizer S to measure the physical particle size. When the particle distribution is measured the de-agglomeration can be calculated knowing the electro-powder particle size distribution. The de-agglomeration is measured at two different rates of flow, flow-rate Q according to USP and at a flow-rate at 1 kPa pressure drop over the inhaler device according to USP. Measuring at two different flow-rates indicates if the electro-dose in the intended DPI is flow dependent or flow independent, as this may be an important aspect for the patient. If the difference in de-agglomeration is less than 25 %, when calculated as (100 - 100x(de-agglomeration(Q1kPa)/de-agglomeration(Q)), then the electro-dose meets the specifications, if the result is outside the electro-dose specifications further optimization of the electro-dose has to be performed by going back to step 310. Figure 17 describes how the de-agglomeration at 3 μm is calculated using the initially input electro-powder under 3 μm represented by the hatched area as a base. The amount of de-agglomerated electro-powder from the electro-dose is then represented by the dark area under the curve showing resulting powder. By dividing the calculated value of the surface of the second area with the calculated value of the surface of the first area and multiplying by a factor 100 the de-agglomerated amount below 3μm is obtained in percent. Figure 18 describes how the de-agglomeration at 5 μm is calculated using the initially input electro-powder under 5 μm represented by the hatched area as a base. The amount of de-agglomerated electro-powder from the electro-dose is then represented by the dark area under the curve showing resulting powder. By dividing the calculated value of the surface of the second area in Figure 18 with the calculated value of the surface of the first area in Figure 18 and multiplying by a factor 100 the de-agglomerated amount below 5 μm is obtained in percent. Figure 19 illustrates an example of a de-agglomeration and mass measurement set-up 71 identical to the inhaler to be used to determine the particle size distribution and mass from a pre-metered electro-dose sucked up from the device member 73 through a mouthpiece 78 using an Andersen Impactor 74 to determine the particle size distribution. The total pressure drop over the de-agglomeration set-up is measured with the pressure gauge 75 and the flow-rate of the air is measured with a flowmeter 76 in liters/minute. Suction may be achieved by means of a pumping device 77. All measurements of the particle size distribution are measured at two different pressure drops over the inhaler device. First all measurements are performed according to USP and then only the pressure is changed for the measurement at a lower pressure lkPa over the inhaler device 71 in point 79. A complementary particle size distribution is also measured at lkPa pressure drop over the de-agglomeration #2 set-up 71 indicated by the pressure gauge 79 as differential pressure to the atmosphere and then the obtained flow rate is noted down and named Q1kPa- The particle size distribution obtained at the flow rate QlkPa is then compared with the particle size distribution obtained at the flow rate Q, using all other settings according to the USP. The results of the test of de-agglomeration #2 at two different pressures over the inhaler device are compared according to Figure 16 to determine if the result meets the specification for an electro-dose and also if the de-agglomeration for 3 and 5 yarn., DD3μm,1kpa and, DD5μm.1kPa are within the specifications of the medicament drug. Thus the method and process according to the present disclosure will result in a very well defined electro-dose for utilization in a dry powder inhaler resulting in a small standard deviation of the doses for repeated administrations. It will be understood by those skilled in the art that various modifications and changes may be made to the present invention without departure from the scope thereof, which is defined by the appended claims. We claim 1. A micronized powder dose of a medical powder for use in a dry powder inhaler, the micronized powder dose having been prepared from an active powder substance or a dry powder medical formulation presenting a fine particle fraction (FPF) of the order 50 % or more of its content having a particle size from 0.5 to 5 μm, said substance or formulation having been metered onto a device constituting a dose carrier thereby having formed said micronized powder dose, the micronized powder dose presenting an optimized porosity of 75 to 99.9 % and further meeting electric specifications regarding absolute specific charge per mass after charging of the order 0.1 to 25 μC/g and presenting a charge decay rate constant Q50 of more than 0.1 sec with a tap density of less than 0.8 g/ml and a water activity aw of less than 0.5. 2. The electro-dose as claimed in claim 1, said metered micronized powder dose having, onto a surface area of said device member which forms a dose carrier, a height less than 800 μm perpendicular to the surface area of the device member onto which the substance or formulation is deposed. 3. The electro-dose as claimed in claim 1, said metered micronized powder dose, by using mechanical vibrations of the device member, having been adjusted to a porosity having in a value between 75 and 99.9 %. 4. The electro-dose as claimed in claim 1, said metered micronized powder dose, by using a frequency oscillation in an electrical field, having been adjusted to a porosity having in a value between 75 and 99.9 %. 5. A method for preparing a metered micronized powder dose of a medical powder for administration into the deep or upper lung airways by oral inhalation using a dry powder inhaler device, characterized by the steps of: charging by means of corona, induction or tribo-effect a medicament powder, being a preparation of chemical and biological substance of the kind such as herein described, with or without one or more excipients, forming a micronized powder; transporting charged particles of the micronized powder towards a device member constituting a dose carrier using electric field techniques; depositing the charged particles onto the dose carrier using electrical field techniques; forming of a metered powder bed onto the dose carrier using electrical field techniques into a chosen state of dose porosity, the micronized powder dose presenting an optimized porosity of 75 to 99.9 % and further meeting electric specifications regarding absolute specific charge per mass after charging of the order 0.1 to 25 μC/g and presenting a charge decay rate constant Q50 of more than 0.1 sec with a tap density of less than 0.8 g/ml and a water activity aw of less than 0.5. 6. The method as claimed in claim 5, comprising the further step of combining the electrical field techniques with a mechanical vibration and/or an applied electrical frequency to adjust the dose porosity. 7. The method as claimed in claim 5, comprising the further step of analyzing the metered powder bed regarding one or more of at least following parameters: dose height, dose area, dose de-agglomeration, dose mass, dose density, dose porosity. 8. The method as claimed in claim 7, comprising the further step of comparing the analysis result with predefined dosing parameters for deciding that the metered micronized powder dose at the dose carrier complies with the basic requirements for administration by the inhaler device. 9. The method as claimed in claim 5, comprising the further step of checking that the metered powder dose has an optimized porosity of 75 to 99.9 %. 10. The method as claimed in claim 5, comprising the further step of utilizing mechanical vibration of the dose receiving device member during the dosing operation to adjust the metered powder porosity to an optimized value between 75 and 99.9 %. 11. The method as claimed in claim 5, comprising the further step of analyzing the metered micronized powder dose by a laser triangular method and a HPLC or weighing operation for a total volume calculation to determine the powder dose mass in order to calculate the powder dose powder porosity in percent as Dp =100 -100x(densitypowder-dose/densitymedicinal-powder) obtaining an optimized value between 75 and 99.9 %. 12. The method as claimed in claim 5, comprising the further step of preparing the metered micronized powder dose onto a surface area of the device member, to obtain a powder dose height of less than 800 μm. 13. The method as claimed in claim 12, comprising the further step of checking the metered micronized powder dose height by means of a triangular laser measuring instrument. 14. The method as claimed in claim 5, comprising the further step of additionally preparing the pre-metered micronized powder dose by using an oscillating electrical field to adjust the porosity of the powder dose to an optimized value of 75 to 99.9 %. 15. The method as claimed in claim 5, comprising the further step of preparing the powder dose using at least one active electrical filter with a control potential switched on and off within a voltage range Vlow electrical field 16. The method as claimed in claim 5, comprising the further step of measuring metered micronized powder dose mass by draining the electrostatic charge into a electrometer determining the specific charge in \|μC'/gmedicinal-powder. 17. The method as claimed in claim 5, comprising the further step of measuring metered micronized powder dose height using a contrast analyzing method and checking height of the powder dose to be less than 800 μm. 18. The method as claimed in claim 5, comprising the further step of measuring metered micronized powder dose height using a laser triangulation method and checking height of the powder dose to be less than 800 μm. 19. The method as claimed in claim 5, comprising the further step of measuring metered micronized powder dose height using an image analyzing method and checking height of the powder dose to be less than 800 μm. - 20. The method as claimed in claim 5, comprising the further step of measuring metered micronized powder dose height using a combination of image analysis, laser triangulation, contrast methods to ensure a height of the powder dose to be less than 800μm, 21. The method as claimed in claim 5, comprising the further step of measuring micronized powder dose deagglomeration using a Andersen Impactor for aerodynamic particle size distribution or a Malvern Mastersizer S to determine the physical particle size distribution for a calculation and optimization of the deagglomeration of the micronized powder dose by changing the porosity. 22. A process of preparing doses of powder to be used for administration by a dry powder inhaler, characterized in that a medicament powder, being a preparation of a chemical and/or biological substance, with or without one or more excipients, is metered onto a device member constituting a dose carrier thereby forming a metered micronized powder dose; a metered micronized powder dose bed is formed on the dose carrier material using electrical field techniques and the micronized powder dose presenting an optimized porosity of 75 to 99.9 % and meeting electric specifications regarding absolute specific charge per mass after charging of the order 0.1 to 25 μC/g and presenting a charge decay rate constant Q50 of more than 0.1 sec with a tap density of less than 0.8 g/ml and a water activity aw of less than 0.5; the obtained metered micronized powder dose bed is analyzed regarding one or more of at least following parameters: dose height, dose area, dose de-agglomeration, dose mass, dose density, dose porosity; and a result of the analysis is compared with predefined dosing parameters for deciding that the prepared metered micronized powder dose on the dose carrier complies with the basic requirements for administration by the inhaler. 23. The process as claimed in claim 22, wherein electrical field technology is combined with a mechanical vibration and/or an applied electrical frequency. 24. The process as claimed in claim 22, wherein the device member material is an isolative plastic material processed before dosing and metering by ionized air to remove electrostatic charges from its surface. 25. The process as claimed in claim 22, wherein the device member material is an isolative plastic material processed before dosing and metering by introducing the device member into humid air to remove electrostatic charge from its surface. 26. The process as claimed in claim 22, wherein the device member material is an isolative plastic material processed before dosing and metering by combination of ionized air and humid air to remove electrostatic charges from its surface. 27. The process as claimed in claim 22, wherein that electro-conductive material is mixed into a plastic material constituting the device member. 28. The process as claimed in claim 22, wherein electro-conductive material is coated onto a plastic material constituting the device member. 29. The process as claimed in claim 27 or 28, wherein the conductive material and the plastic material combination of the device member has a specification presenting a surface resistance of 103 -1012 Ω, and a volume resistivity of 103 - 1012 ohmm. - 30. The process as claimed in claim 22, wherein electro-conductive material used for the device member is obtained from any of materials such as silver powder, platinum powder, gold powder, stainless steal powder, antimony-doped tin oxide, antimony-doped silica oxide, or is a X-doped silica where X is an adamantine semiconductor, e.g., Ge, ZnO, GaSb or an octahedral semiconductor, e.g. SnSe, AgSbSe2, InSb or carbon or any other electro-conductive material approved by FDA and possible to incorporate into plastics. 31. The process as claimed in claim 22, wherein the device member is temporarily given a dissipative surface by applying a thin solvent layer onto the surface e.g. water, carbon dioxide or other non¬toxic and FDA approved solvent with appropriate electrical properties by using a temperature difference or a high humidity chamber and after dosing and metering removing the solvent from the device member. Dated this the 27th day of January, 2003 [JAYANTA PAL] Of Remfry&Sagar Attorney for the Applicants

Full Text

FORM 2
THE PATENTS ACT 1970
[39 OF 1970]
8
THE PATENTS RULES, 2003 COMPLETE SPECIFICATION
[See Section 10; rule 13]
"METERED ELECTRO-DOSE"
MEDERIO AG, of P.O. Box 138, CH-6052 Hergiswil NW, Switzerland,
The following specification particularly describes the invention and
the manner in which it is to be performed:

ORIGINAL
127/MUMNP/2003

GRANTED
22-5-2006

Metered electro-dose
TECHNICAL FIELD The present invention relates to electrostatic dosing and more particularly to an electro-dose using electro-powder as well as a process and a method for preparation of a metered electro-dose for inhalation into the deep or upper lungs by means of an inhaler device.
BACKGROUND
The dosing of drugs is carried out in a number of different ways in the medicament service today. Within health care more and more is focused on the possibility of dosing medicament drugs as a powder directly to the airways and lungs of a patient by means of an inhaler in order to obtain an effective, quick and patient-friendly administration of such substances.
A dry powder inhaler, DPI, represents a device intended for administration of powder into the deep or upper lung airways by oral inhalation. With deep lung should be understood the peripheral lung and alveoli, where direct transport of active substance to the blood can take place. Particle sizes, to reach into the deep lung, should be in a range 0.5-3 μm and for a local lung delivery in the range 3-5 μm. A larger grain size will easily stick in the mouth and throat, and a smaller grain size may accompany the expiration air out again.
To succeed with systemic delivery of medicament powders to the deep lung by inhalation there are some criteria, which have to be fulfilled. The most important is a very high degree of de-agglomeration of the medicament powder but also an exact dose is of great importance. This is not possible with dry powder inhalers of today without special arrangements as for example a so called spacer.
By means of a spacer the small grains are evenly distributed in a container from which the inhalation can take place. Upon inhalation from the spacer the fine powder floating free in the air will effectively reach the alveoli of the

lung. This method in principle has two drawbacks, firstly difficulties to control the amount of medicine emitted to the lung as an uncontrolled amount of powder sticks to the walls of the spacer and secondly difficulties in handling the relatively space demanding apparatus.
Powders for inhalers have a tendency of agglomerating, in other word to clod or to form small or larger lumps, which then have to be de-agglomerated. De-agglomeration is defined as breaking up agglomerated powder by introducing electrical, mechanical, or aerodynamic energy. Usually de-agglomeration is performed as a stage one during dosing and as a final stage two during the patient's inspiration through the DPI.
Inhaler devices normally use the force exerted by the patient's more or less normal inspiration effort for de-agglomerating the medicament substance administered when inhaling in an effort to bring as much as possible of the active substance into the lungs. This often leads to inhaler designs using high pressure drops, which will put the patient's lungpower to the test.
One major problem with some of the techniques described above is to also obtain a low relative standard deviation (RSD) between doses with this type of technique due to lack of in line control possibilities in production making it hard to be in compliance with regulatory demands.
As already noted for an optimum amount of substance to reach the alveoli, an administered powder dose should preferably have a grain size between 0.5 and 3μm. Besides, the inspiration must take place in a calm way to decrease air speed and thereby reduce deposition in the upper respiratory tracts.
Technologies to de-agglomerate today include advanced mechanical and aerodynamic systems and combinations between electrical and mechanical filling systems that can be seen in for instance in U.S. Patent No. 5,826,633. Further there are systems disclosed for dispersing aerosolized doses of

medicaments, e.g. U.S. Patent No. 5,775,320, U.S. Patent No. 5,785,049, and U.S. Patent No. 5,740,794. Furthermore, in our International Publications WO 00/06236 and WO 00/06235 principles for de-agglomeration and classification are disclosed.
5
The term electro-powder refers to a micronized medicament powder presenting controlled electrostatic properties to be suitable for electrostatic administration in an inhaler device. Such an electro-powder provides possibilities for a better dosing from electrostatically operating equipment
such as disclosed in our U.S. Patent No. 6,089,227 as well as our Swedish Patents No. 9802648-7 and 9802649-5, which present excellent inhalation dosing performance.
The state of the art also discloses a number of solutions for depositing powder for dosing. U.S. Patent No. 6,063,194 discloses a powder deposition apparatus for depositing grains on a substrate using an electrostatic chuck having one or more collection zones and using an optical detection for quantifying the amount of grains deposited. U.S. Patent No. 5,714,007 and U.S. patent No. 6,007,630 disclose an apparatuses for electrostatically depositing a medicament powder upon predefined regions of a substrate, the substrates being used to fabricate suppositories, inhalants, tablet capsules and the like. In U.S. Patent No. 5,699,649 and U.S. Patent No. 5,960,609 are presented metering and packaging methods and devices for pharmaceuticals and drugs, the methods using electrostatic phototechnology to package microgram quantities of fine powders in discrete capsule and tablet form.
Often, devices of prior art technology do not reach a sufficiently high degree of de-agglomeration and an exact dose is not well developed and leaves much to be desired when it comes to dosage conformity and lung deposition effectiveness of the medicament substance. Therefore, there is still a demand of pre-fabricated high accuracy pre-metered doses to be loaded into an inhaler device, which then will ensure repeated exact doses to be given. The active dry powder then must possess a fine particle fraction, which

arantees its administration to a position within the lung of a patient where it will exert its expected effect.
SUMMARY
An electro-dose and a method and a process for obtaining an electro-dose are disclosed. The electro-dose constitutes a pre-metered medicament powder intended for use in a dry powder inhaler and is formed from an electro-powder constituting an active powder substance or a dry powder medicament formulation with or without one or more excipients, the electro-dose being loaded onto a device member forming a dose carrier. The electro-dose prepared from an electro-powder presenting a fine particle fraction (FPF) having of the order 50 % or more of its content with a particle size between 0.5 and 5 μm. The electro-powder of such a pre-metered electro-dose further provides electrostatic properties regarding absolute specific charge per mass after charging of the order 0.1 to 25 μC/g and presents a charge decay rate constant Q50 of more than 0.1 sec with a tap density of less than 0.8 g/ml and a water activity aw of less than 0.5.
The electro-dose porosity is adjusted by means of a mechanical and/or electrical vibration of the dose receiving device member during the electro-dose build-up operation to obtain an optimized porosity value of 75 to 99.9% calculated as 100 - 100x(Densityelectro-dose/Densityeletro-powder). A number of parameters must be kept under strict control during the processing in order to obtain the desired electro-dose for utilization in a dry powder inhaler.
An electro-dose according to the present invention is set forth by the independent claim 1 and the dependent claims 2 to 6. Furthermore a method for obtaining an electro-dose is set forth by the independent claim 7 and further embodiments of the method are set forth by the dependent claims 8 to 23. Also a process for the manufacturing of an electro-dose is set forth by the independent claim 24 and the dependent claims 25 to 33.

SHORT DESCRIPTION OF THE ADRAWINGS The invention, together with further objects and advantages thereof, may best be understood by making reference to the following description taken together with the accompanying drawings, in which:
FIG. 1 is a simplified flow chart for creating an electro-dose from an electro-powder;
FIG. 2 is a flow chart illustrating the powder dose analysis when preparing the electro-dose;
FIG. 3 is a summary flow chart illustrating preparation of the electro-dose;
FIG. 4 illustrates a cross section of a dose carrier provided with a conducting or dissipative sheet for the preparation of an electro-dose by electric field technique methods;
FIG. 5 illustrates a cross section of a dose carrier made from a conductive or dissipative material for the preparation of an electro-dose by electric field technique methods;
FIG. 6 illustrates a cross section of a dose carrier containing a buried conductive material sheet inside an isolative material for the preparation of an electro-dose by means of electric field technique methods;
FIG. 7 illustrates a cross section of a dose carrier containing several separate buried conductive material sheets for the preparation of an electro-dose by electric field technique methods;
FIG. 8 illustrates transfer of electro-powder to a carrier by means of electric field techniques;

FIG. 9 illustrates transfer of electro-powder to the carrier by means of an electric field and a focusing means;
FIG. 10 illustrates a control circuitry utilized in the transfer of powder according to FIG. 9;
FIG. 11 illustrates an applied alternating electric field as function of time in transferring powder particles to the carrier;
FIG. 12 illustrates displacement of carrier surface in micrometers as a function of time;
FIG 13 illustrates a "tree" structure in an enlarged view initial positioning of de-agglomerated particles at the carrier surface;
FIG. 14 illustrates a "sponge" structure in an enlarged view of particles positioned at the carrier surface after a compaction operation;
FIG. 15 illustrates in an enlarged view of a "velvet" structure of the particles at the carrier surface;
FIG. 16 is graph representing dose porosity and de-agglomeration for particles of sizes 3 and 5 micrometers;
FIG. 17 is a graph representing calculation of de-agglomeration for particles up to 3 micrometers from an initial electro-powder particle size;
FIG. 18 is a graph representing calculation of de-agglomeration for particles up to 5 micrometers from an initial electro-powder particle size; and

FIG. 19 shows a measurement set-up used for a measurement of size distribution and mass and further calculation of deagglomeration and flow rate.
DESCRIPTION
In a starting step 100 of Figure 1 an electrostatically dosed electro-powder is brought into a powder dose analysis step 110. Dosing parameters are then determined in a step 120 to finally result in an electro-dose in a step 160. Electro-powder here is defined as a prepared active substance with or without one or more excipients meeting a set of electrical specifications for optimum electrostatic dosing properties. Specific charge is expressed in Coulomb per mass unit in this context as μC/g after charging. Such an electro-powder should present an absolute specific charge, after charging by induction, corona, or tribo-charging, of the order of 0.1 to 25 μC/g (0.1x10-6 - 25x10-6 Coulomb/gram of negative or positive charge) and a discharge rate constant Q50 > 0.1 sec. Q50 is defined as the time until 50% of the electrostatic charge is discharged, (for instance after a corona charging in an Electrical Low Pressure Impactor (ELPI) model 3935 from DEKATI LTD): Furthermore the electro-powder should constitute a powder with more than 50 % of fine particle fraction with a particle size less than 5μm and have a water content of less than 4 % together with a water activity aw Water content is defined as the amount of weakly bound water. It's calculated as the difference between the total water content, determined e g by Karl-Fischer titration, and the amount of strongly bound water, e.g. crystal water, characteristic for the substance. Water activity aw is a dimensionless quantity, which may, for instance, be measured with an AquaLab model series 3 TE. Tap density is, for instance, measured by using a Dual Autotap from Quantachrome® Corporation according to British Pharmacopoeia for Apparent Volume method. Both water activity and tap

density are quantities well know to a person skilled in the field of chemistry analysis.
All measurements are performed at room temperature defined as in a range of 18 - 25°C in air or nitrogen atmosphere with a relative humidity less than 5 %. The absolute specific charge is the charge the electro-powder presents after an electrostatic charging being performed and subsequently measured in μ/g with an electrometer, e.g. a Keithley Electrometer 6512 or an Electrical Low Pressure Impactor (ELPI) model 3935 from DEKATI LTD.
The electro-dose is then defined as an electrostatically dosed electro-powder possessing the following specification: Porosity defined as Dpelectro-dose= 100 -100( densitye electro-dose/ densityelectro-powder) > 75 % and having a optimized de-agglomeration of > 25 % and more preferable being more than 50 % and most preferable more than 75 % and meeting a dosage uniformity according to USP 24-NF 19 Supplement 601 Aerosols/Physical Tests pages 2674 -2688, which will hereafter be referred to as USP, and also possessing a de-agglomeration difference measured according to USP compared with the de-agglomeration at a flow representing a pressure drop over the inhaler device reduced to 1 kPa (1 - (de-agglomeration(Q1kpa)/de-agglomeration(Q)) x 100) Particles intended for the deep lung, here defined as the peripheral lung and alveoli, where direct transport of an active substance to the blood can take place, should have a particle size in the range 0.5 - 3 μm, For treatment in the local lung, defined as upper parts of the lung, where treatment normally takes place for instance in asthma treatment, the particle size should be in the range 3-5 μm. All particle sizes are defined as the size of the particles measured with for instance a laser diffraction instrument e.g. a Malvern Mastersizer for physical size classification or an Andersen Impactor for an aerodynamic size classification and if not stated otherwise always referred to as aerodynamic particle size.

The active substance is a pharmacologically active chemical or biological substance, with or without one or more excipients intended for administration into the deep or upper lung airways by oral inhalation from a dry powder inhaler device (DPI), where inhaled macromolecules could be from the following therapeutic areas: Insulin rapid intermediate and slow acting and diabetes peptides, interferons, interleukins and antagonists, antibodies, peptides for immune suppression, nerve growth factors, vaccines, gene therapies, genetically modified virons and/or bacterias, parathyroid hormone, osteoporosis peptides, antiobesity peptides, luteinizing hormone releasing hormone (LHRH) and LHRH analogs, somatostatin analogs, human calcitonin, colony stimulating factor, erythropoietins, growth hormones, erectile dysfunction, anti-pregnancy hormones.
The active substance also could be selected from the pharmacologically active chemical and biological substances vasopressin, a vasopressin analogue, desmopressin, glucagon, corticotropin, gonadotropin, calcitonin, C-peptide of insulin, parathyroid hormone, human growth hormone, growth hormone, growth hormone releasing hormone, oxytocin, corticotropin releasing hormone, a somatostatin analogue, a gonadotropin agonist analogue, atrial natriuretic peptide, thyroxine releasing hormone, follicle stimulating hormone, prolactin, an interleukin, a growth factor, a polypeptide vaccine, an enzyme, an endorphin, a glycoprotein, a lipoprotein kinas, intra-cellular receptors, transcription factors, gene transcription activators/repressors, neurotransmitters (natural or synthetic), proteo¬glycans, a polypeptide involved in the blood coagulation cascade, that exerts its pharmacological effect systemically or any other polypeptide that has a molecular weight (Daltons) of up to 50 kDa or from the group consisting of proteins, polysaccharides, lipids, nucleic acids and combinations thereof or from the group consisting of leuprolide and albuterol or is among opiates or nicotine and nicotine derivates or scopolamin, morphine, apomorphine analoges or equivalent active substances or pharmacologically active chemicals for asthma treatment, e.g. budesonid, salbutamol, terbutalin
.sulphate, salmeterol, flutikason, formoterol or salts thereof.

The first step 110 of the powder dose analysis includes a series of at least five powder doses to be analyzed in a step 210 illustrated in Figure 2. Standard settings of the input parameters are then used, which are well spread over an interval to have a possibility to in a sequence of steps 220 to 270 determine the most important specifications regarding height, area, mass, porosity and dose de-agglomeration at flow rate Q according to USP and Q1kPa. Very important is to determine if a porosity adjustment is necessary to be performed by active use of mechanical and/or electrical methods in the preparation of the electro-powder into an electro-dose by adjusting the dose porosity to an optimum giving an optimum inhalation performance regarding de-agglomeration. The porosity of the electro-dose is then defined as Dp = 100- 100*(densityeiectro-dose/'densityelectro-powder) producing a measure in percent.
Dose height is then measured in step 220 for the powder doses of step 210 using for instance a Laser displacement sensor from Keyence LK-031 with electronics LK-2001 and cables LK-C2 giving the height of the powder bed in μm.
The electro-powder doses tested in step 210 are then brought to step 230 for dose area investigation, wherein the projected size of the powder dose onto the device member is measured with, e.g., a stereo microscope from Olympus and noted down in millimeters with a resolution of 100 μm.
A machine script is a program to control a sequence of operations inside a feeding device 45 in Figure 8, which is a device that in a controlled way is feeding electrostatically charged electro-powder into an electrical field allowing selected electro-powder particles with the right particle size to be transported to the device member and having a set of parameters added to the script to control the flexible settings of a powder dose. This electrostatic dosing device 45 is also performing a check of the absolute specific charge and all other essential parameters, e.g. feeding rate of de-agglomerated

electro-powder by the machine script. The dose de-agglomeration step 240 is defined as breaking up agglomerated electro-powder by introducing electrical, mechanical, or aerodynamic energy. Usually de-agglomeration is performed as a stage one during dosing of the electro-powder and as a final stage two during the patient's inspiration of the electro-dose through the DPI. De-agglomeration is measured, e.g. using a Malvern Mastersizer as an example of a laser diffraction instrument used to measure particle size distribution both in aerosols and in liquids for physical size classification or an Andersen Impactor for an aerodynamic size classification as described in USP.
Table I

Dosing Vibration Frequency Electrical Filter Machine
Time KHz; μm ti;t2;E1;E2 field E Potential Script
(s) s ; V V/mm vf
8 0;0 0.5;0.01;250;-50 250 600 Test QC 1
8 0;0 0.5;0.01;250;-50 250 600 Test QC 1
8 0;0 0.5;0.01;250;-50 250 600 Test QC 1
8 0;0 0.5;0.01;250;-50 250 600 Test QC 1
8 0;0 0.5;0.01;250;-50 250 600 Test QC 1
8 0;0 0.5;0.01;300;-50 300 650 Test QC 1
8 0;0 0.5;0.01;350;-50 350 700 Test QC 1
8 0;0 0.5;0.01;400;-50 400 750 Test QC 1
8 0;0 0.5;0.01;500;-50 500 800 Test QC 1
8 0;0 0.5;0.01;1000;-50 1000 1000 Test QC 1
The electro-powder de-agglomeration is performed in the electrostatic feeding device 45 where de-agglomeration and classifying of the electro-powder is performed then resulting in obtaining a majority of the powder particles being in the correct size range 0.5-5 μm for being dosed onto the device member. This de-agglomeration operation is referred to as de-agglomeration # 1 or electro-powder de-agglomeration.

The electro-dose de-agglomeration or de-agglomeration #2 takes place when sucking off the electro-dose from the device member accompanied with a de-agglomeration of the dose in the mouthpiece.
De-agglomeration #2 is measured as two different airflow values, whereby the first airflow Q is according to USP and the second airflow QlkPa is at a pressure drop over the inhaler device of 1 kPa. The two different airflow values are for determining if an increase in inhalation energy has a major effect on the de-agglomeration #2. It is important to minimize the effect of the inhalation energy by adjusting the de-agglomeration #2 and the dosing properties and de-agglomeration # 1 to meet the electro-dose specification.
The electro-dose de-agglomeration is measured using a mouthpiece with a nozzle in the procedure which is identical to the construction and settings inside the DPI intended to be used and with a same device member as is to be used with the DPI. The portion at the end of the mouthpiece towards the device member has to be aerodynamically correctly constructed to minimize retention.
The de-agglomeration is then calculated using the electro-powder particle size specification as input material and the High Performance Liquid Chromatography HPLC analysis regarding particle size distribution after a standard sucking off from the device member as the output result. The de-agglomeration of the electro-dose is then calculated as percent of de-agglomerated electro-dose at 3 μ.m, DD3μm, and 5 \tm.t DD5μm, compared to the amount of powder less than 3 p,m and 5 pm in the original electro-powder. The de-agglomeration must be more than 25 % to meet the electro-dose specification. Figure 17 and Figure 18 present calculations of de-agglomeration at 3 pm and 5 pxn, respectively, in a graphical representation marking the areas under the particle size distribution curves for the initial and resulting distributions respectively. The curves plotted with dots representing initial electro-powder size distribution and the curves plotted with squares representing resulting electro-dose size distribution.

She dose mass in step 250 is possible to be measured in two different ways. First option is to use a Malvern Mastersizer, where the powder is collected on a filter after analysis through the instrument. The filter is then possible to analyze either using a balance, e.g. a Mettler Toledo UMT5 Ultra Microbalance or by chemical analyzes, e.g. a HPLC SpectraSYSTEM with a UV 6000 detector or any other suitable detector. A second option and also most preferable is to determine the powder mass using an Andersen Impactor and analyze both the aerodynamic particle size distribution and the total mass using for instance the HPLC SpectraSYSTEM with a UV 6000 detector in accordance with USP.
To meet the electro-dose specification the mass must conform to the uniformity of dose stipulated in the USP and more preferably be between 95 % Results from the above analysis: dose height in step 220, dose area in step 230, dose de-agglomeration in step 240 and dose mass in step 250 is noted down for calculations.
Dose density is calculated from dose mass in micrograms from step 250 divided by dose height in millimeters from step 220 and divided by dose area in mm2 from step 230 and noted down as dose density in μg/ mm3 in step 260 Dose porosity in step 265 is here defined in percent as Dp = 100 -100x(density electro-dose/density electro-powder) with the electro-powder density in this example being 1,4 kg/dm3. Dose mass per dose area is calculated in step 270 as dose mass in μg from step 250 divided by dose area from step 230 and noted as μg/mm2. The results are then combined with the settings presented in Table I and are presented with the results in Table II below.
Thus, all analytical results are noted down together with input data in an analytical report as step 280 forming a decision material for the step 120 of

Figure 1 determining dosing parameters. The result of this calculated example illustrates that, in order to obtain a high quality dose with respect to de-agglomeration in step 240, the dose porosity obtained at step 265 should be to approximately 98 % .
Table II

Test Dose Dose Dose de-aggl. Dose Dose Dose Dose
height 220 area 230 240 mass 250 density 260 Porosity 265 mass/area 270

3 μm 5μm

μm mm2 % % μg μg/mm3 % μag/mm2
1 196 40 80 82 77 9 99.4 1.9
2 92 40 81 84 73 20 98.6 1.8
3 76 40 81 85 75 25 98.2 1.9
4 64 40 84 87 78 30 97.9 2.0
5 69 40 83 89 77 28 98.0 1.9
6 124 40 77 84 173 35 97.5 4.3
7 137 40 74 81 214 39 97.2 5.4
8 148 40 66 73 365 62 95.6 9.1
9 135 40 63 68 415 77 94.5 10.4
10 124 40 58 64 520 105 92.5 13.0
The decision in step 120 determining dosing parameters is then used to make, several powder dosages in a step 130 for tests and to verify that the chosen settings are correct and verified in a step 140 according to a repeated step of powder dose analysis. If the result of this powder dose analysis proves to be according to set specification for an electro-dose the settings is noted down for the continued manufacturing process.
On the other hand, if powder dosing according to step 130 results are not within set specification for an electro-dose, the result is in a step 145 returned to the step 120 of determining dosing and parameters for a new optimized parameter settings. The determining preparation of electro-dose as a step 310 in Figure 3 is then taking into account the specification of the electro-powder in step 300 and dosing parameters in step 320 to have a new

set of tests for the preparation of the electro-dose. A very useful tool to optimize the electro-dose is to use a statistical planning method for the tests to reduce the total amount of tests needed and fast finding the optimum preparation scheme for a desired electro-dose.
Figure 4 shows an illustrative cross section a device member with a dissipative or conductive carrier area 14 as a dose receiver for the electro-dose and an isolative material 10, e.g. plastic, having a surface resistance greater than 1011 Ω.
Figure 5 illustrates a cross section with another material as walls where the dissipative or conductive material 11 has a potential defined through an applied voltage 12 and where a conductive material is a material with a surface resistance Figure 6 shows in an illustrative cross section a device member with a dissipative or conductive material area 24 located under or behind a thin layer approximately 10-3000 μm of isolative material 10 and where the dissipative or conductive material is having a set potential through an applied voltage 12.
Figure 7 shows an illustrative cross section of a device member with two separate dissipative or conductive materials 22 and 24 and a isolative material 10, where the dissipative or conductive material 24 forms the dose receiver of the electro-dose through an applied voltage 12 attracting the electrostatically charged electro-powder and the conductive material 22 is a conductive or dissipative material for applying a second electrical field'to guide the powder to the correct position through a second applied voltage 18

In a further illustrative embodiment similar to Figure 5 the device member material forming the dose carrier may be chosen from an isolative plastic material, which is processed before dosing by ionized air to remove electrostatic charges from its surface. In another embodiment an isolative plastic material is processed before dosing by introducing the device member . into humid air to remove electrostatic charge from its surface. In a third embodiment the device member isolative plastic material is processed before dosing by combination of ionized air and humid air to remove electrostatic charges from its surface.
In still a further embodiment the device member is temporarily given a dissipative surface by applying a thin solvent layer onto its surface, e.g. water, carbon dioxide or other non-toxic and FDA approved solvent. Such a solvent layer is then applied with appropriate electrical properties by using a temperature difference or a high humidity chamber and after dosing removing the solvent from the device member.
Figure 8 shows in an illustrative example a dosing and metering set-up where a feeding device 45 for electrostatically charged electro-powder is subject to an electrical field 48 created by a separate applied potential 46 measured in V/mm and intended for transporting the electrostatically charged powder in a controlled way for dosing, metering or measuring purposes. A total field acts between the device member and the electro-powder feeder 45 through two different adjusted potentials 12 and 46. Between the feeder 45 and the device member is situated a filter 44 to shield part of the device member not to be subject to dosing until the device member is in the correct position and then having a transportation of electrostatically charged electro-powder particles 49 metered onto the carrier portion of the device member.
Figure 9 shows an illustrative example of a dosing and metering set-up with a device member 11 made from a dissipative material at which powder is dosed by an applied electrical field between the feeder of electrostatically

Charged electro-powder 45 and the device member utilizing an electrical filter 52 with a applied make-up potential to guide the powder to the correct position onto the carrier portion of the device member. The filter potential also serves as a possibility to control depositing on and off in a simple way by switching the applied voltage to the filter between normal potential and a much lower potential compared to the potential applied to the device member in this example. The guiding of electrostatically charged electro-powder particles 49 is then a function of applied voltage of the feeder of electrostatically charged electro-powder 49 and the voltage applied to the device member 12 and the potential of the filter 52. The filter 52 is supported by an isolative filter holding material 44.
Figure 10 shows in an illustrative example a dosing and metering set-up with a device member 11 in a dissipative material dosed onto by an applied electrical field between the feeder 45 of electrostatically charged electro-powder and the device member utilizing an electrical filter 52 with an applied make-up potential 59 to guide the powder to the correct position at the carrier portion of the device member 11. The filter potential also serves as a possibility to control deposition on and off in a simple way by changing the potential of the filter 52. The guiding of electrostatically charged electro-powder particles 49 is then a function of applied voltage to the feeder 45 of electrostatically charged electro-powder and the applied voltage to the device member 11 and the potential of the filter 52. The filter 52 is supported by an isolative filter holding material 44. The dose is possible to measure during the dosing and metering operation by using the electrometer €6 and switching the voltage 65 in front of a high voltage generator 67. During the dosing and metering operation it is also possible to control the density of the electro-dose by utilizing a mechanical vibration 64 or an electrical frequency utilizing, e.g. the switching box 65 resulting in a possibility to control the electrical field and the mechanical movement according to Figures 11 and 12.

figure 11 shows an example of electrical fields E1 and E2 applied as alternating fields at a pre-selected frequency to have the electro-powder to "dance" at the device member 11 to thereby achieve an optimum porosity for • an optimum of de-agglomeration according to Figure 16. Figure 11 shows how the total dosing time period T is divided up in periods t1 when the electrical field is at a maximum value of Ei and other time periods t2 when the electrical field is at a minimum value of E2, whereby the time periods t1 and t2 are in the range lO6 Figure 12 illustrates an example of a set up with a mechanical vibration having a total dosing time period T and a maximum displacement of D1 during t1 and no displacement during the time period t2 to make the dosed electro-powder particles to "dance" at the device member 11 and thereby, by means of a control of the applied field, having a controlled adjustment of the porosity to an optimum situation for an optimized de-agglomeration according to Figure 16, whereby the time periods t1 and t2 are in the range 10-6 Figure 13 shows a "tree" structure of powder particles at the device member 11 showing the ordering of particles of an electro-dose not being subject to adjustment of dose porosity disclosing chains of powder rising from the device member. The electro-powder particles 72 are forming "trees" of particles resulting in an extremely high porosity. The porosity of an electro-dose is calculated using the width and height of the "tree" structure together with the length to calculate the volume and then dividing the mass of the electro-dose with the volume to obtain the density of the electro-dose. The porosity is then calculated as Dp = 100 - 100-100*(densityelectro-dose /density electro-powder) in percent, where the density of the electro-powder in this example is 1.4kg/dm3.
It should be noted that in the preferred process the carrier is turned with its receiving surface facing downwards as illustrated in Figures 13 to 15 when

picking up the charged particles 72, 82 or 92. However, the process may also be performed as indicated by Figures 6 to 10.
Figure 14 shows an electro-dose on the device member 11 with a "sponge" structure defined as an intermediate structure of the electro-dose, where some of the "tree" structures 82 have collapsed and are connected top to top forming a matrix with a medium to low density and less porosity through a adjusted density by electrical frequency or mechanical vibration during the dosing and metering operation thereby obtaining a lower porosity compared to the "tree" structure of Figure 13.
Figure 15 shows an electro-dose at a device member 11 presenting a velvet structure 92 after being porosity adjusted with the proper electrical frequency or mechanical vibration thereby obtaining a look like a smooth velvet cloth which shows much less porosity than the "sponge" structure.
Figure 16 illustrates the effect of a dose porosity adjustment in which the de-agglomeration of the electro-dose is measured at different porosities showing an optimum de-agglomeration both for particles less than 5 μm and for particles less than 3 μm having a porosity in the range marked as A also indicating that the electro-dose is independent of the flow at porosities inside the range A.
In the range marked B the de-agglomeration is in a transition area and showing medium flow dependence and a lower grade of de-agglomeration. In range C the porosity is lower and the powder much harder to de-agglomerate in dose de-agglomeration and also showing a strong dependence of the flow i.e. the energy level of the de-agglomeration #2 and are not suitable as an dose for inhalation and subject to optimization. DD5μm is the dose de-agglomeration at 5 μm and at a differential pressure according to USP and DD1kPa is also according to USP but at a pressure drop over the inhaler of lkPa.

Measurement of de-agglomeration is performed, e.g., according to Figure 19, using an Andersen Inpactor together with a mouthpiece and a device member in a set-up identical with the intended DPI for the electro-dose or instead of the Andersen Tmpactor using a Malvern Master Sizer S to measure the physical particle size. When the particle distribution is measured the de-agglomeration can be calculated knowing the electro-powder particle size distribution.
The de-agglomeration is measured at two different rates of flow, flow-rate Q according to USP and at a flow-rate at 1 kPa pressure drop over the inhaler device according to USP. Measuring at two different flow-rates indicates if the electro-dose in the intended DPI is flow dependent or flow independent, as this may be an important aspect for the patient. If the difference in de-agglomeration is less than 25 %, when calculated as (100 - 100x(de-agglomeration(Q1kPa)/de-agglomeration(Q)), then the electro-dose meets the specifications, if the result is outside the electro-dose specifications further optimization of the electro-dose has to be performed by going back to step 310.
Figure 17 describes how the de-agglomeration at 3 μm is calculated using the initially input electro-powder under 3 μm represented by the hatched area as a base. The amount of de-agglomerated electro-powder from the electro-dose is then represented by the dark area under the curve showing resulting powder. By dividing the calculated value of the surface of the second area with the calculated value of the surface of the first area and multiplying by a factor 100 the de-agglomerated amount below 3μm is obtained in percent.
Figure 18 describes how the de-agglomeration at 5 μm is calculated using the initially input electro-powder under 5 μm represented by the hatched area as a base. The amount of de-agglomerated electro-powder from the electro-dose is then represented by the dark area under the curve showing resulting powder. By dividing the calculated value of the surface of the

second area in Figure 18 with the calculated value of the surface of the first area in Figure 18 and multiplying by a factor 100 the de-agglomerated amount below 5 μm is obtained in percent.
Figure 19 illustrates an example of a de-agglomeration and mass measurement set-up 71 identical to the inhaler to be used to determine the particle size distribution and mass from a pre-metered electro-dose sucked up from the device member 73 through a mouthpiece 78 using an Andersen Impactor 74 to determine the particle size distribution. The total pressure drop over the de-agglomeration set-up is measured with the pressure gauge 75 and the flow-rate of the air is measured with a flowmeter 76 in liters/minute. Suction may be achieved by means of a pumping device 77.
All measurements of the particle size distribution are measured at two different pressure drops over the inhaler device. First all measurements are performed according to USP and then only the pressure is changed for the measurement at a lower pressure lkPa over the inhaler device 71 in point 79.
A complementary particle size distribution is also measured at lkPa pressure drop over the de-agglomeration #2 set-up 71 indicated by the pressure gauge 79 as differential pressure to the atmosphere and then the obtained flow rate is noted down and named Q1kPa- The particle size distribution obtained at the flow rate QlkPa is then compared with the particle size distribution obtained at the flow rate Q, using all other settings according to the USP. The results of the test of de-agglomeration #2 at two different pressures over the inhaler device are compared according to Figure 16 to determine if the result meets the specification for an electro-dose and also if the de-agglomeration for 3 and 5 yarn., DD3μm,1kpa and, DD5μm.1kPa are within the specifications of the medicament drug.
Thus the method and process according to the present disclosure will result in a very well defined electro-dose for utilization in a dry powder inhaler

resulting in a small standard deviation of the doses for repeated administrations.
It will be understood by those skilled in the art that various modifications and changes may be made to the present invention without departure from the scope thereof, which is defined by the appended claims.

We claim
1. A micronized powder dose of a medical powder for use in a dry powder inhaler, the micronized powder dose having been prepared from an active powder substance or a dry powder medical formulation presenting a fine particle fraction (FPF) of the order 50 % or more of its content having a particle size from 0.5 to 5 μm, said substance or formulation having been metered onto a device constituting a dose carrier thereby having formed said micronized powder dose, the micronized powder dose presenting an optimized porosity of 75 to 99.9 % and further meeting electric specifications regarding absolute specific charge per mass after charging of the order 0.1 to 25 μC/g and presenting a charge decay rate constant Q50 of more than 0.1 sec with a tap density of less than 0.8 g/ml and a water activity aw of less than 0.5.
2. The electro-dose as claimed in claim 1, said metered micronized powder dose having, onto a surface area of said device member which forms a dose carrier, a height less than 800 μm perpendicular to the surface area of the device member onto which the substance or formulation is deposed.
3. The electro-dose as claimed in claim 1, said metered micronized powder dose, by using mechanical vibrations of the device member, having been adjusted to a porosity having in a value between 75 and 99.9 %.
4. The electro-dose as claimed in claim 1, said metered micronized powder dose, by using a frequency oscillation in an electrical field, having been adjusted to a porosity having in a value between 75 and 99.9 %.

5. A method for preparing a metered micronized powder dose of a
medical powder for administration into the deep or upper lung airways
by oral inhalation using a dry powder inhaler device, characterized by
the steps of:
charging by means of corona, induction or tribo-effect a medicament powder, being a preparation of chemical and biological substance of the kind such as herein described, with or without one or more excipients, forming a micronized powder;
transporting charged particles of the micronized powder towards a device member constituting a dose carrier using electric field techniques;
depositing the charged particles onto the dose carrier using electrical field techniques;
forming of a metered powder bed onto the dose carrier using electrical field techniques into a chosen state of dose porosity, the micronized powder dose presenting an optimized porosity of 75 to 99.9 % and further meeting electric specifications regarding absolute specific charge per mass after charging of the order 0.1 to 25 μC/g and presenting a charge decay rate constant Q50 of more than 0.1 sec with a tap density of less than 0.8 g/ml and a water activity aw of less than 0.5.
6. The method as claimed in claim 5, comprising the further step of combining the electrical field techniques with a mechanical vibration and/or an applied electrical frequency to adjust the dose porosity.
7. The method as claimed in claim 5, comprising the further step of analyzing the metered powder bed regarding one or more of at least following parameters: dose height, dose area, dose de-agglomeration, dose mass, dose density, dose porosity.

8. The method as claimed in claim 7, comprising the further step of comparing the analysis result with predefined dosing parameters for deciding that the metered micronized powder dose at the dose carrier complies with the basic requirements for administration by the inhaler device.
9. The method as claimed in claim 5, comprising the further step of checking that the metered powder dose has an optimized porosity of 75 to 99.9 %.
10. The method as claimed in claim 5, comprising the further step of utilizing mechanical vibration of the dose receiving device member during the dosing operation to adjust the metered powder porosity to an optimized value between 75 and 99.9 %.
11. The method as claimed in claim 5, comprising the further step of analyzing the metered micronized powder dose by a laser triangular method and a HPLC or weighing operation for a total volume calculation to determine the powder dose mass in order to calculate the powder dose powder porosity in percent as Dp =100 -100x(densitypowder-dose/densitymedicinal-powder) obtaining an optimized value between 75 and 99.9 %.
12. The method as claimed in claim 5, comprising the further step of preparing the metered micronized powder dose onto a surface area of the device member, to obtain a powder dose height of less than 800 μm.
13. The method as claimed in claim 12, comprising the further step of checking the metered micronized powder dose height by means of a triangular laser measuring instrument.

14. The method as claimed in claim 5, comprising the further step of additionally preparing the pre-metered micronized powder dose by using an oscillating electrical field to adjust the porosity of the powder dose to an optimized value of 75 to 99.9 %.
15. The method as claimed in claim 5, comprising the further step of preparing the powder dose using at least one active electrical filter with a control potential switched on and off within a voltage range Vlow electrical field 16. The method as claimed in claim 5, comprising the further step of measuring metered micronized powder dose mass by draining the electrostatic charge into a electrometer determining the specific charge
in |μC'/gmedicinal-powder.
17. The method as claimed in claim 5, comprising the further step of measuring metered micronized powder dose height using a contrast analyzing method and checking height of the powder dose to be less than 800 μm.
18. The method as claimed in claim 5, comprising the further step of measuring metered micronized powder dose height using a laser triangulation method and checking height of the powder dose to be less than 800 μm.
19. The method as claimed in claim 5, comprising the further step of measuring metered micronized powder dose height using an image analyzing method and checking height of the powder dose to be less than 800 μm.
-

20. The method as claimed in claim 5, comprising the further step of measuring metered micronized powder dose height using a combination of image analysis, laser triangulation, contrast methods to ensure a height of the powder dose to be less than 800μm,
21. The method as claimed in claim 5, comprising the further step of measuring micronized powder dose deagglomeration using a Andersen Impactor for aerodynamic particle size distribution or a Malvern Mastersizer S to determine the physical particle size distribution for a calculation and optimization of the deagglomeration of the micronized powder dose by changing the porosity.
22. A process of preparing doses of powder to be used for administration by a dry powder inhaler, characterized in that
a medicament powder, being a preparation of a chemical and/or biological substance, with or without one or more excipients, is metered onto a device member constituting a dose carrier thereby forming a metered micronized powder dose;
a metered micronized powder dose bed is formed on the dose carrier material using electrical field techniques and the micronized powder dose presenting an optimized porosity of 75 to 99.9 % and meeting electric specifications regarding absolute specific charge per mass after charging of the order 0.1 to 25 μC/g and presenting a charge decay rate constant Q50 of more than 0.1 sec with a tap density of less than 0.8 g/ml and a water activity aw of less than 0.5;
the obtained metered micronized powder dose bed is analyzed regarding one or more of at least following parameters: dose height, dose area, dose de-agglomeration, dose mass, dose density, dose porosity; and
a result of the analysis is compared with predefined dosing parameters for deciding that the prepared metered micronized powder dose on the dose carrier complies with the basic requirements for administration by the inhaler.

23. The process as claimed in claim 22, wherein electrical field technology is combined with a mechanical vibration and/or an applied electrical frequency.
24. The process as claimed in claim 22, wherein the device member material is an isolative plastic material processed before dosing and metering by ionized air to remove electrostatic charges from its surface.
25. The process as claimed in claim 22, wherein the device member material is an isolative plastic material processed before dosing and metering by introducing the device member into humid air to remove electrostatic charge from its surface.
26. The process as claimed in claim 22, wherein the device member material is an isolative plastic material processed before dosing and metering by combination of ionized air and humid air to remove electrostatic charges from its surface.
27. The process as claimed in claim 22, wherein that electro-conductive material is mixed into a plastic material constituting the device member.
28. The process as claimed in claim 22, wherein electro-conductive material is coated onto a plastic material constituting the device member.
29. The process as claimed in claim 27 or 28, wherein the conductive material and the plastic material combination of the device member has a specification presenting a surface resistance of 103 -1012 Ω, and a volume resistivity of 103 - 1012 ohmm.
-

30. The process as claimed in claim 22, wherein electro-conductive material used for the device member is obtained from any of materials such as silver powder, platinum powder, gold powder, stainless steal powder, antimony-doped tin oxide, antimony-doped silica oxide, or is a X-doped silica where X is an adamantine semiconductor, e.g., Ge, ZnO, GaSb or an octahedral semiconductor, e.g. SnSe, AgSbSe2, InSb or carbon or any other electro-conductive material approved by FDA and possible to incorporate into plastics.
31. The process as claimed in claim 22, wherein the device member is temporarily given a dissipative surface by applying a thin solvent layer onto the surface e.g. water, carbon dioxide or other non¬toxic and FDA approved solvent with appropriate electrical properties by using a temperature difference or a high humidity chamber and after dosing and metering removing the solvent from the device member.
Dated this the 27th day of January, 2003
[JAYANTA PAL] Of Remfry&Sagar Attorney for the Applicants

Documents:

127-mumnp-2003-abstract(22-05-2006).pdf

127-mumnp-2003-assignment(21-02-2006).pdf

127-mumnp-2003-cancelled pages(22-05-2006).pdf

127-mumnp-2003-claims(granted)-(22-05-2006).pdf

127-mumnp-2003-correspondence(21-08-2006).pdf

127-mumnp-2003-correspondence(ipo)-(29-08-2006).pdf

127-mumnp-2003-drawing(22-05-2006).pdf

127-mumnp-2003-form 18(01-07-2005).pdf

127-mumnp-2003-form 1a(22-05-2006).pdf

127-mumnp-2003-form 1a(27-01-2003).pdf

127-mumnp-2003-form 2(granted)-(22-05-2006).pdf

127-mumnp-2003-form 3(17-03-2006).pdf

127-mumnp-2003-form 3(27-01-2003).pdf

127-mumnp-2003-form 4(07-03-2006).pdf

127-mumnp-2003-form 5(27-01-2003).pdf

127-mumnp-2003-form 6(21-02-2006).pdf

127-mumnp-2003-form-pct-ipea-409(27-01-2003).pdf

127-mumnp-2003-petition under rule 137(17-03-2006).pdf

127-mumnp-2003-petition under rule 138(22-08-2006).pdf

127-mumnp-2003-power of authority(19-02-2003).pdf

127-mumnp-2003-power of authority(27-02-2006).pdf

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Patent Number

202711

Indian Patent Application Number

127/MUMNP/2003

PG Journal Number

15/2007

Publication Date

13-Apr-2007

Grant Date

29-Aug-2006

Date of Filing

27-Jan-2003

Name of Patentee

MICRODRUG AG

Applicant Address

LANDWEG 1, CH-6052 HERGISWIL NW,

Inventors:

#	Inventor's Name	Inventor's Address
1	THAOMAS NIILSSON	HAGAVAGEN 3, S-647 32 MARIEFRED,
2	LARS-GUNNAR NILSSON	ESPLANDEN 15E, S-731-30 KOPING

PCT International Classification Number

N/A

PCT International Application Number

N/A

PCT International Filing date

2001-07-27

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	003082-5	2000-08-31	Sweden