In vitro dissolution test method for fluticasone propionate and other inhaled drugs

Abstract

An apparatus and method for testing dissolution properties of a drug, especially anti-inflammatory drugs administered by aerosol into the respiratory system. The apparatus shortens the time it takes for a drug to dissolve and thus provides for rapid testing of new drugs for quality control as well as for regulatory purposes. It is suitable for evaluating bioequivalence or to study the pharmacokinetics of drugs administered into the respiratory system. This method shortens dissolution times for testing a drug to about 10 and 20 minutes and thus provides for rapid testing.

Claims

1. A dissolution device, comprising: a rotatable shaft, a cylindrical basket, an impaction insert from a particle impactor, and a vessel, wherein the basket is attached at its top to the rotatable shaft, wherein the basket contains the impaction insert, and wherein the shaft holds the basket within the vessel so that it is immersed when the vessel is filled with a dissolution medium.

2. The dissolution apparatus of claim 1, wherein the basket is configured to hold an impaction insert from a collection cup of a next generation impactor (NGI).

3. The dissolution apparatus of claim 1, wherein the impaction insert is round and has a diameter equal to the inside diameter of the cylindrical basket so as to fit within the cylindrical basket.

4. The dissolution apparatus of claim 1, wherein a bottom base and a top base of the basket are about 90.2 to 110.2 mm in diameter.

5. The dissolution apparatus of claim 1 wherein the basket has a height of about 33 to 41 mm.

6. The dissolution apparatus of claim 1, wherein the basket comprises a clip or fitting for attaching its top base to the rotatable shaft.

7. The dissolution apparatus of claim 1, wherein the basket comprises a fitting for attaching its top base to the rotatable shaft and wherein the fitting comprises a retention spring and a vent hole.

8. The dissolution apparatus of claim 1, wherein the basket comprises cylindrical open mesh shell comprises stainless steel, aluminum or other metal.

9. The dissolution apparatus of claim 1, wherein the cylindrical open mesh shell of the basket ranges from #20 to #40 mesh.

10. The dissolution apparatus of claim 1, wherein the cylindrical open mesh shell of the basket has mesh openings ranging from 0.1 mm to 1.0 mm in diameter.

11. A system comprising: a next generation impactor (NGI) comprising a collection cup having a removable impaction insert in one or more of its collection cups, and the dissolution device of claim 1.

12. The system of claim 11, further comprising a drug impacted on the impaction insert.

13. The system of claim 11, further comprising an inhalable anti-inflammatory drug impacted on the impaction insert.

14. The system of claim 11, wherein the lung simulation membrane is a polycarbonate membrane or is a polyvinylidene difluoride (PVDF) membrane.

15. The system of claim 11, further comprising a rotary mixture attached to the rotatable shaft and/or a chromatography system suitable for determining the concentration of a drug in the aqueous medium.

16. A method for determining dissolution properties of an aerosolized drug comprising applying the drug to a next generation impactor (NGI) under conditions suitable for impacting particles of the drug in collection plates of the NGI, recovering impacted drug particles on one or more impaction inserts from the collection plates, sealing the one or more collection plates in a lung simulation membrane, inserting the collection plate sealed within the lung simulation membrane into the cylindrical basket of claim 1, submerging the cylindrical basket containing the lung simulation membrane covered impaction inserts in a dissolution medium contained in a vessel, and detecting an amount of the drug which dissolves into the dissolution medium.

17. The method of claim 16, wherein the dissolution medium is water, phosphate buffered saline, or a simulated lung fluid.

18. The method of claim 16, wherein the impaction insert contains drug particles ranging in size from 0.45 to 1.1 μm in diameter.

19. The method of claim 16, wherein the impaction insert is sealed with a polycarbonate or polyvinylidene difluoride (PVDF) membrane.

20. The method of claim 16, wherein the amount of drug dissolved into the dissolution medium is detected after a period of no more than 15 minutes.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) A more complete appreciation of the invention and many of the attendant advantages thereof will be readily obtained as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings, wherein:

(2) FIG. 1A depicts the various branches of the respiratory system and their physical dimensions. Adapted from Patton, 1996, Mechanisms of macromolecule absorption by the lung, Advanced Drug Delivery Reviews; 19: 3-36.

(3) FIG. 1B provides a general overview of the fate of inhaled corticosteroid (ICS) drug deposition. Adapted from Bisgaard et al, 2002, Drug delivery to the lung, Marcel Dekker, 162.

(4) FIG. 1C describes approximate sizes of particles impacting different parts of the respiratory system. Adapted from Copley, 2003, Quality solution for inhaler testing. Nottingham, UK.

(5) FIG. 2A depicts the paddle 100, rotatable shaft 101, and vessel 102 of a USP type 1 (paddle) drug dissolution system. USP pharmacopeia (2005) Chapter <601>.

(6) FIG. 2B depicts the basket 200, rotatable shaft 201, and vessel 202 of a USP type 2 (basket) drug dissolution system. Typically, the basket element of the device is larger than the basket element specified by the pharmacopeia or by Marple, et al., J Aerosol Med. 2003 Fall; 16(3):283-99. Advantageously, the size of the basket may be customized to accommodate the impaction insert. (USP pharmacopeia (2005) Chapter <601>); Marple, et al., J Aerosol Med. 2003 Fall; 16(3):283-99.

(7) FIG. 2C depicts a paddle of a USP type 1 (paddle) drug dissolution system depicting paddle 100 and rotatable shaft 101. (USP pharmacopeia (2005) Chapter <601>).

(8) FIG. 2D depicts a basket of a USP type 2 (basket) dissolution system depicting basket 200 and rotatable shaft 201. USP pharmacopeia (2005) Chapter <601> (incorporated by reference).

(9) FIG. 2E shows a closed next generation impactor (NGI) where aerosol is fed into the opening 100 at the left top. Marple, et al., J Aerosol Med. 2003 Fall; 16(3):283-99; adapted from Copley, 2003, Quality solution for inhaler testing. Nottingham, UK.

(10) FIG. 2F shows an open next generation impactor (NGI). Removable cone-shaped cups 102 for receiving impacted drug particles of progressively decreasing sizes through interstage passageways 103 and then through the nozzles 101 shown at the top. Other elements include micro-orifice contactor 104, lid with seal 105, location pin 106, and bottom frame with cup tray in place 107. Marple, et al., J Aerosol Med. 2003 Fall; 16(3):283-99.); Adapted from Copley, 2003, Quality solution for inhaler testing. Nottingham, UK.

(11) FIG. 3A illustrates parts of an NGI collection cup 10 modified to contain a hole 15 which fits an impaction insert 20; impaction insert 20 having a coin-shaped raised central portion 24 that fits through hole 15 and an annular peripheral flange 25; and a sealing ring 30 which can secure a lung simulation membrane over the central portion 24 of the impaction insert once removed from the collection cup. FIG. 3A describes the disassembled parts of the collection cup of the NGI. Insert or disc (25) fits at cup (15). Drug collected on top of the insert or disc is covered by a membrane and then secured with ring (30) prior to transfer to a dissolution vessel. (Marple, et al., J Aerosol Med. 2003 Fall; 16(3):283-99); (adapted from Copley, 2003) “Quality solution for inhaler testing”. Nottingham, UK.

(12) FIG. 3B depicts particle collection cups and a single modified particle collection cup 10 with an impaction insert 20. Marple, et al., J Aerosol Med. 2003 Fall; 16(3):283-99; Adapted from Copley, 2003, Quality solution for inhaler testing. Nottingham, UK.

(13) FIG. 4A depicts the various parts of the dissolution device of the invention including connection to motor or rotation device 60, rotatable shaft 65, basket 50, membrane-sealed impaction insert 40, vessel 70 and dissolution medium 80 and sampling point 85. USP pharmacopeia (2005) Chapter <601>.

(14) FIG. 4B depicts one embodiment of an assembly of the basket 50, impaction insert 20 and rotatable shaft 65 of the invention.

DETAILED DESCRIPTION OF THE INVENTION

(15) The invention provides a rapid, convenient and simple way to determine the dissolution properties of an inhaled drug, such as an anti-inflammatory drug administered in an aerosol form to a patient. Determination of these properties is useful for quality control during production of a drug, assessment of bioequivalence of a generic drug, as well as to comply with regulation. The invention provides a superior dissolution test by use of a modified dissolution basket adapted to easily measure the dissolution properties of drug particle fractions from a modified next generation impactor. Advantageously, a method using the apparatus of the invention can determine dissolution properties of an inhaled drug within 5, 10 to 20 minutes. The method is typically used to determine the quality of an inhaled drug preparation, such as relative distribution of particle sizes and delivered dose uniformity, and thus is a good candidate for use in showing that a drug preparation complies with worldwide regulation.

(16) Respiratory diseases for which inhalable or aerosolized drugs may be tested using the apparatus and methods described herein include, but are not limited to, pneumothorax (a collapsed lung that occurs when air enters the space around lungs); asthma (a condition in which the airways—the tubes that carry air in and out of the lungs—narrow and swell causing reversible obstruction); pleural effusion (an excessive collection of fluid in the pleural cavity); pulmonary edema (a condition where fluid accumulates in lung tissues); upper respiratory tract infections (such as a common cold); pneumonia (an infection of an air sac in one or more lungs such as bacterial or viral pneumonia); atypical pneumonia (an infection of the respiratory tract caused by pathogens that are not commonly associated with pneumonia); atelectasis (a condition where lungs collapse partially or completely); pulmonary fibrosis (a disease in which the lungs become scarred or fibrosed and damaged causing difficulty in breathing); and pneumonitis (inflammation of lung tissue not due to infection). Other respiratory tract diseases include those described by hypertext transfer protocol secure://en.wikipedia.org/wiki/Respiratory_disease (last accessed Oct. 23, 2019, incorporated by reference). Inhalable drugs that target the sites of these diseases in the respiratory system may be tested using the dissolution apparatus disclosed herein.

(17) Such drugs include inhaled corticosteroids such as beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, or mometasone in a preparation designed to be inhaled through the mouth. Inhaled corticosteroids act directly in the lungs to inhibit the inflammatory process that causes asthma. Inhaled corticosteroids help to prevent asthma attacks and improve lung function. They may also be used in the treatment of certain other lung conditions, such as chronic obstructive pulmonary disease (COPD).

(18) The apparatus and method disclosed herein may be used to test particles of pure drug free of excipients or particles of drug in admixture with an excipient such as a surfactant or pharmaceutical carrier.

(19) In some embodiments, the apparatus and method may be used to evaluate dissolution of other kinds of inhaled drugs such as antibiotics, antimicrobial, antifungal, or antiparasitical medicines such as pentamidine, inhalable hormones such as insulin or human growth hormone, nicotine, cannaboids or other plant derived compounds. Such drugs include those which are locally administered and active in the respiratory system as well as those which are systemically administered via the respiratory system.

(20) A next generation impactors (NGI) is an instrument that measures the reach range of a particulate substance as it moves through an opening with the use of aerosol An NGI has seven stages, five of which are in the range 0.5 to 5 microns plus a micro-orifice collector which acts as a final filter and a horizontal planar layout adopted for ease of operation and automation. The air flow passes through the impactor in a saw tooth pattern. Particle sizing is achieved by successively increasing the velocity of the air stream by forcing it through a series of nozzles containing progressively reducing jet diameters.

(21) The resultant samples from each stage are collected in a series of collection cups. A removable tray holds all the sample collection cups such that all the cups can be removed and/or replaced in one single operation.

(22) NGI are known in the art and are commercially available, for example, from Copley Scientific; hypertext transfer protocol secure://www.copleyscientific.com/home/inhaler-testing/aerodynamic-particle-size/next-generation-impactor-ngi (last accessed Oct. 22, 2019; incorporated by reference) or from MPS; hypertext transfer protocol secure: //www.mspcorp.com/pharmaceutical/next-generation-impactor-ngi-170/(last accessed Oct. 22, 2019, incorporated by reference). Particle impactors are also described by and incorporated by reference to U.S. Pat. Nos. 6,453,758; 6,647,758 and 6,723,568.

(23) Examples of NGI are depicted by FIGS. 2E and 2F. NGI designs and design considerations are described by and incorporated by reference to Marple, V. A., et al., Next Generation Pharmaceutical Impactor (A New Impactor for Pharmaceutical Inhaler Testing): Part 1: Design, J. Aerosol. Med. 16(3) 283-299 (2003).

(24) In contrast to conventional designs, the inventors have modified the conventional cone-shaped collection cups of the conventional NGI (a) to contain a round hole fitting a circular impaction insert (b) and securing ring (c); see FIGS. 3A and 3B. Only one NGI collection cup, which collects drug particles of a particular size, may be modified as shown by FIG. 3B, or alternatively two, three, four, five, six, or seven (or all) collection cups may be modified to contain impaction inserts which collect drug particles of different sizes from the NGI.

(25) Basket type or type 1 USP dissolution devices are known. Basket type dissolution devices contain a small basket into which a drug capsule or pill can be inserted and then submerged into a dissolution fluid; see FIGS. 2B and 2D. They differ from type II paddle-style dissolution devices in which a paddle is rotated to dissolve a drug in the dissolution fluid; see FIGS. 2A and 2C. USP type 2 dissolution devices are further described by Karande, et al., hypertext transfer protocol://dissolutiontech.com/DTresour/200602Articles/DT200602_A03.pdf (incorporated by reference).

(26) In contrast to conventional basket-type USP dissolution devices, the modified apparatus as disclosed herein contains a basket that is sized and configured to contain a membrane-sealed collection cup impaction insert as depicted by FIGS. 3A and 3B. In some embodiments, the membrane sealed impaction insert is placed face up or face down into the basket through a movable or removable top. In other embodiments, it is placed face up or face down in the basket from the bottom of the basket which can be movable or removable. In some embodiments, the membrane sealed impaction disk is secured within the basket, for example, by fitting into a groove in the inside of the basket or with a clip or other fitting. Typically, following assembly of the impaction insert, membrane and securing ring, the assembly is transferred to the basket and a lid of the basket is closed.

(27) The basket is submerged into dissolution medium contained in a vessel. The vessel may be a semihemispheric borosilicate glass vessel or other suitable plastic, glass or metal vessels. The vessel holds sufficient fluid to cover the membrane covered impact insert in the basket, for example, about 250, 500, 750, 1,000, 1,500, 2,000 ml of dissolution medium via a shaft, such as a stainless steel shaft. The basket may be described as a rotating basket which smoothly rotates at a speed suitable for dissolving a sample in the dissolution medium, for example from about 50, 100, 150 or 200 rpm, preferably about 100 rpm.

(28) Different dissolution media may be used to assess dissolution properties of a drug for research or clinical purposes. The dissolution medium is selected based on the conditions present where the drug will be administered. For controlled batch-to batch quality control of a drug or for controlled comparisons of different preparations of drugs, such as a comparison between an existing approved drug and anew generic drug, a simple medium such as water, saline or phosphate buffered saline may be selected. To assess dissolution properties of a respiratory drug in particular patients or particular patient populations, a synthetic lung fluid modelling that of fluids in a specific type of patient may be selected.

(29) Some non-limited examples of dissolution media include Survanta®: phospholipids 25 mg/mL (including 11.0-15.5 mg/mL disaturated phosphatidylcholine), triglycerides 0.5-1.75 mg/mL, free fatty acids 1.4-3.5 mg/mL, and protein content less than 1.0 mg/mL. Another example of a dissolution medium is an artificial lung fluid containing DPPC 4.8 mg/mL, DPPG 0.5 mg/mL, cholesterol 0.1 mg/mL, albumin 8.8 mg/mL, IgG 2.6 mg/mL, transferrin 1.5 mg/mL, ascorbate 140 μM, and urate 95 μM, glutathione 170 μM. One or more of the above ingredients or their chemical equivalents may be incorporated into a dissolution medium.

(30) In some embodiments, the device disclosed herein may be used to evaluate dissolution properties of loaded of an active pharmaceutical ingredient (API) such as a drug administered to the respiratory system. In other embodiments, it may be used to evaluate quality of the drug that is drawn by a patient from the device.

(31) In other embodiments, the dissolution fluid may be selected to determine one or more dissolution properties of a drug or other test material (e.g., solubility in distilled water, PBS, saline, mucous, respiratory fluids, etc.) or to model physiological conditions in the respiratory system of a patient (e.g., conditions found in different parts of the respiratory system, conditions during a respiratory disease or disorder asthma, or after exposure to prior drug or after exposure to smoke, chemical irritants, foreign particles, biological materials or irritants (e.g., histamine, serotonin, ECF, heparin), mucus, blood, leukocytes, red blood cells, pathogens, or cellular debris).

(32) A dissolution medium may contain a buffer to maintain pH in a physiological range, such as from 6.5, 7.0 to 7.5. The dissolution medium may have a pH which is within the normal range of blood or lung pH, for example, from pH 7.35 to 7.45.

(33) In some embodiments, a drug sample may be tested in a dissolution medium (or under an atmosphere) containing a concentration one or more atmospheric gases. For example, a dissolution medium may contain an amount of CO.sub.2, O.sub.2, N.sub.2, or argon present in lung fluid during inhalation or exhalation. Thus, CO.sub.2, O.sub.2, N.sub.2 or argon content may correspond to content of these gases in inhaled or exhaled air and their solubility in lung natural lung fluids. The atmospheric concentration of CO.sub.2 is about 0.04%, that of oxygen about 21%, that of nitrogen about 78% and that of argon around 1%. However, in exhaled air the concentration of CO.sub.2 rises to about 4% and oxygen can fall to about 16%.

(34) Normal human body temperature ranges between 37.5 and 38.3 C. Body temperature may be higher up to about ≥38.5, 39, 40, 41 or 41.5° C. during a fever, hyperthermia or hyperpyrexia. Drug testing using the apparatus and methods disclosed herein may be at normal body temperature or at a depressed or elevated temperature, for example, a temperature likely to be found in the respiratory system or tissue to which a drug is administered. Accordingly, in some embodiments, the dissolution apparatus as disclosed herein may contain insulation to maintain a desired temperature or temperature sensors and temperature control devices, such as heaters or cooling elements, to maintain a desired or constant temperature during assessment of the dissolution properties of a drug.

(35) The collection cup 10, impaction insert 15 and securing ring 20 may be made of any suitable material and are typically made of a metal such as stainless steel or aluminum.

EXAMPLES

Dissolution Test

(36) Materials. Materials are purchased from Copley Scientific Limited. (Nottingham, UK). Erweka GmbH. (OttostraBe, Germany); Avanti Polare Lipid, Inc. (Alabaster, Ala., USA); and Sigma Aldrich Chemical Co. (St. Louis, Mo. USA).

(37) Apparatus. The dissolution test is performed using a high-performance cascade next generation impactor, which classifies aerosol particles into size fractions. It tests metered-dose and dry-powder inhalers and other inhaled drug delivery devices such as nebulizers and nasal sprays. It can be used to test inhaled or nasally delivered drugs including those dispensed by metered-dose, dry powder, and aqueous droplet inhalers, nebulizers including jet, ultrasonic and vibrating mesh nebulizers; and nasal sprays including aqueous based, dry powder and propellant based sprays. The collection cups of the NGI were modified to hold a removable impaction insert as shown by FIGS. 3A and 3B. FIG. 3A depicts the modified collection cup 10, hole in collection cup 15, removable impaction insert 20 and securing ring 30.

(38) A modified USP Apparatus 1 dissolution tester type basket; Erweka DT141x/161x Tester station (Erweka GmbH. Germany) is employed to identify and characterize the dissolution properties of an active inhaled drug (fluticasone). A schematic diagram of modifications to the dissolution apparatus is shown in FIGS. 4A and 4B. Modifications include both an increased diameter of the basket (to accommodate the impaction insert) and an increased capacity of the dissolution vessel to accommodate the larger size of the basket. FIG. 4B describes the geometric size of modified basket.

(39) In one embodiment as shown by FIG. 4B, the rotating shaft may be approximately 6.3 to 6.5 or 9.4 to 10.1 mm in diameter and be connected to a cap 54 and clasp 55 which may be approximately 5.1 in thickness (a). The cap may have a vent hole 51 about 2.0 mm (preferably 1-5 mm, 1.5-2.5 mm) in diameter and a retention spring 52 with three tangs on 120° centers. The top of the basket may have a clear opening 53 of 50-200 mm, preferably 75-150 mm or about 100.2 mm. In this embodiment, the basket has a cylindrical shell 25-50 mm preferably about 32 mm in height (b) and 10-50 mm preferably about 27.0 mm open screen (c). Elements 57 and 58 represent the open screen of the basket which in one embodiment is 10-50 mm preferably about 27.0 mm. The basket has bottom base 56. Membrane sealed impaction insert 20 has a central membrane-covered area (d) and a total diameter of 55-205 mm or about 105 mm (e), a peripheral annular portion 25 secured by ring 30. In other embodiments, the size of the device may be customized and thus the measurements described above may vary downward or upward by <5, 5, 10, 20, 30, 40, 50 or >50%. Those skilled in the art may select a mesh that permits circulation of dissolution fluid over or around the membrane covered impaction insert or disc while retaining the insert or disc in the basket.

(40) Drug particle collection. The Next Generation Impactor (NGI) collects dispersed particles (e.g. corresponding to inhaled aerosol drug or dust) at a predetermined flow rate such as that described by Son et al. id. Flow rates include 30, 40, 50, 60, 70, 80 or 90 L/min.

(41) The inhalation flow rate for dry powders depends on the type of inhalation device and inhalation volume of the patient. The inhalation flow rate for a metered dose inhaler ranges between about 28.0 and 28.8 L/min.

(42) For the dissolution studies, the collection cup 10 is assembled together with the impaction insert 20 and secured with ring 30 into the NGI collection tray. Further description of the assembly involving the collection cup is incorporated by reference to Son, Y J, et al. Development of a standardized dissolution test method for inhaled pharmaceutical formulations. Int J Pharm 2009; 382(1-2):15-22.

(43) Dispersed (inhaled) drug particles are actuated through the NGI at a required flow rate. As shown by FIG. 3B, the dispersed drug particles are collected in each unmodified collection cup and one modified collection cup 10 holding an impaction insert 20.

(44) Particle size dictates where aerosolized particles deposit in the respiratory tract. For drugs intended to target trachea and primary bronchi a particle size of 3.3 to 4.7 μm may be selected; for drugs that target secondary and terminal bronchi a particle size of 1.1 to 3.3 μm may be selected and for drugs intended to target alveoli in the lungs a particle size of 0.45 to 1.1 μm may be selected for dissolution testing. Other selectable particle size ranges and the corresponding tissues impacted are shown by FIG. 1C.

(45) Membrane. Any membrane that is porous and sufficiently flexible for use in the dissolution device as described herein may be used, preferably, the membrane is a polycarbonate membrane (PC) or with polyvinylidene difluoride membrane (PVDF). Both hydrophilic and hydrophobic membranes may be selected depending on the chemical properties of the drug being tested.

(46) Some embodiments may employ a porous membrane that is a polyethersulfone membrane, a polysulfone membrane, a glass fiber, a nylon membrane, a polyester membrane, a polycarbonate membrane, a polypropylene membrane, a polyvinylidene difluoride membrane, a cellulose membrane, a nitrocellulose membrane, a cellulose acetate membrane, a nitrocellulose mixed ester membrane, a polyurethane membrane, a polyphenylene oxide membrane, a poly(tetrafluoroethylene-co-hexafluoropropylene membrane, a cellulose phosphate membrane, a cellulose/silica gel paper, a borosilicate glass membrane, a quartz membrane, or a combination thereof.

(47) The membrane will have a pores size sufficient to permit dissolved drug to move into the dissolution buffer, for example, a pore size ranging from 0.1, 0.2, 0.5, 1, 2, to 5 μm, preferably about 0.22 or 0.45 μm. In some embodiments membrane thickness ranges from 50, 75, 100, 125 to 150 μm. In a preferred embodiment, the porosity of the membrane ranges from about 2, 3, 4 to 5 μm.

(48) Sealing of drug particles impacted on impaction insert. Following impaction of inhaled drug, the impaction insert is removed, the side containing impacted drug particles is covered with a membrane and the membrane is sealed in placed using a ring which fits over a peripheral annular surface of the impaction insert. Further description of the impaction method is given by, and incorporated by reference to, the NGI manual and pharmacopeia (Marple, et al., J Aerosol Med. 2003 Fall; 16(3):283-99) or by Son, Y J, et al. Development of a standardized dissolution test method for inhaled pharmaceutical formulations. Int J Pharm 2009; 382(1-2):15-22 who described a method of using membrane-modified collection cups.

(49) After sealing the impaction insert is placed into the basket and separately soaked in a dissolution media contained in a vessel into which the basket is submerged. This process is repeated with several different dissolution media including simulated lung fluid (SLF), 0.2 M phosphate buffer (pH 7.4), phosphate buffered saline (PBS), modified PBS (mPBS) containing dipalmitoylphosphatidylcholine (DPPC), and PBS containing polysorbate 80 (tPBS). The basket is then rotated by the shaft at a speed of 100 rpm.

(50) In one embodiment the following steps are performed:

(51) The NGI device is assembled.

(52) The dispersion (inhalation) device is loaded with a dosage of fluticasone or other drug to be tested and attached to the NGI induction port which receives the dispersed drug.

(53) The flow rate of the NGI is adjusted, for example, to a rate of about 60 L/min for fluticasone and the flow is activated thus impacting drug particles on the surfaces of the collection plates in the modified NGI.

(54) The flow is terminated and the NGI device is disassembled to retrieve one or more impaction inserts (collection plates) of the modified device.

(55) These inserts, which contain impacted drug particles, are covered by a lung simulation membrane.

(56) The impaction insert and membrane are locked together using a securing ring and transferred into the modified dissolution basket which is then attached to the rotatable basket shaft.

(57) The basket containing the sealed impaction insert is inserted into the vessel part of the dissolution apparatus and a dissolution medium, such as simulated lung fluid, is filled into the vessel so as to cover the impaction insert. Alternatively, the basket is immersed in dissolution medium already in the vessel.

(58) The dissolution apparatus is activated and the basket is rotated at a speed of 100 rpm for 5 minutes.

(59) 1 ml samples of dissolution fluid are removed every minute and replaced with a fresh equivalent volume of dissolution medium.

(60) The concentration of fluticasone in these samples is determined by chromatographic analysis using an HPLC system with UV detection.

(61) Data generated are expressed as the mean±SD. The statistical differences of release rates were studied by calculating a similarity factor, f.sub.2. Statistical analytic methods are incorporated by reference to Martin R J, et al., Systemic effect comparisons of six inhaled corticosteroid preparations. Am J Respir Crit Care Med 2002; 165(10):1377-1383, incorporated herein by reference in its entirety. For curves to be considered similar, f.sub.2 values should be close to 100. Generally, f.sub.2 values greater than 50 (i.e., 50-100) ensure sameness or equivalent of the two curves.

(62) Terminology. Terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

(63) As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.

(64) As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items and may be abbreviated as “/”.

(65) Links are disabled by deletion of http: or by insertion of a space or underlined space before www. In some instances, the text available via the link on the “last accessed” date may be incorporated by reference.

(66) As used herein in the specification and claims, including as used in the examples and unless otherwise expressly specified, all numbers may be read as if prefaced by the word “substantially”, “about” or “approximately,” even if the term does not expressly appear. The phrase “about” or “approximately” may be used when describing magnitude and/or position to indicate that the value and/or position described is within a reasonable expected range of values and/or positions. For example, a numeric value may have a value that is +/−0.1% of the stated value (or range of values), +/−1% of the stated value (or range of values), +/−2% of the stated value (or range of values), +/−5% of the stated value (or range of values), +/−10% of the stated value (or range of values), +/−15% of the stated value (or range of values), +/−20% of the stated value (or range of values), etc. Any numerical range recited herein is intended to include all sub-ranges subsumed therein.

(67) Disclosure of values and ranges of values for specific parameters (such as temperatures, molecular weights, weight percentages, etc.) are not exclusive of other values and ranges of values useful herein. It is envisioned that two or more specific exemplified values for a given parameter may define endpoints for a range of values that may be claimed for the parameter. For example, if Parameter X is exemplified herein to have value A and also exemplified to have value Z, it is envisioned that parameter X may have a range of values from about A to about Z. Similarly, it is envisioned that disclosure of two or more ranges of values for a parameter (whether such ranges are nested, overlapping or distinct) subsume all possible combination of ranges for the value that might be claimed using endpoints of the disclosed ranges. For example, if parameter X is exemplified herein to have values in the range of 1-10 it also describes subranges for Parameter X including 1-9, 1-8, 1-7, 2-9, 2-8, 2-7, 3-9, 3-8, 3-7, 2-8, 3-7, 4-6, or 7-10, 8-10 or 9-10 as mere examples. A range encompasses its endpoints as well as values inside of an endpoint, for example, the range 0-5 includes 0, >0, 1, 2, 3, 4, <5 and 5.

(68) As referred to herein, all compositional percentages are by weight of the total composition, unless otherwise specified. As used herein, the word “include,” and its variants, is intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that may also be useful in the materials, compositions, devices, and methods of this technology. Similarly, the terms “can” and “may” and their variants are intended to be non-limiting, such that recitation that an embodiment can or may comprise certain elements or features does not exclude other embodiments of the present invention that do not contain those elements or features.

(69) Spatially relative terms, such as “under”, “below”, “lower”, “over”, “upper”, “in front of” or “behind” and the like, may be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if a device in the figures is inverted, elements described as “under” or “beneath” other elements or features would then be oriented “over” the other elements or features. Thus, the exemplary term “under” can encompass both an orientation of over and under. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly. Similarly, the terms “upwardly”, “downwardly”, “vertical”, “horizontal” and the like are used herein for the purpose of explanation only unless specifically indicated otherwise.

(70) All publications and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference, especially referenced is disclosure appearing in the same sentence, paragraph, page or section of the specification in which the incorporation by reference appears.

(71) The citation of references herein does not constitute an admission that those references are prior art or have any relevance to the patentability of the technology disclosed herein. Any discussion of the content of references cited is intended merely to provide a general summary of assertions made by the authors of the references, and does not constitute an admission as to the accuracy of the content of such references.