DPI formulation containing sulfoalkyl ether cyclodextrin

Abstract

An inhalable dry powder formulation containing SAE-CD and an active agent is provided. The formulation is adapted for administration by DPI. The SAE-CD serves as a carrier rather than as an absorption enhancer. The average particle size of the SAE-CD is large enough to preclude (for the most part) pulmonary deposition thereof. Following release from the DPI device, the SAE-CD-containing particles dissociate from the active agent-containing particles in the buccal cavity or throat, after which the active agent-containing particles continue deeper into the respiratory tract. The physicochemical and morphological properties of the SAE-CD are easily modified to permit optimization of active agent and carrier interactions. Drugs having a positive, neutral or negative electrostatic charge can be delivered by DPI when SAE-CD is used as a carrier.

Claims

1. A pharmaceutical composition comprising an active agent; and a sulfoalkyl ether cyclodextrin composition comprising agglomerated particles comprising sulfoalkyl ether cyclodextrin, wherein the agglomerated particles are made by spray agglomeration wherein the sulfoalkyl cyclodextrin composition has a micro-flow fractal dimension analysis of about 1.0-1.2, wherein the sulfoalkyl ether cyclodextrin composition comprises less than 10% by weight moisture and has a property selected from the group consisting of a bulk density of 0.34 g/cc to 0.55 g/cc, a CARR's index of about 10% to about 40%, and a median particle diameter of about 10 microns to about 300 microns, or a combination thereof, and wherein the agglomerated particles have a rough surface.

2. A pharmaceutical dosage form comprising the pharmaceutical composition of claim 1.

3. The pharmaceutical dosage form of claim 2, wherein the dosage form is a powder.

4. The pharmaceutical composition of claim 1, wherein the sulfoalkyl ether cyclodextrin composition has a bulk density of 0.34 g/cc to 0.55 g/cc.

5. The pharmaceutical composition of claim 1, wherein the sulfoalkyl ether cyclodextrin composition comprises a CARR's index of about 10% to about 40%.

6. The pharmaceutical composition of claim 1, wherein the sulfoalkyl ether cyclodextrin composition comprises particles with a median particle diameter of about 10 microns to about 300 microns.

7. The pharmaceutical composition of claim 1, wherein the sulfoalkyl ether cyclodextrin is a compound, or a mixture of compounds, of the Formula 1: ##STR00003## wherein: n is 4, 5, or 6; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, and R.sub.9 are each, independently, O.sup.− or a O—(C.sub.2-6 alkylene)-SO.sub.3.sup.− group, wherein at least one of R.sub.1 to R.sub.9 is independently a O—(C.sub.2-C.sub.6 alkylene)-SO.sub.3.sup.− group; and S.sub.1, S.sub.2, S.sub.3, S.sub.4, S.sub.5, S.sub.6, S.sub.7, S.sub.8, and S.sub.9, are each, independently, a pharmaceutically acceptable cation.

8. The pharmaceutical composition of claim 1, wherein the sulfoalkyl ether cyclodextrin composition comprises particles with a median particle diameter of about 175 microns to about 277 microns.

9. The pharmaceutical composition of claim 1, wherein the sulfoalkyl ether cyclodextrin composition comprises particles with a median particle diameter of about 37 microns to about 125 microns.

10. The pharmaceutical composition of claim 1, wherein the sulfoalkyl ether cyclodextrin composition comprises a particle size distribution span of about 1.5 to about 2.9.

11. The pharmaceutical composition of claim 1, wherein the sulfoalkyl ether cyclodextrin composition comprises a moisture content of less than 8% by weight.

12. The pharmaceutical composition of claim 1, wherein the sulfoalkyl ether cyclodextrin composition comprises a moisture content of less than 2.5% by weight.

13. The pharmaceutical composition of claim 1, wherein the sulfoalkyl ether cyclodextrin composition comprises a moisture content of less than 1% by weight.

14. The pharmaceutical composition of claim 1, further comprising an excipient selected from the group consisting of an antioxidant, acidifying agent, alkalizing agent, buffering agent, solubility-enhancing agent, penetration enhancer, electrolyte, fragrance, glucose, glidant, stabilizer, bulking agent, cryoprotectant, plasticizer, flavor, sweetener, surface tension modifier, density modifier, volatility modifier, hydrophilic polymer, water soluble polymer, and combinations thereof.

15. The pharmaceutical composition of claim 1, wherein the composition is formulated for administration by inhalation.

16. The pharmaceutical composition of claim 7, wherein n is 5.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) The following drawings are given by way of illustration only, and thus are not intended to limit the scope of the present invention.

(2) FIG. 1 depicts a chart of the fine particle fraction of cromolyn (formulated with lactose and Captisol® attritted foam) as a function of pressure drop differences in the devices used (Mean+SD for CAPTISOL® as compared to the same for lactose).

(3) FIG. 2 depicts a chart of the emitted dose of cromolyn as a fraction of the nominal dose in low and high pressure devices (mean+SD) of FIG. 1.

DETAILED DESCRIPTION OF THE INVENTION

(4) The presently claimed formulation overcomes many of the undesired properties of other known inhalable dry powder formulations. By including SAE-CD in an inhalable dry powder formulation, one is able to adapt the physicochemical, chemical and morphological properties of the powder.

(5) As used herein, the term attritting means to physically abrade a solid to reduce its particle size. Any such process used in the pharmaceutical industry is suitable for use in the process of the invention. Attrition processes include, by way of example and without limitation, micronizing, ball milling, jet milling, hammer milling, pin milling, tumbling, sieving, mortar and pestle. Both low and high energy methods can be used.

(6) The dry powder inhalable DPI formulation includes a therapeutic agent that is suitable for administration via inhalation. The drug is present in an amount sufficient for single dose or multi-dose administration, meaning that the formulation can be packaged in single or multiple use forms.

(7) The dry powder of the invention can be use in any known DPI device. Exemplary ones include those listed herein and many others described in the scientific and patent literature.

(8) The present invention provides SAE-CD based formulations, wherein the SAE-CD is a compound of the Formula 1:

(9) ##STR00002##
wherein: n is 4, 5 or 6; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are each, independently, —O— or a —O—(C.sub.2-C.sub.6 alkylene)-SO.sub.3.sup.− group, wherein at least one of R.sub.1 to R.sub.9 is independently a —O—(C.sub.2-C.sub.6 alkylene)-SO.sub.3.sup.− group, preferably a —O—(CH.sub.2).sub.mSO.sub.3.sup.− group, wherein m is 2 to 6, preferably 2 to 4, (e.g. —OCH.sub.2CH.sub.2CH.sub.2SO.sub.3.sup.− or —OCH.sub.2CH.sub.2CH.sub.2CH.sub.2SO.sub.3.sup.−); and S.sub.1, S.sub.2, S.sub.3, S.sub.4, S.sub.5, S.sub.6, S.sub.7, S.sub.8 and S.sub.9 are each, independently, a pharmaceutically acceptable cation which includes, for example, H.sup.+, alkali metals (e.g. Li.sup.+, Na.sup.+, K.sup.+), alkaline earth metals (e.g., Ca.sup.+2, Mg.sup.+2), ammonium ions and amine cations such as the cations of (C.sub.1-C.sub.6)-alkylamines, piperidine, pyrazine, (C.sub.1-C.sub.6)-alkanolamine and (C.sub.4-C.sub.8)— cycloalkanolamine.

(10) The SAE-CD used is described in U.S. Pat. Nos. 5,376,645 and 5,134,127 to Stella et al, the entire disclosures of which are hereby incorporated by reference. U.S. Pat. No. 3,426,011 to Parmerter et al. discloses anionic cyclodextrin derivatives having sulfoalkyl ether substituents. Lammers et al. (Red Trav. Chim. Pays-Bas (1972), 91(6), 733-742); Staerke (1971), 23(5), 167-171) and Qu et al. (J. Inclusion Phenom. Macro. Chem., (2002), 43, 213-221) disclose sulfoalkyl ether derivatized cyclodextrins. An SAE-CD can be made according to the disclosures of Stella et al., Parmerter et al., Lammers et al. or Qu et al., and optionally purified to remove the major portion of the underivatized parent cyclodextrin, used according to the present invention.

(11) The terms “alkylene” and “alkyl,” as used herein (e.g., in the —O—(C.sub.2-C.sub.6-alkylene)SO.sub.3.sup.− group or in the alkylamines), include linear, cyclic, and branched, saturated and unsaturated (i.e., containing one double bond) divalent alkylene groups and monovalent alkyl groups, respectively. The term “alkanol” in this text likewise includes both linear, cyclic and branched, saturated and unsaturated alkyl components of the alkanol groups, in which the hydroxyl groups may be situated at any position on the alkyl moiety. The term “cycloalkanoyl” includes unsubstituted or substituted (e.g., by methyl or ethyl) cyclic alcohols.

(12) An embodiment of the present invention provides compositions containing a single type of or a mixture of cyclodextrin derivatives, having the structure set out in formula (I), where the composition overall contains on the average at least 1 and up to 3n+6 alkylsulfonic acid moieties per cyclodextrin molecule. The present invention also provides compositions containing a single type of cyclodextrin derivative, or at least 50% of a single type of cyclodextrin derivative. The invention also includes formulations containing cyclodextrin derivatives having a narrow or wide and high or low degree of substitution. These combinations can be optimized as needed to provide cyclodextrins having particular properties.

(13) Exemplary SAE-CD derivatives include SBE4-β-CD, SBE7-β-CD, SBE11-β-CD, and SBE5-γ-CD which correspond to SAE-CD derivatives of the formula I wherein n=5, 5, 5 and 6, respectively; m is 4; and there are on average 4, 7, 11 and 5 sulfoalkyl ether substituents present, respectively. Other exemplary SAE-CD derivatives include those of the formula SAEx-R-CD (Formula 2), wherein SAE is sulfomethyl ether (SME), sulfoethyl ether (SEE), sulfopropyl ether (SPE), sulfobutyl ether (SBE), sulfopentyl ether (SPtE), or sulfohexyl ether (SHE); x (average or specific degree of substitution) is 1-18, 1-21, 1-24, when R (ring structure of parent cyclodextrin) is α, β or γ, respectively; and CD is cyclodextrin.

(14) Since SAE-CD is a poly-anionic cyclodextrin, it can be provided in different salt forms. Suitable counterions include cationic organic atoms or molecules and cationic inorganic atoms or molecules. The SAE-CD can include a single type of counterion or a mixture of different counterions. The properties of the SAE-CD can be modified by changing the identity of the counterion present. For example, a first salt form of SAE-CD can have a greater electrostatic charge than a different second salt form of SAE-CD. The calcium salt form has been found to be more electronegative than the sodium salt form. Likewise, an SAE-CD having a first degree of substitution can have a greater electrostatic charge than a second SAE-CD having a different degree of substitution.

(15) By “complexed” is meant “being part of a clathrate or inclusion complex with”, i.e., a complexed therapeutic agent is part of a clathrate or inclusion complex with a cyclodextrin derivative. By “major portion” is meant at least about 50% by weight. Thus, a formulation according to the present invention contains an active agent of which more than about 50% by weight is not complexed with a cyclodextrin. The actual percent of active agent that is complexed will vary according to the specific cyclodextrin and specific active agent employed. The invention also includes embodiments wherein a minor portion of the active agent is complexed with the derivatized cyclodextrin. It also includes embodiments wherein in substantially all (at least 90% wt., at least 95% wt. or at least 98% wt.) of the active agent is not complexed with an SAE-CD. Embodiments wherein none of the active agent is complexed with SAE-CD are also included.

(16) The present invention also provides compositions containing a mixture of cyclodextrin derivatives wherein two or more different types of cyclodextrin derivatives are included in the composition. By different types, is meant cyclodextrins derivatized with different types of functional groups e.g., hydroxyalkyl and sulfoalkyl, and not to the heterogeneous nature of derivatized cyclodextrins due to their varying degrees of substitution. Each independent different type can contain one or more functional groups, e.g. SBE-CD where the cyclodextrin ring has only sulfobutyl functional groups, and hydroxypropyl-ethyl-β-CD where the cyclodextrin ring has both hydroxypropyl functional groups and ethyl functional groups. The amount of each type of cyclodextrin derivative present can be varied as desired to provide a mixture having the desired properties.

(17) Other cyclodextrin derivatives that can be used in combination with SAE-CD according to the invention include the hydroxyethyl, hydroxypropyl (including 2- and 3-hydroxypropyl) and dihydroxypropyl ethers, their corresponding mixed ethers and further mixed ethers with methyl or ethyl groups, such as methylhydroxyethyl, ethyl-hydroxyethyl and ethyl-hydroxypropyl ethers of alpha-, beta- and gamma-cyclodextrin; and the maltosyl, glucosyl and maltotriosyl derivatives of alpha, beta- and gamma-cyclodextrin, which may contain one or more sugar residues, e.g. glucosyl or diglucosyl, maltosyl or dimaltosyl, as well as various mixtures thereof, e.g. a mixture of maltosyl and dimaltosyl derivatives. Specific cyclodextrin derivatives for use herein include hydroxypropyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-beta-cyclodextrin, glucosyl-alpha-cyclodextrin, glucosyl-beta-cyclodextrin, diglucosyl-beta-cyclodextrin, maltosyl-alpha-cyclodextrin, maltosyl-beta-cyclodextrin, maltosyl-gamma-cyclodextrin, maltotriosyl-beta-cyclodextrin, maltotriosyl-gamma-cyclodextrin and dimaltosyl-beta-cyclodextrin, and mixtures thereof such as maltosyl-beta-cyclodextrin/dimaltosyl-beta-cyclodextrin, as well as methyl-beta-cyclodextrin. Procedures for preparing such cyclodextrin derivatives are well-known, for example, from Bodor U.S. Pat. No. 5,024,998 dated Jun. 18, 1991, and references cited therein.

(18) The carrier of the invention can also include a combination of derivatized cyclodextrin (SAE-CD) and underivatized cyclodextrin.

(19) The HP-β-CD can be obtained from Research Diagnostics Inc. (Flanders, N.J.). HP-β-CD is available with different degrees of substitution. Exemplary products include ENCAPSIN™ (degree of substitution˜4; HP4-β-CD) and MOLECUSOL™ (degree of substitution-8; HP8-β-CD); however, embodiments including other degrees of substitution are also available. Since HPCD is non-ionic, it is not available in salt form.

(20) Dimethyl cyclodextrin is available from FLUKA Chemie (Buchs, CH) or Wacker (Iowa). Other derivatized cyclodextrins suitable in the invention include water soluble derivatized cyclodextrins. Exemplary water-soluble derivatized cyclodextrins include carboxylated derivatives; sulfated derivatives; alkylated derivatives; hydroxyalkylated derivatives; methylated derivatives; and carboxy-β-cyclodextrins, e.g. succinyl-β-cyclodextrin (SCD), and 6.sup.A-amino-6.sup.A-deoxy-N-(3-carboxypropyl)-β-cyclodextrin. All of these materials can be made according to methods known in the prior art. Suitable derivatized cyclodextrins are disclosed in Modified Cyclodextrins: Scaffolds and Templates for Supramolecular Chemistry (Eds. Christopher J. Easton, Stephen F. Lincoln, Imperial College Press, London, UK, 1999) and New Trends in Cyclodextrins and Derivatives (Ed. Dominique Duchene, Editions de Sante, Paris, France, 1991).

(21) The amount of derivatized cyclodextrin required to provide the desired effect in the formulation will vary according to the materials comprising the formulation. The amount of carrier that is useful in the composition of this invention is an amount that serves to uniformly distribute the active agent throughout the composition so that it can be uniformly dispersed when it is to be delivered to a subject in need thereof. It must also serve to dilute the active agent to a concentration at which the active agent can provide the desired beneficial palliative or curative results while at the same time minimizing any adverse side effects that might occur from too high a concentration. Thus, for an active agent that has high physiological activity, more of the carrier will be employed. On the other hand, for an active agent that exhibits a lower physiological activity a lesser quantity of the carrier will be employed. In general, the amount of carrier in the composition will be between about 50% wt. and 99.9% wt. of the total composition.

(22) The formulation of the invention can be administered with any DPI device. Suitable devices include those that are commercially available such as, by way of example and without limitation, those sold under the trademark Aerohaler™ (Boehringer-Ingelheim), Aerolizer™ (Novartis), Clickhaler™ (Innovata Biomed/ML laboratories Celitech), Cyclohaler™ (Pharmachemie), Diskhaler™ (GlaxoSmithKline), Diskus/Accuhaler™ (GlaxoSmithKline), Easyhaler™ (Orion Pharma), Pulvinal™ (Chiesi), Rotohaler™ (GlaxoSmithKline), Spinhaler™ (Aventis), Acu-Breathe™ (Respirics, Inc), Nektar™ DPI (Nektar Therapeutics), Spiros™ DPI (Dura Pharmaceuticals, Inc), SkyeHaler™ (SkyePharma), or Oriel™ Powder Device (Oriel Therapeutics, Inc). Other suitable devices may not yet have been commercialized but are described in the scientific and/or patent literature.

(23) DPI devices are available in formats with different Specific Resistance, R.sub.D, (cmH.sub.2O.sup.0.5/L/min) to the flow of air and are often classified as: high 0.2 to 0.12 cmH.sub.2O.sup.0.5/L/min, medium 0.12-0.07 cmH.sub.2O.sup.0.5/L/min, and low 0.07-0.03 cmH.sub.2O.sup.0.5/L/min pressure drop devices. The Rotahaler (GlaxoSmithKline), Spinhaler(Rhone Poulenc Rorer) Diskus, and Aerolizer have a low resistance, and the Diskhaler (GlaxoSmithKline), has a medium resistance; whereas the Inhalator, Clickhaler, Turbuhaler, Easyhaler (Orion Pharma) and the Twisthaler (Schering Plough) all have a high resistance.

(24) Prior art formulations are generally suitable for use in only a few different DPI devices. For example, a particular lactose-containing formulation might be suitable for use in a high pressure drop device, but that formulation would not be suitable in a low pressure drop device. A study was conducted to determine the suitability of the present formulations for DPI range of devices having different pressure drops. Formulations containing lactose or SAE-CD, each containing sodium cromolyn, were made according to specific processes. The performance of the formulations was evaluated in low resistance (0.065 cmH.sub.2O.sup.0.5/L/min) and high resistance (0.18 cmH.sub.2O.sup.0.5/L/min) devices. The formulations described herein are suitable for use in any of such devices. The SAE-CD containing formulations were found to be suitable for delivery at low (15.2 g/cm.sup.2 at 60 L/min) and high (54.4 g/cm.sup.2 at 60 L/min) pressure drops which are equivalent to the Diskhaler and Inhalator (Handihaler) devices by delivering 25% fine particle fraction with an emitted dose in the 80-90% range. In contrast, lactose containing formulation was pressure drop dependent being substantially equivalent to the SAE-CD at high pressure drop but only delivering 15% FPF and 70% emitted dose at low pressure. The formulations of the invention are therefore capable of use in DPI devices in a substantially pressure drop independent manner.

(25) For administration to the respiratory tract, particularly the lungs, a DPI device is used to deliver appropriately sized aggregates of particles of SAE-CD and active agent such that the aggregates dissociate for the most part into individual particles whereby the major portion of SAE-CD carrier is retained in the buccal cavity or throat and the major portion of active agent is delivered to the trachea or deeper into the respiratory tract.

(26) Generally, decreasing the particle size of the carrier particles positively influences dispersion of active agent from SAE-CD. As noted in the dispersion study below, the fine particle fraction (stage 2 deposition in a twin stage impinger) from the smaller carrier particles was higher than for larger particles. The difference in particle size was determined according to the surface area of the SAE-CD batch used: the larger the surface area, the smaller the particle size. Increased fluidization (Stage 1+2 deposition) with larger carrier sizes was observed when using SAE-CD spray agglomerated powders: 175 to 270 μm median diameter), but this did not improve the fine particle fraction. In contrast, decreases in carrier particle size negatively influenced flow characteristics.

(27) Intermediately dispersed powders (in terms of particle size) appear to possess optimal flow and dispersion properties; although, a degree of dispersity may help reduce inter-particulate interactions similarly to ternary blend mixtures. Intermediate sized carrier particles might be expected to prevent or reduce the direct interactions of drug and carrier particles. Therefore, monodisperse powders generally exhibit lower saturation of the carrier surface binding sites than polydisperse powders. However, polydisperse powders may also influence flow and dispersion properties of carrier systems negatively. Intercalation of smaller particles within larger particles will increase the effective contact area and inter-particulate interactions within the powder. Thus, carrier powder polydispersity is balanced between these competing influences.

(28) Typically, the median particle diameter is between about 0.1 to 10 microns or about, 0.5 to about 6.4 microns. If it is desired that the particles reach the lower regions of the respiratory tract, i.e., the alveoli and terminal bronchi, the preferred median particle diameter size range is between about 0.5 and about 2.5 microns. If it is desired that the particles reach the upper respiratory tract, the preferred particle diameter size range is between 2.5 microns and 10 microns.

(29) In one embodiment, the median diameter of the carrier particles lies between 50 and 1000 microns, or the median diameter of the carrier particles is less than 355 microns and lies between 60 and 250 microns, or between 90 and 250 microns. The relatively large diameter of the carrier particle improves the opportunity for active particles to become attached to carrier particles which is controlled by the above technique to provide good flow and entrainment characteristics and improved release of the active particles in the airways to increase deposition of the active particles in the lower lung.

(30) The span (defined as the ratio=(particle size of the 90.sup.th percentile−particle size of 10.sup.th percentile)/median particle size) of the particle size distribution can also impact performance of the carrier. SAE-CD having broad, moderate and narrow particle size distribution may be used in the invention. Specific embodiments include those wherein the span is about 1.5 and 2.9.

(31) Since particles are present as a distribution, the distribution can be monomodal, bimodal or polymodal.

(32) The influence of particle shape on powder flow and dispersion properties is multifaceted. Generally, spheres, or particles with a high degree of rotational symmetry, are preferred to irregular shapes for good flow and dispersion characteristics. However, spherical particles may have increased inter-particulate forces that restrict flow when polydisperse powders are used.

(33) Particles with a smooth surface are generally preferred over rough particles due to particle-particle interlocking and increases in frictional forces that occur with rough (non-smooth) particles. However, if surface asperities (protrusions) are in the appropriate dimensions, increases in separation distances between particles can lead to decreased inter-particulate forces and improved flow. If asperities are much larger than drug particle size, entrapment of active agent may occur thereby reducing dispersion of the active agent from the carrier during administration with a DPI device.

(34) The morphology of SAE-CD particles can depend upon their method of preparation. Smooth (substantially smooth) surface particles can be prepared by spray drying, freeze drying a liquid or foam. Particles with a rough or substantially dented surface can be prepared by spray agglomeration.

(35) TABLE-US-00002 Shape Surface rugosity Parameter Sphericity Angularity Elongation Material surface Particle appearance Lactose Bulk low high moderate rough Agglomerates Lactose low high moderate rough Agglomerates A high low low smooth Indentations, soccer-ball B high low low smooth Agglomerates C high low low smooth Individual particles D high low low smooth Aggregates E Moderate low low rough Agglomerates F Moderate low low rough Agglomerates G low high moderate smooth Agglomerates “A” denotes SAE-CD prepared by spray drying using two-fluid nozzle atomization. “B” denotes SAE-CD prepared by spray drying as per “A” followed by sieving of the particulate. “C” denotes SAE-CD prepared by spray drying but with counter-current high pressure nozzle atomization. “D” denotes SAE-CD prepared by spray drying with co-current high pressure nozzle atomization. “E” denotes SAE-CD prepared by spray agglomeration at 25% wt./wt. “F” denotes SAE-CD prepared by spray agglomeration at 50% wt./wt. “G” denotes SAE-CD prepared by freeze drying of a frozen foam comprising SAE-CD and water.

(36) In general, SAE-CD particles that are rougher unexpectedly provide increased powder flow in a DPI device.

(37) Within each system tested, per the example below, for dispersion properties (i.e. drug-device and entrainment tube studies) increasing sphericity and particle size distribution decreased the fine particle fraction (deposition to stage 2 of liquid impinger). However, increasing sphericity also decreased drug deposition in the device and throat indicating that sphericity did not influence entrainment of the carrier particle to the extent that it influences drug detachment from the carrier surface. This indicates the powder was entrained via large aggregates rather than as a function of individual particle size. Thus, stage 1 deposition was increased as the carrier particles became more spherical and broadly distributed. Per the two dispersion studies below, SAE-CD carrier derived from a foam provides improved performance over SAE-CD carrier made according to other specific processes.

(38) The SAE-CD containing particles can be provided as individual (not aggregates or agglomerates but otherwise still plural) particles, aggregates and agglomerates. Individual particles can be prepared by spray drying. Aggregated particles can be prepared by spray drying. Agglomerated particles can be prepared by spray agglomeration, spray drying or freeze-drying of a foam.

(39) The bulk flow and microflow properties of SAE-CD solid were obtained according to the examples below. The Carr's Index ranged from 10-40% compressibility. The static angle of repose ranged from 28-45 degrees. The micro-flow properties had a fractal dimension analysis of about 1.00-1.31, preferred embodiments having a range of about 1.0-1.2.

(40) Moisture content of the SAE-CD carrier can vary according to its method of preparation. Batches having a moisture content of less than about 3%, 6%, 8% or 10%, wt. have been prepared.

(41) SAE-CD is a polyanionic material that generally possesses a negative electrostatic charge. The electrostatic charge of the SAE-CD carrier is generally about −1.4 to −3.7, 2 to −3.7, or 2 to −2 nC/g (nC is defined as nanocoulombs) when the material is processed and equilibrated as described herein. Prior to equilibration in a controlled atmosphere, the SAE-CD carrier can be obtained with an even more electronegative charge. By increasing the amount of moisture in the equilibration atmosphere, the electronegative charge of the SAE-CD carrier can be modified as needed.

(42) The electrostatic charge of a blend (comprising active agent and SAE-CD carrier) will vary according to the electrostatic charge of the individual components, among other things. The table below depicts the electrostatic charge of some blends.

(43) TABLE-US-00003 Blend Charge (nC/g) “D” + Na-cromolyn 1.48 “F” + Na-cromolyn −0.17 “G” + Na-cromolyn −0.24 “D” + albuterol sulfate 0.52 “F” + albuterol sulfate 4.04 “G” + albuterol sulfate −0.52 “D” + Na-fluorcscein −0.64 “F” + Na-fluorescein −0.63 “G” + Na-fluorescein −0.27

(44) The above should be read in view of the electrostatic charge of the corresponding drugs, the data for which is summarized in the table below.

(45) TABLE-US-00004 Suggested Electrostatic Approx. Carrier Approx. Charge Magnitude Exemplary Charge Magnitude Range (nC/g) Active Agent Range (nC/g) Highly <−3 Na Neutral to 0 to −1 negative fluorescein low negative Moderately −3 to −2 0 to −1.5 negative Low negative −2 to −0.5 Na Low negative −0.5 to −2 Cromolyn Neutral −0.5 to 0.5 Wide range −2 to +2 Low positive 0.5 to 2 Low positive 0.5 to 2 Moderately 2 to 4 0 to 1.5 positive Highly  >4 Albuterol Neutral to 0 to 1 positive low positive

(46) The table above sets forth approximate operating ranges for the suggested electrostatic charge of the SAE-CD carrier and the corresponding electrostatic charge of the active agent. In other words, the table should be read such that an active agent having a particular electrostatic charge is preferably formulated with an SAE-CD carrier having a particular electrostatic charge. For example, a highly negative or moderately negative drug is preferably formulated in a dry powder DPI device with SAE-CD carrier having a neutral to low negative electrostatic charge. In view of the above and other aspects discussed herein, it should be understood that an SAE-CD can serve as a suitable dry powder carrier for a full range of drugs differing in their electrostatic charges.

(47) Dispersion studies according to the example below of albuterol from Captisol® and lactose blends indicate significant influence of electrostatic charge on the carrier systems. Dynamic electrostatic charge measurements showed that micronized albuterol carries a significant positive charge. Comparison between Captisol® and lactose as carrier particles showed that lactose systems (neutral charge) more efficiently delivered micronized drug to stage 2 (fine particles) than Captisol® systems (moderate to strong negative charge). Thus, without being held bound to a particular mechanism, it is postulated that SAE-CD carrier particles exhibit greater drug attachment than lactose when albuterol is used as the model drug system. The SAE-CD powder (derived from foam) with the smallest negative charge exhibited the most stage 2 deposition of albuterol.

(48) The charge of the carrier particles was compared to dispersion performances from the entrainment tubes for albuterol and cromolyn. Charge neutral carrier particles resulted in significantly greater retention of drug (albuterol or cromolyn) in the entrainment tube. A similar correlation was obtained for Throat deposition. In addition, stage 1 deposition showed an inverse correlation where increasing the negative charge of the carrier resulted in a greater percentage of drug delivered to this stage. Correlations between drug dispersion to stage 2 and electrostatic charge were smaller. Albuterol stage 2 deposition was also related to the electrostatic charge of the carrier. However, the cromolyn (small negative charge) stage 2 deposition appeared to be less dependent on electrostatics.

(49) Accordingly, the polarity and magnitude of charge of the carrier particles and model drugs significantly influences performance of the dry powder formulations. Albuterol (high positive charge), sodium cromolyn (electroneutral), and fluorescein (moderate negative charge) were dispersed more readily using either Lactose (electro-neutral, small size), or SAE-CD derived from foam (moderate negative charge, small size) as compared to spray dried or spray agglomerated SAE-CD carrier.

(50) Electrostatic and morphological characteristics are factors involved in the good dispersion properties observed with SAE-CD carrier derived from foam. Those powder particles had smooth, angular surfaces and were generally minimally aggregated with a slight elongation of the particles. Together with a relatively lower electrostatic charge and small size, dispersion to Stage 2 of the liquid impinger was significantly higher than other SAE-CD based carrier systems.

(51) SAE-CD (high negative charge, large size) fluidized albuterol well (entrainment tube experiments) and dispersed the drug well when a high-resistance (high turbulence) inhaler device was used (Inhalator™). The high inter-particulate forces between carrier and albuterol can be overcome using the Inhalator. This indicates that the fluidization of the SAE-CD powder (due to size and morphology) can be maximized by appropriate selection of device for lung delivery.

(52) Mixing of carrier and micronized drug particles can influence the electrostatics of the system. Mixing may induce triboelectrification and increase electrostatic charge. Drug particle adhesion to carrier particle surface may result in charge shielding and reduce the electrostatics of the system. The electrostatics of the powder blends described above were determined and attempts were made to correlate these results with the dispersion performance observed in the liquid impinger studies. Increasing electrostatic charge of the blend has a beneficial effect on dispersion of the powder formulation from the entrainment tubes. Increasing the charge of the blend correlated with decreased device and throat deposition, while stage 1 deposition was increased. The differences in electrostatic charge of the blends may result from differences in adhesion between drug and carrier particles. Positively charged blends may result from more loosely bound micronized drug particles detaching from the carrier particles during electrostatic charge measurements (i.e. during powder flow). In addition, the positive charge of the blends may represent free micronized drug particles in the blend. This may result from saturation of binding sites on the SAE-CD carrier. In this case, the net electrostatic charge measured will be dominated by micronized drug particle charge (i.e. albuterol carries a positive charge). Conversely, blends with negative electrostatic charge may represent systems in which carrier-drug adhesion is dominant. Thus, in these cases the charge of the blend is a useful predictor of powder dispersion characteristics.

(53) As a result of the good dispersion performance of SAE-CD, derived from foam, in the entrainment tubes, a full dispersion study was performed in comparison with lactose using sodium cromolyn as the model drug in an eight-stage non-viable cascade impactor. The Inhalator™ device was used to provide maximum turbulence. The results indicate that, in this system, the dispersion properties of Lactose and SAE-CD were equivalent at high-pressure drop. However, the performance of SAE-CD derived from foam appears to be pressure drop independent (FIG. 1). Its performance is consistent for different devices (FPF means are not statistically different). In contrast, lactose dispersion performance appears to be significantly influenced by device characteristics (P=0.005).). Variability of the FPF also appears to be higher in the lactose formulation (FIG. 2) (P=0.027 for low pressure device variances, no significant difference for high pressure device variances). There was no significant difference (α=0.05) in the variability of emitted doses for lactose and SAE-CD foam.

(54) An overall evaluation of the impact of the physicochemical and morphological properties of SAE-CD upon performance as a dry powder carrier for DPI administration was conducted.

Albuterol

(55) The model drug albuterol and the commercially available CAPTISOL™ were used. Albuterol is a highly positively charged powder when micronized for respiratory delivery. It has typical particle size and morphological characteristics for micronized drugs that are prepared for inhalation (size 1-5 μm, predominantly crystalline structure). The properties of the SAE-CD were matched with that of albuterol and the following results were obtained.

(56) Size Selection:

(57) Generally, decreasing the particle size of the carrier particles positively influences dispersion characteristics. In contrast, decreases in carrier particle size negatively influenced flow characteristics. Therefore, intermediate particle sizes that balance flow performance with dispersion characteristics are useful for DPI formulations. Lactose and SAE-CD particles derived from foam demonstrate these characteristics. The optimal median particle diameter for dispersion, which depends upon the nature of drug and carrier, can be between about 47 and 125 μm for the specific forms of albuterol and SAE-CD evaluated.

(58) Polydispersity Selection:

(59) Particle size distribution also has an influence on powder flow and dispersion. Intermediately dispersed powders can have optimal flow and dispersion properties. Some degree of dispersity helps reduce inter-particulate interactions similarly to ternary blend mixtures. Intermediate sized carrier particles can prevent or reduce the direct interactions of drug and carrier particles. Therefore, monodisperse powders exhibit lower saturation of the carrier surface binding sites than polydisperse powders. However, polydisperse powders can influence flow and dispersion properties of carrier systems negatively. Intercalation of smaller particles within larger particles will increase the effective contact area and inter-particulate interactions within the powder. Thus, carrier powder polydispersity is balanced between these competing influences. Generally, particle size distributions for carrier particles, for optimal dispersion, should have moderate dispersity, i.e. particle size span should be between 1.5 and 2.9.

(60) Morphology Selection:

(61) The influence of particle shape on powder flow and dispersion properties is multifaceted. In the art, spheres or particles with a high degree of rotational symmetry are preferred over irregular shapes for good flow and dispersion characteristics. However, SAE-CD spherical particles may have increased inter-particulate forces that restrict flow when polydisperse powders are used. In the art and according to the invention, smooth particles are generally preferred over rough particles due to particle-particle interlocking and increases in frictional forces. However, if surface asperities are in the appropriate dimensions, increases in separation distances between particles can lead to decreased inter-particulate forces and improved flow. This was accomplished by using spray agglomerated Captisol® rather than foam derived Captisol®. If asperities are much larger than drug particle size entrapment may occur that reduces dispersion. Therefore, the smooth and irregular (i.e. not planar or geometric) morphology of the SAE-CD derived from foam is desirable for carrier particles with micronized drug particles, when compared to SAE-CD prepared by other processes.

(62) Selection of Charge:

(63) Electrostatic forces generally increase inter-particulate forces and reduce drug dispersion upon administration. SAE-CD derived from foam has relatively lower electrostatic charge than SAE-CD prepared by other methods, so that one can achieve significantly higher drug dispersion performance with albuterol using that particular form of SAE-CD. Electrostatic charge is known to be a function of moisture content (increasing moisture content decreases electrostatic charge), particle size (decreasing particle size generally increases electrostatic charge), surface area (increased charge obtained with increased surface area), and other physico-chemical properties (such as crystallinity and energy input) of the carrier and drug system. For albuterol, with highly positively charged particles, the charge of the carrier should be close to neutral. This is achieved by preparing SAE-CD according to the process described herein.

Cromolyn

(64) The physicochemical and morphological properties of the SAE-CD carrier can be matched to those of other drugs as well. Micronized sodium cromolyn for inhalation has slightly negative electrostatic charge characteristics (−1 to −1.7 nC/g). Otherwise, it has typical particle size and morphological characteristics for micronized drugs that are prepared for inhalation (size 1-5 μm, predominantly crystalline structure).

(65) Size and Polydispersity Selection:

(66) Size and size distribution (polydispersity) selection for appropriate carrier particles for development of a dry powder inhaler system follow the same guidelines as discussed above for albuterol. Moderate particle size (between 45 and 125 μm) and distribution (particle size span should be between 1.5 and 2.9) characteristics are desirable. In addition, morphological features suitable for carrier particles are substantially the same as those described for albuterol: smooth, irregular surfaces (which properties are found in SAE-CD carrier prepared from dried foam).

(67) Selection of Charge:

(68) SAE-CD derived from dried foam had relatively lower charge characteristics that may contributed to the significantly higher drug dispersion performance of it with sodium cromolyn as compared to other SAE-CD carrier systems, such as those prepared by spray drying or spray agglomeration. However, further advantage was gained by using the SAE-CD derived from foam formulation is also better than lactose, which is relatively neutral. By matching the slightly negatively-charged drug particles with low negatively-charged SAE-CD carrier particles, a dry powder system that is flow independent was obtained, i.e. fine particle dose was independent of the pressure drop used to disperse the dry powder formulation. This is truly unexpected and is a direct result of the desired combination of physicochemical and morphological properties that can only be achieved with SAE-CD but not with lactose.

(69) Accordingly, the median particle size, size distribution, morphology and electrostatic charge properties of SAE-CD are readily modified to match the wide variety of micronized drug characteristics that are presented to a formulator of the art. The ionic nature of SAE-CD facilitates the preparation of dry powder carriers of varying degrees of electrostatic charge, which are dependent upon the method of preparation and the chemical structure of the SAE-CD. Thus, a key advantage of the present invention over other cyclodextrin derivatives and lactose, in terms of its use as a carrier, is the ability of an artisan to modulate the physicochemical properties of the SAE-CD to match drug properties thereby resulting in an optimal dry powder formulation suitable for administration by DPI.

(70) Drugs intended for inhalation therapy, carried out by the administration of dry powders, are characterized by a particle size of a few microns. The particle size is quantified by measuring a characteristic equivalent sphere diameter, known as aerodynamic diameter, which expresses the ability of the particles to be transported as a suspension in an air stream (aerosolization). In general, particles with an aerodynamic diameter of less than 10 microns or less than 6.4 microns are regarded as respirable, i.e. capable of penetrating into the lungs.

(71) The dosage form of the invention can be used to administer a wide range of active agents by inhalation when administered with a DPI device. Active agents are suitable for endobronchial (intrapulmonary, intratracheal, intraaveolar) administration.

(72) Corticosteroids that are useful in the present invention generally include any steroid produced by the adrenocortex, including glucocorticoids and mineralocorticoids, and synthetic analogs and derivatives of naturally occurring corticosteroids having anti-inflammatory activity. Suitable synthetic analogs include prodrugs, ester derivatives Examples of corticosteroids that can be used in the compositions of the invention include aldosterone, beclomethasone, betamethasone, butoxicart, budesonide, ciclesonide (Altana Pharma AG), cloprednol, cortisone, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluorometholone, flurandrenolone, fluticasone, halcinonide, hydrocortisone, icomethasone, loteprednol, meprednisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, rofleponide, RPR 106541, tixocortol, triamcinolone, and their respective pharmaceutically acceptable derivatives, such as beclomethasone diproprionate, beclomethasone monoproprionate, dexamethasone 21-isonicotinate, fluticasone propionate, icomethasone enbutate, tixocortol 21-pivalate, and triamcinolone acetonide. Particularly preferred are compounds such as beclomethasone diproprionate, budesonide, flunisolide, fluticasone propionate, mometasone furoate, and triamcinolone acetonide.

(73) Other specific active agents that can be employed according to the invention include pentamidine isethiouate, albuterol sulfate, metaproterenol sulfate, flunisolide, cromolyn sodium, sodium chromoglycate, ergotamine tartrate, levalbuterol, terbutaline, reproterol, salbutamol, salmeterol, formoterol, fenoterol, clenbuterol, bambuterol, tulobuterol, broxaterol, epinephrine, isoprenaline or hexoprenaline, an anticholinergic, such as tiotropium, ipratropium, oxitropium or glycopyrronium; a leukotriene antagonist, such as andolast, iralukast, pranlukast, imitrodast, seratrodast, zileuton, zafirlukast or montelukast; a phosphodiesterase inhibitor, such as filaminast or piclamilast; a paf inhibitor, such as apafant, forapafant or israpafant; a potassium channel opener, such as amiloride or furosemide; a painkiller, such as morphine, fentanyl, pentazocine, buprenorphine, pethidine, tilidine, methadone or heroin; a potency agent, such as sildenafil, alprostadil or phentolamine; a peptide or protein, such as insulin, erythropoietin, gonadotropin or vasopressin; calcitonin, factor ix, granulocyte colony stimulating factor, granulocyte macrophage colony, growth hormone, heparin, heparin (low molecular weight), interferon alpha, interferon beta, interferon gamma, interleukin-2, luteinizing hormone releasing hormone, somatostatin analog, amylin, ciliary neurotrophic factor, growth hormone releasing factor, insulin-like growth factor, insulinotropin, interleukin-1 receptor antagonist, interleukin-3, interleukin-4, interleukin-6, macrophage colony stimulating, factor (m-csf), nerve growth factor, parathyroid hormone, thymosin alpha 1; iib/iiia inhibitor, alpha-1 antitryp sin, anti-rsv antibody, cystic fibrosis transmembrane regulator (cftr) gene, deoxyribonuclase (dnase), bactericidal/permeability (ards), increasing protein anti-cmv antibody, interleukin-1 receptor, or a pharmaceutically acceptable derivative or salt of these compounds.

(74) The weight of a unit dose of dry powder will vary according to the active agent present, its therapeutic activity, its toxicological profile, the amount at which it is present in the dry powder, and other factors known to the artisan. In general, the active agent is present at about 0.1% to about 50% wt. of the dry powder formulation, the balance being the carrier and optionally one or more other materials. The carrier comprises SAE-CD and optionally one or more other materials.

(75) For the treatment of bronchial inflammation, the corticosteroid is preferably either beclomethasone dipropionate, betamethasone, budesonide, dexamethasone, flunisolide, fluticasone propionate, mometasone furoate, or triamcinolone acetonide, and is formulated in the concentrations set forth herein. The daily dose of the corticosteroid is generally about 0.05 to 10 mg, depending on the drug and the disease, in accordance with the Physician's Desk Reference.

(76) The active agent can be present in its neutral, ionic, salt, basic, acidic, natural, synthetic, diastereomeric, epimeric, isomeric, enantiomerically pure, racemic, solvate, hydrate, chelate, derivative, analog, esterified, non-esterified, or other common form. Whenever an active agent is named herein, all such forms available are included.

(77) The formulation of the invention can be used to deliver two or more different active agents. Particular combinations of active agents can be provided by the present formulation. Some combinations of active agents include: 1) a first drug from a first therapeutic class and a different second drug from the same therapeutic class; 2) a first drug from a first therapeutic class and a different second drug from a different therapeutic class; 3) a first drug having a first type of biological activity and a different second drug having about the same biological activity; 4) a first drug having a first type of biological activity and a different second drug having a different second type of biological activity. Exemplary combinations of active agents are described herein.

(78) A corticosteroid, such as budesonide, can be administered in combination with one or more other drugs. Such other drugs include: B.sub.2 adrenoreceptor agonist, D.sub.2 receptor agonist, anticholinergic agent.

(79) B.sub.2-Adrenoreceptor agonists for use in combination with the compositions provided herein include, but are not limited to, Albuterol (alpha.sup.1-(((1,1-dimethylethyl)amino)methyl)-4-hydroxy-1,3-benzenedimethanol); Bambuterol. (dimethylcarbamic acid 5-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,3-phenylene ester); Bitolterol (4-methylbenzoic acid 4-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,2-phenyleneester); Broxaterol (3-bromo-alpha-(((1,1-dimethylethyl)amino)methyl)-5-isoxazolemethanol); Isoproterenol (4-(1-hydroxy-2-((1-methylethyl-)amino)ethyl)-1,2-benzene-diol); Trimethoquinol (1,2,3,4-tetrahydro-1-((3,4-, 5-trimethoxyphenyl)-methyl)-6,7-isoquinolinediol); Clenbuterol (4-amino-3,5-dichloro-alpha-(((1,1-dimethylethyl)amino)methyl)benzenemethanol); Fenoterol (5-(1-hydroxy-2-((2-(4-hydroxyphenyl)-1-methylethyl)amino)ethyl)-1,3-benzenediol); Formoterol (2-hydroxy-5-((1RS)-1-hydroxy-2-(((1RS)-2-(p-methoxyphenyl)-1-methylethyl)amino)ethyl) formanilide); (R,R)-Formoterol; Desformoterol ((R,R) or (S,S)-3-amino-4-hydroxy-alpha-(((2-(4-methoxyphenyl)-1-methyl-ethyl)amino)methyl)benzenemethanol); Hexoprenaline (4,4′-(1,6-hexane-diyl)-bis(imino(1-hydroxy-2, 1-ethanediyl)))bis-1,2-benzenediol); Isoetharine (4-(1-hydroxy-2-((1-meth-ylethyl)amino)butyl)-1,2-benzenediol); Isoprenaline (4-(1-hydroxy-2-((1-methylethyl)amino)ethyl)-1,2-benzenediol); Meta-proterenol (5-(1-hydroxy-2-((1-methylethyl)amino)ethyl)-1,3-benzened-iol); Picumeterol (4-amino-3,5-dichloro-alpha-(((6-(2-(2-pyridinyl)ethoxy)hexyl)-amino)methyl) benzenemethanol); Pirbuterol (.alpha.sup.6-(((1,1-dimethylethyl)-amino)methyl)-3-hydroxy-2,6-pyridinemethanol); Procaterol (((R*,S*)-(.+.)-8-hydroxy-5-(1-hydroxy-2-((1-methylethyl)amino-)butyl)-2(1H)-quinolin-one); Reproterol ((7-(3-((2-(3,5-dihydroxyphenyl)-2-hydroxyethyl)amino)-propyl)-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione)-; Rimiterol (4-(hydroxy-2-piperidinylmethyl)-1,2-benzenediol); Salbutamol ((.+.)-alpha.sup.1-1,1-dimethylethyl)amino)methyl)-4-hydroxy-1,3-b-enzenedimethanol); (R)-Salbutamol; Salmeterol ((.+.)-4-hydroxy-.alpha.sup.1-(((6-(4-phenylbutoxy)hexyl)-amino)methyl)-1,3-benzenedimethanol); (R)-Salmeterol; Terbutaline (5-(2-((1,1-dimethylethyl)amino)-1-hydroxyethyl)-1,3-benzenethiol); Tulobuterol (2-chloro-.alpha.-(((1,1-dimethylethyl)amino)methyl)benzenemethanol); and TA-2005 (8-hydroxy-5-((1R)-1-hydroxy-2-(N-((1R)-2-(4-methoxyphenyl)-1-methylethyl)amino)ethyl)carbostyril hydrochloride).

(80) Dopamine (D.sub.2) receptor agonists include, but are not limited to, Apomorphine ((r)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo[de,g]quinoli-ne-10,11-diol); Bromocriptine ((5′.alpha.)-2-bromo-12′-hydroxy-2′-(1-methylethyl)-5′-(2-methylpropyl)ergotaman-3′,6′, 18-trione); Cabergoline ((8.beta.)-N-(3-(dimethylamino)propyl)-N-((ethylamino)carbony-l)-6-(2-propenyl)ergoline-8-carboxamide); Lisuride (N′-((8-alpha-)-9,10-di-dehydro-6-methylergolin-8-yl)-N,N-diethylurea); Pergolide ((8-beta-)-8-((methylthio)methyl)-6-propylergoline); Levodopa (3-hydroxy-L-tryosine); Pramipexole ((s)-4,5,6,7-tetrahydro-N.sup.6-prop-yl-2,6-benzothiazolediamine); Quinpirole hydrochirodie (trans-(−)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g]qui-noline hydrochloride); Ropinirole (4-(2-(dipropylamino)ethyl)-1,3-dihydro-2H-indol-2-one); and Talipexole (5,6,7,8-tetrahydro-6-(2-propenyl)-4H-thia-zolo[4,5-d]azepin-2-amine). Other dopamine D.sub.2 receptor agonists for use herein are disclosed in International Patent Application Publication No. WO 99/36095.

(81) Anticholinergic agents for use herein include, but are not limited to, ipratropium bromide, oxitropium bromide, atropine methyl nitrate, atropine sulfate, ipratropium, belladonna extract, scopolamine, scopolamine methobromide, homatropine methobromide, hyoscyamine, isopriopramide, orphenadrine, benzalkonium chloride, tiotropium bromide and glycopyrronium bromide. In certain embodiments, the compositions contain an anticholinergic agent, such as ipratropium bromide or tiotropium bromide, at a concentration of about 5 μg/mL to about 5 mg/mL, or about 50 μg/mL to about 200 μg/mL. In other embodiments, the compositions for use in the methods herein contain an anticholinergic agent, including ipratropium bromide and tiotropium bromide, at a concentration of about 83 μg/mL or about 167 μg/mL.

(82) Other active ingredients for use herein in combination therapy, include, but are not limited to, IL-5 inhibitors such as those disclosed in U.S. Pat. Nos. 5,668,110, 5,683,983, 5,677,280 and 5,654,276; antisense modulators of IL-5 such as those disclosed in U.S. Pat. No. 6,136,603; milrinone (1,6-dihydro-2-methyl-6-oxo-[3,4′-bipyridine]-5-carb-onitrile); milrinone lactate; tryptase inhibitors such as those disclosed in U.S. Pat. No. 5,525,623; tachykinin receptor antagonists such as those disclosed in U.S. Pat. Nos. 5,691,336, 5,877,191, 5,929,094, 5,750,549 and 5,780,467; leukotriene receptor antagonists such as montelukast sodium (Singular®, R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl-]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]-propyl]thio]methyl]cyclopro-paneacetic acid, monosodium salt), 5-lypoxygenase inhibitors such as zileuton (Zyflo™, Abbott Laboratories, Abbott Park, Ill.), and anti-IgE antibodies such as Xolair™ (recombinant humanized anti-IgE monoclonal antibody (CGP 51901; IGE 025A; rhuMAb-E25), Genentech, Inc., South San Francisco, Calif.).

(83) The invention includes methods for treatment, prevention, or amelioration of one or more symptoms of bronchoconstrictive disorders. The method further includes administering one or more of (a), (b), (c) or (d) as follows: (a) a b.sub.2-adrenoreceptor agonist; (b) a dopamine (D.sub.2) receptor agonist; (c) a prophylactic therapeutic, such as a steroid; or (d) an anticholinergic agent; simultaneously with, prior to or subsequent to the composition provided herein.

(84) The bronchoconstrictive disorder to be treated, prevented, or whose one or more symptoms are to be ameliorated is associated with asthma, including, but not limited to, bronchial asthma, allergic asthma and intrinsic asthma, e.g., late asthma and airway hyper-responsiveness; and, particularly in embodiments where an anticholinergic agent is used, other chronic obstructive pulmonary diseases (COPDs), including, but not limited to, chronic bronchitis, emphysema, and associated cor pulmonale (heart disease secondary to disease of the lungs and respiratory system) with pulmonary hypertension, right ventricular hypertrophy and right heart failure. COPD is frequently associated with cigarette smoking, infections, environmental pollution and occupational dust exposure.

(85) Other disorders and diseases than can be treated by administration of a unit dose of active agent via a DPI device according to the invention include Osteoporosis Prophylaxis, Paget's Disease, Hypercalcemia, Anemia, Hemophilia, Neutropenia, Bone Marrow Engraft/Transplant Failure, Short stature, Renal Failure, Blood Clotting, Type I and Type II Diabetes, Hepatitis B and C, Hairy Cell Leukemia, Kaposi's Sarcoma, Multiple Sclerosis, Chronic Granulomatous Disease, Renal Cancer, Prostate Cancer, Endometriosis, Gastrointestinal Cancers, Diabetes Insipidus, Bed Wetting, Lou Gehrig's Disease, Osteoporosis, Nutritional Support, Rheumatoid Arthritis, Adjuvant to Chemotherapy, Immunodeficiency Disease, Thrombocytopenia, Fungal Disease, Cancer, Hypercholesterolemia, Peripheral Neuropathies, Refractory Diarrheas, Unstable Angina, Cystic Fibrosis, Respiratory Syncytial Virus, Chronic Bronchitis, Asthma, Adult Respiratory Distress Syndrome, Cytomegalovirus, pneumocystis carinii pneumonia, Bronchospasm, Bronchial asthma, or Migraine.

(86) Even though SAE-CD can be the sole carrier in a dry powder formulation according to the invention, it is possible to add other carriers to the formulation to further improve its performance. Such other carriers include lactose (in any of its known forms suitable for DPI administration), and any of the standard carbohydrate and amino acid carriers that are known in the art to be useful excipients for inhalation therapy, either alone or in combination. These excipients are generally relatively free-flowing particulate solids, do not thicken or polymerize upon contact with water, are toxicologically innocuous when inhaled as a dispersed powder and do not significantly interact with the active agent in a manner that adversely affects the desired physiological action of the agent. Carbohydrate excipients that are particularly useful in this regard include the mono- and polysaccharides. Representative monosaccharides include carbohydrate excipients such as dextrose (anhydrous and the monohydrate; also referred to as glucose and glucose monohydrate), galactose, mannitol, D-mannose, sorbitol, sorbose and the like. Monosaccharides are readily publicly available; for example, dextrose is available from companies such as Mallinckrodt, Inc., Corn Products Co., CPC (UK) Ltd., and/or others. Mannitol and sorbitol are available from companies such as ICI Americas, Inc., McKesson Chemical Co., Merck & Co., Atlas Chemical Industries (UK) Ltd., and/or others. Representative disaccharides, such as lactose, maltose, sucrose, trehalose and the like, can be obtained from companies such as McKesson Chemical Co., Aldrich Chemical Co., Inc., Great Western Sugar Co., and/or others. Representative trisaccharides include those such as raffinose and the like that are readily available from commercial sources.

(87) Suitable amino acid carriers include any of the naturally occurring amino acids that form a powder under standard pharmaceutical processing techniques and include the non-polar (hydrophobic) amino acids and polar (uncharged, positively charged and negatively charged) amino acids, such amino acids are of pharmaceutical grade and are generally regarded as safe (GRAS) by the U.S. Food and Drug Administration. Representative examples of non-polar amino acids include alanine, isoleucine, leucine, methionine, phenylalanine, proline, tryptophan and valine. Representative examples of polar, uncharged amino acids include cystine, glycine, glutamine, serine, threonine, and tyrosine. Representative examples of polar, positively charged amino acids include arginine, histidine and lysine. Representative examples of negatively charged amino acids include aspartic acid and glutamic acid. Of these, glycine is preferred. These amino acids are generally available from commercial sources that provide pharmaceutical-grade products such as the Aldrich Chemical Company, Inc., Milwaukee, Wis. or Sigma Chemical Company, St. Louis, Mo.

(88) Although not necessary, the formulation of the present invention may include a antioxidant, acidifying agent, alkalizing agent, buffering agent, solubility-enhancing agent, penetration enhancer, electrolyte, fragrance, glucose, glidant, stabilizer, bulking agent, cryoprotectant, plasticizer, flavors, sweeteners, surface tension modifier, density modifier, volatility modifier, other excipients known by those of ordinary skill in the art for use in preserved formulations, or a combination thereof. Upon each occurrence, these materials can be independently included in the active agent-containing particles or the carrier particles. For example, the carrier might include one or more of these materials and the active agent-containing particles might also include one or more of these materials.

(89) As used herein, the term “glidant” is intended to mean an agent used to promote flowability of the dry powder. Such compounds include, by way of example and without limitation, magnesium stearate, sodium dodecylsulfate, colloidal silica, cornstarch, talc, calcium silicate, magnesium silicate, colloidal silicon, silicon hydrogel and other materials known to one of ordinary skill in the art.

(90) As used herein, the term “antioxidant” is intended to mean an agent that inhibits oxidation and thus is used to prevent the deterioration of preparations by the oxidative process. Such compounds include, by way of example and without limitation, acetone, potassium metabisulfite, potassium sulfite, ascorbic acid, ascorbyl palmitate, citric acid, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium citrate, sodium sulfide, sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, thioglycolic acid, EDTA, pentetate, and sodium metabisulfite and others known to those of ordinary skill in the art.

(91) As used herein, the term “alkalizing agent” is intended to mean a compound used to provide alkaline medium when the dry powder of the invention is exposed to water. Such compounds include, by way of example and without limitation, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethanolamine, diethanolamine, organic amine base, alkaline amino acids and trolamine and others known to those of ordinary skill in the art.

(92) As used herein, the term “acidifying agent” is intended to mean a compound used to provide an acidic medium when the dry powder of the invention is exposed to water. Such compounds include, by way of example and without limitation, acetic acid, acidic amino acids, citric acid, fumaric acid and other alpha hydroxy acids, hydrochloric acid, ascorbic acid, phosphoric acid, sulfuric acid, tartaric acid and nitric acid and others known to those of ordinary skill in the art.

(93) As used herein, the term “buffering agent” is intended to mean a compound used to resist change in pH upon exposure to a medium of a different pH. Buffers are used in the present compositions to adjust the pH to a range of between about 2 and about 8, about 3 to about 7, or about 4 to about 5. By controlling the pH of the dry powder, irritation to the respiratory tract can be minimized. Such compounds include, by way of example and without limitation, acetic acid, sodium acetate, adipic acid, benzoic acid, sodium benzoate, boric acid, sodium borate, citric acid, glycine, maleic acid, monobasic sodium phosphate, dibasic sodium phosphate, HEPES, lactic acid, tartaric acid, potassium metaphosphate, potassium phosphate, monobasic sodium acetate, sodium bicarbonate, tris, sodium tartrate and sodium citrate anhydrous and dihydrate and others known to those of ordinary skill in the art. Other buffers include citric acid/phosphate mixture, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, Mcllvaine, phosphate, Prideaux-Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagen), veronal acetate, MES (2-(N-morpholino)ethanesulfonic acid), BIS-TRIS (bis(2-hydroxyethyl)imino-tris(hydroxymethyl)methane), ADA (N-(2-acetamido)-2-iminodiacetic acid), ACES (N-(carbamoylmethyl)-2-aminoethanesulfonic acid), PIPES (piperazine-N,N′-bis(2-ethanesulfonic acid)), MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid), BIS-TRIS PROPANE (1,3-bis(tris(hydroxymethyl)methylamino)propane), BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonaic acid), MOPS (3-(N-morpholino)propanesulfonic acid), TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES (N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid), DIPSO (3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonic acid), MOBS (4-(N-morpholino)-butanesulfonic acid), TAPSO (3-(N-tris(hydroxymethyl)methylamino)-2-hydroxypropanesulfonic acid), TRIZMA™ (tris(hydroxymethylaminomethane), HEPPSO (N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonic acid), POPSO (piperazine-N,N′-bis(2-hydroxypropanesulfonic acid)), TEA (triethanolamine), EPPS (N-(2-hydroxyethyl)piperazine-N′-(3-propanesulfonic acid), TRICINE (N-tris(hydroxymethyl)-methylglycine), GLY-GLY (glycylglycine), BICINE (N,N-bis(2-hydroxyethyl)glycine), HEPBS (N-(2-hydroxyethyl)piperazine-N′-(4-butanesulfonic acid)), TAPS (N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid), AMPD (2-amino-2-methyl-1,3-propanediol), and/or any other buffers known to those of skill in the art.

(94) Hydrophilic polymers can be used to improve the performance of formulations containing a cyclodextrin. Loftsson has disclosed a number of polymers suitable for combined use with a cyclodextrin (underivatized or derivatized) to enhance the performance and/or properties of the cyclodextrin. Suitable polymers are disclosed in Pharmazie (2001), 56(9), 746-747; International Journal of Pharmaceutics (2001), 212(1), 29-40; Cyclodextrin: From Basic Research to Market, International Cyclodextrin Symposium, 10th, Ann Arbor, Mich., United States, May 21-24, 2000 (2000), 10-15 (Wacker Biochem Corp.: Adrian, Mich.); PCT International Publication No. WO 9942111; Pharmazie, 53(11), 733-740 (1998); Pharm. Technol. Eur., 9(5), 26-34 (1997); J. Pharm. Sci. 85(10), 1017-1025 (1996); European Patent Application EP0579435; Proceedings of the International Symposium on Cyclodextrins, 9th, Santiago de Comostela, Spain, May 31-Jun. 3, 1998 (1999), 261-264 (Editor(s): Labandeira, J. J. Torres; Vila-Jato, J. L. Kluwer Academic Publishers, Dordrecht, Neth); S.T.P. Pharma Sciences (1999), 9(3), 237-242; ACS Symposium Series (1999), 737(Polysaccharide Applications), 24-45; Pharmaceutical Research (1998), 15(11), 1696-1701; Drug Development and Industrial Pharmacy (1998), 24(4), 365-370; International Journal of Pharmaceutics (1998), 163(1-2), 115-121; Book of Abstracts, 216th ACS National Meeting, Boston, Aug. 23-27 (1998), CELL-016, American Chemical Society; Journal of Controlled Release, (1997), 44/1 (95-99); Pharm. Res. (1997) 14(11), S203; Investigative Ophthalmology & Visual Science, (1996), 37(6), 1199-1203; Proceedings of the International Symposium on Controlled Release of Bioactive Materials (1996), 23rd, 453-454; Drug Development and Industrial Pharmacy (1996), 22(5), 401-405; Proceedings of the International Symposium on Cyclodextrins, 8th, Budapest, Mar. 31-Apr. 2, (1996), 373-376. (Editor(s): Szejtli, J.; Szente, L. Kluwer: Dordrecht, Neth.); Pharmaceutical Sciences (1996), 2(6), 277-279; European Journal of Pharmaceutical Sciences, (1996) 4(SUPPL.), S144; Third European Congress of Pharmaceutical Sciences Edinburgh, Scotland, UK Sep. 15-17, 1996; Pharmazie, (1996), 51(1), 39-42; Eur. J. Pharm. Sci. (1996), 4(Suppl.), S143; U.S. Pat. Nos. 5,472,954 and 5,324,718; International Journal of Pharmaceutics (Netherlands), (Dec. 29, 1995) 126, 73-78; Abstracts of Papers of the American Chemical Society, (2 Apr. 1995) 209(1), 33-CELL; European Journal of Pharmaceutical Sciences, (1994) 2, 297-301; Pharmaceutical Research (New York), (1994) 11(10), S225; International Journal of Pharmaceutics (Netherlands), (Apr. 11, 1994) 104, 181-184; and International Journal of Pharmaceutics (1994), 110(2), 169-77, the entire disclosures of which are hereby incorporated by reference.

(95) Other suitable polymers are well-known excipients commonly used in the field of pharmaceutical formulations and are included in, for example, Remington's Pharmaceutical Sciences, 18th Edition, Alfonso R. Gennaro (editor), Mack Publishing Company, Easton, Pa., 1990, pp. 291-294; Alfred Martin, James Swarbrick and Arthur Commarata, Physical Pharmacy. Physical Chemical Principles in Pharmaceutical Sciences, 3rd edition (Lea & Febinger, Philadelphia, Pa., 1983, pp. 592-638); A. T. Florence and D. Altwood, (Physicochemical Principles of Pharmacy, 2nd Edition, MacMillan Press, London, 1988, pp. 281-334. The entire disclosures of the references cited herein are hereby incorporated by references. Still other suitable polymers include water-soluble natural polymers, water-soluble semi-synthetic polymers (such as the water-soluble derivatives of cellulose) and water-soluble synthetic polymers. The natural polymers include polysaccharides such as inulin, pectin, algin derivatives (e.g. sodium alginate) and agar, and polypeptides such as casein and gelatin. The semi-synthetic polymers include cellulose derivatives such as methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, their mixed ethers such as hydroxypropyl methylcellulose and other mixed ethers such as hydroxyethyl ethylcellulose and hydroxypropyl ethylcellulose, hydroxypropyl methylcellulose phthalate and carboxymethylcellulose and its salts, especially sodium carboxymethylcellulose. The synthetic polymers include polyoxyethylene derivatives (polyethylene glycols) and polyvinyl derivatives (polyvinyl alcohol, polyvinylpyrrolidone and polystyrene sulfonate) and various copolymers of acrylic acid (e.g. carbomer). Other natural, semi-synthetic and synthetic polymers not named here which meet the criteria of water solubility, pharmaceutical acceptability and pharmacological inactivity are likewise considered to be within the ambit of the present invention.

(96) A solubility-enhancing agent can be added to the dry powder formulation of the invention. A solubility-enhancing agent is a compound, or compounds, that enhance(s) the solubility of active agent in an aqueous or moist environment, such as the lining of respiratory tract. Suitable solubility enhancing agents include one or more organic solvents, detergents, soaps, surfactants and other organic compounds typically used in parenteral formulations to enhance the solubility of a particular agent. Suitable organic solvents include, for example, ethanol, glycerin, poly(ethylene glycols), propylene glycol, poly(propylene glycols), poloxomers, and others known to those of ordinary skill in the art.

(97) As used herein, the term “cryoprotectant” is intended to mean a compound used to protect an active agent from physical or chemical degradation during lyophilization. Such compounds include, by way of example and without limitation, dimethyl sulfoxide, glycerol, trehalose, propylene glycol, polyethylene glycol, and others known to those of ordinary skill in the art.

(98) Plasticizers can also be included in the preparations of the invention to modify the properties and characteristics thereof. As used herein, the term “plasticizer” includes all compounds capable of plasticizing or softening a polymer or binder used in invention. The plasticizer should be able to lower the melting temperature or glass transition temperature (softening point temperature) of the polymer or binder. Plasticizers, such as low molecular weight PEG, generally broaden the average molecular weight of a polymer in which they are included thereby lowering its glass transition temperature or softening point. Plasticizers also generally reduce the viscosity of a polymer. It is possible the plasticizer will impart some particularly advantageous physical properties to the osmotic device of the invention.

(99) Plasticizers useful in the invention can include, by way of example and without limitation, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multi-block polymers, single block polymers, low molecular weight poly(ethylene glycol), citrate ester-type plasticizers, triacetin, propylene glycol and glycerin. Such plasticizers can also include ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol and other poly(ethylene glycol) compounds, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutylsebacate, acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and allyl glycolate. All such plasticizers are commercially available from sources such as Aldrich or Sigma Chemical Co. It is also contemplated and within the scope of the invention, that a combination of plasticizers may be used in the present formulation. The PEG based plasticizers are available commercially or can be made by a variety of, methods, such as disclosed in Poly(ethylene glycol) Chemistry: Biotechnical and Biomedical Applications (J. M. Harris, Ed.; Plenum Press, NY) the disclosure of which is hereby incorporated by reference.

(100) As used herein, the term “flavor” is intended to mean a compound used to impart a pleasant flavor and often odor to a pharmaceutical preparation. Exemplary flavoring agents or flavorants include synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits and so forth and combinations thereof. These may also include cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil. Other useful flavors include vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth. Flavors which have been found to be particularly useful include commercially available orange, grape, cherry and bubble gum flavors and mixtures thereof. The amount of flavoring may depend on a number of factors, including the organoleptic effect desired. Flavors will be present in any amount as desired by those of ordinary skill in the art. Particularly flavors are the grape and cherry flavors and citrus flavors such as orange.

(101) As used herein, the term “sweetener” is intended to mean a compound used to impart sweetness to a preparation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, fructose, high fructose corn syrup, maltodextrin, sucralose, sucrose, other materials known to one of ordinary skill in the art, and combinations thereof.

(102) As used herein, a penetration enhancer is an agent or combination of agents that enhances penetration of an active agent through tissue. Penetration enhancers which can be included in the present formulation include, by way of example and without limitation, calcium chelators such as EDTA, methylated P-cyclodextrin, and polycarboxylic acids; surfactants such as sodium lauryl sulfate, sodium dodecyl sulfate, carnitine, carnitine esters, and tween; bile salts such as sodium taurocholate; fatty acids such as oleic and linoleic acid; and non-surfactants such as AZONE™ and dialkyl sulfoxides; E-flux inhibitors such as AV171 (AyMax, Inc., South San Francisco, Calif.), D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), and peppermint oil; chitosan and chitosan derivatives such as N-methyl chitosan, N-trimethyl chitosan, mono-N-carboxymethyl chitosan, quaternized chitosan derivatives; SNAC (N-(8-[2-hydroxybenzoyl] amino) caprylate) and SNAD (N-[10-(2-hydroxybenzoyl)amino]-decanoate) (Emisphere Technologies, Inc., Tarrytown, N.Y.); N-acylated non-alpha amino acids; HEMISPHERE brand delivery agents; Gelucire 44/14 or Vitamin E TPGS; CARBOPOL® 934P; others known to those of ordinary skill in the art; and combinations thereof.

(103) As used herein, a fragrance is a relatively volatile substance or combination of substances that produces a detectable aroma, odor or scent. Exemplary fragrances include those generally accepted as FD&C.

(104) A “surface tension modifier” is a material or combination of materials capable of modifying the surface properties of a composition according to the invention. A surface tension modifier can include a surfactant, detergent or soap. It can be included in the carrier particles, the active agent-containing particles or both.

(105) A “density modifier” is a material or combination of materials that is included in a composition of the invention to increase or decrease the density thereof. It can be included in the carrier particles, the active agent-containing particles or both. A density modifier can be used to increase or decrease (as needed) the density of the carrier in order enhance dispersion of the active agent from the carrier. Likewise, a density modifier can be used to decrease or increase, respectively, (as needed) the density of the active agent containing particles.

(106) A “volatility modifier” is a material or combination of materials added to modify the volatility of an active agent. In one embodiment, the volatility modifier increases the volatility of the active agent. In another, embodiment, the volatility modifier decreases the volatility of the active agent.

(107) As used herein, the term “stabilizer” is intended to mean a compound used to stabilize the therapeutic agent against physical, chemical, or biochemical process that would reduce the therapeutic activity of the agent. Suitable stabilizers include, by way of example and without limitation, albumin, sialic acid, creatinine, glycine and other amino acids, niacinamide, sodium acetyltryptophonate, zinc oxide, sucrose, glucose, lactose, sorbitol, mannitol, glycerol, polyethylene glycols, sodium caprylate and sodium saccharin and other known to those of ordinary skill in the art.

(108) As used herein, the term “bulking agent” is intended to mean a compound used to add bulk to the lyophilized product and/or assist in the control of the properties of the formulation during lyophilization. Such compounds include, by way of example and without limitation, dextran, trehalose, sucrose, polyvinylpyrrolidone, lactose, inositol, sorbitol, dimethylsulfoxide, glycerol, albumin, calcium lactobionate, and others known to those of ordinary skill in the art.

(109) It should be understood that compounds used in the art of pharmaceutical formulations generally serve a variety of functions or purposes. Thus, if a compound named herein is mentioned only once or is used to define more than one term herein, its purpose or function should not be construed as being limited solely to that named purpose(s) or function(s).

(110) An active agent contained within the present formulation can be present as its pharmaceutically acceptable salt. As used herein, “pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds wherein the active agent is modified by reacting it with an acid or base as needed to form an ionically bound pair. Examples of pharmaceutically acceptable salts include conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Suitable non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobrornic, sulfuric, sulfonic, sulfamic, phosphoric, nitric and others known to those of ordinary skill in the art. The salts prepared from organic acids such as amino acids, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and others known to those of ordinary skill in the art. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent active agent which contains a basic or acidic moiety by conventional chemical methods. Lists of other suitable salts are found in Remington's Pharmaceutical Sciences, 17.sup.th. ed., Mack Publishing Company, Easton, Pa., 1985, the relevant disclosure of which is hereby incorporated by reference.

(111) The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

(112) As used herein, the term “patient” or “subject” are taken to mean warm blooded animals such as mammals, for example, cats, dogs, mice, guinea pigs, horses, bovine cows, sheep and humans.

(113) A formulation of the invention will comprise an active agent present in an effective amount. By the term “effective amount”, is meant the amount or quantity of active agent that is sufficient to elicit the required or desired response, or in other words, the amount that is sufficient to elicit an appreciable biological response when administered to a subject.

(114) In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of formulations according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many embodiments contemplated by the present invention.

Example 1

(115) Exemplary formulations according to the invention were made according to the following general procedures.

Method A

(116) A solid composition comprising cyclodextrin is mixed with a solid composition comprising active agent until homogeneity. The materials are kept in a climate-controlled environment to minimize exposure thereof to excessive moisture. The cyclodextrin-containing and active agent-containing compositions contain less than about 10% wt. water. The process is preferably, but optionally, conducted under an anhydrous or substantially anhydrous (less than 30%, 20% or 10% R.H.) atmosphere. Mixing of the two compositions can also include simultaneous attritting thereof or attrition can be performed as a separate process step. For example, the cyclodextrin-containing composition and the active agent-containing compositions are each attritted separately prior to mixing. Following completion of mixing, the dry powder formulation is optionally partitioned into individual DPI device reservoirs, which are then sealed. The process can be conducted in a vacuum or under positive pressure.

Method B

(117) A particulate carrier comprising cyclodextrin is attritted and optionally screened (sieved) to the desired particle size distribution. A particulate composition comprising active agent is attritted and optionally screened to the desired particle size range. The two resulting materials are mixed in a solids mixer until homogeneity to optimize association of carrier and active agent-containing particles to form a dry powder according to the invention. The dry powder is then charged into plural individual DPI device reservoirs, which are then sealed. The process is conducted under a substantially anhydrous atmosphere and optionally with an inert gas purge.

Method C

(118) Lactose and Captisol® (SAE-CD; SBE7-β-CD) blends were prepared in 1 g batches, each containing 2% w/w micronized drug. A pre-blend was prepared using geometric dilution by mixing the drug and carrier in glass vial with a small spatula. The pre-blend was mixed using a Turbula mixer (Glen Mills, N.J.). The pre-blends were mixed at the maximum rotation speed for 10 minutes. The homogeneity of the blends was examined using random samples (5×20 mg) removed from each blend. The drug content of each sample was determined using UV analysis. The mean drug content, standard deviation and coefficient of variation was determined.

Example 2

(119) Preparation of SAE-CD-Containing Carrier.

Method A

(120) An SAE-CD carrier is derived from a foam as follows. A solution of SAE-CD in water is provided and an inert gas is optionally bubbled through the solution. The solution should have a viscosity thick enough to permit formation of a foam. In general, SAE-CD is present at a concentration of about 10% to 80% wt./wt., or 20% to 75% wt./wt. or 30% to 65% wt./wt. The solution is placed in a freezing apparatus equipped with an agitator. (An exemplary apparatus is the ELECTROFREEZE Model 30TN-CAD-132.) As the foam mixture is agitated, it is gradually frozen in the apparatus to form a frozen foam. The frozen foam is then dehydrated, such as by freeze-drying (lyophilizing), to form a friable porous material, which is attritted to provide a carrier having a suitable particle size range.

Method B

(121) An SAE-CD carrier is prepared by spray agglomeration in an FSD-16 fluid spray drier apparatus as follows. Several solutions of Captisol® at 20.1-49.8% solids were agglomerated in the FSD-16 using a Spraying Systems pressure nozzle at atomization pressures of 1,500-2,000 psig. Process conditions were inlet/outlet temperatures of 210-250/83-100° C., fluid bed inlet temperatures of 80-100° C., and fluid product bed temperatures of 67-87° C. Fines return at the nozzle and at the chamber cone was investigated during separate runs. The drying gas flows are heated electrically.

(122) Feed solutions containing SAE-CD were prepared by adding powdered constituents to the required amount of water under heat and agitation in the feed tank. Final feed formulations has viscosities of about 11-32 cps.

(123) Typical FSD agglomerates were obtained during all runs. Product was analyzed to have median sizes of 175-277 microns, residual volatiles (moisture) of 3.17-5.19%, and bulk densities of 0.34-0.55 g/cc.

Method C

(124) SAE-CD carrier is prepared from foam by the following alternate procedure. An aqueous solution containing SAE-CD (30% wt./wt.) is purged with nitrogen and processed in an ELECTROFREFZF™ 30TN-CAD-132 combination freezer/agitator to provide a frozen foam. The foam is then lyophilized to form a friable porous particulate glass. The particulate material is passed through a 40-mesh screen. The material that is retained by the screen is attritted in a TURBULA™ tumble mixer until all of it passes through the 40-mesh screen. This material had a moisture content of 3.4% and an electrostatic charge of about −6.5 nC/g. It was then equilibrated at 30% R.H. for about 24 hours at ambient temperature to reduce the electrostatic to about −2.5 nC/g.

Method D

(125) SAE-CD carrier is prepared from foam by the following alternate procedure. An aqueous solution containing SAE-CD, and optionally one or more other materials, is processed in a drum dryer (such as from BUFLOVAK LLC, Buffalo, N.Y.) having at least one heated drum. As the solution is poured onto the drum under vacuum, the solution turns into foam from which water evaporates leaving behind a brittle foam (or flake) having a low moisture content (less than 10% wt). The foam is then removed from the surface of the drum by scraping. The dried foam is then attritted as detailed herein to the desired particle size range. The vacuum drum dryer can be a single or double drum dryer. It must have at least one internally heated drum. Depending upon the construction of the dryer used, it can be operated in a batch, semi-continuous or continuous mode. The weight percentage of SAE-CD in the feed solution can be modified as desired to provide the desired solution viscosity, process performance or product qualities. Changing the viscosity of the feed solution can vary the thickness of the foam layer. A water soluble organic solvent, such as alcohol or ether, is optionally added to the feed solution. A water insoluble material is optionally included in the feed solution. Prior to evaporation of the water, the SAE-CD solution is optionally degassed by exposure to vacuum and/or treatment with an inert gas. By “degassed” is meant the concentration of air or gas present in the solution is reduced.

Example 3

(126) Determination of the particle size distribution of the dry powder formulation, the active agent-containing formulation and the SAE-CD-containing carrier.

(127) The particle size distributions of lactose, maltodextrin and Captisol® were determined by laser diffraction (Malvern, 2600c, Malvern, UK), using the dry powder feeder attachment (Malvern, PS 40, Malvern, UK), running at 15 psi. The powder was sampled using 500 detector sweeps for statistical validity. The obscuration values were monitored to ensure adequate data acquisition. The 300 mm focal length detector lens was used, providing a size range of 5.8 to 564 mm. Other laser diffraction particle size measurements were performed by Cydex using a Horiba instrument.

(128) The particle size analysis for an exemplary SAE-CD carrier prepared according to Method A of Example 2 is included in the table below.

(129) TABLE-US-00005 Seive Weight of Sample % of total Cumulative % Size (μm) in Seive (g) sample weight Under Size 250 0.2895 14.06 85.94 180 0.1769 8.592 77.35 106 0.3016 14.65 62.70 90 0.1259 6.115 56.59 75 0.1155 5.610 50.98 45 0.3857 18.73 32.24 0 0.6639 32.24 0.00

Example 4

(130) Determination of the moisture content of the dry powder formulation, the active agent-containing formulation and the SAE-CD-containing carrier. The moisture content was measured via the Karl Fisher or moisture balance methods.

Moisture Balance

(131) A Mettler Toledo LJ16 moisture balance (Mettler Toledo, Columbus Ohio) was used to determine the weight loss of selected powder samples over time as the powder was exposed to infrared heating. The powders were weighed (approximately 1 g for each sample), and the following heating program was performed: 105° C. for 30 minutes. At the end of this program the percentage weight loss was calculated.

Example 5

(132) Determination of the morphology (such as surface rugosity) of the SAE-CD-containing carrier.

(133) Surface morphology of carrier particles was determined visually by scanning electron microscopy (SEM). Samples were adhered onto sample stubs using double-sided tape, palladium/gold-coated and viewed using a ten kilovolt (kV) potential difference.

Example 6

(134) Determination of the flow and micro-flow properties of the SAE-CD-containing carrier. The flowability of the powder systems was measured using both static and dynamic means (Carr's compressibility index, static angle of repose, vibrating spatula—strain gauge experiments, and rotating drum).

Static Angle of Repose

(135) A funnel was placed in a ring stand and set to a height so that the bottom of the funnel was 2 inches above a piece of graph paper. The funnel was filled with powder while plugging the bottom of the funnel. The powder was released and the base and height of the resulting pyramid was measured. The following formula was used to determine the static angle of repose:

(136) $\alpha ={\tan }^{-1}\left(\frac{h}{0.5*b}\right)$
where α is the angle of repose, h is the height of the pyramid and b is the diameter of the base.

Carr's Compressibility Index

(137) Bulk density was determined by pouring the powder into a 10 mL graduated cylinder. Record the volume and the weight of the powder to determine the mass/unit volume (g/mL). To determine the tapped density, a graduated cylinder was dropped through a height of 1 inch every 2 seconds onto a wooden surface until the height of the powder does not change. The volume and the weight of the powders was used to determine the mass/unit volume (g/mL). The data were represented in terms of Carr's compressibility index:

Vibrating Spatula

(138) A vibrating spatula method was used to determine the dynamic flow characteristics of the powders during higher energy flow conditions than those during rotating drum experiments.

(139) The vibrating spatula apparatus is a powder flow measurement device, constructed to acquire mass versus time profiles for powder flowing. Powder flowed from the vibrating spatula (Mettler LV3, MettlerToledo, Columbus Ohio) onto a powder collection surface, causing deflection and a change in resistance in semiconductor strain gauges (Micron Instruments, Simi Valley Calif.) mounted above and below the collection surface. After amplification (BP-3629, Burr Brown, Tucson Ariz.) of the differential voltage, the mass data was sampled by a PC data acquisition module (DI-170, Dataq Instruments, Akron Ohio). The data collection rate was user selectable in the range of 1-400 Hz. The filter control and the subsequent analysis of the stride length were controlled by a graphical user interface (GUI) written in the Matlab (The Mathworks, Natick Mass.) environment (higuchigui.m).

(140) The temporal fractal dimension routine used a modification to Higuchi's method of determining the fractal dimension of a time series. The routine stepped iteratively through the flow profile calculating the length of the curve using stride lengths ranging from one data point at a time up to half the number of data points in the curve. The fractal dimension was determined by a linear least-squares regression method from the slope of the linear part of the Richardson plot, where the logarithm of the curve length was graphed as a function of the logarithm of stride length. The fractal dimension was calculated using three replicates of powder flow series for each powder sample. The fractal dimension was taken as the average of three different fractal dimension determinations. The three determinations were taken using the beginning and end points of flow, the beginning to middle and middle to end. This approach was used in order to reduce the effect of any particularly irregular portions of the data series.

Rotating Drum

(141) A Micromeritics rotating drum instrument was used to analyze the powder flow characteristics during dynamic conditions. A 30 ml sample (sample size is by volume) of Captisol® (Lot #02047) was placed in the drum holder and the drum rotation speed was 2 revolutions per minute. Quantitative analysis was not performed as flow patterns could not be fitted to the algorithm.

Example 7

(142) Determination of the electrostatic charge of the SAE-CD-containing carrier and the active agent-containing composition.

(143) Electrostatic charge measurements were performed using a Faraday Cage apparatus that determines the potential difference changes as a function of time during powder flow onto a conducting surface. Samples were weighed and transferred from original containers to wax coated weighing papers. These were mounted to a vibrating spatula (set at maximum vibration level). The angle of the spatula was set at a constant angle (30 degrees). Powder was dispensed to the Faraday cage that was connected to a electrometer. Data collection was performed using Windaq interface and a PC computer sampling at 240 Hz. The area under the electrostatic dissipation curve was determined (Voltage x time) and charge (nC/g) was calculated from the known resistance of the setup.

Example 8

(144) Determination of the dispersion (disassociation) of the SAE-CD-containing carrier from the active agent-containing composition. The dispersion of drug from the model carrier systems was evaluated using several systems (standardized entrainment tube and inhaler devices) with either a twin stage liquid impinger or an eight stage non-viable cascade impactor.

Twin-Stage Liquid Impinger Studies

(145) The in vitro aerosol dispersion of albuterol blends in lactose and Captisol® were determined using a liquid impinger device. An airflow rate of 60 L/min, measured at the mouthpiece prior to impaction, was employed for 5 seconds. The inhaler devices used for dispersion studies were the Rotahaler (GlaxoSmithKline, RTP) and Inhalator (Boehinger Ingelheim, Germany). The powders were loaded into hard gelatin capsules in 20 mg doses.

Cascade Impaction

(146) The in vitro aerosol dispersion efficiency was determined using an eight stage, non-viable cascade impactor (Graseby-Andersen, GA). An airflow rate of 60 L/min, measured at the mouthpiece prior to impaction, was employed for 10 seconds following actuation of the inhaler device. The theoretical aerodynamic cut-off diameters for each stage at 60 L/min are displayed in the table below.

(147) TABLE-US-00006 Cascade Impactor Theoretical Aerodynamic Stage Cut-off Diameter (μm) −1 8.6 −0 6.2 1 4.0 2 3.2 3 2.3 4 1.4 5 0.8 6 0.5

(148) Each impaction plate was pre-coated with a 1% w/v solution of silicon fluid in hexane and allowed to dry prior to impaction. The preseparator contained 10 mL of distilled water. Following impaction, the inhaler, throat and preseparator, each impaction plate and stages were rinsed with distilled water. The rinsing liquid was collected and the drug content was determined (n=3). The temperature and relative humidity of the surrounding environment was measured prior to each impaction. The inhaler devices used for dispersion studies were the Rotahaler (Glaxo Wellcome, RTP, NC) and Inhalator (Boehinger Ingelheim, Germany). Formulations were examine using 2% w/w drug in carrier blends. The powders were loaded into hard gelatin capsules (size 3, Eli Lily and Co., IN) in 20 mg powder doses.

(149) The recovered dose (RD) was defined as the total mass of drug particles collected. The emitted dose (ED) was defined as the mass of particles delivered from the inhaler expressed as a percentage of the RD. The fine particle mass (FPM) was defined as the mass of dispersed particles smaller than 4 μm aerodynamic diameter (particles deposited in stage 2 and lower). The fine particle fraction (FPF) was defined as the mass of dispersed particles smaller than 4 μm aerodynamic diameter (particles deposited in stage 2 and lower), expressed as a percentage of the RD. The mass median aerodynamic diameter (MMAD) was calculated as the 50.sup.th percentile of the aerodynamic particle size distribution by mass. The geometric standard deviation (GSD) was calculated as the ratio of the particle size at the 84.sup.th percentile to the 50.sup.th percentile, assuming a lognormal distribution. The MMAD and GSD were determined from the linear region of the plot (between the 16.sup.th and 84.sup.th percentile) of the cumulative mass distribution as a function of the logarithm of aerodynamic diameter using an Excel template. Linear regression was performed using a least-squares regression method.

Example 9

(150) Materials used for comparative evaluations: Lactose monohydrate was used in various forms: Bulk powder as received, sieved fractions 45-75 μm, 75-125 μm. Lactose monohydrate (Mallinckrodt NF, non-spray dried; Lot number 6270KVMK) was used. A size fraction of 45 to 75 μm was prepared using a sieve shaker (Vibratory 3-Inch Sieve Shaker, Model SS-5, Gilson Company Inc., Worthington, Ohio). A powder loading of 30 g was placed on top of the sieves and tap mode was employed for 2 hours. Multiple sieving runs were combined and mixed.

(151) A single maltodextrin (Maltrin QD 500M, Grain Processing Corporation, Lot number M9424790) was employed.

Example 10

(152) Evaluation of various blends of SAE-CD and active agent with DPI devices.

(153) Dispersion studies were performed from three different dispersion devices: Rotahalor, Inhalator, and controlled flow/pressure drop standardized entrainment tubes. The inhaler devices used for dispersion studies were the Rotahaler (Glaxo Wellcome, RTP) and the Inhalator (Boehringer-Ingelheim). The powders were loaded into hard gelatin capsules in 20 mg doses. The devices used were examples of a low resistance inhaler (Rotahaler) and a high resistance inhaler (Inhalator) as shown in the table below.

(154) TABLE-US-00007 TABLE Comparison of the pressure drop measured in common DPI devices Calculated Pressure Drop (g/cm.sup.3) Device 28.3 L/min 60 L/min Rotahaler 1.04 4.67 Inhalator 12.12 54.46 Entrainment Tube 3.38 15.21

Example 11

(155) Differential scanning calorimetry was performed using a Perkin Elmer DSC 6. Samples tested were from a Captisol® spray dried batch (Lot #CY 3A 02047). The samples were hermitically sealed in aluminum pans (sample weight between 5-10 mg). The heating program was as follows: 1. Hold for 1.0 min at 80.00 deg centigrade. 2. Heat from 80 deg C. to 300 deg C. at 30 deg C./min 3. Return to load temperature

(156) The peak temperature, peak area, and enthalpy were calculated using the PE Pyris software.

Example 12

(157) Surface area analysis was performed using a multi-point BET on a Micromeritics (Norcross, Ga.) surface analyzer. The purge gas used was: 70/30 nitrogen/helium mixture or Krypton. Samples were degassed for at least 30 minutes.

Example 13

(158) Bulk density was determined by pouring the powder into a 10 mL graduated cylinder. Record the volume and the weight of the powder to determine the mass/unit volume (g/mL). To determine the tapped density, a graduated cylinder was dropped through a height of 1 inch every 2 seconds onto a wooden surface until the height of the powder does not change. The volume and the weight of the powders was used to determine the mass/unit volume (g/mL). The data were represented in terms of Carr's compressibility index:

(159) $\%\mathrm{compressibility}=\left(\frac{\mathrm{Tap}\mathrm{Density}-\mathrm{Bulk}\mathrm{Density}}{\mathrm{Tap}\mathrm{Density}}\right)\times 100\%$

Example 14

(160) A spectrofluorometric or a UV/vis assay was employed for determination of albuterol sulfate. Standard and sample solutions were prepared using distilled water as the solvent. The fluorescence absorbance (Luminescense Spectrometer, Perkin Elmer, Norwalk, Conn.) was measured at an excitation wavelength (λ.sub.ex) of 230 nm and emission wavelength (λ.sub.em) of 310 nm. A slit width of 2.5 nm was employed for both excitation and emission. A quartz silica cuvette (1 cm path length) was employed. The UV absorbance was measured at an absorbance wavelength of 230 nm. A linear calibration curve was obtained (r.sup.2>0.99).

Example 15

(161) A dry powder formulation suitable for administration with a DPI device comprises one or more active agents, SAE-CD carrier made according to Example 2 (Method A), and optionally one or more excipients selected from the group consisting of an antioxidant, acidifying agent, alkalizing agent, buffering agent, solubility-enhancing agent, penetration enhancer, electrolyte, fragrance, glucose, glidant, stabilizer, bulking agent, cryoprotectant, plasticizer, flavors, sweeteners, surface tension modifier, density modifier, volatility modifier, or a combination thereof. The following parameters are noted. 1—The one or more excipients are included in the carrier composition or in the active agent composition. 2—The SAE-CD carrier comprises an SAE-CD compound of the Formula 1 or a mixture thereof. 3—The SAE-CD carrier is derived from an SAE-CD foam. 4—The SAE-CD carrier has a median particle diameter in the range of 37 to 125 microns, 5—The active agent composition has a median particle diameter of less than 37 microns or in the range of about 10 microns or less. 6—The carrier has a moisture content of less than 10% wt. 7—The carrier has an electrostatic charge of −1.4 to −3.7 nC/g. 8—The carrier has a substantially smooth surface; although, it can comprise some asperities. 9—The carrier particles have been passed through a 420 micron sieve.

Example 16

(162) A dry powder formulation suitable for administration with a DPI device comprises one or more active agents, SAE-CD carrier comprising SAE-CD selected from the group consisting of SME-β-CD, SEE-β-CD, SPE-β-CD, SBE-β-CD, SPtE-β-CD, SHE-β-CD, SME-α-CD, SEE-α-CD, SPE-α-CD, SBE-α-CD, SPtE-α-CD, SHE-α-CD, SME-γ-CD, SEE-γ-CD, SPE-γ-CD, SBE-γ-CD, SPtE-γ-CD, and SHE-γ-CD and optionally one or more excipients selected from the group consisting of an antioxidant, acidifying agent, alkalizing agent, buffering agent, solubility-enhancing agent, penetration enhancer, electrolyte, fragrance, glucose, glidant, stabilizer, bulking agent, cryoprotectant, plasticizer, flavors, sweeteners, surface tension modifier, density modifier, volatility modifier, or a combination thereof. The SAE-CD carrier comprises about 50%-99.9% wt. of the formulation, and it has a median particle size of less than 420 microns. The active agent-containing particles have a median particle diameter between about 0.1 to 10 microns. The carrier has a span of about 1.5 to 2.9, and the carrier has been made by forming a foam, dehydrating the foam to form a solid, and attritting the solid to form the particulate carrier. The SAE-CD used in the carrier has an average DS in the range of about 1 to 12.

Example 17

(163) A dry powder formulation suitable for administration with a DPI device comprises: a first particulate powdered active agent-containing composition comprising one or more active agents; and a second particulate powdered carrier composition comprising SAE-CD and optionally one or more excipients, wherein the first and second particulate compositions are homogeneously mixed. The carrier composition comprises about 50%-99.9% wt. of the formulation, and it has a median particle size of less than 420 microns. The active agent-containing composition has a median particle diameter between about 0.1 to 10 microns. The carrier has a span of about 1.5 to 2.9. The first particulate composition has an electrostatic charge more negative than about −2 nC/g, and the second particulate composition has an electrostatic charge in the range of about 0 to −1.5

Example 18

(164) A dry powder formulation suitable for administration with a DPI device is made according to Example 17, with the following exception. The first particulate composition has an electrostatic charge in the range of about −2 to −0.5 nC/g, and the second particulate composition has an electrostatic charge in the range of about −0.5 to −2.

Example 19

(165) A dry powder formulation suitable for administration with a DPI device is made according to Example 17, with the following exception. The first particulate composition has an electrostatic charge in the range of about 0.5 to −0.5 nC/g, and the second particulate composition has an electrostatic charge in the range of about −2 to 2.

Example 20

(166) A dry powder particulate carrier composition, which comprises an SAE-CD of the Formula 1 or Formula 2 and optionally one or more excipients, is made according to the invention to possess the following properties: a) a median particle diameter of less than 420 microns, and/or a median particle diameter in the range of about 37 to 125 or about 10 to 300 microns; b) a span of about 1.5 to 2.9; c) an electrostatic charge of −1.4 to −3.7 nC/g or 2 to −3.7 nC/g; d) a Carr's Index of about 10% to 40% compressibility; e) a static angle of repose from about 28 to 45 degrees; f) a fractal dimension analysis of about 1.00 to 1.31; and g) a moisture content of 10% wt. or less.

(167) The following terms are defined as detailed below.

(168) TABLE-US-00008 TERM DEFINITION Adhesion, Adhesive Adhesion and adhesive forces refer to interactions between forces particles of different materials. Agglomerate A collection of particles that are fused together and act as a larger particle. Aggregate Collection of particles that are gathered together but are not chemically bound or fused together. Angle of repose Angle between powder surface and horizontal plane measured after heaping BET Brunauer, Emmett, and Teller derived expression for the Type II adsorption isotherm that is used to calculate surface area materials Bulk density Mass of bulk powder divided by the bulk volume Carr's Index Measure of the bulk flow properties of powders. See description and equation on pages 39-40 CD Cyclodextrin CFC Chlorofluorocarbon propellant Cohesion, Cohesive Cohesion refers to interactions between particles of the same forces material Deaggregation The process by which aggregates (see aggregate) are disrupted into smaller particles or collection of particles Dispersion Term used to describe the generation of fine particles that are available for inhalation DPI Dry powder inhaler DSC Differential scanning calorimetry Eight stage cascade Aerodynamic particle sizing instrument impactor Emitted dose The mass of drug that is emitted from the device, i.e. recovered dose less the mass recovered from the device Entrainment See fluidization Fine particle mass See fine particle dose, FPD. Fluidization Refers to a fluid-solid interaction where solid particles are lifted and agitated by a stream of fluid (typically gas). At lower end of fluidization, solid particles behave like a boiling liquid. At the other extreme, particles are fully suspended in the fluid stream and are carried along with it (entrainment). FPD Fine particle dose, the mass of drug recovered from aerodynamic particle sizing methods that have particle sizes less than 6.4 μm (liquid impinger studies) or 5 μm (cascade impaction studies) FPF Fine particle fraction, fraction of the emitted dose that is below 6.4 μm (liquid impinger studies) or 5 μm (cascade impaction studies) FPM Fine particle mass Fractal dimension Relates to a property of an object to the scale of measurement. Microflow is quantified by fractal dimension. GSD Geometric standard deviation, used to describe the distribution width when a log-normal distribution is fitted to particle size data. It is a dimensionless quantity with values greater than 1. HFA Hydrofluoroalkane propellant Inhaler resistance The air flow resistance of a dry powder inhaler. Related to the smallest orifice size within the geometry of the inhaler and is also proportional to shear forces and turbulence. KF Karl Fisher Analysis LD Laser diffraction MDI Metered dose inhaler, or more correctly, propellant driven metered dose inhaler Microflow Powder flow on scales smaller than that of bulk flow. MMAD Mass median aerodynamic diameter is the median of the distribution that represents aerodynamic diameters on the basis of mass. monodisperse In terms of particle size, refers to a population of particles that have a uniform particle size nC nanoCoulomb, measure of charge ND Not determined pMDI pressurized metered dose inhaler Poly-dispersity In terms of particle size, refers to a population of particles that have wide range of particle sizes Recovered dose (RD) The dose mass of drug recovered from aerodynamic particle sizing experiment Respirable Typically an indication of the particles in the “respirable range” or that are in an aerodynamic particle size range that potentially will result in deposition in the peripheral regions of the lung (1-5 μm). Note: In vitro aerodynamic particle size results do not necessarily infer that particles will or will not be respirable. Rugosity A qualitative description of the surface roughness of a particle or material surface. SA Spray aggregated (when referring to a type of SAE-CD powder), or Surface area SD Standard deviation SEM Scanning electron microscope spheronization The process by which materials are made spherical Tapped density Mass of bulk powder divided by the volume of packed powder (following compaction of the powder by vertical tapping) Ternary blends/ Used in investigative studies for DPI formulations where the components interactions between drug and carrier particles is modified (usually reduced) by the addition of a third component (typically fine particle size) triboelectrication The generation of electrical charge by rubbing and frictional forces during motion of materials Turbulent flow When fluid flows slowly and smoothly, the flow is called laminar. At fast velocities, the inertia of the fluid overcomes fluid frictional forces and turbulent flow results. When a fluid is flowing this way it flows in eddies and whorls (vortices). When a fluid flows turbulently, there is much more drag than when the flow is laminar. Twin stage liquid Aerodynamic particle sizing instrument impinger

(169) The above is a detailed description of particular embodiments of the invention. It will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without departing from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims. All of the embodiments disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure.