WO2010132827A1

WO2010132827A1 - Low-molecular dextran for powder inhalations

Info

Publication number: WO2010132827A1
Application number: PCT/US2010/034992
Authority: WO
Inventors: David T. Vodak; Daniel E. Dobry; David K. Lyon; Dwayne T. Friesen
Original assignee: Bend Research, Inc.
Priority date: 2009-05-15
Filing date: 2010-05-14
Publication date: 2010-11-18

Abstract

Pharmaceutical compositions suitable for inhalation are disclosed. The compositions comprise a dry powder comprising particles having a mean geometric diameter of 0.5 to 100 μm. The particles comprise from 0.01 to 99 wt % of an active and from 1 to 99.99 wt% of a dextran polymer having a molecular weight in the range of 1,000 to 30,000 daltons. The particles may be prepared by dissolving the active and the dextran polymer in a solvent, and spray drying the solution to form the particles.

Description

LOW-MOLECULAR DEXTRAN FOR POWDER INHALATIONS

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of and priority to U.S. Provisional Patent Application No. 61/178,703 filed on May 15, 2009, which is incorporated herein in its entirety by reference.

TECHNICAL FIELD

Pharmaceutical dry powder compositions suitable for inhalation are disclosed. The compositions comprise an active pharmaceutical ingredient and dextran.

BACKGROUND

To deliver an active (e.g., a drug or therapeutic agent) in a dry powder form via inhalation, the active is typically in the form of small particles, typically with an average aerodynamic particle size on the order of 1 to 5 microns. However, it is difficult to mill an active such that a large fraction of the particles are in this size range. In addition, when an active is milled such that its average size is in this range, the active often aggregates into larger particles and cannot be efficiently inhaled. To overcome these and related problems, conventional dry powder pulmonary formulations have consisted of a blend of micronized active crystals and larger crystals of lactose.

A problem with the conventional lactose formulation is that the micronized crystals of the active do not reproducibly aerosolize or release from the lactose crystals, which results in a large variability in the amount of active delivered to the lung. The formulations often have low efficiency with less than 20% of the active dose delivered to the lung. The formulations also have poor physical stability and, while better than the active alone, nevertheless are still prone to aggregation into larger particles, which further reduces dosing efficiency. Additionally, the conventional lactose formulations limit the type of active that can be delivered. The active should have a particular set of physical properties. The active is to be crystalline and have low hygroscopicity. It should reversibly adhere to lactose and cannot overly adhere to itself. It should be micronizable, and should not react with the lactose. These necessary properties limit the types of actives that can be formulated. It is also difficult to administer two or more different actives in such formulations. Each active will have different particle size distributions resulting from the milling process, different adherence to the lactose, and different adherence to itself. The resulting powders often lack content uniformity and result in different degrees of deposition of the different actives to different locations in the lung. What is therefore desired is a dry powder having one or more actives suitable for inhalation that is efficiently and reproducibly dosed, and that may be used with a wide variety of actives having a range of physical properties.

SUMMARY Pharmaceutical compositions suitable for inhalation via the mouth or nose are disclosed. The compositions may comprise a dry powder comprising particles having a mean geometric diameter of 0.5 to 100 μm. The particles may comprise from 0.01 to 99 wt% of an active and from 1 to 99.99 wt% of a dextran polymer. The dextran polymer has an average molecular weight in the range of 1,000 to 30,000 daltons. In general, the active is dispersed in the polymer such that the polymer's beneficial properties and particle size define the inhalation properties of the composition.

Certain embodiments of the dry powders comprising particles of an active and a dextran polymer overcome problems of the prior art by providing particles that are of the appropriate size to be inhaled via the mouth or nose, but which do not rely on milled crystalline active(s) and the concomitant disadvantages of variable particle size and particle aggregation. The particles comprising an active and a dextran polymer can be formed by any suitable method known in the art, including milling, extrusion, or the use of solvent followed by precipitation and solvent removal, or solvent removal alone. Various precipitation or emulsion processes can also be used to form suspensions of the appropriate size particles, followed by drying to form a dry powder. In one embodiment the dry powders may be formed by spray drying. Spray-dry technology of the presently disclosed compositions enables the formation of particles comprising both active and polymer. The particles of the disclosed compositions are an appropriate size to be inhaled, which in turn leads to a high respirable dose with reduced variability.

In some embodiments, the active may occur in the particles as separate crystalline or amorphous domains, such that the particles contain regions of dextran polymer and regions of active. In other embodiments, the active may be dispersed substantially throughout the particle as a molecular dispersion within the polymer. Formation of a molecular dispersion is generally preferred for small-molecule actives as it results in particles that have the beneficial properties of the polymer rather than the properties of the active. Embodiments of the disclosed pharmaceutical compositions allow formation of particles that have beneficial properties which may include one or more of the following (but not limited to): low toxicity, a low propensity to aggregate, good physical and chemical stability, and optimal dissolution properties at the desired delivery site. The dextran polymer may be used to formulate a wide variety of particles comprising different actives. In addition, the particles also easily accommodate more than one active.

In one embodiment, the dry powders comprise particles of an active and a dextran polymer. In another embodiment, the particles are solid dispersions of amorphous active molecularly dispersed in the dextran polymer.

In some embodiments, the active and the dextran polymer constitute at least 5 wt% of the particles, at least 10 wt% of the particles, at least 25 wt% of the particles, at least 50 wt% of the particles, or at least 75 wt% of the particles. In some embodiments, the active and dextran polymer constitute 5-95 wt%, 10-75 wt%, 25-50 wt%, or 50-75 wt% of the particles. In another embodiment, the particles consist essentially of the active and the dextran polymer. In yet another embodiment, the particles have the following composition: from 0.1 to 80 wt% active, and from 20 to 99.9 wt% dextran polymer. In one embodiment, the dry powder consists essentially of the particles. The inventors unexpectedly discovered that the average molecular weight of the dextran was a result-effective variable. The molecular weight affects the dextran's physical properties and also affects its toxico logical properties when inhaled. In some embodiments, the dextran polymer has a molecular weight from 1,000 to 30,000 daltons. In other embodiments, the dextran polymer has a molecular weight from 5,000 to 20,000 daltons, 5,000 to 15,000 daltons, 5,000 to 10,000 daltons, 8,000 to 12,000 daltons, 9,000 to 11,000, or 9,500 to 10,500 daltons.

The foregoing and other objectives, features, and advantages of the invention will be more readily understood upon consideration of the following detailed description of the invention.

DETAILED DESCRIPTION

Dry powder compositions that are suitable for inhalation are disclosed. The dry powder compositions comprise particles, with particles containing an active and a dextran polymer. Dextran polymers, actives, particles suitable for inhalation, and methods for making such particles are described in detail below.

I. Terms and Abbreviations

The following explanations of terms and abbreviations are provided to better describe the present disclosure and to guide those of ordinary skill in the art in the practice of the present disclosure. As used in this application and in the claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Additionally, the terms "includes" or "having" mean "comprises." The term "or" refers to a single element of stated alternative elements or a combination of two or more elements, unless the context clearly indicates otherwise.

Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, percentages, and so forth, as used in the specification or claims are to be understood as being modified by the term "about." Unless otherwise indicated, non-numerical properties such as amorphous, crystalline, homogeneous, and so forth as used in the specification or claims are to be understood as being modified by the term "substantially," meaning to a great extent or degree. Accordingly, unless otherwise indicated, implicitly or explicitly, the numerical parameters and/or non-numerical properties set forth are approximations that may depend on the desired properties sought, limits of detection under standard test conditions/methods, limitations of the processing method, and/or the nature of the parameter or property. When directly and explicitly distinguishing embodiments from discussed prior art, the embodiment numbers are not approximates unless the word "about" is recited.

Unless explained otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and not intended to be limiting. Other features of the disclosure are apparent from the following detailed description and the claims.

An active, as used herein, is a drug, medicament, pharmaceutical, therapeutic agent, nutraceutical, or other compound that may be administered to the respiratory tract. The active may be a "small molecule," generally having a molecular weight of 2000 daltons or less. The active may also be a "biological active." Biological actives include proteins, antibodies, antibody fragments, peptides, oligonucleotides, vaccines, and various derivatives of such materials. Aerodynamic particle diameter or aerodynamic particle size is the diameter of a unit-density sphere having the same terminal settling velocity as the particle in question. In other words, it is an expression of a particle's aerodynamic behavior as if it were a perfect sphere with a density of 1 g/cm³ and a diameter equal to its aerodynamic diameter. Aerodynamic diameter is affected by a particle's density, geometric diameter, and shape. Drug particles for pulmonary delivery are typically characterized by aerodynamic diameter rather than geometric diameter. Aerodynamic diameter can be used to predict where a particle will settle in the respiratory tract. The velocity at which the drug settles is proportional to the aerodynamic diameter.

An aerosol is a suspension of liquid droplets or very fine solid particles in a gaseous medium. A common example of an aerosol is fog, in which fine particles of water are dispersed in air.

Amorphous means non-crystalline, having no molecular lattice structure. All liquids are amorphous. Some solids or semisolids, such as glasses, rubber, and some polymers, are also amorphous. Amorphous solids and semisolids lack a definite crystal structure and a well-defined melting point.

Dextran and dextran polymer mean a polymer of α-D-l,6-glucose-linked glucan. The terms dextran and dextran polymer, as used herein, are interchangeable. Side-chains may be linked to the backbone of the dextran polymer, with the degree of branching being approximately 5%, and the branches typically being 1-2 glucose units long. The term dextran polymer does not exclude derivatized dextran polymers (i.e., dextran polymers in which at least some groups of atoms, such as - OH, are replaced with other groups of atoms) unless otherwise noted in the disclosure thereof or clearly and unambiguously necessary for the disclosed operation thereof. A fragment of the dextran structure is illustrated below:

A dispersion is a system in which particles are dispersed in a continuous phase of a different composition. A solid dispersion is a system in which at least one solid component is dispersed in another solid component. A molecular dispersion is a system in which at least one component is homogeneously or substantially homogeneously dispersed on a molecular level throughout another component. Emitted dose refers to the dose delivered from an inhalation device.

An excipient is a physiologically inert substance that is used as an additive in a pharmaceutical composition. As used herein, an excipient may be incorporated within the particle, or it may be mixed with particles as a component of the dry powder. The excipient can be used to dilute the active, replace some of the dextran in the particles, and/or modify the properties of the composition. For instance, an excipient may improve the rate of particle dissolution in the lung fluid, reduce particle agglomeration, and/or improve reproducibility of the emitted dose. Examples of excipients include but are not limited to polyvinylpyrrolidone (PVP), tocopheryl polyethylene glycol 1000 succinate (also known as vitamin E TPGS, or TPGS), dipalmitoyl phosphatidyl choline (DPPC), trehalose, sodium bicarbonate, glycine, sodium citrate, and lactose.

Fine particle fraction (FPF) is the fraction of particles that would deposit in the deep lungs, or alveoli, typically particles that have an aerodynamic diameter of less than 4.6 μm. FPF can be determined with a "cascade impactor" device. The active dose deposited in the lung can be calculated by multiplying the emitted dose by the fine particle fraction: deposited dose = emitted dose x FPF.

Geometric diameter is the measured diameter of a particle. Geometric "diameter" can be determined, for example, by laser diffraction using a Mastersizer particle analyzer (available from Malvern Instruments Ltd, Malvern, Worcestershire, United Kingdom).

Geometric size distribution span is a measure of the size variability of the particles. The span is defined by the equation:

D_nn - n,

Span = - ^•^90 ^O

D 5.0 where D90, D50, and D₁O are the diameters corresponding to the diameter of particles that make up 90%, 50%, and 10%, respectively, of the total volume containing particles of equal or smaller diameter.

The glass transition temperature, T_g, is the temperature at which an amorphous solid, such as glass or a polymer, becomes brittle on cooling, or soft on heating. T_g can be determined, for example, by differential scanning calorimetry (DSC). DSC measures the difference in the amount of heat required to raise the temperature of a sample and a reference as a function of temperature. During a phase transition, such as a change from an amorphous state to a crystalline state, the amount of heat required changes. A single glass transition temperature indicates that the solid is homogeneous.

Histiocytes are derived from stem cells in the bone marrow. The derived cells travel through the bloodstream to various organs where they differentiate into histiocytes. They are phagocytes, a type of immune cell that ingest foreign substances, such as microorganisms and particles, in an effort to protect the body from infection.

Inflammation is the response of vascular tissue to harmful stimuli, such as pathogens, damaged cells, and irritants, including foreign bodies. Acute inflammation is the initial response and involves movement of plasma and leukocytes (e.g., histiocytes and/or neutrophils) from the blood to the injured tissue. The term "inhalation" refers to delivery to a subject, such as a patient, through the subject's mouth or nose. A dry powder suitable for inhalation may be delivered to the "upper airways." The term "upper airways" refers to nasal, oral, pharyngeal, and laryngeal passages, including the nose, mouth, nasopharynx, oropharynx, and larynx. Alternatively, a dry powder suitable for inhalation may be delivered to the "lower airways." The term "lower airways" refers to the trachea, bronchi, bronchioles, alveolar ducts, alveolar sacs, and alveoli. In some instances, a dry powder suitable for inhalation may be delivered to both the upper airways and lower airways.

Mass median aerodynamic diameter (MMAD) is the median aerodynamic diameter based on particle mass. In a sample of particles, 50% of the particles by weight will have an aerodynamic diameter greater than the MMAD, and 50% of the particles by weigh will have an aerodynamic diameter smaller than the MMAD.

Molecular weight is the sum of the atomic weights of the atoms in a molecule. As used herein with respect to polymers, the terms molecular weight, average molecular weight, and mean molecular weight refer to the number- average molecular weight, which corresponds to the arithmetic mean of the molecular weights of individual macromolecules. The number-average molecular weight is determined by chromatographic methods well known in the art.

A monosaccharide is the basic unit of a polysaccharide. Monosaccharides are simple sugars with the basic chemical formula C_x(H₂O)_x, where x and y are integers. Typically, y = x or y = x-1. Many monosaccharides are pentoses (x = 5) or hexoses (x = 6). Most monosaccharides exist primarily as cyclic structures. Examples of monosaccharides include arabinose, fructose, galactose, glucose, ribose, and xylose, among others.

Neutrophils are a type of white blood cells and are the first immune cells to arrive at a site of infection. Neutrophils are phagocytes and are responsible for much of the body's immune response. Neutrophils also release a number of compounds, including proteins and superoxide (O₂ ^"), resulting in acute inflammation.

The term particle is commonly understood to mean a very small or tiny mass of a material. Particles suitable for inhalation typically have a mass median aerodynamic diameter in the range of 0.5 to 10 μm.

Pharmaceutically acceptable refers to a substance that can be taken into the lungs with no significant adverse toxicological effects on the lungs.

Polar refers to a molecule in which the electrons are not symmetrically arranged, i.e., there is a permanent separation of positive and negative electrical charges or separation of partial positive and partial negative charges.

A polymer is a large molecule of repeating structural units (e.g., monomers) formed via a chemical reaction, i.e., polymerization.

A polysaccharide is a polymer of monosaccharides linked together by glycosidic bonds. Common examples include hemicellulose, cellulose, starch, and dextran.

A powder is a composition comprising dispersed solid particles that are relatively free flowing and capable of being dispersed in an inhalation device and subsequently inhaled by a subject so that the particles reach the lungs. A dry powder means that the powder composition has a moisture content such that the particles are readily dispersible in an inhalation device to form an aerosol. A solid solution is formed when at least one solid component is molecularly dispersed within another solid component, resulting in a homogeneous solid material. A solid solution may be formed, for example, by completely dissolving two solid components in a liquid solvent and then removing the liquid solvent to produce the solid solution.

Soluble means capable of becoming molecularly or ionically dispersed in a solvent to form a solution.

A solution is a homogeneous mixture composed of two or more substances. A solute (minor component) is dissolved in a solvent (major component). "Suitable for inhalation" refers to a composition that has particles capable of being dispersed in an inhalation device and would not produce significant amounts of one or more of the following undesirable side effects when administered via inhalation to a subject: cough, emesis, toxic build-up in the lung, inflammation, reduced lung function. One measure of lung function is the FEV₁ (forced expiratory volume in one second) test, which measures the volume exhaled during the first second of a forced expiratory maneuver started from the level of total lung capacity. The composition is suitable for use in an inhalation device.

A suspension is a heterogeneous mixture in which particles (with a diameter greater than 1 μm) are dispersed substantially uniformly, via mechanical agitation, in a liquid or gaseous medium. Without agitation, the particles tend to separate from the liquid or gaseous medium.

A therapeutically effective dose is the amount of an active agent present in the composition that is needed to provide the desired level of the active agent to a treated subject to give the anticipated or desired physiological response.

II. Dextran

Dextran is an α-D-l,6-glucose-lmked glucan polymer, as defined above. In one embodiment, the dextran polymer has a molecular weight of 1,000 to 30,000 daltons. In other embodiments, the dextran polymer has a molecular weight of 5,000 to 20,000 daltons, 5,000 to 15,000 daltons, 5,000 to 10,000 daltons, 8,000 to 12,000 daltons, 9,000 to 11,000, or 9,500 to 10,500 daltons. The molecular weight of dextran can be determined, for example, by gel permeation chromatography with evaporative light scattering detection.

Dextran polymers with a molecular weight of 1,000 to 30,000 daltons are soluble in mixtures of water and some polar organic solvents. Suitable polar organic solvents include, for example, acetone, methanol, ethanol, methyl acetate, ethyl acetate, tetrahydrofuran, dichloromethane, and mixtures thereof.

In one embodiment, the dextran polymer is well tolerated by the subject when delivered to the respiratory tract as particles comprising an active. A composition is considered to be well tolerated by the subject when the composition does not produce undesirable side effects, such as cough, emesis, toxic build-up in the respiratory tract, inflammation, reduced lung function. In one embodiment, it is believed that the polymer is better tolerated when it does not significantly increase the viscosity of the lung fluid that is present in vivo on the surface of the lung. The effect on viscosity will be determined by the molecular weight of the dextran and by the total amount of dextran administered. Generally, the lower the molecular weight of the dextran polymer and the lower the total amount of dextran administered, the lower the viscosity of the lung fluid. The effect of dextran molecular weight on viscosity may be evaluated in simulated lung fluid. As used herein, simulated lung fluid (SLF) has the following composition:

The molecular weight of the dextran polymer affects its suitability for use in inhaled compositions. The molecular weight of dextran affects its physical properties and also affects its toxicological properties when inhaled. The inventors surprisingly discovered that particles containing dextran having an average molecular weight between 1 kDa daltons and 30 kDa exhibit superior physical and toxicological properties, whereas particles containing dextran with an average dextran molecular weight outside this range exhibit less than desirable or undesirable physical and/or toxicological properties. For example, the molecular weight of the dextran polymer affects its propensity to absorb atmospheric moisture, the viscosity of the lung fluid when the dextran is dissolved therein, and the body's response to the inhaled polymer. When the dextran molecular weight is too small, such as less than 5 kDa, the particles absorb more water from the atmosphere and may even liquefy at ambient temperatures and humidity levels, thus rendering it unsuitable for inhalation as a dry powder. When the polymer average molecular weight is 5 kDa, it was unexpectedly discovered that the inhaled dextran also may produce toxic effects, such as increased lung inflammation. Without being bound by any particular theory, it is thought that smaller polymer molecules include a greater relative proportion of end groups having a glyco-aldehyde moiety that may resemble a bacterial cell coating, resulting in an immune response to the perceived foreign body. As the polymer molecular weight decreases, the ratio of end groups per mass of polymer increases and produces an increased immune response and concomitant inflammation. The glyco- aldehyde end group structure is shown below:

normal end group glyco-aldehyde end group

The inventors surprisingly discovered that dextran molecular weights that are too large, such as more than 20 kDa, produce less than desirable or undesirable properties such as causing increased lung fluid viscosity, and causing various potential side effects such as an influx of additional lung fluid to reduce the viscosity. As the molecular weight increases, the viscosity increases, causing or exacerbating the side effects. Additionally, as molecular weight increases, the polymer solubility in the lung fluid decreases. Reduced solubility can produce particle accumulation in the lungs, leading to an increase in phagocyte activity and associated inflammation. As such, the range of molecular weight from 5 kDa daltons to 20 kDa and especially around 10 kDa is critical to producing a superior inhalation dry powder for delivery of desirable actives.

U.S. Publication No. 2001/0007665 to Ilium et al. discloses a spray-dried powder comprising a drug and a polysaccharide having an aqueous solubility of at least 1 mg/ml. The polysaccharide has a molecular weight between 10,000 and

1,000,000, preferably between 50,000 and 75,000 and particularly between 100,000 and 300,000. Despite the disclosure in Ilium et al. that microspheres comprising polymers having preferred molecular weights of 100,000-300,000 are suitable for inhalation, in fact the disclosed microspheres of such molecular weights would dissolve more slowly than particles comprising polymers having a molecular weight from 5-20 kDa, and the slowness of the dissolution causes inflammation. Additionally, the high molecular weight microspheres disclosed in Ilium et al. cause a substantial increase in lung fluid viscosity, leading to a decrease in lung function. Specifically, in toxicology studies using male rats, it was discovered unexpectedly that dextran with an average molecular weight of from 5 kDa to 20 kDa, such as 10 kDa, provided superior results and was more suitable for inhalation for a variety of reasons, including being less toxic than dextran polymers with molecular weights of less than 5 kDa or greater than 20 kDa. In particular, dextran with an average molecular weight of 10 kDa was especially suitable as it induced no detectable histiocytic and/or neutrophilic inflammation in the centriacinar portion (central bronchioles) of the lung. Because histiocytes and neutrophils are part of the body's initial response to harmful stimuli, histiocytic and/or neutrophilic inflammation in the lungs is a useful marker for determining toxicity of an inhaled agent. Dextran polymers with average molecular weights of 5, 10, and 20 kDa

(Dex5, DexlO, and Dex20, respectively) were administered to male rats by nose- only inhalation for a period of 7 days, as described in Example 4 below. Assessments included clinical observations, body weights, clinical pathology (hematology, clinical chemistry, and coagulation), organ weights, histopathology, complement analyses, and lung lavage parameters. Unexpectedly Dex5 and Dex20 induced minimal inflammatory response in the lung, and especially surprisingly no detectable evidence of histiocytic and/or neutrophilic centriacinar inflammation was found in rats receiving DexlO. Heretofore, it had not been recognized that the molecular weight of the dextran would be a result effective variable and thus, molecular weight ranges of preference were not developed in the prior art.

III. Actives

The particles containing dextran polymer are suitable for use with any biologically active compound desired to be administered to the respiratory tract. The particles may contain one or more actives. In certain embodiments, the active is a small molecule. In particular embodiments, the active is a biological active. In other embodiments, the active is a mixture of two or more components, such as a small molecule and a biological active.

In one embodiment, the active acts locally, such as for treatment of the respiratory tract, such as for treatment of asthma or chronic obstructive pulmonary disease (COPD) in the lungs, or as antihistamines or decongestants in the nasal cavity. In another embodiment, the active may act systemically, such as for pain. In still another embodiment, the active may act upon the immune system, including one or more of the following: bronchus-associated lymphoid tissue (BALT), nasal- associated lymphoid tissue (NALT), mucosa-associated lymphoid tissue (MALT), larynx-associated lymphoid tissue (LALT), gut-associated lymphoid tissue (GALT), salivary-gland-associated lymphoid tissue (SALT), as well as vaccines targeted to other tissues.

In certain embodiments, the active is highly water soluble (i.e., greater than 100 mg/mL), water soluble (i.e., 30-100 mg/mL), sparingly water soluble (i.e., 10- 30 mg/mL), or poorly water soluble (i.e., less than 10 mg/mL). In one embodiment, the active is "poorly water soluble," and the active has a solubility in water (over the pH range of 6.5 to 7.5 at 25°C) of less than 5 mg/mL. In particular embodiments, the active may have lower aqueous solubility, such as less than 1 mg/mL, less than 0.1 mg/mL, or less than 0.01 mg/mL.

Each named active should be understood to include the non-ionized form of the active, pharmaceutically acceptable salts of the active, or any other pharmaceutically acceptable forms of the active. "Pharmaceutically acceptable form" means any pharmaceutically acceptable derivative or variation, including but not limited to stereoisomers, stereoisomer mixtures, enantiomers, solvates, hydrates, isomorphs, polymorphs, pseudomorphs, neutral forms, salt forms and prodrugs. Examples of suitable therapeutic agents include 5 -lipoxygenase (5-LO) inhibitors or 5 -lipoxygenase activating protein (FLAP) antagonists; leukotriene antagonists (LTRAs) including antagonists of LTB₄, LTC₄, LTD₄, and LTE₄; histamine receptor antagonists including Hl and H3 antagonists; (X₁- and α₂- adrenoceptor agonist vasoconstrictor sympathomimetic agents for decongestant use; muscarinic M3 receptor antagonists or anticholinergic agents; PDE inhibitors, e.g. PDE3, PDE4 and PDE5 inhibitors; theophylline; sodium cromoglycate; inhaled glucocorticosteroids, such as DAGR (dissociated agonists of the corticoid receptor); adhesion molecule inhibitors including VLA-4 antagonists; kinin-Bi - and B₂ - receptor antagonists; immunosuppressive agents; inhibitors of matrix metalloproteases (MMPs); tachykinin NK₁, NK₂ and NK3 receptor antagonists; elastase inhibitors; adenosine A2a receptor agonists; inhibitors of urokinase; compounds that act on dopamine receptors, e.g., D2 agonists; modulators of the NFKβ pathway, e.g. IKK inhibitors; modulators of cytokine signaling pathways such as p38 MAP kinase, syk kinase or JAK kinase inhibitor; agents that can be classed as mucolytics or anti-tussive; antibiotics and antiviral agents effective against microorganisms which can colonize the respiratory tract; HDAC inhibitors; PI3 kinase inhibitors; β₂ agonists; dual compounds active as β₂ agonists and muscarinic M3 receptor antagonists; prostaglandin receptor antagonists such as DPI and DP2 antagonists and inhibitors of prostaglandin synthase; agents that enhance responses to inhaled corticosteroids; and CXCR2 antagonists. Preferred examples of therapeutic agents that may be used in the present formulations include, but are by no means limited to: glucocorticosteroids, in particular inhaled glucocorticosteroids with reduced systemic side effects, including prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide, and mometasone furoate; vaccines; muscarinic M3 receptor antagonists or anticholinergic agents including in particular ipratropium salts, namely bromide, tiotropium salts, namely bromide, oxitropium salts, namely bromide, perenzepine, and telenzepine; β2 agonists including in particular salbutamol, terbutaline, bambuterol, fenoterol, salmeterol, formoterol, tulobuterol and their salts.

IV. Particles

The dry powder composition is comprised of particles comprising the active and the dextran polymer. The particles are sized so as to be suitable for inhalation via the mouth or nose.

In one embodiment, the particles have a mass median aerodynamic diameter (MMAD) of 5 to 100 μm. In another embodiment, the particles have a MMAD of 10 to 70 μm. In yet another embodiment, the particles have an average diameter of 50 μm. In one embodiment, such particles are used in devices designed for delivery of particles to the upper airways. In another embodiment, such particles are used in devices designed for delivery of particles via the nose.

Particles suitable for inhalation may be evaluated using a cascade impactor such as the NEXT GENERATION PHARMACEUTICAL IMPACTOR (NGI), Model 170 (available from MSP Corporation, Shoreview, MN). In this device, powders are drawn by vacuum into eight different chambers representing the lung, with each chamber corresponding to a different range of particle sizes. NGI data include mass median aerodynamic diameter (MMAD) and fine particle fraction (FPF). The FPF is the amount of powder deposited in chambers 3-8 of the NGI. The FPF is generally assumed to represent the fraction of particles that would deposit in vivo in the "deep lungs" (alveoli), or particles that have an aerodynamic diameter of less than 4.6 μm. In the examples disclosed herein, the NGI experiment utilizes a Monodose capsule-based inhaler device.

In another embodiment, the particles have a MMAD of 0.5 to 10 μm, or even 1 to 5 μm, or even more preferably 1.5 to 3.5 μm. In another embodiment, the particles have a FPF of at least 50%, and preferably at least 70%. In one embodiment, such particles are used in devices designed for delivery of particles to the lower airways. In another embodiment, such particles are used in devices designed for delivery of particles via the mouth.

In one embodiment, the particles have a MADD of less than or equal to 10 μm, less than or equal to 5 μm, 0.5 to 10 μm, 0.5 to 5 μm, 1 to 5 μm, or 1.5 to 3.5 μm. In particular embodiments, the particles have a FPF of at least 50%, at least 60%, or at least 70%. In some embodiments, the particles have a mean geometric diameter of from 0.5 to 10 μm, 1 to 5 μm, or 2-4 μm. In certain embodiments, the dry particles have a geometric size distribution span of less than 3. In particular embodiments, the span is less than 2.

The dry powder may have a tap density of 0.05 to 1 g/cm³, 0.07 to 0.5 g/cm³, or 0.1 to 0.3 g/cm³. Tap density is determined using a tap density tester, which taps the powder with a fixed impact force and frequency, as specified in the U.S. Pharmacopeia (USP). In another embodiment, the particles have a MMAD ranging from 0.5 to

100 μm. In one embodiment, such particles are used in devises designed for delivery of particles to both the nose and the mouth.

The particles in the dry powder contain one or more active compounds and the dextran polymer. In certain embodiments, the active and dextran polymer constitute at least 5 wt% of the particles, at least 10 wt% of the particles, at least 25 wt% of the particles, at least 50 wt% of the particles, or at least 75 wt% of the particles. In some embodiments, the active and dextran polymer constitute 5-95 wt%, 10-75 wt%, 25-50 wt%, or 50-75 wt% of the particles. In another embodiment, the particles consist essentially of the active and the dextran polymer. In some embodiments, the particles may include optional additional excipients such as polyvinylpyrrolidone (PVP), tocopheryl polyethylene glycol 1000 succinate (also known as vitamin E TPGS, or TPGS), dipalmitoyl phosphatidyl choline (DPPC), trehalose, sodium bicarbonate, glycine, sodium citrate, lactose, and other such known excipients.

The dry powder may have an emitted dose of at least 50%, more preferably at least 70%.

The relative amounts of active and dextran polymer in the particles may range from 0.01 wt% to 99 wt% active, and from 1 wt% to 99.99 wt% dextran polymer. In certain embodiments, the amount of active may range from 0.1 wt% to 80 wt%, from 0.1 to 60 wt%, or from 1 to 40 wt%. The amount of dextran polymer may range from 20 wt% to 99.9 wt%, 40 wt% to 99.9 wt% or from 60 wt% to 99 wt%. In one embodiment, the particles have the following composition: from 0.1 to 80 wt% active, and from 20 to 99.9 wt% dextran polymer. In another embodiment, the particles have the following composition: from 0.1 to 60 wt% active, and from 40 to 99.9 wt% dextran polymer. In still another embodiment, the particles have the following composition: from 1 to 40 wt% active, and from 60 to 99 wt% dextran polymer.

The particles comprising active and dextran polymer may be in any physical state, such as but not limited to a heterogeneous mixture of active-rich and dextran- rich domains, an amorphous (non-crystalline), homogeneous molecular dispersion of active molecules dispersed throughout the dextran polymer, or any state or combination of states in between. In some embodiments, the particles comprise one or more active-rich domains dispersed in the amorphous dextran polymer. The active-rich domains may be amorphous, crystalline, or any combination thereof. The amorphous or crystalline nature of the active-rich domains can be determined by differential scanning calorimetry or powder X ray diffraction.

In certain embodiments, the active present in the particles is completely or substantially amorphous. For example, the active may be at least 60 wt% amorphous, at least 70 wt% amorphous, at least 90 wt% amorphous, or 90-100 wt% amorphous. Preferably at least 90 wt% of the active present in the particles is amorphous. Actives in an amorphous state can dissolve more rapidly in the lung fluid. In particular embodiments, the particles comprise an amorphous molecular dispersion of active molecules dispersed in the dextran polymer. Amorphous molecular dispersions of small-molecule actives are desirable because the active is less likely to crystallize during particle formation and drying. Crystallization can result in uncontrolled growth of particles, resulting in a wide range of particles sizes and formation of particles that are too large (i.e., more than 10 μm in diameter) to be suitable for inhalation.

When the active present in the particles is substantially amorphous (e.g., at least 60 wt% amorphous), the particles comprise a solid dispersion of the active and polymer consisting essentially or primarily of amorphous active molecularly dispersed throughout the polymer. The solid dispersion may be considered a "solid solution" of active and polymer when there are no distinct active-rich and dextran- rich domains in the particles. The term "solid solution" includes both thermodynamically stable solid solutions in which the active is completely dissolved in the polymer, as well as homogeneous materials comprising amorphous active molecularly dispersed throughout the polymer in amounts greater than the solubility of the active in the polymer.

A molecular dispersion is considered a "solid solution" when it displays a single glass transition temperature, T_g, when analyzed by differential scanning calorimetry. A single glass transition temperature indicates that the solid dispersion is a homogeneous solid solution. Preferably, the particles have at least one T_g due to the amorphous character of the polymer. Particles comprising more than one active typically have more than one T_g. Particles with active-rich domains also typically have more than one T_g. In another embodiment, the particles are solid dispersions of the active and polymer consisting essentially of amorphous active molecularly dispersed throughout the polymer. In yet another embodiment, the particles comprise two or more actives. In still another embodiment, the particles comprise one or more actives, a dextran polymer, and additional excipients. Depending on its properties, an excipient may be molecularly dispersed in a particle, or it may form excipient- rich domains. Glass transition temperature also is an indicator of particle stability. T_g is related, in part, to molecular mobility, i.e., how easily or quickly components can diffuse through the composition. Typically, a higher glass transition temperature correlates to improved particle stability. In some embodiments, the relative amounts of active and polymer are chosen so that the particles preferably have a glass transition temperature of at least 50⁰C at 50% relative humidity. When evaluated at a relative humidity of less than 5%, the particles preferably have a glass transition temperature of at least 5O⁰C, at least 8O⁰C, or at least 100⁰C.

V. Particle Formation

The particles may be formed by any method known in the art, including milling, extrusion, precipitation, or solvent addition followed by solvent removal. When the active is present as separate crystalline or amorphous domains in the particles, the active may first be processed by methods such as milling, precipitation, or crystallization to form particles comprising active that have an average geometric diameter of less than 5 μm in largest dimension, and preferably less than 1 μm. The active is then combined with the dextran polymer, followed by milling, dry granulation, wet granulation, extrusion, precipitation, or the addition and removal of solvent to produce the particles. When the active is substantially dispersed in the dextran polymer as a molecular dispersion, the particles may be formed by use of heat or solvent to allow homogenation of the active and the dextran polymer. For example, the active and the dextran polymer may be processed by heat, mechanical mixing and extrusion using, for example, a twin-screw extruder. The product may then be milled to the desired particle size. Alternatively, the active and dextran polymer may be dissolved in a solvent in which both materials are soluble. Particles may then be formed from the solution by any known process, including precipitation in a miscible non-solvent, emulsifying in an immiscible non-solvent, or by forming droplets followed by removal of the solvent by evaporation. In certain embodiments, particles in which the active is molecularly dispersed are formed by spray drying. The fluid that is spray dried may be a suspension of amorphous or crystalline particles, a homogeneous solution, or a combination of dissolved and suspended materials. In one embodiment, the fluid that is spray dried comprises a homogeneous solution of active and dextran polymer dissolved together in a solvent. In another embodiment, the fluid that is spray dried consists essentially of a solution of active and dextran polymer dissolved in a solvent. In still another embodiment, the fluid that is spray dried comprises a suspension of active particles in a solution of dextran polymer dissolved in a solvent. The spray drying solution is prepared by completely or partially dissolving the active(s), dextran polymer, and optional excipients in a solvent. The solvent may be any solvent or mixture of solvents capable of dissolving both the active and polymer having a boiling point above ambient temperature and less than about 15O⁰C. Suitable solvents include water, acetone, methanol, ethanol, methyl acetate, ethyl acetate, tetrahydrofuran (THF), and dichloromethane and mixtures of solvents. Water typically is the major component of the solvent mixtures. When the spray drying solution comprises an organic solvent that is water miscible, such as acetone or methanol, water may be added to the solution so long as the active(s) and polymer completely dissolve or form a homogeneous suspension.

The spray drying solution is then sprayed through an atomizer such as a pressure nozzle or two-fluid nozzle into a spray-drying chamber. The droplets are contacted with a heated drying gas such as dry nitrogen. The droplets dry rapidly, forming particles comprising the active, dextran polymer, and optional excipients. The particles exit the spray dryer and are collected, such as in a cyclone.

In some embodiments, the particles are dried, e.g., in a vacuum desiccator, to completely or substantially remove residual solvent. In certain embodiments, the vacuum-dried particles are subsequently equilibrated for about an hour at ambient temperature and up to 25% humidity. Such equilibration can reduce static electricity amongst the particles, resulting in easier handling. VI. Pharmaceutical Compositions

Pharmaceutical compositions comprising the particles are typically in the form of dry powders. The dry powders may further comprise additional optional excipients, such as diluents, and fillers. In some embodiments, the particles comprising the active and dextran polymer may collectively constitute from 5 wt% to 100 wt% of the dry powder, 5 wt% to 50 wt% of the dry powder, 25 wt% to 75 wt% of the dry powder, 50 wt% to 100 wt% of the dry powder, or 80 wt% to 100 wt% of the dry powder. In another embodiment, the dry powder consists essentially of the particles of active and dextran polymer. The powders may be administered to a subject in any conventional dry powder inhaler. In one embodiment, the powders may be packaged in a packet suitable for insertion into a dry powder inhaler. Typically, the powders are inhaled orally.

VII. Examples

Actives 1 and 2 were used in the examples described below. Active 1 was insulin, available from Millipore (Billerica, MA). Insulin is soluble in water and is a hormone consisting of two polypeptide chains.

Active 2 was PYY 3-36 peptide, available from GenScript Corp. (Piscataway, NJ). PYY has the following amino acid sequence: ILE-LYS-PRO- GLU-ALA-PRO-GLY-GLU-ASP-ALA-SER-PRO-GLU-GLU-LEU-ASN-ARG- TYR-TYR-ALA-SER-LEU-ARG-HIS-TYR-LEU-ASN-LEU-VAL-THR-ARG- GLN-ARG-TYR-NH₂. Active 2 is soluble in water.

Example 1

A dry powder consisting of particles of a solid dispersion of 25 wt% Active 1 and dextran was prepared. Dextran having a molecular weight of 10,000 daltons (lot #298106; available from Amersham Sciences, Piscataway, NJ) was used in this example. A spray solution was formed containing 0.25 wt% Active 1, 0.75 wt% dextran, 49.5 wt% water and 49.5 wt% 0.01 N HCl solution as follows: Active 1, water, and HCl solution were combined in a 40 rnL vial and mixed to form a clear solution; the pH was 2.5. The dextran was then added to the vial, and the solution was mixed to form a clear solution. The solution was adjusted to pH 7.4 using 1.0 N NaOH solution.

The spray solution was pumped to a small-scale spray-drying apparatus at a liquid feed rate of 0.13 mL/min. The spray drying apparatus was equipped with a two-fluid nozzle (Spraying Systems 1650 liquid, 64 air cap, available from Spraying Systems Co.^®, Wheaton, IL). The atomizing/drying gas (nitrogen) was delivered to the nozzle at 120⁰C and a flow rate of 1.0 SCFM. The spray drying vessel was equipped with a 4-inch exit filter containing a Whatman #1, 11 μm microcellulose filter. The evaporated liquids and drying gas exited the spray drier at a temperature of 30⁰C. The solid dispersion particles were then dried under vacuum (less than 0.2 atm) for 12 hours at room temperature.

In Vitro Inhalation Performance

The dry powder of Example 1 was tested using the NEXT GENERATION PHARMACEUTICAL IMPACTOR (NGI), Model 170 (available from MSP Corporation, Shoreview, MN). A 15 mg sample of the solid dispersion particles was evaluated using the NGI. The results of the NGI evaluation for Example 1 are shown in Table 1.

Table 1

*FPF - fine particle fraction, i.e. particles with an aerodynamic diameter of less than 4.6 μm **MMAD - mass median aerodynamic diameter ***ED = emitted dose Example 2

A dry powder consisting of particles of a solid dispersion of 25 wt% Active 2 and dextran was prepared following the procedures outlined for Example 1 , with the following exceptions. Dextran having a molecular weight of 10,000 daltons (lot #298106; available from Amersham Sciences, Piscataway, NJ) was used in this example.

The spray solution containing 0.25 wt% Active 2, 0.77 wt% dextran, and 98.9 wt% water was made as follows: Active 2 and water were combined in a vial and mixed to form a clear solution. The dextran was then added to the solution and mixed until the solution was clear.

The spray drying conditions were identical to those described for Example 1. The solid dispersion particles were dried under vacuum (less than 0.2 atm) for 12 hours at room temperature.

In Vitro Inhalation Performance

The dry powder of Example 2 was tested using the NGI using the procedures described for Example 1. The results of the NGI evaluation for Example 2 are shown in Table 1.

Example 3

A dry powder consisting of particles of a solid dispersion of 70 wt% Active 1 and dextran having a molecular weight of 10,000 daltons (lot #298106; available from Amersham Sciences) was prepared as follows. A spray solution consisting of 0.14 wt% Active 1, 0.06 wt% dextran, and 99.8 wt% water was made by dissolving Active 1 in water to form a clear solution. Dextran was then dissolved into this solution to form the spray solution.

A small-scale spray dryer was used to form the spray-dried particles. Inlet drying gas (nitrogen) was set at 100⁰C. The temperature of the gases exiting the dryer was 55°C. The solution was pumped using a peristaltic pump at 5 g/min to a two-fluid Spray Systems nozzle using a 1650 liquid and 70 air cap. Atomizing gas (nitrogen) was set at 30 psi. The dried material was pneumatically conveyed to a 2- inch diameter cyclone. The resulting solid dispersion particles were collected in a 20 rnL jar attached to the bottom of the cyclone. The evaporated solvent and drying gas exited the drier through the top of the cyclone. The solid dispersion particles were then dried under vacuum (less than 0.2 atm) for 18 hours at room temperature.

In Vitro Inhalation Performance

The dry powder of Example 3 was tested using the NGI using the procedures described for Example 1. The results of the NGI evaluation for Example 3 are shown in Table 1.

In Vivo Inhalation Performance

In vivo inhalation tests were performed using female beagle dogs to demonstrate the effectiveness of the formulation of the particles of Example 3. The solid amorphous dispersion of Example 3 was administered by oral inhalation route utilizing an insufflator (II)/aerochamber device. Four dogs were dosed with the formulation of Example 3. The dogs were anesthetized and intubated. A 2-mg dose was then administered in a single breath. Blood samples were taken using a catheter which was surgically implanted in the femoral artery. The samples were taken 0, 5, 10, 15, 20, 35, 50, 65, 80, 95, 125, 155, 185, 215, and 245 minutes after the dose was administered. Plasma samples were analyzed for insulin and C-peptide (a metabolite of insulin). Results of this study are shown in Table 2. Each value is the average value for the four dogs.

Table 2

*t _max - the time at which the insulin concentration reached a maximum

** C max - the maximum concentration reached

***AUCo-245 - the area under the concentration versus time curve over the time period of 0-245 minutes

These results demonstrate the effectiveness of the insulin-dextran particles formed in Example 3.

Example 4

In vivo inhalation tests of dextran polymer particles were performed using male rats to evaluate toxico logical effects of dextran molecular weight variation. Samples of dextrans having average molecular weights of 5,000 daltons (Dex5, obtained from Pharmacosmos, Holbeak, Denmark, Batch No. B401), 10,000 daltons (Dex 10, obtained from Pharmacosmos, Batch No. HD218), and 20,000 daltons (Dex20, obtained from Amersham Biosciences, Lot No. 298165) were dosed via nose-only inhalation at an amount of 1.1 mg/kg/day to male rats. Six male rats were used to test each polymer. One group of rats was an air-control group and received no dextran. The polymer particles had a MMAD of approximately 1-3 μm to ensure the particles were respirable. Aerosols of the polymers were generated with a rotating brush generator (P ALAS^® RBG 1000, PALAS^® GmbH, Karlsruhe, Germany). Aerosol concentrations were approximately 0.3 mg/mL, providing about 1.1 mg/kg of dextran to the rats over a 60-minute exposure period. Aerosols were dosed each of 7 consecutive days for 60 minutes per day. Assessments included measurement and evaluation of pulmonary histiocytic and neutrophilic inflammatory infiltrates. Severity was determined by the pathologist, as is understood by those of ordinary skill in the art. Table 4 summarizes the results of these tests.

Table 3

There was limited to no evidence of dextran treatment-related changes among the three dextran polymers for hematology, clinical chemistry parameters, or coagulation parameters, with test results remaining substantially similar to the values measured for the air-control group. The histopathology revealed pulmonary macrophage accumulation and enlargement as the predominant finding. However, increases in macrophage size and number are a normal physiological response to inhaled materials and are not generally considered adverse. No histiocytic and/or neutrophilic inflammatory infiltrates were associated with treatment with Dex 10, and minimal histiocytic and/or neutrophilic inflammatory infiltrates were associated with treatment with Dex5 and Dex20. Based on the pulmonary histopathology, a no observed adverse effect level (NOAEL) was determined for DexlO at the administered dose. A NOAEL was not established for Dex5 or Dex20. In one embodiment, a pharmaceutical composition comprises a dry powder comprising particles having a mean geometric diameter of from 0.5 to 100 microns, the particles comprising from 0.01 to 99 wt% of an active and from 1 to 99.99 wt% of a dextran polymer having an average molecular weight of from 1,000 to 30,000 daltons, wherein the dry powder is suitable for inhalation. In one embodiment, the dextran polymer has an average molecular weight of from 5,000 to 20,000 daltons. In another embodiment, the dextran polymer has an average molecular weight of from 5,000 to 15,000 daltons. In yet another embodiment, the dextran polymer has an average molecular weight of 9,500 to 10,500 daltons.

In any or all of the above embodiments, the dextran polymer constitutes at least 50 wt% of said particles.

In any or all of the above embodiments, the particles may have the following composition: from 0.1 to 80 wt% active, and from 20 to 99.9 wt% dextran polymer. In another embodiment, the particles have the following composition: from 1 to 60 wt% drug, and from 40 to 99 wt% dextran polymer. In any or all of the above embodiments, the particles constitute from 50 wt% to 100 wt% of the dry powder. In another embodiment, the dry powder consists essentially of the active and the dextran polymer.

In any or all of the above embodiments, the particles may comprise a second active. In any or all of the above embodiments, the pharmaceutical composition may be suitable for delivery to the lower airways via inhalation through the mouth. In one embodiment, the particles have a mass median aerodynamic diameter of from 0.5 to 10 μm. In still another embodiment, the particles have a mass median aerodynamic diameter of from 1 to 5 μm. In any or all of the above embodiments, the particles may have a fine particle fraction of at least 50%.

Alternatively, the composition may be suitable for delivery to the upper airways via inhalation through the nose. In such embodiments, the particles have a mass median aerodynamic diameter of from 5 to 100 μm. In another embodiment, the particles have a mass median aerodynamic diameter of from 10 to 70 μm.

In some embodiments, the composition is suitable for delivery to the upper and lower airways.

In any or all of the above embodiments, the particles may be solid dispersions of amorphous active molecularly dispersed in the dextran polymer. In one embodiment, a method for making a pharmaceutical composition comprises dissolving at least one active and a dextran polymer in a solvent to form a solution, wherein the dextran polymer has an average molecular weight of from 1,000 to 30,000 daltons, and spray drying the homogeneous solution to form particles comprising the active and the dextran polymer. In one embodiment, the dextran polymer has a molecular weight of from 5,000 to 20,000 daltons. In another embodiment, the dextran polymer has a molecular weight of from 8,000 to 12,000 daltons. In one embodiment, the solvent is water. In some embodiments, the particles comprise a molecular dispersion of the active in the dextran polymer.

In some embodiments, the particles are dried to remove residual solvent. In certain embodiments, the particles are equilibrated for an hour at ambient temperature and up to 25% humidity.

In one embodiment, a pharmaceutical composition comprises a dry powder comprising particles having a mass mean aerodynamic diameter of from 0.5 to 100 microns, the particles comprising from 0.01 to 99 wt% of an active and from 1 to 99.99 wt% of a dextran polymer having an average molecular weight of from 1,000 to 30,000 daltons, wherein the dry powder is suitable for inhalation.

In view of the many possible embodiments to which the principles of the disclosed invention may be applied, it should be recognized that the illustrated embodiments are only preferred examples of the invention and should not be taken as limiting the scope of the invention. Rather, the scope of the invention is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims.

Claims

We claim:

1. A pharmaceutical composition, comprising: a dry powder comprising particles having a mean geometric diameter of from 0.5 to 100 microns, the particles comprising from 0.01 to 99 wt% of an active and from 1 to 99.99 wt% of a dextran polymer having an average molecular weight of from 1,000 to 30,000 daltons, wherein the dry powder is suitable for inhalation.

2. The pharmaceutical composition of claim 1 wherein said dextran polymer has an average molecular weight of from 5,000 to 15,000 daltons.

3. The pharmaceutical composition of claim 1 wherein the dextran polymer has an average molecular weight of 9,500 to 10,500 daltons.

4. The pharmaceutical composition of any one of claims 1-3 wherein the active and the dextran polymer constitute at least 50 wt% of said particles.

5. The pharmaceutical composition of any one of claims 1 -4 wherein the particles have the following composition: from 0.1 to 80 wt% active, and from 20 to 99.9 wt% dextran polymer.

6. The pharmaceutical composition of any one of claims 1-5 wherein the dry powder consists essentially of the active and the dextran polymer.

7. The pharmaceutical composition of any one of claims 1-6 wherein the particles comprise a second active.

8. The pharmaceutical composition of any one of claims 1-7 wherein said composition is suitable for delivery to the lower airways via inhalation through the mouth.

9. The pharmaceutical composition of claim 8 wherein said particles have a mass median aerodynamic diameter of from 0.5 to 10 μm.

10. The pharmaceutical composition of any one of claims 1 -7 wherein said composition is suitable for delivery to the upper airways via inhalation through the nose.

11. The pharmaceutical composition of claim 10 wherein said particles have a mass median aerodynamic diameter of from 5 to 100 μm.

12. The pharmaceutical composition of any one of claims 1-7 wherein said composition is suitable for delivery to the upper and lower airways.

13. The pharmaceutical composition of any one of the preceding claims wherein the particles are solid dispersions of amorphous active molecularly dispersed in the dextran polymer.

14. A method for making a pharmaceutical composition, comprising: dissolving at least one active and a dextran polymer in a solvent to form a solution, wherein the dextran polymer has an average molecular weight of from 1,000 to 30,000 daltons; spray drying the homogeneous solution to form particles comprising the active and the dextran polymer.

15. The method of claim 14, wherein the dextran polymer has a molecular weight of from 8,000 to 12,000 daltons.

16. The method of any one of claims 14-15, wherein the solvent is water.

17. The method of any one of claims 14-16, wherein the particles comprise a molecular dispersion of the active in the dextran polymer.

18. The method of any one of claims 14-17, wherein the particles are dried to remove residual solvent.

19. The method of any one of claims 14-18, wherein the particles are equilibrated for an hour at ambient temperature and up to 25% humidity.

20. A pharmaceutical composition, comprising: a dry powder comprising particles having a mass mean aerodynamic diameter of from 0.5 to 100 microns, the particles comprising from 0.01 to 99 wt% of an active and from 1 to 99.99 wt% of a dextran polymer having an average molecular weight of from 1,000 to 30,000 daltons, wherein the dry powder is suitable for inhalation.