WO2010102066A1

WO2010102066A1 - Dextran polymer powder for inhalation administration of pharmaceuticals

Info

Publication number: WO2010102066A1
Application number: PCT/US2010/026128
Authority: WO
Inventors: David T. Vodak; Daniel E. Dobry; Warren K. Miller; David K. Lyon; Dwayne T. Friesen
Original assignee: Bend Research, Inc.
Priority date: 2009-03-05
Filing date: 2010-03-03
Publication date: 2010-09-10
Also published as: US9757464B2; US8685458B2; US20120003282A1; WO2010102065A1; US20140161895A1

Abstract

Pharmaceutical dry powder compositions suitable for inhalation are provided comprising an active and a dextran polymer derivative. The particles comprise from 0.01 to 99 wt% of an active and from 1 to 99.99 wt% of a dextran polymer derivative. The dextran polymer derivative is selected from dextran acetate, dextran propionate, dextran succinate, dextran acetate propionate, dextran acetate succinate, dextran propionate succinate, dextran acetate propionate succinate, and mixtures thereof. In general, the active is dispersed in the polymer such that the beneficial properties of the polymer and size of the particles define the inhalation properties of the composition.

Description

DEXTRAN POLYMER POWDER FOR INHALATION ADMINISTRATION

OF PHARMACEUTICALS

CROSS REFERENCE TO RELATED APPLICATIONS The present application claims the benefit of United States Provisional Patent

Application No. 61/157,854, filed March 5, 2009, and United States Provisional Patent Application No. 61/178,690, filed May 15, 2009, each of which is incorporated herein in its entirety by reference.

BACKGROUND

Pharmaceutical dry powder compositions suitable for inhalation are provided comprising an active pharmaceutical ingredient and a dextran polymer derivative.

It is well known that to deliver an active in a dry powder form to the lungs, the active must be in the form of small particles, typically with an 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 therefore is not efficiently inhaled. To overcome these and related problems, conventional dry powder pulmonary formulations consist 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 formulation limits the type of active that can be delivered. The active must have a particular set of physical properties. The active must be crystalline, must have low hygroscopicity, must reversibly adhere to lactose and not overly adhere to itself, must be micronizable, and must 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 comprising 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

A pharmaceutical composition suitable for inhalation via the mouth and/or nose comprises a dry powder comprising particles having a mass median aerodynamic diameter of from 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 derivative. The dextran polymer derivative is selected from dextran acetate, dextran propionate, dextran succinate, dextran acetate propionate, dextran acetate succinate, dextran propionate succinate, dextran acetate propionate succinate, and mixtures thereof. In some embodiments, the dextran polymer derivative is selected from the group consisting of dextran acetate, dextran propionate, dextran succinate, dextran acetate propionate, dextran acetate succinate, dextran propionate succinate, dextran acetate propionate succinate, and mixtures thereof. In general, the active is dispersed in the polymer such that the beneficial properties of the polymer and size of the particles define the inhalation properties of the composition.

The dry powders comprising particles of an active and a dextran polymer derivative overcome the problems of the prior art by providing particles that are of the appropriate size to be inhaled via the mouth and/or nose but which do not rely on milled crystalline active. The particles comprising an active and a dextran polymer derivative can be formed by essentially any 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. A preferred process for forming dry powders of the present invention is spray drying. Spray dry technology enables the formation of particles comprising active and polymer having the appropriate size to be inhaled, which in turn leads to a high respirable dose with reduced variability. Active may be dispersed in the polymer of the particles as separate crystalline or amorphous domains or as a molecular dispersion. Formation of a molecular dispersion is generally preferred as it results in particles that have the beneficial properties of the polymer rather than the properties of the drug. The dextran polymer derivative provides particles that have beneficial properties including but not limited to: a low propensity to aggregate, good physical and chemical stability and optimal dissolution properties in the lung. The polymer may be used to formulate a wide variety of 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 derivative, wherein the dextran polymer derivative is selected from dextran acetate succinate, dextran propionate succinate, dextran acetate propionate succinate, and mixtures thereof.

In one embodiment, the dextran polymer derivative has a total degree of substitution of acetate, propionate, and succinate groups of greater than or equal to 0.05. In another embodiment, the dextran polymer derivative has a total degree of substitution of acetate, propionate, and succinate groups of greater than or equal to 0.25.

In another embodiment, the particles are solid dispersions of amorphous active molecularly dispersed in the dextran polymer derivative. In still another embodiment, at least 5 wt% of the particles consists essentially of the active and the dextran polymer derivative. In yet another embodiment, at least 10 wt% of the particles consists essentially of the active and the dextran polymer derivative. In yet another embodiment, at least 50 wt% of the particles consists essentially of the active and the dextran polymer derivative. In still another embodiment, the particles consist essentially of the active and the dextran polymer derivative. - A -

In yet another embodiment, the particles have the following composition: from 0.1 to 80 wt% said active, and from 20 to 99.9 wt% said dextran polymer derivative.

In one embodiment, the dry powder consists essentially of the particles.

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

A dry powder composition is provided that is suitable for inhalation. The dry powder comprises particles each containing an active and a dextran polymer derivative. Dextran polymer derivatives, actives, particles suitable for inhalation, and methods for making such particles are described in detail below.

Unless otherwise indicated, all numbers expressing quantities of components, molecular weights, particle sizes, percentages, temperatures, times, and so forth, as used in the specification or claims are to be understood as being modified by the term "about." Accordingly, unless otherwise indicated, implicitly or explicitly, the numerical parameters set forth are approximations that may depend on the desired properties sought and/or limits of detection under standard test conditions/methods. When directly and explicitly distinguishing embodiments from discussed prior art, the embodiment numbers are not approximates unless the word "about" is recited.

Dextran Polymer Derivatives

Dextran polymer derivatives are polymers formed by the derivatization of dextran with ester-linked groups. The groups ester-linked to the dextran may be acetate, propionate, succinate, or any combination of the three groups. Dextran is an α-D-1,6- glucose-linked glucan. It may have side-chains linked to the backbone of the dextran polymer, with the degree of branching being approximately 5%, and the branches being mostly 1-2 glucose units long. A fragment of the dextran structure is illustrated below.

The term "dextran polymer derivative" refers to any of the family of dextran polymers that have acetate, propionate, and/or succinate groups attached via ester linkages to a significant fraction of the dextran polymer's hydroxyl groups.

In one embodiment, the dextran polymer derivative is selected from the group consisting of dextran acetate, dextran propionate, dextran succinate, dextran acetate propionate, dextran acetate succinate, dextran propionate succinate, dextran acetate propionate succinate, and mixtures thereof. In another embodiment, the dextran polymer derivative is dextran acetate succinate. In yet another embodiment, the dextran polymer derivative is dextran propionate succinate.

For example, a fragment of dextran propionate succinate is illustrated below.

The degree of substitution of each substituent is chosen so that the active combined with the dextran polymer derivative will be suitable for forming particles that may be inhaled. "Degree of substitution" or "DS" refers to the average number of the three hydroxyls per saccharide repeat unit on the dextran chain that have been substituted. For example, if all of the hydroxyls on the dextran chain have been substituted by acetate groups, the degree of substitution of acetate groups is 3. In the structure of dextran propionate succinate shown above, the degree of substitution of propionate groups is 2, while the degree of substitution of succinate groups is 0.33.

In one embodiment, the degree of substitution of the acetate, propionate, and succinate groups are such that when adding the total degree of substitution of acetate, propionate and succinate, the total degree of substitution is greater than or equal to 0.05. In another embodiment, the total degree of substitution is greater than or equal to 0.15. In another embodiment, the total degree of substitution is greater than or equal to 0.25. In still another embodiment, the total degree of substitution is greater than or equal to 0.50. In yet another embodiment, the total degree of substitution is greater than or equal to 0.75.

In one embodiment, the dextran polymer derivative is dextran acetate, wherein the degree of substitution for acetate groups ranges from 0.05 to 2.0. In another embodiment, the dextran polymer derivative is dextran acetate, wherein the degree of substitution for acetate groups ranges from 0.25 to 1.8. In another embodiment, the dextran polymer derivative is dextran acetate, wherein the degree of substitution for acetate groups is greater than 1.0. In still another embodiment, the dextran polymer derivative is dextran propionate, wherein the degree of substitution for propionate groups ranges from 0.05 to 2.0. In another embodiment, the dextran polymer derivative is dextran propionate, wherein the degree of substitution for propionate groups ranges from 0.25 to 2.0. In another embodiment, the dextran polymer derivative is dextran propionate, wherein the degree of substitution for propionate groups ranges from 0.5 to 2.0. In another embodiment, the dextran polymer derivative is dextran propionate, wherein the degree of substitution for propionate groups is greater than 1.0.

In still another embodiment, the dextran polymer derivative is dextran succinate, wherein the degree of substitution for succinate groups ranges from 0.05 to 2.8. In another embodiment, the dextran polymer derivative is dextran succinate, wherein the degree of substitution for succinate groups ranges from 0.5 to 2.5. In another embodiment, the dextran polymer derivative is dextran acetate propionate, wherein the degree of substitution for acetate groups ranges from 0.05 to 2.5, and the degree of substitution for propionate groups ranges from 0.05 to 2.5. In another embodiment, the dextran polymer derivative is dextran acetate propionate, wherein the degree of substitution for acetate groups ranges from 0.1 to 2.0, and the degree of substitution for propionate groups ranges from 0.1 to 2.0.

In another embodiment, the dextran polymer derivative is dextran acetate succinate, wherein the degree of substitution for acetate groups ranges from 0.25 to 2.5, and the degree of substitution for succinate groups ranges from 0.05 to 1.5. In another embodiment, the dextran polymer derivative is dextran acetate succinate, wherein the degree of substitution for acetate groups ranges from 0.5 to 2.5, and the degree of substitution for succinate groups ranges from 0.05 to 1.5. In still another embodiment, the dextran polymer derivative is dextran acetate succinate, wherein the degree of substitution for acetate groups ranges from 1.0 to 2.3, and the degree of substitution for succinate groups ranges from 0.1 to 1.5.

In another embodiment, the dextran polymer derivative is dextran propionate succinate, wherein the degree of substitution for propionate groups ranges from 0.1 to 2.5, and the degree of substitution for succinate groups ranges from 0.05 to 1.5. In another embodiment, the dextran polymer derivative is dextran propionate succinate, wherein the degree of substitution for propionate groups ranges from 0.25 to 2.0, and the degree of substitution for succinate groups ranges from 0.1 to 1.5.

In another embodiment, the dextran polymer derivative is dextran acetate propionate succinate, wherein the degree of substitution for acetate groups ranges from 0.05 to 2.5, the degree of substitution for propionate groups ranges from 0.05 to 2.5, and the degree of substitution for succinate groups ranges from 0.05 to 1.5. In another embodiment, the dextran polymer derivative is dextran acetate propionate succinate, wherein the degree of substitution for acetate groups ranges from 0.1 to 2.0, the degree of substitution for propionate groups ranges from 0.1 to 2.0, and the degree of substitution for succinate groups ranges from 0.1 to 1.5. In one embodiment, the dextran used to form the dextran polymer derivative has a molecular weight that may range from 1,000 to 200,000 daltons. As used herein, by "molecular weight" is meant the number-average molecular weight as determined by chromatographic methods well known in the art. In these methods, the number-average molecular weight corresponds to the arithmetic mean of the molecular weights of individual macromolecules. In one embodiment, the dextran used to form the dextran polymer derivative has a molecular weight of from 1,000 to 200,000 daltons. In another embodiment, the dextran used to form the dextran polymer derivative has a molecular weight of from 2,000 to 60,000 daltons. In still another embodiment, the dextran used to form the dextran polymer derivative has a molecular weight of from 2,000 to 25,000 daltons. Thus, in one embodiment, the dextran polymer derivative has a molecular weight of from 1,000 to 200,000 daltons. In another embodiment, the dextran polymer derivative has a molecular weight of from 2,000 to 60,000 daltons. In still another embodiment, the dextran polymer derivative has a molecular weight of from 2,000 to 25,000 daltons. The degree of substitution of the substituents is chosen so that the polymer is hydrophobic relative to un-derivatized dextran. This increased hydrophobicity leads to increased solubility in organic solvents or mixtures of water and organic solvents. This allows the dextran polymer derivative to be co-dissolved with an active in organic solvents or in mixtures of water and organic solvents. In one embodiment, the degree of substitution of substituents is chosen such that the solubility of the dextran polymer derivative in methanol is at least 1 mg/mL when measured at 25°C. For comparison, the solubility of un-derivatized dextran with an average molecular weight of about 10,000 daltons is less than 0.01 mg/mL.

Ester- linked groups also decrease the tendency of the polymer to absorb water. Following formation of inhalable powders comprising an active and the dextran polymer derivative, the powders absorb less water from the surrounding atmosphere relative to powders formed from un-derivatized polysaccharides, such as dextran. This lower water absorption results in the powders having a reduced tendency to aggregate or agglomerate such that they are more easily dispersed or aerosolized for inhalation. This results in a greater fraction of the dosed powder reaching the airways of the lung. Thus, in one embodiment, the degree of substitution of acetate, propionate, and succinate are chosen such that the mass of water absorbed by the dextran polymer derivative is significantly less than that absorbed by underivatized dextran. Preferably, the mass of water absorbed by the dextran polymer derivative is at least 10% less than that absorbed by underivatized dextran when measured by dynamic vapor absorption at 90% relative humidity (RH) and 25°C. For comparison, the mass of water absorbed by underivatized dextran, when measured by dynamic vapor absorption at 90% RH and 25°C is about 26 wt%. Thus, in one embodiment, the dextran polymer derivative absorbs less than 23 wt% water when measured by dynamic vapor absorption at 90% RH at 25°C. In another embodiment, the dextran polymer derivative absorbs less than 20 wt% water at 90% RH at 25°C. In still another embodiment, the dextran polymer derivative absorbs less than 18 wt% water at 90% RH at 25°C.

The addition of ester-linked acetate, propionate, and succinate groups to the dextran polymer to reduce water absorption also results in the glass-transition temperature (Tg) of the polymer equilibrated with a humid atmosphere being higher than that of the corresponding underivatized dextran. This higher Tg leads to improved properties for the inhalable dry powders of the present invention comprising particles comprising active and dextran polymer derivative. Improved properties may include a reduced tendency to adhere to surfaces or other particles and agglomerate. Another improved property is the improved physical stability of the powder when the powder is a molecular dispersion of active in the dextran polymer derivative. This improved stability may be due to the increased solubility of the active in the dextran polymer derivative, as well as reduced mobility, as evidenced by the higher Tg when equilibrated with humid atmosphere. Thus, in one embodiment, the degree of substitution of acetate, propionate, and succinate is chosen such that the Tg of the dextran polymer derivative is significantly higher than that of underivatized dextran when exposed to a humid atmosphere. In one embodiment, the Tg of the dextran polymer derivative is at least 10⁰C greater than that of underivatized dextran when the powders are exposed to a 50% RH atmosphere at 25°C. For comparison, the Tg of underivatized dextran powder when exposed to a 50% RH atmosphere at 25°C is about 45 to 50⁰C. Thus, in one embodiment, the Tg of the dextran polymer derivative is at least 50⁰C when exposed to a 50% RH atmosphere at 25°C. In another embodiment, Tg of the dextran polymer derivative is at least 60⁰C when exposed to a 50% RH atmosphere at 25°C.

In yet another embodiment, the degree of substitution of acetate, propionate, and succinate and the amount of active included in the particles comprising active and the dextran polymer derivative are chosen such that the Tg of the particles is at least 10⁰C greater than that of underivatized dextran when the particles are exposed to 90% RH at 25°C.

In one embodiment, it is preferable that the dextran polymer derivatives be well tolerated when delivered as a molecular dispersion to the lung. In general, it is believed that the polymer is better tolerated when the polymer has at least some solubility or dispersability in the lung fluid that is present in vivo on the surface of the lung. Thus, in one embodiment, the degree of substitution of acetate, propionate, and succinate is chosen such that the polymer has at least some solubility in in vivo lung fluid or in vitro simulated lung fluid solutions. The solubility of the polymer may be evaluated in simulated lung fluid. As used herein, simulated lung fluid (SLF) consists of the following:

Thus, in one embodiment, the solubility of the polymer in SLF is at least 0.1 mg/ml. In another embodiment, the solubility of the polymer in SLF is at least 1 mg/ml.

In general, the solubility of the dextran polymer derivative in SLF decreases with increasing degree of substitution of acetate and propionate groups, and the solubility of the dextran polymer derivative in SLF increases with increasing degree of substitution of succinate.

Methods for preparation of ester derivatives of carbohydrates are known. See for example Advances in Polymer Science, 205, Polysaccharides II, Edited by Dieter Klemm (Springer- Verlag, Berlin Heidelberg, 2006). Methods for the preparation of the dextran polymer derivatives of the present invention can be derived from such known methods. In certain embodiments, the dextran polymer derivatives are prepared as follows. In a first method, dextran is first modified by substitution with an alkyl group followed by addition of succinate. The dextran may be first dissolved in a suitable solvent system such as formamide, dimethyl formamide (DMF), or N- methylpyrrolidone (NMP), together with a base, such as pyridine or the sodium salt of the carboxylate corresponding to the alkyl group to be substituted. An anhydride of the alkyl group to be substituted onto the dextran backbone may then be added to the mixture. The reaction mixture may then be stirred at temperatures ranging from 0 to 100⁰C for a period of from 30 minutes to 72 hours. The reaction may then be quenched by adding water to precipitate the polymer. The resulting precipitate may be collected by filtration. Alternatively, the polymer may be isolated by extraction into a solvent, such as ethyl acetate or methylene chloride, and the extraction solvent removed, for example, by evaporation or spray drying. The polymer may be further rinsed, filtered and dried prior to use.

The resulting dextran polymer derivative is then dissolved in the carboxylic acid corresponding with the alkyl group that has been substituted together with the sodium salt of the corresponding carboxylate. For example, if dextran propionate has been prepared, then it is dissolved in propionic acid together with sodium propionate. Succinic anhydride is then added. The reaction mixture may then be stirred at temperatures ranging from 0 to 100⁰C for a period of from 30 minutes to 72 hours. The reaction may then be quenched by adding water to precipitate the polymer. The resulting precipitate may be collected by filtration. Alternatively, the polymer may be isolated by extraction into a solvent, such as ethyl acetate or methylene chloride, and the extraction solvent removed, for example, by evaporation or spray drying. The polymer may be further rinsed, filtered and dried prior to use. In another method, dextran is first modified by substitution with an alkyl group followed by addition of succinate, but the dextran alkyl ester is not isolated and purified prior to addition of the succinic anhydride. In this method, the dextran alkyl ester is first formed, followed by addition of succinic anhydride. In yet another method, the dextran is modified by substitution with an alkyl group and succinate simultaneously. In this method, dextran may be first dissolved in a suitable solvent system such as formamide, DMF, or NMP, together with the sodium salt of the carboxylate corresponding to the alkyl group to be substituted. An anhydride of the alkyl group to be substituted onto the dextran backbone and succinic anhydride may then be added to the mixture. The reaction mixture may then be stirred at temperatures ranging from 0 to 100⁰C for a period of from 30 minutes to 72 hours. The reaction may then be quenched by adding water to precipitate the polymer. The resulting precipitate may be collected by filtration. Alternatively, the polymer may be isolated by extraction into a solvent, such as ethyl acetate or methylene chloride, and the extraction solvent removed, for example, by evaporation or spray drying. The polymer may be further rinsed, filtered and dried prior to use.

The degree of substitution of alkyl esters and succinate groups on the dextran polymer may be determined using standard techniques, such as nuclear magnetic resonance (NMR) analysis or high-performance liquid chromatography (HPLC). For example, ¹³C NMR analysis may be used to determine the number of alkyl ester and succinate groups using the ratio of the peak area of the groups to the peak area of the anomeric carbon in the dextran ring.

Actives The particles containing dextran polymer derivatives 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. As used herein, by "active" is meant a drug, medicament, pharmaceutical, therapeutic agent, nutraceutical, or other compound that may be desired to be administered to the lungs. 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, oligoneucleotides, vaccines, and various derivatives of such materials. In one embodiment, the active is a small molecule. In another embodiment, the active is a biological active. In still another embodiment, the active is a mixture of 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, salivary- gland- associated lymphoid tissue (SALT), as well as vaccines targeted to other tissues.

The active may be highly water soluble, sparingly water soluble, or poorly water soluble. In one embodiment, the active is "poorly water soluble," meaning that 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. The active may have an even lower aqueous solubility, such as less than 1 mg/mL, less than 0.1 mg/mL, and even less than 0.01 mg/mL.

Each named active should be understood to include the nonionized form of the active, pharmaceutically acceptable salts of the active, or any other pharmaceutically acceptable forms of the active. By "pharmaceutically acceptable forms" is meant any pharmaceutically acceptable derivative or variation, including 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 (LTPvAs) including antagonists Of LTB₄, LTC₄, LTD₄, and LTE₄; histamine receptor antagonists including Hl and H3 antagonists; α_r 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 NKi, 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 NFiφ 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 micro-organisms which can colonise the respiratory tract; HDAC inhibitors; PB 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 which may be used in the present formulation 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.

Particles Suitable for Inhalation

The dry powder composition is comprised of particles comprising the active and the dextran polymer derivative. The particles are sized so as to be suitable for inhalation. As used herein, the term "inhalation" refers to delivery to a patient through the mouth and/or nose. In one embodiment, the dry powder suitable for inhalation is delivered to the "upper airways." The term "upper airways" refers to delivery to nasal, oral, pharyngeal, and/or laryngeal passages, including the nose, mouth, nasopharynx, oropharynx, and/or larynx. In another embodiment, the dry powder suitable for inhalation is delivered to the "lower airways." The term "lower airways" refers to delivery to the trachea, bronchi, bronchioles, alveolar ducts, alveolar sacs, and/or alveoli. 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, each chamber corresponding to a different range of particle size. 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", or particles that have an aerodynamic diameter of less than 4.6 μm. In these example cases the NGI experiment utilizes a Monodose capsule based inhaler device.

In another embodiment, the particles have a MMAD of 0.5 to 10 μm, more preferably 1 to 5 μm, and even more preferably 1.5 to 3.5 μm. In another embodiment, the particles have a FPF of at least 50%, and more 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 mean geometric diameter of from 0.5 to 10 μm, more preferably 1 to 5 μm, and even more preferably 2-4 μm.

The dry particles may have a native geometric size distribution span of less than 3, more preferably less than 2. The term "span" is defined as follows:

where D₉₀, D₅₀, and Di₀ 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 dry powder may have a tap density of 0.05 to 1 g/cm³, more preferably 0.07 to 0.5 g/cm³, and more preferably from 0.1 to 0.3 g/cm³.

In another embodiment, the particles have a MMAD ranging from 0.5 to 100 μm. In one embodiment, such particles are used in devices designed for delivery of particles to both the nose and the mouth. The particles in the dry powder each contain one or more active compounds and the dextran polymer derivative. In one embodiment, the active(s) are molecularly dispersed in the polymer to give an amorphous solid.

In another embodiment, the active and dextran polymer derivative constitute at least 5 wt% of the particles. In yet another embodiment, the active and dextran polymer derivative constitute at least 10 wt% of the particles. In still another embodiment, the active and dextran polymer derivative constitute at least 25 wt% of the particles. In another embodiment, the active and dextran polymer derivative constitute at least 50 wt% of the particles. In yet another embodiment, the active and dextran polymer derivative constitute at least 75 wt% of the particles. In still another embodiment, the particles consist essentially of the active and the dextran polymer derivative. Thus, in some embodiments, the particles may include optional additional excipients such as: polyvinylpyrrolidone (PVP), tocopherol polyethylene glycol 1000 succinate (also known as vitamin E TPGS, or TPGS), dipalmitoyl phosphatidyl choline (DPPC), trehalose, sodium bicarbonate, glycine, sodium citrate, and lactose. The dry powder may have an emitted dose of at least 50%, more preferably at least 70%. By "emitted dose" is meant dose delivered from the inhalation device.

The relative amounts of active and dextran polymer derivative in the particles may range from 0.01 wt% to 99 wt% active, and from 1 wt% to 99.99 wt% dextran polymer derivative. In one embodiment, each particle may comprise from 0.01 wt% to 99 wt% active, and from 1 wt% to 99.99 wt% dextran polymer derivative. In another embodiment, the amount of active may range from 0.1 wt% to 80 wt%, or from 0.1 to 60 wt%, or from 1 to 40 wt%. The amount of dextran polymer derivative may range from 20 wt% to 99.9 wt%, 40 wt% to 99.9 wt% or from 60 wt% to 99 wt%. In still another embodiment, the particles have the following composition: from 0.1 to 80 wt% active, and from 20 to 99.9 wt% dextran polymer derivative. In yet another embodiment, the particles have the following composition: from 0.1 to 60 wt% active, and from 40 to 99.9 wt% dextran polymer derivative. In another embodiment, the particles have the following composition: from 1 to 40 wt% active, and from 60 to 99 wt% dextran polymer derivative. The particles comprising active and dextran polymer derivative may be in essentially any physical state. As the dextran polymer derivative is amorphous, the particles may comprise one or more active-rich domains dispersed in a dextran polymer derivative phase, or the particles may comprise an amorphous molecular dispersion of active molecules dispersed in the dextran polymer derivative, or the particles may comprise any state or combination of states in between. When the particles comprise active rich domains, the active-rich domains may be amorphous or crystalline or any combination. However, in one embodiment, the active present in the particles is essentially amorphous. Preferably at least 90 wt% of the active present in the particles is amorphous. By "amorphous" is meant that the active is non-crystalline as determined by differential scanning calorimetry or powder X ray diffraction.

In one embodiment, the particles comprise a solid dispersion of amorphous active molecularly dispersed in the dextran polymer derivative.

In another embodiment, when the active present in the particles is essentially amorphous, the particles comprise a solid dispersion of the active and polymer consisting essentially of amorphous active molecularly dispersed throughout the polymer. In this embodiment, the solid dispersion may be considered a "solid solution" of active and polymer. 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 consisting of amorphous active molecularly dispersed throughout the polymer in amounts greater than the solubility of the active in the polymer. A dispersion is considered a "solid solution" when it displays a single Tg when analyzed by differential scanning calorimetry. Preferably, the particles have at least one Tg due to the amorphous character of the polymer. Preferably, at least 90 wt% of the active in the particles is amorphous.

In another embodiment, the particles are solid dispersions of the active and polymer consisting essentially of amorphous active molecularly dispersed throughout the polymer.

In another embodiment, the particles comprise two or more actives. In still another embodiment, the particles comprise one or more actives, one or more dextran polymer derivatives, and additional excipients. These additional excipients include PVP, TPGS, DPPC, trehalose, sodium bicarbonate, glycine, sodium citrate, and lactose.

In still another embodiment, the relative amounts of active and polymer are chosen so that 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 50⁰C, more preferably at least 80⁰C, and even more preferably at least 100⁰C. The solid dispersion has a single glass transition temperature, indicating that the solid dispersion is a homogeneous solid solution.

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 drug may first be processed by processes such as milling, precipitation, or crystallization to form particles comprising active that are less than 5 μm in diameter, and preferably less than 1 μm in diameter. The particles may then be formed by combining the active with the dextran polymer derivative, followed by milling, dry granulation, wet granulation, extrusion, precipitation, or the addition and removal of solvent. A preferred method for forming such particles is by spray drying. The active, the dextran polymer derivative, and optional excipients may be partially or completely dissolved in a solvent. Thus, the fluid that is spray dried may be a suspension of amorphous or crystalline particles or 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 derivative dissolved in a common solvent. In another embodiment, the fluid that is spray dried consist essentially of a solution of active and dextran polymer derivative dissolved in a common solvent. In still another embodiment, the fluid that is spray dried comprises a suspension of active particles in a solution of dextran polymer derivative dissolved in a common solvent.

When the active is substantially dispersed in the dextran polymer derivative, the particles may be formed by use of heat or solvent to allow homogenation of the active and the dextran polymer derivative. For example, active and the dextran polymer derivative 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. Preferably, the active and dextran polymer derivative are 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. A preferred process for forming particles in which the active is molecularly dispersed is spray drying.

The particles may be formed by spray drying a solution comprising one or more actives and the dextran polymer derivative. The spray drying solution is prepared by dissolving the active(s) and dextran polymer derivative 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 of less than 150⁰C. Suitable solvents include water, acetone, methanol, ethanol, methyl acetate, ethyl acetate, tetrahydrofuran (THF), and dichloromethane and mixtures of solvents. 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. 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. Droplets dry rapidly, forming particles comprising the active and dextran polymer derivative. The particles exit the spray dryer and are collected, such as in a cyclone. Dosage Forms and Administration

The dry powders are suitable for inhalation. Compositions comprising the dry powders may further comprise additional optional excipients, such as diluents, and fillers. In one embodiment, the particles comprising the active and dextran polymer derivative may collectively constitute from 5 wt% to 100 wt% of the dry powder. In another embodiment, the particles of active and dextran polymer derivative may constitute from 50 wt% to 100 wt% of the dry powder. In still another embodiment, the particles of active and dextran polymer derivative may constitute from 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 derivative. The powders may be administered to a patient 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.

Examples

Dextran Polymer Derivatives

Polymer 1, dextran propionate succinate, having the degree of substitution shown in Table 1, was synthesized using the following procedures. First 90 g of dextran having a molecular weight of 10,000 daltons (available from Amersham Sciences, Piscataway, NJ) was added to 495 g of formamide at 50⁰C in a 1 L round bottom flask fitted with a glass jacket heated with mineral oil and an overhead mixer paddle stirring at 150 rpm. After 1 hour 30 g of sodium propionate was added to the mixture and stirred for 2.5 hours. To this, 195 g of propionic anhydride was added in 30 g increments over 30 minutes while the mixture stirred at 325 rpm. Finally, 13.5 g of succinic anhydride was added. After one hour the stir rate was reduced to 150 rpm and the solution was stirred overnight.

The polymer was precipitated by pumping 200 mL aliquots of polymer solution into a blender containing 1500 mL water and blended for 45 seconds. The solids were collected using a large Buchner funnel and Whatman type 113 filter paper. The solids were then washed in a 5 gallon plastic container containing 12 L water and stirred using an overhead mixer on a low setting for 20 minutes. The washed polymer was again filtered and collected as described above and blended in aliquots in the blender with water. The polymer/water mixture from the blender was placed into a 5 gallon plastic container with 7.5 L water and stirred by overhead mixing for 20 minutes. The polymer was collected by filtration as described above. The wash method was repeated twice more using the filtered polymer and 12 L water, stirring with overhead mixing for 20 minutes each time. Finally, the wet polymer was spread onto a tray and dried in a 40⁰C oven overnight.

Reverse phase high-performance liquid chromatography (HPLC) was used to calculate the degree of substitution of propionate and succinate groups. For measurement of free acid content, polymer was dissolved in pH 7.4 phosphate buffer at a concentration of 12 mg/mL for 4 hours, then diluted 1 : 1 with 0.1% H₃PO₄ to a final pH of approximately 3. For measurement of propionate and succinate groups the polymer was hydrolyzed in IN sodium hydroxide for 4 hours at a concentration of 3 mg/mL, and then diluted 1:1 to a final pH of approximately 3. HPLC analysis was performed on a Phenomenex Aqua C 18 column with a pH 2.8 phosphate buffer eluent at a flow of lmL/min, and UV detection at 215 nm. Degree of substitution was calculated using the determined amount of anhydride and free acid of the propionate and succinate groups. Results from degree of substitution analysis are shown in Table 1.

Dynamic Vapor Sorption (DVS) was used to determine water uptake. The polymer was weighed into DVS pans in 10 to 50 mg aliquots. The polymer sample was equilibrated to 0% relative humidity (RH) in the DVS and weighed. The polymer sample was then equilibrated to 90% RH and weighed. Water uptake is the difference in mass of the sample at 90% RH and at 0% RH. The measured polymer properties are shown in Table 1. For comparison, the properties of underivatized dextran are included in Table 1 as Polymer C-I. Table 1

* ND = not determined.

Polymer 2, dextran acetate succinate, having the degree of substitution shown in Table 1, was synthesized using the following procedure. First 30 g of dextran having a molecular weight of 10,000 daltons and 1O g of sodium acetate were added to 100 mL formamide at 50⁰C in a large beaker and magnetically stirred. To this, 60 g of acetic anhydride was added and stirred for 15 hours. Next, 8 g of succinic anhydride was added and the solution was stirred for 6 hours. After 21 hours the polymer was precipitated by pouring aliquots of the reaction mixture into 750 mL supersaturated brine in a blender. The mixture was allowed to settle and recovered polymer to dry over night. After this, 350 mL of acetone was added to dissolve the polymer and separate out the salts. The mixture was re-precipitated in 750 mL acidified water and then copious amounts of sodium chloride were added and a yellow gummy substance on the top of the mixture was removed. All solids were re-dissolved in 250 mL acetone. The acetone was then removed by roto-evaporation. Finally, the polymer was collected by filtration and vacuum dried for several hours. HPLC degree of substitution determination and DVS analysis were performed as described for polymer 1.

The Tg of the polymer was determined using modulated differential scanning calorimetry (mDSC) as follows. Samples of the polymer (about 10 mg) were equilibrated at 50% RH overnight in an environmental chamber at ambient temperature. The samples were then loaded into pans and crimped the environmental chamber. The sample was then analyzed on a QlOOO mDSC (TA Instruments, New Castle, Delaware). Samples were scanned over the temperature range of 0⁰C to 200⁰C, at a scan rate of 2.5°C/min, and a modulation rate of ± 1.5°C/min. The Tg was calculated based on half height. The Tg is also reported in Table 1.

Polymer 3, dextran propionate succinate, having the degree of substitution shown in Table 1 , was synthesized using the following procedure. First dextran propionate was synthesized by adding 30 g of dextran having a molecular weight of 3,000 daltons to 150 mL formamide in a large beaker and stirring magnetically until dissolved. To this, 1O g of sodium propionate was added and the mixture was heated to 50⁰C. Next, 50 g of propionic anhydride was added with vigorous stirring. The stir rate was reduced and the solution stirred overnight. The polymer was then precipitated by pouring the solution into a large beaker containing 2500 mL water then saturating with sodium chloride. The solid polymer was collected and transferred to a small beaker. The aqueous portion was discarded and the residual solids left in the large beaker were dissolved with 200 mL acetone and added to the collected polymer in the small beaker. This solution was precipitated into 2 L water and saturated with sodium chloride. The solids were collected and dissolved as described above. The mixture was combined with 200 mL isopropyl alcohol (IPA) and rotary evaporated to dryness. The remaining solids were dissolved in 100 mL acetone and vacuum filtered through a 5 μm nylon filter to remove salts. The acetone was removed by rotary evaporation and the remaining solids consisting of dextran propionate were dried under vacuum.

The dextran propionate described above (8.8 g total) was then dissolved in 80 mL propionic acid with 8.8 g sodium propionate and 2.6 g succinic anhydride, stirring at 85°C for 7.5 hours. The heat was turned off and the mixture sat overnight. The polymer was precipitated by adding the solution to 800 mL rapidly stirred water in a 1 L beaker and then was saturated with sodium chloride. The precipitated polymer was collected and dissolved in 50 mL acetone. The rinse step was repeated twice more, and then 200 mL IPA was added and the solvent removed with rotary evaporation. The remaining solids were dried under vacuum. The solids were then dissolved into 200 mL acetone and vacuum filtered through a 0.2 μm nylon filter to remove salts. The remaining solution was rotary evaporated and the solids dried under vacuum.

HPLC degree of substitution determination and DVS analysis were performed as described for polymer 1. Polymer 4, dextran propionate succinate, having the degree of substitution and water uptake shown in Table 1 , was synthesized using the following procedure. First dextran propionate was synthesized by adding 468 g formamide to a reaction apparatus as described for Polymer 1, stirring at 180 rpm for 30 minutes. To this, 124 g dextran having a molecular weight of 5,000 daltons was added and stirred until dissolved. Next, 44 g sodium propionate was added and stirred until dissolved. Finally, 268 g propionic anhydride was added and the mixture stirred overnight. The solution was pumped from the reactor into a beaker using a peristaltic pump. Polymer was precipitated out of solution by quenching into water; 100 mL aliquots were added to 1.5 L water in a blender as described for polymer 1. The water layer was poured off and 1.5 L water was added to the precipitated polymer. The polymer was then blended for 1 minute.

Next, the polymer was collected in a Buchner funnel with Whatman 113 filter, and then placed in a 5 gallon container. After all 9 polymer aliquots were quenched and placed in the container, 10 L of water was added and the mixture was stirred for at least 15 minutes with an overhead stirrer. The solids were vacuum filtered as described above to remove the water. The large 10 L washes were repeated twice more. The solids consisting of dextran propionate were transferred to a tray lined with foil and dried overnight at 40⁰C and 0 to 15% RH.

To form Polymer 4, 595 g propionic acid was then added to a 1 L reactor using the same apparatus as for dextran propionate synthesis, except that the jacket temperature was at 87°C and the impellor was Teflon, stirring at 200 rpm. To this, 60 g of the above dextran propionate was added and stirred until dissolved. Next, 60 g of sodium propionate was added and stirred for 2 hours. Finally 18 g of succinic anhydride was added and stirred at 180 rpm for 2 hours. Solids were precipitated, blended, re -blended, washed, filtered and dried as described above. HPLC degree of substitution determination and DVS analysis were performed as described for polymer 1.

Polymer 5, dextran propionate succinate, having the degree of substitution and water uptake shown in Table 1 , was synthesized using the procedures described in synthesis of Polymer 5 except that dextran having a molecular weight of 20,000 daltons was used as the starting material.

HPLC degree of substitution determination and DVS analysis were performed as described for polymer 1.

Polymer 6, dextran acetate succinate, having the degree of substitution shown in Table 1, was synthesized using the following procedure. First 30 g of dextran having a molecular weight of 10,000 daltons and 1O g of sodium acetate were added to 100 mL formamide at 50⁰C in a large beaker and magnetically stirred over night. To this, 75 g of acetic anhydride was slowly added and stirred over night. Next, 12 g of succinic anhydride was added and the solution was stirred for 6 hours. After 23 hours the polymer was precipitated by pouring aliquots of the reaction mixture into 750 mL acid/brine in a blender. Allowed mixture to settle and collected via Buchner funnel and filter. All solids were blended with 50OmL water. The solids were then collected by filtering through a Buchner funnel with filter paper. The solids were then dissolved in 35OmL acetone and stirred for 3 days. Precipitated aliquots of solution in acidified water and let settle. The solids were collected by filtering through a Buchner funnel and vacuum desiccated to dry. HPLC degree of substitution determination was performed as described for polymer 1.

Polymer 7, dextran succinate, having the degree of substitution shown in Table 1, was synthesized using the following procedures. First 249.5 g of dextran having an average molecular weight of 5,000 daltons (available from Pharmacosmos, Holbaek, Denmark)) was added to 473.1 g of formamide at 50⁰C in a 1 L round bottom flask fitted with a glass jacket heated with mineral oil and an overhead mixer paddle stirring at 150 rpm. After complete dissolution, typically less than 1 hr, 83.3 g of sodium propionate was added to the mixture and stirred for approximately 2 hours. To this, 79.5 g of succinic anhydride (Fluka Chemical) was added. After approximately 30 minutes a 51.3 g sample was removed using a peristaltic pump. To the remaining solution in the reactor, an additional 88.2 g of succinic anhydride was added. After 1 hr a 50 g sample was collected and washed as follows. Polymer 7 was precipitated using a 20: 1 methanol to polymer ratio, two times, decanting the liquid between washes. The solid material was dried in a 4O⁰C oven overnight. The material was hardened and was milled with a mortar and pestle in methanol, and then washed with acetone, filtered, and re-dried.

Polymer 8, dextran succinate, having the degree of substitution shown in Table 1 , was synthesized using the following procedures. To the solution remaining in the reactor after collection and isolation of Polymer 7 was added 68.7 g of succinic anhydride were added and allowed to react for approximately 1 hr. A 50.08 g sample was removed using a peristaltic pump and an additional 64.7 g succinic anhydride was added in combination with 51.4 g of propionic acid to increase solubility of the substrate. This reaction was allowed to proceed overnight and 50.1 g of polymer 8 was removed from the reactor. Polymer 8 (35 mL) was mixed with 700 mL of acetone at 250 rpm and up to 1400 rpm in a Silverson high shear mixer. The resultant particles were fine and did not settle quickly. The material was filtered and dried overnight at 40⁰C. The dried material was remixed to break up a thin film on the top of a fine powder, and re-dried. Polymer 9, dextran succinate, having the degree of substitution shown in Table

1 , was synthesized using the following procedures. To the solution remaining in the reactor after collection and isolation of Polymer 8 was added a 61.9 g aliquot of succinic anhydride and allowed to react to completion as judged by FTIR. The contents of the reactor (polymer 9) were removed by pumping into a glass vessel. Polymer 9 was washed at a 20: 1 (g/g) acetone :polymer ratio in a Silverson high shear mixer at 2200 rpm up to 5000 rpm. Small particles were obtained. Subsequent washes were performed using a stir bar. The polymer was filtered and dried overnight in a 4O⁰C oven. The dried material was remixed to break up a thin film on the top of a fine powder, and re-dried.

Polymer 10, dextran propionate, having the degree of substitution shown in Table 1 , was synthesized using the following procedures. First 210 g of dextran having an average molecular weight of 5,000 daltons (available from Pharmacosmos, Holbaek, Denmark) was added to 397.4 g of formamide (Sigma-Aldrich) at 50⁰C in a 1 L round bottom flask fitted with a glass jacket heated with mineral oil and an overhead mixer paddle stirring at 300 rpm. After complete dissolution, 74.72 g of sodium propionate (Sigma Aldrich) was added to the mixture and stirred for approximately 1 hour. A background spectrum was collected using FTIR. To this, 196.3 g of propionic anhydride (Sigma Aldrich) was added while the mixture stirred at 325 rpm. After approximately 1 hour, when the reaction neared completion as judged by FTIR, a 50 g sample was removed from the reactor using a peristaltic pump. The polymer was precipitated by washing twice with 400-500 mL each of acetone. For each wash, the polymer and acetone were thoroughly mixed using vortex and manual shaking. The solids were collected each time using a large Buchner funnel and Whatman type 113 filter paper. Finally, the wet polymer was spread onto a tray and dried in a 40⁰C oven overnight. Any pellets found were crushed and dried further. Polymer 11 , dextran propionate, having the degree of substitution shown in

Table 1, was synthesized using the following procedures. To the solution remaining in the reactor after collection and isolation of Polymer 10 was added a 79.4 g aliquot of propionic anhydride and the mixture was allowed to react to apparent completion as judged by FTIR (approximately 40 minutes). A 50 g sample was removed from the reactor. Propionic anhydride was added (61.7 g) and allowed to react to apparent completion. A 50 gram sample was removed by peristaltic pump, and isolated by washing twice with approximately 500 mL of water each time in a WaringPro 3 HP blender, and decanting of the liquid solution. The flocculated material was washed further in a 5 gallon bucket with approximately 5 L of water using an overhead stirrer. The polymer was collected by filtration using a large Buchner funnel and Whatman type 113 filter paper. The wet polymer was spread onto a tray and dried in a 40⁰C oven overnight.

Polymer 12, dextran propionate, having the degree of substitution shown in Table 1, was synthesized using the following procedure. First 165 g of dextran having a molecular weight of 10,000 daltons and 55 g of sodium propionate were added to 495 g formamide at 50⁰C in a 1 L glass reactor equipped with a Heidolph mixer and pitched blade turbine. To this solution, 192.7 g of propionic anhydride was added and stirred at 150 rpm for 1.5 hours. The reaction went to completion as measured by FTIR. Next about 299 g of the reaction mixture was removed from the reactor and quenched in two aliquots by adding about 150 g of reaction mixture to 1.5 L water saturated with NaCl (e.g., brine). The mixture was blended in a blender, vacuum filtered using Whatman filter paper to recover the polymer, and resuspended and washed with 1.7 L salt brine for 6 total washes. Upon completion of washing, the polymer was air dried, and then dissolved in about 500 gm of methanol. The salt crystals were filtered out of the methanol/polymer solution by vacuum filtration using a Whatman glass microfibre filter. The final solution was clear methanol/polymer. This solution was spray dried in a Niro PSD-I spray dryer and residual methanol was removed in a tray dryer for 24 hours at 40⁰C and <10% RH. The final polymer was collected and analyzed for substitution as previously described.

Polymer 13, dextran propionate succinate, having the degree of substitution shown in Table 1, was synthesized using the following procedure. First 30 g of dextran having a molecular weight of 10,000 daltons and 1O g of sodium propionate were added to 150 mL formamide at 50⁰C in a large beaker and magnetically stirred until dissolved. To this, 50 g of propionic anhydride was added and stirred for 30 minutes at 50⁰C. Next, 9 g of succinic anhydride was added and the solution was stirred overnight at 50⁰C. After 17.5 hours the polymer was precipitated by pouring aliquots of the reaction mixture into 750 mL pH 4 brine. This was followed by two washes of solids in 750 mL DI water in a blender. The final wash in DI water was followed by complete dissolution of solids in 20OmL acetone. The solution was filtered through a 5μm nylon filter. 50 mL of IPA was added and the IPA was then removed by roto-evaporation. Finally, the polymer was collected by filtration and dried under vacuum. The solids were then dissolved in 400 mL acetone and sent for spray drying.

HPLC degree of substitution determination was performed as described for polymer 1.

Polymer 14, dextran propionate succinate, having the degree of substitution shown in Table 1, was synthesized using the following procedures. First 140.0 g of dextran having an average molecular weight of 5,000 daltons (available from

Pharmacosmos, Holbaek, Denmark) was added to 265.1 g of formamide at 50⁰C in a 1 L round bottom flask fitted with a glass jacket heated with mineral oil and an overhead mixer paddle stirring at 150 rpm. After complete dissolution 49.9 g of sodium propionate was added to the mixture and stirred for approximately 2 hours. To this, 106.7 g of propionic anhydride was added while the mixture stirred at 325 rpm. Finally, after approximately 30 minutes, 82.7 g of succinic anhydride was added. After one hour the stir rate was reduced to 150 rpm and the solution was stirred overnight.

The polymer (approximately 450 ml) was pumped into a glass vessel and washed at a 7: 1 (v/v) ratio of acetone to polymer, four times. A stir bar was used for mixing, as well as manual shaking. The liquid was decanted in between washes. The solids were collected using a large Buchner funnel and Whatman type 113 filter paper. The polymer was spread onto a tray and dried in a 40⁰C oven overnight.

Polymer 15, dextran acetate, having the degree of substitution shown in Table 1, was synthesized using the following procedure. First 30 g of dextran having a molecular weight of 10,000 daltons and H g of sodium acetate were added to 100 mL formamide at 50⁰C in a large beaker and magnetically stirred until dissolved. To this, 60 g of acetic anhydride was added and stirred overnight at 50⁰C. Approximately 24 hours later, the reaction was precipitated into 2500 mL acidified (pH 4 with acetic acid) brine. The solution was filtered and a sticky polymer was collected. This was then re- dissolved in methanol. A small amount of IPA was added to the methanol solution and filtered. Small aliquots were added to ethyl acetate in two- IL round bottom flasks. The remaining solvent was roto-evaporated off. The polymer was then dissolved in acetone, filtered and roto-evaporated again prior to recovery.

Degree of substitution determination was performed using NMR. DVS was performed as described for polymer 1. Polymer 16, dextran propionate succinate, having the degree of substitution shown in Table 1, was synthesized using the following procedures. First 150.9 g of dextran having an average molecular weight of 5,000 daltons (available from Pharmacosmos, Holbaek, Denmark) was added to 286.1 g of formamide at 50⁰C in a 1 L round bottom flask fitted with a glass jacket heated with mineral oil and an overhead mixer paddle stirring at 150 rpm. After complete dissolution 52.8 g of sodium propionate was added to the mixture and stirred for approximately 2 hours. To this, 110.8 g of propionic anhydride was added while the mixture stirred at 325 rpm. Finally, after approximately 30 minutes, 44.1 g of succinic anhydride was added. After 30 minutes the reaction appeared to be complete as judged by FTIR. The polymer (approximately 460 ml) was pumped into a glass vessel and washed at a 7: 1 (v/v) ratio of acetone to polymer, four times. A stir bar was used for mixing, as well as manual shaking. The liquid was decanted in between washes. The solids were collected using a large Buchner funnel and Whatman type 113 filter paper. The polymer was spread onto a tray and dried in a 40⁰C oven overnight.

Actives Used in Examples

Active 1 was S-(fluoromethyl) 6α,9-difluoro-l lβ,17-dihydroxy-16α-methyl-3- oxoandrosta-l,4-diene-17β-carbothioate, 17-propionate, also known as fluticasone propionate, having the structure:

Active 1 has a solubility of 0.4 μg/mL in pH 7.4 buffer, and a Log P value of 3.7. The T_g of amorphous Active 1 was determined by DSC to be 84°C

Example 1

(Active l :Polymer 1)

A dry powder consisting of particles of a solid dispersion of Active 1 was prepared by forming a spray solution containing 0.02 wt% Active 1, 0.18 wt% Polymer 1, 4.99 wt% water, and 94.81 wt% acetone as follows: the active and solvent were combined in a container and mixed to form a clear solution, then the polymer was added to the solution and mixed for 3 hours.

The spray solution was pumped from a 10-L stainless steel tank using a metering pump into a spray drier (a Niro type XP Portable Spray-Drier with a Liquid- Feed Process Vessel ("PSD-I")), equipped with 3 pressure nozzles (Schlick 1.5 60°; Dusen Schlick, GmbH of Untersiemau, Germany). The PSD-I vessel was equipped with 9-inch and 4-inch chamber extensions to increase the vertical length of the dryer and residence time of the particles in the drying chamber. The inlet nitrogen gas at a flow of 1375g/min was heated to 140⁰C and introduced to the spray drier. The exit temperature of the drying gas was 55°C. The dried material was pneumatically conveyed through 2" ductwork to a cyclone. The resulting solid dispersion particles were collected in a 120 niL jar attached to the bottom of the cyclone via a 2" butterfly valve.

The so-formed solid dispersion particles were then dried under vacuum desiccation for 12 hours at room temperature.

In Vitro Inhalation Performance

The dry powder 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 were evaluated using the NGI. The results of the NGI evaluation for example 1 are shown in Table 2.

Differential Scanning Calorimetry (DSC) DSC was used to measure the glass transition temperature. The solid dispersion samples were equilibrated for a minimum of 14 hours at ambient temperature and <5% RH. Sample pans were crimped and sealed in an environmental chamber, then loaded into a Thermal Analysis QlOOO Differential Scanning Calorimeter equipped with an autosampler (available from TA Instruments, New Castle, DE). The samples were heated by modulating the temperature at ±1.5°C/min, and ramping the temperature up to 200⁰C at 2.5°C/min. The sample had a single Tg at 128°C and no other thermal events, suggesting the composition was amorphous. This was confirmed by powder X ray diffraction (PXRD) which showed an amorphous halo.

Table 2

* FPF - fine particle fraction

**MMAD - mass median aerodynamic diameter Example 2 (Active 1 :Polymer 9)

A dry powder consisting of particles of a solid dispersion of Active 1 was prepared by forming a spray solution containing 0.1 wt% Active 1, 0.9 wt% Polymer 7, and 99 wt% acetone as follows: the active and solvent were combined in a container and mixed to form a clear solution, then the polymer was added to the solution and mixed for 3 hours.

The spray solution was pumped from a 6 L container using a peristaltic pump into a spray drier (a Niro type XP Portable Spray-Drier, PSD-I), equipped with a 2-fluid nozzle (spray systems: liquid is 2050 and air is 120). The PSD-I vessel was equipped with 9-inch and 4-inch chamber extensions to increase the vertical length of the dryer and residence time of the particles in the drying chamber. The inlet nitrogen gas at a flow of 920 g/min was heated to 110⁰C and introduced to the spray drier. The exit temperature of the drying gas was 45°C. The dried material was pneumatically conveyed through 2" ductwork to a cyclone. The resulting solid dispersion particles were collected in a 500 mL jar attached to the bottom of the cyclone via a 2" butterfly valve.

The so-formed solid dispersion particles were then dried under vacuum desiccation for 12 hours at room temperature. The dry powder was tested using the NEXT GENERATION

PHARMACEUTICAL IMPACTOR (NGI), Model 170 (available from MSP Corporation, Shoreview, MN), using the procedures described in Example 1. The results are summarized in Table 2.

Example 3

(In Vivo of Example 2 Formulation)

The dry powder of Example 2 was used in an in vivo test to determine the concentration of Active 1 in the lung, bronchoalveolar lavage fluid (BALF) and plasma of male Sprague Dawley rats after a single inhalation exposure to one of three dose levels of an aerosolized dry powder. Aerosols of the dry powder of Example 2 were generated with a Palas Rotating Brush Generator (RGB) 1000 solid particle disperser (Palas GmbH; Karlsruhean, Germany). The dry powder of Example 2 was loaded into a 14-mm piston and gently packed prior to integration on to the RBG 1000. The RGB 1000 was operated with a brush rotation speed of 1200 revolution/min and a brush feed speed of between 15 and 30 mm/h. Compressed air was added to a final volumetric flow rate of approximately 19.5 L/min. Aerosols were directed through approximately 24 in of a 1.58-cm (diameter) delivery line. Aerosols transited into a flow-past 36-port nose-only rodent exposure chamber. The chamber exhaust flow rate was adjusted to a volumetric flow rate of approximately 22 L/min, slightly higher than the flow rate supplied by the rotating brush aerosol generator. Prior to dosing, aerosols were collected (from the exposure plenum) on 47-mm

Zefluor filters (PALL Life Sciences; Ann Arbor, Mi) at a nominal volumetric flow rate of 0.5 L/min. Particle size distribution was measured using an aerodynamic particle sizer (APS; TSI Model 3321; Shoreview, MN). The MMAD for the dry powder of Example 2 using this aerosol generation technique was determined to be 2.3 μm with a geometric standard deviation (GSD) of 1.6. The concentration of Active 1 in the aerosols was determined to range from 0.4 to 0.8 mg/L.

Eighty-one (81) male Sprague Dawley rats were exposed to the dry powder of Example 2 at target concentrations of 0.1, 1.0, and 2.0 mg/L for 30 minutes, to achieve target doses of 2, 20, and 40 mg/kg, respectively. Animals were sacrificed at nine specified time points post exposure and blood (plasma), BALF, and lungs were harvested. Samples were stored at approximately -70⁰C before and after analysis. Concentrations of Active 1 were determined using an LC/MS/MS method, following liquid-liquid extraction. Table 3 summarizes the results.

Table 4

In a disclosed embodiment, a pharmaceutical composition suitable for inhalation comprises a dry powder comprising particles having a mass median aerodynamic diameter of from 0.5 to 100 μm, said particles comprising: (a) from 0.01 to 99 wt% of an active; and (b) from 1 to 99.99 wt% of a dextran polymer derivative, wherein said dextran polymer derivative is selected from dextran acetate, dextran propionate, dextran succinate, dextran acetate propionate, dextran acetate succinate, dextran propionate succinate, dextran acetate propionate succinate, and mixtures thereof. In some embodiments, said dextran polymer derivative is selected from the group consisting of dextran acetate, dextran propionate, dextran succinate, dextran acetate propionate, dextran acetate succinate, dextran propionate succinate, dextran acetate propionate succinate, and mixtures thereof. The dextran polymer derivative has a total degree of substitution of the acetate, propionate, and succinate groups of greater than or equal to 0.05. In some embodiments, the total degree of substitution of acetate, propionate, and succinate groups is greater than or equal to 0.25.

In any or all of the above embodiments, the dextran polymer derivative has a molecular weight of from 1,000 to 200,000 daltons or from 2,000 to 60,000 daltons.

In any or all of the above embodiments, the particles may be solid dispersions of amorphous active molecularly dispersed in said dextran polymer derivative. In any or all of the above embodiments, at least 50 wt% of said particles consists essentially of said active and said dextran polymer derivative. In any or all of the above embodiments, the particles may consist essentially of said active and said dextran polymer derivative. In any or all of the above embodiments, the particles have the following composition: from 0.1 to 80 wt% said active, and from 20 to 99.9 wt% said dextran polymer derivative. Alternatively, the particles have the following composition: from 0.1 to 60 wt% said active, and from 40 to 99.9 wt% said dextran polymer derivative.

In any or all of the above embodiments, from 50 wt% to 100 wt% of said dry powder comprises said particles. Alternatively, the dry powder may consist essentially of the particles. In any or all of the above embodiments, the particles may comprise two or more actives.

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 such embodiments, the particles have a mass median aerodynamic diameter of from 0.5 to 10 μm or from 1 to 5 μm.

In any or all of the above embodiments, the particles may have a mean geometric diameter of from 0.5 to 10 μm. The particles also may have a fine particle fraction of at least 50%.

Alternatively, the pharmaceutical 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 or from 10 to 70 μm.

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

In any or all of the above embodiments, the particles are formed by spray drying said active and said dextran polymer derivative from a solution comprising said active and said dextran polymer derivative dissolved in a solvent. In any or all of the above embodiments, a packet suitable for insertion into a dry powder inhaler containing the pharmaceutical composition may be provided.

The terms and expressions which have been employed in the foregoing specification are used therein as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding equivalents of the features shown and described or portions thereof, it being recognized that the scope of the invention is defined and limited only by the claims which follow.

Claims

What is claimed is:

1. A pharmaceutical composition suitable for inhalation, comprising a dry powder comprising particles having a mass median aerodynamic diameter of from 0.5 to 100 μm, said particles comprising:

(a) from 0.01 to 99 wt% of an active; and

(b) from 1 to 99.99 wt% of a dextran polymer derivative, wherein said dextran polymer derivative is selected from dextran acetate, dextran propionate, dextran succinate, dextran acetate propionate, dextran acetate succinate, dextran propionate succinate, dextran acetate propionate succinate, and mixtures thereof.

2. The pharmaceutical composition of claim 1 wherein said dextran polymer derivative has a total degree of substitution of the acetate, propionate, and succinate groups of greater than or equal to 0.05.

3. The pharmaceutical composition of claim 2 wherein said total degree of substitution of acetate, propionate, and succinate groups is greater than or equal to 0.25.

4. The pharmaceutical composition of any one of claims 1 -3 wherein said dextran polymer derivative has a molecular weight of from 1,000 to 200,000 daltons.

5. The pharmaceutical composition of claim 4 wherein said dextran polymer derivative has a molecular weight of from 2,000 to 60,000 daltons.

6. The pharmaceutical composition of any one of claims 1-5 wherein said particles are solid dispersions of amorphous active molecularly dispersed in said dextran polymer derivative.

7. The pharmaceutical composition of any one of claims 1-6 wherein at least 50 wt% of said particles consists essentially of said active and said dextran polymer derivative.

8. The pharmaceutical composition of any one of claims 1-7 wherein said particles consist essentially of said active and said dextran polymer derivative.

9. The pharmaceutical composition of any one of claims 1-8 wherein said particles have the following composition: from 0.1 to 80 wt% said active, and from 20 to 99.9 wt% said dextran polymer derivative.

10. The pharmaceutical composition of claim 9 wherein said particles have the following composition: from 0.1 to 60 wt% said active, and from 40 to 99.9 wt% said dextran polymer derivative.

11. The pharmaceutical composition of any one of claims 1-10 wherein from 50 wt% to 100 wt% of said dry powder comprises said particles.

12. The pharmaceutical composition of any one of claims 1-11 wherein said dry powder consists essentially of said particles.

13. The pharmaceutical composition of any one of claims 1-12 wherein said particles comprise two or more actives.

14. The pharmaceutical composition of any one of claims 1 - 13 wherein said composition is suitable for delivery to the lower airways via inhalation through the mouth.

15. The pharmaceutical composition of claim 14 wherein said particles have a mass median aerodynamic diameter of from 0.5 to 10 μm.

16. The pharmaceutical composition of claim 15 wherein said particles have a mass median aerodynamic diameter of from 1 to 5 μm.

17. The pharmaceutical composition of any one of claims 1-16 wherein said particles have a mean geometric diameter of from 0.5 to 10 μm.

18. The pharmaceutical composition of any one of claims 1-17 wherein said particles have a fine particle fraction of at least 50%.

19. The pharmaceutical composition of any one of claims 1 - 13 wherein said composition is suitable for delivery to the upper airways via inhalation through the nose.

20. The pharmaceutical composition of claim 19 wherein said particles have a mass median aerodynamic diameter of from 5 to 100 μm.

21. The pharmaceutical composition of claim 20 wherein said particles have a mass median aerodynamic diameter of from 10 to 70 μm.

22. The pharmaceutical composition of any one of claims 1-13 wherein said composition is suitable for delivery to the upper and lower airways.

23. The pharmaceutical composition of any one of claims 1-22 wherein said particles are formed by spray drying said active and said dextran polymer derivative from a solution comprising said active and said dextran polymer derivative dissolved in a solvent.

24. A packet suitable for insertion into a dry powder inhaler containing the pharmaceutical composition of any one of claims 1-23.