WO2009064469A1 - Pulmonary delivery of a macrolide antibiotic - Google Patents

Abstract

The present invention provides macrolide antibiotic containing compositions for oral inhalation to the lung. The macrolide antibiotic compositions are useful in the treatment and prophylaxis of both pulmonary and systemic bacterial infections.

Description

PULMONARY DELIVERY OF A MACROLIDE ANTIBIOTIC

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of priority to U.S. Provisional Patent

Application Serial No.: 61/003,226, filed November 14, 2007, the disclosure of which is incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to macrolide antibiotic compositions, and to methods for making and administering such compositions. In particular, the invention is directed to macrolide antibiotic powder compositions which can, among other things, be administered via oral inhalation to the lung for the treatment and/or prophylaxis of pulmonary and systemic bacterial infections.

BACKGROUND OF THE INVENTION

[0003] Pulmonary bacterial infections, which are associated with significant levels of morbidity and mortality, represent a major medical challenge. Bacterial infections of the lung, e.g., bacterial pneumonia, and other infections caused gram-positive aerobes (e.g., methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae and other streptococci, Bacillus sp., Corynebacterium sp., as well as gram-negative aerobes (e.g., H. influenzae, M. catarrhalis, and Neisseria sp.) can be addressed with macrolide antibiotic-based therapy.

[0004] Like many antibiotics, macrolide antibiotics can be administered by the oral and intravenous routes. Oral administration of macrolide antibiotics can be limited by associated dose-dependent drug toxicity. Brown et al. (1997) Clin. Infect. Dis. 24(5):958-64. Oral or intravenously administered systemic antibacterials for treating respiratory infections suffer from an added disadvantage - the uncertainty of drug penetration into the lung tissue and infected secretions. Because effective drug therapy for lower respiratory tract infections depends upon not only the susceptibility of the infecting microorganisms, but upon the attainment of effective antibacterial concentrations in the lung tissue and mucus, oral and intravenous delivery of antibiotics for respiratory infections may be ineffective.

[0005] In addition to their antibacterial activity, macrolides also have anti-inflammatory properties. These have been studied extensively in chronic inflammatory airway diseases such as diffuse panbronchiolitis. Macrolides inhibit neutrophil chemotaxis and accumulation as well as proinflammatory cytokine production among other postulated anti-inflammatory mechanisms. Therefore, chronic inflammatory airway disease as well as other respiratory conditions can benefit from the anti-inflammatory properties of macrolides. There remains a need, however, to better leverage the anti-inflammatory properties through improved (e.g., better directed) administration routes.

[0006] Thus, in view of the problems noted above using conventional antibacterial therapies, it would be desirable to provide an inhaleable form of a macro lide antibiotic for localized delivery to the lung, for both the treatment of pulmonary bacterial infections and for therapy of systemic diseases. Inhaleable dry powder formulations can provide high concentrations of antibacterial agent in the lung with negligible concentrations in the blood and body tissues. Moreover, by utilizing a topical administration route, most of the toxicities that are associated with systemic antibacterial agents can be minimized or avoided. Inhalation of antibacterials using a dry powder inhaler maximizes the convenience and speed of administration, and overcomes the disadvantages of alternative inhalation therapies as described above.

SUMMARY OF THE INVENTION

[0007] In one or more embodiments of the invention, a composition is provided, the composition comprising a macrolide antibiotic wherein the composition is in the form of a plurality of dispersed particles.

[0008] In one or more embodiments of the invention, a composition is provided, the composition comprising a macrolide antibiotic wherein the composition is in the form of a plurality of dispersed dry particles. [0009] In one or more embodiments of the invention, a composition is provided, the composition comprising a macrolide antibiotic wherein the composition is in the form of a plurality of dispersed liquid particles.

[0010] In one or more embodiments of the invention, a composition is provided, the composition comprising a macrolide antibiotic in the form of a dry powder in a unit dosage form.

[0011] In one or more embodiments of the invention, a composition is provided, the composition comprising spray-dried particles comprising a macrolide antibiotic.

[0012] In one or more embodiments of the invention, a method is provided, the method dispersing a composition comprising a macrolide antibiotic to form an aerosol, and delivering the aerosol to the lungs of the subject by inhalation of the aerosol by the subject, thereby ensuring delivery of the macrolid antibiotic to the lungs of the subject.

[0013] In one or more embodiments of the invention, a method is provided, the method comprising combining a macrolide antibiotic, optional excipient, and solvent to form a mixture or solution; and spray drying the mixture or solution to obtain a powder.

BRIEF DESCRIPTION OF THE DRAWINGS [0014] FIG. 1 is a schematic of the study designed following in Example 1.

[0015] FIG. 2 are graphs showing the differences between IT and IV administration of azithromycin, as further explained in Example 1.

[0016] FIG. 3 are graphs showing the differences in the kinetic profile of azithromycin after IT administration, as further explained in Example 1.

[0017] FIG. 4 are graphs comparing the pharmacokinetic profiles of IT versus oral administration of azithromycin in rats, as further explained in Example 1.

[0018] FIG. 5 are graphs comparing the pharmacokinetic profiles of azithromycin following IV and IT administration, as further explained in Example 1. DETAILED DESCRIPTION OF THE INVENTION [0019] Definitions

[0020] The following terms as used herein have the meanings indicated.

[0021] "Macrolide antibiotic" refers to any compound whose activity stems from the presence of a macrolide ring (a large, usually a 14-, 15- or 16-membered, lactone ring) to which one or more deoxy sugars may be attached. Non-limiting examples of macrolide antibiotics include azithromycin, clarithromycin, dirithromycin, erythromycin, and roxithromycin.

[0022] "Pharmaceutically acceptable salt" includes, but is not limited to, salts prepared with inorganic acids, such as chloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate salts, or salts prepared with an organic acid, such as malate, maleate, fumarate, tartrate, succinate, ethylsuccinate, citrate, acetate, lactate, methanesulfonate, benzoate, ascorbate, para-toluenesulfonate, palmoate, salicylate and stearate, as well as estolate, gluceptate and lactobionate salts. Similarly salts containing pharmaceutically acceptable cations include, but are not limited to, lithium, sodium, potassium, barium, calcium, aluminum, and ammonium (including substituted ammonium). Pharmaceutically acceptable salts of antibacterial compounds have the same general pharmacological properties as the parent compound from which they are derived.

[0023] "Relative pulmonary bioavailability" is the percentage of an antibacterial dose

(for the treatment of systemic bacterial disease) that is deposited in the lungs that is absorbed and enters the blood of a mammal relative to the percent that is absorbed into the blood from an intravenous injection site. Representative model systems for determining relative pulmonary bioavailabilities include rat, rabbit, and monkey. The antibacterial compositions of the invention are, in one respect, characterized by a relative pulmonary bioavailability of at least about 3% in plasma or blood, with relative pulmonary bioavailabilities generally ranging from about 5% to about 20% or greater. Relative pulmonary bioavailability may be estimated by measuring absorption from direct intratracheal administration or by inhalation of an antibacterial composition.

[0024] "Amino acid" refers to any compound containing both an amino group and a carboxylic acid group, and is meant to encompass pharmaceutically acceptable salts thereof. Although the amino group most commonly occurs at the position adjacent to the carboxy function, the amino group may be positioned at any location within the molecule. The amino acid may also contain additional functional groups, such as amino, thio, carboxyl, carboxamide, imidazole, etc. The amino acid may be synthetic or naturally occurring, and may be used in either its racemic, or optically active (D-, or L-) forms, for example, as a single optically active enantiomer or as any combination or ratio of enantiomers.

[0025] "Enhancer" refers to a compound that enhances the absorption of an antibacterial compound through mucosal membranes, e.g., of the lung.

[0026] "Dry powder" refers to a powdered composition that contains finely dispersed solid particles that are capable of being (i) readily dispersed in an inhalation device, and (ii) inhaled by a subject so that a portion of the particles reach the lungs to permit penetration into the alveoli. Such a powder is considered to be "respirable" or suitable for pulmonary delivery. Unless otherwise stated, a "dry powder composition for delivery to the deep lung" is one that, when aerosolized, is administered as dry powder particles. A dry powder in accordance with the invention is preferably a non-liposomal powder. Additionally, a dry powder of the invention is one that is preferably absent polymeric encapsulating agents or polymeric matrices.

[0027] "Oligopeptides" are peptides comprising two to ten amino acid residues (dimers to decamers).

[0028] "Peptide" as used herein is meant to encompass both naturally occurring and artificially constructed polypeptides in which individual amino acid units are linked together through the standard peptide amide bond (the carboxyl group of one and the amino group of another) and having a molecular weight between about 1,000 and about 6000.

[0029] "Protein" refers to a particular class of polypeptides having molecular weights ranging from about 6000 to more than 1,000,000.

[0030] A "leucyl-containing excipient comprising from 1 to 5 amino acid residues" includes the amino acid leucine, and oligomers composed of from 2 to 5 amino acid residues, one or more of which is leucine. [0031] A powder comprising essentially "neat antibacterial macro lide antibiotic" is one substantially lacking any other excipients or additives besides the antibacterial compound, i.e., contains less than about 3% by weight non-antibacterial component(s), preferably less than about 2% by weight non-antibacterial component, more preferably less than 1% by weight antibacterial component, and in some cases comprises 100% antibacterial compound.

[0032] "Emitted dose" provides an indication of the delivery of a dry powder from the mouthpiece of a suitable inhaler device after a firing or dispersion event. More specifically, the ED is a measure of the percentage of powder which is drawn out of a unit dose package and which exits the mouthpiece of an inhaler device. The ED is defined as the ratio of the dose delivered by an inhaler device to the nominal dose (i.e., the mass of powder per unit dose placed into a suitable inhaler device prior to firing). The ED is an experimentally- determined parameter, and is typically determined in-vitro using a device set up which mimics patient dosing. To determine a ED value, a nominal dose of dry powder, typically in unit dose form, is placed into a suitable dry powder inhaler (such as that described in U.S. Patent No. 5,785,049) which is then actuated, dispersing the powder. The resulting aerosol cloud is then drawn by vacuum from the device, where it is captured on a tared filter attached to the device mouthpiece. The amount of powder that reaches the filter constitutes the delivered dose. For example, for a 5 mg, dry powder-containing dosage form placed into an inhalation device, if dispersion of the powder results in the recovery of 4 mg of powder on a tared filter as described above, then the ED for the dry powder composition is: 4 mg (delivered dose)/5 mg (nominal dose) x 100 = 80%. For homogenous powders, ED values provide an indication of the delivery of therapeutic moiety (i.e.,antibacterial compound) from an inhaler device after firing. Similarly for MDI and nebulizer dosage forms, the ED corresponds to the percentage of drug which is drawn from a dosage form and which exits the mouthpiece of an inhaler device.

[0033] "Fine particle fraction" or "FPF" provides a measure of aerosolized powder delivery efficiency from a unit dosage form (e.g., a blister pack) to the deep lung, and is determined experimentally using a short stack Anderson cascade impactor operated at a vacuum of 28.3 liters per minute. The FPF is defined as the total mass, in milligrams, of aerosolized powder having a particle size less than 3.3 micrometers, relative to the mass of powder contained in a unit dosage form, in milligrams, and expressed as a percentage.

FPF = total aerosolized powder mass less than 3.3 um (mg) unit dosage form fill mass

[0034] A "dispersible" powder is one having an ED value of at least about 30%, preferably at least about 35%, more preferably at least about 40%, and most preferably at least about 50%. Powders of the present invention are highly disperisible, having ED values of at least 60% or greater. Dispersibility, as used herein, refers to the dispersibility of a dry powder in a gas stream (e.g., a stream of air) unless otherwise indicated.

[0035] A dry powder composition suitable for "inhalation therapy", is one which, when aerosolized, may be (i) readily dispersed in an inhalation delivery device, and (ii) inspired through either the mouth by a mammalian subject so that at least a portion of the particles are absorbed into the lung.

[0036] A composition suitable for "oral pulmonary administration" comprises particles at least a portion of which, when delivered via inhalation by the mouth, reach the tissues of the lung, including the deep lung.

[0037] "Mass median diameter" or "MMD" is a measure of mean particle size. MMD values as reported herein are determined by laser diffraction, although any number of commonly employed techniques can be used for measuring mean particle size (e.g., centrifugal sedimentation, electron microscopy, light scattering).

[0038] "Mass median aerodynamic diameter" or "MMAD" is a measure of the aerodynamic size of a dispersed particle. The aerodynamic diameter is used to describe an aerosolized composition in terms of its settling behavior, and is the diameter of a unit density sphere having the same settling velocity, generally in air, as the particle. The aerodynamic diameter encompasses particle shape, density and physical size of a particle. As used herein, MMAD refers to the midpoint or median of the aerodynamic particle size distribution of an aerosolized composition determined by cascade impaction.

[0039] "Pharmaceutically acceptable excipient or carrier" refers to an excipient that may be included in the particles of the invention and taken into the lungs in association with the particles with no significant adverse toxico logical side effects (e.g., toxicity, irritation, and allergic response) to the subject, and particularly to the lungs of the subject.

[0040] "Pharmacologically effective amount" or "physiologically effective amount" of an antibacterial is the amount of an antibacterial compound present in a particulate composition as described herein that is needed to provide a therapeutic or prophylactic level of antibacterial agent, either in the bloodstream or at the infected tissue site (depending upon the fungus to be treated) when such composition is administered by inhalation over a particular duration of time. The precise amount will depend upon numerous factors, e.g., the particular antibacterial(s) contained in the powder, the potency of the antibacterial compound employed, the condition being treated, the delivery device employed, the physical characteristics of the powder, intended patient use (e.g., the number of doses administered per day), and patient considerations, and can readily be determined by one skilled in the art, based upon the information provided herein. Recommended dosage ranges will be described in greater detail below.

[0041] "Bulk density" refers to the density of a powder prior to compaction (i.e., the density of an uncompressed powder), and is typically measured by a well-known USP method.

[0042] The "extent of degradation" of a macrolide antibiotic is the percentage of macrolide antibiotic contained in the dry powder composition determined to be chemically modified from the intact starting material, as determined by a suitable chemical assay (e.g., NMR, HPLC, etc.); 100% of the macrolide antibiotic remaining chemically intact during the spray drying process represents an extent of degradation of 0%.

[0043] Inhaleable Antibacterial Compositions

[0044] The present invention provides compositions for the oral pulmonary delivery of macrolide antibiotic compounds. These compositions overcome many of the problems and inconveniences encountered heretofore in administering antibacterials, and particularly macrolide antibiotics, by other routes.

[0045] In one approach, the composition can be in the form of a solid. In this regard, both dispersed powders and non-dispersed powders are contemplated.

[0046] The powder compositions described herein (i) are readily dispersed by dry powder delivery devices (i.e, demonstrate superior aerosol properties), (ii) exhibit good physical stability during powder manufacture, processing, and storage, and (iii) are reproducibly prepared with minimal degradation of the macrolide antibiotic. Inhaleable macrolide antibiotic compositions in accordance with the invention are preferably dry powders (i.e., for use in dry powder inhalers (DPIs).

[0047] The compositions in accordance with the invention may be crystalline, amorphous (i.e., glassy), or a mixture of both forms. Preferred are solid compositions that, irrespective of their percent crystallinity, are stable with respect to this percentage over time.

[0048] Dry powder antibacterial formulations of the invention are preferably prepared by spray drying. In general, spray drying is a process which combines a highly dispersed liquid and a sufficient volume of a hot gas to produce evaporation and drying of the liquid droplets to produce a powder. The feedstock can be a solution, suspension, slurry, or colloidal dispersion that is atomizable. Spray drying of an antibacterial formulation is carried out, for example, as described generally in the Spray Drying Handbook, 5^th ed., (1991), in European Patent Application EP 520 748 Al, and in international patent publications WO 97/41833, WO 96/32149 and WO 99/16419.

[0049] In one approach for preparing a spray-dried powder, the feedstock comprises a macrolide antibiotic-containing liquid. Preferred liquids are solvents including, for example, water, alcohols such as methanol, ethanol, propanol, isopropanol, and so forth, acidified alcohols, and combinations of any of the foregoing. The liquid feedstock can be a solution or a suspension.

[0050] Thus, the macrolide antibiotic is first combined in a liquid (e.g., water) and optionally contains a physiologically acceptable buffer and/or complexing agent and/or acid or base to adjust the pH. The pH range of the resulting solution is preferably between about 4 and 10. The feedstock optionally contains additional solvents, such as acetone, alcohols and the like.

[0051] In the approach that a suspension is used as the liquid feedstock for spray drying, the macrolide antibiotic can be first suspended in an aqueous solvent such as water and subjected to wet milling. The wet milling process is effective to reduce the particle size of the macrolide antibiotic, typically to less than about 5 microns, and preferably to less than about 3 microns. Most typically, drug particles (and any optional undissolved excipient solids) are reduced to a size of about 1 micron or less during the process. Wet milling processes that may be employed include homogenization (e.g., using a pressurized spray type or ultrasonic homogenizer) or microfiuidization.

[0052] Suspensions will generally contain about 1 mg/mL to about 100 mg/mL macrolide antibiotic, preferably from about 5 to about 100 mg/mL macrolide antibiotic, and even more preferably from about 5 to 20 mg/mL macrolide antibiotic. The wet milling step is effective to decrease both the particle size and distribution; the number of passes will typically range from about 1 to 10,

[0053] Optionally, one or more excipients as described herein can be included in the suspensions of the invention. Such excipients may be added in either solution or dry form to the suspension prior to wet milling. Alternatively, one or more excipients in either dry or solution form may be added to the suspension after wet milling, or added in solution form as a co-spray dry solution during the spray drying step. Optionally, a buffer such as phosphate or citrate or the like is added to the wet milled suspension to form a suspension having near neutral pHs from about 6 to 8, or more preferably from about 7 to 8.

[0054] Alternatively, the macrolide antibiotic may be dry milled prior to suspension formation.

[0055] Optionally, in-line sonication may also be employed to further reduce the particle size of the spray-dried macrolide antibiotic compositions of the invention. For instance, the feed suspension may be passed through a sonicator prior to atomization.

[0056] Additional spray drying processes which may be suitable for preparing the spray-dried antibacterial compositions of the invention are described in U.S. Patent Nos. 5,985,248, 5,976,574, 6,001,336, and 6,077,543.

[0057] The macrolide antibiotic-containing liquid feedstock is spray dried in a conventional spray drier, such as those available from commercial suppliers such as Niro A/S (Denmark), Buchi (Switzerland) and the like, resulting in dispersible, chemically stable dry powders. Optimal conditions for spray drying will vary depending upon the formulation components, and are generally determined experimentally. The gas used to spray dry the material is typically air, although inert gases such as nitrogen or argon are also suitable. Moreover, the temperature of both the inlet and outlet of the gas used to dry the sprayed material is such that it does not cause significant decomposition of the macrolide antibiotic in the sprayed material. Such temperatures are typically determined experimentally, although generally, the inlet temperature will range from about 50° C to about 200° C, more preferably from about 60 ⁰C to about 150⁰C, while the outlet temperature will range from about 30° C to about 150⁰ C.

[0058] An antibacterial dry powder in accordance with the invention may also be prepared by lyophilization, vacuum drying, spray freeze drying, super critical fluid processing, or other forms of evaporative drying. Such drying procedures will preferably be accompanied by additional processing steps, e.g., by blending, grinding or jet milling, to obtain an antibacterial dry powder having suitable chemical, physical and aerosol properties suitable for administration into the deep lung.

[0059] In some instances, it will be desirable to prepare dry powder formulations possessing improved handling/processing characteristics, e.g., reduced static, better flowability, low caking, and the like, by preparing compositions composed of fine particle aggregates, that is, aggregates or agglomerates of the above-described dry powder particles, where the aggregates are readily broken back down to the fine powder components for pulmonary delivery. See U.S. Patent No. 5,654,007. Alternatively, the powders may be prepared by agglomerating the powder components, sieving the materials to obtain the agglomerates, spheronizing to provide a more spherical agglomerate, and sizing to obtain a uniformly-sized product. See WO 95/09616. The dry powders of the invention may also be prepared by blending, grinding or jet milling formulation components directly in dry powder form.

[0060] In one approach, the composition can be in the form of a liquid. In this regard, both dispersed liquids and non-dispersed liquids are contemplated.

[0061] When the composition is a liquid, the composition may be in a liquid suitable for aerosolization. In this regard, the antibiotic composition may be an aqueous composition wherein the macrolide antibiotic is combined with water or a water-based solvent. Typically, the liquid composition will have a pH that is compatible with physiological administration, such as pulmonary administration. For example, the aqueous composition may have a pH ranging from about 3 to about 7, such as about 4 to about 6. In addition, the aqueous compositions typically have an osmolality that is compatible with physiological administration, such as pulmonary administration. In one or more embodiments, the aqueous composition may have an osmolality ranging from about 90 mθsmol/kg to about 500 mθsmol/kg, such as 120 mθsmol/kg to about 500 mθsmol/kg, or about 150 mθsmol/kg to about 300 mθsmol/kg.

[0062] Composition properties

[0063] Compositions of the macrolide antibiotic as described herein will generally comprise from about 0.1% to 100% by weight of a macrolide antibiotic, preferably from about 5% to about 100% by weight macrolide antibiotic, more preferably from about 20% to about 100% by weight macrolide antibiotic, and most preferably will comprise greater than about 30% by weight macrolide antibiotic. Particular compositions of the invention are those comprising one of the following percentages by weight of the macrolide antibiotic: 1%, 3%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0064] The antibacterial compositions of the invention are further characterized by several features, most notably, the ability of the aerosolized composition to reach the tissues of the lung and lower respiratory tract. Passage of the particles into the lung physiology is an important aspect of the present invention, since the concentration of macrolide antibiotic at the site of infection is an important feature in the successful treatment of pulmonary bacterial infections.

[0065] Macrolide antibiotic compositions in particulate form (regardless of whether the particulate form is liquid or solid) are composed of particles effective to penetrate into the alveoli of the lungs, that is, having a mass median diameter (MMD) from about 0.1 to 20 μm. Typically, the MMD of the particles is less than about 10 μm (e.g., ranging from about 0.1 to 10 μm), preferably less than 7.5 μm (e.g., ranging from about 0.5 to 7 microns), and most preferably less than 5 μm, and usually being in the range of 0.1 μm to 5 μm in diameter.

[0066] When the marcolide antibiotic-containing composition is in the form of a solid

(e.g., a powder), the composition can optionally contain non-respirable carrier particles such as lactose, where the non-respirable particles are typically greater than about 40 microns in size. [0067] Macrolide antibiotic compositions in particulate form (regardless of whether the particulate form is liquid or solid) are typically further characterized by an aerosol particle size distribution less than about 10 μm mass median aerodynamic diameter (MMAD), and preferably less than 5 μm, and more preferably less than about 3.5 μm.

[0068] When the marcolide antibiotic-containing composition is in the form of a solid

(e.g., a powder), the composition will generally have a moisture content below about 15% by weight, usually below about 10% by weight, and preferably ranging from about 3% to about 10% by weight. The emitted dose or ED (sometimes also referred to as delivered dose efficiency, DDE) of these powders is greater than 30% and usually greater than 40%. More typically, the emitted dose of the antibacterial powders of the invention is greater than 50%, and is often greater than 60%. Even more preferably, the ED of an antibacterial powder is greater than 65%. Highly preferred are powders having ED values greater than 50% to 60% and MMADs of less than about 3.5 microns. Powders of the invention will typically possess a bulk density value ranging from about 0.05 to 10 gram/cubic centimeter, preferably from about 0.05 to 5 gram/cubic centimeter, more preferably from about 0.10 to 4.0 grams/cubic centimeter, even more preferably from about 0.10 to 1 gram/cubic centimeter, even more preferably from about 0.10-0.75 gram/cubic centimeter, and most preferably from about 0.17 to 0.75 gram/cubic centimeter. An additional measure for characterizing the overall aerosol performance of a dry powder is the fine particle fraction (FPF), which describes the percentage of powder having an aerodynamic diameter less than 3.3 microns. Antibacterial powder compositions are particularly well suited for pulmonary delivery, and will possess FPF values ranging from about 45%-90%. Such powders contain at least about 45 percent of aerosol particle sizes below 3.3 μm to about 0.5 μm and are thus are extremely effective when delivered in aerosolized form, in (i) reaching the tissues of the lung, and, in the case of treatment of systemic bacterial infections, (ii) reaching the alveolar region of the lung, followed by (iii) diffusion to the interstitium and (iv) subsequent passage into the bloodstream through the endothelium.

[0069] The compositions of the invention also possess substantially intact macrolide antibiotic, that is to say, the amount of macrolide antibiotic degradation products is typically less than about 10% relative to (for example) a pre-spray dried control, and more preferably is less than about 5%. In other words, relative to the pre-spray dried starting material, the macrolide antibiotic remains at least 90% chemically intact or pure upon spray drying. Preferably, the spray dried powder contains at least 95% pure or chemically intact macrolide antibiotic relative to the pre-spray dried material.

[0070] Excipients

[0071] The compositions according to the present invention generally include one or more antibacterial compounds, one being a macrolide antibiotic, and optionally a pharmaceutically acceptable excipient. Dry powders composed of neat macrolide antibiotic (i.e., respirable powders composed of one or more macrolide antibiotics and essentially lacking any additional excipients or additives) and demonstrating good aerosol properties are contemplated.

[0072] Optionally, but not necessarily, the compositions of the invention will include one or more pharmaceutical excipients that are suitable for respiratory and pulmonary administration. Such excipients may serve simply as bulking agents when it is desired to reduce the active agent concentration in the powder that is being delivered to a subject. Preferred are excipients that can also serve in one or more of the following capacities: (i) improve the dispersibility and aerosol performance of a powder within a powder dispersion device in order to provide more efficient and reproducible delivery of the compound, (ii) improve the handling characteristics (e.g., flowability and consistency) of the composition to facilitate manufacturing and filling into unit dosage forms, and (iii) improve chemical and/or physical stability. In particular, the excipient materials can often function to optimize the residual moisture content of a powder, hinder excessive moisture uptake, influence particle size, the degree of aggregation, particle surface properties, ease of inhalation, and targeting of the resultant particles to the lung tissue including the deep lung.

[0073] Pharmaceutical excipients and additives useful in the present composition include but are not limited to proteins, peptides, amino acids (which are preferably non- acylated or non-sulfonated), lipids (which, if employed are typically not encapsulating agents, i.e., liposomes), and carbohydrates (e.g., sugars, including monosaccharides, disaccharides, trisaccharides, tetrasaccharides, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, esterified sugars and the like; and polysaccharides), which may be present singly or in combination. Also preferred are excipients having glass transition temperatures (Tg), above about 35 ⁰C, preferably above about 45°C, more preferably above about 55 ⁰C. Illustrative excipients suitable for use in the compositions described herein include those described in International Patent Application No. WO 98/16207.

[0074] Exemplary protein excipients include serum albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Polypeptides and proteins suitable for use in the dry powder composition of the invention are provided in International Patent Publication No. WO96/32096. HSA is a preferred proteinaceous excipient, and has been shown to increase the dispersibility of dry powders for aerosolized delivery to the lungs. See WO 96/32096.

[0075] Representative amino acid/polypeptide components, which may optionally function in a buffering capacity, include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, threonine, tyrosine, tryptophan and the like. Preferred are amino acids and peptides that can also function as dispersibility-enhancing agents. Amino acids falling into this category include hydrophobic amino acids such as leucine (leu), valine (val), isoleucine (isoleu), norleucine, tryptophan (try) alanine (ala), methionine (met), phenylalanine (phe), tyrosine (tyr), histidine (his), and proline (pro). One particularly preferred amino acid is the amino acid, leucine. Leucine, when used in the formulations described herein includes D-leucine, L-leucine, racemic leucine, and combinations of D- and L-leucine at any ratio. Dispersibility enhancing peptides for use in the invention include dimers, trimers, tetramers, and pentamers composed of hydrophobic amino acid components such as those described above, e.g., di-leucine and tri-leucine. Further examples include di- valine, di-isoleucine, di-tryptophan, di-alanine, and the like, tri-valine, tri-isoleucine, tri- tryptophan, etc.; mixed di- and tri-peptides, such as leu-val, isoleu-leu, try-ala, leu-try, etc., and leu-val-leu, val-isoleu-try, ala-leu-val, and the like, and homo-tetramers or pentamers such as tetra-alanine and penta-alanine. Preferred are amino acids and oligomers containing from 1-5 amino acid residues, and more preferably containing 1-3 amino acid residues and containing at least one (i.e., one or more) leucyl-residue. See U.S. Patent No. 6,835,372.

[0076] In some instances, the composition will comprise at least 10% by weight of a leucyl-containing excipient, e.g., leucine, dileucine or trileucine, and more preferably at least 25% to 30% by weight of a leucyl-containing excipient as described above. Representative compositions in accordance with the invention comprise one of the following percentages by weight excipient, preferably a leucyl-containing excipient such as leucine, dileucine or trileucine: 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% or more excipient.

[0077] Carbohydrate excipients suitable for use in the compositions of the invention include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; trisaccharides such as melezitose and raffϊnose; polysaccharides, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), myoinositol and the like. Preferred carbohydrate excipients include mannitol, trehalose, and raffϊnose.

[0078] The compositions may also include a buffer or a pH adjusting agent; typically, the buffer is a salt prepared from an organic acid or base. Representative buffers include organic acid salts such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid; phthalic acid, Tris, and tromethamine hydrochloride. Commonly used inorganic acids/buffers include hydrochloric acid, sulfuric acid, boric acid, carbonic acid and phosphoric acid. Preferred buffers for use in the compositions of the invention are citrate and phosphate buffer.

[0079] Additionally, the compositions of the invention may include small amounts of polymeric excipients/additives such as polyvinylpyrrolidones, derivatized celluloses, such as hydroxymethylcellulose, hydroxyethylcellulose, or hydroxypropylmethylcellulose, Ficolls (a polymeric sugar), hydroxyethylstarch, dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin), polyethylene glycols, polyamino acids (e.g., polyleucine, polyglutamic acid), pectin, generally where such polymers are present as powder additives rather than as encapsulating or coating agents or as components of a polymeric matrix.

[0080] The composition of the invention may also optionally contain salts (e.g., sodium chloride), antioxidants, antistatic agents, surfactants (e.g., polysorbates such as 'TWEEN 20" and 'TWEEN 80"), lecithin, oleic acid, benzalkonium chloride, sorbitan esters, lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol), and chelating agents (e.g., EDTA). Other pharmaceutical excipients and/or additives suitable for use in the compositions of the invention are listed in "Remington: The Science & Practice of Pharmacy," 19^th ed., Williams & Williams, (1995), "Physician's Desk Reference," 52^nd ed., Medical Economics, Montvale, NJ (1998), and "Handbook of Pharmaceutical Excipients", (3^rd Ed.), Vol. 3, Arthur H. Kibbe (Ed.), Ainley Wade, Paul J. Weller (1999).

[0081] Pulmonary Administration of the Composition

[0082] Dry powder formulations as described herein may be delivered using any suitable dry powder inhaler (DPI), i.e., an inhaler device that utilizes the patient's inhaled breath as a vehicle to transport the dry powder drug to the lungs. Preferred dry powder inhalation devices are described in U.S. Patent Nos. 5,458,135, 5,740,794, and 5,785,049. When administered using a device of this type, the powdered medicament is contained in a receptacle having a puncturable lid or other access surface, preferably a blister package or cartridge, where the receptacle may contain a single dosage unit or multiple dosage units. Convenient methods for filling large numbers of cavities (i.e., unit dose packages) with metered doses of dry powder medicament are described in WO 97/41031.

[0083] Also suitable for delivering the antibacterial powders described herein are dry powder inhalers of the type described, for example, in U.S. Patent Nos. 3,906,950 and 4,013,075, wherein a pre-measured dose of FSP dry powder for delivery to a subject is contained within a hard gelatin capsule.

[0084] Other dry powder dispersion devices for pulmonary administration of dry powders include those described, for example, in European Patent Nos. EP 129985, EP 472598 and EP 467172 and U.S. Patent No. 5,522,385. Also suitable for delivering the antibacterial dry powders of the invention are inhalation devices such as the Astra-Draco "TURBUHALER". This type of device is described in detail in U.S. Patent Nos. 4,668,218, 4,667,668 and 4,805,811. Other suitable devices include dry powder inhalers such as ROTAHALER® (Glaxo), DISCUS® (Glaxo), SPIROS™ inhaler (Dura Pharmaceuticals), and the SPINHALER® (Fisons). Also suitable are devices which employ the use of a piston to provide air for either entraining powdered medicament, lifting medicament from a carrier screen by passing air through the screen, or mixing air with powder medicament in a mixing chamber with subsequent introduction of the powder to the patient through the mouthpiece of the device, such as described in U.S. Patent No. 5,388,572.

[0085] An inhaleable antibacterial composition may also be delivered using a pressurized, metered dose inhaler (MDI) containing a solution or suspension of drug in a pharmaceutically inert liquid propellant, e.g., a HFC, chlorofluorocarbon or fluorocarbon, as described in U.S. Patent Nos. 5,320,094 and 5,672,581.

[0086] With respect to liquid composition, these composition can be aerosolized using a nebulizer as described in WO 2004/071368, as well as in U.S. Patent Application Publication Nos. 2004/0011358 and 2004/0035413. Other examples of nebulizers include, but are not limited to: the AERONEB Go or AERONEB Pro nebulizers (Aerogen, Inc., San Carlos, CA), the PARI eFlow and other nebulizers (available from PARI Respiratory Equipment, Inc. of Midlothian, VA); the LUMISCOPE Nebulizer 6600 or 6610 (available from Lumiscope Company, Inc., East Brunswick, N. J.); and the Omron NE-U22 (available from Omron Healthcare, Inc. of Kyoto, Japan).

[0087] It has been found that a nebulizer of the vibrating mesh type, such as one that that forms droplets without the use of compressed gas, such as the AERONEB Pro nebulizer provides unexpected improvement in dosing efficiency and consistency. By generating fine droplets by using a vibrating perforated or imperforated membrane, rather than by introducing compressed air, the aerosolized pharmaceutical formulation can be introduced into the ventilator circuit without substantially affecting the flow characteristics within the circuit and without requiring a substantial re-selection of the ventilator settings. In addition, the generated droplets when using a nebulizer of this type are introduced at a low velocity, thereby decreasing the likelihood of the droplets being driven to an undesired region of the ventilator circuit. Furthermore, the combination of a droplet forming nebulizer and an aerosol introducer as described is beneficial in that there is a reduction in the variability of dosing when the ventilator uses different tidal volumes, thus making the system more universal.

[0088] Using an adaptor, device or system as disclosed in U.S. Patent Application

Publication Nos. 2007/0116649 and 2005/0217666, in connection with the administration of aerosolized antibiotics offers substantial benefits. For example, when using such adaptors, substantially less pharmaceutical formulation is lost to the environment which results in a reduction in bacterial resistance against the antibiotic. In addition, the adaptors, devices or systems are able to deliver a more consistent dose which is particularly useful for antibiotic therapy.

[0089] Prior to use, a packaged antibacterial composition is generally stored under ambient conditions, and preferably is stored at a temperature at or below about 25°C, and relative humidity (RH) ranging from about 30 to 60% or greater as described above.

[0090] Therapeutic Applications

[0091] The antibacterial powders of the invention, when administered pulmonarily, are particularly effective in the treatment of respiratory bacterial infections. The compositions, when inhaled as particulates, penetrate into the airways of the lungs and achieve effective concentrations in the infected secretions and lung tissue, including the epithelial lining fluid, alveolar macrophages, and neutrophils, typically exceeding the MIC₉₀S of most respiratory bacterial pathogens. Moreover, the doses of antibacterial compound that are administered pulmonarily are typically much less than those administered by other routes and required to obtain similar antibacterial effects, due to the efficient targeting of the inhaled powder directly to the site of bacterial infection.

[0092] The compositions of the present invention when administered pulmonarily can also be used in the treatment of lung and airway conditions such as in cystic fibrosis, chronic asthma, diffuse panbronchiolitis and other lung pathologies that benefit from reduction of the inflammatory process.

[0093] The compositions of the present invention are useful in the prophylaxis of pulmonary bacterial infections, particularly for immunocompromised patients, such as individuals undergoing chemotherapy or radiation therapy for cancer, organ transplant recipients, patients suffering from conditions that adversely affect the immune system such as HTV, or any other condition which predisposes a subject to pulmonary bacterial infections.

[0094] For prophylaxis, the amount per dose of antibacterial agent is that amount that is effective to prevent pulmonary infection is generally between about 0.001 mg/kg to about 5.0 mg/kg. Preferably, the amount per dose of the antibacterial (e.g., macrolide antibiotic) that is administered by inhalation to a subject in need thereof is typically from about 0.4 mg/kg to about 4.0 mg/kg, or even more preferably from about 0.7 mg/kg to about 3.0 mg/kg.

[0095] For treating a subject suffering from a pulmonary bacterial infection, the amount per dose of antibacterial agent administered by oral inhalation is that amount which is effective to treat the infection. The amount of antibacterial agent for the treatment of infection will generally be higher than that used for prevention, and will typically range from about 0.01 mg/kg to 7.0 mg/kg. Preferably, the amount administered will be from about 0.2 mg/kg to about 6.0 mg/kg, and more preferably from about 0.8 mg/kg to about 5.0 mg/kg.

[0096] In treating these respiratory bacterial conditions, the macrolide antibiotic is typically administered in doses that are 3-10 or more times the MIC₉₀ of the causative bacterial pathogens; these levels are safely achievable by inhalation. Generally, the dose of antibacterial compound delivered to a subject will be from about 2 mg to about 400 mg daily, preferably from about 10^~to 200 milligrams daily, depending upon the particular antibacterial compound, the condition being treated, the age and weight of the subject, and the like. The antibacterial composition in dry powder form, when administered via a dry powder inhaler, is typically administered in unit dose form, with unit dose sizes varying from about 2 milligrams to 250 milligrams, and more preferably from about 5 milligrams to 100 milligrams. From one up to about 10 unit doses are generally administered daily during the course of therapy, although more preferably a treatment regimen will consist of from one to about 8 unit doses daily by inhalation.

[0097] The disclosure of each publication, patent or patent application mentioned in this specification is incorporated by reference herein to the same extent as if each individual publication, patent or patent application were specifically and individually indicated to be incorporated by reference.

[0098] The following Experimental illustrates, but in no way intended to limit, the scope of the present invention.

EXPERIMENTAL

Example 1 [0099] Azithromycin is a macrolide antibiotic used to treat many respiratory diseases including pneumonia and COPD. The purpose of this study is to: (a) compare the fate of azithromycin after intratracheal and intravenous administration to rats; and (b) examine potential differences in the pharmacokinetic profiles of azithromycin for administration to the lung as solution and suspension.

[00100] The structure of azithromycin and selected physicochemical properties is provided below.

Azithromycin has a solubility of 7 μg/ml, a log P of 4.04, a log D of 1.92, a M_R of 749 g/mol, a Tm of 113-115⁰C, a pKa of 8.1, 8.8 and is lysosomotropic.

[00101] Zithromax® IV (azithromycin dihydrate solution; Pfizer) and an azithromycin suspension (free base; mean particle size 1.5 μm) were used in the study.

[00102] FIG. 1 provides a schematic of the study design to determine azithromycin concentrations in relevant in vivo compartments.

[00103] FIG. 2 provides the amounts of azithromycin detected after 24 hours in: A) lung tissue; B) BAL cellular fraction; C) serum; and D) BAL, after intratracheal (IT) administration of Zithromax® IV. In each plot, the amount of azithromycin recovered in each compartment after an IT dose of 0.1, 0.3 and 1 mg / animal is compared with the amount of drug recovered after IV administration of 1 mg / animal (n=3). [00104] FIG. 3 provides the pharmacokinetic profiles of Zithromax® IV in: A) lung tissue; B) BAL cellular fraction; C) serum; and D) BAL supernatant, over a time period of one week (n=3).

[00105] FIG. 4 provides a comparison of azithromycin lung tissue concentrations after

IT vs. oral administration. A) Zithromax® brand of azithromycin IV was administered via IT instillation (3 mg/kg) and lung concentrations were determined over a period of 96 h (n=3). This is compared with previously reported data showing lung concentrations after oral administration of azithromycin. An IT dose of 3 mg/kg azithromycin generates roughly the same kinetic profile in lung tissue as a 20-50 mg/kg oral dose. B) taken from Girard et al. (1987) Antimicrob Agents Chemother. 12: 1948-54.

[00106] FIG. 5 provides pharmacokinetic profiles of Zithromax® IV and AZS in: A) lung tissue; B) BAL cellular fraction; C) serum; and D) BAL supernatant, over a time period of 8 hours (n=3). No meaningful differences in PK profile were observed between the dihydrate salt and the free base.

[00107] In view of these results, it can be concluded that instillation of Zithromax® at

0.1, 0.3, and 1 mg/kg and quantification after 24 hours showed a dose-dependent increase of azithromycin in all compartments. An approximate 5-fold greater concentration was observed in all lung compartments 24 hours after IT administration of 1 mg/kg Zithromax® compared to IV injection of the same dose with the exception of the serum compartment, which contained ~0.02 μg/ml independent of the route of administration. Approximately 60% was eliminated from the serum and lung compartments within 10 minutes of instillation (1 mg Zithromax IV or AZS). Peaks in the serum and BAL concentration-time profiles were observed within one and two hours, respectively. The remainder of the dose partitioned rapidly into the lung tissue where it was eliminated with a half-life of 16.5 and 16.8 hours for the solution and suspension, respectively. Similar concentrations of azithromycin in the BAL were observed at all time points regardless of the formulation administered. Reports from the literature suggest that the advantage of pulmonary administration over oral delivery is even greater. As with other antiinfectives/antibiotics, delivery to the lung as a target organ results in significantly greater azithromycin exposure, which would be expected to be therapeutically beneficial.

Claims

What is claimed is:

1. A composition comprising a macrolide antibiotic wherein the composition is in the form of a plurality of dispersed particles.

2. The composition of claim 1, wherein the macrolide antibiotic is selected from the group consisting of azithromycin, clarithromycin, dirithromycin, erythromycin and roxithromycin.

3. The composition of claim 2, wherein the macrolide antibiotic is azithromycin.

4. The composition of claim 1, wherein the composition is in the form of a plurality of dispersed liquid particles.

5. The composition of claim 1, wherein the composition is in the form of a plurality of dispersed dry particles.

6. The composition of claim 5, wherein the dry particles are spray-dried particles.

7. A method comprising dispersing a composition comprising a macrolide antibiotic to form an aerosol and delivering the aerosol to the lungs of the subject.

8. The method of claim 7, wherein the macrolide antibiotic is selected from the group consisting of azithromycin, clarithromycin, dirithromycin, erythromycin and roxithromycin.

9. The method of claim 8, wherein the macrolide antibiotic is azithromycin.

10. The method of claim 7, wherein the composition is in the form of a plurality of liquid particles.

11. The method of claim 7, wherein the composition is in the form of a plurality of dry particles.

12. The composition of claim 11, wherein the dry particles are spray-dried particles.