This invention concerns an improved particulate composition for delivering a drug to the pulmonary system. Applicants disclose a method of identifying an optimal form of aerodynamically light particles which are highly dispersible. The particles of the instant invention are made by creating hollow, spherical drug particles (i.e., progenitor particles) that collapse in the process of particle formation, leading to wrinkled, thin-walled drug particles of very low envelope density. Additionally, Applicants have found that such particles are especially optimal for inhaled aerosols when the surface area parameter (.sigma.) is greater than 2, optimally greater than 3.

SUMMARY OF THE INVENTION

This invention concerns an improved particulate composition for delivering a drug to the pulmonary system. A drug may be a therapeutic, diagnostic and/or prophylactic agent. Applicants disclose a method of identifying an optimal form of aerodynamically light particles which are highly dispersible. The particles of the instant invention are made by creating hollow, spherical drug particles (i.e., progenitor particles) that collapse in the process of particle formation, leading to wrinkled, thin-walled drug particles of very low envelope density. Additionally, Applicants have found that such particles are especially optimal for inhaled aerosols when the surface area parameter (.sigma.) is greater than 2, optimally greater than 3.

The invention relates to an improved particulate composition for delivery to the pulmonary system comprising particles having a tap density of less than 0.4 g/cm.sup.3 and a median geometric diameter greater than 5 .mu.m, and an external surface area greater than about 5 m.sup.2/g, preferably greater than about 10 m.sup.2/g. In a further embodiment, the particles further comprise a drug. In another embodiment, the particles further comprise a pharmaceutical excipient. In yet another embodiment, the particles further comprise a dispersibility ratio of between about 1.0 to 1.5 as measured by laser diffraction (RODOS/HELOS system). In a further embodiment, the particles have a skeletal density of at least 1 g/cm.sup.3.

In another embodiment, the invention relates to an improved particulate composition for delivery of a drug to the pulmonary system comprising particles having a tap density of less than 0.4 g/cm.sup.3 and a geometric diameter greater than 5 .mu.m, said particles having a continuous collapsed hollow sphere wall, said wall having a wall thickness less than about 150 nanometers and an external surface area of at least 5 m.sup.2/g. In a further embodiment, at least 70% of the particles of the particulate composition have a fine particle fraction of less than 5.6 .mu.m.

In another embodiment, the invention relates to a method for maximizing drug delivery to the pulmonary system comprising: a) spray drying a mixture comprising the drug and a pharmaceutically acceptable excipient to form spray dried particles; b) measuring an average wall thickness of the spray dried particles; c) adjusting spray drying conditions to minimize the average wall thickness; d) collecting spray dried particles having minimized average wall thickness; and e) administering spray dried particles having minimized average wall thickness to the respiratory tract of a patient in need of the drug.

DETAILED DESCRIPTION OF THE INVENTION

A description of preferred embodiments of the invention follows.

This invention concerns an improved particulate composition for delivering a drug to the pulmonary system. In particular, the improvement relates to the ideal design of an aerodynamically light particle for inhalation. Specifically, it has been determined that there is a synergistic interrelationship of key characteristics of spray-dried particles that results in an optimal aerodynamic performance of particles for inhaled therapeutic aerosols. This synergy promotes finely crumpled yet structurally-robust particles of low tap density (<0.4 g/cm.sup.3) and relatively large particle geometric size (>5 .mu.m) that require less energy to effectively aerosolize than thicker-walled particles of similar size and mass density. Preferably, this design promotes structurally-robust particles of ultra-low tap density (<0.1 g/cm.sup.3) and relatively large particle size (>10 .mu.m). Preferred particles are hollow, extremely thin-walled particles comprising drugs and, optionally, excipients. Further, the particles of the invention relative to particles of alternative morphologies (i.e., non-hollow particles), require less energy to produce. By reducing particle wall thickness to around 1% of the particle spherical envelope diameter, it is possible to achieve large drug-surface-transport area without necessarily creating the large particle-particle contact area that underlies handling drawbacks normally associated with nanoparticle drug delivery systems.

It was the discovery of the synergy of the interrelationships of key characteristics that led to improved methods for producing and selecting for particles with superior dispersibility. For example, the focus on key characteristics has led to innovations such as on-line sizing in which a "real-time" feedback loop is possible which can reduce waste and optimize the process for making such superior particles. (See U.S. patent application Ser. No. 10/101,563 with the title "Method and Apparatus for Producing Dry Particles" filed Mar. 20, 2002), This is especially important in the production of high cost drugs, for example, proteins. Thus, these improved compositions have improved dispersibility due to homogeneity of the particles.

Accordingly, the invention relates to an improved particulate composition. The improvement is that when the median aerodynamic diameter, median geometric diameter and tap density of two different contiguous shell-based particulate compositions of the same formulation are kept equal, there exists a synergistic relationship between the external surface area, wall thickness, and skeletal density that leads to preferred Fine Particle Fraction (FPF) and dispersibility/flowability as measured by RODOS, RODOS/IHA, or both. This synergistic relationship results in superior particles which exhibit better dispersibility with less variability over a wide range of entrainment conditions thereby improving the delivery of the particulate composition.

It is known in the art that spray drying a particle formulation under different "operating" conditions can result in spray-dried particles with various characteristics. However, this invention relates to particles whose performance criteria is tightly controlled to ensure appropriate conformance in other related attributes, for example, particle size, dose content uniformity and lung deposition. Therefore, this invention demonstrates that, although two or more spray-dried powders may have the same median aerodynamic diameter, median geometric diameter and tap density, that altering the spray-drying conditions of one of the spray-dried formulations to optimize the wall thickness and external surface area of the particles results in formulations possessing a larger surface area, and thus roughness, and thinner walls than the other formulations. Applicants further demonstrate that the formulation that has optimized the synergistic relationship among the particle characteristics enhances the dispersibility and flowrate independence for that formulation.

In one embodiment, Applicants disclose a method for selectively modulating the individual factors within an extremely tight range (e.g., within 5% of the mean for the individual factor) without interfering with the synergistic relationship. The resulting particles are able to achieve flowrate independence leading to enhanced dispersibility by selectively choosing those particles that have a large geometric diameter (i.e., >5 .mu.m), a small aerodynamic diameter (i.e., a low density with respect to geometric diameter), a minimum average wall thickness and a large external surface area.

In one embodiment of the instant invention, particles of larger size and the highly convoluted morphology contribute to make them easily dispersable and stable with respect to aggregation during storage. In this embodiment, the particle morphology contributes to enhanced dispersability and stability by decreasing the area of contact between particle. The surface contact is minimized by presence of numerous folds and convolutions. The radially-exposed surface is thus reduced as the particle surface is dominated by crevices which cannot interact chemically during contact with other particles. Particles with diameters of <5 .mu.m are prone to aggregation, with this tendency increasing as diameter decreases.

In one embodiment, the particles can be fabricated with a rough surface texture to reduce particle aggregation and improve flowability of the powder. The spray-dried particles have improved aerosolization properties. The spray-dried particle can be fabricated with features which enhance aerosolization via dry powder inhaler devices, and lead to lower deposition in the mouth, throat and inhaler device.

As used herein, the term "surface area factor" (.sigma.) refers to the ratio of the external and internal surface area of a shell-based particle or particle formulation to the theoretical surface area of a solid spherical particle or particle formulation with the same spherical envelope diameter and tap density. To calculate the surface area factor of a particle, let S=the surface area of a particle of arbitrary shape so that o is defined as: .sigma.=S/(.pi.D.sub.e.sup.2) where D.sub.e=the spherical envelope diameter of the particle. For example, if the particle is a solid sphere, where the wall thickness (h)=D.sub.e/2, S=.pi.D.sub.e.sup.2, resulting in .sigma.=1. However, if the particle is a hollow sphere with a wall thickness approaching zero (0), then S=2.pi.D.sub.e.sup.2, resulting in .sigma.=2. The invention relates to producing hollow spheres with thin walls (yet having sufficient rigidity to prevent disintegration of the wall) that collapse to form crumpled particles, thereby increasing the surface area factor to values greater than 2.

Thus, the invention therefore involves aerodynamically light particles, with improved dispersibilty, wherein the improvement results by collapsing hollow particles with surface area factor between 1 and 2 (1<.sigma.<2), to form collapsed particles with surface area factor greater than 2 (.sigma.>2), ideally greater than 3, and perhaps most ideally greater than 5. The validation of this invention is our finding that drug particles with 1<.sigma.<2 aerosolize less well than particles with .sigma.>2, all other things being equal.

The increased surface areas of the particle distributions disclosed herein can also be described via estimates of particle rugosity. As defined herein, particle rugosity (R) is the ratio of the ratio of the external surface area of a shell-based particle or particle formulation to the theoretical surface area of a solid spherical particle or particle formulation with the same spherical envelope diameter and tap density. Thus, as described above, for shell-based particle formulations with wall thicknesses significantly less than particle spherical envelope diameters, particle rugosity will be approximately equal to one-half of the surface area factor (i.e., R=0.5.sigma.).

In another embodiment of the invention the particles can include a surfactant. As used herein, the term "surfactant" refers to any agent which preferentially adsorbs to an interface between two immiscible phases, such as the interface between water and an organic polymer solution, a water/air interface or organic solvent/air interface. Surfactants generally possess a hydrophilic moiety and a lipophilic moiety, such that, upon absorbing to microparticles, they tend to present moieties to the external environment that do not attract similarly-coated particles, thus reducing particle aggregation. Surfactants may also promote absorption of a therapeutic or diagnostic agent and increase bioavailability of the agent.

Suitable surfactants which can be employed in fabricating the particles of the invention include but are not limited to hexadecanol; fatty alcohols such as polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; a surface active fatty acid, such as palmitic acid or oleic acid; glycocholate; surfactin; a poloxamer; a sorbitan fatty acid ester such as sorbitan trioleate (Span 85); Tween 80 and tyloxapol.

Methods of preparing and administering particles including surfactants, and in particular phospholipids, are disclosed in U.S. Pat. No. RE 37,053 to Hanes et al. (formerly U.S. Pat. No 5,855,913, issued on Jan. 5, 1999) and in U.S. Pat. No. 5,985,309, issued on Nov. 16, 1999 to Edwards et al. The teachings of both are incorporated herein by reference in their entirety.

In a further embodiment, the particles can also include other excipients such as, for example buffer salts, dextran, polysaccharides, lactose, trehalose, cyclodextrins, proteins, polycationic complexing agents, peptides, polypeptides, fatty acids, fatty acid esters, inorganic compounds, phosphates, lipids, sphingolipids, cholesterol, surfactants, polyaminoacids, polysaccharides, proteins, salts, gelatins, polyvinylpyrridolone and others also can be employed.

In another embodiment, the particles of the invention can include one or more phospholipids. Phospholipids suitable for delivery to a human subject are preferred. Specific examples of phospholipids include but are not limited to phosphatidylcholines dipalmitoyl phosphatidylcholine (DPPC), dipalmitoyl phosphatidylethanolamine (DPPE), distearoyl phosphatidylcholine (DSPC), dipalmitoyl phosphatidyl glycerol (DPPG) or any combination thereof.

The phospholipids or combinations thereof and methods of preparing particles having desired release properties are described in U.S. patent application Ser. No. 09/752,106, entitled "Particles for Inhalation Having Sustained Release Properties", filed on Dec. 29, 2000, in U.S. patent application Ser. No. 09/752,109, entitled "Particles for Inhalation Having Sustained Release Properties", filed on Dec. 29, 2000, and in U.S. patent application Ser. No. 10/179,463 entitled "Inhaled Formulations for Sustained Release", filed on concurrently herewith under the entire contents of these three applications are incorporated herein by reference.

The phospholipids can be present in the particles in an amount ranging from about 1 to about 99 weight %. Preferably, they can be present in the particles in an amount ranging from about 10 to about 80 weight %.

In one embodiment, the particles of the invention have a tap density less than about 0.4 g/cm.sup.3. Particles which have a tap density of less than about 0.4 g/cm.sup.3 are referred herein as "aerodynamically light particles". More preferred are particles having a tap density less than about 0.3 g/cm.sup.3. Even more preferred are particles having a tap density less than about 0.2 g/cm.sup.3. Preferably, the particles have a tap density less than about 0.1 g/cm.sup.3. Tap density can be determined using the method of USP Bulk Density and Tapped Density, United States Pharmacopeia convention, Rockville, Md., 10.sup.th Supplement, 4950 4951, 1999. Instruments for measuring tap density, known to those skilled in the art, include but are not limited to the Dual Platform Microprocessor Controlled Tap Density Tester (Vankel, N.C.) or a GeoPyc instrument (Micrometrics Instrument Corp., Norcross, Ga. 30093). Tap density is a standard measure of the envelope mass density. The envelope mass density of an isotropic particle is defined as the mass of the particle divided by the minimum spherical envelope volume within which it can be enclosed. Features which can contribute to low tap density include irregular surface texture and porous structure.

Aerodynamically light particles have a preferred size, e.g., a volume median geometric diameter (VMGD) greater than about 5 microns (.mu.m). In one embodiment, the VMGD is from greater than about 5 .mu.m to about 30 .mu.m. In another embodiment of the invention, the particles have a VMGD ranging from about 10 .mu.m to about 30 .mu.m. In a preferred embodiment, the particles have a VMGD greater than about 5 .mu.m. Even more preferred are particles having a VMGD greater than about 8 .mu.m. Most preferred are particles having a VMGD greater than about 10 .mu.m. In other embodiments, the particles have a median diameter, mass median diameter (MMD), a mass median envelope diameter (MMED) or a mass median geometric diameter (MMGD) greater than about 5 .mu.m, for example from greater than about 5 .mu.m and about 30 .mu.m.

The diameter of the spray-dried particles, for example, the VMGD, can be measured using a laser diffraction instrument (for example Helos, manufactured by Sympatec, Princeton, N.J.). Other instruments for measuring particle diameter are well know in the art. The diameter of particles in a sample will range depending upon factors such as particle composition and methods of synthesis. The distribution of size of particles in a sample can be selected to permit optimal deposition to targeted sites within the respiratory tract.

Aerodynamically light particles preferably have "mass median aerodynamic diameter" (MMAD), also referred to herein as "aerodynamic diameter", between about 1 .mu.m and about 5 .mu.m. In another embodiment of the invention, the MMAD is between about 1 .mu.m and about 3 .mu.m. In a further embodiment, the MMAD is between about 3 .mu.m and about 5 .mu.m.

Other suitable particles which can be adapted for use in oral delivery as described herein, said particles being described in U.S. patent application Ser. No. 10/300,726 "Particulate Compositions for Improving Solubility of Poorly Soluble Agents" and U.S. patent application Ser. No. 10/300,070 "Compositions for Sustained Action Product Delivery and Methods of Use Thereof" filed concurrently herewith and incorporated in their entirety by reference herein.

The dosage to be administered to the mammal, such as a human, will contain a therapeutically effective amount of a compound described herein.

As used herein, the term "therapeutically effective amount" means the amount needed to achieve the desired therapeutic or diagnostic effect or efficacy when administered to the respiratory tract of a subject in need of treatment, prophylaxis or diagnosis. The actual effective amounts of drug can vary according to the biological activity of the particular compound employed; specific drug or combination thereof being utilized; the particular composition formulated; the mode of administration; the age, weight, and condition of the patient; the nature and severity of the symptoms or condition being treated; the frequency of treatment; the administration of other therapies; and the effect desired. Dosages for a particular patient can be determined by one of ordinary skill in the art using conventional considerations, (e.g. by means of an appropriate, conventional pharmacological protocol).

In one embodiment of the invention, delivery to the pulmonary system of particles is by the methods described in U.S. patent application, High Efficient Delivery of a Large Therapeutic Mass Aerosol, application Ser. No. 09/591,307, filed Jun. 9, 2000, and U.S. patent application, Highly Efficient Delivery of A Large Therapeutic Mass Aerosol, application Ser. No. 09/878,146, filed Jun. 8, 2001. The entire contents of both these applications are incorporated herein by reference. As disclosed therein, particles are held, contained, stored or enclosed in a receptacle. Preferably, the receptacle, e.g. capsule or blister, has a volume of at least about 0.37 cm.sup.3 and can have a design suitable for use in a dry powder inhaler. Larger receptacles having a volume of at least about 0.48 cm.sup.3, 0.67 cm.sup.3 or 0.95 cm.sup.3 also can be employed.

The methods of the invention also relate to administering to the respiratory tract of a subject, particles and/or compositions comprising the particles of the invention, which can be enclosed in a receptacle. As described herein, in certain embodiments, the invention is drawn to methods of delivering the particles of the invention, while in other embodiments, the invention is drawn to methods of delivering respirable compositions comprising the particles of the invention. As used herein, the term "receptacle" includes but is not limited to, for example, a capsule, blister, film covered container well, chamber and other suitable means of storing particles, a powder or a respirable composition in an inhalation device known to those skilled in the art.

The invention is also drawn to receptacles which are capsules, for example, capsules designated with a particular capsule size, such as 2, 1, 0, 00 or 000. Suitable capsules can be obtained, for example, from Shionogi (Rockville, Md.). Blisters can be obtained, for example, from Hueck Foils, (Wall, N.J.). Other receptacles and other volumes thereof suitable for use in the instant invention are known to those skilled in the art.

Suitable organic solvents that can be employed include but are not limited to alcohols for example, ethanol, methanol, propanol, isopropanol, butanols, and others. Other organic solvents include but are not limited to perfluorocarbons, dichloromethane, chloroform, ether, ethyl acetate, methyl tert-butyl ether and others.

Suitable spray-drying techniques are described, for example, by K. Masters in "Spray Drying Handbook", John Wiley & Sons, New York, 1984. Generally, during spray-drying, heat from a hot gas such as heated air or nitrogen is used to evaporate the solvent from droplets formed by atomizing a continuous liquid feed. Other spray-drying techniques are well known to those skilled in the art. In a preferred embodiment, a rotary atomizer is employed. Examples of suitable spray driers using rotary atomization include the Mobile Minor spray drier, manufactured by Niro, Denmark. The hot gas can be, for example, air, nitrogen or argon.

Methods and apparatus suitable for forming particles of the present invention are described in U.S. patent application Ser. No. 10/101,536 with the title "Method and Apparatus for Producing Dry Particles" filed Mar. 20, 2002, in U.S. patent application Ser. No. 09/837,620 with the title "Control of Process Humidity to Produce Large, Porous Particles" filed Apr. 18, 2001, and in U.S. patent application Ser. No. 09/383,054 with the title "Stable Spray-Dried Protein Formulations" filed Aug. 25, 1999; the entire contents of these three applications are incorporated by reference herein.

Particles of the invention are suitable for delivery to the pulmonary system. Preferably, particles administered to the respiratory tract travel through the upper airways (oropharynx and larynx), the lower airways which include the trachea followed by bifurcations into the bronchi and bronchioli and through the terminal bronchioli which in turn divide into respiratory bronchioli leading then to the ultimate respiratory zone, the alveoli or the deep lung. In a preferred embodiment of the invention, most of the mass of particles deposits in the deep lung or alveoli.

"Flowability" refers to a powder characteristic that affects the ease of processing. For a material to be considered to be suitably flowable, it must be amenable to processing in automated equipment (such as capsule fillers or tablet making machines) using industry standard techniques. Flowability is measured using a number of techniques referred to as powder rheometric methods such as shear cell methods and dynamic angles of repose.

"Wettability" and "hydroscopicity", can be used interchangably herein, and is a property that affects the interaction of the powder in water. Wettability is a function of surface properties such as surface energy (surface tension) and morphology. This property can be measured using instruments such as dynamic vapor sorption or BET analyzers. Suitable units include water % weight gain.

Powder dispersibility indicators can be obtained via geometric and aerodynamic analytical methods. Geometric size was obtained via laser diffraction (Sympatec RODOS system), with measurements taken at different dispersion pressures used as an indicator of powder dispersibility (e.g, dispersion pressures ranging from 0.25 to 4 bar). The RODOS system can also be used in conjunction with an inhaler attachment system to measure particle size as a function of flowrate (30 90 L/min) through an inhaler, providing another indicator of powder dispersibility. Aerodynamic size distributions of the particles can be obtained via an Aerosizer system utilizing an Aerodisperser (API, Amherst, Mass.).

In a preferred embodiment, the ratio of the sizes obtained at low (0.25 bar) and high (2.0 bar) dispersion pressures (0.25/2 ratio) can be used as an indicator of dispersibility. For example, if a dry powder particle formulation has a 0.25/2 ratio of 3, then the size of the particles measured at low dispersion pressures is three times the size of the particles measured at high dispersion pressures, indicating high levels of particle aggregation at low dispersion pressures. In contrast, if a dry powder particle formulation has a 0.25/2 ratio close to 1, then the size of the particles measured at low dispersion pressures is almost the same as the size of the particles measured at high dispersion pressures, indicating low levels of particle aggregation at low dispersion pressures and flowrate independence.

Similarily, an inhaler to be tested can be attached to the RODOS apparatus (RODOS/IHA) to simulate the conditions under which a powder is emitted from the inhaler. The ratio of the sizes of the powder emitted from an inhaler at low (30 L/min) and high (90 L/min) flowrates (30/90 ratio) can be used as an indicator of dispersibility under clinically relevant conditions. For example, if a dry powder particle formulation has a 30/90 ratio of 3, then the geometric size of the particles measured at low flowrates is three times the size of the particles measured at high flowrates, indicating high levels of particle aggregation at low flowrates. In contrast, if a dry powder particle formulation has a 30/90 ratio close to 1, then the geometric size of the particles measured at low flowrates is almost the same as the size of the particles measured at high flowrates, indicating low levels of particle aggregation at low flowrates, and, thus, enhanced dispersibility and flowrate independence for these particles.

In a prefered embodiment, the invention relates to a method of producing and selecting for particles having a 0.25/2 RODOS ratio that is the same as/similar to the RODOS/IHA 30/90 ratio. The 0.25/2 ratio provides an indication of powder dispersibility under laboratory conditions, whereas the RODOS/IHA 30/90 ratio provides an indication of powder dispersibility under clinical/therapeutic conditions. Thus, by selecting for particles that have a high correlation between these respective ratios one is able to identify compositions with enhanced dispersibility properties.

In a further embodiment, Applicants disclose the increased dispersibility of dry powder particle formulations possessing crumpled morphologies over spherical morphology powder formulations with comparable primary particle geometric and aerodynamic sizes. The critical differences between the particle formulations are based on their morphologies, with the crumpled particles possessing larger surface areas and thinner walls than the spherical particles.
 

Claim 1 of 29 Claims

1. A particulate composition for delivery to the pulmonary system comprising particles having a tap density of less than 0.4 g/cm.sup.3 and a median geometric diameter greater than about 5 .mu.m, and an external surface area greater than about 5 m.sup.2/g wherein the particles have a continuous collapsed hollow sphere wall.

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