Title:  Aerodynamically light particles for pulmonary drug delivery

United States Patent:  6,503,480

Issued:  January 7, 2003

Inventors:  Edwards; David A. (Boston, MA); Caponetti; Giovannia (Piacenza, IT); Hrkach; Jeffrey S. (Somerville, MA); Lotan; Noah (Haifa, IL); Hanes; Justin (Baltimore, MD); Ben-Jebria; Abdell Aziz (State College, PA); Langer; Robert S. (Newton, MA)

Assignee:  Massachusetts Institute of Technology (Cambridge, MA); The Penn State Research Foundation (University Park, PA)

Appl. No.:  194068

Filed:  April 8, 1999

PCT Filed:  May 23, 1997

PCT NO:  PCT/US97/08895

371 Date:  April 8, 1999

102(e) Date:  April 8, 1999

PCT PUB.NO.:  WO97/44013

PCT PUB. Date: November 27, 1997

Improved aerodynamically light particles for delivery to the pulmonary system, and methods for their preparation and administration are provided. In a preferred embodiment, the aerodynamically light particles are made of a biodegradable material and have a tap density less than 0.4 g/cm³ and a mass mean diameter between 5 .mu.m and 30 .mu.m. The particles may be formed of biodegradable mat as biodegradable polymers. For example, the particles may be formed of a functionalized polyester graft copolymer consisting of a linear .alpha.-hydroxy-acid polyester backbone having at least one amino acid group incorporated therein and at least one poly(amino acid) side chain extending from an amino acid group in the polyester backbone. In one embodiment, aerodynamically light particles having a large mean diameter, for example greater than 5 .mu.m, can be used for enhanced delivery of a therapeutic or diagnostic agent to the alveolar region of the lung. The aerodynamically light particles optionally can incorporate a therapeutic or diagnostic agent, and may be effectively aerosolized for administration to the respiratory tract to permit systemic or local delivery of wide variety of incrorporated agents.

DETAILED DESCRIPTION OF THE INVENTION

Aerodynamically light, biodegradable particles for improved delivery to the respiratory tract are provided. The particles can incorporate a therapeutic or diagnostic agent, and can be used for controlled systemic or local delivery of the agent to the respiratory tract via aerosolization. In a preferred embodiment, the particles have a tap density less than about 0.4 g/cm³. Features of the particle which can contribute to low tap density include irregular surface texture and porous structure. Administration of the low density particles to the lung by aerosolization permits deep lung delivery of relatively large diameter therapeutic aerosols, for example, greater than 5 .mu.m in mean diameter. A rough surface texture also can reduce particle agglomeration and provide a highly flowable powder, which is ideal for aerosolization via dry powder inhaler devices, leading to lower deposition in the mouth, throat and inhaler device.

Density and Size of Aerodynamically Light Particles

Particle Size

The mass mean diameter of the particles can be measured using a Coulter Counter. The aerodynamically light particles are preferably at least about 5 microns in diameter. The diameter of particles in a sample will range depending upon depending on 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 within targeted sites within the respiratory tract.

The particles may be fabricated or separated, for example. by filtration, to provide a particle sample with a preselected size distribution. For example, greater than 30%, 50%, 70%, or 80% of the particles in a sample can have a diameter within a selected range of at least 5 .mu.m. The selected range within which a certain percentage of the particles must fall may be, for example, between about 5 and 30 .mu.m, or optionally between 5 and 15 .mu.m. In one preferred embodiment, at least a portion of the particles have a diameter between about 9 and 11 .mu.m. Optionally, the particle sample also can be fabricated wherein at least 90%, or optionally 95% or 99%, have a diameter within the selected range. The presence of the higher proportion of the aerodynamically light, larger diameter (at least about 5 .mu.m) particles in the particle sample enhances the delivery of therapeutic or diagnostic agents incorporated therein to the deep lung.

In one embodiment, in the particle sample, the interquartile range may be 2 .mu.m, with a mean diameter for example of 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0 or 13.5 .mu.m. Thus. for example, at least 30%, 40%, 50% or 60% of the particles may have diameters within the selected ranges of 5.5-7.5 .mu.m, 6.0-8.0 .mu.m, 6.5-8.5 .mu.m, 7.0-9.0 .mu.m, 7.5-9.5 .mu.m, 8.0-10.0 .mu.m, 8.5-10.5 .mu.m, 9.0-11.0 .mu.m, 9.5-11.5 .mu.m, 10.0-12.0 .mu.m, 10.5-12.5.mu.m, 11.0-13.0 .mu.m, 11.5-13.5 .mu.m, 12.0-14.0 .mu.m, 12.5-14.5 .mu.m or 13.0-15.0 .mu.m. Preferably the above-listed percentages of particles have diameters within a 1 .mu.m range, for example, 6.0-7.0 .mu.m, 10.0-11.0 .mu.m or 13.0-14.0 .mu.m.

Particles having a tap density less than about 0.4 g/cm³ and a mean diameter of at least about 5 .mu.m are more capable of escaping inertial and gravitational deposition in the oropharyngeal region than smaller or more dense particles, and are targeted to the airways of the deep lung. The use of larger particles (mean diameter greater than 5 .mu.m) is advantageous since they are able to aerosolize more efficiently than smaller, denser particles such as those currently used for inhalation therapies.

In comparison to smaller, denser particles, the larger (greater than 5 .mu.m) aerodynamically light particles also can potentially more successfully avoid phagocytic engulfment by alveolar macrophages and clearance from the lungs, due to size exclusion of the particles. from the phagocytes' cytosolic space. For particles of statistically isotropic shape (on average, particles of the powder possess no distinguishable orientation), such as spheres with rough surfaces, the particle envelope volume is approximately equivalent to the volume of cytosolic space required within a macrophage for complete particle phagocytosis.

Aerodynamically light particles thus are capable of a longer term release of an incorporated diagnostic or therapeutic agent than smaller, denser particles. Following inhalation, aerodynamically light biodegradable particles can deposit in the lungs (due to their relatively low tap density), and subsequently undergo slow degradation and drug release, without the majority of the particles being phagocytosed by alveolar macrophages. The agent can be delivered relatively slowly into the alveolar fluid, and at a controlled rate into the blood stream, minimizing possible toxic responses of exposed cells to an excessively high concentration of the agent. The aerodynamically light particles thus are highly suitable for inhalation therapies, particularly in controlled release applications.

The particles may be fabricated with the appropriate material, surface roughness, diameter and tap density for localized delivery to selected regions of the respiratory tract such as the deep lung or upper airways. For example, higher density or larger particles may be used for upper airway delivery, or a mixture of different sized particles in a sample, provided with the same or different incorporated agent may be administered to target different regions of the lung in one administration.

Particle Density and Deposition

The particles have a diameter of at least about 5 .mu.m and optionally incorporate a therapeutic or diagnostic agent. The particles are preferably aerodynamically light. As used herein, the phrase "aerodynamically light particles" refers to particles having a tap density less than about 0.4 g/cm³. The tap density of particles of a dry powder may be obtained using a Geo Phy.TM. (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 sphere envelope volume within which it can be enclosed.

Inertial impaction and gravitational settling of aerosols are predominant deposition mechanisms in the airways and acini of the lungs during normal breathing conditions. Edwards, D. A., J. Aerosol Sci. 26:293-317 (1995). The importance of both deposition mechanisms increases in proportion to the mass of aerosols and not to particle (or envelope) volume. Since the site of aerosol deposition in the lungs is determined by the mass of the aerosol (at least for particles of mean aerodynamic diameter greater than approximately 1 .mu.m), diminishing the tap density by increasing particle surface irregularities and particle porosity permits the delivery of larger particle envelope volumes into the lungs, all other physical parameters being equal.

The low tap density particles have a small aerodynamic diameter in comparison to the actual envelope sphere diameter. The aerodynamic diameter, d_aer, is related to the envelope sphere diameter, d (Gonda, I., "Physico-chemical principles in aerosol delivery," in Topics in Pharmaceutical Sciences 1991 (eds. D. J. A. Crommelin and K. K. Midha), pp. 95-117, Stuttgart: Medpharm Scientific Publishers. 1992) by the formula:

d_aer =d.rho.

where the envelope mass .rho. is in units of g/cm³. Maximal deposition of monodisperse aerosol particles in the alveolar region of the human lung (approximately 60%) occurs for an aerodynamic diameter of approximately d_aer =3 .mu.m. Heyder, J. et al., J. Aerosol Sci., 17: 811-825 (1986). Due to their small envelope mass density, the actual diameter d of aerodynamically light particles comprising a monodisperse inhaled powder that will exhibit maximum deep-lung deposition is:

d=3/.rho..mu.m (where .rho.<1 g/cm³);

where d is always greater than 3 .mu.m. For example, aerodynamically light particles that display an envelope mass density, .rho.=0.1 g/cm³. will exhibit a maximum deposition for particles having envelope diameters as large as 9.5 .mu.m. The increased particle size diminishes interparticle adhesion forces. Visser, J., Powder Technology, 58:1-10. Thus, large particle size increases efficiency of aerosolization to the deep lung for particles of low envelope mass density, in addition to contributing to lower phagocytic losses.

Particle Materials

The aerodynamically light particles preferably are biodegradable and biocompatible, and optionally are capable of biodegrading at a controlled rate for release of an incorporated thereapeutic or diagnostic agent. The particles can be made of any material which is capable of forming a particle having a tap density less than about 0.4 g/cm³. Both inorganic and organic materials can be used. Other non-polymeric materials (e.g. fatty acids) may be used which are capable of forming aerodynamically light particles as defined herein. Different properties of the particle can contribute to the aerodynamic lightness including the composition forming the particle, and the presence of irregular surface structure or pores or cavities within the particle.

Polymeric Particles

The particles may be formed from any biocompatible, and preferably biodegradable polymer, copolymer, or blend, which is capable of forming particles having a tap density less than about 0.4 g/cm³.

Surface eroding polymers such as polyanhydrides may be used to form the aerodynamically light particles. For example, polyanhydrides such as poly[(.rho.-carboxyphenoxy)-hexane anhydride] (PCPH) may be used. Biodegradable polyanhydrides are described, for example, in U.S. Pat. No. 4,857,311.

In another embodiment, bulk eroding polymers such as those based on polyesters, including poly(hydroxy acids), can be used. Preferred poly(hydroxy acids) are polyglycolic acid (PGA), polylactic acid (PLA) and copolymers and coblends thereof. In one embodiment, the polyester has incorporated therein a charged or functionalizable group such as an amino acid.

Other polymers include polyamides, polycarbonates, polyalkylenes such as polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly(ethylene terephthalate), poly vinyl compounds such as polyvinyl alcohols, polyvinyl ethers, and polyvinyl esters, polymers of acrylic and methacrylic acids, celluloses and other polysaccharides, and peptides or proteins, or copolymers or blends thereof. Polymers may be selected with or modified to have the appropriate stability and degradation rates in vivo for different controlled drug delivery applications.

Polyester Graft Copolymers

In one preferred embodiment, the aerodynamically light particles are formed from functionalized polyester graft copolymers, as described in Hrkach et al., Macromolecules, 28:4736-4739 (1995); and Hrkach et al., "Poly(L-Lactic acid-co-amino acid) Graft Copolymers: A Class of Functional Biodegradable Biomaterials" in Hydrogels and Biodegradable Polymers for Bioapplications, ACS Symposium Series No. 627, Raphael M. Ottenbrite et al., Eds., .mu.merican Chemical Society, Chapter 8, pp. 93-101, 1996. The functionalized graft copolymers are copolymers of polyesters, such as poly(glycolic acid) or poly(lactic acid), and another polymer including functionalizable or ionizable groups, such as a poly(amino acid). In a preferred embodiment, comb-like graft copolymers are used which include a linear polyester backbone having amino acids incorporated therein, and poly(amino acid) side chains which extend from the amino acid residues in the polyester backbone. The polyesters may be polymers of .alpha.-hydroxy acids such as lactic acid, glycolic acid, hydroxybutyric acid and hydroxyvaleric acid, or derivatives or combinations thereof. The polymers can include ionizable side chains, such as polylysine and polyaniline. Other ionizable groups, such as amino or carboxyl groups, may be incorporated into the polymer. covalently or noncovalently, to enhance surface roughness and porosity.

An exemplary polyester graft copolymer is poly(lactic acid-colysine-graft-lysine) (PLAL-Lys), which has a polyester backbone consisting of poly(L-lactic acid-co- L-lysine) (PLAL), and grafted polylysine chains. PLAL-Lys is a comb-like graft copolymer having a backbone composition, for example, of 98 mol % lactic acid and 2 mol % lysine and poly(lysine) side chains extending from the lysine sites of the backbone.

PLAL-Lys may be synthesized as follows. First, the PLAL copolymer consisting of L-lactic acid units and approximately 1-2% N .epsilon. carbobenzoxy-L-lysine (Z-L-lysine) units is synthesized as described in Barrera et al., J. Am. Chem. Soc., 115:11010 (1993). Removal of the Z protecting groups of the randomly incorporated lysine groups in the polymer chain of PLAL yields the free E-amine which can undergo further chemical modification. The use of the poly(lactic acid) copolymer is advantageous since it biodegrades into lactic acid and lysine, which can be processed by the body. The existing backbone lysine groups are used as initiating sites for the growth of poly(amino acid) side chains.

The lysine .epsilon.-amino groups of linear poly(L-lactic acid-co-L-lysine) copolymers initiate the ring opening polymerization of an amino acid N-.epsilon. carboxyanhydride (NCA) to produce poly(L-lactic acid-co-amino acid) comb-like graft copolymers. In a preferred embodiment, NCAs are synthesized by reacting the appropriate amino acid with triphosgene. Daly et al., Tetrahedron Lett., 29:5859 (1988). The advantage of using triphosgene over phosgene gas is that it is a solid material, and therefore, safer and easier to handle. It also is soluble in THF and hexane so any excess is efficiently separated from the NCAs.

The ring opening polymerization of amino acid N-carboxyanhydrides (NCAs) is initiated by nucleophilic initiators such as amines, alcohols, and water. The primary amine initiated ring opening polymerization of NCAs allows efficient control over the degree of polymerization when the monomer to initiator ratio (M/I) is less than 150. Kricheldorf, H. R. in Models of Biopolymers by Ring-Opening Polymerization, Penczek, S., Ed., CRC Press, Boca Raton, 1990. Chapter 1; Kricheldorf, H. R. .alpha.-Aminoacid-N-Carboxy-Anhydrides and Related Heterocycles, Spriner-Verlag, Berlin, 1987; and Imanishi, Y. in Ring-Opening Polymerization, Ivin, K. J. and Saegusa, T., Eds., Elsevier, London, 1984, Volume 2, Chapter 8. Methods for using lysine .epsilon.-amino groups as polymeric initiators for NCA polymerizations are described in the art. Sela, M. et al., J. Am. Chem. Soc., 78: 746 (1956).

In the reaction of an amino acid NCA with PLAL, the nucleophilic primary .epsilon.-amino group of the lysine side chain attacks C-5 of the NCA. This leads to ring opening to form an amide linkage, accompanied by evolution of a molecule of CO₂. The amino group formed by the evolution of CO₂ propogates the polymerization by attacking subsequent NCA molecules. The degree of polymerization of the poly(amino acid) side chains, the amino acid content in the resulting graft copolymers and the physical and chemical characteristics of the resulting copolymers can be controlled by adjusting the ratio of NCA to lysine .epsilon.-amino groups in the PLAL polymer, for example, by adjusting the length of the poly(amino acid) side chains and the total amino acid content.

The poly(amino acid) side chains grafted onto or incorporated into the polyester backbone can include any amino acid. such as aspartic acid, alanine or lysine, or mixtures thereof. The functional groups present in the amino acid side chains, which can be chemically modified, include amino, carboxylic acid, thiol, guanido, imidazole and hydroxyl groups. As used herein, the term "amino acid" includes natural and synthetic amino acids and derivatives thereof. The polymers can be prepared with a range of side chain lengths. The side chains preferably include between 10 and 100 amino acids, and have an overall amino acid content between 7 and 72%. However, the side chains can include more than 100 amino acids and can have an overall amino acid content greater than 72%, depending on the reaction conditions. Poly(amino acids) can be grafted to the PLAL backbone in any suitable solvent. Suitable solvents include polar organic solvents such as dioxane, DMF, CH₂ Cl₂, and mixtures thereof. In a preferred embodiment, the reaction is conducted in dioxane at room temperature for a period of time between about 2 and 4 days.

Alternatively, the particles may be formed from polymers or blends of polymers with different polyester/amino acid backbones and grafted amino acid side chains. For example, poly(lactic acid-co-lysine-graft-alanine-lysine) (PLAL-Ala-Lys), or a blend of PLAL-Lys with poly(lactic acid-co-glycolic acid-block-ethylene oxide) (PLGA-PEG) (PLAL-Lys-PLGA-PEG) may be used.

In the synthesis, the graft copolymers may be tailored to optimize different characteristics of the aerodynamically light particle including: i) interactions between the agent to be delivered and the copolymer to provide stabilization of the agent and retention of activity upon delivery; ii) rate of polymer degradation and, thereby, rate of drug release profiles; iii) surface characteristics and targeting capabilities via chemical modification; and iv) particle porosity.

Therapeutic Agents

Any of a variety of therapeutic agents can be incorporated within the particles, which can locally or systemically deliver the incorporated agents following administration to the lungs of an animal. Examples include synthetic inorganic and organic compounds or molecules, proteins and peptides, polysaccharides and other sugars, lipids, and nucleic acid molecules having therapeutic, prophylactic or diagnostic activities. Nucleic acid molecules include genes, antisense molecules which bind to complementary DNA to inhibit transcription, ribozymes and ribozyme guide sequences. The agents to be incorporated can have a variety of biological activities, such as vasoactive agents, neuroactive agents, hormones, anticoagulants, immunomodulating agents, cytotoxic agents, prophylactic agents, antibiotics, antivirals, antisense, antigens, and antibodies. In some instances, the proteins may be antibodies or antigens which otherwise would have to be administered by injection to elicit an appropriate response. Compounds with a wide range of molecular weight, for example, between 100 and 500,000 grams per mole, can be encapsulated.

Proteins are defined as consisting of 100 amino acid residues or more; peptides are less than 100 amino acid residues. Unless otherwise stated, the term protein refers to both proteins and peptides. Examples include insulin and other hormones. Polysaccharides, such as heparin, can also be administered.

Aerosols including the aerodynamically light particles are useful for a variety of inhalation therapies. The particles can incorporate small and large drugs, release the incorporated drugs over time periods ranging from hours to months, and withstand extreme conditions during aerosolization or following deposition in the lungs that might otherwise harm the encapsulated agents.

The agents can be locally delivered within the lung or can be systemically administered. For example, genes for the treatment of diseases such as cystic fibrosis can be administered, as can beta agonists for asthma. Other specific therapeutic agents include insulin, calcitonin, leuprolide (or LHRH), G-CSF, parathyroid hormone-related peptide, somatostatin, testosterone, progesterone, estradiol, nicotine, fentanyl, norethisterone, clonidine, scopolomine, salicylate, cromolyn sodium, salmeterol, formeterol, albeterol, and valium.

Diagnostic Agents

Any of a variety of diagnostic agents can be incorporated within the particles, which can locally or systemically deliver the incorporated agents following administration to the lungs of an animal, including gases and other imaging agents.

Gases

Any biocompatible or pharmacologically acceptable gas can be incorporated into the particles or trapped in the pores of the particles. The term gas refers to any compound which is a gas or capable of forming a gas at the temperature at which imaging is being performed. The gas may be composed of a single compound such as oxygen, nitrogen, xenon, argon, nitrogen or a mixture of compounds such as air. Examples of fluorinated gases include CF₄, C₂ F₆, C₃ F₈, C₄ F₈, SF₆, C₂ F₄, and C₃ F₆.

Other Imaging Agents

Other imaging agents which may be utilized include commercially available agents used in positron emission tomography (PET), computer assisted tomography (CAT), single photon emission computerized tomography, x-ray, fluoroscopy, and magnetic resonance imaging (MRI).

Examples of suitable materials for use as contrast agents in MRI include the gatalinium chelates currently available, such as diethylene triamine pentacetic acid (DTPA) and gatopentotate dimeglumine, as well as iron, magnesium, manganese, copper and chromium.

Examples of materials useful for CAT and x-rays include iodine based materials for intravenous administration, such as ionic monomers typified by diatrizoate and iothalamate, non-ionic monomers such as iopamidol, isohexol, and ioversol, non-ionic dimers, such as iotrol and iodixanol, and ionic dimers, for example, ioxagalte.

Particles incorporating these agents can be detected using standard techniques available in the art and commercially available equipment.

Formation of Aerodynamically Light Polymeric Particles

Aerodynamically light polymeric particles may be prepared using single and double emulsion solvent evaporation, spray drying, solvent extraction or other methods well known to those of ordinary skill in the art. The particles may be made, for example, using methods for making microspheres or microcapsules known in the art.

Methods for making microspheres are described in the literature, for example, in Mathiowitz and Langer, J. Controlled Release 5,13-22 (1987); Mathiowitz et al., Reactive Polymers 6, 275-283 (1987); and Mathiowitz et al., J. Appl. Polymer Sci. 35, 755-774 (1988). The selection of the method depends on the polymer selection, the size, external morphology, and crystallinity that is desired, as described, for example, by Mathiowitz et al., Scanning Microscopy 4,329-340 (1990); Mathiowitz et al., J. Appl. Polymer Sci. 45, 125-134 (1992); and Benita et al., J. Pharm. Sci. 73, 1721-1724 (1984).

In solvent evaporation, described for example, in Mathiowitz, et al., (1990), Benita, and U.S. Pat. No. 4,272,398 to Jaffe, a polymer is dissolved in a volatile organic solvent, such as methylene chloride. Several different polymer concentrations can be used, for example, between 0.05 and 0.20 g/ml. An agent to be incorporated, either in soluble form or dispersed as fine particles, is optionally added to the polymer solution, and the mixture is suspended in an aqueous phase that contains a surface active agent such as poly(vinyl alcohol). The resulting emulsion is stirred until most of the organic solvent evaporates, leaving solid microspheres, which may be washed with water and dried overnight in a lyophilizer.

Microspheres with different sizes (typically between 1 and 1000 microns) and morphologies can be obtained. This method is especially useful for relatively stable polymers such as polyesters and polystyrene. However, labile polymers such as polyanhydrides may degrade due to exposure to water. Solvent removal may be a preferred method for preparing microspheres from these polymers.

Solvent removal was primarily designed for use with polyanhydrides. In this method, a therapeutic or diagnostic agent can be dispersed or dissolved in a solution of a selected polymer in a volatile organic solvent like methylene chloride. The mixture can then be suspended in oil, such as silicon oil, by stirring, to form an emulsion. As the solvent diffuses into the oil phase, the emulsion droplets harden into solid polymer microspheres. Unlike solvent evaporation, this method can be used to make microspheres from polymers with high melting points and a wide range of molecular weights. Microspheres having a diameter between one and 300 microns can be obtained using this procedure.

Targeting of Particles

Targeting molecules can be attached to the particles via reactive functional groups on the particles. For example, targeting molecules can be attached to the amino acid groups of functionalized polyester graft copolymer particles, such as PLAL-Lys particles. Targeting molecules permit binding interactions of the particle with specific receptor sites, such as those within the lungs. The particles can be targeted by attaching ligands which specifically or non-specifically bind to particular targets. Exemplary targeting molecules include antibodies and fragments thereof including the variable regions, lectins, and hormones or other organic molecules capable of specific binding to receptors on the surfaces of the target cells.

Administration

The particles can be administered to the respiratory system alone or in any appropriate pharmaceutically acceptable carrier, such as a liquid, for example saline, or a powder. In one embodiment, particles incorporating a prophylactic, therapeutic or diagnostic agent are codelivered with larger carrier particles that do not include an incorporated agent. Preferably, the larger particles have a mass mean diameter between about 50 and 100 .mu.m.

Aerosol dosage, formulations and delivery systems may be selected for a particular therapeutic application, as described, for example, in Gonda, I. "Aerosols for delivery of therapeutic and diagnostic agents to the respiratory tract," in Critical Reviews in Therapeutic Drug Carrier Systems, 6:273-313, 1990; and in Moren, "Aerosol dosage forms and formulations," in: Aerosols in Medicine. Principles, Diagnosis and Therapy, Moren, et al., Eds, Elsevier, Amsterdam, 1985.

The greater efficiency of aerosolization by aerodynamically light particles of relatively large size permits more of an incorporated agent to be delivered than is possible with the same mass of relatively dense aerosols. The relatively large particle size also minimizes potential drug losses caused by particle phagocytosis. When the particles are formed from biocompatible polymers, the system can provide controlled release in the lungs and long-time local action or systemic bioavailability of the incorporated agent. Denaturation of macromolecular drugs can be minimized during aerosolization since macromolecules are contained and protected within a polymeric shell. The enzymatic degradation of proteins or peptides can be minimized by co-incorporating peptidase-inhibitors.

Diagnostic Applications

The particles can be combined with a pharmaceutically acceptable carrier, then an effective amount for detection administered to a patient via inhalation. Particles containing an incorporated imaging agent may be used for a variety of diagnostic applications, including detecting and characterizing tumor masses and tissues.

Claim 1 of 35 Claims

What is claimed is:

1. A particulate system for delivery to the pulmonary system comprising particles which comprise a biodegradable material and a therapeutic, prophylactic or diagnostic agent, have a tap density of less than 0.4 g/cm³ and a mass mean diameter between about 5 .mu.m and about 30 .mu.m.
 

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