The present invention is directed toward particles for delivery of epinephrine to the respiratory system and methods for treating a patient in need of epinephrine. The particles and respirable compositions comprising the particles of the present invention described herein comprise the bioactive agent epinephrine, or a salt thereof, as a therapeutic agent. The particles are preferably formed by spray drying. Preferably, the particles and the respirable compositions are substantially dry and are substantially free of propellents. In a preferred embodiment, the particles have aerodynamic characteristics that permit targeted delivery of epinephrine to the site(s) of action.

Description of the Invention

SUMMARY OF THE INVENTION

The present invention is directed toward particles for delivery of epinephrine to the respiratory system and methods for treating a patient in need of epinephrine. The particles and respirable compositions comprising the particles of the present invention described herein comprise the bioactive agent epinephrine, or a salt thereof, as a therapeutic agent. The particles are preferably formed by spray drying. Preferably, the particles and the respirable compositions are substantially dry and are substantially free of propellents. In a preferred embodiment, the particles have aerodynamic characteristics that permit targeted delivery of epinephrine to the site(s) of action.

The present invention is directed, in part, to a method for treating a patient in need of epinephrine, the method comprising administering an effective amount of substantially dry particles to the respiratory system of the patient, wherein the particles comprise (a) epinephrine, or a salt thereof; and (b) at least one pharmaceutically acceptable excipient. In one aspect, the effective amount of particles possess a fine particle fraction of less than 5.6 microns of at least about 45 percent. In another, the effective amount of particles possess a fine particle fraction of less than 3.4 microns of at least about 15 percent.

The invention is also directed, in part, to a method for treating a patient in need of epinephrine, the method comprising administering an effective amount of substantially dry particles to the respiratory system of the patient, the particles comprising epinephrine, or a salt thereof. For example, the invention comprises a method for treating a patient in need of epinephrine, the method comprising administering an effective amount of particles to the respiratory system of the patient, the particles comprising epinephrine, or a salt thereof; wherein the effective amount of particles possess a fine particle fraction of less than 5.6 microns of at least about 45 percent. As an additional example, the invention also includes a method for treating a patient in need of epinephrine, the method comprising administering an effective amount of particles to the respiratory system of the patient, the particles comprising epinephrine, or a salt thereof; wherein the effective amount of particles possess a fine particle fraction of less than 3.4 microns of at least about 15 percent. In another aspect of the invention, a method for treating a patient in need of rescue therapy for anaphylaxis is provided comprising administering particles to the respiratory system of the patient, the particles comprising a therapeutically effective amount of epinephrine, or a salt thereof; wherein the particles are delivered to the respiratory system and the epinephrine reaches its site of action within a time sufficiently short to provide said rescue therapy.

The claimed invention also includes a method for treating a patient in need of epinephrine, the method comprising administering an effective amount of substantially dry particles to the respiratory system of the patient, wherein the particles comprise epinephrine, or a salt thereof, and wherein a first portion of the particles is deposited in the airways of the respiratory system and a second portion of the particles is deposited to the alveoli region of the lungs.

Additionally, a method for treating a patient in need of rescue therapy for anaphylaxis is contemplated. The method comprises administering particles to the respiratory system of the patient, wherein the particles comprise (a) a therapeutically effective amount of epinephrine, or a salt thereof; and (b) at least one pharmaceutically acceptable excipient, wherein the particles are delivered to the respiratory system and the epinephrine reaches its site of action within a time sufficiently short to provide said rescue therapy. Furthermore, the instant invention comprises a method for treating a patient suffering from anaphylaxis, wherein the method comprises: (a) administering an effective amount of substantially dry particles to the respiratory system of the patient, the particles comprising epinephrine, or a salt thereof; (b) monitoring the patient; and (c) administering additional epinephrine to the patient.

The present invention also comprises a method for treating a patient in need of epinephrine, the method comprising: (a) administering an effective amount of a first mass of substantially dry particles to the respiratory system of the patient, the particles comprising epinephrine, or a salt thereof; and (b) subsequently, administering an effective amount of a second mass of substantially dry particles to the respiratory system of the patient, the particles comprising epinephrine, or a salt thereof. Further, the invention comprises a method for treating a patient suffering from anaphylaxis, comprising: (a) administering an effective amount of a first mass of substantially dry particles to the respiratory system of the patient, the particles comprising epinephrine, or a salt thereof; and (b) subsequently, administering an effective amount of a second mass of substantially dry particles to the respiratory system of the patient, the particles comprising epinephrine, or a salt thereof; wherein the first and second masses of substantially dry particles comprise about 11 to about 21 weight percent epinephrine bitartrate; about 62 to about 82 weight percent leucine; and about 7 to about 17 weight percent sodium tartrate.

In addition to the above mentioned methods for treating a patient, the instant invention is directed to particles for the delivery of epinephrine to the respiratory system, and methods for treating a patient in need of epinephrine comprising administering an effective amount of said particles to the respiratory system of a patient. The particles in various embodiments comprise: (i) epinephrine, or a salt thereof; a carboxylic acid, or a salt thereof; a salt comprising at least one multivalent cation or anion; and a phospholipid; (ii) epinephrine, or a salt thereof; an amino acid; and a sugar; (iii) epinephrine, or a salt thereof; and an amino acid; (iv) epinephrine, or a salt thereof; an amino acid; and a carboxylic acid, or a salt thereof; (v) about 11 to about 21 weight percent epinephrine bitartrate; about 62 to about 82 weight percent leucine; and about 7 to about 17 weight percent sodium tartrate; or (vi) about 12 to about 23 weight percent epinephrine bitartrate; and about 77 to about 88 weight percent leucine.

In one embodiment, the present invention is directed to spray dried particles for delivery of epinephrine to the respiratory system wherein the particles comprise (a) epinephrine, or a salt thereof; and (b) at least one pharmaceutically acceptable excipient and wherein the particles possess a fine particle fraction of less than 5.6 microns of at least about 45 percent. In another embodiment, the spray dried particles possess a fine particle fraction of less than 3.4 microns of at least about 15 percent.

In one aspect, the particles for delivery of epinephrine to the respiratory system are essentially dry and comprise: (a) epinephrine, or a salt thereof; and (b) at least one pharmaceutically acceptable excipient.

The instant invention also includes a propellent-free pharmaceutical composition comprising essentially dry particles for delivery of epinephrine to the respiratory system, wherein the particles comprise: (a) epinephrine, or a salt thereof; and (b) at least one pharmaceutically acceptable excipient. Advantageously, the scope of the instant invention additionally includes a substantially antioxidant-free pharmaceutical composition comprising dry particles for delivery of epinephrine to the respiratory system, wherein the particles comprise: (a) epinephrine, or a salt thereof; and (b) at least one pharmaceutically acceptable excipient.

DETAILED DESCRIPTION OF THE INVENTION

A description of preferred embodiments of the invention follows.

The present invention is directed toward particles for delivery of epinephrine to the respiratory system and methods for treating a patient in need of epinephrine. The particles and respirable compositions comprising the particles of the present invention described herein comprise the bioactive agent epinephrine, or a salt thereof, as a therapeutic agent. The particles are preferably formed by spray drying. Preferably, the particles and the respirable compositions are substantially dry and are substantially free of propellents. In one preferred embodiment, the particles have aerodynamic characteristics that permit targeted delivery of epinephrine to the site(s) of action.

The particles and respirable compositions comprising the particles of the invention, both hereinafter referred to as "particles" or "powders," are also preferably biocompatible, and optionally are capable of affecting the rate of delivery of epinephrine. In addition to epinephrine, the particles can further include a variety of pharmaceutically acceptable excipients. Both inorganic and organic materials can be used. Suitable materials can include, but are not limited to, lipids, phospholipids, fatty acids, inorganic salts, carboxylic acids, amino acids, carbohydrates, tartrate, and various sugars. Preferred particle compositions are further described below.

Practice of the instant invention provides numerous advantages over conventional epinephrine delivery systems. The respirable particles of the invention and the methods of their administration avoid the uncomfortable and often painful injections required by some conventional forms of epinephrine. The availability of a reliable inhaled form of epinephrine is expected to increase patient compliance and to reduce delays in treatment by, for example, providing a needle-free epinephrine delivery system. Epinephrine containing dry powder particles will allow patients to carry a convenient, compact inhaler and reliably self-administer epinephrine non-invasively.

The blood plasma concentrations of epinephrine achieved via dry powder particles of the instant invention have shown to be significantly less variable than current injections, offering another important improvement over existing therapies. Decreased variability, i.e., greater reliability, in peak and time to peak systemic epinephrine concentrations (C.sub.MAX and T.sub.MAX, respectively) through administration of the dry powders of the present invention may result in greater consistency in therapeutic response and an improved safety profile over currently available epinephrine formulations. Moreover, epinephrine delivered via the lungs formulated as dry powder particles has demonstrated relatively rapid absorption and time to peak blood plasma concentrations, which should further improve the therapeutic benefits of epinephrine, for example, the ability of epinephrine to arrest a rapidly progressing anaphylactic reaction. The unique characteristics of aerodynamically light particles comprising epinephrine, or a salt thereof, provide for improved physiological effects such as, for example, increased therapeutic effect(s) or increased duration of therapeutic effect(s).

The epinephrine containing particles can be formulated to modify or control the release of epinephrine and/or the elimination of epinephrine from the patient. For example, the particles of the present invention can have quick elimination of epinephrine from the blood stream relative to conventional epinephrine therapies such as auto-injected epinephrine. A consistent pharmacokinetic profile demonstrating a relatively quick elimination of epinephrine from the blood stream can allow for more precise and predictable treatment of patients in need of epinephrine. Alternatively, particles may be formulated, as described herein, for sustained release and/or action of epinephrine. Particles may be formulated having both a quick onset of action by epinephrine as well as having a sustained release and/or action.

The disclosed respirable particles and methods of their administration allow for the delivery of epinephrine both locally and systemically. Administration of particles comprising epinephrine provides on-demand treatment without the inconvenience of injections. Selective delivery of epinephrine to the site(s) of action can be obtained in a time frame not available with intramuscular, subcutaneous, or auto-injected formulations. By practicing the invention, relief is available to symptomatic patients in a time frame during which the epinephrine of conventional therapies (i.e., intramuscular, subcutaneous, or auto-injected formulations) would still be traveling to the site of action. The particles of the invention are preferably aerodynamically light, as described herein, and are capable of depositing in the airways or in the alveoli, or deep lung, for delivery of epinephrine to the blood stream and subsequent systemic action. The particles of the invention are also capable of depositing locally at sites of obstruction or congestion in the respiratory system for topical delivery of epinephrine. For example, by depositing epinephrine containing particles directly into the airway passages and the lungs, respiratory complications of anaphylactic response (e.g., bronchospasm and laryngeal edema) should be more quickly and more effectively treated. By contrast, parenteral (e.g., intravenous, intramuscular, subcutaneous, and auto-injected) epinephrine administration does not achieve this local delivery component.

Advantageously, the particles of the invention are capable of delivering an effective amount of epinephrine to a patient in a single breath activated step. The dose of epinephrine delivered in a single inhalation can range from about 50 micrograms to several milligrams.

The particles of the present invention comprise epinephrine also referred to herein as the "bioactive agent," "therapeutic agent," "agent," "medicament," or "drug." Epinephrine, a catecholamine, is known chemically as 4-[1-hydroxy-2-(methylamino)ethyl]-1,2-benzenediol and is represented by Structural Formula I -- see Original Patent.

Epinephrine used in the present invention can be obtained from natural sources, such as, for example, from the adrenal glands of animals, or can be synthetically produced, such as, for example, from pyrocatechol. Particles of the invention can comprise salts of epinephrine, including, but not limited to, epinephrine hydrochloride (C.sub.9H.sub.13NO.sub.3.HCl) or epinephrine bitartrate (C.sub.9H.sub.13NO.sub.3.C.sub.4H.sub.6O.sub.6). Alternatively, the particles may comprise epinephrine free base (C.sub.9H.sub.13NO.sub.3), i.e., epinephrine lacking salt or a counterion. The particles of the invention may also comprise a mixture of two or more forms of epinephrine. The particles may also comprise one or more derivatives or analogs of epinephrine. The derivatives or analogs may be obtained from natural sources or from synthetic routes. Examples of derivatives or analogs of epinephrine include, but are not limited to, phenyl epinephrine and norepinephrine.

Epinephrine is a chiral molecule. Particles may comprise the (L)- or (D)-stereoisomers of epinephrine, or a mixture thereof (e.g., an optically active mixture or a racemic mixture). Preferably, the particles contain epinephrine that substantially comprises the (L)-isomer, for example, at least about 70, 80, 90, or 95% of the epinephrine is the (L)-isomer.

The amount of epinephrine, or salt thereof, present in the particles can range from about 1 to about 95 percent by weight. Alternatively, a mixture of epinephrine forms is present in the particles at a concentration of about 1 to about 95 weight percent. The particles of the instant invention can comprise about 1 to about 60, about 1 to 55, about 1 to 50, about 1 to 45, about 1 to 40, or preferably, about 1 to about 30 weight percent epinephrine, or salt(s) thereof. The particles can comprise about 1 to about 20 weight percent epinephrine such as about 1 to about 10 weight percent epinephrine; about 1 to about 15 weight percent epinephrine free base, for example, about 1 to about 10 or about 5 weight percent epinephrine free base; about 1 to about 25 weight percent epinephrine bitartrate such as about 5 to about 20 or about 9 to about 18 weight percent epinephrine bitartrate; and/or about 1 to about 20 weight percent epinephrine hydrochloride such as about 5 to about 15, about 10 to about 15, or about 12 weight percent epinephrine hydrochloride.

In one aspect, the particles of the instant invention comprise epinephrine, or a salt thereof, and at least one pharmaceutically acceptable excipient. Examples of pharmaceutically acceptable excipients are described below. The particles of the invention are essentially, or substantially, free of liquid, that is, the particles are substantially dry. The term "substantially dry," as it is used herein, refers to containing no more than about 10% liquid by weight. Preferably, the particles contain no more than about 10% liquid by weight, for example, the particles can contain about 1 to about 8% liquid, about 2 to about 6% liquid, or about 2 to about 5% liquid (percentages by weight).

The term "substantially propellant-free," as used herein, refers to containing less than 1 percent by weight propellent(s). The particles described herein are preferably completely free of propellents (i.e., are propellent-free).

In one aspect, the particles and respirable compositions comprising the particles of the invention comprise a phospholipid or a combination of phospholipids. Examples of suitable phospholipids include, among others, those listed in U.S. patent application Ser. No. 60/150,742, entitled "Modulation of Release From Dry Powder Formulations by Controlling Matrix Transition," filed on Aug. 25, 1999, the contents of which are incorporated herein in their entirety. Other suitable phospholipids include phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, phosphatidylserines, phosphatidylinositols and combinations thereof. Specific examples of phospholipids include but are not limited to 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1-myristoyl,-2-stearoyl-sn-glycero-3-phosphocholine (MSPC), 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), 1,2-distearoyl-sn-glycero-3-[phospho-rac-(1-glycerol)](DSPG), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), or any combination thereof. Other phospholipids are known to those skilled in the art. In a preferred embodiment, the phospholipids are endogenous to the lung.

In one preferred embodiment, the particles of the instant invention comprise the phospholipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC). DPPC may be present in the particles in a concentration of at least about 50 percent by weight, preferably at least about 55 percent by weight, or more preferably about 55 to about 70 percent by weight, for example, about 58 to about 65 percent by weight.

The phospholipids or combinations thereof can be selected to impart controlled release properties to the highly dispersible particles. The phase transition temperature of a specific phospholipid can be below, around, or above the physiological temperature of a patient. By selecting phospholipids or combinations of phospholipids according to their phase transition temperature, the particles can be tailored to have controlled epinephrine release properties. For example, by administering particles which include a phospholipid or combination of phospholipids which have a phase transition temperature higher than the patient's body temperature, the release of an agent, such as epinephrine, can be slowed down. On the other hand, rapid release can be obtained by including in the particles phospholipids having lower transition temperatures.

Particles having controlled release properties and methods of modulating release of a biologically active agent are described in U.S. patent application Ser. No. 60/150,742 entitled "Modulation of Release From Dry Powder Formulations by Controlling Matrix Transition," filed on Aug. 25, 1999, and in U.S. patent application Ser. No. 09/792,869 entitled "Modulation of Release From Dry Powder Formulations," filed on Feb. 23, 2001. The contents of these applications are incorporated by reference in their entirety.

The particles of the present invention can comprise a charged phospholipid. The term "charged phospholipid," as used herein, refers to phospholipids which are capable of possessing an overall net charge. The charge on the phospholipid can be negative or positive. The phospholipid can be chosen to have a charge opposite to that of epinephrine when the phospholipid and epinephrine are associated. Preferably, the phospholipid is endogenous to the lung or can be metabolized upon administration to a lung endogenous phospholipid. Combinations of charged phospholipids can be used. A combination of charged phospholipids can also have an overall net charge opposite to that of epinephrine.

In one embodiment, the association of epinephrine and an oppositely charged lipid can result from ionic complexation. In another embodiment, association of a therapeutic agent and an oppositely charged lipid can result from hydrogen bonding. In yet a further embodiment, the association of a therapeutic agent and an oppositely charged lipid can result from a combination of ionic complexation and hydrogen bonding.

The charged phospholipid can be a negatively charged lipid such as, a 1,2-diacyl-sn-glycero-3-[phospho-rac-(1-glycerol)].

The 1,2-diacyl-sn-glycero-3-[phospho-rac-(1-glycerol)]phospholipids can be represented by Structural Formula II -- see Original Patent.

Suitable substituents on an aliphatic group include --OH, halogen (e.g., --Br, --Cl, --I and --F), --O(aliphatic, substituted), --CN, --NO.sub.2, --COOH, --NH.sub.2, --NH(aliphatic group, substituted aliphatic), --N(aliphatic group, substituted aliphatic group).sub.2, --COO(aliphatic group, substituted aliphatic group), --CONH.sub.2, --CONH(aliphatic, substituted aliphatic group), --SH, --S(aliphatic, substituted aliphatic group) and --NH--C(.dbd.NH)--NH.sub.2. A substituted aliphatic group can also have a benzyl, substituted benzyl, aryl (e.g., phenyl, naphthyl or pyridyl) or substituted aryl group as a substituent. A substituted aliphatic group can have one or more substituents.

Specific examples of this type of negatively charged phospholipid include, but are not limited to, 1,2-distearoyl-sn-glycero-3-[phospho-rac-(1-glycerol)](DSPG); 1,2-dimyristoyl-sn-glycero-3-[phospho-rac-(1-glycerol)](DMPG); 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)](DPPG); 1,2-dilauroyl-sn-glycero-3-[phospho-rac-(1-glycerol)](DLPG); and 1,2-dioleoyl-sn-glycero-3-[phospho-rac-(1-glycerol)](DOPG).

The particles of the invention can also comprise phospholipids which are zwitterionic and therefore do not possess an overall net charge. Such lipids, can assist in providing particles with the proper characteristics for inhalation. Such phospholipids suitable for use in the invention include, but are not limited to, 1,2-diacyl-sn-glycero-3-phosphocholine, 1,2-diacyl-sn-glycero-3-phosphoethanolamine, and 1,2-diacyl-sn-glycero-3-phospho-[2-trialkylammonioethanol]phospholipids.

The 1,2-diacyl-sn-glycero-3-phosphocholine phospholipids can be represented by Structural Formula III -- see Original Patent.

Specific examples of 1,2-diacyl-sn-glycero-3-phosphocholine phospholipids include, but are not limited to, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC); 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC); 1,2-dilaureoyl-sn-3-glycero-phosphocholine (DLPC); 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC); and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC).

The 1,2-diacyl-sn-glycero-3-phosphoethanolamine and 1,2-diacyl-sn-glycero-3-phospho-[2-trialkylammonioethanol]phospholipids can be represented by Structural Formula IV -- see Original Patent.

Specific examples of this type of phospholipid include, but are not limited to, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE); 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE); 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE); 1,2-dilauroyl-sn-glycero-3-phosphoethanolamine (DLPE); and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE).

The particles of the present invention can comprise an asymmetric phospholipid. "Asymmetric phospholipids" are also known to those experienced in the art as "mixed-chain" or "non-identical chain" phospholipids. Asymmetric phospholipids having headgroups such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, and phosphatidic acids may be used. Examples of asymmetric phospholipid include the 1-acyl, 2-acyl-sn-glycero-3-phosphicholines.

The 1-acyl,2-acyl-sn-glycero-3-phosphocholine phospholipids can be represented by Structural Formula V -- see Original Patent.

Specific examples of this type of phospholipid include, but are not limited to, 1-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine (PSPC); 1-stearoyl-2-palmitoyl-sn-glycero-3-phosphocholine (SPPC); 1-stearoyl-2-myristoyl-sn-glycero-3-phosphocholine (SMPC); 1-myristoyl-2-stearoyl-sn-glycero-3-phosphocholine (MSPC); 1-myristoyl-2-palmitoyl-sn-glycero-3-phosphocholine (MPPC); and 1-palmitoyl-2-myristoyl-sn-glycero-3-phosphocholine (PMPC).

Particles of the present invention may comprise combinations of asymmetric phospholipids, combinations of symmetric phospholipids, or combinations of asymmetric and symmetric (i.e., identical chain) phospholipids.

In one embodiment of the present invention, particles comprise asymmetric phospholipids having individual acyl chains that are naturally present in the lung. Particles comprising disaturated phospholipids are preferred over particles comprising mono- or di-unsaturated phospholipids.

Without being held to any particular theory, Applicants believe that particles containing asymmetric phospholipids may possess unique packing and/or partition of constituent epinephrine molecules and result in entrapment or encapsulation of the drug. It is thought that drug release and subsequent uptake of the drug payload from the aerosol formulation will be slower if the drug is entrapped or encapsulated rather than simply surface-associated. Applicants believe that for entrapped or encapsulated epinephrine molecules, the availability of the agent in the dissolution media or physiological lining fluids is not only determined by drug solubility but also by particle dissolution and/or diffusion of drug molecules from the particle matrix. In contrast, it is believed that in particles in which drug molecules are primarily surface associated, the availability of drug molecules is primarily drug solubility limited. Consequently, entrapment or encapsulation of the drug in the particle matrix may slow release and subsequent uptake of the drug.

Particles comprising asymmetric phospholipids are described in U.S. patent application Ser. No. 60/359,466, entitled "Sustained Release Formulations Utilizing Asymmetric Phospholipids," filed on Feb. 22, 2002, the contents of which are incorporated herein in their entirety.

In one embodiment of the invention, particles comprise one or more amino acids. Hydrophobic amino acids are preferred. In a preferred embodiment, the particles comprise the amino acid leucine. In another preferred embodiment, the particles comprise an analog of leucine. Other suitable amino acids include naturally occurring and non-naturally occurring hydrophobic amino acids. Non-naturally occurring amino acids include, for example, beta-amino acids. Both D, L and racemic configurations of hydrophobic amino acids can be employed. Suitable hydrophobic amino acids can also include amino acid analogs. As used herein, an amino acid analog includes the D or L configuration of an amino acid having the following formula: --NH--CHR--CO--, wherein R is an aliphatic group, a substituted aliphatic group, a benzyl group, a substituted benzyl group, an aromatic group or a substituted aromatic group and wherein R does not correspond to the side chain of a naturally-occurring amino acid. As used herein, aliphatic groups include straight chained, branched or cyclic C1-C8 hydrocarbons which are completely saturated, which contain one or two heteroatoms such as nitrogen, oxygen or sulfur and/or which contain one or more units of desaturation. Aromatic groups include carbocyclic aromatic groups such as phenyl and naphthyl and heterocyclic aromatic groups such as imidazolyl, indolyl, thienyl, furanyl, pyridyl, pyranyl, oxazolyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl and acridintyl.

Suitable substituents on an aliphatic, aromatic or benzyl group include --OH, halogen (e.g., --Br, --Cl, --I and --F), --O(aliphatic, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl group), --CN, --NO.sub.2, --COOH, --NH.sub.2, --NH(aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl group), --N(aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl group).sub.2, --COO(aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl group), --CONH.sub.2, --CONH(aliphatic, substituted aliphatic group, benzyl, substituted benzyl, aryl or substituted aryl group), --SH, --S(aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group) and --NH--C(.dbd.NH)--NH.sub.2. A substituted benzylic or aromatic group can also have an aliphatic or substituted aliphatic group as a substituent. A substituted aliphatic group can also have a benzyl, substituted benzyl, aryl or substituted aryl group as a substituent. A substituted aliphatic, substituted aromatic or substituted benzyl group can have one or more substituents. Modifying an amino acid substituent can increase, for example, the lypophilicity or hydrophobicity of natural amino acids which are hydrophilic.

A number of the suitable amino acids, amino acids analogs and salts thereof can be obtained commercially. Others can be synthesized by methods known in the art. Synthetic techniques are described, for example, in Greene and Wuts, "Protecting Groups in Organic Synthesis," John Wiley and Sons, Chapters 5 and 7 (1991).

Hydrophobicity is generally defined with respect to the partition of an amino acid between a nonpolar solvent and water. Hydrophobic amino acids are those acids which show a preference for the nonpolar solvent. Relative hydrophobicity of amino acids can be expressed on a hydrophobicity scale on which glycine has the value 0.5. On such a scale, amino acids which have a preference for water have values below 0.5 and those that have a preference for nonpolar solvents have a value above 0.5. As used herein, the term "hydrophobic amino acid" refers to an amino acid that, on the hydrophobicity scale, has a value greater or equal to 0.5, or in other words, has a tendency to partition in the nonpolar acid which is at least equal to that of glycine.

Examples of amino acids which can be employed include, but are not limited to: glycine, proline, alanine, cysteine, methionine, valine, leucine, tyrosine, isoleucine, phenylalanine and tryptophan. Preferred hydrophobic amino acids include leucine, isoleucine, alanine, valine, phenylalanine and glycine. Combinations of hydrophobic amino acids can also be employed. Furthermore, combinations of hydrophobic and hydrophilic (preferentially partitioning in water) amino acids, where the overall combination is hydrophobic, can also be employed.

Leucine is the most preferred amino acid. The particles of the instant invention can comprise leucine in a concentration of at least about 40 weight percent. Preferably, the particles comprise at least about 50, 60, or 70 weight percent leucine. For example, the particles can comprise about 60 to about 95, about 70 to about 95, or about 72 to about 91 weight percent leucine.

In one preferred embodiment, particles are spray dried and comprise the hydrophobic amino acid leucine. Without being held to any particular theory, it is believed that due to their hydrophobicity and low water solubility, hydrophobic amino acids, such as leucine, facilitate the formation of a shell during the drying process when an ethanol/water co-solvent mixture is employed. It is also believed that the amino acids may alter the phase behavior of any phospholipids present in such a way as to facilitate the formation of a shell during the drying process.

The particles can additionally comprise a material having a carboxylate moiety. In one embodiment of the invention, the carboxylate moiety includes at least two carboxyl groups. Carboxylate moieties can be provided by carboxylic acids, salts thereof, as well as by combinations of two or more carboxylic acids and/or salts thereof. In a preferred embodiment, the carboxylate moiety is a hydrophilic carboxylic acid or a salt thereof. Suitable carboxylic acids include but are not limited to hydroxydicarboxylic acids (e.g., monohydroxydicarboxylic and dihydroxydicarboxylic acids), hydroxytricarboxilic acids (e.g., monohydroxytricarboxylic and dihydroxytricarboxylic acids), and the like. Citric acid and citrates such as, for example, sodium citrate and tartaric acid and tartrates such as, for example, sodium tartrate are preferred.

The material having a carboxylate moiety can be present in the particles in an amount ranging from about 5 to about 80 percent by weight or about 5 to about 50 weight percent. Preferably, the material having a carboxylate moiety is present in the particles in an amount of about 10 to about 30 percent by weight. In one embodiment, the material having a carboxylate moiety is a salt of a carboxylic acid, preferably sodium citrate. Sodium citrate can be present in the particles at a concentration of about 5 to about 50, about 5 to about 40, about 10 to about 30, or about 15 to about 25 weight percent. Preferably, sodium citrate is present in the particles at a concentration of about 18 to about 22 weight percent, for example, about 20 weight percent. In another preferred embodiment, the salt of a carboxylic acid is sodium tartrate. Sodium tartrate can be present in the particles at a concentration of about 2 to about 50, about 5 to about 40, about 10 to about 30, or about 10 to about 20 weight percent. Preferably, sodium tartrate is present in the particles at a concentration of about 15 to about 20 weight percent, for example, about 16 weight percent. In another preferred embodiment, sodium tartrate is present in the particles in a concentration sufficient to adjust the pH of the solution from which the particles are formed to between about pH 4 and about pH 5, for example, to between about pH 4 and about pH 4.5. For example, if the epinephrine content of the particles is low (e.g., about 5 weight percent or less), the sodium tartrate concentration needed would also be low (e.g., about 2 or 3 weight percent); if the epinephrine content of the particles is higher, the sodium tartrate concentration needed would also be higher.

The particles also can include a salt comprising at least one multivalent cation or anion. As used herein, a "multivalent" cation or anion includes divalent ions. In a preferred embodiment, the salt comprises at least one divalent cation or anion. The salt is preferably a salt of an alkaline-earth metal, such as, for example, calcium chloride. The particles of the invention can also include mixtures or combinations of salts.

The salt comprising at least one multivalent cation or anion can be present in the particles in an amount ranging from about 1 to about 40, about 5 to about 30, or about 5 to about 20 percent by weight. Preferably, the salt comprising at least one multivalent cation or anion is calcium chloride and is present in the particles in a concentration of about 1 to about 40, about 5 to about 30, about 5 to about 20, or, preferably, about 5 to about 15 weight percent. For example, the salt comprising at least one multivalent cation or anion is calcium chloride and is present in the particles in a concentration of about 10 weight percent.

The particles can also comprise a non-reducing sugar, e.g., sucrose, trehalose, or fructose. Sucrose is preferred. Combinations of non-reducing sugars also can be employed. The amount of non-reducing sugar(s), e.g., sucrose, present in the particles of the invention generally is less than about 40 weight percent, preferably less than about 30 weight percent and most preferably less than about 20 weight percent, for example, about 15 weight percent. In one embodiment, sucrose is present in the particles in a concentration of about 1 to about 30 weight percent, preferably about 10 to about 20 weight percent, for example, about 15 weight percent.

Without wishing to be held to a particular interpretation of the invention, it is believed that non-reducing sugars enhance the stability of a drug, such as epinephrine, that has chemical groups, e.g., an amine group, that can potentially react with a sugar that is reducing, e.g., lactose. It is further believed the presence of non-reducing sugars rather than reducing sugars also can benefit compositions that include other bioactive agents or drugs, such as, for example, Carbidopa, Levodopa, and other catecholamines.

The particles of the instant invention can further comprise components such as antioxidants to further stabilize the epinephrine active agent. The particles may comprise one or more antioxidants. Preferred antioxidants include, but are not limited to, oxygen scavengers or reducing agents such as sodium metabisulfite; metal chelators such as ethylenediamine tetra-acetic acid (EDTA) or salts thereof (e.g., disodium EDTA); phenolic antioxidants such as Vitamin E (alpha tocopherol); or any combination thereof. Other suitable antioxidants include cysteine, cysteamine, butylated hydroxytoluene (BHT), and ascorbic acid (Vitamin C). In one embodiment, the particles contain up to about 25 percent by weight antioxidant(s). In other embodiments, the particles contain up to about 15, up to about 10, up to about 5, or up to about 2 percent by weight antioxidant(s).

In one advantageous embodiment, the particles are substantially antioxidant-free. The term "substantially antioxidant-free," as that term is used herein, refers to containing no more than about 2 percent antioxidant(s) by weight, for example, no more than about 1, no more than about 0.5, no more than about 0.25, or no more than about 0.05 percent antioxidant(s) by weight. In one embodiment, the substantially antioxidant-free particles contain no antioxidant(s).

The particles can also include other materials such as, for example, buffer salts, sugars, cholesterol, dextran, polysaccharides, lactose, mannitol, maltodextrin, cyclodextrins, proteins, peptides, polypeptides, fatty acids, fatty acid esters, inorganic compounds, phosphates, and lipids.

In one embodiment of the invention, the particles include a material which enhances the release kinetics of the medicament. Examples of suitable such materials include, but are not limited to, certain phospholipids, amino acids, and carboxylate moieties combined with salts of multivalent metals.

The particles and respirable compositions comprising the particles of the invention may optionally include a surfactant, such as a surfactant which is endogenous to the lung. As used herein, the term "surfactant" refers to any agent which preferentially absorbs 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 agglomeration. Both naturally-occurring and synthetic lung surfactants are encompassed in the scope of the invention.

In addition to lung surfactants such as, for example, phospholipids discussed above, suitable surfactants 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 poloxomer; a sorbitan fatty acid ester, such as sorbitan trioleate (Span 85); and tyloxapol.

A surfactant can be present in the particles in an amount ranging from more than about 1 to about 70 weight percent. In one embodiment, at least about 40 weight percent surfactant is present in the particles, for example, about 50 to about 70 weight percent surfactant.

In one aspect, the present invention is directed to particles for delivery of epinephrine to the respiratory system and methods for treating a patient in need of epinephrine, wherein the method comprises administering an effective amount of the particles to the respiratory system of a patient. Preferred particle formulations exhibiting acceptable chemical and physical characteristics and suitable for the purposes of the instant invention include (1) particles comprising epinephrine, or a salt thereof; a carboxylic acid, or a salt thereof; a salt comprising at least one multivalent cation or anion; and a phospholipid; (2) particles comprising epinephrine, or a salt thereof; an amino acid; and a sugar; (3) particles comprising epinephrine, or a salt thereof; and an amino acid; (4) particles comprising epinephrine, or a salt thereof; an amino acid; and a carboxylic acid, or a salt thereof.

Preferred particles for delivery of epinephrine to the respiratory system comprise: (a) about 6 to about 25 weight percent epinephrine bitartrate; (b) about 62 to about 82 weight percent leucine; and (c) about 2 to about 22 weight percent sodium tartrate. For example, the particles can comprise (a) about 11 to about 21 weight percent epinephrine bitartrate; (b) about 62 to about 82 weight percent leucine; and (c) about 7 to about 17 weight percent sodium tartrate. Other preferred particles for delivery of epinephrine to the respiratory system comprise (a) about 7 to about 28 weight percent epinephrine bitartrate; and (b) about 72 to about 92 weight percent leucine. For example, the particles can comprise (a) about 12 to about 23 weight percent epinephrine bitartrate; and (b) about 77 to about 88 weight percent leucine.

A preferred method for treating a patient in need of epinephrine comprises administering an effective amount of particles to the respiratory system of a patient wherein the particles comprise (a) about 6 to about 25 weight percent epinephrine bitartrate; (b) about 62 to about 82 weight percent leucine; and (c) about 2 to about 22 weight percent sodium tartrate. For example, the particles can comprise (a) about 11 to about 21 weight percent epinephrine bitartrate; (b) about 67 to about 77 weight percent leucine; and (c) about 7 to about 17 weight percent sodium tartrate. Another preferred method for treating a patient in need of epinephrine comprises administering an effective amount of particles to the respiratory system of a patient wherein the particles comprise (a) about 7 to about 28 weight percent epinephrine bitartrate; and (b) about 72 to about 92 weight percent leucine. For example, the particles can comprise (a) about 12 to about 23 weight percent epinephrine bitartrate; and (b) about 77 to about 87 weight percent leucine.

In one embodiment, the particles possess rapid epinephrine release properties. Rapid release properties allow the particles of the present invention to be used in rescue therapy as described herein.

In another embodiment, particles of the present invention are capable of releasing epinephrine in a sustained fashion. As such, the particles can be said to possess sustained release properties. "Sustained release" as that term is used herein, refers to an increase in the time period over which an agent is released from a particle of the present invention as compared to an appropriate control, such as for example, as compared to the time period over which an agent is released from an particle that does not comprise epinephrine, or a salt thereof, and a phospholipid or combination of phospholipids. "Sustained release," as that term is used herein, may also refer to a reduction in the availability, or burst, of agent typically seen soon after administration. For example, "sustained release" can refer to a reduction in the availability of epinephrine in the first half-hour or the first hour following administration, that is, a reduction in the initial burst of epinephrine.

"Sustained release," as that term is used herein, may also refer to a higher amount of epinephrine retained or remaining in the particles after the initial burst as compared to an appropriate control. "Sustained release" is also known to those experienced in the art as "modified release," "prolonged release," or "extended release." "Sustained release," as used herein, also encompasses "sustained action" or "sustained effect." "Sustained action" and "sustained effect," as those terms are used herein, can refer to an increase in the time period over which epinephrine performs its therapeutic activity as compared to an appropriate control. "Sustained action" is also known to those experienced in the art as "prolonged action" or "extended action."

Particles for inhalation possessing sustained drug release properties, and methods for their administration, are also described in U.S. patent application Ser. No. 09/644,736, entitled "Modulation Of Release From Dry Powder Formulations," filed on Aug. 23, 2000; U.S. patent application Ser. No. 09/792,869, entitled "Modulation Of Release From Dry Powder Formulations," filed on Feb. 23, 2001; and U.S. patent application Ser. No. 60/366,497, entitled "Inhalable Sustained Therapeutic Formulations," filed on Mar. 20, 2002. The contents of each of these three applications are incorporated herein in their entirety.

Without being held to any particular theory, Applicants believe that the advantages provided by particles of the instant invention may be influenced, among other factors, by the rate of epinephrine release from the particles. Drug release rates can be described in terms of the half-time of release of a bioactive agent from a formulation. As used herein the term "half-time" refers to the time required to release 50% of the initial epinephrine payload contained in the particles. In one embodiment, the particles of the present invention have a half-time of release of epinephrine from the particles of about 1 to about 20 minutes. In another embodiment, the particles are formulated for extended release of epinephrine and have a longer half-time of release such as, for example, about an hour or more.

Drug release rates can also be described in terms of release constants. The first order release constant can be expressed using one of the following equations: M.sub.pw(t)=M.sub.(.infin.)*e.sup.-k*.sup.t (1) or, M.sub.(t)=M.sub.(.infin.)*(1-e.sup.-k*.sup.t) (2)

Where k is the first order release constant. M.sub.(.infin.) is the total mass of drug in the drug delivery system, e.g. the dry powder, and M.sub.pw(t) is drug mass remaining in the dry powders at time t. M.sub.(t) is the amount of drug mass released from dry powders at time t. The relationship can be expressed as: M.sub.(.infin.)=M.sub.pw(t)+M.sub.(t) (3) Equations (1), (2) and (3) may be expressed either in amount (i.e., mass) of drug released or concentration of drug released in a specified volume of release medium. For example, Equation (2) may be expressed as: C.sub.(t)=C.sub.(.infin.)*(1-e.sup.-k*.sup.t) (4)

Where k is the first order release constant. C.sub.(.infin.) is the maximum theoretical concentration of drug in the release medium, and C.sub.(t) is the concentration of drug being released from dry powders to the release medium at time t.

The `half-time` or t.sub.50% for a first order release kinetics is given by the well-known equation, t.sub.50%=0.693/k (5)

Drug release rates in terms of first order release constant and t.sub.50% may be calculated using the following equations: k=-ln(M.sub.pw(t)/M.sub.(.infin.))/t (6) or, k=-ln(M.sub.(.infin.)-M.sub.(t))/M.sub.(.infin.)/t (7)

In one embodiment, the particles of the invention have extended epinephrine release properties in comparison to the pharmacokinetic/pharmacodynamic profile of epinephrine administered as conventional formulations, such as by intravenous injection (IV), intramuscular injection (IM), subcutaneous injection, auto-injection, or liquid aerosol inhalation routes.

In a preferred embodiment, the particles possess aerosol characteristics that permit effective delivery of the particles to the respiratory system without the use of propellents.

The particles of the present invention have a preferred size, e.g., a volumetric median geometric diameter (VMGD) of at least about 5 microns. In one embodiment of the invention, the VMGD of the particles is about 5 to about 30 microns. Preferably, the particles have a VMGD of about 5 to about 15 microns or, alternatively, about 15 to about 30 microns. The particles can have a median diameter, mass median diameter (MMD), a mass median envelope diameter (MMED) or a mass median geometric diameter (MMGD) of at least about 5 microns, for example about 5 to about 30 microns such as about 5 to about 15 microns.

The diameter of the particles, for example, their VMGD, can be measured using an electrical zone sensing instrument such as a Multisizer IIe, (Coulter Electronic, Luton, Beds, England), or a laser diffraction instrument such as HELOS (Sympatec, Princeton, N.J.). Other instruments for measuring particle geometric diameter are well known 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 within targeted sites within the respiratory system.

Particles suitable for use in the present invention may be fabricated and then separated, for example, by filtration or centrifugation, to provide a particle sample with a preselected size distribution. For example, greater than about 30, 50, 70, or 80% of the particles in a sample can have a diameter within a selected range of at least about 5 microns. The selected range within which a certain percentage of the particles must fall may be, for example, between about 5 and about 30 microns or, optionally, between about 5 and about 15 microns. The particle sample also can be fabricated wherein at least about 90% or, optionally, about 95 to about 99% of the particles, have a diameter within the selected range.

In one embodiment, the interquartile range of the particle sample may be 2 microns, with a mean diameter for example, between about 7.5 and about 13.5 microns. Thus, for example, at least about 30 to about 40% of the particles may have diameters within the selected range. The said percentages of particles can have diameters within a 1 micron range, for example, between 5 and 6; 6 and 7; 7 and 8; 8 and 9; 9 and 10; 10 and 11; 11 and 12; 12 and 13; 13 and 14; or 14 and 15 microns.

Particle aerodynamic diameter can also be used to characterize the aerosol performance of a composition. In one embodiment, the particles have a mass median aerodynamic diameter (MMAD) of about 1 to about 5 microns. In preferred embodiments, the particles have a MMAD of about 1 to about 3 microns, about 2 to about 4 microns, or about 3 to about 5 microns.

Experimentally, aerodynamic diameter can be determined using time of flight (TOF) measurements. For example, an instrument such as the Model 3225 Aerosizer DSP Particle Size Analyzer (Amherst Process Instrument, Inc., Amherst, Mass.) can be used to measure aerodynamic diameter. The Aerosizer measures the time taken for individual particles to pass between two fixed laser beams. The instrument subsequently uses this TOF data to solve a force balance on the particles and aerodynamic diameter is determined based on the relationship d.sub.aer=d .rho. (8) where d.sub.aer is the aerodynamic diameter of the particle; d is the diameter of the particle; and .rho. is the particle density.

Aerodynamic diameter also can be experimentally determined by employing a gravitational settling method, whereby the time for an ensemble of particles to settle a certain distance is used to infer directly the aerodynamic diameter of the particles. Indirect methods for measuring the mass median aerodynamic diameter are the Andersen Cascade Impactor and the multi-stage liquid impinger (MSLI). The methods and instruments for measuring particle aerodynamic diameter are well known in the art.

In a preferred embodiment of the invention, particles administered to a subject's respiratory system have a tap density of less than about 0.4 g/cm.sup.3. Particles having a tap density of less than about 0.4 g/cm.sup.3 are referred to herein as "aerodynamically light." In other preferred embodiments, the particles have a tap density less than or equal to about 0.3 g/cm.sup.3 or less than or equal to about 0.2 g/cm.sup.3. In other embodiments, the particles have a tap density less than or equal to about 0.1 g/cm.sup.3, or less than or equal to about 0.05 g/cm.sup.3. Tap density is a measure of the envelope mass density characterizing a particle. The envelope mass density of a particle of a statistically isotropic shape is defined as the mass of the particle divided by the minimum sphere envelope volume within which it can be enclosed. Features which can contribute to low tap density include irregular surface texture and porous structure.

Tap density can be measured by using instruments known to those skilled in the art such as the Dual Platform Microprocessor Controlled Tap Density Tester (Vankel, N.C.) or a GeoPyc.TM. instrument (Micrometrics Instrument Corp., Norcross, Ga.). Tap density can be determined using the method of USP Bulk Density and Tapped Density, United States Pharmacopia convention, Rockville, Md., 10.sup.th Supplement, 4950-4951, 1999.

In a preferred embodiment, particles of the present invention can be characterized as aerodynamically light. Aerodynamically light particles have a preferred size, e.g., a volume median geometric diameter (VMGD) of at least about 5 microns. In a preferred embodiment of the invention, the VMGD of the particles is about 5 to about 30 microns. Aerodynamically light particles also preferably have a mass median aerodynamic diameter (MMAD), also referred to herein as "aerodynamic diameter," of about 1 to about 5 microns. In one preferred embodiment of the invention, the MMAD of the particles is about 1 to about 5 microns.

Process conditions as well as inhaler efficiency, in particular with respect to dispersibility, can contribute to the size of particles that can be delivered to the respiratory system. Aerodynamically light particles may be fabricated or separated, for example, by filtration or centrifugation to provide a particle sample with a preselected size distribution.

Aerodynamically light particles with a tap density less than about 0.4 g/cm.sup.3, median diameters of at least about 5 microns, and an aerodynamic diameter of between about 1 and about 5 microns, preferably between about 1 and about 3 microns, are more capable of escaping inertial and gravitational deposition in the oropharyngeal region, and are targeted to the airways or the deep lung. The use of larger, more porous particles is advantageous since they are able to aerosolize more efficiently than smaller, denser aerosol particles such as those conventionally used for inhalation therapies.

In comparison to smaller, relatively dense particles, the larger aerodynamically light particles, preferably having a median diameter of at least about 5 microns, 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. Phagocytosis of particles by alveolar macrophages diminishes precipitously as particle diameter increases beyond about 3 microns. Kawaguchi, H., et al., Biomaterials 7:61-66 (1986); Krenis, L. J. and Strauss, B., Proc. Soc. Exp. Med., 107:748-750 (1961); and Rudt, S. and Muller, R. H., J. Contr. Rel., 22:263-272 (1992). For particles of statistically isotropic shape, 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 entrapped agent to the lungs. Following inhalation, aerodynamically light biodegradable particles can deposit in the lungs and subsequently undergo sustained degradation and drug release without the majority of the particles being phagocytosed by alveolar macrophages. Epinephrine 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 drug. 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 system such as the deep lung or upper or central airways. For example, higher density or larger particles may be used for upper airway delivery, or a mixture of varying size particles in a sample, provided with the same or a different therapeutic agent, may be administered to target different regions of the lung in one administration. Particles having an aerodynamic diameter ranging from about 3 to about 5 microns are preferred for delivery to the central and upper airways. Particles having an aerodynamic diameter ranging from about 1 to about 3 microns are preferred for delivery to the deep lung.

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 (i.e., at least for particles of mean aerodynamic diameter greater than approximately 1 micron), 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.sub.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.sub.aer=d .rho. (9) where the envelope mass density, .rho., is in units of g/cm.sup.3. Maximal deposition of monodispersed aerosol particles in the alveolar region of the human lung (.about.60%) occurs for an aerodynamic diameter of approximately d.sub.aer=3 microns. 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/cm.sup.3); (10) where d is always greater than 3 microns. For example, aerodynamically light particles that display an envelope mass density, .rho.=0.1 g/cm.sup.3, will exhibit a maximum deposition for particles having envelope diameters as large as 9.5 microns. 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.

The aerodynamic diameter is calculated to provide for maximum deposition within the lungs, previously achieved by the use of very small particles of less than about 5 microns in diameter, preferably between about I and about 3 microns, which are then subject to phagocytosis. Selection of particles which have a larger diameter, but which are sufficiently light (hence the characterization "aerodynamically light"), results in an equivalent delivery to the lungs, but the larger size particles are not phagocytosed. Improved delivery can be obtained by using particles with a rough or, uneven surface relative to those with a smooth surface.

Mass density and the relationship between mass density, mean diameter and aerodynamic diameter are discussed in U.S. application Ser. No. 08/655,570, filed on May 24, 1996, which is incorporated herein by reference in its entirety.

Fine particle fraction can be used as one way to characterize the aerosol performance of a dispersed powder. Fine particle fraction describes the size distribution of airborne particles. Gravimetric analysis, using Cascade impactors, is one method of measuring the size distribution, or fine particle fraction, of airborne particles. The Andersen Cascade Impactor (ACI) is an eight-stage impactor that can separate aerosols into nine distinct fractions based on aerodynamic size. The size cutoffs of each stage are dependent upon the flow rate at which the ACI is operated.

A two-stage collapsed ACI also can be used to measure fine particle fraction. The two-stage collapsed ACI consists of only the top two stages of the eight-stage ACI and allows for the collection of two separate powder fractions. The ACI is made up of multiple stages consisting of a series of nozzles (i.e., a jet plate) and an impaction surface (i.e., an impaction disc). At each stage an aerosol stream passes through the nozzles and impinges upon the surface. Particles in the aerosol stream with a large enough inertia will impact upon the plate. Smaller particles that do not have enough inertia to impact on the plate will remain in the aerosol stream and be carried to the next stage. Each successive stage of the ACI has a higher aerosol velocity in the nozzles so that smaller particles can be collected at each successive stage.

In one embodiment, the particles of the invention are characterized by fine particle fraction. A two-stage collapsed Andersen Cascade Impactor is used to determine fine particle fraction. Specifically, a two-stage collapsed ACI is calibrated so that the fraction of powder that is collected on stage one is composed of particles that have an aerodynamic diameter of less than 5.6 microns and greater than 3.4 microns. The fraction of powder passing stage one and depositing on a collection filter is thus composed of particles having an aerodynamic diameter of less than 3.4 microns. The airflow at such a calibration is approximately 60 L/min.

The terms "FPF(<5.6)," "FPF(<5.6 microns)," and "fine particle fraction of less than 5.6 microns" as used herein, refer to the fraction of a sample of particles that have an aerodynamic diameter of less than 5.6 microns. FPF(<5.6) can be determined by dividing the mass of particles deposited on the stage one and on the collection filter of a two-stage collapsed ACI by the mass of particles weighed into a capsule for delivery to the instrument.

The terms "FPF (<3.4)," "FPF(<3.4 microns)," and "fine particle fraction of less than 3.4 microns" as used herein, refer to the fraction of a mass of particles that have an aerodynamic diameter of less than 3.4 microns. FPF(<3.4) can be determined by dividing the mass of particles deposited on the collection filter of a two-stage collapsed ACI by the mass of particles weighed into a capsule for delivery to the instrument.

The FPF(<5.6) has been demonstrated to correlate to the fraction of the powder that is able to make it into the lung of the patient, while the FPF(<3.4) has been demonstrated to correlate to the fraction of the powder that reaches the deep lung of a patient. These correlations provide a quantitative indicator that can be used for particle optimization.

A three-stage collapsed Andersen Cascade Impactor can also be used to determine fine particle fraction. Optionally, the three-stage collapsed ACI comprises wetted screens that are used to help diminish particle bounce and re-entrainment. The three-stage collapsed ACI is calibrated so that the fraction of powder that is collected on a collection filter is composed of particles having an aerodynamic diameter of less than 3.3 microns. The airflow at such a calibration is approximately 28 L/min. The terms "FPF (<3.3)," "FPF(<3.3 microns)," and "fine particle fraction of less than 3.3 microns" as used herein, refer to the fraction of a mass of particles that have an aerodynamic diameter of less than 3.3 microns. FPF(<3.3) can be determined by dividing the mass of particles deposited on the collection filter of a three-stage collapsed ACI by the mass of particles weighed into a capsule for delivery to the instrument.

A Multi-Stage Liquid Impinger (MSLI) is another device that can be used to measure fine particle fraction. The Multi-stage liquid Impinger operates on the same principles as the Anderson Cascade Impactor, although instead of eight stages, MSLI has five. Additionally, each MSLI stage consists of an ethanol-wetted glass frit instead of a solid plate. The wetted stage is used to prevent particle bounce and re-entrainment, which can occur when using the ACI.

In one embodiment, a mass of particles of the invention has an FPF(<5.6) of at least about 30%, 35%, 40%, 45% or 50%. In another embodiment, a mass of particles has an FPF (<3.4) of at least about 5%, 10%, 15%, or 20%.

In one aspect the present invention is directed to spray dried particles for delivery of epinephrine to the respiratory system wherein the particles comprise epinephrine, or a salt thereof; and at least one pharmaceutically acceptable excipient; wherein the particles possess a fine particle fraction of less than 5.6 microns of at least about 45 percent. In another aspect the invention is directed to spray dried particles for delivery of epinephrine to the respiratory system wherein the particles comprise epinephrine, or a salt thereof; and at least one pharmaceutically acceptable excipient; wherein the particles possess a fine particle fraction of less than 3.4 microns of at least about 15 percent.

The particles of the invention can be characterized by the chemical stability of the epinephrine that the particles comprise. Without being held to any particular theory, it is believed that several factors can influence the chemical stability of the epinephrine. These factors can include the materials comprising the particles, the stability of the agent itself, interactions between the agent and excipients, and interactions between agents. The chemical stability of the constituent epinephrine can effect important characteristics of a pharmaceutical composition including shelf-life, proper storage conditions, acceptable environments for administration, biological compatibility, and effectiveness of the epinephrine. Chemical stability can be assessed using techniques well known in the art. One example of a technique that can be used to assess chemical stability is reverse phase high performance liquid chromatography (RP-HPLC).

Particles of the invention include epinephrine that is generally stable over a period of at least about 1 year. In one embodiment, at least about 90%, e.g., about 95%, of epinephrine contained in the particles is not degraded as measured by HPLC over a period of at least about 1 year.

The epinephrine, or salt thereof, contained in the particles can be substantially crystalline, semi-crystalline, or substantially amorphous. Without being held to any particular theory, Applicants believe that the epinephrine, or salt thereof, as found in the particles is semi-crystalline or substantially amorphous or in a dispersed form. The pharmaceutically acceptable excipient contained in the particles can be substantially crystalline, semi-crystalline, or substantially amorphous depending upon such factors as spray drying conditions and upon the characteristics of the particular excipient.

In one embodiment, the particles comprise epinephrine in a substantially amorphous or dispersed form in a semi-crystalline excipient matrix (e.g., a leucine matrix). The dispersed form of epinephrine can range from nano-scale domains (i.e., sizes less than about 0.1 microns in characteristic width) of amorphous epinephrine in a semi-crystalline excipient matrix to a solid solution of epinephrine and semi-crystalline excipient.

FIG. 1A (see Original Patent) shows X-Ray Powder Diffraction (XRPD) data for bulk epinephrine bitartrate. The well resolved peaks and reproducible scans demonstrate crystalline, thermally stable behavior up to 145.degree. C. FIG. 1B (see Original Patent) shows XRPD data for bulk leucine at 25.degree. C. The well resolved peaks are characteristic of crystalline material. FIG. 1C (see Original Patent) shows XRPD data for spray dried particles containing leucine, epinephrine bitartrate, and sodium bitartrate. The observable peaks in this data are characteristic of leucine only, indicating that epinephrine is present in an amorphous or dispersed form.

Applicants believe that improved physical stability results from the semi-crystalline or amorphous state of epinephrine in the instant particles and that this physical stability of the epinephrine phase may provide improved epinephrine chemical stability. Furthermore, improved dissolution properties seem to result from particles that comprise a semi-crystalline or amorphous phase of epinephrine in a semi-crystalline excipient matrix.

Methods of preparing and administering particles which are aerodynamically light and include surfactants, and, in particular phospholipids, are disclosed in U.S. Pat. No. 5,855,913, issued on Jan. 5, 1999 to Hanes, et al., 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 and in their entirety.

Highly dispersible particles suitable for use in the methods of the invention may be prepared using single and double emulsion solvent evaporation, spray drying, solvent extraction, solvent evaporation, phase separation, simple and complex coacervation, interfacial polymerization, supercritical carbon dioxide (CO.sub.2) and other methods well known to those of ordinary skill in the art. Particles may be made using methods for making microspheres or microcapsules known in the art, provided that the conditions are optimized for forming particles with the desired aerodynamic properties (e.g., aerodynamic diameter and geometric diameter) or additional steps are performed to select particles with the density and diameter sufficient to provide the particles with an aerodynamic diameter between about 1 and about 5 microns, preferably between about 1 and about 3 microns, or alternatively between about 3 and about 5 microns.

If the particles prepared by any of the above methods have a size range outside of the desired range, particles can be sized, for example, using a sieve, and further separated according to density using techniques known to those of skill in the art. The particles are preferably spray dried. 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 a solvent from droplets formed by atomizing a continuous liquid feed.

An organic solvent or an aqueous-organic solvent can be employed to form a feed for spray drying the particles of the present invention. Suitable organic solvents that can be employed include but are not limited to alcohols such as, 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. Co-solvents that can be employed include an aqueous solvent and an organic solvent, such as, but not limited to, the organic solvents as described above. Aqueous solvents include water and buffered solutions. In one embodiment, an ethanol/water solvent is preferred with the ethanol solution to water solution ratio ranging from about 70:30 to about 30:70 by volume.

The mixture can have a neutral, acidic or alkaline pH. Optionally, a pH buffer can be added to the solvent or co-solvent or to the formed mixture. The pH of the mixture can range from about 3 to about 8. An acidic pH is preferred in mixtures that comprise epinephrine, or a salt thereof. In one embodiment, the pH of the mixture is between about 4 and about 5, for example, between about 4.0 and about 4.5 or between about 4.1 and about 4.4. For example, a mixture can be formed that comprises leucine, epinephrine bitartrate and sodium tartrate wherein sodium tartrate is present in an amount such that the pH of the resulting solution is between about 4.1 and about 4.4.

In one aspect, organic soluble particle components are dissolved in an organic phase and water soluble particle components are dissolved in an aqueous phase. The solutions are heated as necessary to assure solubility. In a preferred embodiment, ethanol soluble particle components are dissolved in an ethanol phase and water soluble particle components are dissolved in an aqueous phase.

Solutions containing particle components are combined or mixed prior to spray drying. For example, in one aspect of the present invention the solutions are bulk mixed prior to being fed to the spray dryer. In one embodiment, the solutions are combined or mixed such that the resulting solution has a total dissolved solids concentration of about 1 g/L. Preferably, the dissolved solids concentration is greater than about 1 g/L, for example about 5, 10, or 15 g/L. Solutions containing particle components can be combined or mixed using a static mixing device prior to spray drying.

In one aspect of the present invention, a hydrophillic component and a hydrophobic component are prepared. The hydrophobic and hydrophilic components are then combined in a static mixer to form a combination. The combination is atomized to produce droplets, which are dried to form dry particles. In a preferred aspect of this method, the atomizing step is performed immediately after the components are combined in the static mixer.

A method for preparing a dry powder composition also is disclosed herein. In such a method, first and second components are prepared, one or both of which comprise epinephrine or a salt thereof. The first and second components are combined in a static mixer to form a combination. In one embodiment, the first and second components are physically and/or chemically incompatible with each other. The first and second components can be such that combining them causes degradation in one of the components. In another aspect, a material present in the first component is incompatible with a material present in the second component. The combination is atomized to produce droplets that are dried to form dry particles. Preferably the first component comprises epinephrine, or a salt thereof, and one or more excipients dissolved in an aqueous solvent, and the second component comprises one or more excipients dissolved in an organic solvent.

For example, in one method for preparing a dry powder composition, a first phase is prepared by combining a solution that comprises water, sodium citrate, and calcium chloride with a solution that comprises water, epinephrine free base, and hydrochloric acid. A second phase is prepared that comprises ethanol and one or more phospholipids. One or both solutions may be separately heated as needed to assure solubility of their components. The first and second phases are combined in a static mixer to form a combination. The combination is atomized to produce droplets that are dried to form dry particles.

In one embodiment, the apparatus used for practice of the present invention includes a static mixer (e.g., a static mixer as more fully described in U.S. Pat. No. 4,511,258, the entirety of which is incorporated herein by reference, or other suitable static mixers such as, but not limited to, Model 1/4-21, made by Koflo Corporation.) having an inlet end and an outlet end. The static mixer is operative to combine an aqueous component with an organic component to form a combination. Means are provided for transporting the aqueous component and the organic component to the inlet end of the static mixer. In a preferred aspect of this method, the aqueous and organic components are transported to the static mixer at substantially the same rate. An atomizer is in fluid communication with the outlet end of the static mixer to atomize the combination into droplets. The droplets are dried to form dry particles.

The apparatus used to practice the present invention also can include a geometric particle sizer that determines a geometric diameter of the dry particles, and an aerodynamic particle sizer that determines an aerodynamic diameter of the dry particles.

Methods and apparatus for producing dry particles are discussed in copending U.S. application Ser. No. 10/101,563, entitled "Method and Apparatus for Producing Dry Particles," filed on Mar. 20, 2002, the entirety of which is incorporated herein by reference.

Spray drying solutions prepared as described above are distributed to a drying vessel via an atomization device. For example, a nozzle or a rotary atomizer may be used to distribute the solutions to the drying vessel. In a preferred embodiment, a rotary atomizer is employed, such as a vaned rotary atomizer. For example, a rotary atomizer having a 4- or 24-vaned wheel may be used. Examples of suitable spray dryers using rotary atomization the Mobile Minor Spray Dryer or the Model PSD-1, both manufactured by Niro, Inc. (Denmark).

Actual spray drying conditions will vary depending in part on the composition of the spray drying solution and material flow rates. In some embodiments, the inlet temperature to the spray dryer is about 100 to about 200.degree. C. Preferably, the inlet temperature is about 105 to about 190.degree. C.

The spray dryer outlet temperature will vary depending upon such factors as the feed temperature and the properties of the materials being dried. In one embodiment, the outlet temperature is about 35 to about 80.degree. C. In another embodiment, the outlet temperature is about 40 to about 70.degree. C.

Optionally, the particles include, a small amount of a strong electrolyte salt such as the preferred salt, sodium chloride (NaCl). Other salts that can be employed include sodium phosphate, sodium fluoride, sodium sulfate and calcium carbonate. Generally, the amount of salt present in the particles is less than 10 weight percent, preferably less than 5 weight percent.

Particles that comprise, by weight, greater than 90% of an agent, e.g., epinephrine, can have local areas of charges on the surface of the particles. This electrostatic charge on the surface of the particles causes the particles to behave in undesirable ways. For example, the presence of the electrostatic charge will cause the particles to stick to the walls of the spray drying chamber or to the pipe leading from the spray dryer or to stick within the baghouse thereby significantly reducing the percent yield obtained. Additionally, the electrostatic charge can tend to cause the particles to agglomerate when placed in a capsule based system. Dispersing these agglomerates can be difficult and that can manifest itself by either poor emitted doses, poor fine particle fractions, or both. Moreover, particle packing can also be affected by the presence of an electrostatic charge. Particles with like charges in close proximity will repel each other, leaving void spaces in the powder bed. This results in a given mass of particles with an electrostatic charge taking up more space than a given mass of the same powder without an electrostatic charge. Consequently, this limits the upper dose that can be delivered in a single receptacle.

Without wishing to be held to a particular interpretation of the invention, it is believed that a salt, such as NaCl, provides a source of mobile counterions and that the counterions associate with charged regions on the surface of the particles. It is believed that the addition of a small salt to particles that have local areas of charge on their surface will reduce the amount of static present in the final powder by providing a source of mobile counterions that would associate with the charged regions on the surface. Thereby the yield of the powder produced is improved by reducing powder agglomeration, improving the Fine Particle Fraction (FPF) and emitted dose of the particles and allowing for a larger mass of particles to be packed into a single receptacle.

Dry powder particles comprising a catecholamine and methods for their administration are further described in co-pending U.S. Provisional Application No. 60/366,471, entitled "Pulmonary Delivery for Levodopa," filed on Mar. 20, 2002, the entire contents of which are incorporated herein by reference.

The present invention provides methods for treating a patient in need of epinephrine. In various embodiments the methods comprise administering an effective amount of particles to the respiratory system wherein the particles comprise epinephrine, or a salt thereof. Epinephrine containing particles can be administered for a variety of reasons including, but not limited to, to stimulate the contraction of some smooth muscles and/or to relax other smooth muscles; to stimulate heart rate; to increase blood pressure; to stimulate glycogenolysis in the liver and/or muscle tissue; to stimulate lipolysis in adipose tissue; to treat bronchoconstriction, bronchospasm, airway constriction, and/or edema; and to treat anaphylaxis, shock, emphysema, chronic obstructive pulmonary disease (COPD), bronchitis, croup (e.g., postintubation and infectious), asthma, and/or allergic conditions.

The term "anaphylaxis," as that term is used herein, refers to a broad class of immediate-type hypersensitivity and anaphylactic conditions well known to those skilled in the art including, but not limited to, anaphylactoid reactions, anaphylactic shock, idiopathic anaphylaxis, allergen induced anaphylaxis, exercise induced anaphylaxis, exercise-induced food-dependent anaphylaxis, active anaphylaxis, aggregate anaphylaxis, antiserum anaphylaxis, generalized anaphylaxis, inverse anaphylaxis, local anaphylaxis, passive anaphylaxis, reverse anaphylaxis, and systemic anaphylaxis. An "episode" of anaphylaxis, as that term is used herein, refers to a continuous manifestation of anaphylaxis in a patient.

The term "respiratory system," as used herein, refers to the anatomical system that performs the respiration function, e.g., the airways, the lungs and their associated structures. The respiratory system includes the "respiratory tract," as it is known in the art. The respiratory system encompasses the upper airways, including the oropharynx and larynx, followed by the lower airways, which include the trachea followed by bifurcations into the bronchi and bronchioli. The upper and lower airways are called the conducting airways. The terminal bronchioli then divide into respiratory bronchioli which then lead to the ultimate respiratory zone, the alveoli, or deep lung.

The present invention is directed, in part, to a method for treating a patient in need of epinephrine wherein the method comprises administering an effective amount of dry powder particles to the respiratory system of the patient. The particles of the invention can be used to provide controlled systemic and/or local delivery of epinephrine to the respiratory system via aerosolization. Administration of the particles to the lung by aerosolization permits delivery of relatively large diameter therapeutic aerosols, for example, greater than about 5 microns in median diameter. Porous or aerodynamically light particles, having a geometric size (or mean diameter) in the range of about 5 to about 30 microns, and tap density less than about 0.4 g/cm.sup.3, such that they possess an aerodynamic diameter of about 1 to about 3 microns, have been shown to display ideal properties for delivery to the deep lung. Larger aerodynamic diameters, ranging, for example, from about 3 to about 5 microns are generally preferred, however, for delivery to the central and upper airways. Particles having a range of aerodynamic diameters may be co-administered to deliver epinephrine to a variety of sites in the respiratory system, for example, to deliver epinephrine to both the airways and to the deep lung.

The present invention also provides a method for treating a patient in need of epinephrine, wherein the method comprises administering an effective amount of substantially dry powder particles to the respiratory system of the patient and wherein the particles comprise epinephrine, or a salt thereof, and at least one pharmaceutically acceptable excipient. Suitable pharmaceutically acceptable excipient are described herein. Administration of particles to the respiratory system can be by means such as are known in the art. For example, the particles are delivered by inhalation. Preferably, the methods comprise administering an effective amount of particles that are substantially solvent-free and substantially propel lent-free.

In one embodiment, the method for treating a patient in need of epinephrine comprises administering an effective amount of particles to the respiratory system of the patient, wherein the particles comprise epinephrine, or a salt thereof, and at least one pharmaceutically acceptable excipient and wherein the effective amount of particles possess a fine particle fraction of less than 5.6 microns of at least about 45 percent. In another, the method for treating a patient in need of epinephrine comprises administering an effective amount of particles to the respiratory system of the patient, wherein the particles comprise epinephrine, or a salt thereof, and at least one pharmaceutically acceptable excipient and wherein the effective amount of particles possess a fine particle fraction of less than 3.4 microns of at least about 15 percent.

The present invention also comprises a method for treating a patient in need of epinephrine wherein an effective amount of substantially dry particles is administered to the respiratory system of the patient, wherein the particles comprise epinephrine, or a salt thereof, and wherein a first portion of the particles is deposited in the airways of the respiratory system and a second portion of the particles is deposited to the alveoli region of the lungs. In one embodiment, the first portion of particles is deposited at a site or at sites of constriction or obstruction of the respiratory system. Examples of sites of constriction or obstruction include, but are not limited to, upper, lower, or both upper and lower airway constrictions; sites of airway smooth muscle constriction; bronchial obstructions, areas of inflammation or edema; and constrictions due to muscle spasm. Airways, as described herein, also include the upper oropharangeal and laryngeal regions. Without being held to any particular theory, Applicants believe that epinephrine released from the first portion of particles, deposited at a site or sites of constriction or obstruction of the respiratory system, may enter into systemic circulation but is generally thought to act locally (i.e., topically at the site of constriction or obstruction, or in the local circulation). Epinephrine released from the second portion of the particles, deposited to the alveoli region of the lungs, may act locally (i.e., topically at the site or in the local circulation) but is generally thought to enter the systemic circulation. Applicants believe that the particles' effectiveness in treating a patient in need of epinephrine is due, in part, to the systemic as well as local distribution of epinephrine that is obtained by practicing the present invention. Moreover, it is thought that the quantity of particles deposited will increase with the severity of the obstruction or constriction at the site of obstruction or constriction, thus effectively increasing the local dose where a higher dose of epinephrine is needed. Applicants also believe that by depositing epinephrine containing particles directly into the airway passages and the lungs, respiratory complications of anaphylactic response (e.g., bronchospasm and laryngeal edema) should be more quickly and more effectively treated. By contrast, parenteral (e.g., intraveneous, intramuscular, subcutaneous, and auto-injected) epinephrine administration does not achieve this local delivery component.

Systemic epinephrine concentrations following either subcutaneous, intramuscular, or auto-injector administration have been shown to be quite variable. (See above Simons, et al., 2001). This variability may be an underlying reason for inconsistent clinical response to epinephrine therapy. The coefficient of variation for the maximum epinephrine concentration (C.sub.MAX) and for the time for maximum epinephrine concentration (T.sub.MAX) in the patient's blood plasma are substantially lower upon administration of the particles of the present invention than with intramuscularly injected epinephrine.

In one embodiment, the coefficient of variation (CV) for the maximum epinephrine concentration, C.sub.MAX, in the patient's blood plasma of a dose of epinephrine is lower than for a non-intravenous injection (e.g. subcutaneous, intramuscular, or auto-injector administration) of the same dose of epinephrine. In another embodiment, the coefficient of variation (CV) for the time for maximum epinephrine concentration, T.sub.MAX, in the patient's blood plasma of a dose of epinephrine is lower than for a non-intravenous injection (e.g. subcutaneous, intramuscular, or auto-injector administration) of the same dose of epinephrine. A lower CV of plasma T.sub.MAX and C.sub.MAX may translate into an important therapeutic advantage for dry powder epinephrine. Decreased variability, i.e., greater reliability, in peak and time to peak systemic epinephrine concentrations may result in greater consistency in therapeutic response and an improved safety profile.

In one aspect of the instant invention, a method is provided for treating a patient in need of epinephrine, wherein the method comprises administering an effective amount of substantially dry powder particles to the respiratory system of the patient, the particles comprising epinephrine, or a salt thereof, and wherein the resulting epinephrine C.sub.MAX in the patient's blood plasma is about 2 to about 3 times greater than epinephrine C.sub.MAX in the patient's blood plasma provided by administration of a liquid-based aerosol, such as Medihaler for example. In one embodiment, C.sub.MAX of epinephrine in a patient's blood plasma provided by administration of a liquid-based aerosol, such as Medihaler, is determined, for example, using the methods described in Warren, J. B., et al., "Systemic Adsorption of Inhaled Epinephrine," Clin. Pharmacol. Ther., 40(6):673-78 (1986) and also in Dahlof, C., et al., "Systemic Adsorption of Adrenaline after Aerosol, Eye-drop and Subcutaneous Administration to Healthy Volunteers," Allergy, 42:215-21 (1987).

The aerodynamic properties of a population of particles can be tailored to generally target deposition sites within the respiratory system. For example, particles can be produced or can be separated so that the particles of a population have a high fine particle fraction, less than 3.4 microns. As is discussed herein, particles having a fine particle fraction of less than 3.4 microns are able to reach the deep lung, or alveoli region of the lung. Alternately, particles can be produced or separated so that a particle population has a low fine particle fraction, less than 3.4 microns. Without being held to any particular theory, Applicants believe that particles having a lower fine particle fraction of less than 3.4 microns are more likely to deposit on surfaces of the respiratory system before the particles reach the deep lung.

In another aspect, the present invention includes a method for treating a patient in need of rescue therapy for anaphylaxis comprising administering particles to the respiratory system of the patient, wherein the particles comprise a therapeutically effective amount of epinephrine, or a salt thereof; and at least one pharmaceutically acceptable excipient, and wherein the particles are delivered to the respiratory system and the epinephrine reaches its site of action within a time sufficiently short to provide said rescue therapy. The method includes administering to the respiratory system of a patient in need of rapid onset or rescue therapy particles comprising an effective amount of epinephrine. The particles are administered to the respiratory system and the epinephrine is released into the patient's blood stream and reaches the epinephrine's site(s) of action in a time interval which is sufficiently short to provide the rescue therapy. As used herein, "rescue therapy" means on demand, rapid delivery of a drug to a patient to help reduce or control disease symptoms.

Rapid release, preferred in the delivery of a rescue therapy medicament, can be obtained for example, by including in the particles materials, such as some phospholipids, characterized by low phase transition temperatures. In another embodiment, a combination of rapid release particles and controlled release particles would allow a rescue therapy coupled with a more sustained release in a single course of therapy.

Rapid delivery of epinephrine to the site(s) of action also is generally preferred. Preferably, the effective amount is delivered on the "first pass" of the blood to the site of action. The "first pass" is the first time the blood carries the drug to and within the target organ or tissue from the point at which the drug passes from the lung to the vascular system. Generally, the medicament is released in the blood stream and delivered to its site(s) of action within a time period which is sufficiently short to provide rescue therapy to the patient being treated. In many cases, the epinephrine can reach the target organ or tissue in less than about 10 minutes. Preferably, the patient's symptoms abate or improve within minutes, for example, within about 5 minutes.

In one embodiment of the invention, the release kinetics of the medicament are substantially similar to the drug's release kinetics achieved via the intravenous route. In another embodiment of the invention, the median T.sub.MAX of epinephrine in the blood stream ranges from about 1 to about 10 minutes, preferably the median T.sub.MAX of epinephrine in the blood stream is less than about 5 minutes. As used herein, the term "T.sub.MAX" refers to the timepoint at which blood levels reach a maximum concentration, for example, the time for maximum epinephrine concentration in the patient's blood plasma. In one embodiment, the average time for maximum epinephrine concentration in the patient's blood plasma of a dose of epinephrine is lower than for a non-intravenous injection (e.g., subcutaneous injection, an intramuscular injection, and an auto-injection, for example, EpiPen.RTM.) of the same dose of epinephrine.

Preferably, the patient's symptoms begin to improve within minutes and generally no later than about 15 minutes. In many cases, the average onset of epinephrine effect obtained by using the methods of the invention, for example, the average onset of effect obtained by local action of epinephrine, is at least about 2 times faster than the average onset of epinephrine effect obtained with intramuscular, subcutaneous or auto-injector administration. Average onset of epinephrine effect obtained by using the methods of the invention can range from about 2 to about 5 times faster than that observed with intramuscular, subcutaneous or auto-injector administration. In one example the average onset of epinephrine effect obtained by using the methods of the invention is about 4 to about 5 times faster than that observed with intramuscular, subcutaneous or auto-injector administration.

A method for treating a patient suffering from anaphylaxis is also disclosed, the method comprising: (a) administering an effective amount of substantially dry particles to the respiratory system of the patient, the particles comprising epinephrine, or a salt thereof; (b) monitoring the patient; and (c) administering additional epinephrine to the patient. The effective amount of substantially dry particles are preferably administered via inhalation. Generally, the patient is monitored for abatement of anaphylaxis, e.g., restored ease of breathing, reduced constriction, etc. The additional epinephrine can be administered by intramuscular injection, subcutaneous injection, or auto-injection or can be administered by inhalation of substantially dry particles. In one embodiment, the particles or additional epinephrine are self-administered, i.e., administered by the patient. In another embodiment, the particles or the additional epinephrine is administered outside the direct supervision of a health care professional, for example, a doctor or nurse. For example, the particles or the additional epinephrine may be administered by the patient or by someone other than the patient. In one embodiment, the additional epinephrine is administered to the patient if symptoms of anaphylaxis continue substantially unabated for at least about 5 to about 30 minutes.

The term "substantially abated," as applied to clinical symptoms herein, refers to the reduction of clinical symptoms such that further treatment is typically unnecessary to achieve the desired therapeutic effect(s). The term "substantially unabated," as applied to clinical symptoms herein, refers to the lack of reduction of clinical symptoms such that further treatment is typically necessary to achieve the desired therapeutic effect(s).

In another embodiment, the present invention is directed to a method for treating a patient in need of epinephrine, the method comprising: (a) administering an effective amount of a first mass of substantially dry particles to the respiratory system of the patient, the particles comprising epinephrine, or a salt thereof, and (b) subsequently, administering an effective amount of a second mass of substantially dry particles to the respiratory system of the patient, the particles comprising epinephrine, or a salt thereof. In some aspects, the methods described herein further comprise the administration of at least one more additional effective amount of substantially dry particles to the respiratory system of a patient. For example, a second, third, fourth, fifth, sixth, or seventh amount of substantially dry particles are administered to the respiratory system of a patient as necessary to achieve the desired therapeutic effect(s).

In one embodiment, the patient in need of epinephrine is experiencing anaphylaxis. Preferably, the effective amount of substantially dry particles is administered while the patient experiences symptoms of anaphylaxis, for example, before the symptoms of anaphylaxis have substantially abated. In one aspect, the effective amount(s) of substantially dry particles are administered during a single episode of anaphylaxis. In another aspect, the effective amount of substantially dry particles is administered while the patient experiences at least one of the conditions selected from the group consisting of bronchoconstriction, bronchospasm, airway constriction, and edema. In some embodiments, the effective amount(s) of substantially dry particles are administered within about 72, 48, 36, 24, 12, or about 6 hours of administration of the effective amount of the first mass of substantially dry particles, for example, within about 5, 4, 3, 2, 1, 0.5, or about 0.25 hour(s) of administration of the effective amount of the first mass of substantially dry particles, for example, the effective amount of the second mass of substantially dry particles is administered within about 30 minutes of the administration of the effective amount of the first mass of substantially dry particles. In yet other embodiments, the effective amount(s) of substantially dry particles are administered at least about 0.5, 1, 2, 3, 4, or about 5 minutes after the immediately prior administration of substantially dry particles, for example, the effective amount of the second mass of substantially dry particles are administered at least about 5 minutes after the administration of the effective amount of the first mass of substantially dry particles. In other embodiments, the effective amount(s) of substantially dry particles are administered at least about 10, 15, 20, 25, or about 30 minutes after the immediately prior administration of substantially dry particles.

For example, in one embodiment, the present invention provides a method for treating a patient suffering from anaphylaxis, comprising: (a) administering an effective amount of a first mass of substantially dry particles to the respiratory system of the patient, the particles comprising epinephrine, or a salt thereof; and (b) subsequently, administering an effective amount of a second mass of substantially dry particles to the respiratory system of the patient, the particles comprising epinephrine, or a salt thereof; wherein the first and second masses of substantially dry particles comprise (a) about 11 to about 21 weight percent epinephrine bitartrate; (b) about 62 to about 82 weight percent leucine; and (c) about 7 to about 17 weight percent sodium tartrate. Alternatively, only one of the first and second masses of substantially dry particles comprises (a) about 11 to about 21 weight percent epinephrine bitartrate; (b) about 62 to about 82 weight percent leucine; and (c) about 7 to about 17 weight percent sodium tartrate.

In one embodiment, the effective amount of the first mass of substantially dry particles comprises about 250 to about 750 about 350 to about 650, about 450 to about 550, or about 500 micrograms of epinephrine. In another embodiment, the effective amount of the second mass of substantially dry particles comprises about 250 to about 750 about 350 to about 650, about 450 to about 550, or about 500 micrograms of epinephrine. In yet another embodiment, both the first and second mass of substantially dry particles comprises about 250 to about 750 about 350 to about 650, about 450 to about 550, or about 500 micrograms of epinephrine. For example, in one embodiment, the effective amount of the first mass of substantially dry particles comprises about 500 micrograms of epinephrine, the effective amount of the second mass of substantially dry particles comprises about 500 micrograms of epinephrine, and the effective amount of the second mass of substantially dry particles is administered about 10 to about 20 minutes after administration of the effective amount of the first mass of substantially dry particles.

In some embodiments, either the first or second mass of substantially dry particles further comprises a pharmaceutically acceptable excipient. Alternatively, both the first and second masses of substantially dry particles further comprise a pharmaceutically acceptable excipient. In other embodiments, either or both of the first and second mass of substantially dry particles comprise epinephrine, or a salt thereof, and leucine. In another aspect, either or both of the first and second masses of substantially dry particles further comprise a carboxylic acid, or a salt thereof such as, for example, tartrate, or a salt thereof. For example, either of both of the first or second masses of substantially dry particles comprises (a) about 11 to about 21 weight percent epinephrine bitartrate; (b) about 62 to about 82 weight percent leucine; and (c) about 7 to about 17 weight percent sodium tartrate.

As described herein, administration of particles to the respiratory system are by means such as those known in the art. For example, either or both of the first and second masses of substantially dry particles are delivered via a breath activated inhaler. The invention further comprises delivery of either or both the first and second masses of substantially dry particles in single breath activated steps. In one embodiment, an effective amount of a first mass of substantially dry particles and subsequent effective amounts of substantially dry particles are delivered via separate inhalation devices. For example, the effective amount of the first mass of substantially dry particles and an effective amount of a second mass of substantially dry particles are delivered via separate inhalation devices. Alternatively, the effective amount of the first mass of substantially dry particles and subsequent effective amounts of substantially dry particles are delivered via a single inhalation device. In another embodiment, the mass(es) of substantially dry particles are delivered via a multi-dose inhalation device, such as when either or both of the first and second masses of substantially dry particles are delivered via a multi-dose inhalation device. For example, the effective amount of the first mass of substantially dry particles and the effective amount of the second mass of substantially dry particles are delivered via a multi-dose inhalation device.

In preferred embodiments, administration of the particles of the present invention result in therapeutic effectiveness that approximates or exceeds the duration and/or magnitude of that observed upon administration of other epinephrine formulations such as, for example, formulations for intravenous injection (IV), intramuscular injection (IM), subcutaneous injection, auto-injection (e.g., EpiPen.RTM.), or liquid aerosol inhalation. In one embodiment, dry powder epinephrine is at least as effective for the delivery of epinephrine (e.g., delivery for the treatment of anaphylaxis) as are epinephrine formulations for intravenous injection (IV), intramuscular injection (IM), subcutaneous injection, auto-injection (e.g., EpiPen.RTM.), or liquid aerosol inhalation.

The particles can be fabricated to reduce particle agglomeration and improve flowability of the powder. The spray-dried particles have improved aerosolization properties. Spray-dried particles can be fabricated with features which enhance aerosolization via dry powder inhaler devices and lead to decreased deposition in the mouth, throat and inhaler device. Alternatively, spray-dried particles can be fabricated with features which enhance aerosolization via dry powder inhaler devices and lead to deposition at sites of obstruction or congestion as well as deposition in the alveoli region of the lungs.

The term "effective amount," as used herein, refers to the amount of agent needed to achieve the desired effect or efficacy. The actual effective amounts of drug can vary according to the particular composition formulated, the mode of administration, and the age, weight, condition of the patient, and severity of the symptoms or condition being treated. Dosages for a particular patient can be determined by one of ordinary skill in the art using conventional considerations, for example, by means of an appropriate pharmacological protocol.

The particles of the invention can be employed in compositions suitable for drug delivery via the respiratory system. For example, such compositions can include the particles and a pharmaceutically acceptable carrier for administration to a patient, preferably for administration via inhalation. The particles can be co-delivered with larger carrier particles, not including a therapeutic agent, the latter possessing mass median diameters for example in the range between about 50 and about 100 microns. The particles can be administered alone or in any appropriate pharmaceutically acceptable carrier, for example, a powder, for administration to the respiratory system.

Particles comprising epinephrine are administered to the respiratory system of a patient in need of epinephrine, for example, a patient suffering from anaphylaxis. Administration of particles to the respiratory system can be by means such as those known in the art. For example, particles can be delivered from an inhalation device. In a preferred embodiment, particles are administered as a dry powder via a dry powder inhaler (DPI). Metered-dose-inhalers (MDI), nebulizers or instillation techniques also can be employed.

The methods of the invention also relate to administering to the respiratory system 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.

In a preferred embodiment, the receptacle is used in a dry powder inhaler. Examples of dry powder inhalers that can be employed in the methods of the invention include but are not limited to, the inhalers disclosed is U.S. Pat. Nos. 4,995,385 and 4,069,819, Spinhaler.RTM. (Fisons, Loughborough, U.K.), Rotahaler.RTM. (GlaxoSmithKline, Research Triangle Technology Park, N.C.), FlowCaps.RTM. (Hovione, Loures, Portugal), Inhalator.RTM. (Boehringer-Ingelheim, Germany), Aerolizer.RTM. (Novartis, Switzerland), Diskhaler.RTM. (GlaxoSmithKline, RTP, NC), Diskus.RTM. (GlaxoSmithKline, RTP, N.C.) and others known to those skilled in the art. In one embodiment, the inhaler employed is described in U.S. patent application Ser. No. 09/835,302, entitled "Inhalation Device and Method," filed on Apr. 16, 2001. The entire contents of this application are incorporated herein by reference.

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

The receptacle encloses or stores particles and/or respirable compositions comprising particles. In one embodiment, the particles and/or respirable compositions comprising particles are in the form of a powder. The receptacle is filled with particles and/or compositions comprising particles. For example, vacuum filling or tamping technologies may be used. Generally, filling the receptacle with powder can be carried out by methods known in the art. In one embodiment of the invention, the particles, powder or respirable composition which is enclosed or stored in a receptacle has a mass of at least about 1.0 mg. Preferably, the mass of the particles or respirable compositions stored or enclosed in the receptacle is at least about 5.0 milligrams or, alternatively, the mass of the particles or respirable compositions stored or enclosed in the receptacle is up to about 10, 20, 25, 30, or 50 milligrams. Generally, the receptacle and the inhalers are used in a temperature range of about 5 to about 35.degree. C. and at about 15 to about 85% relative humidity.

In one embodiment of the invention, the receptacle encloses a mass of particles, especially a mass of highly dispersible particles as described herein. The mass of particles comprises a nominal dose of an epinephrine. As used herein, the phrase "nominal dose" means the total mass of epinephrine which is present in the mass of particles in the receptacle and represents the maximum amount of epinephrine available for administration in a single breath. In some embodiments, the dry powder particles administered to a patient in a single inhalation comprise at least about 50, 100, 150, 200, or 250 micrograms of epinephrine. In other embodiments, the dry powder particles administered to a patient in a single inhalation comprise about 50 micrograms to about 5 milligrams or about 250 micrograms to about 5 milligrams of epinephrine. Preferably, the dry powder particles administered to a patient in a single inhalation comprise about 200 micrograms to about 3 milligrams or about 250 micrograms to about 1 milligram of epinephrine.

Particles and/or respirable compositions comprising particles are stored or enclosed in the receptacles and are administered to the respiratory system of a subject. As used herein, the terms "administration" or "administering" of particles and/or respirable compositions refer to introducing particles to the respiratory system of a subject.

As described herein, in one embodiment, the invention is drawn to a respirable composition comprising carrier particles and epinephrine. Alternatively, the invention is drawn to a method of administering a respirable composition comprising carrier particles and epinephrine. As used herein, the term "carrier particle" refers to particles which may or may not comprise an agent and which aid in the delivery of epinephrine to a subject's respiratory system, for example, by increasing the stability, dispersibility, aerosolization, consistency and/or bulking characteristics of the epinephrine.

It is understood that the particles and/or respirable compositions comprising the particles of the invention which can be administered to the respiratory system of a subject can also optionally include pharmaceutically-acceptable carriers, as are well known in the art. The term "pharmaceutically-acceptable carrier" as used herein, refers to a carrier which can be administered to a patient's respiratory system without any significant adverse toxicological effects. Appropriate pharmaceutically-acceptable carriers, include those typically used for inhalation therapy (e.g., lactose) and include pharmaceutically-acceptable carriers in the form of a liquid (e.g., saline) or a powder (e.g., a particulate powder). In one embodiment, the pharmaceutically-acceptable carrier comprises particles which have a mean diameter ranging from about 50 to about 100 microns, and in particular lactose particles in this size range. It is understood that those of skill in the art can readily determine appropriate pharmaceutically-acceptable carriers for use in administering, accompanying and or co-delivering the particles of the invention.

The particles and/or respirable compositions comprising particles, are preferably administered in a single, breath-activated step. As used herein, the phrases "breath-activated" and "breath-actuated" are used interchangeably. As used herein, "a single, breath-activated step" means that particles are dispersed and inhaled in one step. For example, in single, breath-activated inhalation devices, the energy of the subject's inhalation both disperses particles and draws them into the oral or nasopharyngeal cavity. Suitable inhalers which are single, breath-actuated inhalers that can be employed in the methods of the invention include but are not limited to simple, dry powder inhalers disclosed in U.S. Pat. Nos. 4,995,385 and 4,069,819, Spinhaler.RTM. (Fisons, Loughborough, U.K.), Rotahaler.RTM. (GlaxoSmithKline, Research Triangle Technology Park, N.C.), FlowCaps.RTM. (Hovione, Loures, Portugal), Inhalator.RTM. (Boehringer-Ingelheim, Germany), Aerolizer.RTM. (Novartis, Switzerland), Diskhaler.RTM. (GlaxoSmithKline, RTP, N.C.), Diskus.RTM. (GlaxoSmithKline, RTP, N.C.) and others, such as known to those skilled in the art. In one embodiment, the inhaler employed is described in U.S. patent application Ser. No. 09/835,302, entitled "Inhalation Device and Method," filed on Apr. 16, 2001. The entire contents of this application are incorporated by reference herein. In another embodiment, a dose of epinephrine is contained in a one-time use (e.g., a disposable) inhaler.

"Single breath" administration can include single, breath-activated administration, but also administration during which the particles, respirable compositions or powders are first dispersed, followed by the inhalation or inspiration of the dispersed particles, respirable compositions or powders. In the latter mode of administration, additional energy other than the energy supplied by the subject's inhalation disperses the particles. An example of a single breath inhaler which employs energy other than the energy generated by the patient's inhalation is the device described in U.S. Pat. No. 5,997,848 issued to Patton, et al., on Dec. 7, 1999, the entire teachings of which are incorporated herein by reference.

In a preferred embodiment, the receptacle enclosing the particles, respirable compositions comprising particles or powder is emptied in a single, breath-activated step. In another preferred embodiment, the receptacle enclosing the particles is emptied in a single inhalation. As used herein, the term "emptied" means that at least about 50% of the particle mass enclosed in the receptacle is emitted from the inhaler during administration of the particles to a subject's respiratory system. This is also called an "emitted dose." In one embodiment, the mass of particles emitted is greater than about 60% of the particle mass enclosed in the receptacle. Alternatively, greater than about 70 or about 80% of the particle mass enclosed in the receptacle is emitted. In another embodiment, about 50 to about 90% of the particle mass enclosed in the receptacle is emitted, such as for example, about 80 to about 90% of the particle mass enclosed in the receptacle.

Delivery to the pulmonary system of particles in a single, breath-actuated step is enhanced by employing particles which are dispersed at relatively low energies such as, for example, at energies typically supplied by a subject's inhalation. Such energies are referred to herein as "low." As used herein, "low energy administration" refers to administration wherein the energy applied to disperse and inhale the particles is in the range typically supplied by a subject during inhaling.

The particles of the instant invention are preferably highly dispersible. As used herein, the phrase "highly dispersible" particles or powders refers to particles or powders which can be dispersed by a RODOS dry powder disperser (or equivalent technique) such that at about 1 bar, particles of the dry powder emit from the RODOS orifice with geometric diameters, as measured by a HELOS or other laser diffraction system, that are less than about 1.5 times the geometric particle size as measured at 4 bar. Highly dispersible powders have a low tendency to agglomerate, aggregate or clump together and/or, if agglomerated, aggregated or clumped together, are easily dispersed or de-agglomerated as they emit from an inhaler and are breathed in by the subject. Typically, the highly dispersible particles suitable in the methods of the invention display very low aggregation compared to standard micronized powders which have similar aerodynamic diameters and which are suitable for delivery to the pulmonary system. Properties that enhance dispersibility include, for example, particle charge, surface roughness, surface chemistry and relatively large geometric diameters. In one embodiment, because the attractive forces between particles of a powder varies (for constant powder mass) inversely with the square of the geometric diameter and the shear force seen by a particle increases with the square of the geometric diameter, the ease of dispersibility of a powder is on the order of the inverse of the geometric diameter raised to the fourth power. The increased particle size diminishes interparticle adhesion forces. (Visser, J., Powder Technology, 58:1-10 (1989)). Thus, large particle size, all other things equivalent, increases efficiency of aerosolization to the lungs for particles of low envelope mass density. Increased surface irregularities, and roughness also can enhance particle dispersibility. Surface roughness can be expressed, for example, by rugosity.

Particles suitable for use in the methods of the invention can travel through the upper airways (i.e., the 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 one embodiment of the invention, most of the mass of particles deposit in the deep lung. In another embodiment of the invention, delivery is primarily to the central airways. In another embodiment, delivery is to the upper airways.

The term "dose" of agent refers to that amount that provides therapeutic, prophylactic or diagnostic effect in an administration regimen. A dose may consist of more than one actuation of an inhaler device. In one embodiment, a dose of epinephrine is contained in a one-time use (e.g., a disposable) inhaler. The number of actuations of an inhaler device by a patient are not critical to the invention and may be varied by the physician supervising the administration.

A preferred dosing regimen will elicit an adrenergic response that is similar in magnitude to that observed with injected epinephrine but has a similar or more rapid onset of action and lower variability (e.g., a lower coefficient of variation). Intramuscular epinephrine (300 micrograms) is preferably selected as a reference as it is 1) the most commonly used dose for outpatient treatment for emergency anaphylaxis treatment in Europe and the United States, 2) supported by empiric data, and 3) within current anaphylaxis treatment guidelines.

Models describing the relationship between dose and response provide clinically useful information regarding drug effect and the change of this effect with time. Mathematical models can be constructed to describe the dose-response relationship for key pharmacodynamic (PD) parameters (e.g., blood pressure, serum potassium, pulmonary function, heart rate) following inhaled and injected epinephrine. Modeling approaches include direct (e.g., linear, sigmoid E.sub.MAX) and indirect response models. For some parameters, the model may be expanded to include concentration-response relationships depending on the level of information available.

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., Esevier, Amsterdam (1985).
 

Claim 1 of 8 Claims

1. A method for administering epinephrine to a patient in need of epinephrine, the method comprising: administering spray-dried particles from a dry powder inhaler to the respiratory system of the patient in a single, breath-activated step, the particles comprising: (a) epinephrine, or a salt thereof; and (b) at least one pharmaceutically acceptable excipient; wherein the particles administered to the patient comprise at least about 50 micrograms of epinephrine, have a tap density of less than 0.4 g/cm3 and possess a fine particle fraction of less than 5.6 microns of at least about 45 percent, wherein the particles are amorphous.
 

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