Title:  Pulmonary delivery in treating disorders of the central nervous system

United States Patent:  6,613,308

Issued:  September 2, 2003

Inventors:  Bartus; Raymond T. (Sudbury, MA); Emerich; Dwaine F. (Cranston, RI)

Assignee:  Advanced Inhalation Research, Inc. (Cambridge, MA)

Appl. No.:  877734

Filed:  June 8, 2001

Abstract

A method for treating a disorder of the central nervous system includes administering to the respiratory tract of a patient a drug which is delivered to the pulmonary system, for instance to the alveoli or the deep lung. The drug is administered at a dose which is at least about two-fold less than the dose required by oral administration. Particles that include the drug can be employed. Preferred particles have a tap density of less than about 0.4 g/cm³. In addition to the medicament, the particles can include other materials such as, for example, phospholipids, amino acids, combinations thereof and others.

DETAILED DESCRIPTION OF THE INVENTION

The features and other details of the invention, either as steps of the invention or as combination of parts of the invention, will now be more particularly described and pointed out in the claims. It will be understood that the particular embodiments of the invention are shown by way of illustration and not as limitations of the invention. The principle feature of this invention may be employed in various embodiments without departing from the scope of the invention.

The invention is generally related to methods of treating disorders of the CNS. In particular, the invention is related to methods for pulmonary delivery of a drug, medicament or bioactive agent.

One preferred medical indication which can be treated by the method of the invention is Parkinson's disease, in particular during the late stages of the disease, when the methods described herein particularly well suited to provide 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. The methods of the invention also are suitable for use in patients in acute distress observed in disorders of the CNS. In other embodiments, the methods and particles disclosed herein can be used in the ongoing (non-rescue) treatment of Parkinson's disease.

In addition to Parkinson's disease, forms of epileptical seizures such as occurring in Myoclonic Epilepsies, including Progressive and Juvenile; Partial Epilepsies, including Complex Partial, Frontal Lobe, Motor and Sensory, Rolandic and Temporal Lobe; Benign Neonatal Epilepsy; Post-Traumatic Epilepsy; Reflex Epilepsy; Landau-Kleffner Syndrome; and Seizures, including Febrile, Status Epilepticus, and Epilepsia Partialis Continua also can be treated using the method of the invention.

Attention deficit/hyperactivity disorders (ADHD) also can be treated using the methods and formulations of the invention.

Sleep disorders that can benefit from the present invention include Dyssomnias, Sleep Deprivation, Circadian Rhythm Sleep Disorders, Intrinsic Sleep Disorders, including Disorders of Excessive Somnolence, Idiopathic Hypersomnolence, Kleine-Levin Syndrome, Narcolepsy, Nocturnal Myoclonus Syndrome, Restless Legs Syndrome, Sleep Apnea Syndromes, Sleep Initiation and Maintenance Disorders, Parasomnias, Nocturnal Nyoclonus Syndrome, Nocturnal Paroxysmal Dystonia, REM Sleep Parasomnias, Sleep Arousal Disorders, Sleep Bruxism, and Sleep-Wake Transition Disorders. Sleep interruption often occurs around 2 to 3 a.m. and requires treatment the effect of which lasts approximately 3 to 4 hours.

Examples of other disorders of the central nervous system which can be treated by the method of the invention include but are not limited to appetite suppression, motion sickness, panic or anxiety attack disorders, nausea suppressions, mania, bipolar disorders, schizophrenia and others, known in the art to require rescue therapy.

Medicaments which can be delivered by the method of the invention include pharmaceutical preparations such as those generally prescribed in the rescue therapy of disorders of the nervous system. In a preferred embodiment, the medicament is a dopamine precursor, dopamine agonist or any combination thereof. Preferred dopamine precursors include levodopa (L-Dopa). Other drugs generally administered in the treatment of Parkinson's disease and which may be suitable in the methods of the invention include, for example, ethosuximide, dopamine agonists such as, but not limited to carbidopa, apomorphine, sopinirole, pramipexole, pergoline, bronaocriptine. The L-Dopa or other dopamine precursor or agonist may be any form or derivative that is biologically active in the patient being treated.

Examples of anticonvulsants include but are not limited to diazepam, valproic acid, divalproate sodium, phenytoin, phenytoin sodium, cloanazepam, primidone, phenobarbital, phenobarbital sodium, carbamazepine, amobarbital sodium, methsuximide, metharbital, mephobarbital, mephenytoin, phensuximide, paramethadione, ethotoin, phenacemide, secobarbitol sodium, clorazepate dipotassium, trimethadione. Other anticonvulsant drugs include, for example, acetazolamide, carbamazepine, chlormethiazole, clonazepam, clorazepate dipotassium, diazepam, dimethadione, estazolam, ethosuximide, flunarizine, lorazepam, magnesium sulfate, medazepam, melatonin, mephenytoin, mephobarbital, meprobamate, nitrazepam, paraldehyde, phenobarbital, phenytoin, primidone, propofol, riluzole, thiopental, tiletamine, trimethadione, valproic acid, vigabatrin. Benzodiazepines are preferred drugs. Examples include, but are not limited to, alprazolam, chlordiazepoxide, clorazepate dipotassium, estazolam, medazepam, midazolam, triazolam, as well as benzodiazepinones, including anthramycin, bromazepam, clonazepam, devazepide, diazepam, flumazenil, flunitrazepam, flurazepam, lorazepam, nitrazepam, oxazepam, pirensepine, prazepam, and temazepam.

Examples of drugs for providing symptomatic relief for migraines include the non-steroidal anti-inflammatory drugs (NSAIDs). Generally, parenteral NSAIDs are more effective against migraine than oral forms. Among the various NSAIDs, ketoprofen is considered by many to be one of the more effective for migraine. Its T_max via the oral route, however, is about 90 min. Other NSAIDs include aminopyrine, amodiaquine, ampyrone, antipyrine, apazone, aspirin, benzydamine, bromelains, bufexamac, BW-755C, clofazimine, clonixin, curcumin, dapsone, diclofenac, diflunisal, dipyrone, epirizole, etodolac, fenoprofen, flufenamic acid, flurbiprofen, glycyrrhizic acid, ibuprofen, indomethacin, ketorolac, ketorolac tromethamine, meclofenamic acid, mefenamic acid, mesalamine, naproxen, niflumic acid, oxyphenbutazone, pentosan sulfuric polyester, phenylbutazone, piroxicam, prenazone, salicylates, sodium salicylate, sulfasalazine, sulindac, suprofen, and tolmetin.

Other antimigraine agents include triptans, ergotamine tartrate, propanolol hydrochloride, isometheptene mucate, dichloralphenazone, and others.

Agents administered in the treatment of ADHD include, among others, methylpenidate, dextroamphetamine, pemoline, imipramine, desipramine, thioridazine and carbamazepine.

Preferred drugs for sleep disorders include the benzodiazepines, for instance, alprazolam, chlordiazepoxide, clorazepate dipotassium, estazolam, medazepam, midazolam, triazolam, as well as benzodiazepinones, including anthramycin, bromazepam, clonazepam, devazepide, diazepam, flumazenil, flunitrazepam, flurazepam, lorasepam, nitrazepam, oxazepam, pirenzepine, prazepam, temazepam, and triazolam. Another drug is zolpidem (Ambien.RTM., Lorex) which is currently given as a 5 mg tablet with T_max =1.6 hours; 1/2 Life=2.6 hours (range between 1.4 to 4.5 hours). Peak plasma levels are reached in about 2 hours with a half-life of about 1.5 to 5.5 hours. Still another drug is triazolam (Halcion.RTM., Pharmacia) which is a heterocyclic benzodiazepine derivative with a molecular weight of 343 which is soluble in alcohol but poorly soluble in water. The usual dose by mouth is 0.125 and 0.25 mg. Temazepam may be a good candidate for sleep disorders due to a longer duration of action that is sufficient to maintain sleep throughout the night. Zaleplon (Sonata.RTM., Wyeth Ayerst) is one drug currently approved for middle of night sleep restoration due to its short duration of action.

Other medicaments include analgesics/antipyretics for example, ketoprofen, flurbiprofen, aspirin, acetaminophen, ibuprofen, naproxen sodium, buprenorphine hydrochloride, propoxyphene hydrochloride, propoxyphene napsylate, meperidine hydrochloride, hydromorphone hydrochloride, morphine sulfate, oxycodone hydrochloride, codeine phosphate, dihydrocodeine bitartrate, pentazocine hydrochloride, hydrocodone bitartrate, levorphanol tartrate, diflunisal, trolamine salicylate, nalbuphine hydrochloride, mefenamic acid, butorphanol tartrate, choline salicylate, butalbital, phenyltoloxamine citrate, diphenhydramine citrate, methotrimeprazine, cinnamedrine hydrochloride, meprobamate, and others.

Antianxiety medicaments include, for example, lorazepam, buspirone hydrochloride, prazepam, chlordizepoxide hydrochloride, oxazepam, clorazepate dipotassium, diazepam, hydroxyzine pamoate, hydroxyzine hydrochloride, alprazolam, droperidol, halazepam, chlormezanone, and others.

Examples of antipsychotic agents include haloperidol, loxapine succinate, loxapine hydrochloride, thioridazine, thioridazine hydrochloride, thiothixene, fluphenazine hydrochloride, fluphenazine decanoate, fluphenazine enanthate, trifluoperazine hydrochloride, chlorpromazine hydrochloride, perphenazine, lithium citrate, prochlorperazine, and the like.

One example of an antimonic agent is lithium carbonate while examples of Alzheimer agents include tetra amino acridine, donapezel, and others.

Sedatives/hypnotics include barbiturates (e.g., pentobarbital, phenobarbital sodium, secobarbital sodium), benzodiazepines (e.g., flurazepam hydrochloride, triazolam, tomazeparm, midazolam hydrochloride), and others.

Hypoglycemic agents include, for example, ondansetron, granisetron, meclizine hydrochloride, nabilone, prochlorperazine, dimenhydrinate, promethazine hydrochloride, thiethylperazine, scopolamine, and others. Antimotion sickness agents include, for example, cinnorizine.

Combinations of drugs also can be employed.

In one embodiment of the invention the particles consist of a medicament, such as, for example, one of the medicaments described above. In another embodiment, the particles include one or more additional components. The amount of drug or medicament present in these particles can range 1.0 to about 90.0 weight percent.

For rescue therapy, particles that include one or more component(s) which promote(s) the fast release of the medicament into the blood stream are preferred. As used herein, rapid release of the medicament into the blood stream refers to release kinetics that are suitable for providing rescue therapy. In one embodiment, optimal therapeutic plasma concentration is achieved in less than 10 minutes. It can be achieved in as fast as about 2 minutes and even less. Optimal therapeutic concentration often can be achieved in a time frame similar or approaching that observed with intravenous administration. Generally, optimal therapeutic plasma concentration is achieved significantly faster than that possible with oral administration, for example, 2 to 10 times faster.

In a preferred embodiment, the particles include one or more phospholipids, such as, for example, a phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidylinositol or a combination thereof. In one embodiment, the phospholipids are endogenous to the lung. Combinations of phospholipids can also be employed. Specific examples of phospholipids are shown in Table 1.

The phospholipid can be present in the particles in an amount ranging from about 0 to about 90 weight %. Preferably, it can be present in the particles in an amount ranging from about 10 to about 60 weight %.

The phospholipids or combinations thereof can be selected to impart control release properties to the particles. Particles having controlled release properties and methods of modulating release of a biologically active agent are described in U.S. Provisional Patent Application No. 60/150,742 entitled Modulation of Release From Dry Powder Formulations by Controlling Matrix Transition, filed on Aug. 25, 1999, U.S. Non-Provisional patent application Ser. No. 09/644,736, filed on Aug. 23, 2000, with the title Modulation of Release From Dry Powder Formulations and U.S. Non-Provisional patent application Ser. No. 09/792,869 filed on Feb. 23, 2001, under Attorney Docket No. 2685.1012-004, and with the title Modulation of Release From Dry Powder Formulations. The contents of all three applications are incorporated herein by reference in their entirety. Rapid release, preferred in the delivery of a rescue therapy medicament, can be obtained for example, by including in the particles phospholipids characterized by low transition temperatures. In another embodiment, a combination of rapid with controlled release particles would allow a rescue therapy coupled with a more sustained release in a single cause of therapy. Control release properties can be utilized in non-rescue, ongoing treatment of a disorder of the CNS.

In another embodiment of the invention the particles can include a surfactant. 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. Surfactants may also promote absorption of a therapeutic or diagnostic agent and increase bioavailability of the agent.

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.

The surfactant can be present in the particles in an amount ranging from about 0 to about 90 weight %. Preferably, it can be present in the particles in an amount ranging from about 10 to about 60 weight %.

Methods of preparing and administering particles including 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 in their entirety.

In another embodiment of the invention, the particles include an amino acid. Hydrophobic amino acids are preferred. Suitable amino acids include naturally occurring and non-naturally occurring hydrophobic amino acids. Examples of amino acids which can be employed include, but are not limited to: glycine, proline, alanine, cysteine, methionine, valine, leucine, tyrosine, isoleucine, phenylalanine, tryptophan. Preferred hydrophobic amino acids, include but are not limited to, leucine, isoleucine, alanine, valine, phenylalanine, glycine and tryptophan. Amino acids include combinations of hydrophobic amino acids can also be employed. 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 unsaturation. 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 (--Br, --Cl, --I and --F) --O(aliphatic, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl group), --CN, --NO₂, --COOH, --NH₂, --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)₂, --COO(aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl group), --CONH₂, --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(=NH)--NH₂. 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 hydrophillic.

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 Green 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, in other words, has a tendency to partition in the nonpolar acid which is at least equal to that of 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. Combinations of one or more amino acids and one or more phospholipids or surfactants can also be employed. Materials which impart fast release kinetics to the medicament are preferred.

The amino acid can be present in the particles of the invention in an amount of at least 10 weight %. Preferably, the amino acid can be present in the particles in an amount ranging from about 20 to about 80 weight %. The salt of a hydrophobic amino acid can be present in the particles of the invention in an amount of at least 10% weight. Preferably, the amino acid salt is present in the particles in an amount ranging from about 20 to about 80 weight %. Methods of forming and delivering particles which include an amino acid are described in U.S. patent application Ser. No. 09/382,959, filed on Aug. 25, 1999, entitled Use of Simple Amino Acids to Form Porous Particles During Spray Drying and in U.S. Non-Provisional Patent Application No. 09/644,320, filed on Aug. 23, 2000, titled Use of Simple Amino Acids to Form Porous Particles, the teachings of both are incorporated herein by reference in their entirety.

In another embodiment of the invention, the particles include a carboxylate moiety and a multivalent metal salt. One or more phospholipids also can be included. Such compositions are described in U.S. Provisional Application No. 60/150,662, filed on Aug. 25, 1999, entitled Formulation for Spray-Drying Large Porous Particles, and U.S. Non-Provisional Patent Application No. 09/644,105, filed on Aug. 23, 2000, titled Formulation for Spray-Drying Large Porous Particles, the teachings of both are incorporated herein by reference in their entirety. In a preferred embodiment, the particles include sodium citrate and calcium chloride.

Other materials, preferably materials which promote fast release kinetics of the medicament can also be employed. For example, biocompatible, and preferably biodegradable polymers can be employed. Particles including such polymeric materials are described in U.S. Pat. No. 5,874,064, issued on Feb. 23, 1999 to Edwards et al., the teachings of which are incorporated herein by reference in their entirety.

The particles can also include a material such as, for example, dextran, polysaccharides, lactose, trehalose, cyclodextrins, proteins, peptides, polypeptides, fatty acids, inorganic compounds, phosphates.

In one specific example, the particles include (by weight percent) 50% L-Dopa, 25% DPPC, 15% sodium citrate and 10% calcium chloride. In another specific example, the particles include (by weight percent) 50% L-Dopa, 40% leucine and 10% sucrose. In yet another embodiment the particles include (by weight percent) 10% benzodiazepine, 20% sodium citrate, 10% calcium chloride and 60% DPPC.

In a preferred embodiment, the particles of the invention have a tap density less than about 0.4 g/cm³. Particles which have a tap density of less than about 0.4 g/cm³ are referred herein as "aerodynamically light particles". More preferred are particles having a tap density less than about 0.1 g/cm³. Tap density can be measured by using instruments known to those skilled in the art such as but not limited to the Dual Platform Microprocessor Controlled Tap Density Tester (Vankel, N.C.) or a GeoPyc.TM. instrument (Micrometrics Instrument Corp., Norcross, Ga. 30093). Tap density is a standard measure of the envelope mass density. Tap density can be determined using the method of USP Bulk Density and Tapped Density, United States Pharmacopeia convention, Rockville, Md, 10^th Supplement, 4950-4951, 1999. Features which can contribute to low tap density include irregular surface texture and porous structure.

The envelope mass density of an isotropic particle is defined as the mass of the particle divided by the minimum sphere envelope volume within which it can be enclosed. In one embodiment of the invention, the particles have an envelope mass density of less than about 0.4 g/cm³.

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

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

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

Experimentally, aerodynamic diameter can be 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. An indirect method for measuring the mass median aerodynamic diameter (MMAD) is the multi-stage liquid impinger (MSLI).

The aerodynamic diameter, d_aer, can be calculated from the equation:

d_aer =d_g.rho._tap

where d_g is the geometric diameter, for example the MMGD, and .rho. is the powder density.

Particles which have a tap density less than about 0.4 g/cm³, median diameters of at least about 5 .mu.m, and an aerodynamic diameter of between about 1 .mu.m and about 5 .mu.m, preferably between about 1 .mu.m and about 3 .mu.m, are more capable of escaping inertial and gravitational deposition in the oropharyngeal region, and are targeted to the airways, particularly 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 currently used for inhalation therapies.

In comparison to smaller, relatively denser particles the larger aerodynamically light particles, preferably having a median diameter of at least about 5 .mu.m, 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 .mu.m. 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.

The particles maybe fabricated with the appropriate material, surface roughness, diameter and tap density for localized delivery to selected regions of the respiratory tract such as the deep lung or upper or central airways. For example, higher density or larger particles may be used for upper airway delivery, or a mixture of varying sized particles in a sample, provided with the same or 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 .mu.m are preferred for delivery to the central and upper airways. Particles having and aerodynamic diameter ranging from about 1 to about 3 .mu.m 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 (at least for particles of mean aerodynamic diameter greater than approximately 1 .mu.m), diminishing the tap density by increasing particle surface irregularities and particle porosity permits the delivery of larger particle envelope volumes into the lungs, all other physical parameters being equal.

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

d_aer =d.rho.

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

d=3/.rho. .mu.m (where .rho.<1 g/cm³);

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

The aerodynamic diameter can be calculated to provide for maximum deposition within the lungs. Previously this was achieved by the use of very small particles of less than about five microns in diameter, preferably between about one and about three 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.

In another embodiment of the invention, the particles have an envelope mass density, also referred to herein as "mass density" of less than about 0.4 g/cm³. Particles also having a mean diameter of between about 5 .mu.m and about 30 .mu.m are preferred. 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. In a preferred embodiment, the aerodynamic diameter of particles having a mass density less than about 0.4 g/cm³ and a mean diameter of between about 5 .mu.m and about 30 .mu.m mass mean aerodynamic diameter is between about 1 .mu.m and about 5 .mu.m.

Suitable particles can be fabricated or 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 .mu.m. The selected range within which a certain percentage of the particles must fall may be for example, between about 5 and about 30 .mu.m, or optimally between about 5 and about 15 .mu.m. In one preferred embodiment, at least a portion of the particles have a diameter between about 9 and about 11 .mu.m. Optionally, the particle sample also can be fabricated wherein at least about 90%, or optionally about 95% or about 99%, have a diameter within the selected range. The presence of the higher proportion of the aerodynamically light, larger diameter particles in the particle sample enhances the delivery of therapeutic or diagnostic agents incorporated therein to the deep lung. Large diameter particles generally mean particles having a median geometric diameter of at least about 5 .mu.m.

In a preferred embodiment, suitable particles which can be employed in the method of the invention are fabricated by spray drying. In one embodiment, the method includes forming a mixture including L-Dopa or another medicament, or a combination thereof, and a surfactant, such as, for example, the surfactants described above. In a preferred embodiment, the mixture includes a phospholipid, such as, for example the phospholipids described above. The mixture employed in spray drying can include an organic or aqueous-organic solvent.

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

Co-solvents 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:water ratio ranging from about 50:50 to about 90:10 ethanol:water.

The spray drying 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. Preferably, the pH can range from about 3 to about 10.

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

In a specific example, 250 milligrams (mg) of L-Dopa in 700 milliliters (ml) of ethanol are combined with 300 ml of water containing 500 mg L-Dopa, 150 mg sodium citrate and 100 mg calcium chloride and the resulting mixture is spray dried. In another example, 700 ml of water containing 500 mg L-Dopa, 100 sucrose and 400 mg leucine are combined with 300 ml of ethanol and the resulting mixture is spray dried.

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

The particles of the invention can be employed in compositions suitable for drug delivery to the pulmonary 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 may be administered alone or in any appropriate pharmaceutically acceptable carrier, such as a liquid, for example saline, or a powder, for administration to the respiratory system. They 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 .mu.m and about 100 .mu.m.

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

The method of the invention includes delivering to the pulmonary system an effective amount of a medicament such as, for example, a medicament described above. As used herein, the term "effective amount" means the amount needed to achieve the desired effect or efficacy. The actual effective amounts of drug can vary according to the specific drug or combination thereof being utilized, the particular composition formulated, the mode of administration, and the age, weight, condition of the patient, and severity of the episode being treated. In rescue therapy, the effective amount refers to the amount needed to achieve abatement of symptoms or cessation of the episode. In the case of a dopamine precursor, agonist or combination thereof it is an amount which reduces the Parkinson's symptoms which require rescue therapy. Dosages for a particular patient are described herein and can be determined by one of ordinary skill in the art using conventional considerations, (e.g. by means of an appropriate, conventional pharmacological protocol). For example, effective amounts of oral L-Dopa range from about 50 milligrams (mg) to about 500 mg. In many instances, a common ongoing (oral) L-Dopa treatment schedule is 100 mg eight (8) times a day. During rescue therapy, effective doses of oral L-Dopa generally are similar to those administered in the ongoing treatment.

For being effective during rescue therapy, plasma levels of L-dopa generally are similar to those targeted during ongoing (non-rescue therapy) L-Dopa treatment. Effective amounts of L-Dopa generally result in plasma blood concentrations that range from about 0.5 microgram (.mu.g)/liter(l) to about 2.0 .mu.g/l.

It has been discovered in this invention that pulmonary delivery of L-Dopa doses, when normalized for body weight, result in at least a 2-fold increase in plasma level as well as in therapeutical advantages in comparison with oral administration. Significantly higher plasma levels and therapeutic advantages are possible in comparison with oral administration. In one example, pulmonary delivery of L-Dopa results in a plasma level increase ranging from about 2-fold to about 10-fold when compared to oral administration. Plasma levels that approach or are similar to those obtained with intravenous administration can be obtained. Similar findings were made with other drugs suitable in treating disorders of the CNS, such as, for example, ketoprofen.

Assuming that bioavailability remains the same as dosage is increased, the amount of oral drug, e.g. L-Dopa, ketoprofen, required to achieve plasma levels comparable to those resulting from pulmonary delivery by the methods of the invention can be determined at a given point after administration. In a specific example, the plasma levels 2 minutes after oral and administration by the methods of the invention, respectively, are 1 .mu.g/ml L-Dopa and 5 .mu.g/ml L-Dopa. Thus 5 times the oral dose would be needed to achieve the 5 .mu.g/ml level obtained by administering the drug using the methods of the invention. In another example, the L-Dopa plasma levels at 120 minutes after administration are twice as high with the methods of the invention when compared to oral administration. Thus twice as much L-Dopa is required after administration 1 .mu.g/ml following oral administration in comparison to the amount administered using the methods of the invention.

To obtain a given drug plasma concentration, at a given time after administration, less drug is required when the drug is delivered by the methods of the invention than when it is administered orally. Generally, at least a two-fold dose reduction can be employed in the methods of the invention in comparison to the dose used in conventional oral administration. A much higher dose reduction is possible. In one embodiment of the invention, a five fold reduction in dose is employed and reductions as high as about ten fold can be used in comparison to the oral dose.

At least a two-fold dose reduction also is employed in comparison to other routes of administration, other than intravenous, such as, for example, intramuscular, subcutaneous, buccal, nasal, intra-peritoneal, rectal.

In addition or alternatively to the pharmacokinetic effect, (e.g., serum level, dose advantage) described above, the dose advantage resulting from the pulmonary delivery of a drug, e.g., L-Dopa, used to treat disorders of the CNS, also can be described in terms of a pharmacodynamic response. Compared to the oral route, the methods of the invention avoid inconsistent medicament uptake by intestines, avoidance of delayed uptake following eating, avoidance of first pass catabolism of the drug in the circulation and rapid delivery from lung to brain via aortic artery.

As discussed above, rapid delivery to the medicament's site of action often is desired. 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 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 of action within a time period which is sufficiently short to provide rescue therapy to the patient being treated. In many cases, the medicament can reach the central nervous system in less than about 10 minutes, often as quickly as two minutes and even faster.

Preferably, the patient's symptoms abate within minutes and generally no later than one hour. In one embodiment of the invention, the release kinetics of the medicament are substantially similar to the drug's kinetics achieved via the intravenous route. In another embodiment of the invention, the T_max of the medicament in the blood stream ranges from about 1 to about 10 minutes. As used herein, the term T_max means the point at which levels reach a maximum concentration. In many cases, the onset of treatment obtained by using the methods of the invention is at least two times faster than onset of treatment obtained with oral delivery. Significantly faster treatment onset can be obtained. In one example, treatment onset is from about 2 to about 10 times faster than that observed with oral administration.

If desired, particles which have fast release kinetics, suitable in rescue therapy, can be combined with particles having sustained release, suitable in treating the chronic aspects of a condition. For example, in the case of Parkinson's disease, particles designed to provide rescue therapy can be co-administered with particles having controlled release properties.

The administration of more than one dopamine precursor, agonist or combination thereof, in particular L-Dopa, carbidopa, apomorphine, and other drugs can be provided, either simultaneously or sequentially in time. Carbidopa, for example, is often administered to ensure that peripheral carboxylase activity is completely shut down. Intramuscular, subcutaneous, oral and other administration routes can be employed. In one embodiment, these other agents are delivered to the pulmonary system. These compounds or compositions can be administered before, after or at the same time. In a preferred embodiment, particles that are administered to the respiratory tract include both L-Dopa and carbidopa. The term "co-administration" is used herein to mean that the specific dopamine precursor, agonist or combination thereof and/or other compositions are administered at times to treat the episodes, as well as the underlying conditions described herein.

In one embodiment regular chronic (non-rescue) L-Dopa therapy includes pulmonary delivery of L-Dopa combined with oral carbidopa. In another embodiment, pulmonary delivery of L-Dopa is provided during the episode, while chronic treatment can employ conventional oral administration of L-Dopa/carbidopa.

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

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

Various suitable devices and methods of inhalation which can be used to administer particles to a patient's respiratory tract are known in the art. For example, suitable inhalers are described in U.S. Pat. No. 4,069,819, issued Aug. 5, 1976 to Valentini, et al., U.S. Pat. No. 4,995,385 issued Feb. 26, 1991 to Valentini, et al., and U.S. Pat. No. 5,997,848 issued Dec. 7, 1999 to Patton, et al. Other examples include, but are not limited to, the Spinhaler.RTM. (Fisons, Loughborough, U.K.), Rotahaler.RTM. (Glaxo-Wellcome, Research Triangle Technology Park, N.C.), FlowCaps.RTM. (Hovione, Loures, Portugal), Inhalator.RTM. (Boehringer-Ingelheim, Germany), and the Aerolizer.RTM. (Novartis, Switzerland), the diskhaler (Glaxo-Wellcome, 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, by David A. Edwards, et al., filed on Apr. 16, 2001. The entire contents of this application are incorporated by reference herein.

The invention further is related to methods for administering to the pulmonary system a therapeutic dose of the medicament in a small number of steps, and preferably in a single, breath activated step. The invention also is related to methods of delivering a therapeutic dose of a drug to the pulmonary system, in a small number of breaths, and preferably in one or two single breaths. The methods includes administering particles from a receptacle having, holding, containing, storing or enclosing a mass of particles, to a subject's respiratory tract.

In one embodiment of the invention, delivery to the pulmonary system of particles is by the methods described in U.S. patent application Ser. No. 09/878,146, High Efficient Delivery of a Large Therapeutic Mass Aerosol, application Ser. No. 09/591,307, filed Jun. 9, 2000, and those described in the Continuation-in-Part of U.S. application Ser. No. 09/591,307, which is filed concurrently herewith. The entire contents of both these applications are incorporated herein by reference. As disclosed therein, particles are held, contained, stored or enclosed in a receptacle. Preferably, the receptacle, e.g. capsule or blister, has a volume of at least about 0.37 cm³ and can have a design suitable for use in a dry powder inhaler. Larger receptacles having a volume of at least about 0.48 cm³, 0.67 cm³ or 0.95 cm³ also can be employed.

In one example, at least 50% of the mass of the particles stored in the inhaler receptacle is delivered to a subject's respiratory system in a single, breath-activated step. In another embodiment, at least 10 milligrams of the medicament is delivered by administering, in a single breath, to a subject's respiratory tract particles enclosed in the receptacle. Amounts as high as 15, 20, 25, 30, 35, 40 and 50 milligrams can be delivered.

In one embodiment, 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/or inhale the particles is in the range typically supplied by a subject during inhaling.

The invention also is related to methods for efficiently delivering powder particles to the pulmonary system. In one embodiment of the invention, at least about 70% and preferably at least about 80% of the nominal powder dose is actually delivered. As used herein, the term "nominal powder dose" is the total amount of powder held in a receptacle, such as employed in an inhalation device. As used herein, the term nominal drug dose is the total amount of medicament contained in the nominal amount of powder. The nominal powder dose is related to the nominal drug dose by the load percent of drug in the powder.

In a specific example, dry powder from a dry powder inhaler receptacle, e.g., capsule, holding 25 mg nominal powder dose having at 50% L-Dopa load, i.e., 12.5 mg L-Dopa, is administered in a single breath. Based on a conservative 4-fold dose advantage, the 12.5 mg delivered in one breath are the equivalent of about 50 mg of L-Dopa required in oral administration. Several such capsules can be employed to deliver higher doses of L-Dopa. For instance a size 4 capsule can be used to deliver 50 mg of l-Dopa to the pulmonary system to replace (considering the same conservative 4-fold dose advantage) a 200 mg oral dose.

Properties of the particles enable delivery to patients with highly compromised lungs where other particles prove ineffective for those lacking the capacity to strongly inhale, such as young patients, old patients, infirm patients, or patients with asthma or other breathing difficulties. Further, patients suffering from a combination of ailments may simply lack the ability to sufficiently inhale. Thus, using the methods and particles for the invention, even a weak inhalation is sufficient to deliver the desired dose. This is particularly important when using the particles of the instant invention as rescue therapy for a patient suffering from debilitating illness of the central nervous system for example but not limited to migraine, anxiety, psychosis, depression, bipolar disorder, obsessive compulsive disorder (OCD), convulsions, seizures, epilepsy, Alzheimer's, and especially, Parkinson's disease.

Claim 1 of 24 Claims

What is claimed is:

1. A method for treating Parkinson's disease comprising administering to the respiratory tract of a patient in need of treatment or rescue therapy a drug for treating Parkinson's disease wherein the drug is administered in a dose that is at least about two times less than that required by oral administration and wherein delivery is to the pulmonary system.

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