USOO6514482B1 (12) United States Patent (10) Patent No.: US 6,514,482 B1 Bartus et al. (45) Date of Patent: Feb. 4, 2003

(54) PULMONARY DELIVERY IN TREATING 5,985,309 A 11/1999 Edwards et al...... 424/426 DSORDERS OF THE CENTRAL NERVOUS 6,019.968 A 2/2000 Platz et al...... 424/130.1 SYSTEM 6,048.857 A 4/2000 Ellinwood, Jr. et al. ... 514/221 6,103.270 A 8/2000 Johnson et al...... 424/489 (75) Inventors: Raymond T. Bartus, Sudbury, MA 6,136.295 A 10/2000 Edwards et al...... 424/45 (US); Dwaine F. Emerich, C t RI 6,165,463 A 12/2000 Platz et al...... 424/130.1 (US , UranSLOn, 6,193.954 B1 * 2/2001 Adjei et al...... 424/45 FOREIGN PATENT DOCUMENTS (73) Assignee: Advanced Inhalation Research, Inc., CA 2152684 6/1995 Cambridge, MA (US) EP O 496 307 A1 7/1992 (*) Notice: Subject to any disclaimer, the term of this wo WO E. E. patent is extended or adjusted under 35 WO WO 98/31346 7/1998 U.S.C. 154(b) by 0 days. WO WO 98/46245 10/1998 WO WO OO/72827 A2 12/2000 (21) Appl. No.: 09/665,252 WO WO 01/95874 A2 12/2001 (22) Filed: Sep. 19, 2000 OTHER PUBLICATIONS (51) Int. Cl...... A61K 9/12, A61K 9/14, Journal of the Neurological Sciences, Vol. 150, Issue: 1001, s A61 K 9.75 supplement 1, p. S198, Sep. 1997.* (52) U.S. Cl...... 424/45; 424/43; 424/789; * cited by examiner (8) Field of Styligi514/220; 128/203.15 C.E.O. M. Eitan s s s • -u- as (74) Attorney, Agent, or Firm-Hamilton, Brook, Smith & (56) References Cited Reynolds, P.C. U.S. PATENT DOCUMENTS (57) ABSTRACT 4.814.161 A 3/1989 Jinks et all 424/45 A method of pulmonary delivery of a medicament, for 4805710. A 1900 Radhakrishnana". 424/4s example a dopamine precursor or a dopamine agonist, which 5,118,494. A 6/1992 Schultz et al...... 424/45 includes administering to the respiratory tract of a patient in 5,166,202 A 11/1992 Schweizer ...... 514/220 need of rescue therapy particles comprising an effective 5,284,133 A 2/1994 Burns et al...... 128/200.23 amount of a medicament. The particles are delivered to the 5,354.885. A * 10/1994 Millman et al...... 560/43 pulmonary System and are released into the blood Stream 5,457,100 A : 10/1995 Daniel ...... 514/220 and delivered to the medicament's Site of action in a time 5. E. A . g s et l, ------3.i. Sufficiently short to provide the rescue therapy. In addition to 5756,071 A E. MNN .. ------i.f45 the medicament, the particles can include other materials 5855,913 A 1/1999 Hanes et all ------424/489 Such as, for example, phospholipids, amino acids, combi 5.874.064 A 2/1999 Edwards et al... 424/46 nations thereof and others. Preferred particles have a tap 5,875,776 A 3/1999 Vaghefi ...... 128/203.15 density of less than about 0.4 g/cm. 5,922,354 A 7/1999 Johnson et al...... 424/489 5,981,474. A 11/1999 Manning et al...... 514/2 42 Claims, 9 Drawing Sheets

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Time (hours) FIG. US 6,514,482 B1 1 2 PULMONARY DELIVERY IN TREATING epilepsy) is approximately 250,000. A significant number of DSORDERS OF THE CENTRAL NERVOUS patients also Suffer from So-called “cluster Seizures', SYSTEM wherein an initial Seizure forewarns that a Series of addi tional Seizures will occur within a relatively short time frame. By some reports, 75% of all patients continue to BACKGROUND OF THE INVENTION experience Seizures despite taking medication chronically. Poor compliance with the prescribed medications is believed Parkinson's disease is characterized neuropathologically to be a significant (albeit not Sole) contributing factor. The by degeneration of dopamine neurons in the basal ganglia importance of controlling or minimizing the frequency and and neurologically by debilitating tremors, SlowneSS of intensity of Seizures lies in the fact that incidence of Seizures movement and balance problems. It is estimated that over has been correlated with neuronal deficits and is believed to one million people suffer from Parkinson's disease. Nearly cause loSS of neurons in the brain. all patients receive the dopamine precursor levodopa or Despite chronic treatment, as many as 75% of all patients L-Dopa, often in conjunction with the dopa-decarboxylase continue to exhibit periodic Seizures. The uncontrolled Sei inhibitor, carbidopa. L-Dopa adequately controls Symptoms Zures occur in many forms. In the case of “cluster Seizures,” of Parkinson's disease in the early Stages of the disease. 15 one Seizure Serves notice that a cascade has begun which However, it tends to become less effective after a period will lead to a Series of Seizures before the total episode which can vary from Several months to Several years in the passes. In certain patients, prior to the onset of a Severe course of the disease. Seizure, Some Subjective feeling or Sign is detected by the It is believed that the varying effects of L-Dopa in patient (defined as an aura). In both instances, an opportu Parkinson's disease patients is related, at least in part, to the nity exists for these patients to Significantly reduce the plasma half life of L-Dopa which tends to be very short, in liability of the seizure through “self medication'. While the range of 1 to 3 hours, even when co-administered with many patients are instructed to do So, the drugs currently carbidopa. In the early Stages of the disease, this factor is available to permit effective self medication are limited. mitigated by the dopamine Storage capacity of the targeted 25 Panic attacks purportedly affect about 2.5 million people striatal neurons. L-Dopa is taken up and Stored by the in this country alone. The disorder is characterized by acute neurons and is released over time. However, as the disease episodes of anxiety, leading to difficult breathing, dizziness, progresses, dopaminergic neurons degenerate, resulting in heart palpitations and fear of losing control. The disorder is decreased dopamine Storage capacity. Accordingly, the posi believed to involve a problem with the sympathetic nervous tive effects of L-Dopa become increasingly related to fluc System (involving an exaggerated arousal response, leading tuations of plasma levels of L-Dopa. In addition, patients to overstimulation of adrenaline release and/or adrenergic tend to develop problems involving gastric emptying and neurons). Benzodiazepines are effective against these poor intestinal uptake of L-Dopa. Patients exhibit increas attackS. ingly marked Swings in Parkinson's disease Symptoms, A pure vasogenic etiology/pathogenesis for migraine was ranging from a return to classic Parkinson's disease 35 first proposed in the 1930s; by the 1980s, this was replaced Symptoms, when plasma levels fall, to the So-called by a neurogenic etiology/pathogenesis, which temporarily dyskinesis, when plasma levels temporarily rise too high won favor among migraine investigators. However, it is now following L-Dopa administration. generally recognized that both vasogenic and neurogenic AS the disease progresses, conventional L-Dopa therapy components are involved, interacting as a positive feedback involves increasingly frequent, but lower dosing Schedules. 40 System, with each continuously triggering the other. The Many patients, for example, receive L-Dopa every two to major neurotransmitters implicated include Serotonin (the three hours. It is found, however, that even frequent doses of Site of action of the triptans), Substance P (traditionally L-Dopa are inadequate in controlling Parkinson's disease associated with mediating pain), histamine (traditionally Symptoms. In addition, they inconvenience the patient and associated with inflammation) and dopamine. The major often result in non-compliance. 45 pathology associated with migraine attacks include an It is also found that even with as many as Six to ten inflammation of the dura, an increase in diameter of L-Dopa doses a day, plasma L-Dopa levels can Still fall meningeal vessels and SuperSensitivity of the trigeminal dangerously low, and the patient can experience very Severe cranial nerve, including the branches that enervate the Parkinson's disease Symptoms. When this happens, addi meningeal vessels. The triptans are believed to be effective tional L-Dopa is administered as intervention therapy to 50 because they affect both the neural and Vascular components rapidly increase brain dopamine activity. However, orally of the migraine pathogenic cascade. Migraines include Clas administered therapy is associated with an onset period of sic and Common Migraines, Cluster Headaches and Tension about 30 to 45 minutes during which the patient suffers Headaches. unnecessarily. In addition, the combined effects of the inter Initial Studies with Sumatriptain showed that, when vention therapy, with the regularly Scheduled dose can lead 55 administered intravenously (IV), a 90% efficacy rate was to overdosing, which can require hospitalization. For achieved. However, the efficiency rate is only approximately example, Subcutaneously administered dopamine receptor 60% with the oral form (versus 30% for placebo). The nasal agonist (apomorphine), often requiring a peripherally acting form has proven to be highly variable, requiring training and dopamine antagonist, for example, domperidone, to control skill on the part of the patient, which Some of the patients do dopamine-induced nausea, is inconvenient and invasive. 60 not seem to master. The treatment also induces a bad taste in Other medical indications involving the central nervous the mouth which many patients find highly objectionable. system (CSN) require rapid delivery of a medicament such There currently exists no clear evidence that any of the as but not limited to epilepsy, panic attacks and migraines. recent, more Selective 5HT1 receptor agonists are any more For example, about 2 million people in the USA suffer from efficacious than Sumatriptan (which stimulates multiple Some form of epilepsy, with the majority receiving at least 65 receptor Subtypes; e.g., 1B, 1D, and 1F). one of Several different anti-Seizure medications. The inci In addition to not providing adequate efficacy, current dence of status epilepticus (the more Serious form of dosing of triptans have at least two other deficiencies: (1) US 6,514,482 B1 3 4 vasoconstriction of chest and heart muscles, which produces inconvenience of injections. Selective delivery of a medi chest tightness and pain in Some Subjects; this effect also cament to the central nervous can be obtained in a time presents an unacceptable risk to hypertensive and other CV frame not available with oral formulations. Thus, an effec patients, for whom the triptans are contraindicated, and (2) tive dose can be delivered to the site of action on the “first the duration of action of current formulations is limited, pass of the medicament in the circulatory System. By causing a return of headache in many patients about 4 hours practicing the invention, relief is available to Symptomatic after initial treatment. patients in a time frame during which conventional oral Rapid onset of a hypnotic would also be quite desirable therapies would still be traveling to the Site of action. and particularly useful in Sleep restoration therapy, as middle of night awakening and difficulty in falling asleep again, BRIEF DESCRIPTION OF THE DRAWINGS once awakened, is common in middle aged and aging adults. FIG. 1A is a plot representation of blood levels of L-Dopa Other indications related to the CNS, Such as, for in rats following administration via oral gavage or direct example, mania, bipolar disorders, Schizophrenia, appetite administration to the lungs measured by mass Spectrometer. Suppression, motion Sickness, nausea and others, as known FIG. 1B is a plot representation of blood levels of L-Dopa in the art, also require rapid delivery of a medicament to its 15 in rats following administration via oral gavage or direct Site of action. administration to the lungs measured by HPLC. Therefore, a need exists for a method of the rapid delivery FIG. 2A is a plot representation of blood L-Dopa levels in of medicaments which is at least as effective as conventional ratS. therapies yet minimizes or eliminates the above-mentioned FIG.2B is a plot representation of striatal dopamine levels problems. in rats following delivery of L-Dopa orally or directly into the lungs. SUMMARY OF THE INVENTION FIG. 3 is a plot representation of blood and striatal levels The invention relates to a method of treating a disorder of of “C following administration of "C-L-Dopa either orally the central nervous System. The method includes adminis or directly to the lungs. tering to the respiratory tract of a patient in need of rapid 25 FIG. 4 is a plot representation of plasma "Clevels in rats onset or rescue therapy particles comprising an effective following "C-L-Dopa administration via gavage, trache amount of a medicament. The particles are delivered to the otomy or ventilator. pulmonary System and the medicament is released into the patient's blood Stream and reaches the medicament's site of FIG. 5 is a plot representation of brain "Clevels in rats action in a time interval which is sufficiently short to provide following "C-L-Dopa administration via gavage, trache the rescue therapy. otomy or ventilator. In a preferred embodiment, the disorder of the nervous FIG. 6A is a bar graph showing absolute "C-Carboplatin system is Parkinson's disease. Other disorders of the ner levels in regions of the brain following intravenous (IV) and Vous System, Such as, for example, epileptic and other pulmonary administration. Seizures, panic attacks, Sleep disorders, migraine and others 35 FIG. 6B is a bar graph showing relative "C-Carboplatin can be treated by the method of the invention. In a preferred levels in regions of the brain following intravenous (IV) and embodiment the medicament employed in the methods of pulmonary administration. the invention is a dopamine precursor or a dopamine agonist, FIG. 7A is a bar graph showing absolute "C-Carboplatin levels in animal organs following intravenous (IV) or pull for example levodopa. 40 In one embodiment, particles employed in the method of monary administration. the invention are particles Suitable for delivering a medica FIG. 7B shows relative "C-Carboplatin levels in animal ment to the pulmonary System and in particular to the alveoli organs following intravenous (IV) or pulmonary adminis or the deep lung. In a preferred embodiment, the particles tration. have a tap density which is less than 0.4 g/cm. In another FIG. 8 is a plot representation showing plasma concen preferred embodiment, the particles have a geometric 45 tration of L-Dopa VS. time following oral or pulmonary diameter, of at least 5 um (microns), preferably between administration (normalized for an 8 mg dose). about 5 um and 30 lum. In yet another preferred embodiment, FIG. 9 is a plot representation showing plasma concen the particles have an aerodynamic diameter between about 1 tration of ketoprofen VS. time for oral and pulmonary groups. tim and about 5 um. 50 FIG. 10 is a plot representation showing plasma concen Particles can consist of the medicament or can further tration of ketoprofen VS. time for oral group include one or more additional components. Rapid release of FIG. 11 is a plasma concentration of ketoprofen VS. time the medicament into the blood stream and its delivery to its for pulmonary group. Site of action, for example, the central nervous System, is DETAILED DESCRIPTION OF THE preferred. In one embodiment of the invention, the particles 55 include a material which enhances the release kinetics of the INVENTION medicament. Examples of Suitable Such materials include, The features and other details of the invention, either as but are not limited to, certain phospholipids, amino acids, Steps of the invention or as combination of parts of the carboxylate moieties combined with salts of multivalent invention, will now be more particularly described and metals and others. 60 pointed out in the claims. It will be understood that the Preferably, administration to the respiratory tract is by a particular embodiments of the invention are shown by way dry powder inhaler or by a metered dose inhaler. The of illustration and not as limitations of the invention. The particles of the invention also can be employed in compo principle feature of this invention may be employed in Sitions Suitable for delivery to the pulmonary System Such as various embodiments without departing from the Scope of known in the art. 65 the invention. The invention has many advantages. For example, pull The invention is generally related to a method of provid monary delivery provides on-demand treatment without the ing rescue therapy to patients Suffering from a disorder of the US 6,514,482 B1 S 6 central nervous System. AS used herein, "rescue therapy' Medazepam, Midazolam, Triazolam, as well as means on demand, rapid delivery of a drug to a patient to Benzodiazepinones, including Anthramycin, Bromazepam, help reduce or control disease Symptoms. Clonazepam, Deva Zepide, Diazepam, Flumazenil, One preferred medical indication which can be treated by Flunitrazepam, Flurazepam, Lorazepam, Nitrazepam, the method of the invention is Parkinson's disease, in 5 Oxazepam, Pirensepine, Prazepam, and Temazepam. particular the late Stages of the disease. Examples of drugs for providing Symptomatic relief for In addition, forms of epileptical Seizures Such as occur migraines include the non-Steroidal anti-inflammatory drugs ring in Myoclonic Epilepsies, including Progressive and (NSAIDs). Generally, parenteral NSAIDs are more effective Juvenile, Partial Epilepsies, including Complex Partial, against migraine than oral forms. Among the various Frontal Lobe, Motor and Sensory, Rolandic and Temporal NSIADs, ketoprofen is considered by many to be one of the Lobe; Benign Neonatal Epilepsy; Post-Traumatic Epilepsy; more effective for migraine. Its T. Via the oral route, Reflex Epilepsy; Landau-Kleffner Syndrome; and Seizures, however, is about 90 min. Other NSAIDs include including Febrile, Status Epilepticus, and Epilepsia Partialis Aminopyrine, Amodiaquine, Ampyrone, Antipyrine, Continua also can be treated using the method of the ApaZone, Aspirin, BenZydamine, Bromelains, BufeXamac, invention. 15 BW-755C, Clofazimine, Clonixin, Curcumin, Dapsone, Sleep disorders that can benefit from the present invention Diclofenac, Diflunisal, Dipyrone, Epirizole, Etodolac, include Dyssomnias, Sleep Deprivation, Circadian Rhythm Fenoprofen, Flufenamic Acid, Flurbiprofen, Glycyrrhizic Sleep Disorders, Intrinsic Sleep Disorders, including Disor Acid, Ibuprofen, Indomethacin, Ketorolac, Ketorolac de r S of EXce SSive Somnolence, Idiopathic Tromethamine, Meclofenamic Acid, Mefenamic Acid, HyperSomnolence, Kleine-Levin Syndrome, Narcolepsy, Mesalamine, Naproxen, Niflumic Acid, Oxyphenbutazone, Nocturnal Myoclonus Syndrome, Restless Legs Syndrome, Pentosan Sulfuric Polyester, Phynylbutazone, Piroxicam, Sleep Apnea Syndromes, Sleep Initiation and Maintenance PrenaZone, Salicylates, Sodium Salicylate, SulfaSalazine, Disorders, Parasomnias, Nocturnal Nyoclonus Syndrome, Sulindac, Suprofen, and Tolmetin. Nocturnal Paroxysmal Dystonia, REM Sleep Parasomnias, Other antimigraine agents include triptans, ergotamine Sleep Arousal Disorders, Sleep Bruxism, and Sleep-Wake 25 tartrate, propanolol hydrochloride, isometheptene mucate, Transition Disorders. Sleep interruption often occurs around dichloralphenaZone, and others. 2 to 3 a.m. and requires treatment the effect of which lasts Preferred drugs for sleep disorders include the approximately 3 to 4 hours. be n Zodiazepine S, for instance, Alprazolam, Examples of other disorders of the central nervous System Chlordiazepoxide, CloraZepate Dipotassium, Estazolam, which can be treated by the method of the invention include Medazepam, Midazolam, Triazolam, as well as but are not limited to appetite Suppression, motion Sickness, Benzodiazepinones, including Anthramycin, Bromazepam, panic or anxiety attack disorders, nausea Suppressions, Clonazepam, Deva Zepide, Diazepam, Flumazenil, mania, bipolar disorders, Schizophrenia and others, known Flunitrazepam, Flurazepam, Lorasepam, Nitrazepam, in the art to require rescue therapy. 35 Oxazepam, Pirenzepine, Prazepam, Temazepam, and Tria Medicaments which can be used in the method of the Zolam. Another drug is Zolpidem (Ambien) which is cur invention include pharmaceutical preparations Such as those rently given as a 5 mg tablet with T=1.6 hours; /2 generally prescribed in the rescue therapy of disorders of the Life=2.6 hours (range between 1.4 to 4.5 hours). Peak nervous System. In a preferred embodiment, the medicament plasma levels are reached in about 2 hours with a half-life of is a dopamine precursor, dopamine agonist or any combi 40 about 1.5 to 5.5 hours. Still another drug is Halcion nation thereof. Preferred dopamine precursors include (Ambien) which is a heterocyclic benzodiazepine derivative levodopa (L-Dopa). Other drugs generally administered in with a molecular weight of 343 which is soluble in alcohol the treatment of Parkinson's disease and which may be but poorly soluble in water. The usual dose by mouth is Suitable in the methods of the invention include, for 0.125 and 0.25 mg. Temazepam may be a good candidate for example, ethoSuximide, dopamine agonists Such as, but not 45 Sleep disorders due to a longer duration of action that is limited to carbidopa, apomorphine, Sopinirole, pramipexole, Sufficient to maintain Sleep throughout the night. Zaleplam pergoline, bronaocriptine. The L-Dopa or other dopamine (Sonata, Wyeth) is one drug currently approved for middle precursor or agonist may be any form or derivative that is of night Sleep restoration due to its short duration of action. biologically active in the patient being treated. Other medicaments include analgesicS/antipyretics for Examples of anticonvulsants include but are not limited to 50 example, ketoprofin, flurbiprofen, aspirin, acetaminophen, diazepam, Valproic acid, divalproate Sodium, phenytoin, ibuprofen, naproxen Sodium, buprenorphine hydrochloride, phenytoin Sodium, cloanazepam, primidone, phenobarbital, propoxyphene hydrochloride, propoxyphene napSylate, phenobarbital Sodium, carbamazepine, amobarbital Sodium, meperidine hydrochloride, hydromorphone hydrochloride, methSuximide, metharbital, mephobarbital, mephenytoin, morphine Sulfate, oxycodone hydrochloride, codeine phensuXimide, pararnethadione, ethotoin, phenacemide, 55 phosphate, dihydrocodeine bit artrate, pentazocine Secobarbitol Sodium, cloraZepate dipotassium, trimethadi hydrochloride, hydrocodone bit artrate, levorphanol tartrate, one. Other anticonvulsant drugs include, for example, diflunisal, trolamine Salicylate, nalbuphine hydrochloride, Acetazolamide, Carbamazepine, Chlorimethiazole, mefenamic acid, butorphanol tartrate, choline Salicylate, Clonazepam, CloraZepate Dipotassium, Diazepam, but albital, phenyltoloxamine citrate, diphenhydramine Dimethadione, Estazolam, Ethosuximide, Flunarizine, 60 citrate, methotrimeprazine, cinnamedrine hydrochloride, Lorazepam, Magnesium Sulfate, Medazepam, Melatonin, meprobamate, and others. Mephenytoin, Mephobarbital, Meprobamate, Nitrazepam, Antianxiety medicaments include, for example, Paraldehyde, Phenobarbital, Phenytoin, Primidone, lorazepam, buSpirone hydrochloride, prazepam, chlordizep Propofol, Riluzole, Thiopental, Tiletamine, Trimethadione, oxide hydrochloride, oxazepam, cloraZepate dipotassium, Valproic Acid, Vigabatrin. A preferred drug is the 65 diazepam, hydroxy Zine pamoate, hydroxy Zine be n Zodiazepine S, for instance, Alprazolam, hydrochloride, alprazolam, droperidol, halazepam, Chlordiazepoxide, CloraZepate Dipotassium, Estazolam, chlormeZanone, and others. US 6,514,482 B1 7 8 Examples of antipsychotic agents include haloperidol, Dec. 7, 1999 to Patton, et al. Other examples include, but are loxapine Succinate, loxapine hydrochloride, thioridazine, not limited to, the Spinhaler(F) (Fisons, Loughborough, thioridazine hydrochloride, thiothixene, fluphenazine U.K.), Rotahaler(R) (Glaxo-Wellcome, Research Triangle hydrochloride, flu phenazine decanoate, flu phenazine Technology Park, N.C.), FlowCaps(R (Hovione, Loures, enanthate, trifluoperazine hydrochloride, chlorpromazine Portugal), Inhalator(R) (Boehringer-Ingelheim, Germany), hydrochloride, per phena Zine, lithium citrate, and the Aerolizer(R) (Novartis, Switzerland), the diskhaler prochlorperazine, and the like. (Glaxo-Wellcome, RTP, NC) and others, such as known to One example of an antimonic agent is lithium carbonate those skilled in the art. while examples of Alzheimer agents include tetra amino Preferably, particles administered to the respiratory tract acridine, donapezel, and others. travel through the upper airways (oropharynx and larynx), Sedatives/hypnotics include barbiturates (e.g., the lower airways which include the trachea followed by pentobarbital, phenobarbital Sodium, Secobarbital Sodium), bifurcations into the bronchi and bronchioli and through the benzodiazepines (e.g., flurazepam hydrochloride, triazolam, terminal bronchioli which in turn divide into respiratory tomazeparm, midazolam hydrochloride), and others; bronchioli leading then to the ultimate respiratory Zone, the Hypoglycemic agents include, for example, Ondansetron, 15 alveoli or the deep lung. In a preferred embodiment of the granise tron, meclizine hydrochloride, nabilone, invention, most of the mass of particles deposits in the deep prochlorpe razine, dimenhydrinate, prometha Zine lung. In another embodiments of the invention, delivery is hydrochloride, thiethylperazine, Scopolamine, and others. primarily to the central airways. Delivery to the upper Antimotion Sickness agents include, for example, cinnoriz airways can also be obtained. C. In one embodiment of the invention, delivery to the Combination of drugs and combination of excipients can pulmonary System of particles is in a Single, breath-actuated be prepared and administered. step, as describe in U.S. Patent Application, High Efficient Particles including a medicament, for example, one or Delivery of a Large Therapeutic Mass AeroSol, application more of the drugs listed above, are administered to the 25 Ser. No. 09/591,307, filed Jun. 9, 2000, which is incorpo respiratory tract of a patient in need of rescue therapy. rated herein by reference in its entirety. In another embodi Administration of particles to the respiratory System can be ment of the invention, at least 50% of the mass of the by means Such as known in the art. For example, particles particles Stored in the inhaler receptacle is delivered to a are delivered from an inhalation device. In a preferred Subject's respiratory System in a single, breath-activated embodiment, particles are administered via a dry powder Step. In a further embodiment, at least 5 milligrams and inhaler (DPI). Metered-dose-inhalers (MDI), nebulizers or preferably at least 10 milligrams of a medicament is deliv instillation techniques also can be employed. ered by administering, in a Single breath, to a Subject's Methods of administering particles to patients in acute respiratory tract particles enclosed in the receptacle. Amounts as high as 15, 20, 25, 30, 35, 40 and 50 milligrams distreSS are disclosed. These particles of the instant inven can be delivered. tion are capable of being delivered to the lung and absorbed 35 into the System when other conventional means of delivering In one embodiment of the invention the particles consist drugs fail. In one embodiment, delivery to the pulmonary of a medicament, Such as, for example, one of the medica System of particles in a single, breath-actuated Step is ments described above. In another embodiment, the particles enhanced by employing particles which are dispersed at include one or more additional components. The amount of relatively low energies, Such as, for example, at energies 40 drug or medicament present in the particles can range 1.0 to typically Supplied by a Subjects inhalation. Such energies about 90.0 weight percent. are referred to herein as “low.” As used herein, “low energy Preferably, the particles include one or more component administration” refers to administration wherein the energy (s) which promote(s) the fast release of the medicament into applied to disperse and/or inhale the particles is in the range the blood Stream. AS used herein, rapid release of the typically Supplied by a Subject during inhaling. 45 medicament into the blood Stream refers to release kinetics In particular, properties of the particles enable delivery to that are Suitable for providing rescue therapy. In a preferred patients with highly comprised lungs where other particles embodiment, optimal therapeutic concentration is achieved prove ineffective for those lacking the capacity to Strongly in less than 10 minutes. inhale, Such as young patients, old patients, infirm patients, In a preferred embodiment, the particles include one or or patients with asthma or other breathing difficulties. 50 more phospholipids, Such as, for example, a Further, patients Suffering from a combination of ailments phosphatidylcholine, phosphatidyle thanolamine, may simply lack the ability to Sufficiently inhale. Thus, using phosphatidylglycerol, phosphatidylserine, phosphatidyli the methods and particles for the invention, even a weak nositol or a conbination thereof. In one embodiment, the inhalation is Sufficient to deliver the desired dose. This is phospholipids are endogenous to the lung. Specific particularly important when using the particles of the instant 55 examples of phospholipids are shown below. 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), Dilaurylolyphosphatidylcholine (C12:0) DLPC Dimyristoylphosphatidylcholine (C14:0) DMPC convulsions, Seizures, epilepsy, Alzheimer's, and especially, 60 Dipalmitoylphosphatidylcholine (C16:0) DPPC Parkinson's disease. Distearoylphosphatidylcholine (18:0) DSPC Various Suitable devices and methods of inhalation which Dioleoylphosphatidylcholine (C18:1) DOPC can be used to administer particles to a patient's respiratory Dilaurylolylphosphatidylglycerol DLPG Dimyristoylphosphatidylglycerol DMPG tract are known in the art. For example, Suitable inhalers are Dipalmitoylphosphatidylglycerol DPPG described in U.S. Pat. No. 4,069,819, issued Aug. 5, 1976 to 65 Distearoylphosphatidylglycerol DSPG Valentini, et al., U.S. Pat. No. 4,995,385 issued Feb. 26, Dioleoylphosphatidylglycerol DOPG 1991 to Valentini, et al., and U.S. Pat. No. 5,997.848 issued US 6,514,482 B1 9 10 Examples of amino acids which can be employed include, -continued but are not limited to: glycine, proline, alanine, cysteine, Dimyristoyl phosphatidic acid DMPA methionine, Valine, leucine, tyrosine, isoleucine, Dipalmitoyl phosphatidic acid DPPA phenylalanine, tryptophan. Preferred hydrophobic amino Dimyristoyl phosphatidylethanolamine DMPE acids, include but not limited to, leucine, isoleucine, alanine, Dipalmitoyl phosphatidylethanolamine DPPE Valine, phenylalanine, glycine and tryptophan. Amino acids Dimyristoyl phosphatidylserine DMPS Dipalmitoyl phosphatidylserine DPPS include combinations of hydrophobic amino acids can also Dipalmitoyl sphingomyelin DPSP be employed. Non-naturally occurring amino acids include, Distearoyl sphingomyelin DSSP for example, beta-amino acids. Both D, L and racemic configurations of hydrophobic amino acids can be Combinations of phospholipids can also be employed. employed. Suitable hydrophobic amino acids can also The phospholipid can be present in the particles in an include amino acid analogs. AS used herein, an amino acid amount ranging from about 0 to about 90 weight %. analog includes the D or L configuration of an amino acid Preferably, it can be present in the particles in an amount having the following formula: -NH-CHR-CO-, ranging from about 10 to about 60 weight 9%. 15 wherein R is an aliphatic group, a Substituted aliphatic The phospholipids or combinations thereof can be group, a benzyl group, a Substituted benzyl group, an Selected to impart control release properties to the particles. aromatic group or a Substituted aromatic group and wherein Particles having controlled release properties and methods R does not correspond to the Side chain of a naturally of modulating release of a biologically active agent are occurring amino acid. AS used herein, aliphatic groups described in U.S. Provisional Patent Application No. include straight chained, branched or cyclic C1-C8 hydro 60/150,742 entitled Modulation of Release From Dry Pow carbons which are completely Saturated, which contain one der Formulations by Controlling Matrix Transition, filed on or two heteroatoms Such as nitrogen, oxygen or Sulfur and/or Aug. 25, 1999 and U.S. Non-Provisional Patent Application, which contain one or more units of unsaturation. Aromatic filed on Aug. 23, 2000, with the title Modulation of Release groups include carbocyclic aromatic groups Such as phenyl From Dry Powder Formulations under Ser. No. 09/644,736. 25 and naphthyl and heterocyclic aromatic groups Such as The contents of both are incorporated herein by reference in imidazolyl, indolyl, thienyl, furanyl, pyridyl, pyranyl, their entirety. Rapid release, preferred in the delivery of a Oxazolyl, benzothienyl, benzofuranyl, quinolinyl, isoquino rescue therapy medicament, can be obtained for example, by linyl and acridintyl. including in the particles phospholipids characterized by low Suitable Substituents on an aliphatic, aromatic or benzyl transition temperatures. In another embodiment, a combi group include -OH, halogen (-Br, -Cl, -I and -F) nation of rapid with controlled release particles would allow -O(aliphatic, Substituted aliphatic, benzyl, Substituted a rescue therapy coupled with a more Sustained release in a benzyl, aryl or substituted aryl group), -CN, -NO, Single cause of therapy. -COOH, -NH, -NH(aliphatic group, substituted In another embodiment of the invention the particles can aliphatic, benzyl, Substituted benzyl, aryl or Substituted aryl include a Surfactant. AS used herein, the term "Surfactant” 35 group), -N(aliphatic group, Substituted aliphatic, benzyl, refers to any agent which preferentially absorbs to an Substituted benzyl, aryl or Substituted aryl group), -COO interface between two immiscible phases, Such as the inter (aliphatic group, Substituted aliphatic, benzyl, Substituted face between water and an organic polymer Solution, a benzyl, aryl or substituted aryl group), -CONH,-CONH water/air interface or organic Solvent/air interface. Surfac (aliphatic, Substituted aliphatic group, benzyl, Substituted tants generally possess a hydrophilic moiety and a lipophilic 40 benzyl, aryl or Substituted aryl group)), -SH, -S(aliphatic, moiety, Such that, upon absorbing to microparticles, they Substituted aliphatic, benzyl, Substituted benzyl, aromatic or tend to present moieties to the external environment that do substituted aromatic group) and -NH-C(=NH)-NH. A not attract similarly-coated particles, thus reducing particle Substituted benzylic or aromatic group can also have an agglomeration. Surfactants may also promote absorption of aliphatic or Substituted aliphatic group as a Substituent. A a therapeutic or diagnostic agent and increase bioavailability 45 Substituted aliphatic group can also have a benzyl, Substi of the agent. tuted benzyl, aryl or Substituted aryl group as a Substituent. In addition to lung Surfactants, Such as, for example, A Substituted aliphatic, Substituted aromatic or Substituted phospholipids discussed above, Suitable Surfactants include benzyl group can have one or more Substituents. Modifying but are not limited to hexadecanol, fatty alcohols Such as an amino acid Substituent can increase, for example, the polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; 50 lypophilicity or hydrophobicity of natural amino acids a Surface active fatty acid, Such as palmitic acid or oleic acid; which are hydrophillic. glycocholate, Surfactin; a poloXomer; a Sorbitan fatty acid A number of the Suitable amino acids, amino acids ester Such as Sorbitan trioleate (Span 85); and tyloxapol. analogs and Salts thereof can be obtained commercially. The Surfactant can be present in the particles in an amount Others can be synthesized by methods known in the art. ranging from about 0 to about 90 weight %. Preferably, it 55 Synthetic techniques are described, for example, in Green can be present in the particles in an amount ranging from and Wuts, “Protecting Groups in Organic Synthesis”, John about 10 to about 60 weight 9%. Wiley and Sons, Chapters 5 and 7, 1991. Methods of preparing and administering particles includ Hydrophobicity is generally defined with respect to the ing Surfactants, and, in particular phospholipids, are dis partition of an amino acid between a nonpolar Solvent and closed in U.S. Pat. No 5,855,913, issued on Jan. 5, 1999 to 60 water. Hydrophobic amino acids are those acids which show Hanes et al. and in U.S. Pat. No. 5,985,309, issued on Nov. a preference for the nonpolar Solvent. Relative hydropho 16, 1999 to Edwards et al. The teachings of both are bicity of amino acids can be expressed on a hydrophobicity incorporated herein by reference in their entirety. Scale on which glycine has the value 0.5. On Such a Scale, In another embodiment of the invention, the particles amino acids which have a preference for water have values include an amino acid. Hydrophobic amino acids are pre 65 below 0.5 and those that have a preference for nonpolar ferred. Suitable amino acids include naturally occurring and Solvents have a value above 0.5. As used herein, the term non-naturally occurring hydrophobic amino acids. hydrophobic amino acid refers to an amino acid that, on the US 6,514,482 B1 11 12 hydrophobicity Scale has a value greater or equal to 0.5, in 1999. Features which can contribute to low tap density other words, has a tendency to partition in the nonpolar acid include irregular Surface texture and porous Structure. which is at least equal to that of glycine. The envelope mass density of an isotropic particle is Combinations of hydrophobic amino acids can also be defined as the mass of the particle divided by the minimum employed. Furthermore, combinations of hydrophobic and Sphere envelope Volume within which it can be enclosed. In hydrophilic (preferentially partitioning in water) amino one embodiment of the invention, the particles have an acids, where the overall combination is hydrophobic, can envelope mass density of less than about 0.4 g/cm. also be employed. Combinations of one or more amino acids Aerodynamically light particles have a preferred size, and one or more phospholipids or Surfactants can also be e.g., a volume median geometric diameter (VMGD) of at employed. Materials which impart fast release kinetics to the least about 5 microns (um). In one embodiment, the VMGD medicament are preferred. is from about 5 um to about 30 um. In another embodiment The amino acid can be present in the particles of the of the invention, 15 the particles have a VMGD ranging invention in an amount of at least 10 weight %. Preferably, from about 10 um to about 30 um. In other embodiments, the the amino acid can be present in the particles in an amount particles have a median diameter, mass median diameter ranging from about 20 to about 80 weight %. The salt of a 15 (MMD), a mass median envelope diameter (MMED) or a hydrophobic amino acid can be present in the particles of the mass median geometric diameter (MMGD) of at least 5um, invention in an amount of at least 10% weight. Preferably, for example from about 5 um and about 30 lum. the amino acid Salt is present in the particles in an amount The diameter of the Spray-dried particles, for example, the ranging from about 20 to about 80 weight %. Methods of VMGD, can be measured using an electrical Zone Sensing forming and delivering particles which include an amino instrument such as a Multisizer IIe, (Coulter Electronic, acid are described in U.S. patent application Ser. No. 09/382, Luton, Beds, England), or a laser diffraction instrument (for 959, filed on Aug. 25, 1999, entitled Use of Simple Amino example Helos, manufactured by Sympatec, Princeton, Acids to Form Porous Particles During Spray Drying, the N.J.). Other instruments for measuring particle diameter are teachings of which are incorporated herein by reference in well know in the art. The diameter of particles in a Sample their entirety and in U.S. Non-Provisional Patent Applica 25 will range depending upon factorS Such as particle compo tion filed on Aug. 23, 2000, titled Use of Simple Amino sition and methods of synthesis. The distribution of size of Acids to Form Porous Particles, under Ser. No. 09/644,320; particles in a Sample can be Selected to permit optimal the teachings of both are incorporated herein by reference in deposition to targeted Sites within the respiratory tract. their entirety. Aerodynamically light particles preferably have “mass In another embodiment of the invention, the particles median aerodynamic diameter” (MMAD), also referred to include a carboxylate moiety, Such as a hydroxydicarboxylic herein as “aerodynamic diameter', between about 1 um and acid or Salt thereof, a hydroxytricarboxylic acid or Salt about 5 um. In another embodiment of the invention, the thereof, and a multivalent metal salt. One or more phospho MMAD is between about 1 um and about 3 tum. In a further lipids also can be included. Such compositions are described embodiment, the MMAD is between about 3 um and about in U.S. Provisional Application No. 60/150,662, filed on 35 5 um. Aug. 25, 1999, entitled Formulation for Spray-Drying Large Experimentally, aerodynamic diameter can be determined Porous Particles, and U.S. Non-Provisional Patent Applica by employing a gravitational Settling method, whereby the tion filed on Aug. 23, 2000, titled Formulation for Spray time for an ensemble of particles to Settle a certain distance Drying Large Porous Particles, under Ser. No. 09/644,105; is used to infer directly the aerodynamic diameter of the the teachings of both are incorporated herein by reference in 40 particles. An indirect method for measuring the mass median their entirety. In a preferred embodiment, the particles aerodynamic diameter (MMAD) is the multi-stage liquid include Sodium citrate and calcium chloride. impinger (MSLI). Other materials, preferably materials which promote fast The aerodynamic diameter, d ge can be calculated from release kinetics of the medicament can also be employed. the equation: For example, biocompatible, and preferably biodegradable 45 polymers can be employed. Particles including Such poly ter dgwpiapi meric materials are described in U.S. Pat. No. 5,874,064, where d is the geometric diameter, for example the MMGD issued on Feb. 23, 1999 to Edwards et al., the teachings of and p is the powder density. which are incorporated herein by reference in their entirety. Particles which have a tap density less than about 0.4 The particles can also include a material Such as, for 50 g/cm, median diameters of at least about 5 um, and an example, dextran, polysaccharides, lactose, trehalose, aerodynamic diameter of between about 1 um and about 5 cyclodextrins, proteins, peptides, polypeptides, fatty acids, tim, preferably between about 1 um and about 3 um, are inorganic compounds, phosphates. more capable of escaping inertial and gravitational deposi In a preferred embodiment, the particles of the invention tion in the oropharyngeal region, and are targeted to the have a tap density less than about 0.4 g/cm. Particles which 55 airways, particularly the deep lung. The use of larger, more have a tap density of less than about 0.4 g/cm are referred porous particles is advantageous Since they are able to herein as “aerodynamically light particles'. More preferred aeroSolize more efficiently than Smaller, denser aeroSol are particles having a tap density less than about 0.1 g/cm. particles Such as those currently used for inhalation thera Tap density can be measured by using instruments known to ple.S. those skilled in the art Such as but not limited to the Dual 60 In comparison to Smaller, relatively denser particles the Platform Microprocessor Controlled Tap Density Tester larger aerodynamically light particles, preferably having a (Vankel, N.C.) or a GeoPyCTM instrument (Micrometrics median diameter of at least about 5 tim, also can potentially Instrument Corp., Norcross, Ga. 30093). Tap density is a more Successfully avoid phagocytic engulfment by alveolar Standard measure of the envelope maSS density. Tap density macrophages and clearance from the lungs, due to Size can be determined using the method of USP Bulk Density 65 exclusion of the particles from the phagocytes cytosolic and Tapped Density, United States Pharmacopeia Space. Phagocytosis of particles by alveolar macrophages convention, Rockville, Md., 10" Supplement, 4950-4951, diminishes precipitously as particle diameter increases US 6,514,482 B1 13 14 beyond about 3 um. Kawaguchi, H., et al., Biomaterials 7: about five microns in diameter, preferably between about 61-66 (1986); Krenis, L.J. and Strauss, B., Proc. Soc. Exp. one and about three microns, which are then Subject to Med., 107: 748-750 (1961); and Rudt, S. and Muller, R. H., phagocytosis. Selection of particles which have a larger J. Contr. Rel, 22: 263-272 (1992). For particles of statisti diameter, but which are Sufficiently light (hence the charac cally isotropic shape, Such as Spheres with rough Surfaces, terization “aerodynamically light”), results in an equivalent the particle envelope Volume is approximately equivalent to delivery to the lungs, but the larger Size particles are not the Volume of cytosolic Space required within a macrophage phagocytosed. Improved delivery can be obtained by using for complete particle phagocytosis. particles with a rough or uneven Surface relative to those The particles may be fabricated with the appropriate with a Smooth Surface. material, Surface roughness, diameter and tap density for In another embodiment of the invention, the particles localized delivery to Selected regions of the respiratory tract have an envelope mass density, also referred to herein as Such as the deep lung or upper or central airways. For “mass density” of less than about 0.4 g/cm. Particles also example, higher density or larger particles may be used for having a mean diameter of between about 5 um and about 30 upper airway delivery, or a mixture of varying sized particles tum are preferred. Mass density and the relationship between in a Sample, provided with the same or different therapeutic 15 mass density, mean diameter and aerodynamic diameter are agent may be administered to target different regions of the discussed in U.S. application Ser. No. 08/655,570, filed on lung in one administration. Particles having an aerodynamic May 24, 1996, which is incorporated herein by reference in diameter ranging from about 3 to about 5 um are preferred its entirety. In a preferred embodiment, the aerodynamic for delivery to the central and upper airways. Particles diameter of particles having a mass density less than about having and aerodynamic diameter ranging from about 1 to 0.4 g/cm and a mean diameter of between about 5 um and about 3 um are preferred for delivery to the deep lung. about 30 um mass mean aerodynamic diameter is between Inertial impaction and gravitational Settling of aerosols about 1 um and about 5 um. are predominant deposition mechanisms in the airways and Suitable particles can be fabricated or Separated, for acini of the lungs during normal breathing conditions. example by filtration or centrifugation, to provide a particle Edwards, D. A., J. Aerosol Sci., 26: 293–317 (1995). The 25 Sample with a preselected Size distribution. For example, importance of both deposition mechanisms increases in greater than about 30%, 50%, 70%, or 80% of the particles proportion to the mass of aerosols and not to particle (or in a Sample can have a diameter within a Selected range of envelope) volume. Since the site of aerosol deposition in the at least about 5 um. The Selected range within which a lungs is determined by the mass of the aerosol (at least for certain percentage of the particles must fall may be for particles of mean aerodynamic diameter greater than example, between about 5 and about 30 um, or optimally approximately 1 um), diminishing the tap density by between about 5 and about 15 lum. In one preferred increasing particle Surface irregularities and particle poros embodiment, at least a portion of the particles have a ity permits the delivery of larger particle envelope Volumes diameter between about 9 and about 11 lim. Optionally, the into the lungs, all other physical parameters being equal. particle Sample also can be fabricated wherein at least about The low tap density particles have a Small aerodynamic 35 90%, or optionally about 95% or about 99%, have a diameter diameter in comparison to the actual envelope sphere diam within the Selected range. The presence of the higher pro eter. The aerodynamic diameter, daer, is related to the portion of the aerodynamically light, larger diameter par envelope sphere diameter, d (Gonda, I., “Physico-chemical ticles in the particle Sample enhances the delivery of thera principles in aerosol delivery,” in Topics in Pharmaceutical peutic or diagnostic agents incorporated therein to the deep Sciences 1991 (eds. D. J. A. Crommelin and K. K. Midha), 40 lung. Large diameter particles generally mean particles pp. 95-117, Stuttgart: Medpharm Scientific Publishers, having a median geometric diameter of at least about 5 um. 1992)), by the formula: 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 45 forming a mixture including L-Dopa or another where the envelope mass p is in units of g/cm. Maximal medicament, or a combination thereof, and a Surfactant, Such deposition of monodispersed aeroSol particles in the alveolar as, for example, the Surfactants described above. In a pre region of the human lung (~60%) occurs for an aerodynamic ferred embodiment, the mixture includes a phospholipid, diameter of approximately de 3 um. Heyder, J. et al., J. Such as, for example the phospholipids described above. The AeroSol Sci., 17: 811-825 (1986). Due to their small enve 50 mixture employed in Spray drying can include an organic or lope mass density, the actual diameter d of aerodynamically aqueous-organic Solvent. light particles comprising a monodisperse inhaled powder Suitable organic Solvents that can be employed include that will exhibit maximum deep-lung deposition is: but are not limited to alcohols for example, ethanol, d=3/vpum (where p<1 g/cm); methanol, propanol, isopropanol, butanols, and others. Other 55 organic Solvents include but are not limited to per where d is always greater than 3 um. For example, aerody fluorocarbons, dichloromethane, chloroform, ether, ethyl namically light particles that display an envelope mass acetate, methyl tert-butyl ether and others. density, p=0.1 g/cm, will exhibit a maximum deposition for Co-Solvents include an aqueous Solvent and an organic particles having envelope diameters as large as 9.5 lim. The Solvent, Such as, but not limited to, the organic Solvents as increased particle size diminishes interparticle adhesion 60 described above. Aqueous Solvents include water and buff forces. Visser, J., Powder Technology, 58: 1-10. Thus, large ered Solutions. In one embodiment, an ethanol water Solvent particle size increases efficiency of aeroSolization to the is preferred with the ethanol: water ratio ranging from about deep lung for particles of low envelope mass density, in 50:50 to about 90:10 ethanol: water. addition to contributing to lower phagocytic losses. The Spray drying mixture can have a neutral, acidic or The aerodynamic diameter can be calculated to provide 65 alkaline pH. Optionally, a pH buffer can be added to the for maximum deposition within the lungs. Previously this solvent or co-solvent or to the formed mixture. Preferably, was achieved by the use of very Small particles of less than the pH can range from about 3 to about 10. US 6,514,482 B1 15 16 Suitable Spray-drying techniques are described, for action within a time period which is sufficiently short to example, by K. Masters in “Spray Drying Handbook”, John provide rescue therapy to the patient being treated. In many Wiley & Sons, New York, 1984. Generally, during spray cases, the medicament can reach the central nervous System drying, heat from a hot gas Such as heated air or nitrogen is in less than about 10 minutes. Preferably, the patient's used to evaporate the solvent from droplets formed by Symptoms abate within minutes and generally no later than atomizing a continuous liquid feed. Other spray-drying one hour. In one embodiment of the invention, the release techniques are well known to those skilled in the art. In a kinetics of the medicament are Substantially similar to the preferred embodiment, a rotary atomizer is employed. An drugs kinetics achieved via the intravenous route. In examples of Suitable Spray driers using rotary atomization another embodiment of the invention, the T of the includes the Mobile Minor spray drier, manufactured by medicament in the blood Stream ranges from about 1 to Niro, Denmark. The hot gas can be, for example, air, about 10 minutes. AS used herein, the term T, means the nitrogen or argon. point at which levels reach a maximum concentration. The particles can be fabricated with a rough Surface If desired, particles which have fast release kinetics, texture to reduce particle agglomeration and improve Suitable in rescue therapy, can be combined with particles flowability of the powder. The spray-dried particles have 15 having Sustained release, Suitable in treating the chronic improved aeroSolization properties. The Spray-dried particle aspects of a condition. For example, in the case of Parkin can be fabricated with features which enhance aeroSolization Son's disease, particles designed to provide rescue therapy Via dry powder inhaler devices, and lead to lower deposition can be co-administered with particles having controlled in the mouth, throat and inhaler device. release properties. The particles of the invention can be employed in com The administration of more than one dopamine precursor, positions Suitable for drug delivery to the pulmonary System. agonist or combination thereof, in particular L-Dopa, For example, Such compositions can include the particles carbidopa, apomorphine, and other drugs can be provided, and a pharmaceutically acceptable carrier for administration either Simultaneously or Sequentially in time. These com to a patient, preferably for administration via inhalation. The pounds or compositions can be administered before, after or particles may be administered alone or in any appropriate 25 at the same time. Thus, the term “co-administration' is used pharmaceutically acceptable carrier, Such as a liquid, for herein to mean that the Specific dopamine precursor, agonist example Saline, or a powder, for administration to the or combination thereof and/or other compositions are respiratory System. They can be co-delivered with larger administered at times to treat the episodes, as well as the carrier particles, not including a therapeutic agent, the latter underlying conditions described herein. possessing mass median diameters for example in the range The present invention will be further understood by between about 50 um and about 100 um. reference to the following non-limiting examples. AeroSol dosage, formulations and delivery Systems may Examplifications be selected for a particular therapeutic application, as described, for example, in Gonda, I. “Aerosols for delivery EXAMPLE 1. of therapeutic and diagnostic agents to the respiratory tract,” 35 In Vivo tests were performed to compare oral and tracheal in Critical Reviews in Therapeutic Drug Carrier Systems, 6: administration of L-Dopa in an a rat model. Animals 273-313, 1990; and in Moren, “Aerosol dosage forms and received an IP injection of the peripheral decarboxylase formulations,” in: Aerosols in Medicine. Principles, Diag inhibitor carbidopa (Sigma, St. Louis, Mo.) (200 mg/kg) one nosis and Therapy, Moren, et al., Eds, ESevier, Amsterdam, hour prior to administration of L-Dopa. Under ketamine 1985. 40 anesthesia, the animals were divided into two groups. In the The method of the invention includes administering to the first group of animals (N=4), L-Dopa (8 mg) was Suspended pulmonary System an effective amount of a medicament in Saline containing 2% methylcellulose and given via oral Such as, for example, a medicament described above. AS gavage. In the Second group (N=5) a Small tracheotomy was used herein, the term “effective amount’ means the amount performed to permit placement of a pipette tip with a needed to achieve the desired effect or efficacy. The actual 45 modified 2 mm opening through the trachea and into the effective amounts of drug can vary according to the Specific lungs. The pipette tip was pre-loaded with powdered L-Dopa drug or combination thereof being utilized, the particular (8 mg) and was interfaced with an oxygen tank using composition formulated, the mode of administration, and the Silicone tubing. Coinciding with the respiratory cycle of the age, weight, condition of the patient, and Severity of the animal, L-Dopa was pushed into the lungs using a burst of episode being treated. In rescue therapy, the effective 50 oxygen (5 liters/minute). Blood samples (200 ul) were amount refers to the amount needed to achieve abatement of withdrawn from a previously placed femoral cannula at the Symptoms or cessation of the episode. In the case of a following time points: 0 (immediately prior to L-Dopa dopamine precursor, agonist or combination thereof it is an administration), 1, 5, 15, 30, 45 and 60 minutes following amount which reduces the Parkinson's symptoms which L-Dopa administration. require rescue therapy. Dosages for a particular patient are 55 Blood levels of L-Dopa, measured, respectively, by mass described herein and can be determined by one of ordinary spectrometry or HPLC, following administration via oral skill in the art using conventional considerations, (e.g. by gavage or direct administration into the lungs are shown in means of an appropriate, conventional pharmacological FIGS. 1A and 1B. The increase in blood levels of L-Dopa protocol). For example, effective amounts of L-Dopa range over time following oral administration was modest. In from about 50 to about 500 mg. 60 contrast, administration into the lungs produced a robust and Rapid delivery to the medicament's site of action also is rapid rise in L-Dopa levels which peaked between 1 and 5 preferred. Preferably, the effective amount is delivered on minutes post drug administration. L-Dopa levels in this the “first pass” of the blood to the site of action. The “first group decreased between 5 and 15 minutes and remained pass” is the first time the blood carries the drug to and within stable thereafter. Data are presented as the meant-SEM ng the target organ from the point at which the drug passes from 65 L-Dopa level/ml blood. the lung to the vascular System. Generally, the medicament Relationship between blood L-Dopa levels and striatal is released in the blood stream and delivered to its site of dopamine levels following delivery of L-Dopa either orally US 6,514,482 B1 17 18 or directly into the lungs, as described above, are shown in volume of 1 ml and 100 strokes/minutes. Blood samples FIGS. 2A and 2B. FIG. 2A shows blood L-Dopa levels were taken at 10 minutes post drug administration dopa immediately prior to L-Dopa (baseline) and at 2, 15 and 45 (N=6 per time point for each group). Brains were removed minutes following L-Dopa (N=4-6 per time point for each and dissected into various regions including the olfactory, group). Once again, the levels following administration into frontal, and occipital cortices, the hippocampus, striatum, the lungs show a robust and rapid increase in L-Dopa levels, and cerebellum. Peripheral organs included the kidneyS, relative to the modest increases following oral administra Spleen, heart, testes, and muscle. All Samples were then tion. processed for determininations of ''C levels using Scintilla FIG. 2B shows dopamine levels in the striatum from the tion. same animals shown in FIG. 2A. Immediately following 1O Results are shown in Table 1 and in FIGS. 6A-6B and withdrawal of the blood sample, the brains were removed 7A-7B. Absolute plasma levels of "C were higher follow and striatum dissected free. Tissue levels of dopamine were ing IV administration. However, the absolute brain levels determined using high performance liquid chromatography were comparable Suggesting that delivery to the brain at this (HPLC). Note that the marked difference in blood L-Dopa time point was relatively Selective. This point is clearer levels Seen between the two treatments at two minutes was 15 when the ratio of brain to blood 'C levels was calculated. followed, later in time, by more modest but significant Following pulmonary delivery, ''C levels were 2833% differences in striatal levels of dopamine. Blood levels are higher than observed following IV administration. Absolute presented as the meant-SEM ng L-Dopa levels/ml blood. levels of "C in peripheral tissue was also lower following Striatal levels of dopamine are presented as the meant-SEM pulmonary administration (92% lower relative to IV). In ng dopamine/mg protein. contrast to the large differences in Selectivity Seen in the Blood and striatal levels of "C following administration brain, the relative peripheral selectivity (derived from divid of "C-L-Dopa as generally described above were also ing the levels of radioactivity in peripheral organs by that in determined and are shown in FIG. 3. A total of 25 uCi of the blood) was only 47% higher in the pulmonary group. radiolabeled L-Dopa was mixed with unlabelled L-Dopa to Interestingly though, the highest levels of ''C in peripheral provide a total drug concentration of 8 mg/rat. Blood 25 tissue were found in the heart. Together, these data Suggest Samples were taken at 2, 5 and 15 minutes post drug that the brain and the heart may represent Sites of preferen administration L-Dopa (N=6 per time point for each group). tial delivery at time point immediately following pulmonary At 5 or 15 minutes post L-Dopa, the striatum was removed drug administration. and both the blood and tissues samples were assayed for 'C levels using Scintillation. The Zero minute plasma values are TABLE 1. deduced from other many Studies using radioactive agents. Scintillation Counts of "C-Levels in Plasma, Brain and Peripheral Once again, a robust and rapid increase in plasma levels Qrgans Following "C-Carboplatin (100 uCi/8 mg) Administration was achieved via the pulmonary route, which was reflected in increased dopamine activity in the brain at both the 5 1O minute and 15 minute time points (relative to oral 35 Minutes administration). Plasma Levels IV 994.348 Lung (n = 6) Direct comparison of plasma “C following administra (%. Difference) 102.215 tion of "C-L-Dopa via oral gavage, inhalation using a -89.72% tracheotomy (as described above) or ventilator (Harvard 40 (n = 6) Absolute Brain IV 29.47 Apparatus, Inc., Holliston, Mass.) is shown in FIG. 4. Levels Lung 27.29 Corresponding brain 'C-L-Dopa levels are shown in FIG. (nGi?gram) 5. All animals were briefly anesthetized using 1% Isoflurane Relative Brain IV O.O3 and immobilized in a harness to allow blood removal via a Selectivity Lung O.88 previously placed femoral cannula. Blood Samples were (Brain/Blood) (%. Difference) +2833% 45 (Brain/Blood) IV(Br/Bl)/Lung(Br/BI) removed at 0, 2, 5, and 15 minutes post administration. For (Brain/Blood) L-Dopa administration using the ventilator, a 24 gauge Absolute Tissue IV O.O3 catheter was placed within the trachea and the L-Dopa (25 Levels Lung O.88 (Peripheral Organs) (%. Difference) +2833% puCi) was administered over a 3–5 second period using a tidal *excludes kidney IV(Br/Bl)/Lung(Br/BI) volume of 1 ml and 100 strokes/minutes. Striatal tissue 50 Relative IV 0.44 Samples were processed for determinations of levels of Peripheral Lung O.65 radioactivity using Scintillation counts. Both the plasma and Selectivity (%. Difference) +47.727% brain levels of ''C were comparably elevated using both the (Peripheral/Blood) IV(Per/Bl)/Lung(Per/BI) conventional tracheotomy methods and the ventilator. *excludes kidney 55 EXAMPLE 2 Blood, brain and peripheral organ levels of ''C were EXAMPLE 3 determined following administration of "C-Carboplatin via Particles comprising L-Dopa and Suitable for inhalation either IV or pulmonary administration. A total of 100 uCi of were produced as follows. 2.00123 g DPPC (Avanti Polar radiolabeled carboplatin was mixed with unlabelled carbo 60 Lipids, Lot #G160PC-25) was added to 2.80 L of ethanol platin to provide a total drug concentration of 8 mg/rat. All and stirred to dissolve. 0.0817 g L-Dopa (Spectrum, Lot animals were anesthetized using ketamine. For IV 0Q0128, Laguna Hills, Calif.), 0.9135 g Sodium Citrate administration, carboplatin was administered via a previ (Dehydrate) (Spectrum Lot NXO195), and 0.5283 g Calcium ously placed femoral cannula. For pulmonary Chloride (Dehydrate) (Spectrum Lot NT0183) were added administration, a 24 gauge catheter was placed within the 65 to 1.2 L of water and dissolved. The Solutions were com trachea and the carboplatin was administered using a Har bined by adding the water solution to the ethanol solution vard ventilator over a 3–5 Second period using a tidal and then the Solutions were allowed to stir until the Solution US 6,514,482 B1 19 20 was clear. The weight percent of the formulation was factors as the gas and liquid feed rates: it varied between 50 approximately: 20% L-Dopa, 50% DPPC, 20% Sodium C. And 130 C. A container was tightly attached to the 6" Citrate, 10% Calcium Chloride. cyclone for collecting the powder product. The Spraying The final Solution was then spray dried in a Niro dryer conditions for each solution is given in Table 3, which shows (Niro, Inc., Columbus, Md.) using a rotary atomizer and that the Spraying conditions were held nearly constant nitrogen drying gas following the direction of the throughout the study. The total recovery and yield for each manufacturer, using the following spray conditions: T= Solution is given in Table 4. 120 C, T=54C, Feed Rate=65 ml/min, Heat Nitrogen= The particles were characterized using the Aerosizer (TSI, 38 mm H20, Atomizer Speed=20,000 rpm (V24 atomizer Inc., Amherst, Mass.) and the RODOS dry powder dispenser used). (Sympatec Inc., Princeton, N.J.) as instructed by the manu The resulting particle characteristics were: Mass Median facturer. For the RODOS, the geometric diameter was Aerodynamic Diameter (MMAD)=2.141 um and Volume measured at 2 bars. The material from run #5 was also Median Geometric Diameter (VMGD)= 10.51 um. characterized using a gravimetric collapsed Andersen Cas Under etamine anesthesia, Six rats received pulmonary cade Impactor (ACI, 2 stage, Anderson Inst., Sunyra, Ga.). administration of the formulation described above (20/50/ 15 The Samples were examined using a Scanning electron 20/10 L-Dopa/DPPC/Sodium Citrate/Calcium Chloride). microscope (SEM). The results are shown in FIG.8. This figure shows blood Table 4 indicates that increasing the weight % of keto levels of L-Dopa following administration via oral gavage or profen led to a decrease in yield. The addition of ketoprofen direct administration into the lungs via insufflation. L-Dopa to the Stock Solution linearly decreased yield. This may be levels were measured using both HPLC. Animals received due to a decrease in melting temperature for DPPC when an IP injection of the peripheral decarboxylase inhibitor mixed with ketoprofen, leading to the yield loSS. carbi-dopa (200 mg/kg) 1 hour prior to administration of L-Dopa. Under ketamine anesthesia, the animals were Table 5 shows that the particles ranged in diameter from divided into 2 groups. In the first group, animals were fasted 8.8 to 10.2 mm (VMGD) and from 2.65 to 3.11 (MMAD). overnight and L-Dopa (8 mg) was Suspended in Saline 25 The lowest MMAD particles were for the 8.4% loading contained 1% methylcellulose and given via oral gavage. In material (run #5). the Second group, insufflation was used to delivery the Table 6 shows the results of a Andersen Collapsed Impac L-Dopa formulation directly into the lungs. Blood Samples tor study (ACI, gravimetric, n=2) of the material from run (200ul) were withdrawn from a previously placed femoral #5, the 8.4% loading material. The FPF below 5.6 um and cannula at the following time points: 0 (immediately prior to below 3.4 um are consistent with respirable powders which L-Dopa administration), 2, 5, 15, and 30 minutes following are reasonably respirable. L-Dopa administration. The increase in blood levels of L-Dopa Over time following oral administration was modest. TABLE 2 In contrast, administration into the lungs produced a robust 35 Total and rapid rise in L-Dopa levels. L-Dopa levels in this group Sample Ketoprofen solids % remained elevated relative to oral delivery at 30 minutes ID added (mg) (g/L) Ketoprofen post drug administration. Data were normalized to a dose of Run #1 O 1.OOO O 8 mg/kg (the total oral gavage dose). Data are presented as Run #2 8.0 1.016 1.6 the meant-SEM ng 1-Dopa levels/ml blood. 40 Run #3 15.1 1.030 3.0 Run #4 30.1 1.060 5.7 EXAMPLE 4 Run #5 46.0 1.092 8.4 Ketoprofen/DPPC/maltodextrin particles were prepared Run #6 63.0 1.126 11.2 and administered in Vivo. Ketoprofen (99.5%) was obtained from Sigma, (St. Louis, 45 Mo.), dipalmitoyl phosphatidylcholine (DPPC) from Avanti TABLE 3 Polar Lipids, (Alabaster, Ala.) and maltodextrin.M100 Inlet (Grain Processing Corp., Muscatine, Iowa). Temperature Liquid Gas Rotor Dew To prepare ketoprofin/DPPC/Maltodextrin solutions, mal Sample o C. Feed Pressure Speed point todextrin (0.598 g) was added to 0.60 L USP water. DPPC 50 (0.901 g) was added to 1.40 L ethanol and stirred until ID Inlet Outlet (ml/min) (mm H2O) (RPM) ( C.) dissolved. The water and ethanol Solutions were combined, Run #1 115 36 75 40 18,600 -27.0 resulting in a cloudy solution. 500 ml of this stock solution Run #2 113 38 85 40 18,400 -26.8 was used for each run. The addition of ketoprofen to the Run #3 110 38 85 39 18,300 -26.4 Run #4 110 39 85 38 18,400 -25.9 55 DPPC/Maltodextrin stock Solution is described in Table 2. Run #5 110 38 86 39 18,400 -25.4 A Niro Atomizer Portable Spray Dryer (Niro, Inc., Run #6 110 38 85 38 18,400 -25.0 Columbus, Md.) was used to produce the dry powders. Compressed air with variable pressure (1 to 5 bar) ran a rotary atomizer (2,000 to 30,000 rpm) located above the dryer. Liquid feed of the ketoprofin/DPPC/Maltodextrin 60 TABLE 4 Solutions, with varying rate (20 to 66 ml/min), was pumped Sample Weight Theoretical Yield Actual Yield continuously by an electronic metering pump (LMI, model ID Collected (mg) (mg) (%. Theoretical) #A151-192s) to the atomizer. Both the inlet and outlet Run #1 86 500 37.2 temperatures were measured. The inlet temperature was Run #2 195 508 38.4 controlled manually; it could be varied between 100° C. and 65 Run #3 47 515 28.5 400° C., with a limit of control of 5° C. The outlet tem Run #4 127 530 24.O perature was determined by the inlet temperature and Such US 6,514,482 B1 22 At t=0, all rats showed ketoprofen levels below the TABLE 4-continued detection limit for the assay. From t=5 minto t=60 min, the insulflated rats had significantly higher plasma levels of Sample Weight Theoretical Yield Actual Yield ketoprofen. At t=120 min and t=240 min, the plasma levels ID Collected (mg) (mg) (%. Theoretical) of ketoprofen of the two groups were Statistically equivalent. Run #5 89 546 16.3 At t=360 min and t=480, the plasma levels of ketoprofen for Run #6 67 563 11.9 both groupS approached the detection limit for the assay. The ratio of the AUCs for insulflated rats vs. orally dosed was about 2. Since the plasma concentrations for ketoprofen at the early time points were Statistically significant as well. TABLE 5 1O C for the insulflated rats clearly occurred <15 min and C for the orally dosed rats occurred between 15-60 min. Sample MGVD (um, Due to the large Standard error and the relatively low plasma ID MMAD (um) Std Dev 2 bar) levels for this group, it is not possible to accurately deter Run #1 3.11 1.48 9.O mine the time required for C. Run #2 3.01 1.37 9.3 15 Run #3 2.83 140 10.3 Pulmonary administration resulted in C, occurring very Run #4 2.84 1.41 10.4 quickly (<15 min) compared to oral dosing (t=15 to 60 min). Run #5 2.65 1.39 9.8 The insulflated rats showed higher bioavailability com Run #6 2.83 1.38 8.8 pared to the orally dosed rats. This is unexpected as previous Studies have shown ketoprofen to have consistently high (>90%) bioavailability in humans when dosed orally, Sub TABLE 6 cutaneously or rectally. Since the pharmokinetic behavior of ketoprofen delivered orally is well-known, the anomalous Stage O 1.33 mg Stage 2 2.75 mg results seen here for the orally dosed group do not invalidate Stage F 3.17 mg 25 the results Seen for the insufflation group. Capsule Fill 12.37 mg Weight < 5.6 um 5.92 TABLE 7 FPFs, O.479 Weight < 3.4 um 3.17 Oral Dosing FPF. O.256 Dosing Group Pulmonary Group Time Avg. St. AVg. Std. P Min. (ug/ml) Dew. (ug/ml) Dew. Value 350 mg of 8% ketoprofen in 60/40 DPPC/maltodextrin were produced as described above and administered to 20 Sprague O 1.O N/A 1.O N/A 5 1.7 0.75 9.6 1.27 O.OOO3 Dawley rats. Each of 8 rats were given 7 mg of powder via 15 2.1 O.76 7.6 O.28 OOOOO insufflation, and each of 7 rats were given 7 mg of powder 3O 1.9 O.12 5.5 O.76 O.OO12 dissolved in 50% ethanol orally. Time points were set at 0, 35 60 2.O O.13 4.5 O.60 O.OOO2 5, 15, 30, 60, 120, 240, 360 and 480 minutes. For t=0, 4 12O 1.7 O.31 2.4 0.44 O.O929 animals were tested without dosing. For each time point 240 1.4 O.OS 1.8 O.63 O.2554 after, Samples were taken from either 3 or 4 rats. Each rat 360 1.O O.O6 1.8 O.35 O.O224 was used for 4 time points, with 3 or 4 animals each in four 48O 1.O O.OO 1.3 O.47 O.2174 groups. The animals were distributed as follows: 3 animals 40 oral 5, 30, 120,360; 4 animals insufflation 15, 60,240, 480. While this invention has been particularly shown and Sufficient blood was drawn at each time point for the described with references to preferred embodiments thereof, ketoprofen plasma assay. Blood Samples were centrifuged, it will be understood by those skilled in the art that various the plasma collected and then frozen at -20° C. prior to changes in form and details may be made therein without Shipment to the contract laboratory for analysis. The assay departing from the Scope of the invention encompassed by used in this study has a lower detection limit of 1.0 mg/ml. 45 Rats were dosed with ketoprofen via either oral or pull the appended claims. monary administration to determine if the pulmonary route What is claimed is: would alter the time required to achieve maximum plasma 1. A method of providing rescue therapy in the treatment concentration. The results show that the pulmonary delivery of Parkinson's disease comprising: route leads to a very rapid uptake with C. occurring at 50 administering to the respiratory tract of a patient in need s 10 minutes. The rats that received oral doses of ketoprofen of rescue therapy particles comprising an effective displayed Somewhat anomalous pharmacokinetic behavior, amount of a dopamine precursor, a dopamine agonist or with the relative bioavailability being about half of that any combination thereof, displayed for rats dosed via the pulmonary route. This result wherein the particles are delivered to the pulmonary was unexpected as ketoprofen is 90% orally bioavailable in 55 System and the dopamine precursor, the dopamine the human model. This anomaly for the orally dosed rats agonist or the combination thereof is released in the does not, however, invalidate the Significance of the early blood Stream of the patient and reaches the central C. Seen for the rats dosed via the pulmonary route. nervous System to provide Said rescue therapy. The results are provided in Table 7. The averages were 2. The method of claim 1 wherein the particles comprise calculated along with the Standard errors and p values. The 60 levodopa. results are also presented graphically in FIGS. 9-11, wherein 3. The method of claim 2 wherein the levodopa is present FIG. 9 shows both data sets, FIG. 10 gives the oral dosing in the particles in an amount ranging from about 1 to about results and FIG. 11 shows the insufflation results. For FIG. 90 weight percent. 9, points with p-0.05 are marked with “*” and points with 4. The method of claim 2 wherein the particles further p-0.01 are marked with “**'. For FIGS. 10 and 11, AUC 65 comprise carbidopa. (area under the curve) was performed via numerical inte 5. The method of claim 1 wherein the particles comprise gration of the curve with Smooth interpolation. apomorphine. US 6,514,482 B1 23 24 6. The method of claim 1 wherein the particles further 27. The particles of claim 23 wherein the particles com comprise a material Selected from the group consisting of a prise apomorphine. phospholipid or combination of phospholipids, an amino 28. The particles of claim 23 wherein the particles com acid, a hydroxydicarboxylic acid, a hydroxytricarboxylic prise a phospholipid or combination of phospholipids. acid, a Salt of any of Said acids, a multivalent metal Salt and 29. The particles of claim 28 wherein the phospholipid or any combination thereof. combination of phospholipids is present in the particles in an 7. The method of claim 6 wherein the particles comprise amount ranging from about 10 weight percent to about 99 a phospholipid or combination of phospholipids. weight percent. 8. The method of claim 7 wherein the phospholipid or combination of phospholipids is present in the particles in an 30. The particles of claim 28 wherein the particles have a amount ranging from about 10 weight percent to about 99 matrix transition temperature that is no higher than the weight percent. patient's physiological temperature. 9. The method of claim 1 wherein the particles have a 31. The particles of claim 23 wherein the particles com matrix transition temperature that is no higher than the prise a hydroxydicarboxylic acid, a hydroxytricarboxylic patient's physiological temperature. 15 acid, or any Salt of Said acids. 10. The method of claim 6 wherein the particles comprise 32. The particles of claim 31 wherein the particles com a hydroxydicarboxylic acid, a hydroxytricarboxylic acid or prise citrate. a Salt of any of Said acids. 33. The particles of claim 31 wherein the particles further 11. The method of claim 10 wherein the particles com comprise a multivalent metal Salt. prise citrate. 34. The particles of claim 33 wherein the multivalent 12. The method of claim 10 wherein the particles further metal Salt is calcium chloride. comprise a multivalent metal Salt. 35. The particles of claim 23 wherein the material is 13. The method of claim 12 wherein the multivalent metal present in the particles in an amount of at least 10 weight Salt is calcium chloride. percent. 14. The method of claim 9 wherein the material is present 25 36. The particles of claim 23 wherein the particles have a in the particles in an amount of at least 10 weight percent. tap density less than about 0.4 g/cm. 15. The method of claim 1 wherein the particles have a tap 37. The particles of claim 36 wherein the particles have a density less than about 0.4 g/cm. tap density less than about 0.1 g/cm. 16. The method of claim 15 the particles have a tap 38. The particles of claim 23 wherein the particles have a density less than about 0.1 g/cm. Volume median geometric diameter of between about 5 17. The method of claim 1 wherein the particles have a micrometers and about 30 micrometers. Volume median geometric diameter of between about 5 39. The particles of claim 23 wherein the particles have an micrometers and about 30 micrometers. aerodynamic diameter of between about 1 and about 5 18. The method of claim 1 wherein the particles have an microns. aerodynamic diameter of between about 1 and about 5 35 40. The particles of claim 39 wherein the particles have an microns. aerodynamic diameter of between about 1 and about 3 19. The method of claim 18 wherein the particles have an microns. aerodynamic diameter of between about 1 and about 3 41. Particles suitable for delivery to the pulmonary system microns. comprising: 20. The method of claim 1 wherein delivery to the 40 a dopamine precursor, a dopamine agonist or any com pulmonary System is by means of a dry powder inhaler. bination thereof; 21. The method of claim 1 wherein delivery to the a phospholipid or combination of phospholipids, and pulmonary System is by means of a metered dose inhaler. a material Selected from the group consisting of an amino 22. The method of claim 1 wherein the patient is suffering acid, a hydroxydicarboxylic acid, a hydroxytricarboxy with late Stage Parkinson's disease. 45 lic acid, a Salt of any of Said acids, a multivalent metal 23. Particles suitable for delivery to the pulmonary system Salt and any combination thereof. comprising a dopamine precursor, a dopamine agonist or 42. Particles suitable for delivery to the pulmonary system any combination thereof and a material Selected from the comprising: group consisting of a phospholipid or combination of phospholipids, an amino acid, a hydroxydicarboxylic acid, a 50 a dopamine precursor, a dopamine agonist or any com hydroxytricarboxylic acid, a Salt of any of Said acids, a bination thereof; multivalent metal Salt and any combination thereof. a Saccharide; and 24. The particles of claim 23 wherein the particles com a material Selected from the group consisting of a phos prise levodopa. pholipid or combination of phospholipids, an amino 25. The particles of claim 24 wherein the levodopa is 55 acid, a hydroxydicarboxylic acid, a hydroxytricarboxy present in the particles in an amount ranging from about 1 lic acid, a Salt of any of Said acids, a multivalent metal to about 90 weight percent. Salt and any combination thereof. 26. The particles of claim 24 wherein the particles further comprise carbidopa. k k k k k UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION

PATENT NO. : 6,514,482 B1 Page 1 of 1 DATED : February 4, 2003 INVENTOR(S) : Raymond T. Bartus and Dwaine F. Emerich

It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

Column 23 Line 13, delete “1” and insert -- 7 --, Line 29, after “15” insert -- wherein --.

Signed and Sealed this Tenth Day of June, 2003

JAMES E ROGAN Director of the United States Patent and Trademark Office