Pulmonary delivery in treating disorders of the central nervous system   

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.

This application is a continuation of U.S. application Ser. No. 12/166,704, filed Jul. 2, 2008 which is a continuation of U.S. application Ser. No. 10/895,577, filed Jul. 21, 2004, now abandoned, which is a continuation of U.S. application Ser. No. 10/762,200, filed Jan. 21, 2004, now abandoned, which is a continuation of U.S. application Ser. No. 10/441,968, filed May 20, 2003, now U.S. Pat. No. 6,979,437, which is a continuation of U.S. application Ser. No. 09/877,734, filed Jun. 8, 2011, now U.S. Pat. No. 6,613,308, which is a continuation-in-part of U.S. application Ser. No. 09/665,252, filed on Sep. 19, 2000, now U.S. Pat. No. 6,514,482. The entire teachings of the above applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Parkinson\'s disease is characterized neuropathologically by degeneration of dopamine neurons in the basal ganglia and neurologically by debilitating tremors, slowness of movement and balance problems. It is estimated that over one million people suffer from Parkinson\'s disease. Nearly all patients receive the dopamine precursor levodopa or L-Dopa, often in conjunction with the dopa-decarboxylase inhibitor, carbidopa. L-Dopa adequately controls symptoms of Parkinson\'s disease in the early stages of the disease. However, it tends to become less effective after a period which can vary from several months to several years in the course of the disease.

It is believed that the varying effects of L-Dopa in Parkinson\'s disease patients is related, at least in part, to the plasma half life of L-Dopa which tends to be very short, in the range of 1 to 3 hours, even when co-administered with carbidopa. In the early stages of the disease, this factor is mitigated by the dopamine storage capacity of the targeted striatal neurons. L-Dopa is taken up and stored by the neurons and is released over time. However, as the disease progresses, dopaminergic neurons degenerate, resulting in decreased dopamine storage capacity. Accordingly, the positive effects of L-Dopa become increasingly related to fluctuations of plasma levels of L-Dopa. In addition, patients tend to develop problems involving gastric emptying and poor intestinal uptake of L-Dopa. Patients exhibit increasingly marked swings in Parkinson\'s disease symptoms, ranging from a return to classic Parkinson\'s disease symptoms, when plasma levels fall, to the so-called dyskinesis, when plasma levels temporarily rise too high following L-Dopa administration.

As the disease progresses, conventional L-Dopa therapy involves increasingly frequent, but lower dosing schedules. Many patients, for example, receive L-Dopa every two to three hours. It is found, however, that even frequent doses of L-Dopa are inadequate in controlling Parkinson\'s disease symptoms. In addition, they inconvenience the patient and often result in non-compliance.

It is also found that even with as many as six to ten L-Dopa doses a day, plasma L-Dopa levels can still fall dangerously low, and the patient can experience very severe Parkinson\'s disease symptoms. When this happens, additional L-Dopa is administered as intervention therapy to rapidly increase brain dopamine activity. However, orally administered therapy is associated with an onset period of about 30 to 45 minutes during which the patient suffers unnecessarily. In addition, the combined effects of the intervention therapy, with the regularly scheduled dose can lead to overdosing, which can require hospitalization. For example, subcutaneously administered dopamine receptor agonist (apomorphine), often requiring a peripherally acting dopamine antagonist, for example, domperidone, to control dopamine-induced nausea, is inconvenient and invasive.

Other medical indications involving the central nervous system (CNS) require rapid delivery of a medicament such as but not limited to epilepsy, panic attacks and migraines. For example, about 2 million people in the USA suffer from some form of epilepsy, with the majority receiving at least one of several different anti-seizure medications. The incidence of status epilepticus (the more serious form of epilepsy) is approximately 250,000. A significant number of patients also suffer from so-called “cluster seizures”, wherein an initial seizure forewarns that a series of additional seizures will occur within a relatively short time frame. By some reports, 75% of all patients continue to experience seizures despite taking medication chronically. Poor compliance with the prescribed medications is believed to be a significant (albeit not sole) contributing factor. The importance of controlling or minimizing the frequency and intensity of seizures lies in the fact that incidence of seizures has been correlated with neuronal deficits and is believed to cause loss of neurons in the brain.

Despite chronic treatment, as many as 75% of all patients continue to exhibit periodic seizures. The uncontrolled seizures occur in many forms. In the case of “cluster seizures,” one seizure serves notice that a cascade has begun which will lead to a series of seizures before the total episode passes. In certain patients, prior to the onset of a severe seizure, some subjective feeling or sign is detected by the patient (defined as an aura). In both instances, an opportunity exists for these patients to significantly reduce the liability of the seizure through “self medication”. While many patients are instructed to do so, the drugs currently available to permit effective self medication are limited.

Panic attacks purportedly affect at least about 2.5 million people in this country alone. The disorder is characterized by acute episodes of anxiety, leading to difficult breathing, dizziness, heart palpitations and fear of losing control. The disorder is believed to involve a problem with the sympathetic nervous system (involving an exaggerated arousal response, leading to overstimulation of adrenaline release and/or adrenergic neurons). Current pharmacotherapy combines selective serotonin re-uptake inhibitors (SSRIs), or other antidepressant medications, with the concomitant use of benzodiazapines.

A limitation of the pharmacotherapies in current use is the delay in the onset of efficacy at the beginning of treatment. Like treatments for depression, the onset of action of the SSRIs requires weeks rather than days. The resulting requirement for continuous prophylactic treatment can, in turn, lead to significant compliance problems rendering the treatment less effective. Therefore, there is a need for rapid onset therapy at the beginning of treatment to manage the anticipation of the panic attacks, as well as a treatment for aborting any attacks as soon as possible after their occurrence.

A pure vasogenic etiology/pathogenesis for migraine was first proposed in the 1930s; by the 1980s, this was replaced by a neurogenic etiology/pathogenesis, which temporarily won favor among migraine investigators. However, it is now generally recognized that both vasogenic and neurogenic components are involved, interacting as a positive feedback system, with each continuously triggering the other. The major neurotransmitters implicated include serotonin (the site of action of the triptans), substance P (traditionally associated with mediating pain), histamine (traditionally associated with inflammation) and dopamine. The major pathology associated with migraine attacks include an inflammation of the dura, an increase in diameter of meningeal vessels and supersensitivity of the trigeminal cranial nerve, including the branches that enervate the meningeal vessels. The triptans are believed to be effective because they affect both the neural and vascular components of the migraine pathogenic cascade. Migraines include Classic and Common Migraines, Cluster Headaches and Tension Headaches.

Initial studies with sumatriptain showed that, when administered intravenously (IV), a 90% efficacy rate was achieved. However, the efficiency rate is only approximately 60% with the oral form (versus 30% for placebo). The nasal form has proven to be highly variable, requiring training and skill on the part of the patient, which some of the patients do not seem to master. The treatment also induces a bad taste in the mouth which many patients find highly objectionable. There currently exists no clear evidence that any of the recent, more selective 5HT1 receptor agonists are any more efficacious than sumatriptan (which stimulates multiple receptor subtypes; e.g., 1B, 1D, and 1F).

In addition to not providing adequate efficacy, current dosing of triptans have at least two other deficiencies: (1) vasoconstriction of chest and heart muscles, which produces chest tightness and pain in some subjects; this effect also presents an unacceptable risk to hypertensive and other CV patients, for whom the triptans are contraindicated, and (2) the duration of action of current formulations is limited, causing a return of headache in many patients about 4 hours after initial treatment.

Rapid onset of a hypnotic would also be quite desirable and particularly useful in sleep restoration therapy, as middle of night awakening and difficulty in falling asleep again, once awakened, is common in middle aged and aging adults.

Other indications related to the CNS, such as, for example, mania, bipolar disorders, schizophrenia, appetite suppression, motion sickness, nausea and others, as known in the art, also require rapid delivery of a medicament to its site of action.

Therefore, a need exists for methods of delivery of medicaments which are at least as effective as conventional therapies yet minimize or eliminate the above-mentioned problems.

SUMMARY

The invention relates to methods of treating disorders of the central nervous system (CNS). More specifically the invention relates to methods of delivering a drug suitable in treating a disorder of the CNS to the pulmonary system and include administering to the respiratory tract of a patient in need of treatment particles comprising an effective amount of the medicament. In one embodiment, the patient is in need of rapid onset of the treatment, for instance in need of rescue therapy; the medicament is released into the patient\'s blood stream and reaches the medicament\'s site of action in a time interval which is sufficiently short to provide the rescue therapy or rapid treatment onset. In another embodiment, the invention is related to providing ongoing, non-rescue therapy to a patient suffering with a disorder of the CNS.

Disorders of the nervous system include, for example, Parkinson\'s disease, epileptic and other seizures, panic attacks, sleep disorders, migraines, attention deficit hyperactivity disorders, Alzheimer\'s disease, bipolar disorders, obsessive compulsive disorders and others.

The methods of the invention are particularly useful in the ongoing treatment and for rescue therapy in the course of Parkinson\'s disease. The drug or medicament employed in the methods of the invention is a dopamine precursor or a dopamine agonist, for example, levodopa (L-DOPA).

In one embodiment, the invention is related to a method for treating Parkinson\'s disease includes administering to the respiratory tract of a patient in need of treatment or rescue therapy a drug for treating Parkinson\'s disease, e.g., L-Dopa. The drug is delivered to the pulmonary system, for instance to the alveoli region of the lung. In comparison to oral administration, at least about a two fold dose reduction is employed. Doses generally are between about two times and about ten times less than the dose required with oral administration.

In other embodiments, a method for treating a disorder of the CNS includes administering to the respiratory tract of a patient in need of treatment a drug for treating the disorder. The drug is administered in a dose which is at least about two times less than the dose required with oral administration and is delivered to the pulmonary system.

The doses employed in the invention generally also are at least about two times less than the dose required with routes of administration other than intravenous, such as, for instance, subcutaneous injection, intramuscular injection, intra-peritoneal, buccal, rectal and nasal.

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 a single breath. The methods include administering particles from a receptacle which has a mass of particles, to a subject\'s respiratory tract. Preferably, the receptacle 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. The receptacle can be held in a single dose breath activated dry powder inhaler.

In one embodiment of the invention, the particles deliver at least about 10 milligrams (mg) of the drug. In other embodiments, the particles deliver at least about 15, 20, 25, 30 milligrams of drug. Higher amounts can also be delivered, for example the particles can deliver at least about 35, 40 or 50 milligrams of drug.

The invention also is related to methods for the efficient delivery of particles to the pulmonary system. In one embodiment, the invention is related to delivering to the pulmonary system particles that represent at least about 70% and preferably at least about 80% of the nominal powder dose. In another embodiment of the invention, a method of delivering a medicament to the pulmonary system, in a single, breath-activated step, includes administering particles, from a receptacle which has a mass of particles, to the respiratory tract of a subject, wherein at least 50% of the mass of particles is delivered.

Preferably, administration to the respiratory tract is by a dry powder inhaler or by a metered dose inhaler. The particles of the invention also can be employed in compositions suitable for delivery to the pulmonary system such as known in the art.

In one embodiment, particles employed in the method of the invention are particles suitable for delivering a medicament to the pulmonary system and in particular to the alveoli or the deep lung. In a preferred embodiment, the particles have a tap density which is less than 0.4 g/cm3. In another preferred embodiment, the particles have a geometric diameter, of at least 5 μm (microns), preferably between about 5 μm and 30 μm. In yet another preferred embodiment, the particles have an aerodynamic diameter between about 1 μm and about 5 μm. In another embodiment, the particles have a mass median geometric diameter (MMGD) larger than 5 μm, preferably around about 10 μm or larger. In yet another embodiment, the particles have a mass median aerodynamic diameter (MMAD) ranging from about 1 μm to about 5 μm. In a preferred embodiment, the particles have an MMAD ranging from about 1 μm tobout 3 μm.

Particles can consist of the medicament or can further include one or more additional components. Rapid release of the medicament into the blood stream and its delivery to its site of action, for example, the central nervous system, is preferred. In one embodiment of the invention, the particles include a material which enhances the release kinetics of the medicament. Examples of suitable such materials include, but are not limited to, certain phospholipids, amino acids, carboxylate moieties combined with salts of multivalent metals and others.

In a preferred embodiment, the energy holding the particles of the dry powder in an aggregated state is such that a patient\'s breath, over a reasonable physiological range of inhalation flow rates is sufficient to deaggregate the powder contained in the receptacle into respirable particles. The deaggregated particles can penetrate via the patient\'s breath into and deposit in the airways and/or deep lung with high efficiency.

The invention has many advantages. For example, pulmonary delivery provides on-demand treatment without the inconvenience of injections. Selective delivery of a medicament to the central nervous system can be obtained in a time frame not available with other administration routes, in particular conventional oral regimens. Thus, an effective dose can be delivered to the site of action on the “first pass” of the medicament in the circulatory system. By practicing the invention, relief is available to symptomatic patients in a time frame during which conventional oral therapies would still be traveling to the site of action. The reduced doses employed in the methods of the invention result in a plasma drug level which is equivalent to that obtained with the oral dose. Blood plasma levels approaching those observed with intravenous administration can be obtained. Dose advantages over other routes of administration, e.g., intramuscular, subcutaneous, intra-peritoneal, buccal, rectal and nasal, also can be obtained. Furthermore, a therapeutic amount of the drug can be delivered to the pulmonary system in one or a small number of steps or breaths.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a plot representation of blood levels of L-Dopa in rats following administration via oral gavage or direct administration to the lungs measured by mass spectrometer.

FIG. 1B is a plot representation of blood levels of L-Dopa in rats following administration via oral gavage or direct administration to the lungs measured by HPLC.

FIG. 2A is a plot representation of blood L-Dopa levels in rats following delivery orally or directly into the lungs.

FIG. 2B is a plot representation of striatal dopamine levels in rats following delivery of L-Dopa orally or directly into the lungs. FIG. 3 is a plot representation of blood and striatal levels of 14C following administration of 14C-L-Dopa either orally or directly to the lungs.

FIG. 4 is a plot representation of plasma 14C levels in rats following 14C-L-Dopa administration via oral (gavage), tracheotomy or ventilator.

FIG. 5 is a plot representation of brain 14C levels in rats following 14C-L-Dopa administration via oral (gavage), tracheotomy or ventilator.

FIG. 6A is a bar graph showing absolute 14C-Carboplatin levels in regions of the brain following intravenous (IV) and pulmonary (lung) administration.

FIG. 6B is a bar graph showing relative 14C-Carboplatin levels in regions of the brain following intravenous (IV) and pulmonary (lung) administration.

FIG. 7A is a bar graph showing absolute 14C-Carboplatin levels in animal organs following intravenous (IV) or pulmonary (lung) administration.

FIG. 7B shows relative 14C-Carboplatin levels in animal organs following intravenous (IV) or pulmonary (lung) administration.

FIG. 8 is a plot representation showing plasma concentration of L-Dopa vs. time following oral or pulmonary administration (normalized for an 8 mg dose).

FIG. 9 is a plot representation showing plasma concentration of ketoprofen vs. time for oral and pulmonary groups.

FIG. 10 is a plot representation showing plasma concentration of ketoprofen vs. time for oral group.

FIG. 11 is a plasma concentration of ketoprofen vs. time for pulmonary group.

FIG. 12 is a plot showing RODOS curves for different powder formulations that include L-DOPA.

FIGS. 13A and 13B are HPLC chromatograms that depict L-DOPA recovery from powders (FIG. 13A) compared to a blank sample (FIG. 13B).

FIG. 14A depicts L-DOPA plasma levels following pulmonary (lung), and oral routes.

FIG. 14B depicts L-DOPA plasma levels following pulmonary (lung), oral and intravenous administration.

FIGS. 15A and 15B show results, respectively, of oral (p.o.) and pulmonary (lung) L-DOPA on functional “placing task” in a rat model of Parkinson\'s disease.

FIGS. 16A and 16B show results, respectively of oral (p.o.) and pulmonary (lung) L-DOPA on functional “bracing task” in a rat model of Parkinson\'s disease.

FIGS. 17A and 17B show results, respectively of oral (p.o.) and pulmonary (lung) L-DOPA on functional akinesia task in a rat model of Parkinson\'s disease.

FIG. 18 shows results of oral (p.o.) and pulmonary (lung) delivery of L-DOPA on functional rotation in a rat model of Parkinson\'s disease.

FIG. 19A depicts time to seizure onset after delivery of pulmonary and oral alprazolam 10 minutes prior to PZT administration.

FIG. 19B depicts duration of seizure after delivery of pulmonary and oral alprazolam 10 minutes prior to PZT administration.

FIG. 20A depicts time to seizure onset after delivery of pulmonary and oral alprazolam 30 minutes prior to PZT administration.

FIG. 20B depicts duration of seizure after delivery of pulmonary and oral alprazolam 30 minutes prior to PZT administration.

FIG. 21A depicts time to seizure onset for pulmonary alprazolam 10 and 30 minutes prior to PZT administration.

FIG. 21B depicts duration of seizure for pulmonary alprazolam 10 and 30 minutes prior to PZT administration.

DETAILED DESCRIPTION

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 Tmax 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®, Lorex) which is currently given as a 5 mg tablet with Tmax=1.6 hours; ½ 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®, 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®, 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.

TABLE 1 Dilaurylolyphosphatidylcholine (C12;0) DLPC Dimyristoylphosphatidylcholine (C14;0) DMPC Dipalmitoylphosphatidylcholine (C16:0) DPPC Distearoylphosphatidylcholine (18:0) DSPC Dioleoylphosphatidylcholine (C18:1) DOPC Dilaurylolylphosphatidylglycerol DLPG Dimyristoylphosphatidylglycerol DMPG Dipalmitoylphosphatidylglycerol DPPG Distearoylphosphatidylglycerol DSPG Dioleoylphosphatidylglycerol DOPG Dimyristoyl phosphatidic acid DMPA Dimyristoyl phosphatidic acid DMPA Dipalmitoyl phosphatidic acid DPPA Dipalmitoyl phosphatidic acid DPPA Dimyristoyl phosphatidylethanolamine DMPE Dipalmitoyl phosphatidylethanolamine DPPE Dimyristoyl phosphatidylserine DMPS Dipalmitoyl phosphatidylserine DPPS Dipalmitoyl sphingomyelin DPSP Distearoyl sphingomyelin DSSP

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 Ser. 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 60/150,662, filed on Aug. 25, 1999, entitled Formulation for Spray-Drying Large Porous Particles, and U.S. Non-Provisional patent application Ser. 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™ 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., 10th 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 (μm). In one embodiment, the VMGD is from about 5 μm to about 30 μm. In another embodiment of the invention, the particles have a VMGD ranging from about 10 μm to about 30 μm. 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 μm, for example from about 5 μm and about 30 μm.

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 known in the art. The diameter of particles in a sample will range depending upon factors such as particle composition and methods of synthesis. The distribution of size of particles in a sample can be selected to permit optimal deposition 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 μm and about 5 μm. In another embodiment of the invention, the MMAD is between about 1 μm and about 3 μm. In a further embodiment, the MMAD is between about 3 μm and about 5 μm.

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, daer, can be calculated from the equation:

daer=dg√ρtap