(12) Patent Application Publication (10) Pub. No.: US 2006/00398.69 A1 Wermeling Et Al
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US 200600398.69A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/00398.69 A1 Wermeling et al. (43) Pub. Date: Feb. 23, 2006 (54) INTRANASAL DELIVERY OF Publication Classification ANTIPSYCHOTC DRUGS (51) Int. Cl. A6IK 9/14 (2006.01) A61 K 3/445 (2006.01) A6IL 9/04 (2006.01) (76) Inventors: Daniel Wermeling, Lexington, KY (52) U.S. Cl. .............................................. 424/46; 514/317 (US); Jodi Miller, Acworth, GA (US) (57) ABSTRACT An intranasal drug product is provided including an antip Correspondence Address: Sychotic drug, Such as haloperidol, in Sprayable Solution in MAYER, BROWN, ROWE & MAW LLP an intranasal metered dose Sprayer. Also provided is a P.O. BOX2828 method of administering an antipsychotic drug, Such as CHICAGO, IL 60690-2828 (US) haloperidol, to a patient, including the Step of delivering an effective amount of the antipsychotic drug to a patient intranasally using an intranasal metered dose Sprayer. A (21) Appl. No.: 10/920,153 method of treating a psychotic episode also is provided, the method including the Step of delivering an antipsychotic drug, Such as haloperidol, intranasally in an amount effective (22) Filed: Aug. 17, 2004 to control the psychotic episode. Patent Application Publication Feb. 23, 2006 US 2006/00398.69 A1 30 525 2 20 -- Treatment A (M) S 15 - Treatment B (IM) 10 -- Treatment C (IN) i 2 O 1 2 3 4 5 6 Time Post-dose (hours) F.G. 1 US 2006/0039869 A1 Feb. 23, 2006 INTRANASAL DELIVERY OF ANTIPSYCHOTC therefore the dosage form of choice in acute situations. In DRUGS addition, the oral Solution cannot be "cheeked' by patients. One study has shown the onset of action of the oral Solution STATEMENT REGARDING FEDERAL is comparable to that of the intramuscular dose. Patients in SUPPORT these mental States may not readily accept oral medications. 0001. Not Applicable However, offering the patient a choice in treatment results in creating a safer environment and restores Some Sense of BACKGROUND autonomy to the patient, which may be particularly helpful 0002) 1. Field of the Invention when treating psychotic patients. Oral administration of haloperidol results in approximately 65% absolute bioavail 0.003 Methods and devices for intranasal delivery of ability. A wide interindividual variation in the oral absorp antipsychotics, Such as haloperidol. tion of haloperidol has been demonstrated. 0004 2. Description of the Related Art 0010) Ideally a product should provide both rapid effect 0005. A recent focus of antipsychotic drug development and assured dose bioavailability while still allowing the for the treatment of acute psychosis is to decrease adverse events related to drug administration, while achieving patient to feel included in their treatment and comfortable in desired psychiatric control. In the treatment of psychotic their Surroundings. This could be accomplished through episodes, the primary emphasis is to provide both Safe and avoidance of invasive or possibly perceived threatening rapid therapy. Currently, the intramuscular route is both the treatment and delivering the drug in a manner that consis fastest and Safest approved method for achieving chemical tently provides expected, reliable plasma drug concentra restraint. tions. Optimum treatment Such as this necessitates the 0006 The treatment of patients experiencing psychotic development of an alternative route of administration. Symptoms Such as delirium, agitation, and Violence is both 0.011 U.S. Patent Publication No. 2003/0017118A1 dis challenging as well as dangerous for the patient and health closes an inhaled dosage form for delivery of antipsychotic care provider. This is especially relevant in the emergency room and intensive care Settings. In many cases, psycho drugs. Although that publication describes an effective route logical and behavioral methods for obtaining control are not of administration for antipsychotics for pulmonary inhala adequate. It becomes necessary to treat patients using phar tion, the delivery of drugs to the lungs often causes coughing macological avenues that are both Safe and rapid. For and gagging, which can Serve to exacerbate the already treatment during acute psychotic episodes, desirable char difficult antipsychotic treatment process. Delivery of medi acteristics of an agent include rapid onset, moderate duration cations by oral inhalation is challenging. In Standard oral of therapeutic action, minimal side effects, predictable bio inhalation with a metered dose inhaler, it is common that availability, ease and Safety of administration, and minimal only 15% of the drug actually makes it to the lung for patient discomfort on administration. To date, haloperidol absorption. Most of the drug formulation impacts in the has been the mainstay of treatment for this purpose. To pharyngeal area and is Swallowed. Oral inhalation requires achieve rapid tranquilization, the drug is usually given either a trained and cooperative patient. Particle Size for oral intramuscularly or intravenously off-label. inhalation needs to be less than 10 microns, with optimal 0007. In uncooperative patients, the routes of delivery particle sizes of less than 3 microns, to be respirable. most commonly used are intravenous (IV) and intramuscu Further, propellants are commonly used for pulmonary lar. Although the intravenous route of administration is not administration. FDA approved, it is used for both continuous infusions and 0012 Haloperidol is an ideal antipsychotic drug for use bolus injections. For this type of delivery, intravenous acceSS in emergency situations due to its rapid onset of action, lack is necessary and the patient should be in an inpatient of cardiovascular adverse events, decreased respiratory environment. The intravenous route is commonly used in depression, and a low to moderate Sedation profile compared intensive care Settings. to other agents Such as chlorpromazine and the benzodiaz 0008. The primary route of administration for uncoop epines. Haloperidol is associated with a high incidence of erative patients is intramuscular injection. This route is the extrapyramidal Symptoms that can be treated effectively Simplest in uncooperative, aggressive patients. Maximum with anticholinergic agents. Newer antipsychotic agents concentrations can be reached in approximately 20 minutes have been developed to minimize the incidence of adverse via this route. Nevertheless, intramuscular administration events while improving treatment. Despite efforts to identify can be painful and cause a patient already in a psychotic, a Superior antipsychotic, haloperidol remains the most fragile State of mind to feel even more insecure and increase widely used and cost-effective agent for rapid neuroleptiza their Sense of being attacked. In addition, muscle enzyme levels may be affected. Both the intravenous and intramus tion and is commonly used in Studies as a Standard measure cular routes require the use of needles which poses an of efficacy. infrequent but real risk of infection by blood-borne patho 0013 Haloperidol, a potent butyrophenone, has been gens to both patients and Staff. used in clinical practice for more than three decades and is 0009 If the patient is cooperative, the current desired an effective antipsychotic used in a wide variety of psychi route of administration is oral. Haloperidol, for example, is atric conditions. Haloperidol is a central dopaminergic available both as a tablet and as an oral Solution. The oral receptor antagonist. The first literature descriptions of Syn Solution has a faster onset of action than the tablet and is thesis and testing of this medication date to the late 1950s. US 2006/0039869 A1 Feb. 23, 2006 0014) The structure of haloperidol is given below (For delivering intranasally an amount of an antipsychotic drug, mula I). Such as haloperidol lactate, effective to treat a psychotic episode in a Sprayable, aqueous Solution. 0019. A method of treating a psychotic episode also is Formula I provided. The method includes the step of delivering intra OH nasally an effective amount of an antipsychotic drug, Such as F C-C-C-C-N haloperidol lactate, in a Sprayable, aqueous Solution. H. H. H. 0020 Lastly, a sprayable solution for use in an intranasal O metered dose sprayer is provided. The Solution comprises from greater than 0.25% wt. to about 10% wt. haloperidol or a dose equivalent thereof of an antipsychotic drug other than C haloperidol, and a pharmaceutically acceptable excipient. BRIEF DESCRIPTION OF THE DRAWINGS 0.015 The chemical formulation of haloperidol is C.H.CIFNO, with a molecular weight of 375.87. It occurs 0021 FIG. 1 is a graph showing serum concentration as a white to faintly yellowish, amorphous or microcrystal levels of haloperidol after intranasal, intravenous and intra line powder. The lactate Salt is used to formulate the oral muscular drug delivery. Solution and immediate release injectable dosage forms. Lactic acid is used to adjust the injection to a pH of 3-3.8. DETAILED DESCRIPTION Haloperidol is well-accepted in the medical community as a Safe and effective antipsychotic agent. Typical intramuscular 0022. The use of numerical values in the various ranges doses range from 2-5 mg/dose in clinical practice. The Specified in this application, unless eXpressly indicated injection may be repeated as often as every hour although otherwise, are Stated as approximations as though the mini dosing intervals of 4 to 8 hours usually are sufficient. The mum and maximum values within the Stated ranges were peak plasma concentration following intramuscular admin both preceded by the word “about.” In this manner, slight istration occurs at approximately 20 minutes. Haloperidol is variations above and below the Stated ranges can be used to metabolized by the liver into inactive metabolites except for achieve Substantially the same results as values within the reduced haloperidol, which has very limited clinical activity. ranges. Also, the disclosure of these ranges is intended as a This metabolism is primarily mediated by the CYP3A4 continuous range including every value between the mini isoenzyme. The half-life of the lactate formulation in man mum and maximum values. ranges from 10 to 38 hours.