Cardiac safe, rapid medication delivery

• US 20060120962A1
• Filed: 10/12/2005
• Published: 06/08/2006
• Est. Priority Date: 10/12/2004
• Status: Abandoned Application

• Current Assignee: Alexza Pharmaceuticals Inc. (Grupo Ferrer Internacional SA)
• Original Assignee: Alexza Pharmaceuticals Inc. (Grupo Ferrer Internacional SA)
• Inventors: Lloyd, Peter M., Rabinowitz, Joshua D.
• Application Number:
  US11/248,598
• Publication Number:
  US 20060120962A1
• Time in Patent Office: Days
• US Class Current: 424/9.200
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/007 Pulmonary tract; Aromatherapy
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 23/00 Anaesthetics
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 39/02 Antidotes
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

The disclosure provides methods and compositions for providing an effective dose of an active agent and/or drug composition to a subject by inhalation. The methods of the disclosure are useful in determining a maximal effective dose that limits cardiovascular damage upon inhalation.

Claims

1. A method of identifying a cardiovascular safe dose of a drug active agent for delivery by inhalation, the method comprising:

(a) determining a peak arterial concentration of the drug active agent following

(i) inhalation delivery of the drug active agent, and

(ii) intravenous delivery of the drug active agent,

(b) identifying a cardiovascular safe intravenous dose of the drug active agent based on cardiovascular safety measurements taken after intravenous delivery of the drug active agent; and

(c) defining a cardiovascular safe inhaled dose of the drug active agent as less than or equal to the cardiovascular safe intravenous dose divided by the ratio of the peak drug active agent concentration produced by the inhalation delivery relative to that produced by the intravenous delivery.

5. The method of claim 1, further comprising:

(a) identifying an effective intravenous dose of the drug active agent that produces a desirable response in a mammal,

(b) defining an effective inhalation dose by dividing the effective intravenous dose by the ratio of the peak active agent concentration produced by inhalation relative to that produced by the intravenous delivery to yield an effective inhalation dose, wherein the effective inhalation dose is less than the safe inhalation dose; and

(c) selecting a therapeutic inhalation dose of the drug active agent, wherein the therapeutic inhalation dose is less than or equal to the safe inhalation dose and greater than or equal to the effective inhalation dose.

6. The method of claim 1, wherein the drug active agent comprises a drug selected from the group consisting of acebutolol, acetaminophen, alprazolam, amantadine, amitriptyline, apomorphine diacetate, apomorphine hydrochloride, atropine, azatadine, betahistine, brompheniramine, bumetanide, buprenorphine, bupropion hydrochloride, butalbital, butorphanol, carbinoxamine maleate, celecoxib, chlordiazepoxide, chlorpheniramine, chlorzoxazone, ciclesonide, citalopram, clomipramine, clonazepam, clozapine, codeine, cyclobenzaprine, cyproheptadine, dapsone, diazepam, diclofenac ethyl ester, diflunisal, disopyramide, doxepin, estradiol, ephedrine, estazolam, ethacrynic acid, fenfluramine, fenoprofen, flecainide, flunitrazepam, galanthamine, granisetron, haloperidol, hydromorphone, hydroxychloroquine, ibuprofen, imipramine, indomethacin ethyl ester, indomethacin methyl ester, isocarboxazid, ketamine, ketoprofen, ketoprofen ethyl ester, ketoprofen methyl ester, ketorolac ethyl ester, ketorolac methyl ester, ketotifen, lamotrigine, lidocaine, loperamide, loratadine, loxapine, maprotiline, memantine, meperidine, metaproterenol, methoxsalen, metoprolol, mexiletine HCl, midazolam, mirtazapine, morphine, nalbuphine, naloxone, naproxen, naratriptan, nortriptyline, olanzapine, orphenadrine, oxycodone, paroxetine, pergolide, phenytoin, pindolol, piribedil, pramipexole, procainamide, prochloperazine, propafenone, propranolol, pyrilamine, quetiapine, quinidine, rizatriptan, ropinirole, sertraline, selegiline, sildenafil, spironolactone, tacrine, tadalafil, terbutaline, testosterone, thalidomide, theophylline, tocainide, toremifene, trazodone, triazolam, trifluoperazine, valproic acid, venlafaxine, vitamin E, zaleplon, zotepine, amoxapine, atenolol, benztropine, caffeine, doxylamine, estradiol 17-acetate, flurazepam, flurbiprofen, hydroxyzine, ibutilide, indomethacin norcholine ester, ketorolac norcholine ester, melatonin, metoclopramide, nabumetone, perphenazine, protriptyline HCl, quinine, triamterene, trimipramine, zonisamide, bergapten, chlorpromazine, colchicine, diltiazem, donepezil, eletriptan, estradiol-3,17-diacetate, efavirenz, esmolol, fentanyl, flunisolide, fluoxetine, hyoscyamine, indomethacin, isotretinoin, linezolid, meclizine, paracoxib, pioglitazone, rofecoxib, sumatriptan, tolterodine, tramadol, tranylcypromine, trimipramine maleate, valdecoxib, vardenafil, verapamil, zolmitriptan, zolpidem, zopiclone, bromazepam, buspirone, cinnarizine, dipyridamole, naltrexone, sotalol, telmisartan, temazepam, albuterol, apomorphine hydrochloride diacetate, carbinoxamine, clonidine, diphenhydramine, thambutol, fluticasone proprionate, fluconazole, lovastatin, lorazepam N,O-diacetyl, methadone, nefazodone, oxybutynin, promazine, promethazine, sibutramine, tamoxifen, tolfenamic acid, aripiprazole, astemizole, benazepril, clemastine, estradiol 17-heptanoate, fluphenazine, protriptyline, ethambutal, frovatriptan, pyrilamine maleate, scopolamine, and triamcinolene acetonide.

7. The method of claim 1, wherein the inhaled drug active agent comprises aerosol particles produced by drug heating and vaporization characterized by an MMAD of 1-3 μ

m less than 5% drug degradation products by weight.

8. The method of claim 1, wherein drug active agent comprises a drug selected from the group of anesthetics, anticonvulsants, antidepressants, antidiabetic agents, antidotes, antiemetics, antihistamines, anti-infective agents, antineoplastics, antiparkisonian drugs, antirheumatic agents, antipsychotics, anxiolytics, appetite stimulants and suppressants, blood modifiers, cardiovascular agents, central nervous system stimulants, drugs for Alzheimer'"'"'s disease management, drugs for cystic fibrosis management, diagnostics, dietary supplements, drugs for erectile dysfunction, gastrointestinal agents, hormones, drugs for the treatment of alcoholism, drugs for the treatment of addiction, immunosuppressives, mast cell stabilizers, migraine preparations, motion sickness products, drugs for multiple sclerosis management, muscle relaxants, nonsteroidal anti-inflammatories, opioids, other analgesics, stimulants, opthalmic preparations, osteoporosis preparations, prostaglandins, respiratory agents, sedatives and hypnotics, skin and mucous membrane agents, smoking cessation aids, Tourette'"'"'s syndrome agents, urinary tract agents, and vertigo agents.

9. An inhalation device comprising a dose of a drug active agent identified by the methods of claim 1.

2. A method of identifying a cardiovascular safe dose of a drug active agent for systemic delivery by inhalation, the method comprising:

(a) determining a rate of absorption of the drug active agent into the arterial circulation by inhalation delivery, and

(b) determining the cardiovascular safety of the drug active agent delivered at a substantially identical rate at one or more doses by intravenous delivery,

wherein the cardiovascular safe dose of the inhaled active agent is equal to or less than the dose that is determined to be safe when delivered at a substantially identical rate by the intravenous delivery.

3. An aerosol-releasing device for inhalation therapy, wherein the device releases one or more doses of aerosol that, when inhaled by a mammal, results in a spike index of between about 1.5 and 10, wherein the spike index is determined by:

(a) administering to a subject an equal amount of a drug active agent by both inhalation delivery and intravenous delivery;

(b) identifying an inhaled peak arterial plasma concentration after delivery of drug active agent in an aerosol by inhalation;

(c) identifying an intravenous peak arterial plasma concentration after delivery of a substantially identical dose of the drug active agent by IV injection; and

(d) dividing the inhaled peak arterial plasma concentration by the intravenous peak arterial plasma concentration to determine the spike index.

4. A method of delivering a drug active agent to a mammal, the method comprising administering the drug active agent by inhalation in the form of an aerosol, wherein the administration produces a spike index between 2 and 6, and wherein the peak left ventricular plasma concentration of the drug active agent is achieved in less than 30 seconds.

10. A method of delivering a heat stable drug active agent to a mammal to achieve a rapid therapeutic effect, the method comprising

generating an aerosol of the drug active agent, and

delivering the aerosol into the pulmonary tract of the mammal to produce a peak arterial plasma concentration, wherein the peak plasma concentration is achieved more rapidly than following intravenous bolus delivery of the same medication.

11. The method of claim 10, wherein the peak plasma concentration of the drug active agent following inhalation is between 0.5 times and 1.5 times the peak plasma concentration following intravenous bolus delivery.

12. A method of delivering a heat stable drug active agent to a mammal, the method comprising

generating an aerosol of the medication, and

delivering the aerosol into the pulmonary tract of the mammal to produce (a) a peak arterial plasma concentration and (b) a peak venous plasma concentration, wherein the peak arterial plasma concentration is between 2 and 10 times greater than the peak venous plasma concentration.