US 20030077300A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0077300 A1 Wermeling (43) Pub. Date: Apr. 24, 2003 (54) SYSTEM AND METHOD FOR INTRANASAL Publication Classi?cation ADMINISTRATION OF OPIOIDS (51) Int. Cl.7 ........................ ..A61K 31/485; A61L 9/04; (76) Inventor: Daniel P. Wermeling, Lexington, KY A61K 9/00 (US) (52) US. Cl. ........................... .. 424/400; 424/45; 514/282 Corres ondence Address: Kalowp& Springut LLP (57) ABSTRACT 19th Floor . 488 Madison Avenue The invention relates to pharmaceutical drug compositions New York, NY 10022 (Us) and preparations that are narcotic antagonists and analge sics, speci?cally opioids, more speci?cally morphine and its (21) APPL NO: 10/155’624 pharmaceutically active derivatives, analogues, homo logues, and metabolites, and still more speci?cally hydro (22) Filed; May 24, 2002 morphone and butorphanol. This invention also relates to pharmaceutical drug delivery devices, speci?cally to devices for the intranasal administration of drugs classi?ed as con Related US, Application Data trolled substances. The invention also relates to the ?eld of acute pain management through pharmaceutical interven (63) Continuation of application No. 09/569,125, ?led on tion, particularly as practiced in an institutional setting, such May 10, 2000. as a hospital. Patent Application Publication Apr. 24, 2003 Sheet 1 0f 5 US 2003/0077300 A1 Patent Application Publication Apr. 24, 2003 Sheet 2 0f 5 US 2003/0077300 A1 m2:@505 ooow Sow wllooow coo?ll (1w/6d) 'ONOO vwsvw Patent Application Publication Apr. 24, 2003 Sheet 4 0f 5 US 2003/0077300 A1 .@Iw oooi ooowv 0002 ooow ooow Sow Patent Application Publication Apr. 24, 2003 Sheet 5 0f 5 US 2003/0077300 A1 GIm 585mg: 80m| hull/6d) 'ONOO vwsvw US 2003/0077300 A1 Apr. 24, 2003 SYSTEM AND METHOD FOR INTRANASAL iting the symptom. This is of particular advantage When the ADMINISTRATION OF OPIOIDS patient is a child. Most people have some familiarity With nasal sprays in the form of over-the-counter decongestants FIELD OF THE INVENTION for alleviating the symptoms of colds and allergies, that they or a family member have used routinely. Another important [0001] The invention relates to pharmaceutical drug com consideration is that the patient can self-administer the positions and preparations that are narcotic antagonists and prescribed dosage(s) of nasal spray. An empty nasal spray narcotic analgesics, speci?cally opioids, more speci?cally device, or one containing only saline solution or the like, can morphine and its pharmaceutically active derivatives, ana be given to the patient to practice the technique for proper logues, homologues, and metabolites, and still more speci? insertion and activation for self-administration. cally hydromorphone and butorphanol. This invention also relates to pharmaceutical drug delivery devices, speci?cally [0005] In vieW of the aforementioned advantages and to devices for the intranasal administration of drugs classi bene?ts afforded by the intranasal administration, it Would ?ed as controlled substances. The invention also relates to be expected that many knoWn compounds exhibiting sys the ?eld of acute pain management through pharmaceutical temic pharmacological activity, including opioid analgesics, intervention, particularly as practiced in an institutional that have been approved for and commercially used for setting, such as a hospital. many years, Would presently be available for intranasal administration. The only opioid available in an FDA BACKGROUND OF THE INVENTION approved intranasal manual-metering spray device is butor phanol sold by Bristol-Myers Squibb under the brand name [0002] Marketers of opioids and other therapeutic com STADOL®NS. pounds that act as systemic analgesics that have been approved by the US. Food and Drug Administration [0006] Butorphanol nasal spray dosage received FDA (“FDA”) and long used for oral, intramuscular and/or intra approval subsequent to the issuance of US. Pat. No. 4,464, venous administration, have generally not sought regulatory 378 Which issued to Hussain in 1984 and is assigned to the approval from the FDA for liquid compositions of the same University of Kentucky. The Hussain patent discloses vari therapeutic compound for intranasal administration. This is ous forms for nasal administration of this class of com surprising since it is Well-knoWn from the literature that the pounds, including ointments and gels, and suggests that intranasal administration of a pharmacologically active liquid nasal solutions for use ad drops or sprays be formu compound generally results in a more rapid bioavailability lated. HoWever, Hussain disclosed in vitro test results only of the compound, or of its desired active metabolite than if on rats and no human test data or results are provided. In a the compound is administered orally. Moreover, the total comparative study three groups of three rats each Were quantitative dosage required to achieve the same concentra administered the drug naloxone by IV injection, orally (via tion of the active compound in the bloodstream is generally injection directly through the duodenum) and nasally by less via the intranasal route compared to oral administration, injecting a liquid solution from a syringe via a polyethylene because in oral administration a portion of the active com tube surgically inserted into the rat’s nasal cavity. Blood pound is often converted to a non-active metabolite by samples Were draWn from the femoral cavity to determine passage through the GI tract and in the liver. plasma levels of the drug. [0003] The intranasal route of administration also pro [0007] Despite the remarkable commercial success that vides numerous advantages over intravenous (IV) and intra has been enjoyed by those drugs that have been made muscular (IM) injections. One principal advantage of intra available in intranasal form, in fact, only a very limited nasal administration is convenience. An injectable system number of compounds are commercially available to phy requires steriliZation of the hypodermic syringe and in the sicians to prescribe and dispense to their patients in that institutional setting, leads to concerns among medical per form. No opioids or other controlled substances have here sonnel about the risk of contracting disease if the they are tofore been made available as intranasal formulations. accidentally stuck by a contaminated needle. Strict require [0008] Only one multiple-dose spray device has appar ments for the safe disposal of the used needle and syringe ently been approved by the FDA for intranasal administra must also be imposed in the institutional setting In contrast, tion of an opioid solution that is categoriZed as controlled intranasal administration requires little time on the part of the patient and the attending medical personnel, and is far substance. The devices that are presently available exhibit several de?ciencies. One spray device intended for multiple less burdensome on the institution than injectables. There is uses must be primed before use by expelling a portion of the no signi?cant risk of infection of medical personnel or liquid contents in order to assure that the pump mechanism others in the institutional setting that is associated With nasal and delivery tube are ?lled. Up to seven or eight activations spray devices. are required to prime the device. It is also indicated that [0004] Asecond important advantage of intranasal admin further priming to disperse one or tWo sprays is to be istration over IM and IV is patient acceptance of the drug performed if the device is not used for 48 hours or longer. delivery system. Many, if not most, patients experience These procedures necessarily result in the dispenser being anxiety and exhibit symptoms of stress When faced With over?lled in order to assure that there Will be suf?cient liquid hypodermic injections via the IM or IV routes. In some to deliver the labelled number of doses. It has been found cases, the after-effects of the injection include burning, that a substantial volume of the controlled substance often edema, sWelling, turgidity, hardness and soreness. In con remains in the device, even after the labelled number of trast, intranasal administration is perceived as non-invasive, doses have been administered. In practice, it has also been is not accompanied by pain, has no after-effects and pro found that medical personnel and Workers at health care duces the grati?cation of prompt relief in the patient exhib facilities routinely abscond With the dispensers, sometimes US 2003/0077300 A1 Apr. 24, 2003 after the patient has had only one or a feW of the prescribed administration and a formulation for a systemic opioid doses in a multi-dose container. This improper diversion and analgesic that meet the requirements for FDA approval. use of controlled substances as so-called “recreational drugs” is Well-known among medical facility managers and [0015] It is a further object of this invention to provide a dosage form and method of administration of an analgesic laW enforcement authorities. So far as is presently knoWn, that exhibits a rapid onset, moderate duration of therapeutic no preventative measures have been reported that are effec tive in dealing With this problem. activity, minimal side effects, predictable bioavailability, ease and safety of administration, and minimal physical [0009] A further problem resides in dispensing to a patient discomfort and anxiety to the patient occasioned by admin