This application is a continuation of pending U.S. application Ser. No. 11/674,803, filed Feb. 14, 2007, which is a continuation of U.S. application Ser. No. 10/647,789, filed Aug. 23, 2003, which is a continuation-in-part of U.S. application Ser. No. 09/790,199 filed Feb. 20, 2001, which is a continuation-in-part of U.S. application Ser. No. 09/569,125 filed May 10, 2000, now abandoned. The entire disclosure of these applications is herein incorporated by reference.
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OF THE INVENTION
Pain is a major symptom of many diseases, (e.g., cancer, arthritis, neurological diseases, heart attacks, etc.). Inadequate treatment of pain can lead to depression, anger, fear of disease progression and in some extreme cases, suicide.
Unfortunately, a patient's non-compliance or failure to take medication as prescribed, has been linked to inadequate treatment of pain. This is not surprising, since many pain treatment regimens involve administering pain medications by injection route (e.g., intravenous (IV), intramuscular (IM) or subcutaneous injection). The intravenous route is normally regarded as one of the most in-convenient routes to administer pain medication to achieve rapid pain relief. Intravenous administration may cause non-compliance, because not only do patients fear getting the injection, but unpleasant experiences such as pain, irritation and infection resulting at the injection site may also lead to non-compliance.
The intranasal route is currently receiving special interest, especially in the area of pain management. When medication is administered via the intranasal route, the medication is applied to the nasal mucosa where it is absorbed. The extensive network of blood capillaries under the nasal mucosa is particularly suited to provide rapid and effective systemic absorption of drugs. The intranasal route of administration should achieve similar dose to plasma concentration (bioavailability) and efficacy to that of the intravenous route.
Intranasal administration of medication provides numerous advantages over the intravenous route. The principal advantages of intranasal route are non-invasive delivery, rapid drug absorption, and convenience. The intravenous route, unlike the intranasal route, requires sterilization of hypodermic syringes and, in the institutional setting, leads to concerns among medical personnel about the risk of contracting disease if they are accidentally stuck by a contaminated needle. Strict requirements for the safe disposal of needles and syringes have also been imposed.
In contrast, intranasal administration requires little time on the part of the patient and attending medical personnel, and is far less burdensome on the institution than injectable routes. There is no significant risk of infection of the patient or medical personnel in the institutional setting when dealing with the intranasal delivery of medication.
A second important advantage of intranasal administration over intravenous is patient acceptance of the intranasal delivery route. In some cases, the injections cause burning edema, swelling, turgidity, hardness and soreness. In contrast, intranasal administration is perceived as non-invasive, is not accompanied by pain, has no after-effects and produces prompt relief in the patient exhibiting pain symptoms. This is of particular advantage when the patient is a child. Many, if not most, patients experience anxiety and exhibit symptoms of stress when faced with hypodermic injections via the IM or IV routes. Further, most people have some familiarity with nasal sprays in the form of over-the-counter decongestants for alleviating the symptoms of colds and allergies that they or a family member have used routinely. Another important consideration is that the patient can self-administer the prescribed dosage(s) of nasal spray without the need for trained medical personnel.
Among the many medications available to treat pain, opioids (e.g., morphine, methadone, hydromorphone, butorphanol, etc.) play one of the most important roles. The major advantage of the opioids is that they have an extensive history of use and are much more effective in treating severe pain than other classes of medications e.g. aspirin, acetaminophen, ibuprofen, etc. Another major advantage is that opioids exhibit few adverse effects on organs such as the stomach, liver, or kidney, other than very minor problems such as nausea or constipation. This is a major benefit over other medications such as aspirin or anti-inflammatory drugs that may cause ulcers, kidney problems, high blood pressure, or liver inflammation. In addition to relieving pain, opioids have other beneficial effects, such as, for example, peripheral arterial vasodilation, when treating heart attacks, provides the benefit of reducing oxygen demand on the heart.
There are different intranasal opioid formulations known in the pharmaceutical arts. However, some intranasal opioid formulations have reduced bioavailability at conventional doses. These formulations require more pain medication to be administered to the patient or else the pain will be inadequately treated.
Given the problems associated with inadequate treatment of pain and patient noncompliance, there is a need for intranasal opioid compositions that have improved bioavailability. There is also a need for intranasal compositions that improve patient compliance.
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OF THE INVENTION
In various embodiments, the present invention provides intranasal opioid compositions that have improved bioavailability when compared to intranasal prior art opioid compositions. In other embodiments, the present invention provides intranasal opioid compositions that improve patient compliance.
In one embodiment, the present invention provides a pharmaceutical composition for intranasal administration to a mammal; comprising: an effective amount of an opioid; a liquid nasal carrier for the opioid; and one or more sweeteners, flavoring agents, or masking agents or combinations thereof.
In another embodiment, the present invention provides a pharmaceutical composition having improved bioavailability for intranasal administration to a mammal; comprising: an effective amount of butorphanol; a preservative-free liquid nasal carrier.
In still another embodiment, the present invention provides a pharmaceutical composition having improved bioavailability for intranasal administration to a mammal; comprising: an effective amount of hydromorphone; a liquid nasal carrier having the essential absence of a preservative and the composition containing at least one sweetener, flavoring agent or masking agent.
In one preferred embodiment, the present invention provides a pharmaceutical composition for intranasal administration to a mammal; comprising: an effective amount of hydromorphone; a preservative-free liquid nasal carrier comprising sodium chloride, citric acid, water and at least one sweetener, flavoring agent or masking agent.
In still another preferred embodiment, the present invention provides a method of treating a mammal suffering from pain comprising intranasally administering to the mammal an effective amount of butorphanol or hydromorphone; a preservative-free liquid nasal carrier comprising sodium chloride, citric acid, water and at least one sweetener, flavoring agent or masking agent.
For a better understanding of the present invention together with other and further advantages and embodiments, reference is made to the following description taken in conjunction with the examples, the scope of which is set forth in the appended claims.
BRIEF DESCRIPTION OF THE FIGURES
Preferred embodiments of the invention have been chosen for purposes of illustration and description, but are not intended in any way to restrict the scope of the invention. The preferred embodiments of certain aspects of the invention are shown in the accompanying figures, wherein:
FIG. 1 is a graphic representation of the concentration of butorphanol in blood plasma versus time after administration of the test formulation from a unit-dose spray device (Invention)) and the administration of the test formulation in a multi-dose spray device (Prior Art).
FIG. 2 is a graphic representation of the data of FIG. 1 over a longer time period.
FIG. 3 is a graphic representation of the concentration of hydromorphone in blood plasma versus time for IV, IM and intranasal (IN) doses (mean (n=9) Hydromorphone concentration versus time graphs following IV, IM, and IN doses of 2 mg Hydromorphone HCI (6 hrs after dose).
FIG. 4 is a graphic representation of the data of FIG. 3 over a longer period of time (mean (n=9) Hydromorphone concentration versus time graphs following IV, IM, and IN doses of 2 mg Hydromorphone HCI (16 hrs after dose).
FIG. 5 is a graphic representation of the concentration of hydromorphone in blood plasma versus time for a group of subjects (graph of Hydromorphone concentrations versus time following IN doses of 2 mg Hydromorphone HCI to 9 subjects).
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OF THE INVENTION
The invention will now be described in connection with preferred embodiments. These embodiments are presented to aid in an understanding of the present invention and are not intended to, and should not be construed to, limit the invention in any way. All alternatives, modifications and equivalents that may become obvious to those of ordinary skill on reading the disclosure are included within the spirit and scope of the present invention.
In accordance with one embodiment of the present invention, it has now been surprisingly found that intranasal pharmaceutical compositions can be made having improved bioavailability in terms of plasma opioid levels. These intranasal compositions contain an opioid; and a liquid nasal carrier for the opioid. For example, it has been unexpectedly discovered, among other things, that at least about 10 to about 20% higher plasma levels of butorphanol can be achieved by administering an intranasal formulation from a unit-dose spray device. Improved bioavailability includes increases in plasma or serum opioid concentration when compared to prior art opioid formulations. Preferred increases include, but are not limited to, increases of more than 5% to 40% in bioavailability of the opioid.
Opioids as herein include any substance naturally or synthetically derived from opium. Suitable opioids for use in the present invention include, but are not limited to, morphine, apomorphine, hydromorphone, oxymorphone, dihydromorphine, levorphanol, levallorphan, levophenacylmorphan, norlevorphanol, nalorphine, nalbuphine, buprenorphine, butorphanol, naloxone, naltrexone, nalmexone, oxilorphan, cyclorphan, ketobemidone, fentanyl, sufentanil, alfentanyl, or combinations thereof. The most preferred opioids for use in the present invention include butorphanol and/or hydromorphone.