Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-08-16
2003-11-04
Ponnaluri, Padmashri (Department: 1627)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C424S434000
Reexamination Certificate
active
06642275
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to formulations and methods for the intranasal and inhalation administration of analgesics having low opioid receptor binding affinity.
BACKGROUND OF THE INVENTION
Pharmacologically active compounds are most commonly administered by the oral route. In particular, analgesics are preferably taken by mouth. However, this convenient route of administration is not always possible for certain patients. Contraindications to oral administration of analgesics can include nausea and/or emesis, oral or gastrointestinal surgery and dysphagia. In addition, rate of analgesia onset is slower and more variable due to first pass effects which compromise the apparent potency of some analgesics and complicate their use. The alternative of administration by injection, e.g., parenteral, intramuscular or subcutaneous injection, is generally not preferred due to patient discomfort and the attendant increased costs associated with the production of and administration of injectable products.
Another, less invasive form of administration is transmucosal administration. Transmucosal administration can be via oral, nasal and/or upper respiratory tract, rectal or vaginal mucosal surfaces, to name the more common non-oral transmucosal routes of administration. Transmucosal administration has the advantage that patients who are unable to swallow can be medicated without recourse to injection. Importantly, transmucosal administration may often provide a more rapid relief of pain, compared to oral administration, by providing direct access to the blood circulation and bypassing the gastrointestinal tract and portal vein circulation and liver metabolism.
A particularly preferred route for transmucosal delivery is intranasal administration for absorption by the nasal mucosal surfaces and/or inhalation for absorption in the bronchial passages of the lungs.
Heretofore, it has been taught that only certain opioid analgesic compounds would be suitable for intranasal transmucosal administration. For example, given the difficulties of delivering compounds across the mucosal barrier and the limited mucosal area that is conveniently available to intranasal administration, only the most potent opioid analgesics, antagonists or mixed agonist/antagonist drugs were taught to be candidates for intranasal delivery. In addition, only those opioid compounds for which oral delivery was variable and problematic were generally considered for intranasal delivery.
For example, U.S. Pat. No. 4,464,378, by Hussain (1984), discloses the intranasal transmucosal administration of certain potent narcotic agonists, antagonists and mixed agonist/antagonists. The Hussain disclosure relates to two classes of compounds, morphine and certain of its structurally close relatives and &Dgr;
9
-tetrahydrocannabinol (“delta-9-THC”). The opioid compounds disclosed to be intranasally effective by Hussain are morphine-like compounds retaining a phenolic group, that are also of high potency (typically exhibiting high mu receptor potency, whether agonist, antagonist or mixed agonist/antagonist) and are stated to be rarely used orally because of inefficient and variable absorption by that route. However, Hussain does not teach the intranasal administration of analgesics that are either weak opioids or non-opioid analgesics, which are also well absorbed orally with predictable efficacy.
Wenig et al., U.S. Pat. No. 4,778,810, issued in 1988, discloses the administration of caffeine by nasal administration. Caffeine is a xanthine derivative completely unrelated to the opioids and unrelated to the non-opioid analgesics.
Frost, U.S. Pat. No. 4,880,813, issued in 1989, discloses a method of treatment of allergic rhinitis by the intranasal administration of the narcotic antagonist nalmefene. Nalmefene, (6-methylene-6-desoxy-N-cyclopropylmethyl-14-dihydronomorphine) is a pure opioid antagonist with a prolonged duration of action. Frost states that Nalmefene is believed to act locally on nasal tissues by inhibiting mast cell degranulation provoked by endogenous opioids acting on receptors in the nasal mucosa and the upper respiratory tract. Thus, Frost does not disclose or suggest any systemic delivery of malmefene or any other opioid compound into the blood circulation.
Cohen, U.S. Pat. No. 4,973,596, issued in 1990, discloses a method of intranasally administering the synthetic narcotic analgesic, meperidine, which is a synthetic opioid drug, in a suitable dosage form. However, the effectiveness of intranasal and/or inhalation administration of a weak opioid or non-opioid analgesic is unpredictable from the disclosures of the intranasal effectiveness of morphine or its derivatives, or meperidine, which are conventional strong opioid receptor binding agents. Therefore, the art does not disclose that a weak opioid receptor binding compound, such as the analgesic tramadol, or its derivatives and pharmaceutically acceptable salts, can be delivered by transmucosal and/or inhalation administration.
Tramadol, which has the chemical name (±) trans-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol, is an orally active opioid analgesic. Conventional release preparations in the form of capsules, drops, suppositories and formulations for systemic injection, containing tramadol, or more particularly its hydrochloride salt, have been commercially available for many years for use in the treatment of moderate to severe pain (e.g., ZYDOL, by Searle; more recently ULTRAM, by Ortho-McNeil Pharmaceutical). Tramadol hydrochloride is currently administered in single oral doses of 50, 75, 100, 150 and 200 mg to patients with, e.g., postoperative pain. In addition, controlled release preparations for oral administration of tramadol are disclosed by co-owned application, U.S. Ser. No. 08/241,129, filed on May 10, 1994, the disclosure of which is incorporated herein by reference.
Tramadol is a centrally acting synthetic analgesic compound. Unlike conventional opioids, the mechanism of action of tramadol is not completely understood. However, it is known that tramadol binds opioid receptors at low affinity and that the tramadol metabolite mono-O-desmethyltramadol (denoted “M1”) binds to opioid receptors at high affinity. The M1 metabolite exhibits substantially greater analgesic activity in animal models than does tramadol. It is also known that tramadol antagonizes reuptake of both norepinephrine and serotonin (in vitro), which may also contribute to the analgesic action of tramadol. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in opioid receptor binding. However, the contribution to human analgesia of tramadol relative to tramadol metabolite M1 is unknown. The unconventional nature of tramadol-induced antinociception is confirmed by reports that the opioid antagonist naloxone only partially antagonizes tramadol-induced antinociception in animal models. Thus, tramadol exhibits both a unique chemical structure and mechanism of action relative to conventional opioids.
Heretofore there has been no acceptable method or formulation for the transmucosal administration of tramadol, an analgesic which is believed to provide analgesic activity by either or both opioid and non-opioid mechanisms, which is readily absorbed by the oral route and which is not of the highest opioid receptor binding.
OBJECTS OF THE INVENTION
It is accordingly an object of the present invention to provide a pharmaceutical dosage form of an opioid that binds weakly to opioid receptors that can be administered intranasally and/or by inhalation.
Another object of the present invention is to provide a pharmaceutically acceptable dosage form of tramadol that can be administered intranasally and/or by inhalation.
Still another object of the present invention is to provide a method of treating a patient with a pharmaceutically acceptable dosage form of tramadol or its derivatives or pharmaceutically acceptable salts via intranasal and/or inhalation administration.
SUMMARY OF THE INV
Alfonso Mark
Goldenheim Paul
Sackler Richard
Davidson Davidson & Kappel LLC
Euro- Celtique, S.A.
Ponnaluri Padmashri
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