Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-08
2003-02-25
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06525062
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to methods and compositions for treating pain in humans using a combination of the kappa-opioid nalbuphine, in a relatively low dosage, with a low dosage of an opioid antagonist selected from naloxone, naltrexone, and nalmefene.
Nalbuphine is a kappa-opioid, a member of the larger opioid group of agonists that includes many well-known agents used to relieve pain. The most well known member of this class is the mu-opioid morphine.
Morphine, of course, is a widely known compound, administered for various purposes, including analgesia. Morphine, in fact, is the compound most often used to treat moderate to severe pain. However, it has known limitations. With time, patients can develop tolerance to it and/or become dependent on it or addicted to it. In addition, morphine can cause severe constipation.
In general, clinical pain conditions can be classified into two categories—traumatic or inflammatory pain, which results from injury to non-neural tissue, for example as occurs after surgery, and in individuals with arthritis, and neuropathic pain, which results from injury to the nervous system. Neuropathic pain, in particular, can be quite severe and not very responsive to narcotic analgesics (see Portenoy, et al., Pain. 43(3): 273-286, 1990. and Hanks, et al., Acta Anaesthesiol. Scand. 1997 Jan; 41(1 Pt. 2): 154-158, 1997). To the knowledge of the inventor, kappa-opioids have not hitherto been tried as a treatment for neuropathic pain, and the use of nalbuphine with an opioid antagonist selected from naloxone, naltrexone, and nalmefene for this purpose in general is new and forms an aspect of this invention.
Levine et al. (1988, J. Clin. Invest. 82(5):1574-77) discloses that, in a study of human patients with postoperative pain after removal of impacted third molars (wisdom teeth), the analgesia produced by administration of 60 mg of the kappa-opioid pentazocine is potentiated by co-administration of a low dose (0.4 mg) of naloxone. The analgesia produced by administration of 8 mg of the mu-opioid morphine is attenuated by co-administration of 0.4 mg of naloxone. Analogous results were obtained in experiments in rats. Levine et al., however, does not disclose administration of a combination of 5 mg of the kappa-opioid nalbuphine with an opioid antagonist such as naloxone. Indeed, Levine et al., does not disclose the administration of a combination comprising nalbuphine in any amount at all.
Crain et al. (U.S. Pat. No. 5,472,943, issued Dec. 5, 1995; U.S. Pat. No. 5,512,578, issued Apr. 30, 1996; U.S. Pat. No. 5,580,876, issued Dec. 3, 1996; U.S. Pat. No. 5,767,125, issued Jun. 16, 1998; U.S. Pat. No. RE. 36,547, reissued Feb. 1, 2000; U.S. Pat. No. 6,096,756, issued Aug. 1, 2000) discloses opiate combinations for enhancing analgesic potency and attenuating dependence liability, in particular, combinations of a bimodally-acting opioid agonist and an excitatory opioid receptor antagonist. According to Crain et al., the bimodally-acting opioid agonist is selected from the group consisting of morphine, codeine, fentanyl analogs, pentazocine, buprenorphine, methadone, enkephalins, dynorphins, endorphins and similarly acting opioid alkaloids and opioid peptides. The excitatory opioid receptor antagonist is selected from the group consisting of naltrexone, naloxone, etorphine, diprenorphine, dihydroetorphine, and similarly acting opioid alkaloids and opioid peptides. Crain et al., however, does not disclose, as a combination for enhancing analgesia, the combination of the kappa-opioid nalbuphine (in any amount, much less 5 mg) and an excitatory opioid antagonist.
Previous studies by the inventor and co-workers determined that nalbuphine's analgesic effects are greater and more consistent in women than in men, suggesting that the pain modulation mechanism activated by nalbuphine is sexually dimorphic (Gear et al., Pain, 83, 339, 1999). In a placebo-controlled dose-response study of human patients with postoperative pain after removal of impacted wisdom teeth, a low dose of nalbuphine (5 mg) did not produce pain modulation effects in women that were any better than those achieved by administration of a dose of placebo. Moreover, administration of a 5 mg dose of nalbuphine in men unexpectedly increased postoperative pain, leading Gear et al. to conclude that in men, the administration of low (5 mg) doses of nalbuphine should be avoided altogether. Gear et al. also does not disclose administration to either women or men of a combination of nalbuphine with an excitatory opioid receptor agonist for pain modulation.
This invention now provides methods and compositions for using the kappa-opioid nalbuphine for treatment of pain of both men and women patients.
BRIEF SUMMARY OF THE INVENTION
According to this invention, it has now been found that administration of a relatively low dosage of nalbuphine can have a dramatic effect on mediation of pain, including both inflammatory and neuropathic pain, when combined with administration (together or sequentially) of a low dosage of an opioid antagonist selected from naloxone, naltrexone, and nalmefene.
In one aspect, the invention comprises a method of treating pain comprising administering to a human in need of such treatment (a) from about 3 to about 8 mg of nalbuphine or a pharmaceutically acceptable salt or prodrug of nalbuphine and (b) from about 0.2 to about 0.8 mg of an opioid antagonist selected from naloxone, naltrexone, and nalmefene, pharmaceutically acceptable salts thereof, and prodrugs therefor, and wherein, if either ingredient is in the form of a salt thereof or a prodrug therefor, said ingredient is present in an amount that, when administered to a patient, produces in the patient the same blood concentration of nalbuphine, or of the narcotic antagonist, as would be produced by administration of from about 3 to about 8 mg of nalbuphine or from about 0.2 to about 0.8 mg of the opioid antagonist, respectively.
In a second aspect, this invention comprises pharmaceutical compositions comprising from about 3 to about 8 mg of nalbuphine or a pharmaceutically acceptable salt or prodrug of nalbuphine and from about 0.2 to about 0.8 mg of an opioid antagonist selected from naloxone, naltrexone, and nalmefene, pharmaceutically acceptable salts thereof, and prodrugs therefor, and wherein, if either ingredient is in the form of a salt thereof or a prodrug therefor, said ingredient is present in an amount that, when administered to a patient, produces in the patient the same blood concentration of nalbuphine, or of the narcotic antagonist, as would administration of from about 3 to about 8 mg of nalbuphine or from about 0.2 to about 0.8 mg of the narcotic antagonist, respectively. These compositions may also comprise one or more pharmaceutically acceptable carriers, such as saline.
In a third aspect, this invention comprises a more concentrated composition that may be used to prepare compositions for administration to patients, namely pharmaceutical compositions comprising (a) nalbuphine, a pharmaceutically acceptable salt of nalbuphine or a prodrug of nalbuphine and (b) an opioid antagonist selected from naloxone, naltrexone, and nalmefene, pharmaceutically acceptable salts thereof, and prodrugs therefor, wherein the weight ratio of ingredient (a) to ingredient (b) is from about 16:1 to about 4:1, and wherein, if either ingredient is in the form of a salt thereof or a prodrug therefor, said ingredient is present in an amount that, when diluted for administration and administered to a patient, produces in the patient the same blood concentration of nalbuphine, or of the narcotic antagonist, as would administration of from about 3 to about 8 mg of nalbuphine or form about 0.2 to about 0.8 mg of the narcotic antagonist, respectively. This composition also may comprise a pharmaceutically acceptable carrier.
Another aspect of this invention, as mentioned above, is the use, in general, of nalbuphine with an opioid antagonist selected from naloxone, naltrexone, and nalmefene, as a treatment for neu
Criares Theodore J.
Kim Jennifer
The Regents of the University of California
Townsend and Townsend / and Crew LLP
LandOfFree
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