Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-03-13
2002-12-17
Pryor, Alton (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
active
06495605
ABSTRACT:
1. FIELD OF THE INVENTION
This invention relates to methods and pharmaceutical compositions for aiding smoking cessation, treating nicotine addiction, and pain, including chronic pain, neuropathetic pain and reflex sympathetic dystrophy, and other disorders.
2. BACKGROUND OF THE INVENTION
Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes (+) and (−) or d and l are employed to designate the sign of rotation of plane-polarized light by the compound, with (−) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric or racemic mixture.
Stereochemical purity is of importance in the field of pharmaceuticals, where 16 of the 20 most prescribed drugs exhibit chirality. A case in point is provided by the L-form of the &bgr;-adrenergic blocking agent, propranolol, which is known to be 100 times more potent than the D-enantiomer.
Furthermore, optical purity is important since certain isomers may actually be deleterious rather than simply inert. For example, it has been suggested that the D-enantiomer of thalidomide was a safe and effective sedative when prescribed for the control of morning sickness during pregnancy, while the corresponding L-enantiomer was a potent teratogen.
Bupropion is available only as a racemic mixture. That is, bupropion is available as an approximate 50/50 mixture of optical isomers, called enantiomers. The racemic mixture of bupropion which is commercially available is administered as a hydrochloride salt. In addition, European Patent Application No. 84101070.5 published Sep. 12, 1984 discloses the benefits of bupropion maleate over bupropion hydrochloride. The racemic mixture of bupropion is available as Wellbutrin® and Wellbutrin SR® for the treatment of depression and Zyban® to achieve smoking cessation, respectively.
Bupropion is used primarily in the treatment of depression, which along with mania, falls under the heading of affective disorders. Particularly, racemic bupropion is used in patients who do not respond to, or cannot tolerate other antidepressants, such as the tricyclic agents or monoamine oxidase inhibitors. Additionally, the racemic mixture of bupropion is useful in the management of patients with bipolar and schizo-affective disorder, attention-deficit disorder, psycho-sexual dysfunction, bulimia and other eating disorders, and Parkinson's disease.
Affective disorders, including major depression, and the bipolar, manic-depressive illness, are characterized by changes in mood as the primary clinical manifestation. Major depression, the most common of the significant mental illnesses, is characterized by feelings of intense sadness, and despair, mental slowing and loss of concentration, pessimistic worry, agitation, and self-deprecation. Physical changes can also occur, including insomnia, anorexia, and weight loss, decreased energy and libido, and disruption of hormonal circadian rhythms.
Through an as yet unknown mechanism of action, bupropion has been demonstrated to be an effective treatment in depression in short-term and longer duration clinical studies. The racemic mixture of bupropion has been reported to have antidepressant activity equal to amitriptyline, the tricyclic antidepressant, with fewer anticholinergic, sedative and cardiovascular side effects than with amitriptyline.
As mentioned above, racemic bupropion is used primarily in the treatment of depression and in smoking cessation and is available for these indications in the United States as Wellbutrin® and WellbutrinSR® (for depression) and Zyban® for smoking cessation), respectively (Physicians Desk Reference 1998 52nd edition, pp. 1120-1127 and 1139-1144). Studies regarding the mechanism of bupropion's antidepressant activity have shown that bupropion is an atypical antidepressant that demonstrates a significant and unusual pattern of noradrenergic activity including some but not all of the effects seen after chronic administration of reuptake inhibitors. Bupropion produces a unique spectrum of biochemical effects that differ significantly from those produced by other antidepressants. However, the exact mechanism by which bupropion produces its antidepressant effects is still not completely understood. See Ascher, J. A., et al., 1995,
J. Clin. Psychiatry
56:395-401.
The persistence of cigarette smoking despite widespread public awareness of the adverse health effects in large part results from an underlying addiction to nicotine. Nicotine is a highly addictive substance, which has been said to be as addictive as heroin. A number of nicotinic receptor subtypes have been discovered, which differ in both regional distribution in the nervous system and functional significance. Nicotine binds to these nicotine receptors to open a cation channel that causes depolarization and cell firing. Nicotine has been shown to increase neuronal firing rates in ventral tegmental area dopamine cells, and nicotine enhances dopamine release in striatal areas, including the nucleus accumbeus, which is implicated in drug reinforcement. Thus, it is known that nicotine activates the dopamine reward system. This reinforcement of activation of the dopamine reward system leads to nicotine addiction and difficulty in smoking cessation.
Bupropion inhibits dopamine reuptake, although this inhibition occurs at doses higher than needed for antidepressant activity. Racemic bupropion has been reported to increase success rates in smoking cessation treatment. Rose, J. E., 1996, “Nicotine Addiction and Treatment,”
Annu. Rev. Med.
47:493-507; Ferry, L. H. et al., 1994, “Efficacy of Bupropion for Smoking Cessation in Non-Depressed Smokers,”
J. Addict. Dis.
13:A9. However, one researcher reported a case in which the cycle of smoking cessation, associated with weight gain, followed by depression and resumption of smoking was interrupted by the use of bupropion as a preventative measure. Lief, H. I., March 1996, “Bupropion Treatment of Depression to Assist Smoking Cessation,”
Am. J. Psychiatry
153:3, p. 442. In this case, it was thought that the administration of racemic bupropion had an indirect effect in preventing smoking resumption by treating the patient's depression, which had been caused by weight gain associated with smoking cessation. Cf. Ferry, L. H. et al., 1992, “Enhancement of Smoking Cessation Using the Anti-Depressant Bupropion Hydrochloride” (abstract),
Circulation
1992, 86:671; Ferry, L. H. et al., 1994, “Evaluation of Bupropion Versus Placebo for Treatment of Nicotine Dependence,” New Research Program and Abstracts, 147
th
Annual Meeting of the American Psychiatric Association, Wash., D.C., APA, pp. 199-200.
Patients who suffer from chronic pain may also experience depression. In studies on patients having chronic pain, the incidence of clinical depression ranges from 22 to 78%. Similarly, in studies on depression patients, the frequency of persistent pain complaints ranges from 30 to 100%. Bonica, J. J.,
The Management of Pain
, Second Edition, Vol. I, Chapter 18, pp. 310-319 (1990). In comparison, the occurrence of major depression in the general population is about 4 or 5% with about 3% of men and 6% of women being depressed at any given time. Thus, it is generally believed that the occurrence of depression is greater in patients with chronic pain than in the normal population, but there is no consensus on the extent to which pain and depression may coexist.
In addition, pain and depression may coexist more often in certain clinical populations, such as women, perhaps because of the higher p
McCullough John R.
Rubin Paul D.
Pennie & Edmonds LLP
Pryor Alton
Sepracor Inc.
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