Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2001-08-27
2003-03-04
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S400000, C424S436000, C424S448000, C424S435000, C424S422000, C424S449000, C514S654000
Reexamination Certificate
active
06528082
ABSTRACT:
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not applicable.
REFERENCE TO A “MICROFICHE APPENDIX”
Not Applicable
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention pertains to methods and pharmaceutical compositions for using the selegiline metabolite R(−) desmethylselegiline (also referred to simply as “desmethylselegiline” or “R(−)DMS”) alone; its enantiomer ent-desmethylselegiline (also referred to as “S(+)desmethylselegiline” or “S(+)DMS”) alone; or a combination, such as, for example, a racemic mixture, of the two enantiomers. In particular, the present invention provides compositions and methods for using these agents in the treatment of selegiline-responsive diseases and conditions, particularly diseases or conditions involving neoplastic cells, such as cancerous cells, or those cells that proliferate for no physiologically advantageous purpose.
2. Description of Related Art
Two distinct monoamine oxidase enzymes are known in the art: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). The cDNAs encoding these enzymes show different promoter regions and distinct exon portions, indicating they are encoded independently at different gene positions. In addition, analysis of the two proteins has shown differences in their respective amino acid sequences.
The first compound found to selectively inhibit MAO-B was (R)-N-&agr;-dimethyl-N-2-propynylbenzeethanamine, also known as L-(−)-N-&agr;-N-2-propynylphenethylamine, (−)-deprenil, L-(−)-deprenil, R-(−)-deprenyl, or selegiline. Selegiline has the following structural formula:
Selegiline is the active ingredient of a human drug product and is known in the art as a component of a therapeutic package. In particular, see Physicians Desk Reference (1995) pp. 2430-2432 (1995 PDR), describing Eldepryl® Tablets, manufactured by Somerset Pharmaceutical, Inc. and marketed by Sandoz, the active ingredient of which is selegiline. For example, the 1995 PDR describes a 5 mg selegiline hydrochloride tablet and further describes the manner in which selegiline-containing therapeutic packages are supplied for commercial use or sale. In particular, the 1995 PDR discloses that 5.0 mg Eldepryl Tablets are sold in “NDC 39506-011-25 bottles of 60 tablets.”
In commercial use, selegiline-containing therapeutic packages are labeled and otherwise indicated for use in Parkinsonian patients receiving levodopa/carbidopa therapy. The 1995 PDR cited above provides an example of the complete approved labeling that is employed in known therapeutic packages. Accordingly, known in the prior art are therapeutic packages providing one or more unit doses of selegiline as an active ingredient thereof, supplied in a finished pharmaceutical container that contains said unit doses, and further contains or comprises labeling directing the use of said package in the treatment of a human disease or condition as described above.
In addition to Parkinson's disease, other diseases and conditions for which selegiline is disclosed as being useful include: drug withdrawal (WO 92/21333, including withdrawal from psychostimulants, opiates, narcotics, and barbiturates); depression (U.S. Pat. No. 4,861,800); Alzheimer's disease and Parkinson's disease, particularly through the use of transdermal dosage forms, including ointments, creams and patches; macular degeneration (U.S. Pat. No. 5,242,950); age-dependent degeneracies, including renal function and cognitive function as evidenced by spatial learning ability (U.S. Pat. No. 5,151,449); pituitary-dependent Cushing's disease in humans and nonhumans (U.S. Pat. No. 5,192,808); immune system dysfunction in both humans (U.S. Pat. No. 5,387,615) and animals (U.S. Pat. No. 5,276,057); age-dependent weight loss in mammals (U.S. Pat. No. 5,225,446); schizophrenia (U.S. Pat. No. 5,151,419); and various neoplastic conditions including cancers, such as mammary and pituitary cancers (see, e.g., Thyagarajan et al. (1995)). PCT published application WO 92/17169 discloses the use of selegiline in the treatment of neuromuscular and neurodegenerative disease and in the treatment of CNS injury due to hypoxia, hypoglycemia, ischemic stroke or trauma. In addition, the biochemical effects of selegiline on neuronal cells have been extensively studied (e.g., see Tatton, et al., “Selegiline Can Mediate Neuronal Rescue Rather than Neuronal Protection,”
Movement Disorders
8 (Supp. 1):S20-S30(1993); Tatton, et al., “Rescue of Dying Neurons,”
J. Neurosci. Res
. 30:666-672 (1991); and Tatton, et al., “(−)-Deprenyl Prevents Mitochondrial Depolarization and Reduces Cell Death in Trophically-Deprived Cells,” 11
th Int'l Symp. on Parkinson's Disease
, Rome, Italy, March 26-30, 1994.)
Selegiline is known to be useful when administered to a subject through a wide variety of routes of administration and dosage forms. For example U.S. Pat. No. 4,812,481 (Degussa AG) discloses the use of concomitant selegiline-amantadine in oral, peroral, enteral, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intraarterial, intracardial, intramuscular, intraperitoneal, intracutaneous, and subcutaneous formulations. U.S. Pat. No. 5,192,550 (Alza Corporation) describes a dosage form comprising an outer wall impermeable to selegiline but permeable to external fluids. This dosage form may have applicability for the oral, sublingual or buccal administration of selegiline. Similarly, U.S. Pat. No. 5,387,615 discloses a variety of selegiline compositions, including tablets, pills, capsules, powders, aerosols, suppositories, skin patches, parenterals, and oral liquids, including oil-aqueous suspensions, solutions, and emulsions. Also disclosed are selegiline-containing sustained release (long acting) formulations and devices.
Although a highly potent and selective MAO-B inhibitor, selegiline's practical use is circumscribed by its dose-dependent specificity for MAO-B, and the adverse pharmacology of selegiline metabolites generated after administration.
The selectivity of selegiline in the inhibition of MAO-B is important to its safety profile following oral administration. Inhibition of MAO-A in peripheral sites (such as, for example, gastric epithelium, liver parenchyma, and sympathetic neurons) may cause toxic side effects by interfering with the metabolism of tyramine. Tyramine is normally metabolized in the gastrointestinal tract by MAO-A but when MAO-A is inhibited, tyramine absorption is increased following consumption of tyramine-containing foods such as cheese, beer, herring, etc. This results in the release of catecholamines which can precipitate a hypertensive reaction, producing the “cheese effect.” This effect is characterized by Goodman and Gilman as the most serious toxic effect associated with MAO-A inhibitors.
Selegiline is metabolized into its N-desmethyl analog (and their various potentially harmful methamphetamines). Structurally, this N-desmethyl metabolite is the R(−) enantiomeric form R(−)DMS of a secondary amine of the formula:
Heretofore, R(−)DMS was not known to have pharmaceutically useful MAO-related effects, i.e., potent and selective inhibitory effects on MAO-B. In the course of determining the usefulness of R(−)DMS for the purposes of the present invention, the MAO-related effects of R(−)DMS were more completely characterized. This characterization has established that desmethylselegiline has exceedingly weak MAO-B inhibitory effects and no advantages in selectivity with respect to MAO-B compared to selegiline.
For example, the present characterization established that selegiline has an IC
50
value against MAO-B in human platelets of 5×10
−9
M whereas R(−)DMS has an IC
50
value of 4×10
−7
M, indicating the latter is approximately 80 times less potent as an MAO-B inhibitor than the former. Similar characteristics can be seen in the following data measuring inhibition of MAO-B and MAO-A in rat cortex mitochondrial-rich fractions:
TABLE 1
Inhibition
Blume Cheryl D.
DiSanto Anthony R.
Channavajjala Lakshmi
Somerset Pharmaceuticals, Inc.
Vinson & Elkins L.L.P.
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