Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2002-06-17
2003-10-21
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
active
06635628
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to camptothecin compounds, in particular, irinotecan hydrochloride composition formulations, and methods of administering camptothecin compounds such as irinotecan hydrochloride for the treatment of cancer and AIDS, with reduced side effects.
BACKGROUND OF THE INVENTION
Camptothecin is a quinoline-based alkaloid found in the barks of the Chinese Camptotheca tree and the Asian nothapodytes tree. It is a close chemical relative to aminocamptothecin, CPT-11 (irinotecan), DX-8951F and topotecan. These compounds are useful in treating breast cancers, ovarian cancer, colon cancer, malignant melanoma, small cell lung cancer, thyroid cancers, lymphomas and leukemias. These compounds are also used for the treatment of AIDS.
Irinotecan hydrochloride (CPT-11) (4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino)carbonyloxy]1H-pyrano [3′,4′:6,7] indolizino[1,2-b]quinoline-3,14(4 h, 12H)dione hydrochloride, has a novel mechanism of antitumor activity, namely the inhibition of DNA topoisomerase I. Topoisomer-ases are the enzymes which wind and unwind the DNA that makes up the chromosomes. As the chromosomes must be unwound to make proteins, camptothecin compounds keep the chromosomes wound tight so that they cannot make proteins. Because cancer cells grow at a much faster rate than normal cells, they are more vulnerable to topoisomerase inhibition than normal cells.
CPT-11 has shown effective antitumor activity clinically (2, 3), and, recently, a survival benefit by CPT-11 was shown in colorectal cancer. However, it has major toxicities of leukopenia and diarrhea in clinical practice. The clinical use of CPT-11 at higher dosages was associated with an unexpected and significant incidence of diarrhea (4, 6, 7, 12), and diarrhea is now recognized as a dose-limiting toxicity of this drug (4-7). Although many pharmacokinetic analyses, which have shown a great interpatient variability, have been made to predict the incidence of diarrhea, there are somewhat conflicting results (8-11).
CPT-11 and its metabolites, SN-38 and SN-38-Glu, were detected in not only human plasma but also human bile. Of the three compounds, SN-38 has strong cytotoxicity, SN-38-Glu is a deactivated, glucuronidated form of SN-38, and CPT-11 has much less cytotoxicity compared to SN-38. These compounds have an &agr;-hydroxy-3-lactone ring, which undergoes reversible hydrolysis at a rate that depends mainly on pH (15, 16, 17). At more than physiological pH, the lactone form is unstable and the equilibrium favors hydrolysis to open the lactone ring and yield the carboxylate form. Under acidic conditions, the reverse reaction, with formation of the lactone, is favored. Similar reactions also occur with CPT-11 and SN-38-Glu.
From several reports, it is considered that major metabolic pathways in human are as follows; CPT-11 is hydrolyzed by carboxylesterase of mainly liver origin to the active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38). Some of SN-38 undergoes subsequent conjugation by the hepatic enzyme, UDP-glucuronyltransferase, to SN-38 &bgr;-glucuronide (SN-38-Glu), and is excreted into bile along with the other components, CPT-11 and SN-38 (13, 14). The three compounds are believed to be reabsorbed by intestinal cells to enter the enterohepatic circulation. Recently, it has been found that hepatic cytochrome P-450 3A enzymes metabolize CPT-11 to 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin, which has 500-fold weaker antitumor activity than SN-38 (Rivory et al., 1996b; Haaz et al., 1997). CPT-11, SN-38 and SN38-Glu have an &agr;-hydroxy-3-lactone ring, which undergoes reversible hydrolysis at a rate which is mainly pH-dependent (Fassberg et al., 1992). At physiological pH and higher, the lactone form is unstable and the equilibrium favors hydrolysis to open the lactone ring and yield the carboxylate form. Under acidic conditions, lactone-carboxylate interconversion is shifted toward the lactone form. CPT-11, SN-38 and SN38-Glu are excreted into bile and along with it are released into the small intestinal lumen (Atsumi et al., 1991; Lokiec et al., 1995; Chu et al., 1997a, b). Furthermore, although minor (Atsumi et al 1995), an additional pathway involves direct transport of CPT-11 and its metabolites from serum to lumen across the intestinal epithelial cells. Once in the intestine, SN38-Glu can be deconjugated in the cecum and colon to SN-38 by bacterial &bgr;-glucuronidase (Takatsuna et al., 1996). CPT-11, SN-38 and SN38-Glu are believed to be reabsorbed to a certain extent by intestinal cells and to enter the enterohepatic circulation.
To date, there is little information about the intestinal uptake and transport mechanism of CPT-11 and its derivatives. This knowledge is a critical step in the understanding of the mechanism by which CPT-11 induces diarrhea. In the present study, the uptake of CPT-11 and SN-38 by intestinal epithelial cells was estimated and correlated to their respective effect on cell toxicity.
The structure of several camptothecin derivatives are known.
In addition, U.S. Pat. No. 5,552,154 discloses that camptothecin (CPT) and derivatives thereof of the closed lactone ring form are administered intramuscularly or orally. In such cases, it was possible to obtain total remissions of a vast spectrum of human cancers without the toxicity observed previously with CPT Na+. The derivatives of CPT used were 9-Amino-20 (S)-Camptothecin (9AC). 9-Nitro-20(S)-Camptothecin (9NO
2
).
U.S. Pat. No. 5,468,754 describes that CPT 11 and other camptothecin derivatives undergo an alkaline, pH-dependent hydrolysis of the E-ring lactone. The slow reaction kinetics allow one to assess whether both lactone and non-lactone forms of the drug stabilize the topoisomerase-cleaved DNA complex. Studies indicate that only the closed lactone form of camptothecin helps stabilize the cleavable complex. Therefore, the patent recommends that pH levels of below 7 be used to allow the lactone form of camptothecin to predominate. The patent suggests the administration of the compounds with a pharmaceutically acceptable acid.
U.S. Pat. No. 5,447,936 describes that the HECPT form of the drug is more effective in inhibiting topoisomerase-I in an acidic environment, than in cells having higher intracellular pH levels. The patent describes the administration of the drug with an acid which is an organic carboxylic acid such as citric acid.
U.S. Pat. No. 5,225,404 describes the administration of a camptothecin compound with water-based solvents for water-soluble compounds such as normal saline or phosphate buffered saline solutions. The patent indicates that signs of diarrhea and cystitis were prevented and no overall toxicity was obtained.
U.S. Pat. No. 5,637,770 describes the creation of a hexacyclic compound obtained by the addition of a water-soluble ring to camptothecin, which had superior characteristics to camptothecin. U.S. Pat. No. 5,633,016 describes a combination cancer therapy including administering an effective amount of topotecan with cisplatin.
U.S. Pat. No. 5,633,260 discloses a 7-11-substituted camptothecin derivative. The patent also describes that maintaining an acidic pH (3 to 4) in the formulation is important to reduce the slow conversion of 11,7-HECPT lactones with the E-ring-hydrolyzed carboxylate which occurs at physiological pH. This patent prescribes regulated dosages to eliminate toxicity of the compound.
U.S. Pat. No. 5,652,244 describes a method of treating human carcinoma with camptothecin derivatives. U.S. Pat. No. 5,658,920 describes a hexacyclic compound derivative of camptothecin.
U.S. Pat. No. 5,597,829 discloses that CPT is excreted unchanged by the kidneys, although a large percentage of the drug administered cannot be accounted for in the urine. The patent suggests that enhanced renal excretion of the carboxylate form of CPT occurs when exposed to a pH lower than 5. Therefore, it is recommended the administration of the drug to assure an acidic pH value by a
Bouscarel Bernard
Kobayashi Kunihiko
Antonelli Terry Stout & Kraus LLP
Goldberg Jerome D.
The George Washington University
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