Method for administering camptothecins via injection of...

Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert

Reexamination Certificate

Rate now

  [ 0.00 ] – not rated yet Voters 0   Comments 0

Details

C424S450000

Reexamination Certificate

active

06534080

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to compositions an methods for delivering camptothecin, in particular, 9-nitro-camptothecin, to patients by injection and treating diseases associated with abnormal cell proliferation such as cancer.
2. Description of Related Art
Camptothecin was isolated from the plant, Camptotheca acuminata, in the 1960's (Wall, M. et al. (1966) J. Am. Chem. Soc. 88: 3888-3890). Camptothecin has a pentacyclic ring system with only one asymmetric center in ring E with a 20(S)-configuration. The pentacyclic ring system includes a pyrrole quinoline moiety (rings A, B and C), a conjugated pyridone (ring D), and a six-membered lactone (ring E) with an &agr;-hydroxyl group (i.e., an &agr;-hydroxy lactone).
Camptothecin itself is highly lipophilic and poorly water-soluble. Sodium camptothecin that is solubilized by sodium hydroxide in water was used in clinical trials in the early 70's and found to have antitumor activity. However, this formulation of camptothecin administered via i.v. caused unpredictable side effects such as myelosuppression and hemorrhagic cystitis. Clinical trials with sodium camptothecin were eventually discontinued because of these toxicities and the lack of consistent antitumor activity.
Continued evaluation of this agent showed that the sodium carboxylate salt is only 10% as potent as the native camptothecin with the closed &agr;-hydroxy lactone ring intact (Wall et al. in (1969) “International Symposium on Biochemistry and Physiology of the Alkaloids, Mothes et al. eds. Academic Verlag, Berlin, 77; Giovanella et al. (1991) Cancer Res. 51:3052). Studies also showed that camptothecin and its derivatives undergo an alkaline hydrolysis of the E-ring &agr;-hydroxy lactone, resulting in a carboxylate form of camptothecin. At pH levels below 7.0, the &agr;-hydroxy lactone E-ring form of camptothecin predominates. However, intact lactone ring E and &agr;-hydroxyl group have been shown to be essential for antitumor activity of camptothecin and its derivatives.
Camptothecin and its derivatives have been shown to inhibit DNA topoisomerase I by stabilizing the covalent complex (“cleavable complex”) of enzyme and strand-cleaved DNA. Inhibition of topoisomerase I by camptothecin induces protein-associated DNA single-strandbreaks which occur during the S-phase of the cell cycle. Since the S-phase is relatively short compared to other phases of the cell cycle, longer exposure to camptothecin should result in increased cytotoxicity of tumor cells. Studies indicate that only the closed &agr;-hydroxy lactone form of the drug helps stabilize the cleavable complex, leading to inhibition of the cell cycle and apoptosis.
To preserve the &agr;-hydroxy lactone form of camptothecin, camptothecin and its water insoluble derivatives have been dissolved in N-methyl-2-pyrrolidinone in the presence of an acid (U.S. Pat. No. 5,859,023). Upon dilution with an acceptable parenteral vehicle, a stable solution of camptothecin was obtained. The concentrated solution of camptothecin was also filled in gel capsules for oral administration. It is believed that such formulations increase the amount of lipophilic &agr;-hydroxy lactone form of camptothecin that diffuse through the cellular and nuclear membranes in tumor cells.
T. G. Burke, A. E. Staubus, A. K. Mishra and H. Malak (“Liposomal Stabilization of Camptothecin's Lactone Ring.” J. Am. Chem. Soc. 1992, 114, 8318) and T. G. Burke, A. K. Mishra, M. C. Wani and M. E. Wall (“Lipid bilayer partitioning and stability of camptothecin drugs.” Biochemistry 1993 May 25;32 (20):5352-64) have demonstrated that harboring of camptothecin drugs into phospholipid bilayer membranes stabilized the &agr;-hydroxy lactone moiety of camptothecin drugs against hydrolysis. In comparison to hydrolysis half-lives in PBS at 37° C. of approximately 15 to 30 min, lipid bilayer membrane-bound camptothecin drugs were found to be stable even for periods up to 72 hours. These authors have determined an iodide ion induced quenching behavior of camptothecin's fluorescence indicative of intercalation of camptothecin molecules between the phospholipid acyl chains of membrane bilayers, a protected environment removed from the aqueous interface. The potential for stabilization of camptothecin's &agr;-hydroxy lactone ring structure in this environment led to the expectation that lipid bilayer intercalation might conserve the biologically active form in vivo, thereby permitting the active form to be delivered via liposomal bilayers into a biological host (U.S. Pat. No. 5,552,156).
Z Mi and T. G. Burke (“Differential interactions of camptothecin lactone and carboxylate forms with human blood components.” Biochemistry 1994 Aug 30;33 (34):10325-36) exploited the intrinsic fluorescent emissions from the &agr;-hydroxy lactone and carboxylate forms of camptothecin in order to elucidate their markedly different interactions with the various components of human blood. It was found that in PBS at pH 7.4, human serum albumin (HSA) preferentially binds the carboxylate form of camptothecin with a 150-fold higher affinity than the &agr;-hydroxy lactone form. These interactions cause camptothecin's &agr;-hydroxy lactone ring to open more rapidly and completely in the presence of HSA than in the protein's absence. In human plasma, at pH 7.4 and 37° C., they have observed camptothecin's &agr;-hydroxy lactone ring to open rapidly and fully to the carboxylate form (half-life=11 min; % &agr;-hydroxy lactone at equilibrium, 0.2%). They concluded that camptothecin carboxylate's fluorophore locates in a hydrophobic binding pocket in native HSA. In whole blood versus plasma, camptothecin's &agr;-hydroxy lactone was found to display enhanced stability resulting in an increased half-life of 22 min and an equilibrium &agr;-hydroxy lactone concentration of 5.3%. The enhanced stability of camptothecin in human blood was found to be due to drug associations with the lipid bilayers of red blood cells. Although camptothecin &agr;-hydroxy lactone hydrolysis slows down and the equilibrium &agr;-hydroxy lactone form concentration rises on intercalation within phospholipid bilayers, the membrane-bound drug still remains thermodynamically and kinetically too labile in the presence of albumin and the concentration of the active &agr;-hydroxy lactone form in plasma remains insufficient. Thus, the liposomal bilayers cannot be considered as a pragmatic delivery system for this drug. It is speculated that a principal deactivation channel of membrane bilayer-bound camptothecin is facilitated via high affinity of the carboxylate form of the drug with albumin in-vivo compared to a relatively lower affinity of the &agr;-hydroxy lactone form of the drug with the membrane bilayers.
U.S. Pat. Nos. 5,552,156 and 5,736,156 describe liposomes and micelles of surfactant molecules for intravenous delivery of camptothecins. In liposomes, the camptothecin can reside bound to and partially in the membrane interlayer or dissociate into the internal enclosed aqueous layer in direct contact with water where the camptothecin lactone is not stable to hydrolysis. In micelles of surfactant molecules, the camptothecin is either in the central hydrocarbon portion of the micelle, bound to the micelle membrane or bound to the outside of the micelle. However, while camptothecins are less stable in micelles than in liposomes, especially in poly(ethylene oxide)-containing micelles, the amount of camptothecin compound that can bind to the membrane layer in a liposome is limited to the dimensions of the membrane and to the requirement that the membrane remain intact to prevent rupture of the liposome. The ratio of lipid to camptothecin in liposomes is generally greater than 150, and the lactone of the camptothecin slowly hydrolyzes because of the reported equilibrium between bound and free camptothecin.
SUMMARY OF THE INVENTION
The present invention provides novel injectable formulations of camptothecin, including analogs, derivatives

LandOfFree

Say what you really think

Search LandOfFree.com for the USA inventors and patents. Rate them and share your experience with other people.

Rating

Method for administering camptothecins via injection of... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Method for administering camptothecins via injection of..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for administering camptothecins via injection of... will most certainly appreciate the feedback.

Rate now

     

Profile ID: LFUS-PAI-O-3039964

  Search
All data on this website is collected from public sources. Our data reflects the most accurate information available at the time of publication.