Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Reexamination Certificate
1997-06-10
2003-04-15
Mullis, Jeffrey (Department: 1711)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
C424S484000, C514S283000
Reexamination Certificate
active
06548071
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a pharmaceutically acceptable dosage form for water insoluble camptothecins and, more particularly 9-amino 20(S)-camptothecin (hereafter 9-AC) and 9-amino-20(R)-camptothecin which can be reconstituted and administered to a patient intravenously or subcutaneously or formulated for oral use in the treatment of cancer and other diseases.
Camptothecin and analogues thereof, display antitumor activities against colon cancer, leukemia, and experimentally transplanted carcinoma such as leukemia L-1210 in mice or Walker 256 tumors in rats. See Potsmiesel, M., DNA Topoisomerases in Cancer. Camptothecin is a pentacyclic alkaloid including a characteristic fused 5-ring system of quinoline (rings A and B), pyroline (ring C), &agr;-pyridone (ring D) and a six-membered lactone (ring E). The intact lactone ring, ring E, and hydroxyl group at position 20 have been found to be essential to its antitumor activity.
Studies of camptothecin analogs have suggested a correlation between the compound's ability to induce DNA breakage and its antitumor activity. It has a unique mechanism of action which produces DNA damage in the presence of topoisomerase I, a monomeric enzyme that is capable of altering DNA topology in eukaryotic cells. Topoisomerase I binds to the DNA to allow the double helix to unwind and subsequently reseals the break before dissociating from the DNA strand. Camptothecin is believed to bind to and stabilize a covalent DNA-topoisomerase I complex in which one strand of the DNA helix is broken and thereby prevent the DNA from recombining.
The therapeutic use of camptothecin and its analogs has been severely limited by their poor water solubility and high toxicity. A number of attempts have been made to reduce the toxicity of camptothecin without reducing its antitumor activity through the development of derivatives. Camptothecin derivatives substituted at the 5-, 7-, 9-, 10-, and 11-positions have been investigated. At least three camptothecin derivatives are in various stages of clinical development, namely: 7-ethyl-[14-(1-piperidino)-1-piperidine] carbonyloxycamptothecin (CPT-11); 20-(S)-camptothecin; 10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)dione monohydrochloride (topotecan hydrochloride); and 9-amino-20(s)-camptothecin.
9-AC is quite water insoluble (0.002 mg/ml). This makes it difficult to formulate as a sterile, storage stable, dosage form. In studies carried out by the National Cancer Institute (NCI) 9-AC was formulated in an organic solvent, dimethylacetamide (DMA), to overcome the solubility limitations of the drug. The NCI formulation consists of 5 mg of 9-AC in 1 ml of DMA. At the point of use, the product is diluted using a diluent consisting of polyethylene glycol 400, USP, and phosphoric acid. The diluent is added to the NCI formulation in an amount of 49 ml diluent to 1 ml formulation.
The NCI formulation has drawbacks which make the formulation inconvenient for commercial use. Because the DMAC attacks rubber stoppers, the product cannot be supplied in stoppered vials and must be supplied in ampules. Ampules are inconvenient to use because they must be scored and broken to open them and this presents some risk of injury and contamination to workers. Additionally, glass chips in the product from breaking open the ampules need to be filtered out.
DMA is not a desirable vehicle for intravenous (IV) administration and a potential source of toxic side effects. DMA has an LD
50
value of 5.4 ml/kg, which is a factor which also must be considered in administering the drug.
Another approach to designing camptothecin dosage forms which has been investigated involves the use of liposomes. T. G. Burke et al. in
Biochemistry
1993, 32, 5352-64 (1993) suggest using liposomes as a drug delivery system for camptothecin. Burke et al. found that camptothecin binds with dimyristoylphosphatidylglycerol (DMPG) lipids and dimyristoylphosphatidylcholine (DMPC) lipids and is stable in both DMPC and DMPG liposome bilayers. They postulate that the lactone ring penetrates the liposome layer. The liposome-associated camptothecin showed stabilization of the lactone ring.
No satisfactory pharmaceutically acceptable formulation of 9-AC is currently available for administration to humans. There is a need for a stable pharmaceutical dosage form which may be conveniently administered to a cancer patient while retaining the structural elements that are essential for 9-AC's pharmacological activity.
SUMMARY
It is an object of the present invention to provide a pharmaceutically acceptable dosage form of 9-AC or another water insoluble camptothecin. It is another object of the present invention to provide lipid complexes of 9-AC and other water insoluble camptothecins. It is still another object of the invention to provide lyophilizates of three lipid complexes. The lyophilizate can be reconstituted with water, saline, or another electrolyte to give a colloidal dispersion for intravenous or subcutaneous administration or can be formulated into a paste or filled into a soft gelatin or hard gelatin capsule for oral administration. Previously, cam ptothecins have not been administered subcutaneously because they are necrotic. However, it appears that the lipid complex may sufficiently slow the release of water insoluble camptothecins that subcutaneous administration is possible.
While the invention will hereafter be described with respect to the preparation of lipid complexes and lyophilizates of lipid complexes of 9-AC, those skilled in the art will appreciate that the methods taught herein are also applicable to the preparation of lipid complexes and lyophilizates of other camptothecins which are considered water insoluble such as camptothecin itself.
In accordance with the present invention, a lyophilizate of a phospholipid complex of 9-AC is prepared which can be reconstituted with pharmaceutically acceptable aqueous diluent such as water for injection and which, in comparison to solutions of 9-AC in dimethylacetamide, is less toxic, more stable and particularly importantly, its formulation and administration are not limited by the solubility of 9-AC.
In accordance with the invention, the lyophilizate is prepared by a process comprising the steps of preparing a solution of 9-AC in a first organic solvent, preparing a solution of a phospholipid in a second organic solvent, mixing the phospholipid solution and the 9-AC solution, adding water to the mixed solutions to cause formation of a lipid complex of 9-AC, removing the first and second organic solvents to provide a dispersion of the lipid complex in water as an aqueous phase, dissolving a pharmaceutically acceptable excipient in the aqueous phase of the dispersion, and lyophilizing the dispersion of the lipid complex to form a lyophilizate. This lyophilizate forms a colloidal dispersion when reconstituted with a physiologically acceptable aqueous diluent.
In accordance with a preferred embodiment of the present invention, the lyophilizate is prepared by a method comprising the steps of forming a concentrated solution of 9-AC in dimethyl sulfoxide, forming a concentrated solution of the phospholipids DMPC and DMPG in chloroform, mixing the phospholipid solution and the 9-AC solution, adding an aqueous solution such as water for injection to form the lipid complex of 9-AC and provide a dispersion of the lipid complex in water as an aqueous phase, sparging and diafiltering the dispersion to remove the solvents, reducing the particle size of the dispersion of the lipid complex, adding an aqueous solution of mannitol as a pharmaceutically acceptable lyophilization excipient to the dispersion, and lyophilizing, wherein a lyophilizate is obtained which upon reconstituting with water provides a colloidal dispersion of a 9-AC lipid complex.
In accordance with a further embodiment of the present invention, a lyophilized composition containing 9-aminocamptothecin or anothe
Mullis Jeffrey
Pharmacia & Upjohn Company
Thompson Hine LLP
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