Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-10-04
2003-08-19
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S188000, C514S410000, C514S427000, C514S428000, C514S429000, C424S400000, C424S499000, C424S500000, C556S081000
Reexamination Certificate
active
06608050
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a pharmaceutically acceptable dosage form of water insoluble porphyrins, particularly metal containing porphyrins such as tin porphyrin, which can be complexed with a lipid, reconstituted from a lyophilizate and administered to a patient in the treatment of cancer and other diseases.
Porphyrins are biologically active compounds, usually consisting of four pyrrole rings. Typically, they have a centrally located metal atom and are activated by light radiation of suitable wavelength. Porphyrins display antitumor activity in photodynamic therapy (PDT) where the porphyrins are administered to a patient and localize in neoplastic tissues. Typically, the neoplastic tissues are irradiated with light at a wavelength which corresponds to an absorption band of the porphyrin resulting in the activation of the porphyrin and preferential destruction of the neoplastic tissues. It has been suggested in U.S. Pat. No. 5,162,519 to Bonnett et al. that the mechanism involved is due to the production of the highly reactive singlet oxygen which is produced by transfer of energy from the light-excited porphyrin molecule to an oxygen molecule. Such photodynamic therapy is the subject of a series of articles making up a special issue of Photochemistry and Photobiology, Volume 46, number 5, November, 1987 (hereinafter “P&P 46-5”). According to these articles, photodynamic therapy has been used in the treatment of a wide variety of cancers including such solid tumors as cancers of the bronchial tubes, bladder, esophagus, lung, skin, head and neck, brain, and colon and intraocular and gynecologic cancers.
A major disadvantage to the use of porphyrins in the treatment of cancer is that when used in high concentrations to destroy the tumor cells, the porphyrins exhibit toxic side effects. The porphyrin is generally injected intravenously or intraperitoneally at a dose of about 2 mg per kg of body weight. At lower concentrations which might be more easily tolerated by the patient, the porphyrins tend to exhibit very little effect on the tumor cells.
It has been reported that porphyrins may be incorporated into a liposome and injected intraperitoneally. Spikes et al., “Photodynamic Behavior of Porphyrins in Model Cell, Tissue and Tumor Systems”; in Photodynamic Therapy of Tumors and Other Diseases (Edited by G. Jori and C. A. Perria); pages 45-53; Libreria Progetto, Padua (1985) and references cited therein.
There is a need for compositions containing porphyrins which are effective for the treatment of cancer and yet exhibit less toxic effects towards the patient.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a less toxic pharmaceutically acceptable dosage form of porphyrins for use in therapies such as chemotherapy and photodynamic therapy.
One manifestation of the present invention is complexes of a porphyrin and a phospholipid. Another manifestation of the invention is a lyophilizate of a complex of a porphyrin and a phospholipid, and a pharmaceutically acceptable excipient. Still another manifestation of the present invention is a method for preparing a lipid complex of a porphyrin.
The lipid complexes in accordance with this invention appear to be desirable for several reasons. It appears that the lipid complexes may sufficiently slow the release of the porphyrins that the porphyrins can be administered at higher dosage levels with less toxicity thereby improving treatment. The lipid complexes also appear to be more stable to ambient light and UV radiation than the porphyrin alone thus simplifying their handling. While it has not been confirmed, the lipid complexes may also preferentially accumulate in tumor tissues.
While the invention will hereafter be described with respect to the preparation of lipid complexes and lyophilizates of lipid complexes of tin porphyrin, 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 porphyrins, particularly other metalloporphyrins.
In accordance with one embodiment of the invention, a lyophilizate of a phospholipid-porphyrin complex is prepared by a process comprising the steps of preparing a concentrated solution of a porphyrin and a phospholipid in an organic solvent, adding water to the solution to cause formation of a lipid complex of the porphyrin, removing the organic solvent 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.
In accordance with a preferred embodiment of the present invention, the lyophilizate is prepared by a method which comprises forming a concentrated solution of tin porphyrin and a mixture of dimyristoyl phosphatidylcholine (DMPC) and dimyristoyl phosphatidylglycerol (DMPG) in chloroform, adding an aqueous solution such as water for injection to form the lipid complex of tin porphyrin and provide a dispersion of the lipid complex in water as an aqueous phase, sparging the dispersion to remove the chloroform, 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 the composition, wherein a lyophilizate is obtained which upon reconstituting with water provides a colloidal dispersion of a porphyrin-lipid complex. It is possible to prepare the solution of the prophyrin and the phospholipids by dissolving the porphyrin in one organic solvent, dissolving the phospholipids in another organic solvent, mixing the two solutions, and then removing the solvents after addition of water.
DETAILED DESCRIPTION OF THE INVENTION
The term “water insoluble porphyrin” as used herein means porphyrins having a solubility in water which is less than about 1.5 mg/ml at 23° C. and, more typically, is less than 0.5 mg/ml at 23° C. and still more typically less than 0.1 mg/ml at 23° C.
The term “lipid complex” is an art recognized term. Lipid complexes are characterized by a noncovalent bond between the lipid and the porphyrin which is observed by a phase change in differential scanning calorimetry. Liposomes are not lipid complexes within the meaning of the term.
The term “pharmaceutically acceptable aqueous diluent” as used herein refers to water for injection, saline, and other known aqueous vehicles.
The term “lyophilization excipient” refers to a substance which is added to a solution prior to lyophilization to enhance characteristics such as the color, texture, strength, and volume of the cake. Examples of lyophilization excipients are provided below.
The term “photodynamic therapy” (PDT) as used herein refers to a therapy treatment of a patient having a disease such as cancer wherein the patient is treated with a drug such as a porphyrin which has the tendency to preferentially accumulate in neoplastic tissues relative to normal tissues. The drug, when irradiated becomes toxic to the neoplastic tissue.
Porphyrins are biologically active nitrogen-containing compounds having a conjugated cyclic structure consisting of four pyrrole rings linked together through their 2- and 5-positions by methine bridges. The term “porphyrin” includes derivatives wherein a metal atom is chelated into the ring structure, presumably complexed or bonded to at least two of the nitrogens of the pyrrole ring. The metal atom inserted into the ring structure includes, e.g., tin, zinc, lanthanides, actinides, and those metals of the transition series of which chromium, manganese, iron, cobalt, nickel, and copper are exemplary. The preferred porphyrins for use in the present invention are metalloporphyrins, particularly tin porphyrins
Tin porphyrin and other porphyrins useful in this invention are described in the literature. It is known to irradiate tumors and cancerous tissues in the human body with intensive light following administration of a hematoprophyrin der
Apte Shireesh Prakash
Cherian Mathew
Jones Dwayne C.
McDonnell & Boehnen Hulbert & Berghoff
Pharmacia & Upjohn Company
LandOfFree
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