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Claims for Patent: 4,866,168

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Claims for Patent: 4,866,168

Title: Hematoporphyrin derivatives and process of preparing
Abstract:To obtain tumor-selective, photosensitizing drugs useful in the localization of neoplastic tissue and treatment of abnormal neoplastic tissue such as tumors, one of two methods is used. In the first method, a hydrolyzed mixture of the products of reaction of hematoporphyrin with acetic acid and sulfuric acid is cycled through a microporous membrane system to exclude low molecular weight products. In the second method, drugs are synthesized or derived from other pyrrole compounds. The drugs: (1) include two covalently bound groups, each with four rings, some of which are pyrroles such as phlorins, porphyrins, chlorins, substituted pyrroles, substituted chlorins or substituted phlorins, each group being arranged in a ring structure, connected covalently to another group and have a triplet energy state above 37.5 kilocalories per mole; (2) are soluble in water, forming an aggregate of over 10,000 molecular weight in water and have an affinity for each other compared to serum protein such that 10 to 100 percent remain self aggregated in serum protein; and (3) are lipophyllic and able to disaggregate and attach to cell plasma, nuclear membrane, mitochondria, lysosomes and tissue. The drug obtained by the first method has an empirical formula of approximately C.sub.68 H.sub.70 N.sub.8 O.sub.11 or C.sub.68 H.sub.66 N.sub.8 O.sub.11 Na.sub.4. Neoplastic tissue retains the drug after it has cleared normal tissues and illumination results in necrosis. Moreover, other photosensitizing materials may be combined with a carrier that enters undesirable tissues and cells of the reticular endothelial system such as macrophages. These photosensitizing materials: (1) must have a triplet energy state above 3.5 kilocalories per mole; (2) cannot be easily oxidized; and (3) not physically quench any required energy state. Preferably, this photosensitizing material should be lipophlic.
Inventor(s): Dougherty; Thomas J. (Grand Island, NY), Potter; William R. (Grand Island, NY), Weishaupt; Kenneth R. (Sloan, NY)
Assignee: Health Research, Inc. (Buffalo, NY)
Application Number:06/889,829
Patent Claims: 1. A process to prepare a composition consisting essentially of 10 kd aggregates of porphyrins which are fluorescent, photosensitizing, and capable of localizing and being retained in tumor cells for a longer time than normal tissues, which process comprises

raising the pH of a hematoporphyrin derivative preparation in aqueous medium to 6.5-12 to obtain aggregates of 10 kd or greater, and

separating said aggregates from the remainder of the hematoporphyrin derivative preparation,

wherein hematoporphyrin derivative preparation has been prepared by treating hematoporphyrin hydrochloride with a mixture of acetic acid and sulfuric acid.

2. The process of claim 1 wherein the pH is approximately 9.5.

3. The process of claim 1 wherein the separation is effected by filtering in a process which retains aggregates of molecular weight above 10,000.

4. The process of claim 3 wherein the pH range of 6.5-12 is maintained during filtration.

5. The process of claim 4 wherein the pH is maintained at approximately 9.5 during filtration.

6. The process of claim 1 wherein the separation is by affinity chromatography.

7. The process of claim 6 wherein the chromatography is on a reverse phase column with a packing of 5 micron spheres, using THF as solvent.

8. The process of claim 7 wherein the reverse phase column is a C18 column and elution is successively with methanol:water:acetic acid (20:5:1) followed by tetrahydrofuran:water (4:1), and the porphyrin mixture recovered corresponds to the fourth component eluted as shown in FIG. 5.

9. The process of claim 1 wherein hematoporphyrin derivative is prepared by adding a first mixture of acetic acid and sulfuric acid to hematoporphyrin hydrochloride, stirring for one hour to obtain a second mixture, adding the second mixture to a solution of 5% soldium acetate to obtain a red precipitate, and recovering the red precipitate.

10. A composition prepared by the process of claim 1.
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