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Claims for Patent: 5,028,621

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Claims for Patent: 5,028,621

Title: Drugs comprising porphyrins
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:07/352,774
Patent Claims: 1. A biologically active composition being fluorescent, photosensitizing, and having the capability of localizing in and being retained in tumor tissue as compared to normal tissues which composition comprises conjugates containing two or more covalently-linked porphyrin molecules wherein at least one porphyrin has the formula ##STR3## wherein the bond shown attaches said porphyrin to the conjugate or the pharmaceutically acceptable salts thereof;

which conjugates form aggregates of >10 kd in aqueous environments but are sufficiently lipophilic so that said aggregates dissociate in tissue, said conjugates having triplet energy of >37.5 kcal/mol, being not readily oxidized, and not capable of physically quenching any required energy state.

2. A biologically active composition being fluorescent, photosensitizing, and having the capability of localizing in and being retained in tumor tissue as compared to normal tissues which composition comprises conjugates containing two or more covalently-linked chlorin molecules wherein at least one chlorin has the formula ##STR4## wherein the bond shown attaches said chlorin to the conjugate or the pharmaceutically acceptable salts thereof;

which conjugates form aggregates of >10 kd in aqueous environments but are sufficiently lipophilic so that said aggregates dissociate in tissue, said conjugates having triplet energy of >37.5 kcal/mol, being not readily oxidized, and not capable of physically quenching any required energy state.

3. A biologically active composition being fluorescent, photosensitizing, and having the capability of localizing in and being retained in tumor tissues as compared to normal tissues which composition comprises conjugates containing two or more covalently-linked phlorin molecules wherein at least one phlorin has the formula ##STR5## wherein the bond shown attaches said phlorin to the conjugate or the pharmaceutically acceptable salts thereof;

which conjugates form aggregates of >10 kd in aqueous environments but are sufficiently lipophilic so that said aggregates dissociate in tissue, said conjugates having triplet energy of >37.5 kcal/mol, being not readily oxidized, and not capable of physically quenching any required energy state.

4. A composition comprising porphyrins which are fluorescent, photosensitizing, and capable of localizing in and being retained in tumor cells for a longer time than in normal tissues, which composition contains porphyrin conjugates wherein at least one porphyrin has the formula ##STR6## wherein the bond shown attaches said porphyrin to the conjugate or the pharmaceutically acceptable salts thereof;

which conjugates form aggregates of >10 kd in aqueous environments but are sufficiently lipophilic so that said aggregates dissociate in tissue, said conjugates having triplet energy of >37.5 kcal/mol, being not readily oxidized, and not capable of physically quenching any required energy state and wherein said composition has adsorption peaks in the visible spectrum in water at approximately 365, 505, 537, 575 and 615 nanometers, adsorption peaks in the infrared spectrum at approximately 3.0, 3.4, 6.4, 7.1, 8.1, 9.4, 12 and 15 microns, adsorption peaks in carbon-13 nuclear magnetic resonance study at approximately 9.0, 18.9, 24.7, 34.5, 62, 94.5, 130-145, 171.7 ppm and possibly 118 and 127 relative to a 37.5 ppm resonance peak of dimethyl sulfoxide and additional adsorption peaks in carbon-13 nuclear magnetic study at approximately 27.9 ppm and 68.4 ppm relative to the resonance peak of tetramethylsilane in deuterated chloroform solvent.

5. A drug comprising:

a mixture of porphyrins;

at least some of the molecules of said porphyrin mixture having conjugates of the molecular formula: ##STR7## wherein one or more hydroxyethyl substituent is replaced by a vinyl group, wherein said porphyrins are fluorescent, photosensitizing, and capable of localizing in and being retained in tumor cells for a longer time than in normal tissues, and wherein said composition has adsorption peaks in the visible spectrum in water at approximately 365, 505, 537, 575 and 615 nanometers, adsorption peaks in the infrared spectrum at approximately 3.0, 3.4, 6.4, 7.1, 8.1, 9.4, 12 and 15 microns, adsorption peaks in carbon-13 nuclear magnetic resonance study at approximately 9.0, 18.9, 24.7, 34.5, 62, 94.5, 130-145, 171.7 ppm and possibly 118 and 127 relative to a 37.5 ppm resonance peak of dimethyl sulfoxide and additional adsorption peaks in carbon-13 nuclear magnetic study at approximately 27.9 ppm and 68.4 ppm relative to the resonance peak of tetramethylsilane in deuterated chloroform solvent, and

which conjugates form aggregates of >10 kd in aqueuos environments but are sufficiently lipophilic so that said aggregates dissociate in tissue, said conjugates having triplet energy of >37.5 kcal/mol, being not readily oxidized, and not capable of physically quenching any required energy state.

6. A pharmaceutical composition which consists essentially of the composition of claim 1 as active ingredient along with a pharmaceutically acceptable excipient.

7. A pharmaceutical composition which consists essentially of the composition of claim 2 as active ingredient along with a pharmaceutically acceptable excipient.

8. A pharmaceutical composition which consists essentially of the composition of claim 3 as active ingredient along with a pharmaceutically acceptable excipient.
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