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Details for Patent: 6,890,555

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Details for Patent: 6,890,555

Title: Liposome compositions of porphyrin photosensitizers
Abstract:Liposomal pharmaceutical formulations incorporating porphyrin photosensitizers useful for photodynamic therapy or diagnosis of malignant cells. The liposomal formulations comprise a porphyrin photosensitizer, particularly the hydro-mono benzoporphyrine (BPD) having light absorption maxima in the range of 670-780 nanometers, a disaccharide or polysaccharide and one or more phospholipids.
Inventor(s): Desai; Narendra Raghunathji (Danbury, CT), Agha; Bushra J. (Durham, NC), Kale; Kalidas Madhavrao (Harriman, NY), Lawter; James R. (Goshen, NY)
Assignee: QLT, Inc. (Vancouver, CA)
Filing Date:Jun 08, 2000
Application Number:09/589,358
Claims:1. A liposomal formulation comprising liposomes that comprise phosphatidyl choline, phosphatidyl glycerol and a porphyrin macrocycle photosensitizer, wherein said liposomes have a mean particle size distribution of between about 130 nm and less than 200 nm.

2. The liposomal formulation of claim 1 in freeze dried form.

3. The liposomal formulation of claim 1 wherein the lipid bilayer of said liposomes consists essentially of dimyristoyl phosphatidyl choline and egg phosphatidyl glycerol.

4. The liposomal formulation of claim 1 wherein said porphyrin macrocycle photosensitizer is a hydro-monobenzoporphyrin (Gp) of any one of the following formulas ##STR3## ##STR4## and having a light absorption maximum between 670-780 nm, mixtures thereof, and the metalated and labeled forms thereof, wherein each R.sup.1 and R.sup.2 is independently selected from the group consisting of carbalkoxy (2-6C), alkyl (1-6C) sulfonyl, aryl (6-10C) sulfonyl, aryl (6-10C); cyano; and --CONR.sup.5 CO-- wherein R.sup.5 is aryl (6-10C) or alkyl (1-6C); each R.sup.3 is independently carboxyalkyl (2-6C) or a salt, amide, ester or acylhydrazone thereof, or is alkyl (1-6C); and R.sup.4 is --CH.dbd.CH.sub.2, --CHOR.sup.4', --CHO, --COOR.sup.4', --CH(OR.sup.4')CH.sub.3, --CH(OR.sup.4')CH.sub.2 OR.sup.4', --CH(SR.sup.4')CH.sub.3, --CH(NR.sup.4'.sub.2)CH.sub.3, --CH(CN)CH.sub.3, --CH(COOR.sup.4')CH.sub.3, --CH(OOCR.sup.4')CH.sub.3, --CH(halo)CH.sub.3, or --CH(halo)CH.sub.2 (halo), wherein R.sup.4' is H, alkyl (1-6) optionally substituted with a hydrophilic substituent, an organic group of less than 12C resulting from direct or indirect derivatization of vinyl, or 1-3 tetrapyrrole-type nuclei of the formula --L--P wherein --L-- is selected from the group consisting of: ##STR5## and P is selected from the group consisting of Gp which is of the formula of FIGS. 1-2, but lacking R.sub.4 and conjugated through the position shown as occupied by R.sup.4 to L; with the proviso that, if R.sup.4 is --CH.dbd.CH.sub.2, both R.sup.3 groups cannot be carbalkoxyethyl.

5. The liposomal formulation of claim 4 wherein each R.sup.3 is --CH.sub.2 CH.sub.2 COOH or salt, amide, ester or acylhydrazone thereof.

6. The liposomal formulation of claim 4 wherein each of R.sup.1 and R.sup.2 is carbalkoxy (2-6C).

7. The liposomal formulation of claim 5 wherein each of R.sup.1 and R.sup.2 is carbalkoxy (2-6C).

8. The liposomal formulation of claim 4 wherein said hydro-monobenzoporphyrin (Gp) is selected from the group consisting of: BPD-DA wherein R.sup.1 and R.sup.2 thereof are carbomethoxy; BPD-DB wherein R.sup.1 and R.sup.2 thereof are carbomethoxy; BPD-MA wherein R.sup.1 and R.sup.2 thereof are carbomethoxy and R is methyl; and BPD-MB wherein R.sup.1 and R.sup.2 thereof are carbomethoxy and R is methyl.

9. The liposomal formulation of claim 8 wherein said hydro-monobenzoporphyrin (Gp) is BPD-MA wherein R.sup.1 and R.sup.2 thereof are carbomethoxy and R is methyl.

10. The liposomal formulation of claim 3 wherein the amounts of photosensitizer, dimyristoyl phosphatidyl choline, and egg phosphatidyl glycerol in said liposomes are, relative to each other on a per weight basis, about 0.2 to 0.4 of porphyrin; 0.94 to 1.88 of dimyristoyl phosphatidyl choline; and 0.65 to 1.30 of egg phosphatidyl glycerol.

11. The liposomal formulation of claim 10 wherein the amount of sugar, relative to said amounts of photosensitizer, dimyristoyl phosphatidyl choline, and egg phosphatidyl glycerol in said liposomes on a per weight basis, is about 8.0 to 12.0 of sugar when said sugar is a disaccharide, or about half that amount if said sugar is a monosaccharide.

12. The liposomal formulation of claim 3 further comprising an antioxidant.

13. The liposomal formulation of claim 12 wherein said antioxidant is butylated hydroxytoluene or L-ascorbic acid 6-palmitate.

14. The liposomal formulation of claim 1 further comprising a pharmaceutically acceptable excipient.

15. A method of providing photodynamic therapy to a subject comprising administering a formulation according to claim 1 to said subject wherein the porphyrin macrocycle photosensitizer, after release from said formulation, is capable of localizing to target tissues or cells, and irradiating said tissues or cells at an appropriate wavelength of light after passage of sufficient time for said porphyrin macrocycle photosensitizer to localize.

16. A method of providing photodynamic therapy to a subject comprising administering a formulation according to claim 3 to said subject wherein the porphyrin macrocycle photosensitizer, after release from said formulation, is capable of localizing to target tissues or cells, and irradiating said tissues or cells at an appropriate wavelength of light after passage of sufficient time for said porphyrin macrocycle photosensitizer to localize.

17. The liposomal formulation of claim 1 wherein the ratio of sugar to phospholipid is about 10-20 to 0.5-6.

18. The liposomal formulation of claim 17 wherein the ratio of sugar to phospholipid is 10 to 1.5-4.0.

19. The liposomal formulation of claim 1, wherein said liposomes are fast breaking and rapidly release the photosensitizer into the bloodstream to associate with lipoproteins upon in vivo administration.

20. The liposomal formulation of claim 1, wherein the osmolarity of said liposomes is that of human blood.

21. A pharmaceutical composition comprising the liposomal formulation of claim 1.

22. The liposomal formulation of claim 1, wherein said phosphatidyl choline is dimyristoyl phosphatidyl droline.

23. The liposomal formulation of claim 1, wherein said phosphatidyl glycerol is egg phosphatidyl glycerol.

24. The liposomal formulation of claim 1, wherein said liposomes further comprise one or more sugars.

25. The liposomal formulation of claim 24, wherein said sugars are selected from disaccharides or polysaccharides.

26. The liposomal formulation of claim 25 wherein said disaccharides are selected from lactose or trehalose.
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