Patent Application: US-201514878515-A

Abstract:
a treatment of cancer , such as , for example , bladder cancer , uses a formulation that contains sodium hypericinate that is bonded to polyvinylpyrrolidone or complexed with polyvinylpyrrolidone .

Description:
surprisingly enough , it has been shown that the formulation of hypericin according to the invention can be applied in a stable manner and thus under clinical conditions in the therapy according to the invention only when hypericin is present as a salt . an evaluation of the therapy according to the invention with use of the formulation of hypericin according to the invention in animal experiments has shown , surprisingly enough , that in the case of a dose of 30 μm of hypericin in a stable formulation with pvp according to example 1 , a required light intensity of 5 or 25 mw / cm 2 at a wavelength of 595 nm and a 120 - minute exposure time in the bladder ( instillation time ) is sufficient to kill 98 % of the tumor cells . the same result of 98 % killed tumor cells is also achieved at the same light intensity and 40 μm of hypericin at a 15 - or 30 - minute exposure time and treatment with light of a wavelength of 610 nm . also , an instillation time of 1 hour , with 20 μm of hypericin , equal light intensity , and 570 nm of light frequency , achieves a kill rate of 97 %, and an instillation time of 120 minutes , with 9 μm of hypericin , equal light intensity , and treatment at 600 nm , achieves a kill rate of 95 %. thus , in the case of light intensities of 5 to 25 mw / cm 2 with light frequencies of 570 to 610 nm , hypericin concentrations of 9 to 40 μm , and exposure times of between 15 and 120 minutes , a kill rate of 95 to 98 % of the tumor cells ( practical examples 1 , 2 , 3 , and 4 ) is achieved . the effectiveness of a pdt is essentially dependent upon the total amount of light . at the same time , the probability of local side effects is increased with increasing light intensity . using therapy according to the invention , in particular with use of the formulation according to the invention , an improved accumulation in malignant tissue is achieved , by which a considerably reduced light intensity of already 5 to at most 25 mw / cm 2 is sufficient in order to kill tumor cells . the selective concentration of the formulation of hypericin according to the invention and the surprisingly low light intensity , which was required for a pdt in the animal model during application of the formulation of hypericin according to the invention , allows the application in the treatment of lesions in various cavities of the body that can be reached with the necessary light dose . below , examples of the formulation of hypericin ( hypericin - pvp complex ) according to the invention are presented . general procedure for the production of a formulation with the active ingredient sodium hypericinate : the goal is the production of a hypericin - containing formulation for application as a photosensitizer in the field of photodynamic therapy . the formulation according to the invention is produced from a hypericin salt , in particular from sodium hypericinate . in order to define the hypericin content of the starting material , in addition to the determination of contents , primarily water content and , in the case of sodium hypericinate , the proportion of sodium are specified . the chemical - physical properties can have an influence on the formulation of the pharmaceutical agent . for the clinical application , a stability of the formulation according to the invention is necessary . the stability is ensured through the composition of the finished product and at the same time also relates to the production method . because of the buffer systems used , adequate stability of the bulk solution can also be achieved during production until lyophilization of the finished product takes place . as buffer systems , various additives can be used , which preferably both for the bulk solution and for the reconstituted solution achieve a physiologically compatible ph and an osmotic pressure of 290 mosmol / kg after reconstitution with 50 ml of water for injection . phosphate or citrate buffer systems can be used primarily . after the bulk solution is made up from the above - mentioned components , the corresponding amount of the bulk solution is decanted into injection flasks and freeze - dried . from sodium hypericinate , a solution with a target weighed - in amount of 90 . 0 mg of hypericin is produced . 5 . 0 g of the hypericin solution is added to 1 , 875 mg of pvp k25 and completely dissolved . this solution is quantitatively made up to 250 . 0 g with a phosphate buffer solution . the final concentration of this solution is 0 . 0225 mg of hypericin / g of solution . for lyophilization , a defined amount of the thus obtained bulk solution is decanted into injection flasks , and the finished lyophilizate is produced with a corresponding lyo program . the procedure is the same as indicated in example 1 , whereby instead of pvp k25 , pvp k17 is used for complexing sodium hypericinate . the procedure is the same as indicated in example 1 , whereby instead of pvp k25 , pvp k30 is used for complexing sodium hypericinate . the procedure is the same as indicated in examples 1 , 2 , or 3 , whereby instead of the phosphate buffer solution , a citric acid buffer solution is used . the bulk solutions that are produced as described in examples 1 to 4 can be produced with different hypericin contents . the effectiveness of the therapy according to the invention with use of the formulation of hypericin according to the invention was examined in a preclinical study with use of the formulation as example 1 . to this end , the formulation of hypericin according to the invention for the pdt was studied in a preclinical , orthotopic bladder tumor model in rats . in all examples , the tumors were treated with the formulation of hypericin according to the invention in different concentrations of 9 to 40 μm , with different light intensities of 5 or 25 mw / cm 2 , different light frequencies of 570 to 610 nm , and different instillation times . after a 2 - hour instillation with 30 μm of the formulation of hypericin according to the invention and different light intensities ( 5 or 25 mw / cm 2 ) with light of a wavelength of 595 nm , up to 98 % of the tumor cells were killed . after a 1 - hour instillation with 20 μm of the formulation of hypericin according to the invention and different light intensities ( 5 or 25 mw / cm 2 ) with light of a wavelength of 570 nm , up to 97 % of the tumor cells were killed . after a 15 - or 30 - minute instillation with 40 μm of the formulation of hypericin according to the invention and different light intensities ( 5 or 25 mw / cm 2 ) with light of a wavelength of 610 nm , up to 98 % of the tumor cells were killed . after a 2 - hour instillation with 9 μm of the formulation of hypericin according to the invention and different light intensities ( 5 - 25 mw / cm 2 ) with light of a wavelength of 600 nm , up to 95 % of the tumor cells were killed . the results of the studies on the rat model are presented in the figure . in the diagrams , “ ns ” stands for “ not significant ,” and “*” stands for “ significant .” the diagrams of the figure show the survival of tumor cells after treatment with the formulation of hypericin according to the invention and light . 24 hours after the treatment , the bladder tissue was dissociated , and the surviving cells were determined using a clonogenic assay in comparison to the control ( without pvp - hypericin and light ). the relative survival of the cells under pdt conditions ( pvp - hypericin according to example 1 and treatment with light ) is ( depicted as mean value + sd ): 7 . 4 (+/− 6 . 4 )% with use of 5 mw / cm 2 and 2 . 4 (+/− 4 . 0 )% at 25 mw / cm 2 and a treatment period with light of 60 minutes . this is depicted in two diagrams in the figure . agostinis , p . ; berg , k . ; cengel , k . a . ; foster , t . h . ; girotti , a . w . ; gollnick , s . o . ; hahn , s . m . ; hamblin , m . r . ; juzeniene , a . ; kessel , d . ; korbelik , m . ; moan , j . ; mroz , p . ; nowis , d . ; piette , j . ; wilson , b . c . ; golab , j . photodynamic therapy of cancer : an update . ca cancer j clin . 2011 july - august ; 61 ( 4 ): 250 - 281 agostinis p . ; vantieghem , a . ; merlevede , w . ; de witte , p . a . hypericin in cancer treatment : more light on the way . int j biochem cell biol . 2002 march ; 34 ( 3 ): 221 - 241 allison , r . r . ; sibata , c . h . oncologic photodynamic therapy photosensitizers : a clinical review . photodiagnosis photodyn ther . 2010 june ; 7 ( 2 ): 61 - 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