Drug and Device System for Pressurized Aerosol Therapies into a Mammalian Hollow Space

Abstract

The invention relates to a drug and device system for the directed application of a substance into a hollow space, such as a hollow organ, or into a body cavity of a patient, i.e. a mammalian patient, in particular for use in the course of a therapeutic pneumoperitoneum. In particular, herein the present invention is for use in cancer/tumor treatment, including metastatic forms thereof, and is also directed to a kit and its use in a method of treatment, comprising the said drug and device system for the said directed application. Especially, the invention pertains to a sterile and closed prefilled drug containing (medical) device system for administering at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or preferably in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum, comprising a flexible package, comprising at least one container comprising at least one pharmaceutically active substance in powder, lyophilisate, solution, liquid, gel or other form (suspension, emulsion), and being provided with breakable, an openable, or perforable cap; and a bag of liquid diluent), wherein the bag is optionally equipped with at least one drain tube provided with a closing device; and wherein the bag is equipped with a mixing tube, optionally equipped with an openable closure, and which optionally ends with a perforation device, which container is preferably a vial, syringe, single-use syringe, ampoule, phial, or bottle, comprising the said pharmaceutically active substance, and which container is provided with breakable, an openable, or perforable cap; and wherein said package is comprising at least one flexible airtight sterile casing, containing said container, preferably a vial, syringe, single-use syringe, ampoule, phial, or bottle, of the said pharmaceutically active substance, and said perforation device, said container being housed in the casing; and wherein the said container is manually maneuverable from the outside of the casing in order to be opened inside the closed casing, optionally is manually maneuverable from the outside of the casing up to a perforating position of said cap through the same perforation device; and whereupon after opening of the said container and of the said closure, and selectively mixing (i.e. dissolving, reconstituting) the at least one pharmaceutically active substance (drug) with the liquid diluent through the mixing tube, a solution of the at least one pharmaceutically active substance (drug) in the liquid diluent is provided for administering by pressurized aerosol therapy (PAT) in a hollow organ, or preferably in a body cavity of a patient.

Claims

1. A sterile and closed prefilled drug containing device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by PAT (pressurized aerosol therapy) in a hollow organ, or preferably in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum, comprising a flexible package (100, 101), comprising: at least one container (9) comprising at least one pharmaceutically active substance (70) in powder, lyophilisate, solution, liquid, gel or other form (suspension, emulsion), and being provided with breakable, an openable, or perforable cap (60); and a bag (2) of liquid diluent (50), in particular connectable to an aerosol generating means, preferably connectable to an application lance and/or injection lance with nozzle and/or a pumping system, preferably a micro-pump, for use with an application lance and/or injection lance with nozzle, wherein the liquid diluent (50) is preferably a physiologically acceptable aqueous diluent; wherein the bag (2) is optionally equipped with at least one drain tube (4) provided with a closing device (5); preferably wherein the optional at least one drain tube (4), after removal of the closing device (5), serves as connector to an aerosol generating means, preferably as connector to an application lance and/or injection lance with nozzle and/or to a pumping system, preferably to a micro-pump, for use with an application lance and/or injection lance with nozzle; and wherein the bag (2) is equipped with a mixing tube (6), optionally equipped with an openable closure (7), and which optionally ends with a perforation device (8), or which optionally ends with a coupling and perforation device (8), for a container (9), which container (9) is preferably a vial, syringe, single-use syringe, ampoule, phial, or bottle (9), comprising the pharmaceutically active substance (70) in powder, lyophilisate, solution, liquid, gel or other form (suspension, emulsion), and which container (9) is provided with breakable, an openable, or perforable cap (60); and wherein said package (100, 101) is comprising at least one flexible airtight sterile casing (12), containing said container (9), preferably a vial, syringe, single-use syringe, ampoule, phial, or bottle (9), of the said pharmaceutically active substance, and said perforation device (8), optionally the said coupling and perforation device (8), said container (9) being housed in the casing (12), optionally in a coupling position with the said optional coupling and perforation device (8); and wherein the said container (9) is manually maneuverable from the outside of the casing (12) in order to be opened inside the closed casing (12), optionally is manually maneuverable from the outside of the casing (12) up to a perforating position of said cap (60) through the same perforation device (8), optionally through the same coupling and perforation device (8); and whereupon after opening of the said container (9) and of the said closure (7), and selectively mixing (i.e. dissolving, reconstituting) the at least one pharmaceutically active substance (drug) (70) with the liquid diluent (50) through the mixing tube (6), a solution of the at least one pharmaceutically active substance (drug) (70) in the liquid diluent (50) is provided for administering by PAT (pressurized aerosol therapy) in a hollow organ, or preferably in a body cavity of a patient; and with the proviso that in case the at least one container (9) is a single container selected from a vial, phial or bottle, then the sterile and closed prefilled drug containing device system is solely for use in a treatment of administering at least one pharmaceutically active substance (drug) by PAT (pressurized aerosol therapy) in a hollow organ, or preferably in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum.

2. A sterile and closed prefilled drug containing device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by PAT (pressurized aerosol therapy) in a hollow organ, or in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum, comprising a flexible package (100, 101), comprising: at least one container (9) comprising at least one pharmaceutically active substance (70) in powder, lyophilisate, solution, liquid, gel or other form (suspension, emulsion), and being provided with breakable, an openable, or perforable cap (60); and a bag (2) of liquid diluent (50), in particular connectable to an aerosol generating means, preferably connectable to an application lance and/or injection lance with nozzle and/or a pumping system, preferably a micro-pump, for use with an application lance and/or injection lance with nozzle, wherein the liquid diluent (50) is preferably a physiologically acceptable aqueous diluent; wherein the bag (2) is optionally equipped with at least one drain tube (4) provided with a closing device (5); preferably wherein the optional at least one drain tube (4), after removal of the closing device (5), serves as connector to an aerosol generating means, preferably as connector to an application lance and/or injection lance with nozzle and/or to a pumping system, preferably to a micro-pump, for use with an application lance and/or injection lance with nozzle; and wherein the bag (2) is equipped with a mixing tube (6), optionally equipped with an openable closure (7), and which optionally ends with a perforation device (8), or which optionally ends with a coupling and perforation device (8), for a container (9), which container (9) is preferably a vial, syringe, single-use syringe, ampoule, phial, or bottle (9), comprising the pharmaceutically active substance (70) in powder, lyophilisate, solution, liquid, gel or other form (suspension, emulsion), and which container (9) is provided with breakable, an openable, or perforable cap (60); and wherein said package (100, 101) is comprising at least one flexible airtight sterile casing (12), containing said container (9), preferably a vial, syringe, single-use syringe, ampoule, phial, or bottle (9), of the said pharmaceutically active substance, and said perforation device (8), optionally the said coupling and perforation device (8), said container (9) being housed in the casing (12), optionally in a coupling position with the said optional coupling and perforation device (8); and wherein the said container (9) is manually maneuverable from the outside of the casing (12) in order to be opened inside the closed casing (12), optionally is manually maneuverable from the outside of the casing (12) up to a perforating position of said cap (60) through the same perforation device (8), optionally through the same coupling and perforation device (8); and whereupon after opening of the said container (9) and of the said closure (7), and selectively mixing (i.e. dissolving, reconstituting) the at least one pharmaceutically active substance (drug) (70) with the liquid diluent (50) through the mixing tube (6), a solution of the at least one pharmaceutically active substance (drug) (70) in the liquid diluent (50) is provided for administering by PAT (pressurized aerosol therapy) in a hollow organ, or preferably in a body cavity of a patient; and further or alternatively comprising at least one multiple-way valve (10) connectable to or connecting the interior space of bag (2) and the interior space of at least one flexible airtight sterile casing (12) of said package (100, 101), preferably wherein the multiple-way valve (10) is preferably selected from the group of a three-way valve, a three-way slipper valve, a three-way cock, a three-way stopcock.

3. A sterile and closed prefilled drug containing device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by PAT (pressurized aerosol therapy) in a hollow organ, or in a body cavity, of a patient, according to claim 1, wherein the said prefilled drug containing device system is in compliance, preferably is obtained by manufacturing is in compliance, with the guidelines of a competent drug regulatory authority applicable for pre-filled systems, preferably for pre-filled systems for long-term storage.

4. A sterile and closed prefilled drug containing device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by PAT (pressurized aerosol therapy) in a hollow organ, or in a body cavity, of a patient, according to claim 1, for non-systemic (therapeutic) efficacy, preferably for local and/or topical (therapeutic) efficacy in a hollow organ, or in a body cavity, of a patient.

5. A sterile and closed prefilled drug containing device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by PAT (pressurized aerosol therapy) in a hollow organ, or in a body cavity, of a patient, according to claim 4, wherein the therapeutically effective dose for local and/or topical efficacy of the at least one pharmaceutically active substance per treatment: (vi) is the same as the therapeutically effective dose of the corresponding systemic treatment, in particular based on the maximum dose of the corresponding systemic treatment; or (vii) is less than the therapeutically effective dose of the corresponding systemic treatment, in particular based on the maximum dose of the corresponding systemic treatment; and preferably (viii) is less than 100%, about equal or less than one of 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, each relative to the therapeutically effective dose of the corresponding systemic treatment, in particular based on the maximum dose of the corresponding systemic treatment; and more preferably, in particular, but not limited to, in case the PAT (pressurized aerosol therapy) is selected from pressurized intra-peritoneal aerosol chemotherapy (PIPAC), (ix) is about equal or less than 50%, about equal or less than 45%, about equal or less than 40%, about equal or less than 35%, about equal or less than 30%, about equal or less than 25%, about equal or less than 20%, about equal or less than 15%, about equal or less than 10%, each relative to the therapeutically effective dose of the corresponding systemic treatment, in particular based on the maximum dose of the corresponding systemic treatment; or (x) is about 5-50%, about 5-45%, about 5-40%, about 5-35%, about 5-30%, about 5-25%, about 5-20%, about 5-15%, about 6-15%, about 7-15%, about 8-15%, about 9-15%, about 10-15%, about 8-14%, about 9-14%, about 8-13%, about 9-13%, about 8-12%, about 9-12%, about 9-11%; preferably about 10% 3%, about 10%2%, about 10%1%; each relative to the therapeutically effective dose of the corresponding systemic treatment, in particular based on the maximum dose of the corresponding systemic treatment.

6. A sterile and closed prefilled drug containing device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by PAT (pressurized aerosol therapy) in a hollow organ, or preferably in a body cavity, of a patient, according to claim 1, wherein as a hollow space the body cavity is selected from the group consisting of each hollow space in the body that is lined by mesothelium and epithelium, self-contained or connected with other cavities or the outside world, such as the abdomen, peritoneal cavity, thoracic cavity, luminal cavity, vesical cavity, cranial cavity, nasal cavity, oral cavity, pharynx, subarachnoid spaces, or joint cavities; preferably wherein the body cavity is selected from the group consisting of the peritoneal cavity (peritoneum), thoracic cavity (thorax), luminal cavity (lumen), vesical cavity (vesicel), uterus; or wherein as hollow space the hollow organ is selected from the group consisting of such as the cavity of the heart, blood vessels, bile duct, urinary tract, gastrointestinal tract, uterus or brain ventricles.

7. A sterile and closed prefilled drug containing device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by PAT pressurized aerosol therapy) is in a body cavity of a patient, according to claim 1, wherein the PAT (pressurized aerosol therapy) is selected from the group consisting of PIPAC (pressurized intra-peritoneal aerosol chemotherapy), PITAC (pressurized intra-thoracic aerosol chemotherapy), PILAC (pressurized intra-luminal aerosol chemotherapy), PIVAC (pressurized intra-vesical aerosol chemotherapy), and PIRAC (pressurized intra-rectal aerosol chemotherapy).

8. A sterile and closed prefilled drug containing device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by PAT (pressurized aerosol therapy) in a hollow organ, or in a body cavity, of a patient, according to claim 1, for combination therapy is comprising in the at least a flexible airtight sterile casing (12), more than one of container (9), preferably two to three containers (9a, 9b, 9c), more preferably two containers (9a, 9b), each container comprising independently at least one pharmaceutically active substance (drug).

9. A sterile and closed prefilled drug containing device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by PAT (pressurized aerosol therapy) in a hollow organ, or in a body cavity, of a patient, according to claim 1, wherein the package (100, 101), is further characterized in that said coupling and perforation device (8) comprises a first element (21) slidably coupled with a second element (22) and movable between said coupling position of the bottle (9) and said perforating position of the cap (60) of the bottle (9), in which said first element (21) comprises a ring (23) from which at least two flaps (24) equipped with notches (25, 26) suitable to accommodate the bottle (9) in the coupling position, vertically branch off, and in that said openable closure (7) is surmounted by a circular base (28) from which pairs of further flaps (27), in turn equipped with notches (52) suitable to accommodate the bottle (9) in the perforating position of the cap (60), perimetrally and vertically side by sidebranch off, said second element (22) having gaps (30) between said couples of further flaps (27) in correspondence of said at least two flaps (24), said gaps (30) being suitable to accommodate the at least two flaps (24) with the bottle (9) in the perforating position of the cap (60).

10. Kit, preferably a single-use kit, for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by PAT (pressurized aerosol therapy) in a hollow organ, or in a body cavity, in particular a therapeutic pneumoperitoneum, of a patient, comprising (a) a sterile and closed prefilled drug containing device system for administering, preferably for use in administering, at least one pharmaceutically active substance (drug) by PAT (pressurized aerosol therapy) in a hollow organ, or in a body cavity, of a patient, comprising a flexible package (100, 101) as defined in claim 1, but wherein the proviso of claim 1 does not apply; and (b) an application lance and/or injection lance with nozzle, preferably a single use (or disposable) application lance and/or injection lance with nozzle, for applying, i.e. for use in administering, the at least one pharmaceutically active substance (drug) by PAT (pressurized aerosol therapy) in a hollow organ, or in a body cavity, of a patient; and/or (c) a pumping system, preferably a micro-pump, for use with an application lance and/or injection lance with nozzle for applying, i.e. for use in administering, the at least one pharmaceutically active substance (drug) by PAT (pressurized aerosol therapy) in a hollow organ, or in a body cavity, of a patient; and optionally (d) (conventional) tubes and/or (conventional) connectors, for use with the (a) the sterile and closed prefilled drug containing device system, (b) the application lance and/or injection lance with nozzle, and/or (c) the pumping system, preferably a micro-pump.

11. Kit, preferably a single use kit, as defined in claim 10, for use in a treatment of administering at least one pharmaceutically active substance (drug) by PAT (pressurized aerosol therapy) in a hollow organ, or in a body cavity, in particular a therapeutic pneumoperitoneum, of a patient.

12. Kit, preferably a single use kit, as defined in claim 10, for use in a treatment of cancer and/or tumor treatable by rinsing and/or perfusion, preferably in a treatment of cancer and/or tumor, including but not limited to as well as metastatic forms thereof, selected from the group consisting of cancer/tumor of the peritoneum, cancer/tumor of the urinary tract, in particular bladder cancer, ovarian cancer, cancer/tumor of the colorectum, and most preferably of cancer/tumor of the peritoneum; and/or in a treatment of cancer and/or tumor selected from the group consisting of in particular colorectal cancer, cervical cancer, uterine cancer, bladder cancer, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, peritoneal cancer, and prostate cancer, as well as metastatic forms thereof.

13. Syringe, especially a single-use syringe, as a container (9) comprising at least one pharmaceutically active substance (drug) (70) in powder, lyophilisate, solution, liquid, gel or other form, preferably in solution, liquid, gel form, for use in a sterile and closed prefilled drug containing device system, preferably as defined claim 1, or for use in a kit comprising (a) a sterile and closed prefilled drug containing device system and (b) an application lance and/or injection lance with nozzle, preferably in a kit, preferably for use in a treatment of administering at least one pharmaceutically active substance (drug) (70) by PAT (pressurized aerosol therapy) in a hollow organ, or preferably in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum.

14. Syringe, especially a single-use syringe, as a container (9) comprising at least one pharmaceutically active substance (drug) (70) in powder, lyophilisate, solution, liquid, gel or other form, preferably in solution, liquid, gel form, for use in the preparation of a sterile and closed prefilled drug containing device system, preferably as defined in claim 1, or in the preparation of a kit comprising (a) a sterile and closed prefilled drug containing device system and (b) an application lance and/or injection lance with nozzle, preferably a kit, preferably for use in a treatment of administering at least one pharmaceutically active substance (drug) (70) by PAT (pressurized aerosol therapy) in a hollow organ, or preferably in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum.

15. Syringe, especially a single-use syringe, according to claim 13 as a container (9) in a sterile and closed prefilled drug containing device system, or in a kit comprising said sterile and closed prefilled drug containing device system, for administering, preferably for use in a treatment for administering, at least one pharmaceutically active substance (drug) by PAT (pressurized aerosol therapy) in a hollow organ, or preferably in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum, or a syringe, especially a single-use syringe, as a container (9) for use in the preparation of such a sterile and closed prefilled drug containing device system, or in a kit comprising said sterile and closed prefilled drug containing device system, wherein the said final drug containing device system, or said final drug containing device system of the kit, is comprising a flexible package (100, 101), comprising: at least one syringe, especially a single-use syringe, as container (9) comprising at least one pharmaceutically active substance (70) in powder, lyophilisate, solution, liquid, gel or other form (suspension, emulsion), preferably in solution, liquid, gel form, and being provided with breakable, an openable, or perforable cap (60); and a bag (2) of liquid diluent (50), wherein the liquid diluent (50) is preferably a physiologically acceptable aqueous diluent; wherein the bag (2) is optionally equipped with at least one drain tube (4) provided with a closing device (5); and wherein the bag (2) is equipped with a mixing tube (6), optionally equipped with an openable closure (7), and which optionally ends with a perforation device (8), or which optionally ends with a coupling and perforation device (8), for a syringe, especially a single-use syringe, as a container (9), comprising the pharmaceutically active substance (70) in powder, lyophilisate, solution, liquid, gel or other material (suspension, emulsion), preferably in solution, liquid, gel form, and which syringe, especially single-use syringe, as container (9) is provided with breakable, an openable, or perforable cap (60); and (i) wherein in the said final drug containing device system, the said package (100, 101) optionally is comprising at least one flexible airtight sterile casing (12), containing said syringe, especially a single-use syringe, as container (9) of the said pharmaceutically active substance, and said perforation device (8), optionally the said coupling and perforation device (8), said container (9) being housed in the casing (12), optionally in a coupling position with the said optional coupling and perforation device (8); and wherein the said syringe, especially single-use syringe, as the container (9) is manually maneuverable from the outside of the optional casing (12) in order to be opened inside the closed optional casing (12), optionally is manually maneuverable from the outside of the optional casing (12) up to a perforating position of said cap (60) through the same perforation device (8), optionally through the same coupling and perforation device (8); or (ii) wherein in case of a syringe, especially single-use syringe, as the container (9), the said package (100, 101) is devoid of a flexible airtight sterile casing (12) the syringe, especially single-use syringe, as the container (9) is already fixed to the bag (2) in a coupling position with the said optional coupling and perforation device (8); and whereupon after opening of the said syringe, especially single-use syringe, as the container (9) and of the said closure (7), and selectively mixing (i.e. dissolving, reconstituting) the at least one pharmaceutically active substance (drug) (70) with the liquid diluent (50) through the mixing tube (6), a solution of the at least one pharmaceutically active substance (drug) (70) in the liquid diluent (50) is provided for administering by PAT (pressurized aerosol therapy) in a hollow organ, or preferably in a body cavity of a patient.

16. A method of treating a hollow organ, or preferably in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum, wherein the method comprises providing a sterile and closed prefilled drug containing device system for administering, preferably for use in administering, at least one pharmaceutically active substance (drug) by PAT (pressurized aerosol therapy) in a hollow organ, or in a body cavity, of a patient, comprising a flexible package (100, 101) as defined in claim 1; optionally as part of a kit; and mixing the at least one pharmaceutically active substance (70) comprised in powder, lyophilisate, solution, liquid, gel or other form (suspension, emulsion) in the at least one container (9) being provided with breakable, an openable, or perforable cap (60), with the liquid diluent (50) comprised in the bag (2), to result in a solution of the at least one pharmaceutically active substance (70) in the liquid diluent (50); and then generating a pressurized aerosol from the said solution of the at least one pharmaceutically active substance (70) in the liquid diluent (50), and thereby administering the said solution of the at least one pharmaceutically active substance (drug) by PAT (pressurized aerosol therapy) in a hollow organ, or preferably in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum.

17. A method of treating a hollow organ, or preferably in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum, wherein the method comprises providing a sterile and closed prefilled drug containing device system for administering, preferably for use in administering, at least one pharmaceutically active substance (drug) by PAT (pressurized aerosol therapy) in a hollow organ, or in a body cavity, of a patient, comprising a flexible package (100, 101) as defined in claim 1; optionally as part of a kit; and mixing the at least one pharmaceutically active substance (70) comprised in powder, lyophilisate, solution, liquid, gel or other form (suspension, emulsion) in the at least one container (9) being provided with breakable, an openable, or perforable cap (60), with the liquid diluent (50) comprised in the bag (2), to result in a solution of the at least one pharmaceutically active substance (70) in the liquid diluent (50); and then generating a pressurized aerosol from the said solution of the at least one pharmaceutically active substance (70) in the liquid diluent (50), and thereby administering the said solution of the at least one pharmaceutically active substance (drug) by PAT (pressurized aerosol therapy) in a hollow organ, or preferably in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum; wherein the said generated pressurized aerosol is administered by means of an application lance and/or injection lance with nozzle, preferably a single use (or disposable) application lance and/or injection lance with nozzle, for applying, i.e. for use in administering, the at least one pharmaceutically active substance (drug) by PAT (pressurized aerosol therapy) in a hollow organ, or in a body cavity, of a patient.

18. The method of treating a hollow organ, or preferably in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum, according to claim 16, wherein as a hollow space the body cavity is selected from the group consisting of each hollow space in the body that is lined by mesothelium and epithelium, self-contained or connected with other cavities or the outside world, such as the abdomen, peritoneal cavity, thoracic cavity, luminal cavity, vesical cavity, cranial cavity, nasal cavity, oral cavity, pharynx, subarachnoid spaces, or joint cavities; preferably wherein the body cavity is selected from the group consisting of the peritoneal cavity (peritoneum), thoracic cavity (thorax), luminal cavity (lumen), vesical cavity (vesicel), uterus; or wherein as hollow space the hollow organ is selected from the group consisting of such as the cavity of the heart, blood vessels, bile duct, urinary tract, gastrointestinal tract, uterus or brain ventricles.

19. The method of treating a hollow organ, or preferably in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum, according to claim 16, wherein the PAT (pressurized aerosol therapy) is selected from the group consisting of PIPAC (pressurized intra-peritoneal aerosol chemotherapy), PITAC (pressurized intra-thoracic aerosol chemotherapy), PILAC (pressurized intra-luminal aerosol chemotherapy), PIVAC (pressurized intra-vesical aerosol chemotherapy), and PIRAC (pressurized intra-rectal aerosol chemotherapy).

20. The method of treating a hollow organ, or preferably in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum, according to claim 16, wherein the method is in a treatment of cancer and/or tumor treatable by rinsing and/or perfusion, preferably in a treatment of cancer and/or tumor, including but not limited to as well as metastatic forms thereof, selected from the group consisting of cancer/tumor of the peritoneum, cancer/tumor of the urinary tract, in particular bladder cancer, ovarian cancer, cancer/tumor of the colorectum, and most preferably of cancer/tumor of the peritoneum; and/or in a treatment of cancer and/or tumor selected from the group consisting of in particular colorectal cancer, cervical cancer, uterine cancer, bladder cancer, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, peritoneal cancer, and prostate cancer, as well as metastatic forms thereof.

Description

EMBODIMENTS OF THE INVENTION

[0037] In particular, in embodiment 1, the present invention pertains to a sterile and closed prefilled drug containing (medical) device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or preferably in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum, comprising a flexible package (100, 101), comprising: [0038] at least one container (9) comprising at least one pharmaceutically active substance (70) in powder, lyophilisate, solution, liquid, gel or other form (suspension, emulsion), and being provided with breakable, an openable, or perforable cap (60); and [0039] a bag (2) of (pharmaceutically or physiologically acceptable) liquid diluent (50), in particular connectable to an aerosol generating means, preferably connectable to an application lance and/or injection lance with nozzle and/or a pumping system, preferably a micro-pump, for use with an application lance and/or injection lance with nozzle, [0040] wherein the liquid diluent (50) is preferably a physiologically acceptable aqueous diluent; [0041] wherein the bag (2) is optionally equipped with at least one drain tube (4) provided with a closing device (5); preferably wherein the optional at least one drain tube (4), after removal of the closing device (5), serves as connector to an aerosol generating means, preferably as connector to an application lance and/or injection lance with nozzle and/or to a pumping system, preferably to a micro-pump, for use with an application lance and/or injection lance with nozzle; [0042] and wherein the bag (2) is equipped with a mixing tube (6), optionally equipped with an openable closure (7), and which optionally ends with a perforation device (8), or which optionally ends with a coupling and perforation device (8), for a container (9), which container (9) is preferably a vial, syringe, single-use syringe, ampoule, phial, or bottle (9), comprising the pharmaceutically active substance (70) in powder, lyophilisate, solution, liquid, gel or other form (suspension, emulsion), and which container (9) is provided with breakable, an openable, or perforable cap (60);
and [0043] wherein said package (100, 101) is comprising at least one flexible airtight sterile casing (12), containing said container (9), preferably a vial, syringe, single-use syringe, ampoule, phial, or bottle (9), of the said pharmaceutically active substance, and said perforation device (8), optionally the said coupling and perforation device (8), said container (9) being housed in the casing (12), optionally in a coupling position with the said optional coupling and perforation device (8); and [0044] wherein the said container (9) is manually maneuverable from the outside of the casing (12) in order to be opened inside the closed casing (12), optionally is manually maneuverable from the outside of the casing (12) up to a perforating position of said cap (60) through the same perforation device (8), optionally through the same coupling and perforation device (8); and [0045] whereupon after opening of the said container (9) and of the said closure (7), and selectively mixing (i.e. dissolving, reconstituting) the at least one pharmaceutically active substance (drug) (70) with the liquid diluent (50) through the mixing tube (6), a solution of the at least one pharmaceutically active substance (drug) (70) in the liquid diluent (50) is provided for administering by pressurized aerosol therapy (PAT) in a hollow organ, or preferably in a body cavity of a patient.

[0046] Regarding the before said embodiment 1 of the present invention, a proviso applies such that in case the at least one container (9) is a single container selected from a vial, phial or bottle, then the sterile and closed prefilled drug containing (medical) device system is solely for use in a treatment of administering at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or preferably in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum.

[0047] Item (8) which may be shown or only indicated as not shown in the Figures represent a perforation device (8), optionally combined as a coupling and perforation device (8), which may be of conventional nature and applicable as known in the art, or may be constructed as described herein. Item (3) shown in the Figures may be a conventional supply tube, optionally also terminally equipped with an optionally perforable closing (5), said item (3) allowing the prefilling with the (pharmaceutically or physiologically acceptable) liquid diluent (50), and optionally, if desired and/or in case of therapeutic or other treatment need, may also be used for introducing an additional medication and/or agent and/or solvent and/or additional same or different and/or different liquid diluent (50). Item (3), after the prefilling, may also be present as perforable or dead-end closed, welded up or otherwise sealed, tube-end. Item (16) shown in the Figures represents the separating wall between the casing (12) and the bag (2) for the liquid diluent.

[0048] Regarding the optional at least one drain tube (4) it is noted that, after removal of the closing device (5), it may serve as connector to an aerosol generating means, preferably as connector to an application lance and/or injection lance with nozzle and/or to a pumping system, preferably to a micro-pump, for use with an application lance and/or injection lance with nozzle.

[0049] Prefilling according to the invention can be achieved by methods known to the person skilled in the art. For example the prefilling can be achieved in the following two ways:

[0050] In the normal pharmaceutical manufacturing procedure, the drug containing (medical) device system and/or any materials and components thereof is tested for stability (stability test) for every single drug, and its distribution in a prefilled form requires a complete marketing authorization file, or a file for changes made in the drug containing (medical) device system and/or any materials and components, or packaging thereof, i.e., from material a to material b, or the same material but in a different size, since drugs are generic supported by a different file. Pharmaceutical prefilling is preferably carried out under vacuum or modified atmosphere in an authorized pharmaceutical company under the supervision of the relevant authorities, observing all the necessary specifications and in a controlled-storage system for controlled substances (in a locked warehouse).

[0051] In the second way, prefilling is meant as compounding, filling in a pharmaceutical compounding facility inside an already sterilized container, preferably under vacuum or modified atmosphere conditions, wherein the test data (in specific authorized labs) show stability duration of more than one month or longer as specified herein, time considered to be necessary for storage and/or for the patient's benefits in distribution, the avoidance of unnecessary moves by the nursing staff and the destruction of expired prefilled drugs owing to the short stability duration. The present invention enables the normal operation of a pharmaceuticals warehouse, avoiding quick circulation (import-export) of drugs with short expiration times.

[0052] In the context of the invention, any pharmaceutically or physiologically acceptable solution, in particular aqueous solution, for example but not limited to, of physiologically acceptable inorganic and/or organic salts, sugars, buffers (e.g. phosphate as a buffer) and the like, and combinations thereof, may be used as the diluent. Non-limiting examples of a physiological diluent, in particular aqueous physiological diluent, are saline, also known as saline solution, i.e. normal saline; physiological glucose solution; physiological mannitol solution; Ringer's solution, Ringer's lactate solution, Tyrode's solution; and other or physiological solution known in the art.

[0053] Saline, also known as saline solution, is a mixture of sodium chloride in water and has a number of uses in medicine, including its use to dilute other medications, for example, to be given by injection or infusion. Normal saline (NSS, NS or N/S) is the commonly used phrase for a solution of 0.90% w/v of NaCl, or 9.0 g per litre. This solution is also referred to as physiological saline or isotonic saline (because it closely approximates isotonic, that is, physiologically normal, solution).

[0054] In an example of the present invention, the pharmaceutically or physiologically acceptable solution (diluent), in particular aqueous solution (diluent), may be a physiologically acceptable aqueous solution of sodium chloride (0.9% w/v) and/or glucose (5% w/v).

[0055] Ringers solution is a solution of several salts dissolved in water for the purpose of creating an isotonic solution relative to the body fluids of an animal. Ringers solution typically contains sodium chloride, potassium chloride, calcium chloride and sodium bicarbonate, with the last used to balance the pH. Other additions can include chemical fuel sources for cells, including ATP and dextrose, as well as antibiotics and antifungals. To produce a standard isotonic solution 6.5 g NaCl, 0.42 g KCl, 0.25 g CaCl.sub.2) and 0.2 g of sodium bicarbonate is dissolved in one litre of distilled water.

[0056] Ringers lactate solution, also known as sodium lactate solution and Hartmann's solution, is a mixture of sodium chloride, sodium lactate, potassium chloride, and calcium chloride in water. It is normally used for replacing fluids and electrolytes in those who have low blood volume or low blood pressure.

[0057] Tyrode's solution is a solution that is roughly isotonic with interstitial fluid and used in physiological experiments and tissue culture. It resembles lactated Ringers solution, but contains magnesium, a sugar (usually glucose) and uses bicarbonate and phosphate as a buffer instead of lactate. Some variations also include phosphate and sulfate ions. It must be gassed with 95% oxygen 5% carbon dioxide when used for cell culture applications and physiology experiments in order to achieve an appropriate pH.

[0058] In an embodiment 2, the present invention pertains to a sterile and closed prefilled drug containing (medical) device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum, comprising a flexible package (100, 101), comprising: [0059] at least one container (9) comprising at least one pharmaceutically active substance (70) in powder, lyophilisate, solution, liquid, gel or other form (suspension, emulsion), and being provided with breakable, an openable, or perforable cap (60); and [0060] a bag (2) of liquid diluent (50), in particular connectable to an aerosol generating means, preferably connectable to an application lance and/or injection lance with nozzle and/or a pumping system, preferably a micro-pump, for use with an application lance and/or injection lance with nozzle, [0061] wherein the liquid diluent (50) is preferably a physiologically acceptable aqueous diluent; [0062] wherein the bag (2) is optionally equipped with at least one drain tube (4) provided with a closing device (5); preferably wherein the optional at least one drain tube (4), after removal of the closing device (5), serves as connector to an aerosol generating means, preferably as connector to an application lance and/or injection lance with nozzle and/or to a pumping system, preferably to a micro-pump, for use with an application lance and/or injection lance with nozzle; [0063] and wherein the bag (2) is equipped with a mixing tube (6), optionally equipped with an openable closure (7), and which optionally ends with a perforation device (8), or which optionally ends with a coupling and perforation device (8), for a container (9), which container (9) is preferably a vial, syringe, single-use syringe, ampoule, phial, or bottle (9), comprising the pharmaceutically active substance (70) in powder, lyophilisate, solution, liquid, gel or other form (suspension, emulsion), and which container (9) is provided with breakable, an openable, or perforable cap (60);
and [0064] wherein said package (100, 101) is comprising at least one flexible airtight sterile casing (12), containing said container (9), preferably a vial, syringe, single-use syringe, ampoule, phial, or bottle (9), of the said pharmaceutically active substance, and said perforation device (8), optionally the said coupling and perforation device (8), said container (9) being housed in the casing (12), optionally in a coupling position with the said optional coupling and perforation device (8); and [0065] wherein the said container (9) is manually maneuverable from the outside of the casing (12) in order to be opened inside the closed casing (12), optionally is manually maneuverable from the outside of the casing (12) up to a perforating position of said cap (60) through the same perforation device (8), optionally through the same coupling and perforation device (8); and
whereupon after opening of the said container (9) and of the said closure (7), and selectively mixing (i.e. dissolving, reconstituting) the at least one pharmaceutically active substance (drug) (70) with the liquid diluent (50) through the mixing tube (6), a solution of the at least one pharmaceutically active substance (drug) (70) in the liquid diluent (50) is provided for administering by pressurized aerosol therapy (PAT) in a hollow organ, or preferably in a body cavity of a patient;
and further or alternatively comprising at least one multiple-way valve (10) connectable to or connecting the interior space of bag (2) and the interior space of at least one flexible airtight sterile casing (12) of said package (100, 101), preferably wherein the multiple-way valve (10) is selected from the group of a three-way valve, a three-way slipper valve, a three-way cock, a three-way stopcock.

[0066] In an embodiment 3, the present invention pertains to a sterile and closed prefilled drug containing (medical) device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (or drug) by pressurized aerosol therapy (PAT) in a hollow organ, or in a body cavity, of a patient, according to embodiment 1 or embodiment 2, wherein the said prefilled drug containing (medical) device system is in compliance, preferably is obtained by manufacturing is in compliance, with the guidelines of a competent drug regulatory authority applicable for pre-filled systems, preferably for pre-filled systems for long-term storage.

[0067] In an embodiment 4, the present invention pertains to a sterile and closed prefilled drug containing (medical) device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (or drug) by pressurized aerosol therapy (PAT) in a hollow organ, or in a body cavity, of a patient, according to any of the preceding claims, for non-systemic (therapeutic) efficacy, preferably for local and/or topical (therapeutic) efficacy in a hollow organ, or in a body cavity, of a patient.

[0068] In an embodiment 5, the present invention pertains to a sterile and closed prefilled drug containing (medical) device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or in a body cavity, of a patient, according to embodiment 4, wherein the therapeutically effective dose for local and/or topical efficacy of the at least one pharmaceutically active substance per treatment: [0069] (i) is the same as the therapeutically effective dose of the corresponding systemic treatment, in particular based on the maximum dose of the corresponding systemic treatment; or [0070] (ii) is less than the therapeutically effective dose of the corresponding systemic treatment, in particular based on the maximum dose of the corresponding systemic treatment;
and preferably [0071] (iii) is less than 100%, about equal or less than one of 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, each relative to the therapeutically effective dose of the corresponding systemic treatment, in particular based on the maximum dose of the corresponding systemic treatment; [0072] and more preferably, [0073] in particular, but not limited to, in case the pressurized aerosol therapy (PAT) is selected from pressurized intra-peritoneal aerosol chemotherapy (PIPAC), [0074] (iv) is about equal or less than 50%, about equal or less than 45%, about equal or less than 40%, about equal or less than 35%, about equal or less than 30%, about equal or less than 25%, about equal or less than 20%, about equal or less than 15%, about equal or less than 10%, each relative to the therapeutically effective dose of the corresponding systemic treatment, in particular based on the maximum dose of the corresponding systemic treatment; or [0075] (v) is about 5-50%, about 5-45%, about 5-40%, about 5-35%, about 5-30%, about 5-25%, about 5-20%, about 5-15%, about 6-15%, about 7-15%, about 8-15%, about 9-15%, about 10-15%, about 8-14%, about 9-14%, about 8-13%, about 9-13%, about 8-12%, about 9-12%, about 9-11%; preferably about 10%3%, about 10%2%, about 10%1%; each relative to the therapeutically effective dose of the corresponding systemic treatment, in particular based on the maximum dose of the corresponding systemic treatment.

[0076] In an embodiment 6, the present invention pertains to a sterile and closed prefilled drug containing (medical) device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or in a body cavity, of a patient, according to any of the preceding embodiments, wherein the patient is a mammalian patient, preferably a human patient.

[0077] In an embodiment 7 (see claim 6), the present invention pertains to a sterile and closed prefilled drug containing (medical) device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or preferably in a body cavity, of a patient, according to any of the preceding embodiments, [0078] wherein as a hollow space the body cavity is selected from the group consisting of each hollow space in the body that is lined by mesothelium and epithelium, self-contained or connected with other cavities or the outside world, such as the abdomen, peritoneal cavity, thoracic cavity, luminal cavity, vesical cavity, cranial cavity, nasal cavity, oral cavity, pharynx, subarachnoid spaces, or joint cavities; preferably wherein the body cavity is selected from the group consisting of the peritoneal cavity (peritoneum), thoracic cavity (thorax), luminal cavity (lumen), vesical cavity (vesicel), uterus; [0079] or wherein as hollow space the hollow organ is selected from the group consisting of such as the cavity of the heart, blood vessels, bile duct, urinary tract, gastrointestinal tract, uterus or brain ventricles.

[0080] In an embodiment 8 (see claim 7), the present invention pertains to a sterile and closed prefilled drug containing (medical) device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) is in a body cavity of a patient, according to any of the preceding embodiments, wherein the pressurized aerosol therapy (PAT) is selected from the group consisting of pressurized intra-peritoneal aerosol chemotherapy (PIPAC), pressurized intra-thoracic aerosol chemotherapy (PITAC), pressurized intra-luminal aerosol chemotherapy (PILAC), and pressurized intra-vesical aerosol chemotherapy (PIVAC), pressurized intra-rectal aerosol chemotherapy (PIRAC).

[0081] PIPAC is technically as simple as a diagnostic laparoscopy. The treatment occurs minimally invasive. By using two small incisions (cuts) in the abdominal wall, the medicationunder pressure, by means of a laparoscopic nebulizeris blown as a fine mist into the abdominal cavity, where it is pressed into the diseased tissue. Thereby it has a substantially better effect on the tumor. This result comes up with only 10 percent of the usual dose of medication. The side effects are very small, therefore the therapy is very well tolerated by the patients. PIPAC aims for an extension of life by means of the control of symptoms. PIPAC's first results demonstrate both: PIPAC is associated with fewer side effects than traditional therapies and furthermore the performance index increases with the therapy. The first data regarding the chances of survival are encouraging.

[0082] Ovarian cancer (ovarian carcinoma) and metastases in the peritoneum: Ovarian cancer (ovarian carcinoma) is the second most common malignant disease of females' genital organs. In a current study of the Marien Hospital Herne (University Hospital of the RuhrUniversity Bochum), under the direction of Prof. Dr. Clemens Tempfer (chief physician of the clinic of gynecology and obstetrics), the use of compression-aerosol chemotherapy in patients with recurrent ovarian cancer and metastases in the peritoneum was examined. First results are encouraging. During the so-called PIPAC therapy (Pressurized Intra Peritoneal Aerosol Chemotherapy) chemotherapy agents are specifically introduced into the abdominal cavity. This happens in order to directly reach and push back the cancerous tumors. This new way with already approved medication, was chosen for the therapy against ovarian and peritoneal cancer, as these agents immediately penetrate into the diseased tissue.

[0083] PITAC (Pressurized IntraThoracic Aerosol Chemotherapy): The pressure aerosol chemotherapy can also be used in the chest, for example regarding malignant pleural effusion or regarding pleural mesothelioma. PITAC is a further preferred aspect of the present invention as it described herein. PITAC is technically as simple as a diagnostic thoracoscopy.

[0084] PILAC (Pressurized Intraluminal Aerosol Chemotherapy): In the treatment of PILAC the pressure aerosol chemotherapy is applied with a mirroring between two balloons into the esophagus. As in the treatment of PIVAC this innovative method only has been applied in the animal. Besides the technical feasibility has been demonstrated, and the penetration depth of a drug (small-molecule drug) into the muscular wall of the esophagus was documented.

[0085] PIVAC (Pressurized IntraVesical Aerosol Chemotherapy): In matters of PIVAC the pressure aerosol chemotherapy is administered into the bladder. Up to now, this innovative method was only used in animal testing, and the technical feasibility was demonstrated.

[0086] PIRAC (Pressurized IntraRectal Aerosol Chemotherapy): The pressure aerosol chemotherapy can also be used via the rectum, for example regarding malignant cancer of the lower intestinal tract, e.g., the colon and/or the small intestine.

[0087] In an embodiment 9, the present invention pertains to a sterile and closed prefilled drug containing (medical) device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or in a body cavity, of a patient, according to any of the preceding embodiments, wherein the at least one pharmaceutically active substance (drug) is selected from [0088] (a) the group consisting of antitumor, anticancer, cytostatic, antinecrotic, antimicrobial, antimycotic, antibacterial, antiviral, antiseptic, antibiotic substances or a combination thereof; preferably anticancer, antitumor or cytostatic substances, or a combination thereof; and/or [0089] (b) the group consisting of anticancer, antitumor, cytostatic substances or a combination thereof, preferably selected from the group consisting of [0090] aflibercept, amsacrin, alemtuzumab, arsene trioxide, asparaginase, azacitidine, bendamustin hydrochloride, bevacizumab, bleomycin, blinatumomab, bortezomib, busulfan, cabacitaxel, carboplatin, carfilzomib, carmustine, 2 CdA/cladribin, cetuximab, cidofovir, cisplatin, clofarabin, cyclophosphamide, cytarabin, dacarbacin, dactinomycin, daratumab, daunorubicin, decitabin, docetaxel, doxorubicin, liposomales doxorubicin, eribulin mesilate, epirubicin, etoposid, fludarabin, 5-flourouracil, foscarnet, gemicitabin, glancyclovir, idarubicin, ifosfamide, ipilmumab, irinotecan, melphalan, methotrexat, mifamurtid, mitomycin, mitoxantron, nelarabin, nivolumab, obinituzumab ofatumumab, oxaliplatin, paclitaxel, panitumab, pemetrexed, pertuzumab, prembolizumab, ramucirumab, rituximab, romidepsin, thiotepa, topotecan, trabectedin, trastuzumab, trastuzumab-emtansin, treosulfan, vinblastine, vincristin, vindesin, vinflunin, vinorelbin, [0091] more preferably selected from the group consisting of doxorubicin, cisplatin, oxaliplatin, topotecan, paclitaxel, pemetrexed, bendamustin, carboplatin, irinotecan, docetaxel, mitomycin, epirubicin, vinorelbin, or a combination thereof;

[0092] preferably is selected from one of: [0093] (c) a combination of doxorubicin, cisplatin, oxaliplatin, topotecan, and paclitaxel; [0094] (d) a combination of pemetrexed, bendamustin, topotecan, and carboplatin; [0095] (e) a combination of irinotecan and docetaxel; [0096] (f) a combination of doxorubicin, mitomycin, and epirubicin; [0097] (g) a combination of docetaxel, oxaliplatin, paclitaxel, and vinorelbin.

[0098] As an example, the said drug combinations may be used in dosages as exemplified in Table I (based on body surface area BSA):

TABLE-US-00001 TABLE I Dosages of Drug Combination Table Ia: Dosage PIPAC (IntraPeritoneal) Doxorubicin Cisplatin Topotecan Oxaliplatin Paclitaxel [mg] [mg] [mg] [mg] [mg] For very small, petite women the dosage is usually: BSA 1.25 1.88 9.38 0.50 16.25 25.00 For very tall, heavy men the dosage is usually: BSA 3.00 4.50 22.50 1.20 39.00 60.00 For assumption of a constant dosage, the dosage is usually: BSA 2.00 3.00 15.00 0.80 26.00 40.00 Table Ib: Dosage PITAC (IntraThoracic) Pemetrexed Bendamustin Topotecan Carboplatin [mg] [mg] [mg] [mg] For very small, petite women the dosage is usually: BSA 1.25 62.50 12.50 0.50 50.00 For very tall, heavy men the dosage is usually: BSA 3.00 150.00 30.00 1.20 120.00 For assumption of a constant dosage, the dosage is usually: BSA 2.00 100.00 20.00 0.80 80.00 Table Ic: Dosage PILAC (IntraLuminal) Irinotecan Docetaxel [mg] [mg] For very small, petite women the dosage is usually: BSA 1.25 43.75 12.50 For very tall, heavy men the dosage is usually: BSA 3.00 105.00 30.00 For assumption of a constant dosage, the dosage is usually: BSA 2.00 70.00 20.00 Table Id: Dosage PIVAC (IntraVessical) Doxorubicin Mitomycin Epirubicin [mg] [mg] [mg] For very small, petite women the dosage is usually: BSA 1.25 1.88 For very tall, heavy men the dosage is usually: BSA 3.00 4.50 For assumption of a constant dosage, the dosage is usually: BSA 2.00 3.00 8.00 10.00 Table Ie: Dosage PIRAC (IntraRectal) Docetaxel Vinorelbin Oxaliplatin Paclitaxel [mg] [mg] [mg] [mg] For very small, petite women the dosage is usually: BSA 1.25 12.50 3.75 16.25 25.00 For very tall, heavy men the dosage is usually: BSA 3.00 30.00 9.00 39.00 60.00 For assumption of a constant dosage, the dosage is usually: BSA 2.00 20.00 6.00 26.00 40.00

[0099] Typical standard and maximum dosages of cytostactic compounds may be exemplified as indicated in the following Table II.

TABLE-US-00002 TABLE II Listing of Typical Standard (normal) and Maximum Dosages of Cytotsatic Compounds (conventional treatments). Substance Standard Dosage Maximum Dosage Paclitaxel 125 mg/m2 275 mg human serum (adenocarcinoma albumin of the pancreas) bonded 260 mg/m2 570 mg nanoparticles (Breast cancer) Doxorubicin 60-75 mg/m2 120 mg 1 every 2 weeks 150 mg 1 every 3 weeks Cumulative anthracyclines: maximum 450 mg/m2 Pemetrexed 500 mg/m2 1100 mg every 3 weeks Melphalan 8-30 mg/m2 36 mg/intravesikular 100 mg Amsacrin 120 mg/m2 hematology up to 300 mg Ofatumumab 300 mg (1st dose) 300 mg (1st dose) 2000 mg (following dose) 2000 mg (following dose) Asparaginase hematology: 10000 IU/m2 20000 IU/m2 Nelarabin 1500 mg/m2 (3 per cycle) 3500 mg/m2 Bevacizumab 5 mg/kg, resp. 10 mg/kg 5/7.5/10/15 mg/kg every 2 weeks resp. 15 mg/kg every 3 weeks Bleomycin Over 80 years: 15,000 IU 15 mg/ week Cumulative: 100000 IU = 100 mg 70-79 years: 30000 IU = 30 mg/ week Cumulative: 150000-200000 = 150-200 mg 60-69 years: 30000 IU-60000 IU = 30-60 mg/week Cumulative: 200000-300000 IU = 200-300 mg Less than 60 years: 30000 IU-60000 IU = 30-60 mg/week Cumulative: 400000 IU = 400 mg (In pleurodesis 60,000 IU 60 mg) Cumulatively maximum 270 mg (Corresponding to 3 BEP) Blinatumomab 9 g/day 1 cycle 1st week 28 g/day the following administrations Liposomal Doxorubicin 0.8 mg/kg/dose 4 daily Total dose per cycle or 0.8 mg/kg/6-h. 3.2 mg/kg as single dose 1 3.2 mg/kg/d = daily over 2-4 days 4 0.8 mg/kg/d (total 16 single doses) Alemtuzumab 30 mg 3 per week Carboplatin 200-400 mg/m2 1500 mg (AUC 7) (AUC 2, 4-7) 1300 mg (AUC 6) 1 every 3 weeks 1100 mg (AUC 5) 1 every 3 weeks 900 mg (AUC 4) 1 every 3 weeks 450 mg (AUC 2) weekly Carmustine 80-200 mg/m2 600 mg once only 300 mg/m2 Cisplatin 15-100 mg/m2 220 mg 40 mg/m2 weekly 1 every 3 weeks Dactinomycin 0.4-0.6 mg/m2 1 mg daily during 5 days, every 3 weeks Gancyclovir Initial and maintenance dose Creatinine Clearance according to requirements of (ml/min/1.73 m2) compendium >50 5.0 mg/kg - 12 h 25-50 2.5 mg/kg - 12 h 10-25 2.5 mg/kg - 24 h 0-10 1.25 mg/kg - 24 h Ramucirumab 8 mg/kg 8 mg/kg Cytarabin 100-2000 mg/m.sup.2 4200 mg at Hyper-CVAD at Hyper-CVAD 3000 mg/m.sup.2 6300 mg 4 every 12 h 4 every 12 h Dacarbazin 150-800 mg/m2 1700 mg every 3 weeks Decitabin 20 mg/m2 on 5 subsequent days, every 4 weeks Daratumumab 16 mg/kg 16 mg/kg Daunorubicin 40-60 mg/m2 120 mg Cytarabin 50 mg intrathekal 50 mg intrathekal every 2 weeks every 2 weeks Vindesin 3-4 mg/m2 6 mg per week Oxaliplatin 130 mg/m2 280 mg per 3 weeks Cyclophosphamid 80-1600 mg/m.sup.2 3300 mg Cetuximab first dose 400 mg/m2, then 250 mg/m2/ 900 mg first dose week otherwise 600 mg 500 mg/m2 every 2 weeks every 2 weeks 1200 mg Etoposid (VP-16) 60-125 mg/m2 280 mg 150 mg/m2 daily at 3 days (VIDE) every 3 weeks for testicular cancer for testicular cancer (BEP-scheme): (BEP-scheme): 100 mg/m2 250 mg daily over 5 days daily over 5 days Clofarabin 30 mg/m2 50 mg/m2 Epirubicin 60-120 mg/m2 240 mg every 3 weeks cumulative anthracycline: 900 mg/m2 Fludarabin 25 mg/m2 5-Fluorouracil 375-500 mg/m2 (bolus) 1200 mg (bolus) 1 per week 1 per week 1000 mg/m2/24 h 2600 mg/24 h continuous infusion over 4 to 5 continuous infusion over 4 to days 2300 mg/m2/24 h 5 days 6000 mg/24 h continuous infusion over 24 h continuous infusion over 24 h 1 per week 1 per week 2800 mg/m2/48 h 7300 mg/48 h FOLFIRI continuous infusion 2000 mg/m2/48 h every 2 weeks FOLFOX (FOLFIRI, FOLFOX) Foscarnet 60 mg/kg 8 each hour or 90 mg/kg 12 each hou. Obinituzumab 1000 mg 1000 mg day 1, 8, 15 (cycle 1) the every 28 days Gemcitabin 1250 mg/m2 2600 mg 1 per week Eribulin mesilate 1.4 mg/m2 3 mg day 1 and 8 of a 3- weeks cycle Trastuzumab 8 mg once, then 6 mg/kg 2/4/6/8 mg/kg every 3 weeks resp. 4 mg/kg every 2 weeks resp. 2 mg/kg weekly Ifosfamid 800-5000 mg/m2 10 g as single dose 6 g per day at daily administration over 3-5 days Topotecan 1.25-1.5 mg/m2/d over 5 days 2.5 mg/d at max. 5 consecutive gynecology 4 mg/m2 weekly days gynecology 8 mg day 1, 8, 15 in 28-days cycle Irinotecan/CPT-11 300-350 mg/m2 700 mg every 3 weeks Romidepsin 14 mg/m2 Vinflunin 320 mg/m2 700 mg every 3 weeks Cabacitaxel 25 mg/m2 55 mg every 3 weeks Trastuzumab- 3.6 mg/kg every 3 weeks 3.6 mg/kg Emtansin Pembrolizumab 2 mg/kg every 3 weeks 2 mg/kg Carfilzomib 20 mg/m2 first cycle or day 1 + 2 27 mg/m2 from second cycle or 56 mg/m2 from day 8 2 CdA/Cladribin 0.1-0.25 mg/kg Rituximab 375 mg/m2 1050 mg Mifamurtid 2 mg/m2 Methotrexat 40-50 mg/m2 with leucovorin to 100 mg with leucovorin to 24 g 12000 mg/m2 1 per week Mitomycin 10-15 mg/m2 30 mg 1 every 6 weeks Mitoxantron 8-14 mg/m2 28 mg 1 every 3 weeks Nivolumab 3 mg/kg 3 mg/kg Treosulfan 8 g/m2 (every 3 weeks) Pertuzumab 840 mg (1. Dosis) 840 mg (1. Dosis) 420 mg (subsequent doses) 420 mg (subsequent doses) Bendamustin hydrochloride 80-100 mg/m2 240 mg at 2 subsequent days every 3-4 weeks Paclitaxel 135-200 mg/m2 400 mg (Taxol) 80-100 mg/m2 weekly 1 every 3 weeks wochentlich 200 mg weekly Docetaxel 75-100 mg/m2 220 mg 1 every 3 weeks Thiotepa 0.3-5.0 mg/kg 400 mg Arsene trioxide 0.15 mg/kg/day 15 mg Panitumumab 6 mg/kg 6 mg/kg every 2 weeks Vinblastin 4-6 mg/m2 13 mg 1 per week Bortezomib 1.3 mg/m2 day 1, 4, 8, 11 every 2.7 mg per dose 3 weeks 3.2 mg per dose 1.6 mg/m2 day 1, 8, 15, 22 every 5 weeks Azacitidin 100 mg/m2 per day 200 mg per day Vincristin 1-1.4 mg/m2 2 mg every 2 weeks Vinorelbin 25-30 mg/m2 70 mg Cidofovir 3-5 mg/kg 1 per 1 or 2 weeks (depending on serum creatinine) Ipilimumab 3 mg/kg 3 mg/kg every 3 weeks for in total 4 doses Trabectedin 1.5 mg/m2 3.3 mg Aflibercept 4 mg/kg (in combination with 4 mg/kg FOLFIRI) Idarubicin 8-12 mg/m2 25 mg

[0100] In an embodiment 10, the present invention pertains to a sterile and closed prefilled drug containing (medical) device system for administering at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or in a body cavity, of a patient, according to any of the preceding embodiments, wherein the at least one container (9) is a vial, syringe, single-use syringe, ampoule, phial, or bottle, preferably a vial, syringe, or single-use syringe.

[0101] In an embodiment 11 (see claim 8), the present invention pertains to a sterile and closed prefilled drug containing (medical) device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or in a body cavity, of a patient, according to any of the preceding embodiments, for combination therapy is comprising in the at least a flexible airtight sterile casing (12), more than one of container (9), preferably two to three containers (9a, 9b, 9c), more preferably two containers (9a, 9b), each container comprising independently at least one pharmaceutically active substance (drug). The container may particularly also be a syringe, or especially single-use syringe, (9s), which is displayed as an alternative example to the bottle (9) displayed for illustration. See FIGS. 3 and 4, and in particular FIG. 5 wherein a syringe or especially single-use syringe, (9s) is displayed; optionally also in combination with a so-called Primed Sharp connector.

[0102] In an embodiment 12, the present invention pertains to a sterile and closed prefilled drug containing (medical) device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or in a body cavity, of a patient, according to any of the embodiments 1 to 10, wherein said package (100, 101) is comprising more than one of flexible airtight sterile casings (12) separated from each other, and each of the said casings is comprising independently at least one container (9), and each container is comprising independently at least one pharmaceutically active substance (drug); preferably two to three separate casings (12a, 12b, 12c), and each of the said casings (12a, 12b, 12c) is comprising independently one of the said containers (9a, 9b, 9c); more preferably two separate casings (12a, 12b), each of the said casings (12a, 12b) is comprising independently one of the said containers (9a, 9b), each container comprising independently at least one pharmaceutically active substance (drug).

[0103] In an embodiment 13 (see claim 9), the present invention pertains to a sterile and closed prefilled drug containing (medical) device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or in a body cavity, of a patient, according to any of the embodiments 1, or 3 to 10, wherein the package (100, 101), is further characterized in that said coupling and perforation device (8) comprises a first element (21) slidably coupled with a second element (22) and movable between said coupling position of the bottle (9) and said perforating position of the cap (60) of the bottle (9), in which said first element (21) comprises a ring (23) from which at least two flaps (24) equipped with notches (25, 26) suitable to accommodate the bottle (9) in the coupling position, vertically branch off, and in that said openable closure (7) is surmounted by a circular base (28) from which pairs of further flaps (27), in turn equipped with notches (52) suitable to accommodate the bottle (9) in the perforating position of the cap (60), perimetrally and vertically side by sidebranch off, said second element (22) having gaps (30) between said couples of further flaps (27) in correspondence of said at least two flaps (24), said gaps (30) being suitable to accommodate the at least two flaps (24) with the bottle (9) in the perforating position of the cap (60).

[0104] In an embodiment 14, the present invention pertains to a sterile and closed prefilled drug containing (medical) device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or in a body cavity, of a patient, according to embodiment 13, wherein the package (100, 101) is further characterized in that [0105] said ring (23) is inserted externally to said further flaps (27) and is configured to slide coaxially with respect to the circular base (28), and that said further flaps (27) have a curvature at their free ends such as to constitute a first limit to said first element (21) in correspondence of the bottle (9) in the coupling position, and said notches (26) are configured to contrast with said base circular (28) and form a second limit to said first element (21) in correspondence of the bottle (9) in the position of perforation of the cap (60).

[0106] In an embodiment 15, the present invention pertains to a sterile and closed prefilled drug containing (medical) device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or in a body cavity, of a patient, according to embodiment 13 or embodiment 14, wherein the package (100, 101) is further characterized in that [0107] said further flaps (27) of the second element (22) comprise externally locking notches (53) suitable to lock the first element (21) in coupling position of the bottle (9).

[0108] In an embodiment 16, the present invention pertains to a sterile and closed prefilled drug containing (medical) device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or in a body cavity, of a patient, according to any of the embodiments 13 to 15, wherein the package (100, 101) is further characterized in that [0109] said openable closure (7) of the coupling and perforation device (8) has internally a channel (57) ending at the top with a hollow tip (18) and inferiorly with an initial portion (17) which is frangible to allow passage of the pharmacological substance (70) in powder or another from the bottle (9), through the mixing tube (6) towards the bag (2) of liquid diluent (50).

[0110] In an embodiment 17, the present invention pertains to a sterile and closed prefilled drug containing (medical) device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or in a body cavity, of a patient, according to any of the embodiments 13 to 16, wherein the package (100, 101) is further characterized in that [0111] said casing (12) is arranged in a position aligned with said bag (2) of liquid diluent (50) so as to be hermetically separated by a single wall (16), said mixing tube (6) being configured to extend through said single wall (16) for the communication between said bottle (9) and said bag (2) in order to introduce inside the bag (2) the pharmacological or nutritional substance (70) in powder or other contained within the bottle (9).

[0112] In an embodiment 18, the present invention pertains to a sterile and closed prefilled drug containing (medical) device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or in a body cavity, of a patient, according to any of the embodiments 13 to 17, wherein the package (100, 101) is further characterized in that [0113] said bag (2) of liquid diluent (50) is provided with a supply tube (3) terminating with a closing device (5).

[0114] In an embodiment 19, the present invention pertains to a sterile and closed prefilled drug containing (medical) device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or in a body cavity, of a patient, according to any of the embodiments 13 to 18, wherein the package (100, 101) is further characterized in that [0115] said casing (12) comprises internally said bag (2) of liquid diluent (50) with said drain tube (4) and said mixing tube (6) equipped with the coupling and perforation device (8) and the bottle (9).

[0116] In a particular embodiment 20 (see claim 10), the present invention pertains to a kit, preferably a single-use kit, for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (or drug) by pressurized aerosol therapy (PAT) in a hollow organ, or in a body cavity, in particular a therapeutic pneumoperitoneum, of a patient, comprising [0117] (a) a sterile and closed prefilled drug containing (medical) device system for administering, preferably for use in administering at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or in a body cavity, of a patient, comprising a flexible package (100, 101) as defined in any of the embodiments 1 to 19, [0118] but wherein the proviso of embodiment 1 does not apply;
and [0119] (b) an application lance and/or injection lance with nozzle, preferably a single use (or disposable) application lance and/or injection lance with nozzle, for applying, i.e. for use in administering, the at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or in a body cavity, of a patient;
and/or [0120] (c) a pumping system, preferably a micro-pump, for use with an application lance and/or injection lance with nozzle for applying, i.e. for use in administering, the at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or in a body cavity, of a patient;
and optionally [0121] (d) (conventional) tubes and/or (conventional) connectors, for use with the (a) the sterile and closed prefilled drug containing (medical) device system, (b) the application lance and/or injection lance with nozzle, and/or (c) the pumping system, preferably a micro-pump.

[0122] The before note on embodiment 20 (see claim 10), of the present invention that the proviso of embodiment 1 does not apply means that under (a) the sterile and closed prefilled drug containing (medical) device system for administering, preferably for use in a treatment of administering, at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or preferably in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum, is defined as comprising a flexible package (100, 101), comprising: [0123] at least one container (9) comprising at least one pharmaceutically active substance (70) in powder, lyophilisate, solution, liquid, gel or other form (suspension, emulsion), and being provided with breakable, an openable, or perforable cap (60); and [0124] a bag (2) of (pharmaceutically or physiologically acceptable) liquid diluent (50), in particular connectable to an aerosol generating means, preferably connectable to an application lance and/or injection lance with nozzle and/or a pumping system, preferably a micro-pump, for use with an application lance and/or injection lance with nozzle, [0125] wherein the liquid diluent (50) is preferably a physiologically acceptable aqueous diluent; [0126] wherein the bag (2) is optionally equipped with at least one drain tube (4) provided with a closing device (5); preferably wherein the optional at least one drain tube (4), after removal of the closing device (5), serves as connector to an aerosol generating means, preferably as connector to an application lance and/or injection lance with nozzle and/or to a pumping system, preferably to a micro-pump, for use with an application lance and/or injection lance with nozzle; [0127] and wherein the bag (2) is equipped with a mixing tube (6), optionally equipped with an openable closure (7), and which optionally ends with a perforation device (8), or which optionally ends with a coupling and perforation device (8), for a container (9), which container (9) is preferably a vial, syringe, single-use syringe, ampoule, phial, or bottle (9), comprising the pharmaceutically active substance (70) in powder, lyophilisate, solution, liquid, gel or other form (suspension, emulsion), and which container (9) is provided with breakable, an openable, or perforable cap (60);
and [0128] wherein said package (100, 101) is comprising at least one flexible airtight sterile casing (12), containing said container (9), preferably a vial, syringe, single-use syringe, ampoule, phial, or bottle (9), of the said pharmaceutically active substance, and said perforation device (8), optionally the said coupling and perforation device (8), said container (9) being housed in the casing (12), optionally in a coupling position with the said optional coupling and perforation device (8); and [0129] wherein the said container (9) is manually maneuverable from the outside of the casing (12) in order to be opened inside the closed casing (12), optionally is manually maneuverable from the outside of the casing (12) up to a perforating position of said cap (60) through the same perforation device (8), optionally through the same coupling and perforation device (8); and [0130] whereupon after opening of the said container (9) and of the said closure (7), and selectively mixing (i.e. dissolving, reconstituting) the at least one pharmaceutically active substance (drug) (70) with the liquid diluent (50) through the mixing tube (6), a solution of the at least one pharmaceutically active substance (drug) (70) in the liquid diluent (50) is provided for administering by pressurized aerosol therapy (PAT) in a hollow organ, or preferably in a body cavity of a patient.

[0131] In another particular embodiment 21 (see claim 11), the present invention pertains to a kit (or use of a kit), preferably a single use kit, as defined in embodiment 20 or a sterile and closed prefilled drug containing (medical) device system (or the use thereof) comprising a flexible package (100, 101) as defined in any of the embodiments 1 to 19, for use in a treatment of administering at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or in a body cavity, in particular a therapeutic pneumoperitoneum, of a patient.

[0132] In another particular embodiment 22 (see claim 12), the present invention pertains to the a kit (or use thereof) as defined in embodiment 20 or a sterile and closed prefilled drug containing (medical) device system (or use thereof) comprising a flexible package (100, 101) as defined in any of the embodiments 1 to 19, for use in a treatment of cancer and/or tumor treatable by rinsing and/or perfusion, preferably in a treatment of cancer and/or tumor, including but not limited to as well as metastatic forms thereof, selected from the group consisting of cancer/tumor of the peritoneum, cancer/tumor of the urinary tract, in particular bladder cancer, ovarian cancer, cancer/tumor of the colorectum, and most preferably of cancer/tumor of the peritoneum; and/or in a treatment of cancer and/or tumor selected from the group consisting of in particular colorectal cancer, cervical cancer, uterine cancer, bladder cancer, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, peritoneal cancer, and prostate cancer, as well as metastatic forms thereof.

[0133] In a further particular embodiment 23, the present invention pertains to a method of treatment, wherein a kit as defined in embodiment 20 is used or a sterile and closed prefilled drug containing (medical) device system comprising a flexible package (100, 101) as defined in any of the embodiments 1 to 19 is used, in a treatment of administering at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or in a body cavity, in particular a therapeutic pneumoperitoneum, of a patient.

[0134] In a still further particular embodiment 24, the present invention pertains to a method of treatment according to embodiment 23, wherein a cancer and/or tumor is treated that is treatable by rinsing and/or perfusion, preferably wherein a cancer and/or tumor, including but not limited to as well as metastatic forms thereof, is treated selected from the group consisting of cancer/tumor of the peritoneum, cancer/tumor of the urinary tract, in particular bladder cancer, ovarian cancer, cancer/tumor of the colorectum, and most preferably of cancer/tumor of the peritoneum; and/or colorectal cancer, cervical cancer, uterine cancer, bladder cancer, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, peritoneal cancer, and prostate cancer, as well as metastatic forms thereof.

[0135] In a yet further particular embodiment 25 (see claim 13), the present invention pertains to a syringe (or use thereof), especially a single-use syringe, as a container (9) comprising at least one pharmaceutically active substance (drug) (70) in powder, lyophilisate, solution, liquid, gel or other form, preferably in solution, liquid, gel form, in a sterile and closed prefilled drug containing (medical) device system, preferably as defined above, and in any of the claims 1 to 9, or for use in a kit comprising (a) a sterile and closed prefilled drug containing (medical) device system and (b) an application lance and/or injection lance with nozzle, preferably in a kit as defined in any of the claims 10 to 12, preferably for use in a treatment of administering at least one pharmaceutically active substance (drug) (70) by pressurized aerosol therapy (PAT) in a hollow organ, or preferably in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum.

[0136] In a yet another particular embodiment 26 (see claim 14), the present invention pertains to a syringe (or use thereof), especially a single-use syringe, as a container (9) comprising at least one pharmaceutically active substance (drug) (70) in powder, lyophilisate, solution, liquid, gel or other form, preferably in solution, liquid, gel form, for use in the preparation of a sterile and closed prefilled drug containing (medical) device system, preferably as defined above, and in any of the claims 1 to 9, or in the preparation of a kit comprising (a) a sterile and closed prefilled drug containing (medical) device system and (b) an application lance and/or injection lance with nozzle, preferably a kit as defined in any of the claims 10 to 12, preferably for use in a treatment of administering at least one pharmaceutically active substance (drug) (70) by pressurized aerosol therapy (PAT) in a hollow organ, or preferably in a body cavity of a patient, in particular a therapeutic pneumoperitoneum.

[0137] In a yet another particular embodiment 27 (see claim 15), the present invention pertains to a syringe (or use thereof), especially a single-use syringe, according to embodiment 25 as a container (9) in a sterile and closed prefilled drug containing (medical) device system, or in a kit comprising said sterile and closed prefilled drug containing (medical) device system, for administering, preferably for use in a treatment for administering, at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or preferably in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum, or a syringe (or use thereof), especially a single-use syringe, according to embodiment 26 as a container (9) for use in the preparation of such a sterile and closed prefilled drug containing (medical) device system, or in a kit comprising said sterile and closed prefilled drug containing (medical) device system, wherein the said final drug containing (medical) device system, or said final drug containing (medical) device system of the kit, is comprising a flexible package (100, 101), comprising: [0138] at least one syringe, especially a single-use syringe, as container (9) comprising at least one pharmaceutically active substance (70) in powder, lyophilisate, solution, liquid, gel or other form (suspension, emulsion), preferably in solution, liquid, gel form, and being provided with breakable, an openable, or perforable cap (60); and [0139] a bag (2) of liquid diluent (50), [0140] wherein the liquid diluent (50) is preferably a physiologically acceptable aqueous diluent; [0141] wherein the bag (2) is optionally equipped with at least one drain tube (4) provided with a closing device (5); [0142] and wherein the bag (2) is equipped with a mixing tube (6), optionally equipped with an openable closure (7), and which optionally ends with a perforation device (8), or which optionally ends with a coupling and perforation device (8), for a syringe, especially a single-use syringe, as a container (9), comprising the pharmaceutically active substance (70) in powder, lyophilisate, solution, liquid, gel or other material (suspension, emulsion), preferably in solution, liquid, gel form, and which syringe, especially single-use syringe, as container (9) is provided with breakable, an openable, or perforable cap (60);
and [0143] (i) wherein in the said final drug containing (medical) device system, the said package (100, 101) optionally is comprising at least one flexible airtight sterile casing (12), containing said syringe, especially a single-use syringe, as container (9) of the said pharmaceutically active substance, and said perforation device (8), optionally the said coupling and perforation device (8), said container (9) being housed in the casing (12), optionally in a coupling position with the said optional coupling and perforation device (8); and wherein the said syringe, especially single-use syringe, as the container (9) is manually maneuverable from the outside of the optional casing (12) in order to be opened inside the closed optional casing (12), optionally is manually maneuverable from the outside of the optional casing (12) up to a perforating position of said cap (60) through the same perforation device (8), optionally through the same coupling and perforation device (8); [0144] or [0145] (ii) wherein in case of a syringe, especially single-use syringe, as the container (9), the said package (100, 101) is devoid of a flexible airtight sterile casing (12) the syringe, especially single-use syringe, as the container (9) is already fixed to the bag (2) in a coupling position with the said optional coupling and perforation device (8); [0146] and
whereupon after opening of the said syringe, especially single-use syringe, as the container (9) and of the said closure (7), and selectively mixing (i.e. dissolving, reconstituting) the at least one pharmaceutically active substance (drug) (70) with the liquid diluent (50) through the mixing tube (6), a solution of the at least one pharmaceutically active substance (drug) (70) in the liquid diluent (50) is provided for administering by pressurized aerosol therapy (PAT) in a hollow organ, or preferably in a body cavity of a patient.

[0147] Any features as defined in any of the embodiments 2 to 19 are equally applicable for the embodiments 25 to 27 pertaining to embodiments of the invention involving a syringe, especially a single-use syringe. Also, the embodiments 25 to 27 pertaining to embodiments of the invention involving a syringe, especially a single-use syringe, may be applied in a kit as defined in the embodiments 20 to 21, and as well may be applied in a method of treatment as defined in the embodiments 23 to 24.

[0148] In a further embodiment a pump, in particular a micro-pump, for transporting the pressurized substance into the nozzle system is connectable to the nozzle system, such that the substance is convertible into the aerosol by means of a needle nozzle or a needle valve. According to this embodiment of the invention comprising a micro-pump for transporting the liquid drug substance, the drug substance may be a suitable liquid, which may include additional substances for various purposes such as cancer treatment, treatment of infection, and the prevention of adhesions. The micro-pump can be formed in one embodiment by a syringe, having a piston and a cylinder, wherein the syringe can be loaded in a device, and wherein said device compresses the piston, thereby generating a fluid pressure.

[0149] According to one embodiment an insufflator is connectable to the trocar system, said insufflator providing the insufflation gas for forming a hollow space, in particular a therapeutic pneumoperitoneum, in a patient at 12 to 15 mm Hg.

[0150] According to one embodiment of the invention having a nozzle system, to which the micro-pump is connected. The micro-pump and the nozzle system are connected to each other in a fluid conductive manner, so that a drug substance, which is transported in a pressurized manner by the micro-pump, is atomized to a mist-like aerosol by needle nozzle. In addition, the aerosol may be electrostatically charged by a voltage applied to the trocar system. The substance may include in particular drugs suitable for chemotherapy, such as cytostatics, such as doxorubicin, Cisplatin or other chemotherapeutic agents, or others as described herein above.

[0151] The invention is particularly useful in combination and/or can be performed in connection with a method and device for aerosol therapy as described in the DE 10 2013 109 896 A1, which is incorporated herein in its entirety.

[0152] The embodiments of the invention can be used in a method for the directed application of a substance in a hollow space, such as a hollow organ, of a body cavity, in particular, a therapeutic pneumoperitoneum, especially by a pressurized aerosol (chemo)therapy as any one of those defined herein above, comprising at least one step of: [0153] (i) inserting a trocar sleeve a trocar system with a trocar sleeve; [0154] (ii) supplying the trocar sleeve with an insufflation gas; [0155] (iii) penetration of the trocar sleeve with a nozzle system, which in its interior forms a lumen, with a proximal end and a distal end, wherein the nozzle system has a needle nozzle fixed at the distal end with the lumen and is guided by the trocar sleeve; [0156] (iv) generating an aerosol in the hollow space, such as a hollow organ, of a body cavity, via the needle nozzle.

[0157] According to one embodiment of the method according to the invention, mainly carbon dioxide is provided as insufflation gas.

[0158] The invention further pertains to and can be illustrated by the following exemplary and representative method of treatment embodiments.

Embodiment A

[0159] A method of treating a hollow organ, or preferably in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum, wherein the method comprises [0160] providing a sterile and closed prefilled drug containing (medical) device system for administering, preferably for use in administering, at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or in a body cavity, of a patient, comprising a flexible package (100, 101) as defined above, and in any of the claims 1 to 9; optionally as part of a kit as defined above, and in any of the claims 10 to 12;
and [0161] mixing the at least one pharmaceutically active substance (70) comprised in powder, lyophilisate, solution, liquid, gel or other form (suspension, emulsion) in the at least one container (9) being provided with breakable, an openable, or perforable cap (60), with the liquid diluent (50) comprised in the bag (2), to result in a solution of the at least one pharmaceutically active substance (70) in the liquid diluent (50); [0162] and then generating a pressurized aerosol from the said solution of the at least one pharmaceutically active substance (70) in the liquid diluent (50), and thereby administering the said solution of the at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or preferably in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum.

Embodiment B

[0163] A method of treating a hollow organ, or preferably in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum, wherein the method comprises [0164] providing a sterile and closed prefilled drug containing (medical) device system for administering, preferably for use in administering, at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or in a body cavity, of a patient, comprising a flexible package (100, 101) as defined above, and in any of the claims 1 to 9; optionally as part of a kit as defined above, and in any of the claims 10 to 12;
and [0165] mixing the at least one pharmaceutically active substance (70) comprised in powder, lyophilisate, solution, liquid, gel or other form (suspension, emulsion) in the at least one container (9) being provided with breakable, an openable, or perforable cap (60), with the liquid diluent (50) comprised in the bag (2), to result in a solution of the at least one pharmaceutically active substance (70) in the liquid diluent (50); [0166] and then generating a pressurized aerosol from the said solution of the at least one pharmaceutically active substance (70) in the liquid diluent (50), and thereby administering the said solution of the at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or preferably in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum; [0167] wherein the said generated pressurized aerosol is administered by means of an application lance and/or injection lance with nozzle, preferably a single use (or disposable) application lance and/or injection lance with nozzle, for applying, i.e. for use in administering, the at least one pharmaceutically active substance (drug) by pressurized aerosol therapy (PAT) in a hollow organ, or in a body cavity, of a patient.

Embodiment C

[0168] The method of treating a hollow organ, or preferably in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum, according to embodiment A or embodiment B, [0169] wherein as a hollow space the body cavity is selected from the group consisting of each hollow space in the body that is lined by mesothelium and epithelium, self-contained or connected with other cavities or the outside world, such as the abdomen, peritoneal cavity, thoracic cavity, luminal cavity, vesical cavity, cranial cavity, nasal cavity, oral cavity, pharynx, subarachnoid spaces, or joint cavities; preferably wherein the body cavity is selected from the group consisting of the peritoneal cavity (peritoneum), thoracic cavity (thorax), luminal cavity (lumen), vesical cavity (vesicel), uterus; [0170] or wherein as hollow space the hollow organ is selected from the group consisting of such as the cavity of the heart, blood vessels, bile duct, urinary tract, gastrointestinal tract, uterus or brain ventricles.

Embodiment D

[0171] The method of treating a hollow organ, or preferably in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum, according to embodiment A or embodiment B, wherein the pressurized aerosol therapy (PAT) is selected from the group consisting of pressurized intra-peritoneal aerosol chemotherapy (PIPAC), pressurized intra-thoracic aerosol chemotherapy (PITAC), pressurized intra-luminal aerosol chemotherapy (PILAC), and pressurized intra-vesical aerosol chemotherapy (PIVAC), pressurized intra-rectal aerosol chemotherapy (PIRAC).

Embodiment E

[0172] The method of treating a hollow organ, or preferably in a body cavity, of a patient, in particular a therapeutic pneumoperitoneum, according to embodiment A or embodiment B, wherein the method is in a treatment of cancer and/or tumor treatable by rinsing and/or perfusion, preferably in a treatment of cancer and/or tumor, including but not limited to as well as metastatic forms thereof, selected from the group consisting of cancer/tumor of the peritoneum, cancer/tumor of the urinary tract, in particular bladder cancer, ovarian cancer, cancer/tumor of the colorectum, and most preferably of cancer/tumor of the peritoneum; and/or in a treatment of cancer and/or tumor selected from the group consisting of in particular colorectal cancer, cervical cancer, uterine cancer, bladder cancer, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, peritoneal cancer, and prostate cancer, as well as metastatic forms thereof.

IN THE DRAWINGS

[0173] Further advantageous embodiments of the invention and exemplary embodiments thereto, as compared to the prior art (see e.g., FIG. 2) will be explained in more detail below in conjunction with the accompanying drawings. Similarly functioning parts or components are partially provided with the same reference numerals. For better understanding in the following figures the respective features are schematic and exaggerated and are not shown to scale.

[0174] FIG. 1 shows, as an exemplification of the context of the invention, a schematic view of a typical PIPAC setting.

[0175] FIG. 2 shows a schematic view of a typical cartridge as it is currently used in the prior art, for example, in a typical PIPAC setting, for individually preparing, e.g. reconstituting, a dosage to be administered by a pressurized aerosol therapies (PAT), by a (hospital) pharmacy under (more or less) sterile and environmental conditions.

[0176] FIGS. 3 to 7 show, as an exemplification but not limiting, simplified drug and device systems according to the present invention, for the directed application of a substance by means of a pressurized aerosol therapy (PAT) into a hollow space, such as a hollow organ, or into a body cavity of a patient, i.e. a mammalian patient.

[0177] The patient may, as mentioned, be a human. The invention, however, is not limited to humans but can be applied to other organisms. The term patient shall therefore describe organism being that requires medical treatment and can be treated with the embodiments according to the invention.

[0178] An example of a hollow space target in the context of the present invention is the abdominal cavity (abdomen): Peri- and postoperative pain treatment, destruction of tumor cells (gastric cancer, ovarian cancer, or other cancers), destruction of bacteria (peritonitis), prevention and treatment of peritoneal carcinomatosis, prevention of adhesions. Chest (thorax): Peri- and postoperative pain treatment, destruction of tumor cells (lung cancer, pleural cancer, other cancers), destruction of bacteria (pleuritis), prevention and treatment of pleural carcinosis. Further applications can be found in endoscopic surgeries in a non-preformed space (e.g. in the retroperitoneum).

[0179] Variations and modifications from the described embodiments exist. Any number disclosed herein should be construed to mean approximate, regardless of whether the word about or approximately is used in describing the number. The appended claims intend to cover all those modifications and variations as falling within the scope of the invention.