Apparatus for removing chemotherapy compounds from blood
10 claims: 7 independent, 3 dependent
- 1Zastrzeżenia patentowe 1. Zestaw części do złożenia w celu podania małocząsteczkowego środka chemioterapeutycznego do wątroby pacjenta, obejmujący:cewnik izolacyjno-aspiracyjny obejmujący dwa rozszerzalne elementy okluzyjne, aparat filtracyjny obejmujący obudowę posiadającą wlot i wylot, czynniki ekstrakcyjne zawierające pokryte krwiozgodnym polimerem rdzenie węglowe umieszczone w obudowie, przy czym rdzenie węglowe odznaczają się ciężarem nasypowym mniejszym od 0,2 g/cm 3 i przy czym rdzenie węglowe odznaczają się objętością porów od około 1,68 cm 3 /g do około 2,19 cm 3 /g oraz powrotną koszulkę żylną lub cewnik powrotny.
- 2Zestaw części według zastrzeżenia 1 obejmujący ponadto cewnik zapewniający dostęp do tętnicy wątroby.
- 3Zestaw części według zastrzeżenia 1 albo 2 obejmujący ponadto chlorowodorek melfalanu.
- 4Zestaw części według dowolnego z poprzednich zastrzeżeń, przy czym dwa rozszerzalne elementy okluzyjne są balonikami.
- 5Zestaw części według dowolnego z poprzednich zastrzeżeń, przy czym cewnik izolacyjnoaspiracyjny to cewnik możliwy do umieszczenia przezskórnie w żyle głównej dolnej pacjenta wymagającego leczenia, cewnik obejmuje krwiozgodną rurkę z końcem górnym i końcem dolnym, przy czym krwiozgodna rurka definiuje światło główne dla odpływającej krwi, dwa baloniki umieszczone na stałe w odstępie na krwiozgodnej rurce i związane z nią w celu ich napełnienia w takim miejscu, przy czym jeden leży przylegle do końca górnego, a baloniki po napełnieniu mają wielkość wystarczającą do zablokowania przepływu krwi w żyle lub tętnicy, w której zgodnie z jego projektem ma być umieszczany pierwszy cewnik;otwory w krwiozgodnej rurce umieszczone między balonikami i otwierające się do głównego światła;drugie i trzecie światło krwiozgodnej rurki, przy czym drugie światło jest połączone z jednym z baloników, a trzecie światło — z drugim z baloników lub innych elementów rozszerzalnych w celu napełniania lub opróżniania baloników, górny koniec krwiozgodnej rurki skutecznie blokuje napływ krwi.
- 6Zestaw części według dowolnego z poprzednich zastrzeżeń, przy czym małocząsteczkowym środkiem chemioterapeutycznym jest chlorowodorek melfalanu, a aparat filtracyjny odznacza się skutecznością ekstrakcji przekraczającą 98% w zakresie usuwania chlorowodorku melfalanu z krwi z użyciem kasety filtra w układzie in vitro, w którym przepływ krwi przez kasetę filtra wynosi około 250 ml/min.
- 7Zestaw części według dowolnego z poprzednich zastrzeżeń, przy czym aparat filtracyjny obejmuje jedną lub większą liczbę kaset filtra.
- 8Zestaw części według dowolnego z poprzednich zastrzeżeń, przy czym aparat filtracyjny jest aparatem dwufiltrowym, który obejmuje podwójną kasetę filtra z kasetami filtra w układzie równoległym.
- 9Zestaw części według dowolnego z poprzednich zastrzeżeń, przy czym rdzenie węglowe są pokryte półprzepuszczalnym polimerem z materiału wybieranego z grupy złożonej z celulozy, polimeru metakrylanu wybieranego z grupy złożonej z polimetakrylanu metylu (PMMA), polimetakrylanu etylu (PEMA), polimetakrylanu hydroksyetylu (PHEMA), metakrylanu i ich kombinacji.
- 10Układ do podawania wysokiego stężenia małocząsteczkowego środka chemioterapeutycznego osobnikowi wymagającemu leczenia z jednoczesnym ograniczeniem ogólnoustrojowego narażenia na małocząsteczkowy środek chemioterapeutyczny, przy czym układ obejmuje:cewnik możliwy do umieszczenia przezskórnie w żyle głównej dolnej pacjenta wymagającego leczenia, cewnik obejmuje krwiozgodną rurkę z końcem górnym i końcem dolnym, przy czym krwiozgodna rurka definiuje światło główne dla odpływającej krwi, dwa baloniki umieszczone na stałe w odstępie na krwiozgodnej rurce i związane z nią w celu ich napełnienia w takim miejscu, przy czym jeden leży przylegle do końca górnego, a baloniki po napełnieniu mają wielkość wystarczającą do zablokowania przepływu krwi w żyle lub tętnicy, w której zgodnie z jego projektem ma być umieszczany pierwszy cewnik;otwory w krwiozgodnej rurce umieszczone między balonikami i otwierające się do głównego światła;drugie i trzecie światło krwiozgodnej rurki, przy czym drugie światło jest połączone z jednym z baloników, a trzecie światło — z drugim z baloników lub innych elementów rozszerzalnych w celu napełniania lub opróżniania baloników, górny koniec krwiozgodnej rurki skutecznie blokuje napływ krwi, aparat filtracyjny obejmujący obudowę posiadającą wlot i wylot, czynniki ekstrakcyjne zawierające pokryte krwiozgodnym polimerem rdzenie węglowe umieszczone w obudowie, przy czym rdzenie węglowe odznaczają się ciężarem nasypowym mniejszym od 0,2 g/cm 3 i przy czym rdzenie węglowe odznaczają się objętością porów od około 1,68 cm 3 /g do około 2,19 cm 3 /g do usuwania małocząsteczkowych środków chemioterapeutycznych z krwi, przy czym aparat filtracyjny może być połączony za pomocą łącznika z cewnikiem możliwym do umieszczenia przezskórnego w żyle głównej dolnej i z urządzeniem przepływowym w celu przepompowania krwi osobnika przez aparat filtracyjny, cewnik do wlewu do tętnicy wątrobowej do podawania chemioterapii oraz powrotną koszulkę żylną lub cewnik powrotny do podania pacjentowi przefiltrowanej krwi pobranej od pacjenta. Figura 1 Figura 2
Independent claims10
195 paragraphs in 11 sections, as filed
REPUBLIC OF POLAND (12)
TRANSLATION OF THE EUROPEAN PATENT (19) PL (11)
PL / EP 3241576 (96)
Date and European Patent Application Number:
07.11.2012 17176952.4 (13) (51)
T3
Int.CI.
(97)
Patent Office of the Republic of Poland
The grant of the European patent was announced:
24.07.2019 European Patent Bulletin 2019/30 EP 3241576 B1
A61M 1/34 (2006.01) A61M 1/36 (2006.01) B01J 20/28 (2006.01) B01J 20/20 (2006.01) B01J 20/26 (2006.01) B01J 20/30 (2006.01) B01J 20/32 (2006.01) C01B 32/354 (2017.01) C01B 32/372 (2017.01) (43) (45) (43) (45)
Title of the invention:
Apparatus for removing chemlotherapeutic compounds from blood
Priority:
07.11.2011 US 201161556819 P.
The application was announced:
11.11.2017 in the European Patent Bulletin No. 2017/45
The filing of the patent translation was announced:
31.01.2020 News Patent Office 2020/01 (73) (72) f <0 10 i<sup>74</sup>)
CM
M
Q_
UJ (73) (72) f <0 10 (74)
CM
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UJ
Patent holder:
Delcath Systems, Inc., New York, US
The inventor (s) of the invention:
DANIEL S. JOHNSTON, Trappe, US JACOUES CHAMMAS, Walpole, US WILLIAM M. APPLING, Granville, US SAMANTHA BARTON, Hudson Falls, US
Proxy:
thing, pat. Alicja Piotrowicz KULIKOWSKA & KULIKOWSKI SP.K.
ul. Nowogrodzka 47 A 00-695 Warsaw, nine months after the publication of information on the grant of a European patent, any person may lodge an objection to the European Patent Office regarding a European patent. The objection shall be made in the form of a reasoned statement. It is considered to be filed only when the fee for volume 99 (1) of the Convention on the Grant of European Patents is paid).
30085 / EP / 19
EP3241576 B1
REFERENCES TO RELATED APPLICATIONS [0001] This patent application is an international patent application filed in accordance with the Patent Cooperation Agreement, with all countries being parties to the agreement indicated. This international application claims the benefit of the priority of the U.S. Provisional Patent Application No. 61 / 556,819, filed November 7, 2011, under the title "APPARATUS FOR REMOVING CHEMIOTHERAPEUTIC COMPOUNDS FROM BLOOD".
BACKGROUND [0002] The presence of toxic chemotherapeutic agents in the body of patients undergoing chemotherapy has been the cause of significant suffering and interruption of potentially life-prolonging or salvage therapy. For localized tumor incidence, various approaches have been used to reduce systemic exposure to toxic chemotherapeutic agents.
[0003] An important example is the liver because primary and metastatic liver tumors are one of the most common causes of death in the course of oncological disease worldwide. One of the most common and deadly cancers is hepatocellular carcinoma. Curley et al., Annals of Surgical Oncology 1 (5): 389-399 (1994). In addition, liver metastases are the most common secondary tumors associated with the progression of many cancers of varying primary origin, such as colorectal adenocarcinoma, ocular melanoma, neuroendocrine tumors and gastrointestinal sarcoma, and are often in the form of multifocal, inoperable liver tumors. Pingpank et al., J. Clin. Oncol. Bars 23 (15): 3465-3474 (2005).
[0004] High doses of chemotherapy have been shown to be effective in treating liver cancer. However, due to the toxicity of chemotherapeutic agents, the use of high-dose therapy is limited. Various approaches to reduce systemic exposure have been used to overcome problems with systemic exposure to chemotherapy. For the supply of high doses of chemotherapeutics locally to the liver, surgical treatment requiring selective hepatic medication using extracorporeal circulation (ant. Isolated hepatic perfusion (IHP) was used. The disadvantage of this approach is, among others patient lack of repeatability and high perioperative mortality. Pingpank et al., J. Clin. Oncol. Bars 23 (15): 3465-3474 (2005).
[0005] Another highly promising approach has been called chemosaturation - it is a technique that uses a catheter to percutaneously supply a high dose of chemotherapy to an affected organ, followed by removal from the blood organ containing chemotherapeutic agents, subjecting blood to extracorporeal filtration, and re-administering blood to the patient after removal of the agent chemotherapeutic.
[0006] For e.g. chemosaturation treatment of the liver by percutaneous hepaticperfusion (PHP), high doses of chemotherapy (anti-cancer agents) are administered intra-arterially directly to an isolated liver, causing saturation of both liver cells and tumor cells. Then the blood from the liver is drawn through the isolation and aspiration catheter and directed outside the body to the filter system, which reduces the concentration of the chemotherapeutic agent in the blood before it returns to the body.
[0007] The targeted supply of high doses of chemotherapy (anti-cancer agents) to organs, removal of toxic substances from blood in the extracorporeal system, and re-administration of blood to a patient are described in US Patent No. 5,069,662 to Bodden and WO2011 / 056181.
SUMMARY [0008] The present invention results from the inventors' awareness that there is an urgent need to limit the concentration of chemotherapeutic agents in the body during cancer therapy and to maintain the quality parameters of the blood of treated patients after extracorporeal filtration. Progress in this area could significantly improve the prospects and quality of life of cancer patients. The inventors have found that in order to achieve the goal of reducing or eliminating the systemic effects of chemotherapy, while conducting targeted chemotherapy for specific organs, it is necessary to achieve progress in the effective removal of toxic, small molecule chemotherapeutic agents from the blood. The present invention, in some of its embodiments, addresses such an urgent necessity by providing systems and kits for highly effective extracorporeal removal of low molecular weight chemotherapeutic agents from blood and blood products, such as plasma, while maintaining good platelet, leukocyte and erythrocyte status. The increased efficacy of the removal of chemotherapeutic agents reduces the systemic exposure to the chemotherapeutic agent and associated toxic effects such as myelosuppression. Various embodiments are given below. The invention is defined by the appended claims.
[0009] In some embodiments, a filter apparatus is provided herein for removing small molecule chemotherapeutic agents from the blood, including a housing having an inlet and an outlet, extraction media comprising polymer coated carbon cores housed in the housing, the carbon cores having a pore volume of from about 1.68 cm<sup>3</sup>/ g to about 2.17 cm<sup>3</sup>/ G.
[0010] In some embodiments, a filter apparatus is provided herein for removing small molecule chemotherapeutic agents from the blood, including a housing having an inlet and an outlet, extraction media comprising polymer coated carbon cores housed in the housing, the carbon cores having a pore volume of from about 1.68 cm<sup>3</sup>/ g to about 2.17 cm<sup>3</sup>/ g and particle size of carbon cores from about 0.45 mm to about 1.15 mm.
[0011] In some embodiments, a filter apparatus is provided herein for removing low molecular weight chemotherapeutic agents from the blood, including a housing having an inlet and an outlet, extraction media comprising polymer coated carbon cores housed in the housing, the carbon cores having a pore volume of from about 1.68 cm<sup>3</sup>/ g to about 2.17 cm<sup>3</sup>/ g, and the bulk density of carbon cores is from about 0.19 to about 0.2.
[0012] In some embodiments, a filter apparatus is provided herein for removing small molecule chemotherapeutic agents from the blood, comprising a housing having an inlet and an outlet, extraction media comprising polymer coated carbon cores housed in the housing, the carbon cores having a pore volume of from about 1.68 cm<sup>3</sup>/ g to about 2.17 cm<sup>3</sup>/ g and a median diameter of micropores (D50, micro) of carbon cores from about 9.3 A to about 10.5 A.
[0013] In some embodiments, a filter apparatus is provided herein for removing small molecule chemotherapeutic agents from the blood, including a housing having an inlet and an outlet, extraction media comprising polymer coated carbon cores housed in the housing, the carbon cores having a pore volume of from about 1.68 cm<sup>3</sup>/ g to about 2.17 cm<sup>3</sup>/ g and a median mesopores diameter (D50, meso) from about 30 A to about 156 A.
[0014] In some embodiments, a filter apparatus is provided herein for removing low molecular weight chemotherapeutic agents from the blood, including a housing having an inlet and an outlet, extraction media comprising polymer coated carbon cores housed in the housing, the carbon cores having a pore volume of from about 1.68 cm<sup>3</sup>/ g to about 2.17 cm<sup>3</sup>/ g, and the percentage of micropores in carbon cores is from about 18% to about 28% of the pore volume.
[0015] In some embodiments, a filter apparatus is provided herein for removing small molecule chemotherapeutic agents from the blood, including a housing having an inlet and an outlet, extraction media comprising polymer coated carbon cores housed in the housing, the carbon cores having a pore volume of from about 1.68 cm<sup>3</sup>/ g to about 2.17 cm<sup>3</sup>/ g and specific surface area MBET of carbon cores ranging from about 1825 m<sup>2</sup>/ g to about 2058 m<sup>2</sup>/ G.
[0016] In some embodiments, a filter apparatus is provided herein for removing small molecule chemotherapeutic agents from the blood, including a housing having an inlet and an outlet, extraction media comprising polymer coated carbon cores housed in the housing, the carbon cores having a pore volume of from about 1.68 cm<sup>3</sup>/ g to about 2.17 cm<sup>3</sup>/ g and a specific surface area of DFT of carbon cores ranging from about 1483 m<sup>2</sup>/ g to about 1778 m<sup>2</sup>/ G.
[0017] In some embodiments, a filter apparatus is provided herein for removing small molecule chemotherapeutic agents from the blood, including a housing having an inlet and an outlet, extraction media comprising polymer coated carbon cores housed in the housing, the carbon cores having a pore volume of from about 1.68 cm<sup>3</sup>/ g to about 2.17 cm<sup>3</sup>/ g and the housing is a filter cassette.
[0018] In some embodiments, a filter apparatus is provided herein for removing low molecular weight chemotherapeutic agents from the blood, including a housing having an inlet and an outlet, extraction media comprising polymer coated carbon cores housed in the housing, the carbon cores having a pore volume of from about 1.68 cm<sup>3</sup>/ g to about 2.17 cm<sup>3</sup>/ g, the casing is a filter cassette, and the low molecular weight chemotherapeutic agent is melphalan hydrochloride, and the filtration apparatus has an extraction efficiency exceeding 98% in the removal of melphalan hydrochloride from the blood using a filter cassette in an in vitro system in which blood flow through the filter cassette is about 250 ml / min.
[0019] In some embodiments, a filter apparatus is provided herein for removing low molecular weight chemotherapeutic agents from the blood, including a housing having an inlet and an outlet, extraction media comprising polymer coated carbon cores housed in the housing, the carbon cores having a pore volume of from about 1.68 cm<sup>3</sup>/ g to about 2.17 cm<sup>3</sup>/ g and the casing is a filter cassette and the low molecular weight chemotherapeutic agent is melphalan hydrochloride, and the filtration apparatus has an extraction efficiency of about 95% to about 98% in the field of removing melphalan hydrochloride from the blood using the filter cassette in an in vitro system which blood flow through the filter cassette is about 500 ml / min.
[0020] In some embodiments, a filter apparatus is provided herein for removing small molecule chemotherapeutic agents from the blood, including a housing having an inlet and an outlet, extraction media comprising polymer coated carbon cores housed in the housing, the carbon cores having a pore volume of from about 1.68 cm<sup>3</sup>/ g to about 2.17 cm<sup>3</sup>/ g, the casing is a filter cassette, and the low molecular weight chemotherapeutic agent is melphalan hydrochloride, and the filtration apparatus has an extraction efficiency exceeding 95% in the removal of melphalan hydrochloride from the blood using an in vitro filter cassette.
[0021] In some embodiments, a filter apparatus is provided herein for removing small molecule chemotherapeutic agents from the blood, including a housing having an inlet and an outlet, extraction media comprising polymer-coated carbon cores housed in the housing, the carbon cores having a pore volume from about 1.68 cm<sup>3</sup>/ g to about 2.17 cm<sup>3</sup>/ g and the casing is a filter cassette and the low molecular weight chemotherapeutic agent is doxorubicin, and the filtration apparatus has an extraction efficiency exceeding about 95% in removing doxorubicin from the blood using an in vitro filter cassette in which the blood flow through the filter cassette is about 250 ml / min.
[0022] In some embodiments, a filter apparatus is provided herein for removing low molecular weight chemotherapeutic agents from the blood, including a housing having an inlet and an outlet, extraction media comprising polymer coated carbon cores housed in the housing, the carbon cores having a pore volume of from about 1.68 cm<sup>3</sup>/ g to about 2.17 cm<sup>3</sup>/ g and the casing is a filter cassette and the low molecular weight chemotherapeutic agent is topotecan, and the filtration apparatus has an extraction efficiency in excess of about 89% in removing topotecan from the blood using the filter cassette in an in vitro system in which the blood flow through the filter cassette is about 250 ml / min.
[0023] In some embodiments of the filtration apparatus for removing low molecular weight chemotherapeutic agents from blood, the polymer-coated carbon cores are coated with a semi-permeable polymer coating of a material selected from the group consisting of cellulose, methacrylate polymer and combinations thereof.
[0024] In some embodiments of the filtration apparatus for removing low molecular weight chemotherapeutic agents from the blood, the semipermeable polymer coating is a methacrylate selected from the group consisting of polymethyl methacrylate (PMMA), polymethyl ethyl methacrylate (PEMA), polymethyl methacrylate (PHEMA) and combinations thereof.
[0025] In some embodiments of the filtration apparatus for removing low molecular weight chemotherapeutic agents from the blood, the semipermeable polymer coating is polymethyl hydroxyethyl acrylate (PHEMA).
[0026] In some embodiments of the filtration apparatus for removing low molecular weight chemotherapeutic agents from blood, the weight ratio of carbon to methacrylate is from about 52: 1 to about 25: 1.
[0027] In some embodiments, a filtration apparatus is provided for removing low molecular weight chemotherapeutic agents from the blood, including a housing having an inlet and an outlet, extraction media comprising polymer-coated carbon cores housed in the housing, the carbon cores having a pore volume from about 1.68 cm<sup>3</sup>/ g to about 2.17 cm<sup>3</sup>/ g and an MBET specific surface area from about 1825 m<sup>2</sup>/ g to about 2059 m<sup>2</sup>/ G.
[0028] In some embodiments, a filtration apparatus is provided for removing low molecular weight chemotherapeutic agents from blood, the carbon cores having a pore volume of about 1.68 cm<sup>3</sup>/ g to about 2.17 cm<sup>3</sup>/ g, specific MBET surface area from about 1825 m<sup>2</sup>/ g to about 2059 m<sup>2</sup>/ g and a specific surface area of DFT from approximately 1483 m<sup>2</sup>/ g to about 1778 m<sup>2</sup>/ G.
[0029] In some embodiments, a filtration apparatus is provided for removing small molecule chemotherapeutic agents from blood, the carbon cores having a pore volume of about 1.68 cm<sup>3</sup>/ g to about 2.17 cm<sup>3</sup>/ g, specific MBET surface area from about 1825 m<sup>2</sup>/ g to about 2059 m<sup>2</sup>/ g, DFT specific surface area from approximately 1483 m<sup>2</sup>/ g to about 1778 m<sup>2</sup>/ g and bulk density from about 0.185 to about 0.195.
[0030] In some embodiments, a filtration apparatus is provided for removing low molecular weight chemotherapeutic agents from the blood, wherein the low molecular weight chemotherapeutic agent is melphalan hydrochloride and the filtration apparatus has an extraction efficiency in excess of 98% in removing melphalan hydrochloride from the blood using a filter cassette in the system in vitro, in which the blood flow through the filter cassette is about 250 ml / min.
[0031] In some embodiments, a filtration apparatus is provided for removing melphalan hydrochloride from the blood, comprising a housing having an inlet and an outlet, extraction media comprising polymer-coated carbon cores housed in the housing, the carbon cores having a bulk density of less than 0.2 g / cm<sup>3</sup>, and extraction efficiency exceeds 98% in removing melphalan hydrochloride from the blood.
[0032] In some embodiments, a filtration apparatus is provided for removing melphalan hydrochloride from the blood, comprising a housing having an inlet and an outlet, extraction media comprising polymer-coated carbon cores housed in the housing, the carbon cores having a bulk density of less than 0.2 g / cm<sup>3</sup>, and the extraction efficiency exceeds 98% in the removal of melphalan hydrochloride from the blood, and the carbon cores have a pore volume of about 1.68 cm<sup>3</sup>/ g to about 2.19 cm<sup>3</sup>/ G.
[0033] In some embodiments, a filtration apparatus is provided for removing melphalan at a concentration below 15,000 ng / mL from blood, comprising one or more filter cassettes containing extraction media containing polymer-coated carbon cores housed in the filter cassette, wherein the carbon cores are distinguished pore volume from approximately 1.68 cm<sup>3</sup>/ g to about 2.19 cm<sup>3</sup>/ g and with a bulk density less than about 0.2 g / cm<sup>3</sup>, and wherein the filtration apparatus has an extraction efficiency relative to melphalan exceeding 98% when the blood flow through the filtration apparatus is 500 ml / L or less.
[0034] In some embodiments, a filtration apparatus is provided for removing melphalan at a concentration below 15,000 ng / ml from blood, comprising one or more filter cassettes containing extraction media containing polymer-coated carbon cores housed in the filter cassette, the carbon cores having a volume pores from about 1.68 cm<sup>3</sup>/ g to about 2.19 cm<sup>3</sup>/ g and with a bulk density less than about 0.2 g / cm<sup>3</sup>, and wherein the filtration apparatus has an extraction efficiency relative to melphalan exceeding 98% when the blood flow through the filtration apparatus is 500 ml / L or less, the filtration apparatus comprising two filter cassettes.
[0035] In some embodiments, a filtration apparatus is provided for removing melphalan at a concentration below 15,000 ng / mL from blood, comprising one or more filter cassettes containing extraction media containing polymer-coated carbon cores housed in the filter cassette, the carbon cores having a volume pores from about 1.68 cm<sup>3</sup>/ g to about 2.19 cm<sup>3</sup>/ g and with a bulk density less than about 0.2 g / cm<sup>3</sup>, and wherein the filtration apparatus has an extraction efficiency relative to melphalan exceeding 98% when the blood flow through the filtration apparatus is 500 ml / l or less, the two filter cassettes are parallel to each other and the flow is divided so that the fluid flows in parallel through both filter cassettes.
[0036] In some embodiments, there is provided a method of treating a subject with liver cancer, comprising: isolating the outflow of blood from the liver, administering the chemotherapeutic agent to the isolated liver, collecting the blood containing the chemotherapeutic agent from the isolated liver and filtering the blood containing the chemotherapeutic agent using a filtration apparatus comprising a housing having an inlet and an outlet, extraction agents containing polymer coated carbon cores housed in the housing, the polymer-coated carbon cores have a bulk density of less than 0.21 g / cm3<sup>3</sup>.
[0037] In some embodiments, there is provided a method of treating a subject with liver cancer, comprising: isolating the outflow of blood from the liver, administering the chemotherapeutic agent to the isolated liver, collecting the blood containing the chemotherapeutic agent from the isolated liver and filtering the blood containing the chemotherapeutic agent using a filtration apparatus comprising a housing having an inlet and an outlet, extraction agents containing polymer coated carbon cores housed in the housing, the polymer-coated carbon cores have a bulk density of less than 0.21 g / cm3<sup>3</sup> and wherein the chemotherapeutic agent is melphalan hydrochloride. In some embodiments, an extraction efficiency greater than 98% is achieved in removing melphalan hydrochloride from the blood. In some embodiments, an extraction efficiency greater than 98% is obtained in removing melphalan hydrochloride from the blood with blood flow through the filtration apparatus at a level of about 500 ml / L or less.
[0038] In some embodiments, the carbon cores have a bulk density of less than 0.21 g / cm<sup>3</sup>.
[0039] In some embodiments, there is provided a method of treating a subject with a liver cancer, comprising: isolating the outflow of blood from the liver, administering the chemotherapeutic agent to the isolated liver, collecting the blood containing the chemotherapeutic agent from the isolated liver and filtering the blood containing the chemotherapeutic agent using a filtration apparatus comprising a housing having an inlet and an outlet, extraction agents containing polymer coated carbon cores housed in the housing, the polymer-coated carbon cores have a bulk density of less than 0.21 g / cm3<sup>3</sup> and wherein the chemotherapeutic agent is doxorubicin or topotecan.
[0040] In some embodiments, there is provided a method of treating a subject with liver cancer, comprising: isolating the outflow of blood from the liver, administering the chemotherapeutic agent to the isolated liver, collecting the blood containing the chemotherapeutic agent from the isolated liver and filtering the blood containing the chemotherapeutic agent using a filtration apparatus comprising a housing having an inlet and an outlet, extraction agents containing polymer coated carbon cores housed in the housing, the polymer-coated carbon cores have a bulk density of less than 0.21 g / cm3<sup>3</sup> and wherein the chemotherapeutic agent, wherein the filtration apparatus comprises one or more filter cassettes.
[0041] In some embodiments, there is provided a method of treating a subject with a liver cancer, comprising: isolating the outflow of blood from the liver, administering the chemotherapeutic agent to the isolated liver, collecting the blood containing the chemotherapeutic agent from the isolated liver and filtering the blood containing the chemotherapeutic agent using a filtration apparatus comprising a housing having an inlet and an outlet, extraction agents containing polymer coated carbon cores housed in the housing, the carbon cores have a bulk density of less than 0.21 g / cm<sup>3</sup> and wherein the chemotherapeutic agent, further comprising re-administering blood to the patient after filtering it to reduce the amount of chemotherapeutic agent in the blood.
[0042] In some embodiments, there is provided a method of treating liver cancer in a patient in need of treatment, including inserting a first catheter into the femoral artery to access the hepatic artery proper area, directing the first catheter to the hepatic artery proper area for administering melphalan hydrochloride. insertion of an isolation-aspiration catheter with two balloons or expandable occlusive elements into the femoral vein and directing of the isolation-aspiration catheter to the inferior vena cava, then two balloons or expandable occlusive elements are filled or dilated to block the normal venous outflow of blood from the liver to the heart and isolate liver a dose of melphalan from about 2.0 mg / kg to about 3.5 mg / kg is administered to the liver using the first catheter over a period of about 15 to about 45 minutes. subject, the drainage blood containing melphalan is then taken from the area between the two filled balloons or the expandable occlusion elements of the isolation and aspiration catheter and passed at a rate of from about 250 ml / min to about 1000 ml / min through a filter apparatus according to some embodiments of the invention in to remove over 98% melphalan hydrochloride from the blood, and blood after passing through the filtration apparatus (filtration) is re-administered to the patient through a third catheter inserted into the internal jugular vein.
[0043] In some embodiments, the invention provides a system for administering a high concentration of a small molecule chemotherapeutic agent to a subject in need of treatment, while limiting systemic exposure to the small molecule chemotherapeutic agent, wherein the system includes a catheter placed transdermally in the inferior vena cava of a patient in need of treatment, the catheter includes a blood-compatible tube upper end and lower end, where the blood-conforming tube defines the headlamp for the outgoing blood, two balloons permanently spaced on the blood-compatible tube and associated with it for filling in such a place, one being adjacent to the upper end, and the balloons having a size sufficient to fill blocking blood flow in a vein or artery where the first catheter is to be placed according to its design; holes in the blood-compatible tube placed between the balloons and opening into the main lumen; the second and third lumen of the blood-conforming tube, the second light connected to one of the balloons, and the third light with the other of the balloons or other expandable elements to fill or empty the balloons, the upper end of the blood-compatible tube effectively blocks blood flow; a filtration apparatus in accordance with some embodiments of the invention for removing a small molecule chemotherapeutic agent from the blood, wherein the filtration apparatus can be connected by means of a connector to the first catheter and flow device to pump the subject's blood through the apparatus, and a sheath or back catheter for re-administration to the filtered patient blood removed from the patient.
[0044] In some embodiments, the subject in a system for administering high concentration of low molecular weight chemotherapeutic agents is human.
[0045] In some embodiments of the invention, a system for administering a high concentration of low molecular weight chemotherapeutic agents to a subject may be provided in the form of a kit or assembly.
[0046] In other embodiments of the invention, a series of hemofiltration cassettes are used as a constant source of fresh extraction medium. In some embodiments of the invention, a series of filters placed upstream of the pump in the hemofiltration system or downstream of the pump are changed during treatment by mechanical or electronic components. In some embodiments, a microprocessor is used to control filter changes. In some embodiments, the filtration efficiency or extraction efficiency is monitored in real time and the filter cassettes are switched in response to any decrease in extraction efficiency. In some embodiments, a series of filtration apparatus is placed on a rotary table apparatus or other structure that moves the filter cassettes.
[0047] In some embodiments, the invention provides a method of administering a small molecule chemotherapeutic agent to a selected organ or organ part of a mammalian subject, while limiting the mammalian subject to systemic exposure to the small molecule chemotherapeutic agent, comprising:
a. placing one or more catheters in venous vasculature draining blood from an organ, wherein at least one of the catheters has two or more expandable elements,
b. isolating the organ or part of the organ by stopping blood flow in the venous vascular system draining blood from the organ or part of the organ by filling expandable elements,
c. administration of a chemotherapeutic agent to an isolated organ or an isolated part of the organ,
d. ensuring sufficient time for perfusion of the chemotherapeutic agent in an isolated organ to achieve a therapeutic effect,
e. removing blood from an isolated organ, wherein the blood contains a small molecule chemotherapeutic agent,
f. filtering the blood to remove the small molecule chemotherapeutic agent by passing the blood through a filtration apparatus for removing the small molecule chemotherapeutic agents from the blood, comprising a housing having an inlet and an outlet, extraction agents containing polymer-coated carbon cores housed in the housing, the carbon cores having a density of from about 0.185 g / ml to about 0.195 g / ml, and the efficiency of the filtration apparatus with respect to low molecular weight chemotherapeutic agents exceeds about 95%.
[0048] An important advantage of this highly efficient removal of chemotherapeutic agents by the filtration apparatus, systems, methods and kits according to some embodiments of the invention is to enable reduction of systemic exposure to toxic chemotherapeutic agents (anti-cancer drugs), which leads to less bone marrow suppression, which in turn, reduces the incidence and severity of neutropenia, thrombocytopenia and anemia, which results in the patient being able to continue treatment and feel less debilitating. Reducing the incidence and severity of these conditions reduces the patient's discomfort, suffering and susceptibility to infection. This allows doctors to restart treatment faster than was previously possible. Reduced systemic exposure to chemotherapeutic agents also reduces the incidence and severity of other known toxic effects, including but not limited to nausea, vomiting, sores, hair loss, interstitial pneumonia, infertility, rash and pruritus.
BRIEF DESCRIPTION OF THE DRAWINGS [0049]
Fig. 1 shows the extracorporeal circulation used for in vitro testing of the efficiency of the filter apparatus.
Fig. 2 shows a system for performing chemosaturation by percutaneous drug delivery to the hepatic circulation procedure.
DETAILED DESCRIPTION OF THE INVENTION [0050] The inventors have unexpectedly found that a filtration apparatus comprising low density activated carbon cores coated with a polymer and systems, methods and kits utilizing such a filtration apparatus can reduce the concentration of small molecule chemotherapeutic agents (chemotherapeutic drugs) with efficacy of - in some embodiments - over 98%. While in preferred embodiments of the invention it is useful to remove low molecular weight chemotherapeutic agents from blood, some embodiments of the invention may be used to remove other toxic low molecular weight organic compounds from blood or other body fluids.
[0051] In some embodiments, the invention is particularly useful in transdermal techniques where specific organs have been isolated. An important embodiment of the invention, due to the urgent need to develop new approaches in the treatment of primary and metastatic liver tumors, is the use of the filtration apparatus of the invention as part of the transdermal drug delivery system for hepatic circulation to administer high-dose chemotherapy to the liver, while significantly reducing systemic exposure to chemotherapy. The filtration apparatus described herein, in some embodiments of the invention, may be part of the percutaneous organ isolation and cancer treatment systems described, e.g., in US Patent Nos. 5,069,662 and 5,411,479 to Bodden. In US Patent Nos. 5,069,662 and 5,411,479 - as here - an important application is percutaneous supply of drugs for hepatic circulation.
[0052] According to some embodiments of the invention, high concentrations of small molecule chemotherapy (anti-cancer agents) can be perfused by an organ of the tumor-containing organism and then removed from the organ with outflowing blood. Blood contaminated with small molecule chemotherapy can then be transferred to the extracorporeal circulation including the filtration apparatus described here, and small molecule chemotherapy is removed from the blood with an efficiency of over 98%, and the purified blood is then administered back to the body, allowing it to be used for infusion of much higher from the usual doses of small molecule chemotherapy, while preventing the release of toxic low-molecular chemotherapy levels to the rest of the patient's body.
[0053] The use of the singular in the present specification may mean one or more, as is commonly understood in the construction of claims.
[0054] The term "small molecule chemotherapeutic agents" as used herein refers to organic compounds with a molecular weight in the range of about 200 to about 1500 that are useful as chemotherapeutic agents. Chemotherapeutic agents are medicines used to treat any form of cancer. The terms chemotherapeutic agents, anti-cancer agents and chemotherapy are used interchangeably herein.
[0055] In some embodiments, the filter apparatus of the invention is used to remove small molecule chemotherapeutic agents from the blood of patients receiving chemotherapy targeted cancer in specific organs, glands or areas that may be isolated. The scope of the invention includes, e.g. cancerous organs such as the liver, kidneys, pancreas and bladder, glands such as adrenals, pancreas, prostate, thyroid and parathyroid glands and pelvic area. In some embodiments, the invention includes, e.g., a system comprising a filtration apparatus for isolating and treating liver cancer. However, embodiments of the present invention find use in the treatment of small molecule chemotherapeutic agents of cancer in any finite, isolable area of the body. [0056] In some embodiments, hypoxic abdominal perfusion (HAP) is used to isolate all or part of the abdominal cavity, prior to administration of the chemotherapeutic agent or chemotherapeutic agents. In some embodiments, intraperitoneal hyperthermic perfusion chemotherapy (IPHC) is used to isolate the peritoneal cavity prior to administration of the chemotherapeutic agent or chemotherapeutic agents. Melphalan, paclitaxel or combinations thereof for the treatment of primary colorectal cancer. In some embodiments of the invention, blood from these isolated areas is filtered after chemotherapeutic treatment using the apparatus disclosed herein in various embodiments.
[0057] Small molecule chemotherapeutic agents (anti-cancer agents) that may be removed from the blood in some embodiments of the invention include melphalan hydrochloride (also known to those skilled in the art under the names: melphalan, alkaran, L-phenylalanine mustard, phenylalanine mustard, L-PAM or L-sarcolysin), doxorubicin (also known as adriamycin). Although not an exhaustive list, other small molecule chemotherapeutic agents that may be removed from the blood, some embodiments of the invention include doxorubicin (adriamycin), fluorinated pyrimidines (5-fluorouracil, 5-FU, or floxurudin, FURD), cisplatin, oxaliplatin, topotecan. Mitomycin C, cyclophosphamide, methotrexate, vincristine, bleomycin, FAMT and any other small molecule anti-cancer agents. Removal of toxic substances from the blood can be e.g. achieved by hemoperfusion through a filter cassette comprising a filtration apparatus as described herein and in accordance with some embodiments of the invention.
[0058] The coating surrounding the carbon cores in some embodiments is composed of 2-hydroxyethyl polymethacrylate). The thickness of the coating covering the particles is largely determined by the weight ratio of carbon cores to 2-hydroxyethyl polymethacrylate) used in the coating process. During the preparation of polymer cores, poly (2-hydroxyethyl methacrylate) is dissolved in ethanol, and the carbon cores are soaked in solution to dryness, leaving a coating of poly (2-hydroxyethyl methacrylate) on the particles. The weight ratios of carbon to 2-hydroxyethyl polymethacrylate ranging from 52: 1 to 25: 1, and in vitro extraction efficiency tests were found to be statistically equivalent. In some embodiments, the weight ratio of carbon cores to 2-hydroxyethyl methacrylate is from 52: 1 to 25: 1. In other embodiments, the weight ratio of carbon cores to 2-hydroxyethyl polymethacrylate is about 25: 1 (4% polymethacrylate 2 hydroxyethyl)).
[0059] In some embodiments of the invention, the small molecule chemotherapeutic agents are selected from melphalan, doxorubicin (also known as hydroxydaunorubicin and sold under the trade name Adriamycin, Adriamycin PFS, Adriamycin RDF or Rubex), docetaxel, paclitaxel, fluorinated pyrimidinyl 5-FU, or floxuridine, FURD), cisplatin, oxaliplatin, topotecan. Mitomycin C, cyclophosphamide, methotrexate, vincristine, bleomycin, FAMT, their pharmaceutically acceptable salts, combinations thereof and other such compounds known to a person skilled in the art.
[0060] In some embodiments, pharmaceutically acceptable salts of any of the chemotherapeutic agents disclosed herein are used. The term "pharmaceutically acceptable salts" includes all salts commonly used to form alkali metal and free acid or free base addition salts. The nature of the salt is not critical provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable addition salts of melphalan, paclitaxel and oxaliplatin can be prepared from inorganic acid or organic acid. Inorganic acids include, for example, hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acids. Suitable organic acids can be selected from organic acids from the group of aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic compounds, examples of which are formic, acetic, adipic, butyric, propionic, succinic, glycolic, gluconic, lactic, and malic acids. tartaric, lemon, ascorbic, glucuronic, maleic, fumaric, pyruvic, asparagine, glutamine, benzoic, anthranilic, mesyl, 4-hydroxybenzoic, phenylacetic, mandelic, pamoic, methanesulfonic, ethanesulfonic, ethanedisulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclamic acid, camphoric acid, camphorsulfonic acid, diglukonowy, cyclopentanepropionic dodecylsulfate, glucoheptonic glicerylofosfonowy, heptanoic, hexanoic, 2-hydroxyethanesulfonic, nicotinic, 2-naphthalenesulfonic, oxalic, palmoin, pectic, peroxodisulfite, 2-phenylpropionic, picric, Pivalon, propionic, amber, tartaric, thiocyanate, mesyl, undecane, stearic, algenic, β-hydroxybutyric, salicylic, mucous or galacturonic. Pharmaceutically acceptable base addition salts include metal salts such as salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or salts made from organic bases, including primary, secondary and tertiary, substituted amines, including cyclic amines such as caffeine, arginine, diethylamine, N-ethylpiperidine, aistidine, glucamine, isopropylamine, lysine, morpholine, Netylmorpholine, piperazine, piperidine, triethylamine, trimethylamine. All of these salts can be prepared by conventional methods from the appropriate compound of the invention by reacting, e.g., the appropriate acid or base with the compound [0061] In some embodiments, the chemotherapeutic agent is melphalan. Melphalan is commercially available under the trade name Alkeran (manufactured by GlaxoSmithKline) and is a cytotoxic and alkylating agent used in cancer chemotherapy. It is a phenylalanine derivative of nitrogen mustard, also called L-phenylalanine mustard (L-PAM), phenylalanine mustard or L-sarcolysin. The systematic name according to IUPAC is 4- [bis) 2-chloroethyl) amino] -L-phenylalanine.
[0062] In some embodiments, doxorubicin hydrochloride, also called hydroxydaunorubicin, is used, available under the trade names Adriamycin PFS, Adriamycin RDF or Rubex. [0063] The filtration apparatus described herein, methods and systems can also be removed to remove toxic compounds from the blood of patients with poisoning by various small molecule compounds, such as those associated with various non-therapeutic, therapeutic and renal failure substances.
[0064] The term "blood" as used herein may be the blood normally found in a mammalian subject such as a human, but the term used herein may also refer to other blood products such as plasma.
[0065] As used herein in connection with a filter apparatus, the term "housing" refers to a blood-compatible and biocompatible structure having an inlet and an outlet that is used to contain the extraction agents therein. In some embodiments, the housing may be a cylindrical structure provided with an inlet and an outlet.
[0066] The term "filter cassette" as used herein refers to a cylindrical column about 7.8 inches between the sieves at the ends of the columns that are used to retain extraction agents, and about 2.4 inches in diameter, having an inlet and outlet, consisting of blood-compatible thermoplastic material and containing about 101-111 grams of filtration media (extraction media), the filtration media having a bulk volume from about 535 ml to about 544 ml.
[0067] The thermoplastic material used herein refers to polysulfone, polycarbonate, polyacrylate, polyurethane, etc., as interpreted by those skilled in the art. In general, polymers that provide rigid structures and are blood-compatible can be used in the embodiments described herein. In some embodiments, the thermoplastic material is transparent. In some embodiments, the thermoplastic material is polysulfone.
[0068] The term "polymer coating" as used herein refers to a semi-porous polymer that coats the activated carbon particles used in the present invention and makes them blood-compatible. Suitable polymers that can be used for this purpose include cellulose and methacrylate polymers. In some embodiments, e.g., polymethyl methacrylate (PMMA), polymethyl ethyl methacrylate (PEMA), polymethyl hydroxyethyl (PHEMA), and combinations thereof may be used. Other polymers that can be used in some embodiments of the invention include, without limitation, poly (N-vinylpyrrolidone), poly (hydroxyethyl acrylate), hydroxyethyl cellulose, hydroxypropyl cellulose, poly (acrylic acid) salts, poly (methacrylic acid) salts, poly (dimethylaminoethyl methacrylate), poly (dimethylaminoethyl acrylate), poly (diethylaminoethyl acrylate), poly (diethylaminoethyl methacrylate), poly (vinyl alcohol) etc.
[0069] Starting monomeric materials that can be used to form the polymer coating in some embodiments of the invention include, e.g., acrylic or (meth) acrylic acid derivatives, including dimethylaminoethyl (meth) acrylate, diethylaminoethyl meth (acrylate), dimethylaminopropyl (meth) acrylate, 3-dimethylamino-2-hydroxypropyl (meth) acrylate, acrylamide or methacrylamide derivatives. In addition, acrylics and methacrylamide such as N-dimethylaminoethyl (meth) acrylamide, N-diethylaminoethyl (meth) acrylamide may be used. In some embodiments of the invention, vinyl derivatives of such nitrogen-containing compounds may also be used, such as 2-vinylpyridine, 4-vinylpyridine, 2-methyl-5-vinylpyridine, 4-vinylimidazole, N-vinyl-2-ethylimidazole, vinylpyrrolidinone, N-vinylpyrrole 2-methylimidazole. Combinations of monomers may also be used in some embodiments of the invention to form a series of copolymers that, according to the knowledge of one of skill in the art, will confer properties in accordance with some embodiments of the invention.
[0070] In some embodiments, the polymer-coated carbon cores have a bulk density of about 0.19 g / cm3.<sup>3</sup> up to 0.21 g / cm<sup>3</sup>.
[0071] As used herein, the terms "density" or "bulk density" refer to the mass of a set of carbon cores divided by the total volume they occupy. The terms "density" or "bulk density" are used interchangeably herein.
[0072] The term "extraction efficiency" as used herein refers to the result of the following calculation after a single pass through the filter according to the following calculation: extraction efficiency = (concentration before filter - concentration after filter / concentration before filter) x 100.
Examples
Materials [0073] The coating material used in the examples, i.e. poly (2-hydroxyethyl methacrylate) purchased from Sigma Aldrich in powder form, is also referred to herein as poly (2-HEMA) or poly-HEMA. Melfalen (Alkeran®) (2-amino-3- [4- [bis (2-chloroethyl) amino] phenyl] propionic acid) was purchased from BioNiche for animal testing and Sigma Aldrich for in vitro testing. Other chemicals, unless otherwise stated, were purchased from Sigma Aldrich. Hydrochloric acid, 37%, methanol> 99.8%, Sigma Aldrich [0074] Bovine blood and sodium heparin were purchased from Lampire (Pipersville, PA). Before performing each series, heparain (1000 units / L) was added.
Example 1. Preparation of polymer-coated carbon cores (activated carbon agents or filter media) [0075] This example describes the preparation of polymer-coated activated carbon particles used in extraction agents. Activated carbon or carbon may be obtained from commercial sources, e.g., Siemens or Rohm & Haas, or prepared according to methods known in the art, see, e.g., US Patent Nos. 3,909,449; 4,273,675 and 5,236,688. A wide range of literature is available on the properties and preparation of activated carbon. See, e.g. "Active Carbon", aut. Bansal, RC, Donnet, JG and Stoeckli, HF, Marcel Dekker, New York, 1988. Activated carbon beads as starting materials have been purchased, but they can also be obtained by mixing oil tar or coal tar with a viscosity regulating agent, forming the mixture into the shape of beads by melting, extracting the agent from the spheres with a solvent and imparting properties of flame-retardant in accordance with practices commonly known to a person skilled in the art.
[0076] A subsequent pyrolysis (carbonization) process was used to adapt the activated carbon particles to properties effective in producing the extraction agents of the present invention. In the pyrolysis stage, the starting material was extruded at a high temperature, usually above 500 ° C, preferably above 800 ° C.
[0077] Additional pyrolysis under conditions understood by those skilled in the art was carried out to create carbon decomposition conditions that form pores and provide optimal surface area. High-temperature carbon decomposition and atmosphere change between series selectively burns carbon regions, providing surface area, pore size, and density appropriate for use in the present invention. Activated carbon cores (hereinafter "carbon cores") were prepared by using selective degradation or oxidation of the activated carbon starting product and then testing it in the filtration apparatus of the present invention for absorption capacity against low molecular weight chemotherapeutic agents.
[0078] Activated carbon cores (carbon cores) were then coated with a polymer coating for blood compatibility. In the coating process, about 9.0 grams of poly-HEMA (2-hydroxyethyl polymethacrylate)) was slowly added to about 1800 ml of ethanol and stirred at about 60-80 ° C for at least about 2 hours, until the poly-HEMA dissolved and obtained homogeneously transparent polyHEMA solution. About 1800 ml of the clear poly-HEMA solution was then transferred to about 1200 ml of dry activated carbon cores, and the mixture was shaken for at least 27 hours until the product contained no liquid. The activated carbon cores were then dried by heating in an oven at about 90 ° C for at least 24 hours.
Example 2. Characterization of carbon cores [0079] Carbon cores were characterized by Quantachrome®ASiQwin ™ (Autosorb IQ instrument, Quantachrome Instruments), Camsizer® (Retsch® Technology) and based on mass.
[0080] For Quantachrome®ASiQwin ™, the samples were placed in a dry and clean sample cell and degassed at 300 ° C for about 5 hours under vacuum. The samples were analyzed using nitrogen gas at a temperature of about 77 K. Nitrogen was introduced into the vacuum from an initial partial pressure of 1.0e-7, gradually increased to about 0.995, obtaining an adsorption curve. Then nitrogen gas was slowly removed to a partial pressure of 0.10, resulting in a desorption curve. Specific surface area was then analyzed by the multi-point BET (MBET) method and the density functional theory (QSDFT) for slit / cylindrical pores, using nitrogen at 77 K to determine MBET and DFT surface areas. Such methods are known in the art, see, e.g., "Characterization of Porous Solids and Powders: Surface Area, Pore Size and Density", Lowell et al. (Springer, 2006). Autosorb iQ software was used for calculations using adsorption and desorption curves. The surface area according to multi-point BET was analyzed for partial pressure in the range 0.005-0.200.
[0081] Density functional theory (DFT) is known in the art and is based on molecular mechanics theory of statistical thermodynamics that associates an isotherm with microscopic properties of a system. The DFT method gives information about the pore size and surface area as a function of half pore width, while the MBET method gives the total surface area.
[0082] The term "micropores" as used herein means pores with a half width (diameter, D) of less than 20 angstroms (A).
[0083] The term "mesopores" as used herein means pores with a half width above 20 A and below 250 A.
[0084] The term "median diameter (D50)" as used herein refers to a diameter for which 50% of the pore volume in the sample lies below the indicated pore size and 50% of the pore volume in the sample lies above the indicated pore size. The term "D50, micro" as used herein refers to the median pore diameter in the microporosity range.
[0085] The term "D50, meso," as used herein, refers to the median pore diameter in the mesoporosity range.
[0086] The term "% of microporous pores" as used herein refers to the percentage of the pore volume occupied by the micropores.
[0087] The diameter and density of the solid core of the carbon core was determined according to the manufacturer's instructions using a particle size and shape analyzer by digital image processing CAMSIZER®-L. (Retsch® Technology) The results are shown in [0088] Table 1 below.
Table 1. Carbon core measurements
<td>Parameter</td><td>Marking method</td><td>Average</td><td>Range</td>
<td>Bulk density (g / cm<sup>3</sup>)</td><td>weight</td><td> 0,188</td><td> 0,185-0,195</td>
<td>MBET surface area (m<sup>2</sup>/ G)</td><td>Quantachrome</td><td> 1946</td><td> 1825-2058</td>
<td>DFT surface area (m<sup>2</sup>/ G)</td><td>Quantachrome</td><td> 1644</td><td> 1483-1778</td>
<td>Pore volume (cm<sup>3</sup>/ G)</td><td>Quantachrome</td><td> 2,03</td><td> 1,68-2,19</td>
<td>Pore size range (A) Median diameter of mesoporous pores, Ds0micro (A) Median diameter of mesoporous pores, D50meso (AND)</td><td>Quantachrome</td><td> 9,7 105</td><td> 9,3-10,5 30-156</td>
<td>Percentage of microporous pores (%)</td><td>Quantachrome</td><td> 22,37</td><td> 18-28</td>
<td>Particle diameter (mm)</td><td>CAMSIZER</td><td> 0,73</td><td> 0,45-1,15</td>
Example 3. Extraction efficiency
Filter cassettes used in extraction efficiency and animal studies [0089] A filter cassette (cylindrical column) about 7.8 inches between screens, used to retain filter media, about 2.4 inches in diameter, made of thermoplastic material, was filled about 101-111 g of filter media used with an average bulk volume of about 535 ml to about 544 ml. In some examples, a single filter cassette is used. In some examples, two filter cassettes are used simultaneously. If the use of two cassettes is not indicated, the data relate to the use of a single filter cassette.
Example 3A. In vitro extraction efficiency [0090] The purpose of this example is to demonstrate the ability of the filtration apparatus to extract a low molecular weight chemotherapeutic agent from blood. The extraction efficiency was determined for using the extracorporeal circuit shown in Fig. 1.
[0091] Fig. 1 is a schematic of an in vitro experimental cycle. In Fig. 1, the various elements of the experimental circulation are illustrated in a manner that will be understood by one of ordinary skill in the art. An apparatus for removing small molecule chemotherapeutic agents from blood 1 is shown. In Fig. 1. 2 means the sample port for collecting the blood sample after filtration, 3 means the waste line used to remove saline from the system, 4 means the infusion pump for the supply of chemotherapeutic agent, 5 means the port for collecting the sample from the bag, 6 means the sample port for collecting the blood sample before filtration .
Preparation of the experiment [0092] The bags were filled with about 2.5 L blood and warmed to at least 37 ° C. Blood was heparinized (1000 U / L) and the bags were suspended in an incubator set at about 50 ° C.
[0093] The filter was primed and the bubbles removed completely using plain saline.
[0094] The packaging of Delcath extracorporeal tubes was prepared according to the following scheme.
Preparation of the chemotherapeutic agent [0095] Melphalan hydrochloride (HCl) was dissolved in a solution of methanol and hydrochloric acid. The solution was then diluted with 0.9% saline.
[0096] Doxorubicin HCl was dissolved in 0.9% saline.
[0097] Topotecan was dissolved in dimethyl sulfoxide (DMSO) and then diluted with 0.9% saline.
Experimental procedure [0098] The syringes were filled with a chemotherapeutic solution and connected to the extracorporeal tube with a two-way stopcock system with a 1/8 female Luer fitting fitted to the two-way stopcock in the extracorporeal circuit. An initial blood sample was taken to determine the baseline concentration of the chemotherapeutic drug. The blood was then circulated and the fluid routed through the waste line until all visible saline was removed from the system. The waste line was closed by clamping, and the clamp on the circuit was released, thus closing the circuit. The infusion chemotherapy was then circulated within 30 minutes using a syringe pump.
[0099] During the procedure, samples were taken at predetermined intervals before the filter, downstream of the filter, as well as blood bag filters.
[0100] All samples were immediately placed on ice for less than 20 minutes and centrifuged at 6000 rpm for 10 min in a refrigerated centrifuge at 4 ° C. Samples after centrifugation were placed back on ice and the supernatant transferred to microcentrifuge tubes. Samples were then analyzed for chemotherapeutic concentration using liquid chromatography with tandem mass spectrometry.
Sample Evaluation [0101] All plasma samples were analyzed for chemotherapeutic concentration using tandem mass spectrometry liquid chromatography.
[0102] The extraction efficiency for each time point was calculated by the following equation:
Extraction efficiency = (pre-filter concentration - pre-filter concentration / pre-filter concentration) χ 100 [0103] The average extraction efficiency for each time point was used to determine the total efficiency for the individual experiment. The effectiveness given for the experimental group is the average effectiveness of the experiments in this group.
Table 2 shows the results of experiments of several in vitro studies using bovine blood, and Table 3 shows the results of experiments of an in vitro study using human blood and melphalan hydrochloride.
Table 2. Summary of in vitro experiments using bovine blood
<td rowspan="2">chemotherapeutic</td><td rowspan="2">Dose (mg)</td><td rowspan="2">Sample Size</td><td colspan="2">Variables</td><td colspan="2">Efficiency (%)</td>
<td>Flow per cassette (ml / min)</td><td>Percentage of hydrogel (g factor / g hydrogel)</td><td>Average</td><td>Range</td>
<td>Melphalan HCl</td><td> 110</td><td> 6</td><td> 250</td><td> 25:1</td><td> 99.1</td><td> 98.5-99.7</td>
<td>Melphalan HCl</td><td> 110</td><td> 36</td><td> 500</td><td> 25:1</td><td> 97.2</td><td> 95.0-98.5</td>
<td>Doxorubicin HCl</td><td> 150</td><td> 5</td><td> 400</td><td> 25:1</td><td> 95.4</td><td> 93.4-96.8</td>
<td>Doxorubicin HCl</td><td> 90</td><td> 2</td><td> 250</td><td> 25:1</td><td> 96.4</td><td> 95.9-97.0</td>
<td>Doxorubicin HCl</td><td> 150</td><td> 2</td><td> 400</td><td> 25:1</td><td> 96.9</td><td> 96.9-96.9</td>
<td>topotecan</td><td> 6.25 12.5 18.75</td><td> 3</td><td> 250</td><td> 25:1</td><td> 90.3</td><td> 89.4-91.2</td>
<td>topotecan</td><td> 6.25 12.5 18.75</td><td> 3</td><td> 500</td><td> 25:1</td><td> 84.3</td><td> 84.0 - 85.0</td>
Table 3. Summary of the in vitro experiment using human blood and melphalan hydrochloride
<td rowspan="2">chemotherapeutic</td><td rowspan="2">Dose (mg)</td><td rowspan="2">Sample Size</td><td colspan="2">Variables</td><td colspan="2">Efficiency (%)</td>
<td>Flow per cassette (ml / min)</td><td>Percentage of hydrogel (g factor / g hydrogel)</td><td>Average</td><td>Range</td>
<td>Melphalan HCl</td><td> 110</td><td> 4</td><td> 250</td><td> 25:1</td><td> 99.4</td><td> 99.2-99.5</td>
<td>Melphalan HCl</td><td> 110</td><td> 3</td><td> 500</td><td> 25:1</td><td> 96.7</td><td> 96.3-97.2</td>
Example 3Β · Extraction efficiency in vivo [0104] This example demonstrates the efficiency of chemotherapeutic extraction obtained in a porcine chemostaturation model using transdermal drug delivery for hepatic circulation (CS-PHP) using two parallel filter cassettes.
Animals and pre-treatment care [0105] Yorkshire pigs (4-6 months, approx. 158-216 Ibs) were used in four acute studies. Food was turned off about 12-24 hours before the procedure.
[0106] General anesthesia was used and a cuff was inserted. An intravenous catheter was inserted for fluid and drug delivery. General anesthesia was maintained with isoflurane administered with oxygen through the anesthesia apparatus. A respirator was used to assist breathing.
Procedure [0107] An experimental pig model of transdermal drug delivery to the hepatic circulation was used. A schematic representation of the CS-PHP system with experimental sample ports and pressure control sites is shown in Fig. 2. Fig. 2 shows the system shown according to some embodiments of the present invention for performing chemosaturation by percutaneous drug delivery procedure for hepatic circulation. Various elements are understood by one of ordinary skill in the art. In fig. 2 9 means two filtration apparatus in a parallel system for the removal of small molecule chemotherapeutic agents from the blood, 10 means the sample port for collecting blood samples behind the filter, 11 means the vestibular filter or the bubble trap to reduce the risk of air bubbles entering the systemic circulation, 12 means systemic return venous sheath placed in the internal jugular vein, 13 means the sample port located in the carotid artery, 14 catheter with two balloons placed in the inferior vena cava, such as e.g. used in the Chemosat® system from Delcath, 15 means the catheter for intra-arterial infusion for hepatic circulation used for chemotherapeutic administration, 16 means introducing sheaths in the femoral vein and artery, 17 means the sample port for collecting blood samples upstream of the filter, and 18 means bypassing the filter.
[0108] Using a standard technique of cutting or placing percutaneous insertion, an introducer sheath was placed into the femoral vein (for guiding a two balloon catheter), femoral artery (for insertion of the catheter for intra-arterial infusion and monitoring of invasive arterial pressure), jugular vein (for reintroduction) blood) and carotid artery (for taking blood samples from systemic circulation). After putting on the shirts, heparin (approx. 300 IU / kg) was given. Coagulation was assessed based on the coagulation time after activation (ACT), with a target ACT> 300 seconds. ACT was monitored throughout the procedure and additional heparin doses were administered as necessary. [0109] Under fluoroscopy, the hepatic arterial infusion catheter was inserted below the gastro-duodenal artery to prepare for administration of the chemotherapeutic agent. Under fluoroscopy, the two-balloon catheter was moved on the guide wire to the inferior vena cava and its end was placed at the level of the diaphragm gap. The venous catheter was connected to the hemofiltration cycle, and the venous return sheath was connected to the perfusion apparatus. Air was removed from the entire system.
[0110] After the hemofiltration cycle had been established, venous blood was sucked from the central lumen through the opening in the two balloon catheter. Blood flowed through the two balloon catheter to the pump, through the filter, and was re-administered to the animal through the venous return tube.
[0111] Two balloon catheter balloons with two balloons were filled with diluted contrast agent prior to starting the drug infusion. The upper balloon closed the lumen of the inferior vena cava above the highest situated hepatic vein, and the lower balloon closed the lumen of the inferior vena cava below the lowest located hepatic vein. The hemofiltration system was started. When the hemofiltration system was operating satisfactorily, administration of the chemotherapeutic agent began.
[0112] In some studies, phenylephrine was administered if necessary to maintain mean blood pressure. To maintain the pH at an acceptable level, sodium bicarbonate bolus may be given. During the procedure, in addition to saline, a solution of dextrose (5%) in saline could be administered intravenously.
[0113] The chemotherapeutic agent was administered through the catheter for intraarterial infusion into the hepatic circulation during the 30 minute infusion period. After the infusion, a washout period of 30 minutes followed by in vitro filtration.
[0114] At the end of the procedure, the blood supply to the filter cassettes was blocked separately by closing the appropriate clamps on the circulation tubes. The IsoFuse lower balloon fill was then removed, followed by the upper balloon fill was removed. All catheters were removed from the animal and the animal was euthanized under maintained general anesthesia.
Sample collection [0115] Plasma samples were obtained from blood drawn from ports in the extracorporeal circulation before and after the arterial filter to determine the efficiency of chemotherapeutic removal by the filter. Peripheral blood plasma samples were used to determine the total body dose administered to the animal.
[0116] An initial peripheral plasma sample was obtained from blood collected from the internal carotid artery immediately after initiation of the chemotherapeutic infusion to obtain baseline PK parameters.
[0117] During the infusion period and after the infusion period, pre-filter, post-filter and peripheral plasma samples were obtained from blood collected at set intervals, from the start of the infusion to the end of the washout period.
[0118] After each blood sample was taken, it was immediately placed in moist ice. Samples were centrifuged at about 3600 rpm for about 10 min at about 4 ° C and placed on wet ice before further processing. An aliquot of plasma from each sample was transferred to a microcentrifuge tube. Plasma samples were stored at -80 ° C for two hours from the initial blood collection.
Sample Evaluation [0119] Plasma samples were analyzed for chemotherapeutic concentration using tandem mass spectrometry liquid chromatography.
[0120] The extraction efficiency for each time point was calculated by the following equation:
Extraction efficiency = (concentration before filter - concentration after filter / concentration before filter) χ
100 [0121] The average extraction efficiency for each time point was used to determine the total efficiency for an individual animal. The efficacy reported for the study is the average efficacy in the animals in this study.
[0122] Table 4 summarizes the parameters of each animal study in the pig model and the resulting extraction efficiency after 60 minutes of hemofiltration.
Table 4. Summary of animal studies
<td>Research</td><td> 1</td><td></td><td> 3</td><td> 4</td>
<td>Sample Size</td><td> 6</td><td> 5</td><td> 10</td><td> 5</td>
<td>chemotherapeutic</td><td>Melphalan HCl</td><td>Melphalan HCl</td><td>Melphalan HCl</td><td>doxorubicin</td>
<td>Dose (mg)</td><td> 220</td><td> 209</td><td> 220</td><td> 152</td>
<td>Duration of the procedure (min) Infusion period</td><td> 30</td><td> 30</td><td> 30</td><td> 30</td>
<td>Washing out period</td><td> 30</td><td> 3«</td><td> 30</td><td> 30</td>
<td>Together</td><td> 60</td><td> 60</td><td> 60</td><td>6Ω</td>
<td>Phenylephrine (yes or no)</td><td>No</td><td>Yes</td><td>Yes</td><td>Yes</td>
<td>Bicarbonate (yes or no)</td><td>No</td><td>Yes</td><td>Yes</td><td>Yes</td>
<td>Dextrose (5%) in physioloic salts (yes or no)</td><td>No</td><td>No</td><td>No</td><td>Yes</td>
<td>Animal weight range (Ibs)</td><td> 206-216 \</td><td> 158-209</td><td> 169-209</td><td> 158 - 180</td>
<td>Target flow rate (ml / min)</td><td>500 and</td><td> 500</td><td> 500</td><td>SCXJ</td>
<td>Percentage of hydrogel (g factor / g hydrogel)</td><td> 25</td><td> 25</td><td> 25</td><td> 25</td>
<td>Sampling interval (min)</td><td> 3</td><td>f></td><td> 6</td><td> 5</td>
<td>Chemotherapeutic removal efficiency (%) Mean ± standard deviation</td><td> 98.5 * 0.5</td><td> 96.3 ± 0.3</td><td> 97.5 ±0,5</td><td> 71.4 ±5.1</td>
<td>Range</td><td>978-In 1</td><td> 96,0 - 96.7</td><td> 96,4 - 98.2</td><td> 65,4-79.2</td>
Contents11
4 sheets
Sheet 1 Sheet 2 Sheet 3 Sheet 4
34 members in 8 offices
Priority claims13
| Document | Office | Kind | Date |
|---|---|---|---|
| 201161556819 | United States of America | P | |
| 201161556819 | United States of America | P | |
| 12847108 | European Patent Office (EPO) | A | |
| 12847108 | European Patent Office (EPO) | A | |
| 17176952 | European Patent Office (EPO) | A | |
| 2012064002 | United States of America | W | |
| 2012064002 | United States of America | W | |
| 171769524 | – | – | – |
| 201161556819P | – | – | – |
| EP20120847108 | – | – | – |
| EP20170176952 | – | – | – |
| US201161556819P | – | – | – |
| WO2012US64002 | – | – | – |
Members34
| Document | Office | Kind | |
|---|---|---|---|
| US2013116658A1 | United States of America | A1 | |
| WO2013070809A2 | World Intellectual Property Organization (WIPO) | A2 | |
| EP2776086A2 | European Patent Office (EPO) | A2 | |
| WO2013070809A3 | World Intellectual Property Organization (WIPO) | A3 | |
| EP2776086A4 | European Patent Office (EPO) | A4 | |
| US9707331B2 | United States of America | B2 | |
| EP3241576A1 | European Patent Office (EPO) | A1 | |
| US2018028740A1 | United States of America | A1 | |
| US10098997B2 | United States of America | B2 | |
| EP2776086B1 | European Patent Office (EPO) | B1 | |
| US2019001044A1 | United States of America | A1 | |
| EP2776086B8 | European Patent Office (EPO) | B8 | |
| EP3241576B1 | European Patent Office (EPO) | B1 | |
| US10369264B2 | United States of America | B2 | |
| US2019290823A1 | United States of America | A1 | |
| ES2728280T3 | Spain | T3 | |
| PT3241576T | Portugal | T | |
| EP3590561A1 | European Patent Office (EPO) | A1 | |
| PL3241576T3This record | Poland | T3 | |
| US10569004B2 | United States of America | B2 | |
| ES2750846T3 | Spain | T3 | |
| HUE046954T2 | Hungary | T2 | |
| US2020147288A1 | United States of America | A1 | |
| US11241522B2 | United States of America | B2 | |
| US2022111132A1 | United States of America | A1 | |
| US11633528B2 | United States of America | B2 | |
| EP3590561B1 | European Patent Office (EPO) | B1 | |
| US2023211063A1 | United States of America | A1 | |
| FI3590561T3 | Finland | T3 | |
| EP4242176A2 | European Patent Office (EPO) | A2 | |
| ES2950585T3 | Spain | T3 | |
| EP4242176A3 | European Patent Office (EPO) | A3 | |
| US12364797B2 | United States of America | B2 | |
| US20260027276A1 | United States of America | A1 |
Numbers
- Publication
- 3241576
- Publication, DOCDB
- 3241576
- Publication, EPODOC
- PL3241576T
- Application
- 17176952
- Application, DOCDB
- 17176952
- Application, EPODOC
- PL20170176952T
Titles2
- English
- APPARATUS FOR REMOVING CHEMOTHERAPY COMPOUNDS FROM BLOOD
- Polish
- Aparat do usuwania związków chemioterapeutycznych z krwi
Classification
- CPC, 19
- A61M1/34
- A61M1/3615
- B01J20/28066
- B01J20/28076
- B01J20/20
- B01J20/261
- B01J20/3078
- B01J20/3204
- B01J20/327
- B01J20/3293
- B01J20/28078
- B01J20/28011
- A61M2205/3306
- A61M2205/50
- A61M1/3406
- C01B32/354
- C01B32/372
- A61M1/3687
- A61M2210/1071
- IPC, 9
- A61M1 34
- A61M1 36
- B01J20 20
- B01J20 26
- B01J20 28
- B01J20 30
- B01J20 32
- C01B32 354
- C01B32 372
