CN115955969A - Compositions and methods for oral treatment of leukemia - Google Patents
Compositions and methods for oral treatment of leukemia Download PDFInfo
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- CN115955969A CN115955969A CN202180038959.2A CN202180038959A CN115955969A CN 115955969 A CN115955969 A CN 115955969A CN 202180038959 A CN202180038959 A CN 202180038959A CN 115955969 A CN115955969 A CN 115955969A
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- leukemia
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Abstract
The present invention discloses a method of treating a mammalian subject having hematologic non-neoplastic cancer cells. The method comprises the following steps: (A) A therapeutically effective amount of a halogenated xanthene, pharmaceutically acceptable salt, lactone or C thereof 1 ‑C 4 The alkyl ester is administered to the mammalian subject as a first cancer cytotoxic agent dissolved or dispersed in a pharmaceutically acceptable aqueous medium. The mammalian subject is maintained for a period of time sufficient to induce death of the hematologic non-tumor cancer cells. The administration involved is usually repeated. The contemplated methods of treatment may also be performed in conjunction with administering to the mammalian subject a second therapeutically effective amount of a second, differently-acting cancer cytotoxic agent dissolved or dispersed in a pharmaceutically acceptable medium. The second cancer cytotoxic agent can be a small molecule or an intact antibody or a site-containing portion thereof.
Description
Technical Field
The present invention relates to oral treatment regimens for the treatment of hematological (hematological) cancers, such as leukemia, particularly in children.
Background
Adults have about 7000 leukocytes per microliter (μ L) of blood. Of these leukocytes, about 65% are granulocytes (about 4500/. Mu.L), about 30% are monocytes (about 2100/. Mu.L) and about 5% are lymphocytes (about 350/. Mu.L). Geyton, textbook of Medical Physiology, seventh edition, W.B. Saunders Co., philadelphia (1986). Of course, the above cell numbers are broad averages and the granulocytic count of normal patients (i.e., patients without disease) is typically about 2000 to about 7000 cells/μ L.
Acute Lymphoblastic Leukemia (ALL) is a cancer of the lymphoid lineage of blood cells that begins in the bone marrow and is characterized by the development of large numbers of immature lymphocytes (lymphoblasts). There are two basic types of this disease. One affecting B cells (B-ALL) and the other affecting T cells (T-ALL). As an acute leukemia, ALL progresses rapidly and, if left untreated, is usually fatal within weeks or months.
ALL occurs in children and adults, with the highest rates observed between the ages of three and seven. Approximately 75% of cases occur before the age of 6 years, with secondary elevations after the age of 40 years. The total incidence of ALL in children in the united states during 2001-2014 was 34.0 cases per 100 million, and occurred in ALL races/ethnic groups.
ALL is usually initially treated with chemotherapy intended to cause remission. This is followed by further chemotherapy, usually for more than three years. Treatment also typically includes intrathecal chemotherapy (spinal cord injection) as systemic chemotherapy may have limited penetration into the central nervous system, and the central nervous system is a common site of ALL relapse.
Chronic Lymphocytic Leukemia (CLL) is a type of cancer in which the bone marrow produces too many lymphocytes, particularly B cells. Although it is generally considered incurable, CLL progresses slowly in most cases. Thus, CLL treatment focuses on controlling the disease and its symptoms, rather than a complete cure. The initiation of CLL treatment is decided when symptoms or blood counts of a person indicate that the disease has progressed to a point that may affect quality of life.
CLL is primarily a disease of the elderly, most commonly occurring in people over 50 years of age, with a median age at diagnosis of 70 years. Although less common, CLL sometimes affects people between 30 and 39 years of age. The incidence of CLL increases very rapidly with age. In the united states, five-year survival after diagnosis is about 83%.
Acute Myeloid Leukemia (AML) begins as a disorder of the hematopoietic stem cells in the bone marrow and is the most common form of leukemia in adults. It occurs in children and adults. Without treatment, AML can progress rapidly in vivo as new leukocytes are continuously produced.
Chronic Myelogenous Leukemia (CML), also known as chronic myeloid leukemia (CGL), also begins in the bone marrow, but does not progress as rapidly as AML. In its early stages, CML is characterized by leukocytosis, the presence of increased numbers of immature granulocytes in the peripheral blood, splenomegaly and anemia. These immature granulocytes include basophils, eosinophils and neutrophils. Immature granulocytes also accumulate in bone marrow, spleen, liver, and occasionally in other tissues. Patients presenting with this disease characteristically have over 75,000 leukocytes per microliter (μ L) and can count over 500,000/μ L.
CML accounts for about 20% of all leukemias in the united states. About 15 new cases per million are reported annually, resulting in about 3,000 to 4,000 new cases per year. The disease is rare in people under the age of 45, but the incidence rapidly rises to age 65 and remains elevated thereafter. The median life span from diagnosis in patients with chronic myelogenous leukemia is approximately 4 years.
About 60% to 80% of CML patients develop blast crisis. Blast crisis represents a manifestation of acute leukemia. The presence of certain markers on the blast cells sometimes indicates the lymphoid origin of these cells during blast crisis.
The chemotherapeutic agents used to treat blast crisis are the same as those used to treat other acute leukemias. For example, cytarabine and daunorubicin, used in the treatment of acute myeloid leukemia, are used in the treatment of the CML blast crisis. Prednisone and vincristine, a therapeutic regimen for the treatment of acute lymphocytic leukemia, and also for the treatment of CML blast crisis. However, these drug therapies for the blast crisis stage of CML are not even as successful as the treatment of other acute leukemias.
Childhood cancer is rare, with an incidence of 140-155 parts per million per year (age <15 years). This means that about 1/7,000 children are diagnosed with cancer each year. Although cancer is rare, malignancies are the most common cause of death after accidents in children 5 to 14 years of age, accounting for 23% of mortality. The survival rate of childhood cancers, many of which were fatal in the pre-chemotherapy period, has increased dramatically from 20% to 30% in the 60's of the 20 th century to 62% in the 70's of the 20 th century, and more recently to 83%. Saletta et al, transl Pediatr 3 (2): 156-182 (2014).
Leukemia is the most common childhood cancer, accounting for about 30% of all pediatric (1-14 years) cancer diagnoses. Acute Lymphoblastic Leukemia (ALL) accounts for about 25% of childhood cancers, while Acute Myeloid Leukemia (AML) accounts for the remaining about 5%. Saletta et al, transl Pediatr 3 (2): 156-182 (2014).
Current treatments for ALL include pegylated aspartase, liposomal daunorubicin, liposomal anastamomycin, sphingosine vincristine, and liposomal cytarabine. Current treatments for AML include the use of all-trans retinoic acid (ATRA), arsenic trioxide, a combination of anthracyclines and ATRA, as well as idarubicin and high dose cytarabine. Combinations of sorafenib (a multikinase inhibitor) with clofarabine and cytarabine have found success in phase I studies [ Inaba et al, J Clin Oncol 29]And a calicheamicin conjugated CD33 antibody gemtuzumab ozogamicinZong Mi Xing, commercially known as Zong 5363Has shown promise [ Zwaan et al, br J Haematol 148]。
Although survival rates for childhood leukemia have improved greatly, relapse is a major cause of treatment failure. Approximately 15% to 20% of pediatric ALL patients and 30% to 40% of AML patients relapse, wherein relapsed ALL is identified as the fourth most common malignancy in children.
Treatment of relapsed pediatric leukemia includes intensive chemotherapy regimens and the use of Bone Marrow Transplantation (BMT). However, increasing the intensity of combination chemotherapy and introducing second-line drugs is often accompanied by cumulative toxicity with marginal incremental benefits.
A key factor in understanding immune system interactions against pediatric cancers is the availability of an applicable animal model. Current xenograft models are limited because they are established in Severe Combined Immunodeficiency (SCID) mice and therefore do not provide information about the contribution of the immune system. Other methods, such as reconstitution of human hematopoietic stem cells in immunocompetent animals, are cumbersome, expensive, and often introduce complex biological variables into the system.
Recently, a new xenograft tumor model was developed in immunocompetent mice by tolerizing the mouse fetus to human tumor cells [ Basel et al, cancer Lett.412:256-263 (2018) ]. This model is advantageous because it can be used to better describe the complex interactions between cancer cells and the immune system by xenograft techniques.
One useful group of anticancer agents for adult cancerous tumors is halogenated xanthenes or pharmaceutically acceptable salts thereof. See U.S. Pat. Nos. 6,331,286, 7,390,668, 7,648,695, 9,107,887, 9,808,524, 9,839,688 and 10,130,658. Of these halogenated xanthenes, disodium rose bengal (4,5,6,7-disodium tetrachloro-2 ',4',5',7' -tetraiodofluorescein; RB) has been found to be particularly effective and readily available.
Solutions of iodine-131 radiolabeled RB have been used clinically for measurementLiver function in infants [ Yvart et al, eur J Nucl Med 6 (1981)]。An injectable sterile 10% w/v RB disodium solution in 0.9% aqueous sodium chloride solution is a more recent formulation manufactured by Provectus Biopharmaceutics, inc. of Knoxville, tenn.
Previous studies have shown thatRB or its salts in aqueous RB disodium solution accumulate in cancer cell lysosomes [ Watter et al, proceedings of SPIE, multiphoton Microcopy in the Biomedical Sciences II, periasamy, A. And So, P.T.C. (eds.), bellingham, washington:4620 (2002)]And induce Cell Death in a range of adult cancers [ Qin et al, cell Death Dis 8; toome et al, PLoS ONE 8 (7): e68561 (2013); koevary et al, int J Physiol Pathophysiol Pharmacol 4 (2): 99-107 (2012); thompson et al, melanoma Res 18 (6): 405-411 (2008); and Zamani et al, J immunotoxin 11 (4): 367-375 (2014)]。
Aqueous RB disodium solution has been used as a single anti-cancer agent and in combination with a monoclonal antibody anti-cancer agent in several clinical trials, where it has been administered to solid tumor cancers by Intralesional (IL) administration. Several of those tests are discussed below. Using individual->Phase I and II clinical studies of aqueous solutions of RB disodium as a cytotoxic agent illustratively reported "adverse events were primarily mild to moderate and localized to the treatment site with no treatment-related grade 4 or 5 adverse events" [ Thompson et al, ann Surg Oncol 22 (7): 2135-2142 (2015)]And "Treatment of Emergency Adverse Event (TEAE) was consistent with an established pattern for each drug, primarily due to +zen>Grade 1-2 injection site reactions of RB disodium in water and grade 1-3 immune mediated reactions due to pembrolizumab had no significant overlap or unexpected toxicity: … "[ Agarwala et al, J Clin Oncol 37 (15) suppl 9559-9559 (5 months and 26 days 2019)]. Thus, RB has been shown to be toxic to cancer cells but not to non-cancer cells.
Since the characteristics of adult tumors are often very different from pediatric tumors, it is not known whether RB and similar halogenated xanthenes are effective when used against pediatric cancer cells, particularly pediatric cancerous blood cells. One of the inventors and colleagues of the present invention reported preliminary in vitro and xenograft studies against neuroblastoma cell lines in cell cultures supplemented with RB alone or in combination with known anticancer agents, respectively, and solid tumor xenografts established by intralesional injection into mice, showing killing of pediatric cancer cells. Swift et al, oncotargets Ther, 12.
In addition, the halogenated xanthene compound is administered intralesionally into the tumor, providing the active cytotoxic agent directly to the tumor at its highest concentration. In the presently contemplated treatment techniques discussed below, administration is generally away from the target cancerous blood cells, thereby potentially reducing the effectiveness of the anticancer halogenated xanthene compound drug (agent).
Intralesional injection in phase II clinical trials in patients with refractory metastatic melanomaThe RB disodium solution induced tumor regression with a total response rate of 51% [ Thompson et al, ann Surg Oncol 22 (7): 2135-2142 (2015)]. In a phase II clinical trial, in patients with in-transit or metastatic melanoma, intralesional->The efficacy was also demonstrated by the combination of RB disodium solution with radiation therapy with a total response rate of 86.6% [ Foote et al, J Surg Oncol 115 (7): 891-897 (2017)]。
In addition to inducing direct cancer cell death,intralesional administration of RB disodium in water solution has also been studied in two mice [ Qin et al, cell Death Dis 8 (2017); toome et al, PLoS ONE 8 (7): e68561 (2013); and Liu et al, oncotarget 7 (25): 37893-37905 (2016)]And human clinical trials [ Lippey et al, J Surg Oncol 114 (3): 380-384 (2016); ross, J Surg Oncol 109 (4): 314-319 (2104); liu et al, PLoS ONE 13 (4): e0196033 (2018); and Basel et al, cancer Lett 412:256-263 (2018)]Show induction of tumor specific immune responses. In a murine model of melanoma, with ^ er>Intralesional treatment with aqueous RB disodium solution induces necrosis of melanoma cells and local increase in mononuclear tumor-infiltrating lymphocytes [ Lippey et al, J Surg Oncol 114 (3): 380-384 (2016)]。
Has already shown thatAqueous RB disodium induces immunogenic cell death, releases tumor antigens to nearby Antigen Presenting Cells (APCs), and promotes activation of anti-tumor T and B cells. Will use ^ in a syngeneic murine colon cancer model>Injection of RB disodium aqueous solution in vitro treated cancer cells into mice with the same tumor resulted in slower tumor growth [ Qin et al, cell Death Dis 8]. Furthermore, in syngeneic murine melanoma models, intralesional->Combination therapy of aqueous RB disodium and anti-PD-1 antibodies delayed tumor growth and enhanced T cell activation [ Liu et al, PLoS ONE 13 (4): e0196033 (2108)]。
Parent U.S. application Ser. No.16/688,319, filed 11/19/2019, teachesBy reacting with a compound containing a halogenated xanthene, a pharmaceutically acceptable salt thereof or C 1 -C 4 The aqueous composition of alkyl esters is contacted and can successfully treat (kill) hematological cancer cells, such as leukemia cells. Commonly assigned U.S. application Ser. No.17/214,590, filed on 26/3/2021, teaches that solid cancerous tumors can be successfully treated by oral administration of a halogenated xanthene, lactone thereof, or a pharmaceutically acceptable salt or ester thereof. The orally administered drug may be in solid or liquid form.
The following disclosure describes the invention in question and provides the results of studies using orally administered halogenated xanthene compounds (e.g., rose bengal) for the treatment of pediatric and adult leukemias.
Brief description of the invention
The present invention relates to methods of treating a mammalian subject having leukemia. The method comprises administering to such a mammalian subject a therapeutically effective amount of a Halogenated Xanthene (HX), lactone, pharmaceutically acceptable salt thereof, or C 1 -C 4 An alkyl or aromatic ester (collectively referred to herein as the "HX compound") as the first leukemia cytotoxic agent, dissolved or dispersed in a pharmaceutically acceptable diluent solid or liquid medium. The application referred to is usually repeated.
The contemplated methods of treatment may also be performed in combination with administering to the same mammalian subject a second therapeutically effective amount of a second, different acting systemic leukemia cytotoxic agent dissolved or dispersed in a pharmaceutically acceptable medium. The second systemic leukemia cytotoxic agent may be a small molecule, ionizing radiation or whole antibody or a complementary antibody moiety, such as those protein antibody molecules that inhibit inflammatory chemokine activity or immune checkpoint antibodies. The first and second leukemia cytotoxic agents may be administered together in the same or different medium, or at different times in the same or different medium. The second leukemia cytotoxic agent may be administered as a solid tablet, capsule, pill, etc., in a liquid medium or as an intravenous injection or infusion.
In one aspect, it relates to the use of small molecule leukemia cytotoxic agents having a molecular weight of about 200 to about 1000 Da. Preferred are compounds that act synergistically with the HX compound, such as doxorubicin, etoposide and vincristine. Intact antibodies or the complementary antibody portions are a second group of leukemia cytotoxic agents. Preferred among these agents are those known as immune checkpoint inhibitors. [ see, e.g., darvin et al, exp Mol Med,50 (2018) ].
The invention also relates to the use of a therapeutically effective amount of a HX compound as a first leukemia cytotoxic agent dissolved or dispersed in a pharmaceutically acceptable aqueous medium for treating a mammalian subject having leukemia, wherein a halogenated xanthene compound (HX compound) is maintained in the mammalian subject for a period of time sufficient to induce leukemia cell death. In another embodiment, the first leukemia cytotoxic agent HX compound is rose bengal, a pharmaceutically acceptable salt, lactone, or C thereof 1 -C 4 Alkyl or aromatic esters. In yet another embodiment, the HX compound is rose bengal disodium salt. In addition, the leukemia cells that are typically treated are acute B-cell or T-cell lymphoblastic leukemia cells, chronic lymphocytic leukemia cells, or acute myelogenous leukemia cells.
Any cancer, not to mention solid cancerous tumors of the gastrointestinal tract, such as colorectal cancer, can be affected in any way by orally administered HX compounds disclosed in U.S. application serial No.17/214,590 filed 3/26/2021, which is highly unexpected because of the low HX compound bioavailability, the first pass loss of drug, and also because of the relatively short circulatory half-life (about 30 minutes) previously reported in other articles for HX compounds such as Rose Bengal (RB). Thus, it was unexpected that orally dissolved disodium rose bengal (an exemplary HX compound) in the form of a pharmaceutically acceptable salt in an aqueous diluent could slow the progression of colorectal tumors in animals specifically bred to develop colorectal tumors without any treatment. Even more unexpectedly, the HX compounds involved, delivered orally, can prevent the formation of colorectal cancer tumors in those specially bred animals.
As disclosed herein, an effective amount of HX compound administered orally can also be effective in killing leukemia cells, for the reasons described above, coupled with the fact that leukemia cells are distributed throughout the body's bloodstream and bone marrow, is still more unexpected. Thus, leukemia cells provide a more diffuse target for the "discovery" and uptake of leukemia cytotoxic HX compounds at lower concentrations than solid tumor cells, which are relatively more concentrated and fed directly by the tumor arteries or directly into the tumor by intralesional administration.
Drawings
In the accompanying drawings which form a part of this disclosure:
figure 1 is a graph showing survival of CB17 SCID mice from Charles River Laboratories International, inc. Exponentially growing SEM cells (2.5X 10 labeled with GFP) 6 Personal ALL cells) were injected intravenously into each animal and tumor establishment was monitored. After allowing the tumor to grow for 4 weeks, the mice were randomized into three groups. Group 1 (n =9 control animals) received 100 μ L PBS given orally twice weekly for two weeks. Group 2 (n =8 treatment group I animals) received 25 μ L of disodium rose bengal present in 10% w/v in 0.9% aqueous nacl solution diluted in PBS to a final volume of 100 μ L, taken orally twice a week for 2 weeks. Group 3 (n =8 treated group II animals) received 12.5 μ L of 10% w/v in the above 0.9% nacl aqueous solution, diluted in PBS to a final volume of 100 μ L, administered orally twice a week for 2 weeks. Evidence of disease progression was monitored in all animals and survival was followed up to 120 days after treatment initiation. Data are presented as Kaplan-Meier estimates. The area between 50 and 100 days was examined, the line closest to the X axis representing the data for the control, the middle line representing the data for group II animals and the uppermost line representing the data for group I animals.
FIG. 2 is a log-log plot of data from several different studies plotting the log of the concentration (molar concentration) of rose bengal administered versus the log of the duration of HX compound in a subject until the time of assessment of solid tumor treatment, and also in an early formFormula (I) is presented in U.S. application Ser. No.17/214,590 filed on 26/3/2021. "intralesional administration" represents the data presented in Thompson et al, melanoma Res 18 (2008); "Swift 2018,2019" from Swift et al, J Clin Oncol 36; abstr10557 (2018) and Swift et al, oncotargets Ther 12; "oral Apc Min "is data from a study reported in U.S. application Ser. No.17/214,590; whereas "oral leukemia" is new data presented in this application.
Detailed description of the preferred embodiments
In one aspect, the present invention relates to an orally administered pharmaceutical composition for treating (killing) leukemia cells present in a mammalian subject. The primary cytotoxic agent in the oral pharmaceutical composition is Halogenated Xanthene (HX), a lactone thereof, a pharmaceutically acceptable salt thereof, or C thereof 1 -C 4 Alkyl or aryl esters, which are collectively referred to herein as "HX compounds" present in a leukemia treating effective amount. Pharmaceutical compositions for oral administration may be in solid or liquid form.
The halogenated xanthene molecules involved include rose bengal (4,5,6,7-tetrachloro-2 ',4',5',7' -tetraiodofluorescein; RB) (particularly preferred), erythrosine B, phloxin B, 4,5,6,7-tetrabromo-2 ',4',5',7' -tetraiodofluorescein, 2',4,5,6,7-pentachloro-4', 5',7' -triiodofluorescein, 4,4',5,6,7-pentachloro-2', 5',7' -triiodofluorescein, 2',4,5,6,7,7' -hexachloro-4 ',5' -diiodofluorescein, 4,4',5,5',6,7-hexachloro-2 ',7' -diiodofluorescein; 2',4,5,5',6,7-hexachloro-4 ',7' -diiodofluorescein; 4,5,6,7-tetrachloro-2 ',4',5' -triiodofluorescein; 4,5,6,7-tetrachloro-2 ',4',7' -triiodofluorescein; 4,5,6,7-tetrabromo-2 ',4',5 '-triiodo-fluorescein and 4,5,6,7-tetrabromo-2', 4',7' -triiodo-fluorescein.
The reader is referred to Berge, j.pharm.sci.1977 (1): 1-19 to obtain a list of commonly used pharmaceutically acceptable acids and bases that form pharmaceutically acceptable salts with pharmaceutical compounds such as the halogenated xanthenes described above. Exemplary cations include alkali metals, such as sodium, potassium, and ammonium, and alkaline earth metal salts, such as magnesium and calcium. The disodium salt of rose bengal is particularly preferred.
The lactone form of the halogenated xanthene referred to may be synthetically formed and is the preferred precursor for very pure rose bengal. In addition, the carboxylic acid form of the halogenated xanthene salt spontaneously forms the lactone form in a strongly acidic aqueous environment, such as that found in the stomach of a mammal. When formed from carboxylic acid or carboxylate salts in the mammalian stomach or similar acidic aqueous media, not only are the lactones formed, but they are shown to aggregate into clumps that do not readily dissolve in the duodenum and adjacent regions of the small intestine or in aqueous media having a duodenal pH.
C of one of the above halogenated xanthene compounds may also be used 1 -C 4 Alkyl esters, preferably C 2 (ii) a I.e. ethyl ester. In vitro studies using each of RB, ethyl-red 3 (erythroerythrine ethyl ester; 2',4',5',7' -tetraiodo-fluorescein ethyl ester), 4,5,6,7-tetrabromo-2 ',4',5',7' -tetraiodo-fluorescein, and ethyl-fluorescein B (4,5,6,7-tetrachloro-2 ',4',5',7' -tetrabromo-fluorescein ethyl ester) showed similar antitumor activity against CCL-142 renal adenocarcinoma.
The aromatic esters involved are formed by reaction of HX molecules with aromatic alcohols having 5-or 6-membered aromatic rings (including benzyl alcohol) or 5,6-or 6,6-fused aromatic ring systems containing 0,1 or 2 heterocyclic atoms which are independently nitrogen, oxygen or sulfur. When an aromatic ester is used, it is preferably a benzyl, phenyl or 2-, 3-or 4-pyridyl (pyridyl) ester, other related aromatic monocyclic and fused ring containing esters are contemplated as discussed below. It should be understood that while benzyl esters are generally considered to be "aralkyl esters," for purposes of this invention, benzyl esters are considered to be fragrant esters.
Illustrative examples of such aromatic alcohol ester moieties are shown and named below, where O is an oxygen atom, and the line-O represents any available carbon from which the ring-oxygen may come from the ring, and the O-line intersecting the wavy line indicates that the depicted alkoxy group is part of another molecule (the esterified HX molecule).
Rose bengal is the preferred HX molecule, and its disodium salt, rose bengal disodium, is the most preferred HX compound. The structural formula of rose bengal disodium is shown below:
further details of the medical use of pharmaceutical compositions containing the HX compounds described above are described in U.S. Pat. Nos. 5,998,597, 6,331,286, 6,493,570, 7,390,688, 7,648,695, 8,974,363, 9,107,887, 9,808,524, 9,839,688, 10,130,658 and 10,471,144, the disclosures of which are incorporated herein by reference in their entirety.
administration-FIG. 2
When tumor cells are exposed to HX compounds in aqueous media containing 0.9% sodium chloride, irreversible HX compound accumulation occurs in tumor lysosomes, causing immunogenic tumor autolysis once sufficient concentrations are reached to destabilize lysosomal integrity [ washer et al, SPIE 4620. This suggests that this immunogenic mechanism of cell death can be triggered under a range of exposure conditions based on (concentration) · (function of time), where cytotoxicity is proportional to the product of these two parameters [ i.e. cytotoxicity = f ([ HX ] · t), where "t" is time ].
For example, when RB is administered in vivo by intralesional injection into a series of solid tumors (e.g., melanoma, hepatocellular carcinoma, breast cancer), acute tumor cytotoxicity is evident within about 30 minutes for intratumoral RB concentrations of about 25-50mg/g tumor tissue (25-50 mM) [ Thompson et al, melanoma Res 18.
Swift et al [ Oncotargets Ther 12. Furthermore, swift et al [ J Clin Oncol 36; abstr10557 (2018) ] shows cytotoxicity in otherwise therapeutically refractory pediatric solid tumors (ewing sarcoma, osteosarcoma and rhabdomyosarcoma) at equivalent exposure.
Prolonged exposure to RB in the context of continuous oral feeding has been shown to occur in murine Apc, as disclosed in the parent U.S. Serial No.17/214,590 filed 3/26/2021 Min Prevention of colon cancer formation (prophylactic activity) and prevention of colon cancer (therapeutic activity) in colorectal tumor models. For therapeutic use, the mean survival of symptomatic mice receiving RB at a concentration of 1mg/mL ad libitum in drinking water was increased by about 38% (12.3. + -. 0.5 weeks versus 9.8. + -. 0.8 weeks) relative to untreated mice. The daily rate of consumption of drinking water is assumed to be about 2mL/10g body weight, which corresponds to the consumption of about 2mg RB/10g (200 mg/kg).
Based on mass balance studies conducted by the inventors, the bioavailability of disodium RB administered in aqueous solution via the oral route was shown to be limited and could be estimated to be 0.1-1%, corresponding to daily systemic exposure of 0.2-2 mg/kg. This amount is assumed to be distributed through the blood flow and the blood volume is about 10% of the body weight, which corresponds to an estimated concentration of 2-20 μ M RB in the blood.
This same approach was used to plot the data presented in figure 1 of the present application, which shows the survival of CB17 SCID mice bearing xenografts of established pediatric B Acute Lymphoblastic Leukemia (ALL) tumor cell lines; therapeutic activity was observed for mice in two treatment groups receiving RB by gavage twice weekly for two consecutive weeks. Assuming that the bioavailability of this oral RB is 1%, the intestinal transit time for each administration is 6 hours, and the blood volume is about 10% of body weight, both treatment groups correspond to an estimated 125-250 μ M RB in blood.
Plotting these data confirms that the assumed relationship (i.e., cytotoxicity = f ([ HX ] · t)) is supported by experimental results, as shown in figure 2.
More importantly, this functional relationship allows prediction of dosage levels and schedules suitable for achieving antitumor therapeutic outcomes upon systemic administration. For equality with Apc Min Extended systemic treatment regimen for model studies, low micromolar concentration(i.e., about 10 μ M) of circulating HX compound is sufficient to achieve lysosomal accumulation and tumor cell destruction over a period of about 3 months, while micromolar to submicromolar concentrations (i.e., about 1 μ M) are sufficient to achieve tumor cell destruction over a period of about 12 months.
Conversely, shorter duration or intermittent repeated systemic administrations at higher dose levels, as used in the oral leukemia model of the invention, can also achieve tumor destruction.
For a particular indication, such as the treatment of a pediatric patient with leukemia, the relationship of fig. 2 illustrates that standard methods routinely used by those skilled in the art of drug development can be applied to select appropriate dose levels and schedules to maximize therapeutic outcomes while minimizing potential safety risks.
Apc of application Ser. No.17/214,590 Min The data and the oral leukemia therapy data of the present application indicate that a simple formulation of the disodium salt of RB is sufficient to deliver a therapeutically active level of RB; however, this may be less than the ideal effective level in terms of bioavailability. Thus, the identification of suitable formulations to achieve effective release and absorption of orally delivered HX compounds is a standard drug development issue well known to those skilled in the art, wherein the properties of the formulation can be varied to achieve the desired bioavailability by controlled release (disintegration, disaggregation and dissolution) at appropriate points within the gastrointestinal tract to maximize absorption of the dissolved HX compound into the bloodstream.
Formulation optimization may be guided by standard pharmacokinetic studies of absorption, such that dose levels and formulations are adjusted to achieve the necessary systemic exposure at the desired dose schedule (e.g., about 100 μ M for short duration exposures on the order of days, about 1 to about 10 μ M for intermediate duration exposures on the order of months, to about <1 μ M or less for long term exposures on the order of one year or more in the bloodstream).
The binary salt form of the HX compound is present in solution at a pH greater than about 5, whereas at pH <5 the HX compound spontaneously converts to its lactone form. Since the dibasic salt form is highly soluble in aqueous media, while the lactone form is insoluble in aqueous media, the former exhibits higher bioavailability in the gastrointestinal tract than the latter. Therefore, optimizing the formulation to properly compensate for the pH of the gastrointestinal tract may be the most important parameter affecting bioavailability. For example, in the stomach, at pH <4, dissolved HX compounds are rapidly converted to insoluble lactone forms. Once in the lactone form, the HX compound exhibits hysteresis and hinders saponification back to the absorbable salt form, delaying or inhibiting downstream bioavailability.
However, intraluminal pH increases rapidly from high acidity in the stomach to about pH6 in the duodenum and further increases from pH6 in the small intestine to about pH7.4 in the terminal ileum; the pH in the cecum drops to 5.7 and then gradually increases in the rectum to pH6.7.[ pumped. Ncbi. Nlm. Nih. Gov/10421978/]. Thus, by applying standard means in the field of pharmaceutical formulation to achieve an intestinal release, wherein a favourable pH value facilitates the release of the HX compound in the form of a soluble, absorbable binary salt, the bioavailability is optimized.
For a 12 month treatment regimen, these data indicate that a target concentration of about 1 μ M (1 mg/L) is achieved in the bloodstream. For a 70kg adult, where the blood volume is about 10% of the body weight (i.e., about 7L), this means that 7mg HX compound is absorbed per day. If bioavailability is limited to 1% of the HX compound administered, 700mg of HX compound per day needs to be orally administered (PO) to reach this target blood level.
However, by optimizing absorption to 50% of the administered dose, the necessary PO dose is reduced to about 15mg per day. For shorter treatment regimens (i.e., 3 months), these data indicate that a target blood concentration of about 10 μ M (10 mg/L) is achieved. Assuming 1% bioavailability, PO 7g HX compound is required per day, whereas at 50% bioavailability the required dose is reduced to about 150mg per day.
A related pharmaceutical composition comprises an aqueous medium (as a liquid) of 0.1% to about 20% (w/v) of a first leukemia cytotoxic agent that is a halogenated xanthene compound (HX compound). More preferably, the concentration is from about 0.2 to about 10% (w/v), and most preferably, the concentration is from about 0.2 to about 5% (w/v). Thus, for example, a daily dosage of 150mg as described above can be readily achieved by using 3mL of a 5% (w/v) aqueous solution.
A particularly preferred halogenated xanthene salt is rose bengal (4,5,6,7-tetrachloro-2 ',4',5',7' -tetraiodofluorescein) disodium (RB disodium) salt. The pharmaceutical composition is administered orally to provide a therapeutically effective amount of a first leukemia cytotoxic agent to a mammal (e.g., a human) having leukemia, or more specifically, acute Lymphoblastic Leukemia (ALL), chronic Lymphocytic Leukemia (CLL), or Acute Myelogenous Leukemia (AML) such as T-ALL or B-ALL.
Mammalian subjects are typically treated multiple times. The fact and relative amount of leukemia cell killing can be determined by conventional means for determining the status of a given leukemic mammalian subject. The duration of maintenance and the choice of further administration may depend on the species of mammal, the individual mammalian subject, the severity of the disease, the type of disease, the age and health of the subject and the observed effect on leukemic cell burden resulting from the treatment. These factors are usually handled by physicians in the field of treating leukemia.
Furthermore, while it is often desirable to remove detectable leukemic cells in the body, this is not always possible. Sometimes enough to kill enough leukemia cells to control the arrested disease, or to reduce the leukemic burden of the cells, so that other therapies can be performed.
The data presented below show the IC against several leukemia cell lines in vitro for RB 50 Values are about 50 to about 100 μ M upon exposure for one to several days. Considering that the molecular weight of RB disodium is 1018g/mol, the IC described above 50 Values were calculated to be about 50 to about 100mg RB/liter. Preferably, the concentration of exposed leukemia cells is achieved during in vivo treatment.
Classical Intravenous (IV) diagnostic assays for liver function were performed using RB, using 100mg RB as a single IV dose. In thatIn a clinical study of an aqueous RB disodium solution, delivery of 1500mg RB in IV was tolerated. The standard adult blood volume is about 5L. Thus, it is possible to provideTo achieve 100mg/L in the blood, an adult patient would need to receive about 500mg RB IV to achieve IC in the bloodstream 50 The value is obtained. Due to the rapid clearing of RB from the cycle (t) 1/2 About 30 minutes) so IV administration may require continuous infusion to maintain peak levels of RB in the circulation (i.e., for hours or more).
IC 50 Administration at a value level would not be toxic to all circulating hematological, non-neoplastic leukemia cells; that is, only about half of the cells will be in IC 50 The value is affected. Therefore, IC may be preferable 50 Multiples of value RB were administered up to about 1500mg (i.e., 300 μ M).
Alternatively, it may be sufficient to kill only a portion of the leukemic cells to elicit a functional immune response against the remaining leukemic burden. The latter case may be preferred to avoid toxic reactions due to the presence of large numbers of rapidly killing leukemia cells (i.e., so-called "tumor lysis syndrome"). In this case, leukemia cell debris resulting from cytotoxicity of the halogenated xanthene to leukemia cells releases intracellular contents, such as potassium, causing non-specific cell death. This process can also activate the immune system specifically against malignant cells.
Similarly useful halogenated xanthene compounds previously listed and pharmaceutically acceptable salts thereof may have molecular weights that differ from one another by about three times (see table 3, U.S. patent No.7,390,688, columns 15-16). The exact amount of the other RB halogenated xanthene to be used is preferably calculated based on the molecular weight of each such compound disclosed as well as the molecular weight of RB or RB disodium.
A mammalian subject (mammalian subject) suffering from leukemia in need of treatment and to which a pharmaceutical composition containing a halogenated xanthene compound may be administered may be a primate, such as a human, an ape (e.g., a chimpanzee or gorilla), a monkey (e.g., a cynomolgus monkey or macaque), an experimental animal (e.g., a rat, a mouse, or a rabbit), a companion animal (e.g., a dog, a cat, a horse), or a food animal (e.g., a cow or a steer, a sheep, a lamb, a pig, a goat, a llama, etc.).
In one aspect of the invention, the HX compound of interest for oral administration is typically dissolved or dispersed for use in a sterile aqueous pharmaceutical composition. Sterile tap water or sterile water from other sources may be used.
Features of the liquid pharmaceutical compositions involved
The HX compound is typically present in the aqueous pharmaceutical composition of interest at about 0.1 to about 20% (w/v). More preferably, the concentration is from about 0.2 to about 10% (w/v), and most preferably, the concentration is from about 0.2 to about 5% (w/v). Thus, for example, a dosage of 150 mg/day as described above can be readily achieved by using 3mL of a 5% (w/v) aqueous solution.
The bioavailability of various HX compounds (e.g., disodium rose bengal) has not been well characterized. The study committed by one of the assignee concluded that the study was based on a radiolabeling study in which the compound in water was incubated 14 C-RB oral administration to mice shows that the bioavailability of rose bengal disodium is less than that of (A)<) 1 percent. At pH value<4, the HX compound may be in the lactone form. The conversion to the lactone in the stomach does not destroy the HX compound, but this conversion to the lactone form can provide a kinetic and/or thermodynamic barrier to reconversion to the soluble salt form required for absorption in the intestine.
Use of an Apc as discussed in U.S. patent application Ser. No.17/214,590 min Studies in mice have shown that the onset of disease is prevented by ad libitum consumption of 4mg/mL in drinking water. Those Apc min Mice are understood to have thus consumed approximately 8mg/10 g/day =800 mg/kg/day. This amount is consistent with toxicological data, indicating that such dosage is tolerated. Therefore, ito et al, J Natl Cancer I,77, 277-281 (1986) studied rose bengal as a food color (food Red No. 105), and found that mice fed C57BL6N ad libitum continuously at a dose of 970 mg/kg/day had good tolerance to rose bengal for 2 years. The previously used Intravenous (IV) liver diagnostic delivered 112mg rose bengal as a bolus; for a standard 60kg adult, it is equal to 1.9mg/kg; this is not reported to produce morbidity.
Preferably, the osmolality (osmolity) of the liquid pharmaceutical composition for oral administration is less than the osmolality of plasma. The normal (healthy) human reference range for osmolality in plasma is about 275-299 milliosmoles per kilogram (mOsm/kg).
More preferably, the composition is free of tonicity agents (or tonicity modifiers), such as sugars, e.g., mannitol and dextrose, C 3 -C 6 Polyols such as propylene glycol, glycerol and sorbitol, isotonic salts such as sodium chloride or potassium chloride, and/or buffers other than those such as citric acid, malic acid, acetic acid and other food acids and their salts, which can provide for flavor and mild buffering (less than 5mmol buffer). The stomach and lower gastrointestinal tract are well suited to provide adequate tension to the material flowing therethrough so that no additional salts and/or buffers are required. One or more pharmaceutically acceptable taste masking or flavoring agents, as are known, may be present in up to about 5% by weight to enhance the drinkability of the composition.
Preferably, the pharmaceutically acceptable aqueous diluent has a pH of about 5 to about 9 to produce maximum solubility of the HX compound in the aqueous carrier and to ensure compatibility with biological tissues. Particularly preferred pH values are from about 5 to about 8, more preferably from about 6 to about 7.5. At these pH values, the halogenated xanthene generally remains in the binary form, rather than the lactone formed at low pH values.
HX compounds (e.g., rose bengal) are binary with pKa values of 2.52 and 1.81. pKa values for several of the halogenated xanthenes involved can be determined in Batsitela et al, spectrochim Acta Part A79 (5): 889-897 (9 months 2011).
In the present invention, it is believed that the specific amount of halogenated xanthene compound in the pharmaceutical composition is not as important as in the case where the composition is injected intralesionally to the tumor, since the objective herein is to ultimately provide a cytotoxic concentration of the halogenated xanthene compound to the environment of the leukemic cells, and wherein these leukemic cells can be contacted with the halogenated xanthene compound. The data provided below show that for leukemia cells cultured in vitro, the IC50 concentration of disodium rose bengal is from about 50 to about 100 μ M.
The above results using leukemia cells cultured in vitro surprisingly provide a new comparison to Swift et al, oncoTargets and Therapy 12:1-15 (2019) ofIn some similar respects, swift et al are data obtained from in vitro cytotoxicity studies of cultured SK-N-AS, SK-N-BE (2), IMR5, LAN1, SHEP and SK-N-SH neuroblastoma cells, SK-N-MC neuroepithelial tumor cells, and normal primary, BJ and WI38 fibroblasts. Those authors reportHalf maximal Inhibitory Concentration (IC) of cells 96 hours after treatment with aqueous RB disodium solution 50 ) Values were 65-85 μ M for the neuroblastoma line tested and 49 μ M for the neuroepithelial line SK-N-MC. Those authors also tested toxicity against human epithelial cells from three tissue sources and reported an IC of 93-143. Mu.M 50 The value is obtained.
In thatIn a clinical study of an aqueous solution of RB disodium, RB was tolerated at 1500mg IL delivery. Due to the rapid clearing of RB from the cycle (t) 1/2 About 30 minutes), IV administration may require continuous infusion to maintain peak levels of RB in the circulation (i.e., for up to several hours or more) during a single administration.
Features of the solid pharmaceutical compositions concerned
The invention further relates to the administration of an HX compound (such as RB or RB disodium) or an HX compound lactone (such as RB lactone) in a solid pharmaceutical composition for oral administration that is enterically coated to release the HX compound through the stomach and in the intestine. The HX compound is typically dissolved or dispersed in or on a solid diluent medium.
There are several factors contributing to the dissolution of orally administered solid pharmaceutical products in the body of mammals. These factors include the residence time of the drug at different locations in the gastrointestinal tract, the particle size, the solubility of the individual components of the drug in the body fluids that may be encountered from the mouth to the anus, the order in which the various coating layers (when present) are applied to the drug, and the pH at which a particular coating layer is soluble.
For example, the highly acidic gastric environment (pH 1.5-2 in the fasted state; pH 3-6 in the fed state) rapidly rises in the duodenum to about pH6 and increases along the small intestine to pH7.4 at the terminal ileum. The pH in the cecum drops to just below pH6 and rises again in the colon, reaching a pH of 6.7[ Hua, front Pharmacol 11. A solution of RB disodium mixed into an aqueous solution having the pH of the human stomach was observed, showing a rapid turbidity of the mixture, and the previously soluble RB disodium was presumed to aggregate to the lactone form.
The process through the stomach may range from 0 to 2 hours in the fasted state and may extend up to 6 hours in the fed state. Generally, transit times in the small intestine are considered to be relatively constant at about 3 to 4 hours, but may range from 2 to 6 hours in healthy individuals. Colon transit time can be highly variable, reported to range from 6 to 70 hours [ Hua, front Pharmacol 11 (month 4 2020) ].
The drug must pass through or penetrate the epithelial cells lining the inner wall of the gastrointestinal tract in order to be absorbed into the circulatory system. A cellular barrier that can prevent epithelial cells from absorbing a given drug is the cell membrane. The cell membrane is essentially a lipid bilayer forming a semi-permeable membrane.
Pure lipid bilayers are generally permeable only to small uncharged solutes. Thus, whether a molecule is ionized will affect its absorption because the ionic molecules are charged. Solubility favors charged species and permeability favors neutral species.
Generally, ions cannot passively diffuse through the gastrointestinal tract because the epithelial cell membrane consists of a phospholipid bilayer. The bilayer consists of two layers of phospholipids, with the charged hydrophilic head facing outward and the uncharged hydrophobic fatty acid chain in the middle of the layer. Uncharged fatty acid chains repel ionized charged molecules. This means that ionized molecules cannot easily pass through the intestinal membrane and are absorbed.
Chemical modification by esterification can be used to control solubility. For example, C of HX compounds 2 -C 4 The alkyl and aromatic ester forms generally have reduced solubility in aqueous liquids and, due to their neutral ionic charge, are generally more than their carboxylate formsAre better absorbed by the intestinal epithelial cells. Subsequently, esterases in the wall of the gastrointestinal tract and in the blood hydrolyze the esters to release the parent drug.
Furthermore, the coating film on the tablet or pill may act as a barrier to reduce the rate of dissolution and/or disintegration of the composition in aqueous media (typically, particularly in the stomach). Coatings may also be used to alter where dissolution occurs. For example, an enteric coating may be applied to a drug-containing medicament such that the coating and the drug dissolve only in the alkaline environment of the intestine. One method that can be used to predictably release a drug from a pharmaceutical agent at a particular location in the intestinal portion of the gastrointestinal tract and/or the gastrointestinal tract relies on a pH-specific coating and matrix that dissolves or disintegrates at a preselected pH value in the gastrointestinal tract, such as those previously mentioned.
The following table shows some examples of pH-dependent polymer coatings for targeted release (topical therapy) purposes, alone or in combination, including some methacrylic resins (available from Evonik Industries, AG, essen, germany, toCommercially available) and hydroxypropylmethylcellulose (HPMC; available as Methocel from DuPont, wilmington, DE TM Obtained, and by Benecel, ashland, inc TM Obtained, wilmington, DE) derivatives. In addition to triggering release within a particular pH range, enteric coatings can protect incorporated active agents from the harsh gastrointestinal environment (e.g., gastric juices, bile acids, and microbial degradation), and can produce extended and delayed drug release profiles to enhance therapeutic efficacy.
The "published pH release" values for each polymer were from the manufacturer. For all compositions or environments, the "published pH release" values are not absolute, and the pH values for dissolution or disintegration described herein are based on those published values.
pH-dependent Polymer coating
* [ Hua, front Pharmacol 11: article 524 (2020, 4 months)
For colonic release, colon targeted drug delivery systems have been actively developed because conventional non-targeted therapies may have undesirable side effects and low efficacy due to systemic absorption of the drug before reaching the target site. Liu et al, eur.j.pharm.biopharm.74:311-315 (2010) is coated in a double coating process by usingAn alkaline aqueous solution of S is applied to the inner layer and->The organic solution of S is applied to the outer layer to accelerate the dissolution of the drug at a pH greater than 7. Subsequently, varum et al, eur.j.pharm.biopharm.84:573-577 (2013) evaluates the in vivo performance of this dual coating system in humans, demonstrating a more consistent disintegration of the dual coated tablets, primarily in the lower intestinal tract.
Hashme et al, br.J. Physiol.Res.3:420-434 (2013) developed microspheres that bind to the time-and pH-dependent system for colonic delivery of prednisolone. By usingS and ethylcellulose, which achieve greater colonic drug delivery while preventing premature release of the drug in the upper intestine.
Is another example of a multiple unit technique that provides targeted drug delivery to the colon with delayed and uniform drug release. Such a system is based on a combination of on and off>RL/RS and->FS 30D pellets were coated with pH-and time-dependenceMeans to provide colon specific drug release [ Patel, expert Opin. Drug Deliv.8:1247-1258 (2011)]。
One composition for targeting the small intestine comprises a diluent medium of sugar/sucrose beads coated with particulate Rose Bengal (RB) coated with one or more layers of a (meth) acrylate copolymer polymerized from about 60 to about 95% by weight of a free radical of acrylic or methacrylic acid C 1 -C 4 And about 5 to about 40 wt% of a (meth) acrylate ester monomer having an acid group in the alkyl group.
Particularly suitable (meth) acrylate copolymers comprise about 10 to about 30 weight percent methyl methacrylate, about 50 to about 70 weight percent methyl acrylate, and about 5 to about 15 weight percent methacrylic acid (meth)FS type). Similarly suitable are about 20 to about 40% by weight of methacrylic acid and about 80 to about 60% by weight of methyl methacrylate (` ml `)>S type) of (meth) acrylate ester copolymer. The word "(meth) acrylate" is used herein to indicate that either or both of the acrylate and methacrylate monomers may be used.
These coating polymers allow little, if any, HX compound to be released before the particles leave the stomach. The pH of the fluid in the duodenum is typically about 6 and rises to about 7.4 towards the ileum.
A typical tablet or lozenge can be prepared by mixing lactose (20%) and the active ingredient (80%, HX compound) in a high speed mixer (DIOSNA type P10, osnabruck, germany). A small amount of an aqueous solution containing the excipient polyvinylpyrrolidone (PVP), such as povidone (Sigma-Aldrich International GmbH, buchs, CH), was added until a homogeneous composition was obtained. The wet powder mixture was sieved. From which tablets are then prepared and dried as is well known.
The resulting tablets or lozenges are then preferably coated with a protective polymeric film, usually using a fluidized bed apparatus. The film-forming polymer is generally mixed with the plasticizer and the release agent by well-known methods. In this case, the film former may be in the form of a solution or suspension. Excipients for film formation may likewise be dissolved or suspended. Organic or aqueous solvents or dispersants may be used. In addition, to stabilize the dispersion, a stabilizer (for example:80 or other suitable emulsifiers or stabilizers).
Examples of mould release agents are glycerol monostearate or other suitable fatty acid derivatives, silicic acid derivatives or talc. Examples of plasticizers include propylene glycol, phthalates, polyethylene glycol, sebacates or citrates, as well as the other substances mentioned above and in the literature.
Another preferred type of medicament is a water soluble capsule or blister (blister) containing a plurality of particles of HX compound (e.g. disodium mengladesh or mengladesh lactone) covered by one or more layers of a polymer resin which releases the HX compound rapidly upon dissolution or disintegration of the capsule in water or body fluids. Capsules are typically made of gelatin and are commonly referred to as soft gelatin capsules. Gelatin is an animal product. Vegetarian capsules are typically made from Hydroxypropylmethylcellulose (HPMC).
In some embodiments, the HX compound is directly layered with one or more polymer coatings to form a generally spherical particle. Such particles are commonly referred to as beads. In a preferred aspect, the size of the particles (beads) is adjusted so that about 90% by weight passes through a 20 mesh (openings =850 μm) screen and about 90% by weight remains on an 80 mesh (openings =180 μm) screen.
Exemplary pH sensitive coating polymer resins are discussed above. The pH sensitivity of the coating polymer resin should be understood in terms of the physiologically occurring pH values along the gastrointestinal tract, such as those discussed above.
In other embodiments, pellets (such as sugar/starch granules (seed), bare pellet cores (non-pareil) or beads, which are small, generally spherical cores, are coated with one or more layers of an HX compound and one or more layers of a polymer coating an illustrative sugar/starch core is a sugar sphere NF that passes through a about 40 mesh (425 mm openings) screen to a about 50 mesh (300 mm openings) screen, which contains not less than 62.5% and not more than 91.5% sucrose (on a dry basis), the remainder consisting essentially of starch (USP NF 1995 2313).
In an illustrative example, 100 kilograms (kg) of disodium rose bengal, 7.1kg of croscarmellose (preferably sodium croscarmellose NF), and 11.9kg of starch NF are each split into two halves and the three ingredients are blended together to form two identical batches. Each batch is milled through an 80 mesh screen using a mill (e.g., a Fitzpatrick mill). The two mill batches were then blended to form a mixture, the composition of which was tested according to accepted quality assurance testing methods well known to those skilled in the art.
The disodium rose bengal mixture was then divided into three equal portions, the first portion remaining all, and the second and third portions divided into 50%, 30%, and 20% batches, respectively. An amount of 25.6kg of 40-50 mesh sugar/starch granules (e.g., sugar spheres NF) was placed in a stainless steel coating pan. An amount of 80 liters (L) of a 5% povidone/isopropyl alcohol (IPA) solution was prepared for spraying onto the granules.
The coating pan started with sugar spheres, onto which povidone-alcohol solution was sprayed (about 0.173kg per application) and onto which the rose bengal disodium mixture from the first part (the part that remained intact) was sieved (about 0.32 kg). Sieving was performed using a standard sieve. The spraying and sieving steps are continued until the first portion of the mixture has been applied to the sugar spheres to form a batch of partially coated spheres.
The partially coated spheres were then divided into two equal batches, each of which was placed in a coating pan. Separately, for each of the two batches, the povidone/IPA solution was sprayed and the rose bengal disodium blend was sieved into 50% batches until 50% of the batch had been applied to the spheres. After 50% of the batch is applied, the spheres can be sieved using a 25 mesh sieve, if desired.
Spraying of the povidone/IPA solution was started and the rose bengal disodium mixture was sieved into 30% batches and continued until 30% of the batch had been applied to the ball. The coated spheres may be rescreened using a 25 mesh screen.
The spraying of the povidone/IPA solution and sieving of the rose bengal disodium mixture was continued using the mixture divided into 20% batches until 20% of the batch had been applied to the spheres. At this point in the process, the full amount of the disodium rose bengal mixture was applied to the spheres and about 50kg of a 5% povidone/IPA solution was applied to the spheres.
A 7.5% povidone/IPA solution was prepared and applied as a sealant to the ball. The sealed spheres were tumble dried for about 1 hour, weighed, and placed in an oven at about 122 ° f (50 ℃) for 24 hours. After drying, the spheres were sieved through a 20 mesh and a 38 mesh sieve to form immediate (faster or faster than delayed) release granules.
The spheres containing the HX compound or capsules (or blisters) thereof as described above may also be coated with a pH sensitive enteric coating polymer as described previously, such that once released in the gastrointestinal tract, the spheres do not provide their active ingredient HX compound to their surroundings unless the pH is at least that of the desired location of the gastrointestinal tract.
Another method of controlling the location of the HX compound release is to further coat the above-described spheres (HX coated particles), wherein a dissolution controlling coating of a polymer resin is applied to the surface of the spheres such that the release of the HX compound from the spheres is controlled and released over a period of 6-10 hours. Materials for this purpose may be, but are not limited to, ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose, cellulose nitrate, carboxymethyl cellulose, and copolymers of ethyl acrylic acid and methacrylic acid may be usedOr any other acrylic acid derivative (` H `)>Etc.).
In addition, enteric coating materials may also be used alone or in combination with the non-pH sensitive coatings described above. These materials include, but are not limited to, hydroxypropyl methylcellulose phthalate and the phthalates of all cellulose ethers. Furthermore, phthalic acid esters of acrylic acid derivativesOr cellulose acetate phthalate.
These coating materials may be used to coat surfaces in amounts of about 1.0% (w/w) to about 25% (w/w). Preferably, these coating materials are present at about 8.0% to about 12.0% (w/w).
Excipient(s)
Pharmaceutically customary excipients can be used in a manner known per se for the preparation of the HX-containing compound. These excipients may be present in the core or in the coating agent.
Polymer and process for producing the same
When a coating of the HX compound is used, a polymeric material that acts as a binder to help adhere the HX compound to the pellets or spheres is considered an excipient. Illustrative of such polymers are polyvinylpyrrolidone and polyvinyl alcohol, as well as other water-soluble, pharmaceutically acceptable film-forming polymers, such as hydroxypropyl cellulose.
Desiccant (non-stick agent)
The desiccant had the following properties: they have a large specific surface area, are chemically inert, are free-flowing and contain fine particles. Due to these properties, they reduce the viscosity of polymers containing polar comonomers as functional groups. Examples of desiccants are: alumina, magnesia, kaolin, talc, fumed silica, barium sulfate and cellulose.
Disintegrating agent
Disintegrants are added to the oral solid dosage form to aid in its deagglomeration. Disintegrants are formulated to cause rapid disintegration of the solid dosage form upon exposure to moisture. Disintegration is generally considered the first step in the dissolution process. Exemplary disintegrants include croscarmellose sodium, internally croscarmellose sodium, crospovidone (crospovidone), and sodium starch glycolate.
Release agent
Examples of release agents are: esters of fatty acids or fatty amides, aliphatic long-chain carboxylic acids, fatty alcohols and esters thereof, montan wax or paraffin wax, and metal soaps; particular mention should be made of glycerol monostearate, stearyl alcohol, glyceryl behenate, cetyl alcohol, palmitic acid, carnauba wax, beeswax and the like. Typical proportional amounts are in the range from 0.05 to 5% by weight, preferably from 0.1 to 3% by weight, based on the copolymer.
Other excipients commonly used in pharmacy
Mention should be made here, for example, of stabilizers, colorants, antioxidants, wetting agents, pigments, gloss agents. They are generally used as processing aids and are intended to ensure a reliable and reproducible production process and good long-term storage stability. Other excipients which are customary in pharmacy may be present in an amount of from 0.001 to 10% by weight, preferably from 0.1 to 10% by weight, based on the polymer coating.
Plasticizer
Substances suitable as plasticizers generally have a molecular weight of 100 to 20,000 and contain one or more hydrophilic groups in the molecule, such as hydroxyl, ester or amino groups. Citrate, phthalate, sebacate, castor oil are suitable. Examples of other suitable plasticizers are alkyl citrates, glycerol esters, alkyl phthalates, alkyl sebacates, sucrose esters, sorbitan esters, dibutyl sebacate and polyethylene glycols 4000 to 20000. Preferred plasticizers are tributyl citrate, triethyl citrate, acetyl triethyl citrate, dibutyl sebacate and diethyl sebacate. The amount used is from 1 to 35% by weight, preferably from 2 to 10% by weight, based on the (meth) acrylate copolymer.
Optimizing systemic bioavailability
The amount of HX compound delivered by the solid pharmaceutical composition is substantially the same as the amount of HX compound delivered by the aqueous composition. Sufficient RB (as an exemplary HX compound) is applied to achieve IC 50 HorizontalCirculating RB concentrations, by definition, will not be toxic to all circulating leukemia cells (i.e., only about half of the leukemia cells are in IC) 50 The following is affected). In some embodiments, it may be preferred to use an IC 50 RB is administered in an amount that is a multiple of the level, up to about 1500mg (i.e., 300 mM). Alternatively, however, it may be sufficient to kill only a portion of the tumor cells as a result of the administration alone.
The latter case may be preferred to avoid toxic reactions that may be caused by a rapidly killing tumor cell burden (i.e., "tumor lysis syndrome"). Thus, howard et al, N Engl JMed 364 (19): 1844-1854 (5/12/2011) reported that the tumor lysis syndrome is the most common disease-related emergency encountered by physicians treating hematological cancers, such as leukemia.
As discussed in more detail below, it may also be advantageous to kill only a portion of the leukemia cells during a single treatment to initiate a functional immune response against the remaining leukemia cell burden. The RB-elicited functional immune system response is believed to occur at least in part due to the effect of RB-induced necrotic cell debris circulating in the body that induces an immune response that can prolong the effect of the initial administration of the halogenated xanthene (e.g., RB).
The induced immune response may take longer to develop than killing the exposed leukemia cells more immediately. A delay in effect may occur due to the time required to induce the appropriate B and T cell populations to attack and kill leukemia cells and induce long-lasting memory T cells, which can protect patients from relapse. This initial delay may increase the longevity of the subject due to the memory immune cells so induced.
Combination therapy
In another aspect, the above pharmaceutical composition is used in combination with a second, different, acting systemic cytotoxic antileukemic agent; that is, a cytotoxic antileukemic agent whose mechanism of action is different from the first cytotoxic agent HX compound. As previously described, halogenated xanthenes localize in cancer cell lysosomes, increase the percentage of cells in the G1 phase of the cell cycle, and induce cell death by apoptosis [ Swift et al, oncotargets Ther,12 (2 months 2019) ].
The first type of second anti-leukemic systemic cytotoxic agent is a so-called "small molecule". Such small molecules can be considered semi-specific cytotoxic agents because they are generally more specific in killing leukemia cells than non-leukemia cells. Almost all small molecule anticancer agents have lower leukemia specificity than the HX compounds involved and may cause disease, baldness, and other trauma to their recipient subjects, which may cause the subjects to leave their treatment regimen.
These small molecules generally have a molecular weight of about 150 to about 1000 daltons (Da), preferably about 250 to about 850 Da. This group of small molecules includes many those used to treat hematological leukemias, such as calicheamicin (calicheamicin, 1368 Da), vinblastine (811 Da), vincristine (825 Da), imatinib (494 Da), monomethyl auristatin (718 Da), etoposide (589 Da), daunorubicin (528 Da), doxorubicin (544 Da), cladribine (286 Da), fludarabine (365 Da), mitoxantrone (444 Da), 6-thioguanine (167 Da), methotrexate (454 Da), 6-mercaptopurine (152 Da), azacytidine (244 Da), anamycin (640 Da), sorafenib (465 Da), clofarabine (304 Da), cisplatin (300 Da), irinotecan (587 Da), and cytarabine (cytabarine) (cytabane 243 Da). One or more of the above-described small molecule anti-leukemic agents can comprise a second leukemic cytotoxic agent. It should be noted that many of these small molecules are used in the form of their salts, prodrugs and/or esters, and therefore have a molecular weight greater than the above-mentioned approximate values.
Pharmaceutical compositions having a second systemic cytotoxic antileukemic agent may also contain small molecules as described above conjugated to larger molecules such as proteins, detergents and/or polymers such as poly (ethylene glycol) [ PEG ]. Such conjugation typically minimizes the toxicity of the small molecule and enhances the site of delivery when using antibodies that bind to leukemia cells. In addition, the small molecule cytotoxic agent may be encapsulated within a liposome, micelle, or cyclodextrin molecule, which may be adapted to specifically bind to and/or be endocytosed by the leukemia cells. This group of encapsulated and conjugated small molecules is included in the group of small molecules of the second systemic cytotoxic agent discussed previously because their active cytotoxic agents are small molecules.
Examples of such second systemic anti-leukemia cytotoxic agents are liposomal daunorubicin, liposomal ansamycin, sphingosine vincristine, liposomal cytarabine, a calicheamicin-conjugated CD33 antibody known as gemtuzumab ozogamicin, and a chimera of a CD30 antibody known as netuximab vistin and monomethyl auristatin E.
Briefly, liposomes are generally spherical artificial vesicles, usually prepared from cholesterol and phospholipid molecules, which constitute one or two bilayers and encapsulate a small molecule secondary systemic cytotoxic agent to aid delivery. See Akbarzadeh et al, nanoscale Res Lett,8 (2013).
Calicheamicin is a high molecular weight small molecule (1368 Da) and contains four linked sugars interrupted by a benzothioate S-ester linkage and an ene-diynyl group that cleaves DNA sequences. Calicheamicin is too toxic to use alone, LD in nude mice 50 At 320. Mu.g/kg [ DiJoseph et al, blood 103]. Similarly, monomethyl auristatins exhibit general (broad range), high toxicity [ IC50 for several cancer cell lines<1nM;ApexBio Technology Product Catalog(2013)]Which is mediated by the attachment of antibodies against CD30 (TNF receptor family members, which are cell membrane proteins and cancer markers), reportedly useful against large cell lymphomas and hodgkin's disease [ Francisco et al, blood 102, 1458-1465 (2003)]While monoclonal ligation with anti-CD 79b provided advantages in three xenograft models for treating NHL [ Dornan et al, blood 114]。
A systemic anti-leukemia drug, either a small molecule (non-protein, less than about 1000 grams/mole) or a larger protein molecule, is administered to the subject mammal to be treated, allowing the drug to diffuse throughout the subject mammal. Intravenous administration is one preferred method of achieving drug diffusion. Imatinib, on the other hand, is typically administered orally.
Exemplary small molecule anticancer drugs for the treatment of leukemia include doxorubicin, etoposideTopoponin, vincristine, cisplatin, irinotecan, and cytarabine, which are used in parent application Ser. No.16/688,319, while an exemplary protein molecule is elasparase. Among those small molecule drugs, doxorubicin, etoposide and vincristine, each of which will be administered intravenously to a mammalian subject, are in sub-lethal dosesThe treatment with aqueous RB disodium solution showed synergistic effects and is preferred.
It is to be understood that the administration of any of the second leukemia systemic cytotoxic agents discussed herein can be performed multiple times. Such multiple administrations are within the scope of the treating physician and may be combined with the administration of the HX compound first leukemia cytotoxic agent, or may be performed separately.
Useful effective doses of small molecule systemic anti-leukemia drugs are those listed in label information for drugs approved by FDA, national or international agencies. Typically, monotherapy dose schedules are set by determining the Maximum Tolerated Dose (MTD) in early clinical trials. The MTD (or its approximate change) is then published to later clinical trials to assess efficacy and more detailed safety assessments. These MTDs are often established as therapeutic doses after completion of clinical testing. However, because small molecule systemic antileukemic drugs are expected to be used with HX compounds in solid or liquid formulations, the MTD is the maximum amount that is commonly used, and this amount will be titrated down (to be titrated) according to conventional procedures.
Exemplary dosing regimens of several systemic anti-cancer (anti-leukemia) drugs (agents) that can be combined with the halogenated xanthene therapy of the present invention are provided in table a below. It should be noted that several of the drugs listed below are "small molecules" as defined above, while others are large protein molecules, such as antibodies, preferably monoclonal antibodies, that inhibit inflammatory chemokine activity. Nevertheless, they are administered systemically. The agents of table a are typically used as single active agents. However, one or more may also be used together, in particular antibodies, as is the case with the immune checkpoint inhibitor antibodies discussed below.
TABLE A
Exemplary systemic immunomodulating or targeted anticancer agents
The combination therapies and treatment methods of the present invention, when used with IV administration therapies (such as those described below), generally allow for the use of systemic agents at levels at or below typical dosing schedules for systemic agents (such as those described in table a) due to additive or synergistic effects. However, the dosing schedule provided in table a provides useful guidance for initiating treatment from which the dose can be titrated to a reduced amount as deemed appropriate by the physician attending a given patient.
It should be noted that the HX compound and the second cytotoxic anti-leukemia agent need not be administered together, nor need they be administered by the same mode of administration. Thus, a pill or capsule form can be used to administer the HX compound first cytotoxic anti-leukemia agent, while a small or large molecule second anti-leukemia agent is administered IV or orally, such as imatinib. Various methods of administering anti-leukemic agents are known to those skilled in the art.
A second type of second systemic cytotoxic agent useful in combination therapy with a halogenated xanthene, such as that present in an aqueous RB disodium solution or the aforementioned solid dosage forms, is an immune checkpoint inhibitor, which may also be considered a specific systemic anti-leukemia drug. Immune checkpoint inhibitors are drugs that bind to and block certain checkpoint proteins produced by cells of the immune system (such as T cells and some leukemia cells). When not blocked, those proteins suppress the immune response, help maintain the immune response under examination and prevent T cells or other immune cells from killing leukemia cells. Blocking those immune checkpoint proteins releases the "brakes" of the immune system, allowing immune cells to be activated and killing leukemia cells.
Useful immune checkpoint inhibitors are preferably human or humanized monoclonal antibodies or binding portions thereof, the administration of which blocks the action of those particular proteins. This blockade allows the immune system to recognize leukemia cells as foreign and helps to eliminate those leukemia cells from the body.
Illustrative immune checkpoint inhibitors include the anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) monoclonal antibodies ipilimumab (ipilimumab) and tremelimumab (tremelimumab) designed to downregulate the anti-immune system by blocking CTLA-4 activity and thus enhance T cell responses against leukemia. Similarly, monoclonal antibodies, such as Pi Deli mab (pidilizumab), nivolumab (nivolumab), tirezazuab (tiselizumab), spartalizumab, cimepril mab (cemipimab), pembrolizumab (pembrolizumab), carprilizumab (camrelizumab), fudi Li Shankang (sintilimab), teripril mab (toripilimumab), and multi-tower Li Shankang (dostarlizab) bind to PD-1 (programmed death 1) receptors to counteract the down-regulation of the immune system and enhance the response of T cells to cancer cells. Three monoclonal antibodies targeting the immune checkpoint protein ligand (anti-PD-L1) of the PD-1 receptor (anti-PD-1) are atelizumab, avizumab and dulvacizumab. Initial work on antibodies to PD-1 receptor ligands PD-L1 and PD-L2, such as BMS-936559 and MEDI4736 (bevacizumab) against PD-L1, also demonstrated inhibition of down-regulation of the immune system and enhanced T cell responses against leukemia.
The above immune checkpoint inhibitor antibodies have been found to be useful when administered alone with an HX compound as well as when two different types of immune checkpoint inhibitors are used with an HX compound. Patel et al, an article of International SOCIETY of CLINICAL ONCOLOGY (ASCO) 2020VIRTUAL SCIENTIFIC PROGRAM,2020 5 months 29-31 days provides data from a study that utilizes intratumoral injection of disodium rose bengal into uveal melanoma tumors that metastasize to the liver, with either systemic administration of anti-PD-1 or systemic administration of both anti-PD-1 and CTLA-4 antibodies.
Recently, several additional groups of antibodies have been identified that have checkpoint inhibitor activity and, due to their similarity of action, are considered herein to be immune checkpoint inhibitors. An illustrative group immunoreacts with the cell surface receptor OX40 (CD 134) to stimulate proliferation of memory and effector T lymphocytes, thereby stimulating a T cell-mediated immune response against cancer cells. Exemplary such humanized anti-OX 40 monoclonal antibodies include those currently referred to in the literature as gsk3174998 (IgG 1), pogalizumab (pogalizumab) (MOXR 0916), MED10562, and the human anti-OX 40 IgG2 antibody designated PF-04518600 (PF-8600).
The other group immunoreacts with lymphocyte activator gene 3 protein (anti-LAG-3 cd223), which negatively regulates T lymphocytes by binding to the extracellular domain of the ligand, thereby avoiding autoimmunity caused by T cell overactivation. LAG-3 is an important immune checkpoint in vivo and plays a balanced regulatory role in the human immune system [ Shan et al, oncol Lett 20 (2020) ].
Molecular LAG-3 blocks the signal transduction pathway of T cell activation; however, the intracellular segment of the LAG-3 molecule produces immunosuppressive signals that have been found to modulate CD4+ T cell activity. LAG-3 modulates the immune response of T cells in three ways: first, it directly inhibits proliferation and activation of T cells through negative regulation of T cells. Secondly, it may promote the suppressive function of regulatory T cells (tregs) which may then indirectly suppress T cell responses. Third, it can prevent T cell activation by modulating the function of Antigen Presenting Cells (APCs) [ Joller et al, curr Top Microbiol Immunol 410 (2017) ].
To date, no monoclonal antibody directed to LAG-3 is known to be approved for sale and use by the U.S. food and drug administration. Studies are being performed using a humanized IgG4 monoclonal antibody from Merck called MK-4280 and another monoclonal antibody from Bristol Myers Squibb under the INN name reiatlimab.
Yet another type of immune checkpoint inhibitor is monoclonal antibodies directed against CD47 and macrophage checkpoint inhibitors that interfere with the recognition of CD47 by sirpa receptors on macrophages, thereby blocking the "do not eat me" signal used by cancer cells from being taken up by macrophages. This monoclonal antibody, whose INN name is magrolimab, is being developed by gilead Sciences, inc. Magrolimab has been FDA approved for rapid channel nomenclature for the treatment of myelodysplastic syndrome (MDS), acute Myelogenous Leukemia (AML), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma. Magrolimab is also FDA approved for orphan drug nomenclature for MDS and AML, and is approved by the european drug administration for orphan drug nomenclature for AML.
Monoclonal antibodies against T cell immunoglobulin and mucin domain 3 (anti-TIM-3), another checkpoint marker, are being developed early by Novartis Oncology co, under the INN name sabatolimab (early MBG-453), for differential leukemia stem cell expression-based therapies of MDS and AML that function as co-inhibitory T cell co-receptors and may have a role in promoting antibody-dependent cell phagocytosis (ADCP). TIM-3 is expressed on AML leukemia progenitor cells, but not on normal hematopoietic stem cells, and its expression correlates with the severity of myelodysplastic syndrome and the likelihood of progression to AML. Multiple trials of the TIM-3 antibody MBG-453, currently present in first-line myelodysplastic syndrome and AML, exhibit encouraging anti-leukemia activity when used in combination with decitabine.
Intact monoclonal antibodies, as well as complementary portions thereof (portions containing binding sites), such as the Fab, fab ', F (ab') 2 and Fv regions, and single chain peptide binding sequences, are useful as inhibitors of immune checkpoint proteins.
Most of these antibodies were administered via the IV route. Intact checkpoint inhibitory monoclonal antibodies have a half-life in humans of about one to three weeks [ e.g.,(ipilimumab) terminal t 1/2 Day = 15.4; package inserts 12/2013;(pembrolizumab) terminal t 1/2 =23 days; package insert 03/2017]And single-stranded oligonucleotides or polypeptides tend to have shorter half-lives in vivo.
Because of the relatively short half-lives of the small molecule second cytotoxic antileukemic agent and the drug containing the halogenated xanthene compound, these two drugs may be administered in a single composition or in separate compositions. If administered separately, the two types of anti-cancer (anti-leukemia) agents are preferably administered within minutes to about 3 hours of each other. More preferably, both are administered within less than 1 hour of the other.
The word "administering" is used herein to mean the beginning of a treatment regimen. Thus, swallowing a tablet or other oral dosage form is the beginning of the treatment regimen, as is the time when IV flow begins. When the first and second cytotoxic anti-leukemia agents are present together in the same single composition, administration begins when the single composition enters the subject.
When the second cytotoxic systemic anti-leukemia agent is an immune checkpoint inhibitor (e.g., a monoclonal antibody), the halogenated xanthene compound and the second cytotoxic anti-leukemia agent immune checkpoint inhibitor may be administered together or one before the other, with the second cytotoxic anti-leukemia agent immune checkpoint inhibitor being administered up to about one month prior to the halogenated xanthene. Preferably, the two cytotoxic anti-leukemia agents are administered together, or the second systemic cytotoxic anti-leukemia agent immune checkpoint inhibitor is administered within a few days after the halogenated xanthene. The second systemic cytotoxic anti-leukemia agent immune checkpoint inhibitor may also be administered about one month after the halogenated xanthene.
Study of
Mice:
female C17 SCID mice from Charles River
Cell lines used in xenotransplantation:
SEM cell lines were initially established from 5 year old women with B acute lymphoblastic leukemia. It carries an MLL-AFFF1 gene fusion and is heterozygous for CDKN2A and TP 53. The utility of this cell line in anticancer drug sensitivity studies has been described (Barretina et al, nature 483 603-607, 2012.
2.5X 10 6 Exponentially growing SEM cells (labeled with Green Fluorescent Protein (GFP)) were injected intravenously into each animal and tumor establishment was monitored. After allowing the tumor to grow for 4 weeks, the mice were randomized into three groups.
Group 1 (n = 9). Comparison:
these animals received 100 μ L PBS and were orally administered twice weekly for two weeks.
Group 2 (n = 8). Treatment group I:
these animals received 25. Mu.L diluted in PBS to a final volume of 100. Mu.L(10% rose bengal disodium w/v in 0.9% saline) and administered orally by gavage twice weekly for 2 weeks.
Group 3 (n = 8). Treatment group II.
These animals received 12.5. Mu.L diluted in PBS to a final volume of 100. Mu.L(as described above) and administered orally by gavage twice weekly for 2 weeks.
Evidence of disease progression was monitored in all animals and survival was followed up to 120 days after treatment initiation. The data are presented as Kaplan-Meier estimates in FIG. 1.
As can be seen from the graph of fig. 1, the oral delivery of HX compound is clearly demonstrated by the dose-dependent survival of the treated mice.
The results disclosed in parent application Ser. No.16/688,319 indicate that incremental doses are administeredCan kill 11 kinds of leukemia cells on the marketLines derived from a combination of 11 commercially available leukemia cell lines>Patients with primary or recurrent pediatric leukemia and two primary leukemia samples in cell culture were treated. Cell viability was measured by alamar blue assay 96 hours after treatment.
Administration of 11 pediatric leukemia cell lines (mean IC) with reduced examination in a concentration and time dependent manner 50 92.8 μ M) and three primary leukemia samples (average IC50122.5 μ M). The results indicate that PV-10 is cytotoxic to leukemic cell lines, with average IC 50 The value was 92.8. Mu.M (Table 1 below) and was cytotoxic to two primary leukemia samples, the average IC 50 The value was 122.5. Mu.M (Table 2 below).
TABLE 1
* By usingHalf maximal Inhibitory Concentration (IC) for 96 hours of treatment of pediatric leukemia cell lines 50 )
Table 2 x
Cell type | PV-10IC50μM |
T- |
150 |
AML for babies | 95 |
Average | 122.5 |
* Use byHalf maximal Inhibitory Concentration (IC) for 96 hours of treatment of Primary pediatric leukemia samples 50 ) The value is obtained.
Similar results were obtained using leukemia cell lines CCRF-CEM, HL-60 (TB), K-562, MOLT-4, RPMI-8226 and SR, respectively.
Surprisingly, at the concentrations of disodium RB used in these studies, leukemia cells were completely killed, with results of about 10 based on IC50 values -4 To about 10 -5 And (3) mol. Even so, the concentrations of HX compound required were greater than those achieved by oral administration in the study discussed previously. Thus, still more surprising, 62.5% of the HX compound-treated leukemic mice survived for 120 days, while untreated leukemic mice and those treated with lower amounts of HX compound exhibited much lower survival rates, as shown by the data in figure 1.
Each of the patents, patent applications, and articles cited herein is hereby incorporated by reference. The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. Each of the patents, patent applications, and articles cited herein is hereby incorporated by reference.
The foregoing description and examples are intended to be illustrative, and are not to be construed as limiting. Other variations within the spirit and scope of the invention are possible and will be readily apparent to those skilled in the art.
Claims (30)
1. A method of treating a mammalian subject having leukemic cells comprising dissolving or dispersing a therapeutically effective amount of a halogenated xanthene, pharmaceutically acceptable salt thereof, lactone, or C in a pharmaceutically acceptable solid or liquid composition 1 -C 4 A step of orally administering an alkyl or aromatic ester (HX compound) as a first leukemia cytotoxic agent to said mammalian subject having leukemia cells.
2. The method according to claim 1, wherein said oral administration is repeated.
3. The method according to claim 1, wherein the composition is a solid.
4. A process according to claim 3, wherein the HX compound is dissolved in or dispersed in or on a solid dilution medium.
5. A process according to claim 3 wherein the solid composition is in the form of a tablet, lozenge or a plurality of substantially spherical dragees.
6. A method according to claim 5, wherein said solid composition consists of substantially spherical pellets coated with one or more layers of said HX compound.
7. A method according to claim 3, wherein the solid composition is coated with a barrier film which reduces the rate of dissolution and/or disintegration of the composition in an aqueous medium.
8. The method according to claim 7, wherein the barrier film coating is an enteric coating that dissolves and/or disintegrates at physiological pH values of 5 or higher.
9. The method of claim 1 wherein said first cancer cytotoxic agent halogenated xanthene compound is rose bengal, a pharmaceutically acceptable salt thereof,Lactones or C 1 -C 4 Alkyl or aromatic esters.
10. The method according to claim 1, wherein the HX compound is rose bengal, a pharmaceutically acceptable salt thereof, a lactone, or C 1 -C 4 Alkyl or aromatic esters.
11. The method according to claim 1, wherein the composition is an aqueous liquid.
12. The method according to claim 11, wherein the osmolality of the aqueous liquid composition is less than the osmolality of a normal human.
13. The method according to claim 1, wherein said administering step is performed in conjunction with administering a second therapeutically effective amount of a second, different acting, systemic leukemia cytotoxic agent dissolved or dispersed in a pharmaceutically acceptable vehicle to said mammalian subject, wherein the systemic leukemia cytotoxic agent is a small molecule, a proteinaceous molecule that inhibits inflammatory chemokine activity, ionizing radiation therapy, and an intact checkpoint inhibitor antibody, or a site-containing portion thereof.
14. The method according to claim 13, wherein the second leukemia cytotoxic agent is dissolved or dispersed in a pharmaceutically acceptable solid medium.
15. The method according to claim 14, wherein the pharmaceutically acceptable solid medium containing the second leukemia cytotoxic agent is administered orally.
16. The method according to claim 13, wherein the second leukemia cytotoxic agent is ionizing radiation.
17. The method according to claim 13, wherein said small molecule exhibits synergistic effects with said first leukemia cytotoxic agent.
18. The method according to claim 13, wherein the second leukemia cytotoxic agent is dissolved or dispersed in a pharmaceutically acceptable aqueous medium.
19. The method according to claim 18, wherein the pharmaceutically acceptable aqueous medium containing the second leukemia cytotoxic agent is administered intravenously.
20. The method according to claim 13, wherein the second leukemia cytotoxic agent is a small molecule having a molecular weight of about 150 to about 1000 Da.
21. The method according to claim 20, wherein the small molecule is selected from one or more of vinblastine, vincristine, imatinib, monomethyl auristatin, etoposide, daunorubicin, doxorubicin, cladribine, fludarabine, mitoxantrone, 6-thioguanine, methotrexate, 6-mercaptopurine, azacytidine, ansamycin, sorafenib, clofarabine, cisplatin, irinotecan, and cytarabine (cytabaine).
22. The method of claim 19, wherein the second leukemia cytotoxic agent comprises an intact monoclonal antibody or a complementary-containing portion thereof.
23. The method of claim 22, wherein said intact monoclonal antibody or a complementary portion thereof is an immune checkpoint inhibitor.
24. A method according to claim 23, wherein the immune checkpoint inhibitor binds to one or more proteinaceous substances selected from one or more of the following: anti-CTLA-4, anti-PD-1, anti-PD-L2, anti-OX 40, anti-LAG-3, anti-CD 47, and anti-TIM-3.
25. The method according to claim 22, wherein said intact monoclonal antibody is a protein molecule that inhibits inflammatory chemokine activity and is selected from the group consisting of adalimumab, brodatumumab, certolizumab, etanercept, golimumab, gucekumab, infliximab, exelizumab, sariluzumab, secukinumab, and ustlizumab.
26. The method according to claim 19, wherein the antibody or the complementary-containing moiety thereof is administered after the HX compound is administered.
27. The method according to claim 19, wherein the antibody or the complementary-containing moiety thereof is administered prior to administration of the HX compound.
28. The method according to claim 19, wherein the antibody or the complementary-containing moiety thereof is administered simultaneously with the administration of the HX compound.
29. The method according to claim 19, wherein the first HX compound and the second leukemia cytotoxic agent are administered simultaneously within about 3 hours of each other.
30. The method according to claim 13, wherein the HX compound is rose bengal, a pharmaceutically acceptable salt thereof, a lactone, or C 1 -C 4 Alkyl esters or aromatic esters.
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CN202180038959.2A Pending CN115955969A (en) | 2021-04-16 | 2021-04-16 | Compositions and methods for oral treatment of leukemia |
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JP (1) | JP7525638B2 (en) |
KR (1) | KR20230171854A (en) |
CN (1) | CN115955969A (en) |
AU (1) | AU2021440597A1 (en) |
CA (1) | CA3175637A1 (en) |
MX (1) | MX2022012945A (en) |
WO (1) | WO2022220841A1 (en) |
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US7648695B2 (en) * | 1998-08-06 | 2010-01-19 | Provectus Pharmatech, Inc. | Medicaments for chemotherapeutic treatment of disease |
KR20070022308A (en) * | 2004-05-10 | 2007-02-26 | 로버트 에프 호프만 | Use of targeted oxidative therapeutic formulation in treatment of cancer |
CN102482347B (en) * | 2009-01-12 | 2017-04-26 | 希托马克斯医疗有限责任公司 | Modified antibody compositions, and methods of making and using thereof |
US8765725B2 (en) * | 2012-05-08 | 2014-07-01 | Aciex Therapeutics, Inc. | Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof |
WO2018047917A1 (en) * | 2016-09-09 | 2018-03-15 | 国立大学法人 東京大学 | Synergistic antitumor effect of combination of hmg protein, anti-cd4 antibody or immune checkpoint control agent |
CA3059882A1 (en) * | 2017-04-12 | 2018-10-18 | Aura Biosciences, Inc. | Targeted combination therapy |
AU2018254577B2 (en) * | 2017-04-21 | 2024-06-13 | Epizyme, Inc. | Combination therapies with EHMT2 inhibitors |
EP3773548B1 (en) * | 2018-05-16 | 2023-08-09 | Provectus Pharmatech, Inc. | In vitro and xenograft anti-tumor activity of a halogenated-xanthene against refractory pediatric solid tumors |
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- 2021-04-16 CN CN202180038959.2A patent/CN115955969A/en active Pending
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JP7525638B2 (en) | 2024-07-30 |
MX2022012945A (en) | 2023-03-16 |
CA3175637A1 (en) | 2022-10-20 |
EP4117668A1 (en) | 2023-01-18 |
AU2021440597A1 (en) | 2022-11-10 |
WO2022220841A1 (en) | 2022-10-20 |
EP4117668A4 (en) | 2023-12-06 |
KR20230171854A (en) | 2023-12-21 |
JP2023529262A (en) | 2023-07-10 |
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