Combination therapy for the treatment of leukemia
阅读说明：本技术 用于治疗白血病的联合疗法 (Combination therapy for the treatment of leukemia ) 是由 维克拉姆·马修斯 桑吉夫·克里希纳 于 2019-01-17 设计创作，主要内容包括：本发明涉及白血病(例如急性骨髓性白血病,AML)的治疗,使用以下三联组合：三氧化二砷；铁；和青蒿素,例如青蒿琥酯。(The present invention relates to the treatment of leukemia (e.g. acute myeloid leukemia, AML) using the following triple combination: arsenic trioxide; iron; and artemisinin, such as artesunate.)
1. A pharmaceutical composition comprising:
(a) arsenic trioxide;
(b) iron; and
(c) artemisinin;
can be used for treating leukemia.
2. Use of arsenic trioxide in the treatment of leukemia, wherein the arsenic trioxide is administered in combination with iron and artemisinin.
3. The use of arsenic trioxide according to claim 2, wherein the artemisinin is artesunate.
4. Use of arsenic trioxide according to claim 2 or 3, wherein the iron is an iron complex.
5. Use of arsenic trioxide according to claim 4, wherein the iron complex is a porphyrin complex.
6. The use of arsenic trioxide according to claim 5, wherein the porphyrin complex is hemin.
7. Arsenic trioxide for use according to any of claims 2-6, wherein the leukemia is Acute Myeloid Leukemia (AML).
8. Use of iron in the treatment of leukemia, wherein the iron is administered in combination with arsenic trioxide and artemisinin.
9. Use of iron according to claim 8 wherein the artemisinin is artesunate.
10. Use of iron according to claim 8 or 9, wherein the iron is an iron complex.
11. Use of iron according to claim 10, wherein the iron complex is a porphyrin complex.
12. Use of iron according to claim 11, wherein the porphyrin complex is hemin.
13. The iron use according to any one of claims 8-12, wherein the leukemia is Acute Myeloid Leukemia (AML).
14. Use of artemisinin in the treatment of leukemia, wherein artemisinin is administered in combination with arsenic trioxide and iron.
15. The use of artemisinin according to claim 14, wherein artemisinin is artesunate.
16. The use of artemisinin according to claim 14 or 15, wherein the iron is an iron complex.
17. The use of artemisinin according to claim 16, wherein the iron complex is a porphyrin complex.
18. The use of artemisinin according to claim 17, wherein the porphyrin complex is hemin.
19. The use of artemisinin according to any of claims 14-18, wherein the leukemia is Acute Myelogenous Leukemia (AML).
20. A method of treating a patient with leukemia, said method comprising administering arsenic trioxide, iron and artemisinin to said patient in combination.
21. A product comprising (a) arsenic trioxide; (b) iron; and (c) artemisinin as a combined preparation for simultaneous, concurrent, separate or sequential use in the treatment of a patient with leukemia.
22. Use of arsenic trioxide in the manufacture of a medicament for the treatment of leukaemia by administration in combination with iron and artemisinin.
23. Use of iron in the manufacture of a medicament for the treatment of leukaemia by administration in combination with arsenic trioxide and artemisinin.
24. Use of artemisinin for the manufacture of a medicament for the treatment of leukaemia by administration in combination with arsenic trioxide and iron.
25. A pharmaceutical composition comprising:
(a) arsenic trioxide;
(b) iron; and
(c) artemisinin.
26. A kit comprising the following components:
(a) arsenic trioxide;
(b) iron; and
(c) artemisinin;
wherein the components (a), (b) and (c) are each formulated in a separate pharmaceutical composition, or any two of the components (a), (b) and (c) are formulated together in a first pharmaceutical composition and the remaining components are formulated in a second pharmaceutical composition.
27. Use of a pharmaceutical composition according to claim 1, a method according to claim 20, a product according to claim 21, a use according to any one of claims 22-24, a pharmaceutical composition according to claim 25, or a kit according to claim 26, wherein the leukemia is Acute Myeloid Leukemia (AML).
28. Use of a pharmaceutical composition according to claim 1 or 27, a method according to claim 20 or 27, a product according to claim 21 or 21, a use according to any one of claims 22-24 and 27, a pharmaceutical composition according to claim 25 or 27, or a kit according to claim 26 or 27, wherein
The artemisinin is artesunate; or
The iron is an iron complex, preferably a porphyrin iron complex, and more preferably hemin; or
The artemisinin is artesunate and the iron is an iron complex, preferably a porphyrin iron complex, and more preferably hemin.
Technical Field
The present invention relates to the treatment of leukemia, such as Acute Myeloid Leukemia (AML), using a triple combination of (i) arsenic trioxide, (ii) iron, and (iii) artemisinin, such as artesunate.
Background
Leukemia is a cancer of the white blood cells. The types of leukemia include Acute Myelogenous Leukemia (AML), Acute Lymphatic Leukemia (ALL), Chronic Myelogenous Leukemia (CML), Chronic Lymphatic Leukemia (CLL), and hairy cell leukemia. Over 200 million people worldwide have reported leukemia in 2015 and caused death in over 35 million people. It is the most common type of cancer in children, three-quarters of the cases of leukemia in children belonging to the ALL type. However, about 90% of all leukemias are diagnosed in adults, with AML and CLL forms being most common in adults.
For example, the current backbone therapy for Acute Myeloid Leukemia (AML) is a combination of daunorubicin and cytarabine, which are myelosuppressive and have significant bystander effects on normal cells.
Acute promyelocytic leukemia (AML-M3; APL) is a subtype of AML and, at least in non-high risk groups, therapy for acute promyelocytic leukemia has evolved as a therapy that no longer requires conventional myelosuppressive therapy. Instead, a combination therapy using all-trans retinoic acid (ATRA) and Arsenic Trioxide (ATO) together induce differentiation of the malignant cell population and relatively specific apoptosis of the malignant cell population. Thus, the conventional side effects of chemotherapy, such as recurrent cytopenia, alopecia and mucositis, are not seen. In most studies, the currently expected cure rate for APL using this non-myelosuppressive regimen is over 90%. However, in some APL patients, treatment is adversely affected by drug resistance, such as ATO resistance.
Furthermore, most AML patients are certain to develop disease recurrence after treatment, especially in adults, in contrast to APL, and this remains a major cause of mortality. In addition, most elderly AML patients, as well as elderly patients diagnosed with significant comorbid disease, are unable to receive standard intensive chemotherapy regimens due to the associated toxicity of these regimens.
The main focus of research and rationalization to explain the rate of leukemia recurrence lies firstly in the acquired somatic genetic and epigenetic mutations that confer resistance to subcloning against chemotherapy and secondly in the presence of the leukemic origin compartment (also known as leukemic stem cell population) that is inherently resistant to chemotherapy and persists with minimal residual disease. However, it is increasingly recognized that there are other biological processes that can lead to the recurrence of leukemia following conventional chemotherapy. Recognition and study of these new resistance mechanisms may lead to the identification of new therapeutic targets.
There is an urgent need to develop new therapeutic strategies for the treatment of leukemia (including AML), in particular therapeutic strategies that combine high efficacy and specificity for malignant cells and reduce off-target side effects. It is also desirable to develop therapeutic strategies suitable for treating the types of leukemia currently associated with high disease recurrence (e.g., AML), for treating ATO resistant leukemia and/or for treating patients for whom conventional chemotherapy regimens are not feasible.
Disclosure of Invention
It has now been found that: (i) arsenic trioxide; (ii) iron; and (iii) artemisinin can be used to treat leukemia. It has also been found that such triple combination therapy results in benefits (e.g., synergistic benefits) as compared to the effects of the administration of the corresponding compounds alone or in "dual" combinations (i.e., combinations of any two of the above-mentioned active agents). Still further, it has been found that such a triple combination has clinically acceptable toxicity profiles which can be contrasted with combination therapies using similar active agents, such as-aminolevulinic acid as an agent for increasing intracellular iron concentration.
Accordingly, the present invention provides:
[1] a pharmaceutical composition comprising: (a) arsenic trioxide; (b) iron; and (c) artemisinin (e.g., artesunate); for the treatment of leukemia (e.g. AML).
[2] Use of arsenic trioxide in combination with iron and artemisinin (e.g. artesunate) for the treatment of leukemia (e.g. AML).
[3] Use of iron in the treatment of leukemia (e.g. AML) in combination with arsenic trioxide and artemisinin (e.g. artesunate).
[4] Use of artemisinin (e.g. artesunate) in the treatment of leukemia (e.g. AML) in combination with arsenic trioxide and iron.
[5] A method of treating a leukemia (e.g., AML) patient comprising co-administering arsenic trioxide, iron and artemisinin (e.g., artesunate) to the patient.
[6] A product comprising (a) arsenic trioxide; (b) iron; and (c) artemisinin (e.g. artesunate) as a combined preparation for simultaneous, concurrent, separate or sequential use in the treatment of leukemia (e.g. AML) patients.
[7] Use of arsenic trioxide in the manufacture of a medicament for the treatment of leukemia (e.g. AML) by administration in combination with iron and artemisinin (e.g. artesunate).
[8] Use of iron for the manufacture of a medicament for the treatment of leukemia (e.g. AML) by administration in combination with arsenic trioxide and artemisinin (e.g. artesunate).
[9] Use of artemisinin (e.g. artesunate) in the manufacture of a medicament for the treatment of leukemia (e.g. AML) by administration in combination with arsenic trioxide and iron.
[10] A pharmaceutical composition comprising: (a) arsenic trioxide; (b) iron; and (c) artemisinin (e.g., artesunate).
[11] A kit comprising the following components: (a) arsenic trioxide; (b) iron; and (c) artemisinin (e.g., artesunate); wherein each of said components (a), (b) and (c) is formulated in a separate pharmaceutical composition or any two of said components (a), (b) and (c) are formulated together in a first pharmaceutical composition and the remaining components are formulated in a second pharmaceutical composition.
Other aspects of the invention are summarized in detail below.
Drawings
Fig. 1 shows the basal levels of mitochondrial membrane potential for various cell lines, as described in example 1. The Y-axis corresponds to the relative fluorescence intensity [ RFU 590nm/530nm ], while the bars from left to right along the X-axis are the results of the ATO sensitive NB4 cell line, the ATO resistant APL cell line generated by NB4 ("NB 4-
Figure 2 shows the basal amounts of glucose uptake for various cell lines, as described in example 1. The Y-axis corresponds to the relative fluorescence intensity [ RFU 485nm/595nm ], while the bars from left to right along the X-axis are the result of the ATO sensitive NB4 cell line, the ATO resistant APL cell line generated by NB4 ("NB 4-
FIG. 3 shows the glycolytic inhibitor (i) 2-DG; (ii) ATO; and (iii) the effect of the combination of 2-DG and ATO on various cell lines as described in example 1 (n-4; time period 48 hours). The Y-axis corresponds to% survival. Four groups of three bars are shown along the X-axis. For each set of three bars, the leftmost bar shows the results for NB4 naive cells, the middle bar shows the results for ATO-resistant APL cell lines generated by NB4 ("NB 4-EVAsR 1"), and the rightmost bar shows the results for innate ATO-resistant UF1 cell lines. From left to right, these groups correspond to: (i) untreated cells (i.e., control); (ii) treatment with ATO only; (iii) treatment with 2-DG only; and (iv) treatment with a combination of ATO and 2-DG.
Figure 4 shows (i) an oxidative phosphorylation decoupling agent FCCP; (ii) ATO; and (iii) the effect of the combination of FCCP and ATO on various cell lines as described in example 1 (n-4; time period 48 hours). The Y-axis corresponds to% survival. Five groups of four bars per group are shown along the X-axis. For each set of four bars, the bars correspond from left to right to: (i) untreated cells (control); (ii) treatment with ATO only; (iii) processing with FCCP only; and (iv) treatment with a combination of ATO and FCCP. From left to right, these groups correspond to: (i) results from the NB4 naive cell line; (ii) results of ATO-resistant APL cell lines generated by NB4 ("NB 4-EVAsR 1"); (iii) results for the UF1 cell line; (iv) results for the U937 cell line; and (v) effects on normal peripheral blood mononuclear cells (PBMNC).
FIG. 5 shows (i) ATO; (ii) ART; and (iii) the effect of the combination of ATO and ART on various cell lines as described in example 1 (n-8; time period-48 hours). Y-axis corresponds to annexin V-/7AAD-And (4) cell percent. Six groups of four bars are shown along the X-axis. For each set of four bars, the bars correspond from left to right to: (i) untreated cells (control); (ii) treatment with 2 μ M ATO only; (iii) treatment with only 5 μ M ART; and (iv) treatment with a combination of ATO and ART. From left to right, these groups correspond to: (i) results for the ATO sensitive NB4 naive cell line; (ii) results of ATO-resistant APL cell lines generated by NB4 ("NB 4-EVAsR 1"); (iii) results for ATO resistant U937 cell line; (iv) results of ATO-resistant THP-1 cell lines; (v) results for ATO sensitive Kasumi cell lines; and (vi) results of ATO resistant Jurkat cell lines.
Fig. 6 shows the results of in vitro cytotoxicity assays on normal PBMNC, where ATO was used at two different concentrations, while ART was used at various varying concentrations, as described in example 1 (n-3; time period 48 hours). The Y-axis corresponds to% reduction of MTT (normalized to control). The X-axis corresponds to the log concentration of artesunate (μ M). The results of using ART alone are shown as circles with the best fit line going to the right of the graph, between the other two best fit lines. The results of the treatment with 1 μ M ATO and ART are shown as squares with the best fit line going to the right side of the graph, the top line. The results of the treatment with 2 μ M ATO and ART are shown in triangles with the best fit line going to the right side of the graph, the lowest line.
FIG. 7 shows processing U937 thin in the following mannerResults for the cells: (i) untreated (control); (ii) ATO (1. mu.M); (iii) ART (5. mu.M); (iv) ART (5. mu.M) and ALA (1 mM); (v) ATO (1. mu.M) and ART (5. mu.M); (vi) ATO (1. mu.M) and ART (5. mu.M) and ALA (1 mM); (vii) ART (5. mu.M) and ALA (1mM) and DFO (20. mu.M); and ATO (1 μ M) and ART (5 μ M) and ALA (1mM) and DFO (20 μ M) as described in example 1 (n ═ 4; time period ═ 48 hours). (third bar on right) also shows the results of treating NB4 naive cells with ATO (2. mu.M). Y-axis corresponds to annexin V-/7AAD-And (4) cell percent.
Figure 8 shows the results of treatment on U937 cells as described in example 2 (n-5; time period 48 hours). Panel (Panel) a shows the results of treatment with ATO, ART and/or hemin in various combinations and concentrations. Group B shows the elimination of the potency of the co-administration with DFO (for each pair of bars, the leftmost bar shows the results of no DFO administration, and the rightmost bar shows the results of the co-administration of DFO). The Y-axis in both figures corresponds to annexin V-/7AAD-And (4) cell percent.
Detailed Description
Definition of
As used herein, and unless otherwise specified, the term "pharmaceutically acceptable salt" includes, but is not limited to: salts of acidic or basic moieties of the compounds described herein (including but not limited to artemisinin, artesunate, -aminolevulinic acid, and iron). The basic moiety is capable of forming a wide variety of salts with a wide variety of inorganic and organic acids. Acids which can be used for the preparation of pharmaceutically acceptable acid addition salts of such basic compounds are those which form non-toxic acid addition salts, for example salts containing a pharmacologically acceptable anion. Suitable organic acids include, but are not limited to, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, acetic acid, formic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, mandelic acid, cinnamic acid, oleic acid, tannic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, glutamic acid, gluconic acid, glucuronic acid, saccharic acid, isonicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, or pamoic acid (e.g., 1,1' -methylenebis- (2-hydroxy-3-naphthoic acid)). Suitable inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, or nitric acid. In addition to the acids described above, compounds that include an amine moiety can also form pharmaceutically acceptable salts with various amino acids. Chemical moieties that are acidic in nature are capable of forming basic salts with a variety of pharmacologically acceptable cations. Examples of such salts are alkali metal or alkaline earth metal salts, in particular calcium, magnesium, sodium, lithium, zinc, potassium or iron salts.
As used herein, and unless otherwise specified, the term "solvate" is meant to also include a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.
As used herein, and unless otherwise specified, the term "stereoisomer" encompasses all enantiomerically pure/stereoisomerically pure compounds and enantiomerically/stereoisomerically enriched compounds provided herein.
As used herein, and unless otherwise specified, the term "stereomerically pure" refers to an ingredient that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of the compound. For example, a stereomerically pure component of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure component of a compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound, greater than about 98% by weight of one stereoisomer of the compound and less than about 2% by weight of other stereoisomers of the compound, alternatively, greater than about 99 wt% of one stereoisomer of the compound and less than about 1 wt% of other stereoisomers of the compound.
As used herein, and unless otherwise specified, the term "stereoisomerically enriched" refers to an ingredient comprising greater than about 55 wt% of one stereoisomer of a compound, greater than about 60 wt% of one stereoisomer of a compound, greater than about 70 wt% of one stereoisomer of a compound, or, greater than about 80 wt% of one stereoisomer of a compound.
As used herein, and unless otherwise specified, the term "enantiomerically pure" refers to a stereomerically pure component of a compound having one chiral center. Similarly, the term "enantiomerically enriched" refers to a stereoisomerically enriched component of a compound having one chiral center.
Artemisinin
Artemisinin is a well-known compound having the following structural formula:
artemisinin and its derivatives (collectively referred to herein as "artemisinin") have been widely used as a drug for the treatment of malaria.
Artemisinin itself and the active metabolite of artemisinin species are usually Dihydroartemisinin (DHA), which has the following formula:
non-limiting examples of artemisinin classes include: artesunate, artemisinin, artemether, arteether, artelinic acid, arteether, arteanone, and dihydroartemisinin. Thus, in the present invention, the artemisinin may for example be a compound selected from the group consisting of: artesunate, artemisinin, artemether, arteether, artelinic acid, arteether, arteanone, and dihydroartemisinin.
The chemical structural formula of the artesunate is as follows:
artesunate has hemisuccinate groups which impart water solubility and high oral bioavailability of the substance to the compound. In the present invention, the artemisinin is preferably artesunate.
Previous studies have suggested that artemisinin species, including artesunate, may have anti-cancer properties. For example, preclinical studies of anti-leukemic activity of artesunate are described in Leukemia study 59,2017,124-135 (Leukemia Research 59,2017, 124-135).
Artemisinin species (e.g., artesunate) can be conveniently administered by a variety of means, including parenteral means (e.g., intramuscular intravenous or rectal) and oral means.
Artemisinin may be administered as such or in any physiologically acceptable physical form. For example, artemisinin may be present in the form of a physiologically acceptable salt or solvate. In this regard, it is emphasized that the term "artemisinin" as used herein includes physiologically acceptable salts or solvates thereof (e.g., "artesunate" includes any physiologically acceptable salt or solvate thereof). It is common practice in the art to prepare physiologically acceptable physical forms of known drugs, including salts and solvates, and no fundamental description of such methods is provided herein. One common formulation of artesunate is its sodium salt (i.e., sodium artesunate).
Artemisinin may also exist in any enantiomeric form, e.g., racemic, enantiomerically/stereoisomerically enriched and/or enantiomerically/stereoisomerically pure.
Arsenic trioxide
Arsenic trioxide, i.e. As2O3It is a known chemotherapeutic agent. For example, it has been marketed as the drug Trisenox for the treatment of acute promyelocytic leukemia.
For example, arsenic trioxide can be conveniently used as a concentrate for infusion, e.g., for dilution and subsequent intravenous administration. In another embodiment, arsenic trioxide can be formulated for oral administration (e.g., as described by Au et al in the yearbook of hematology (2013)92:417 (Au et al in ann Hematol (2013)92: 417)).
-aminolevulinic acid
-aminolevulinic acid (also known as 5-aminolevulinic acid) has the following formula:
it is marketed as the drug Ameluz in the form of the hydrochloride salt for the treatment of mild to moderately severe actinic keratosis and regional canceration on the face and scalp.
In humans, -aminolevulinic acid is a precursor of heme. Aminolevulinic acid undergoes a series of transformations in the cytosol and finally intramitochondrial conversion to protoporphyrin IX. In the presence of ferrochelatase, the protoporphyrin molecule chelates iron to produce heme. Thus, administration of aminolevulinic acid can be used to elevate intracellular heme levels and increase intracellular iron concentrations.
The aminolevulinic acid can be administered as such or in any physiologically acceptable physical form. For example, -aminolevulinic acid can be present in the form of a physiologically acceptable salt or solvate. In this connection, it is emphasized that the term "-aminolevulinic acid" as used herein comprises physiologically acceptable salts or solvates thereof. It is common practice in the art to prepare physiologically acceptable physical forms of known drugs, including salts and solvates, and no fundamental description of such methods is provided herein. As mentioned above, one common formulation of aminolevulinic acid is its hydrochloride salt.
A surprising aspect of the present invention is the discovery that: direct administration of iron (e.g. in the form of an iron complex such as hemin) may involve improved results such as lower bystander toxicity/side effects in the case of a triple combination for the treatment of leukemia which also comprises arsenic trioxide and artemisinin, compared to the corresponding triple combination using aminolevulinic acid instead of iron.
Iron
Iron has been used medically for hundreds of years, particularly for the treatment of anemia. It is in the WHO's basic drug list.
For the avoidance of doubt, when iron is used as the active agent according to the present invention, it may be present in any physical form as long as it is capable of increasing the intracellular iron concentration of the individual to which it is administered. Thus, references herein to "iron" should not be construed as limited to elemental iron metal. For example, non-limiting acceptable forms of iron active agents include elemental iron and pharmaceutically acceptable iron salts and complexes. Thus, the "iron" active agent may be present in the form of an iron-rich compound, provided, of course, that the compound is capable of delivering iron to a subject after administration, e.g., provided that the compound is capable of increasing intracellular iron concentration after administration.
Iron (II) sulfate is a well-known commercially available form of iron for medical use. Iron (II) fumarate is another common and exemplary pharmaceutically acceptable form of iron. Both represent exemplary forms of iron for use in accordance with the present invention.
Other exemplary forms of iron include Heme Iron Polypeptide (HIP), ferrous sulfate glycinate, ferric carboxymaltose, ferric dextran, ferric sucrose, and ferric isomaltose anhydride.
In a preferred aspect of the invention, the iron is present in the form of an iron complex. For example, such a complex may be a divalent iron (II) complex or a trivalent iron (III) complex. One preferred iron complex is a porphyrin iron complex, such as an iron (III) porphyrin complex. One preferred porphyrin is protoporphyrin IX or a derivative thereof. For example, iron complexes of protoporphyrin IX (e.g., iron (III) complexes) are a preferred type of iron for use in the present invention. Hemin and hemin are exemplary of such substances, i.e., the coordinating anion therein (Cl in hemin)-(ii) a OH in hemin-) A compound substituted with another pharmaceutically acceptable anion. In the present inventionIn one presently preferred embodiment of the invention, the iron active agent comprises hemin. It has been surprisingly found that such iron complexes are associated with low bystander toxicity/more acceptable side effect profile in the triple combination therapy practiced by the present invention.
When iron is to be administered according to the present invention, it may be prepared in any suitable form and formulated for administration by any suitable means. Common modes of administration of iron include oral and parenteral administration.
Administration of iron directly increases intracellular iron levels.
Combinations of active ingredients
The present invention relates to the use of a triple combination of arsenic trioxide, iron and artemisinin. The arsenic trioxide, the iron, and the artemisinin are referred to herein as "active ingredients" or "active agents".
In one aspect, the present invention provides a pharmaceutical composition for treating leukemia, comprising: (a) arsenic trioxide; (b) iron; and (c) artemisinin. The pharmaceutical composition according to the invention will typically further comprise one or more pharmaceutically acceptable excipients or carriers.
The invention extends to the case of the combined administration of the active ingredients mentioned above. When the active ingredients are administered in combination, they may be present in a single pharmaceutical composition, or in different multiple pharmaceutical compositions, including in different multiple pharmaceutical compositions that are optimized for administration by the same or different modes. For example, the active ingredients may each be administered orally in a single pharmaceutical composition, or more preferably, in different multiple pharmaceutical compositions.
For the avoidance of doubt, in the case of a composition comprising (a) arsenic trioxide; (b) iron; and (c) artemisinin, which may comprise any of the following as a combined preparation for simultaneous, concurrent, separate or sequential use:
(i) comprises (a); (b) (ii) a And (c) all of the single pharmaceutical compositions;
(ii) two (different) pharmaceutical compositions, wherein (a); (b) (ii) a Any two of (a) and (c) are formulated together in a first pharmaceutical composition, while the remaining components are formulated in a second pharmaceutical composition; or
(iii) Three (different) pharmaceutical compositions, wherein (a) is formulated in a first pharmaceutical composition, (b) is formulated in a second pharmaceutical composition, and (c) is formulated in a third pharmaceutical composition.
The combined administration of the active ingredients according to the invention includes simultaneous, separate and sequential administration.
In general, the pharmaceutical compositions used in the present invention may be adapted for administration by any means known in the art, for example, oral administration, mucosal administration (e.g., nasal, sublingual, vaginal, buccal or rectal administration), parenteral administration (e.g., subcutaneous, intravenous, bolus, intramuscular or intraarterial injection), topical administration (e.g., eye drops or other ophthalmic preparations), transdermal administration or transdermal administration.
For oral administration, the pharmaceutical compositions of the invention may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or dibasic calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium glycolate); or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated by methods well known in the art. For example, liquid preparations for oral administration may take the form of solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous carriers or preservatives. The formulations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents as appropriate.
For ophthalmic formulations, the pharmaceutical compositions of the present invention may be conveniently formulated as a micronized suspension in isotonic, pH adjusted, sterile saline, with or without preservatives, such as bactericides or fungicides, e.g., phenylmercuric nitrate, benzalkonium chloride or chlorhexidine acetate. Alternatively, for ophthalmic administration, the compounds may be formulated as ointments, such as petrolatum.
For rectal administration, the pharmaceutical compositions of the invention may be conveniently formulated as suppositories. These suppositories can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at room temperature and liquid at the rectal temperature and will therefore melt in the rectum to release the active ingredient. Such materials include, for example, cocoa butter, beeswax and polyethylene glycols.
For topical administration, the pharmaceutical compositions according to the invention may take the form of any formulation customarily used for topical administration, in particular solutions, lotions, emulsions of liquid consistency, emulsions of semi-solid consistency, emulsions of solid consistency, creams, gels or ointments. Emulsions are obtained by dispersing the oil phase in water (O/W) or the aqueous phase in oil (W/O). For example, some pharmaceutical compositions for topical administration contain an oil phase. For example, such pharmaceutical compositions may be water-in-oil emulsions (i.e., emulsions in which water is the dispersed phase and oil is the dispersion medium) or substantially non-aqueous emulsions.
The topical compositions according to the present invention may further comprise one or more emollients, emulsifiers, thickeners and/or preservatives. The emollients are typically long chain alcohols such as cetyl alcohol, stearyl alcohol and cetearyl alcohol; hydrocarbon compounds such as vaseline and light mineral oil; or acetylated lanolin. The total amount of emollient in the formulation is preferably from about 5 wt% to about 30 wt%, and more preferably from about 5 wt% to about 10 wt%, based on the total weight of the formulation. The emulsifier is typically a non-ionic surfactant, for example, polysorbate 60 (available from Sigma Aldrich), sorbitan monostearate, polyglycerol-4 oleate and tetrapolyethylene glycol monolaurate or a trivalent cation. Generally, the total amount of emulsifier is preferably from about 2 wt% to about 14 wt%, and more preferably from about 2 wt% to about 6 wt%, based on the total weight of the formulation. Pharmaceutically acceptable thickeners may be used, such as veegum.k (available from r.t. vanderbilt Company, Inc.) and long chain alcohols (i.e., cetyl, stearyl or cetostearyl alcohols). The total amount of thickener present is preferably from about 3 wt% to about 12 wt%, based on the total weight of the formulation. Preservatives such as methylparaben, propylparaben and benzyl alcohol may be present in the formulation.
Optionally, additional solubilizing agents may be included in the formulation, such as benzyl alcohol, lactic acid, acetic acid, stearic acid, or hydrochloric acid. If an additional solubilizer is used, the additional solubilizer is preferably present in an amount of about 1 wt% to about 12 wt%, based on the total weight of the cream.
Optionally, the formulation may include a humectant (such as glycerin) and a skin penetration enhancer (such as butyl stearate).
It is known to those skilled in the art that a single ingredient may serve more than one function in a composition, i.e., cetyl alcohol may serve as both an emollient and a thickener.
The pharmaceutical compositions of the present invention optionally comprise an oily phase. In this case, the amount of oil in the composition is generally at least 10 wt.%, preferably at least 30 wt.%, more preferably at least 50 wt.%, more preferably at least 80 wt.%, based on the total weight of the composition. The oil phase as used herein is typically a liquid or solid phase that is substantially immiscible with water. More typically, the oil phase as used herein has a solubility in water at 25 ℃ of less than or equal to 1mg/L, preferably less than 0.1 mg/L.
The oily phase of the emulsion may be any oily phase of emulsions typically used for topical administration. For example, such oil phases include: hydrocarbon bases such as hard paraffin, soft paraffin, ozokerite, and microcrystalline wax; absorbent bases such as lanolin and beeswax; emulsifying bases such as emulsifying wax and cetrimide; and vegetable oils such as olive oil, coconut oil, sesame oil, almond oil and peanut oil. Other oil phases useful according to the present invention are mineral oil, liquid petroleum, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol and 2-octyldodecanol.
It will be appreciated by those skilled in the art that by varying the ratio of water to oil in the emulsion, the result may be viewed as a lotion, cream or ointment in increasing order of oil proportion. Emulsions comprising similar proportions of oil and water phases are generally considered creams, while ointments generally comprise substantially higher proportions of oil phase compared to water phase, e.g., greater than 60 wt% of oil phase, preferably greater than 70 wt% of oil phase, more preferably greater than 80 wt% of oil phase, based on the total weight of oil and water phases. Lotions typically contain a lower proportion of an oil phase than creams, for example, less than 25 wt% of an oil phase, less than 20 wt% of an oil phase, less than 15 wt% of an oil phase, less than 10 wt% of an oil phase or less than 5 wt% of an oil phase, based on the total weight of the oil and water phases.
Generally, the creams used according to the present invention comprise an oil phase and an aqueous phase which are mixed together to form an emulsion. Preferably, the water is present in the cream of the present invention in an amount of from about 45 wt% to about 85 wt%, more preferably from about 45 wt% to about 65 wt%, even more preferably from about 45 wt% to about 55 wt%, based on the total weight of the cream.
Where the composition is an ointment, a pharmaceutically acceptable ointment base will be used. Examples of ointment bases include: hydrocarbon bases such as hard paraffin, soft paraffin, ozokerite, and microcrystalline wax; absorbent bases such as lanolin and beeswax; water-soluble bases such as polyethylene glycol (e.g.,
The pharmaceutical compositions used according to the invention may also be lotions comprising the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Specific carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2-octyldodecanol and water.
Parenteral administration to a patient can be by various routes, including but not limited to: subcutaneous injections, intravenous injections (including bolus injections), intramuscular injections, and intraarterial injections. Because their administration typically bypasses patients' natural defenses against contaminants, pharmaceutical compositions for parenteral administration are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of such pharmaceutical compositions include, but are not limited to: solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
Some suitable carriers that may be used to provide pharmaceutical compositions for parenteral administration include, but are not limited to: water for injection USP; aqueous carriers such as, but not limited to, sodium chloride injection, ringer's injection, dextrose and sodium chloride injection, and sodium lactate ringer's injection; water soluble carriers such as, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
Suitable dosages of the active ingredients may be determined by the skilled practitioner. The actual dosage level of the active ingredient can be varied to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. Thus, the dose is generally an effective or therapeutically effective dose.
The selected dosage level will depend on a variety of pharmacokinetic factors including: the activity of the particular composition of the invention employed, the route of administration, the time of administration, the rate of excretion of the particular compound employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular composition employed, the age, sex, body weight, condition, general health and past medical history of the patient being treated, and like factors well known in the medical arts.
The dosage regimen may be adjusted to provide the best desired response. For example, a single dose may be administered (e.g., a single dose per day), several divided doses may be administered over time, or the dose may be reduced or increased in proportion to the exigencies of the therapeutic situation. Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
In the compositions and products according to the invention, the active ingredients may each be present in a concentration of, for example, 0.001 to 20 wt%, preferably 0.01 to 10 wt%, more preferably 0.02 to 5 wt%, and more preferably 1 to 4 wt%, relative to the total weight of the composition or product. In a particular embodiment, each of the three active ingredients is present at a concentration of 1-3 wt%.
In a presently preferred aspect, artemisinin (e.g., artesunate) is formulated for administration at 50 to 500mg (more preferably 100 to 300mg, e.g., about 200mg) per day (based on about 70 kg body weight; the dose can be adjusted proportionally to body weight). Preferably, artemisinin (e.g., artesunate) is formulated for oral or parenteral administration. Preferably, artemisinin (e.g., artesunate) is administered for a period of 3 to 30 days, more preferably 10 to 20 days, such as about 14 days. The time period may correspond to one treatment cycle in a dosing regimen comprising a plurality of such treatment cycles (e.g., at least two, three, four, five, six, or more cycles, e.g., for such cycles until a desired therapeutic effect is achieved). Each treatment cycle may be separated by an interruption of artemisinin (e.g., artesunate) administration; for example, such interruptions may allow bone marrow to recover. Discontinuation of dosing may comprise not administering artemisinin (e.g. artesunate) for a period of 3 to 14 days, more preferably 5 to 10 days, such as about 7 days.
In an exemplary aspect, artemisinin (e.g., artesunate) is administered at about 200mg per day for a two-week treatment period, with one week of discontinuation after each period.
In a presently preferred aspect, the arsenic trioxide is formulated for administration at 1 to 30mg (more preferably 5 to 20mg, such as about 10mg) per day (based on about 70 kg of body weight; the dosage may be adjusted proportionally to the body weight). Preferably, the arsenic trioxide is formulated for parenteral or oral administration, most preferably for parenteral administration, e.g. for intravenous infusion. Preferably, the arsenic trioxide is administered for a period of 3 to 60 days, more preferably 20 to 40 days, such as about 30 days. The time period may correspond to one treatment cycle in a dosing regimen comprising a plurality of such treatment cycles (e.g., at least two, three, four, five, six, or more cycles, e.g., for such cycles until a desired therapeutic effect is achieved). Each treatment cycle may be separated by an interruption in the administration of arsenic trioxide; for example, such interruptions may allow bone marrow to recover. Discontinuing the administration may comprise not administering arsenic trioxide for a period of 3 to 14 days, more preferably 5 to 10 days, such as about 7 days.
In an exemplary aspect, arsenic trioxide is administered at about 10mg per day over a 30 day treatment period, with administration discontinued for one week after each period.
In a presently preferred aspect, the iron is formulated for administration at 50 to 500mg (more preferably 100 to 250mg, such as about 150mg) per day. Preferably, the iron is formulated for oral or parenteral administration. Preferably, the iron is administered for a period of 3 to 30 days, more preferably 10 to 20 days, such as about 14 days. The time period may correspond to one treatment cycle in a dosing regimen comprising a plurality of such treatment cycles (e.g., at least two, three, four, five, six, or more cycles, e.g., for such cycles until a desired therapeutic effect is achieved). Each treatment cycle may be separated by an interruption of iron administration; for example, such interruptions may allow bone marrow to recover. Discontinuing the administration may comprise not administering the iron for a period of 3 to 14 days, more preferably 5 to 10 days, such as about 7 days. In an exemplary aspect, iron is administered at about 200mg per day for a two-week treatment period, with administration interrupted for one week after each period.
As discussed elsewhere herein, in one embodiment of the invention, the iron is provided in the form of an iron-rich complex, such as hemin. In a presently preferred aspect, hemin is formulated for intravenous infusion at a dose of 1-4 mg/kg/day for more than 10-15 minutes, according to a schedule, for 3-14 days. Preferably, hemin is administered for a period of 3-25 days, more preferably 10-20 days, e.g. about 14 days. The time period may correspond to one treatment cycle in a dosing regimen comprising a plurality of such treatment cycles (e.g., at least two, three, four, five, six, or more cycles, e.g., for such cycles until a desired therapeutic effect is achieved). Each treatment cycle may be separated by an interruption in hemin administration; for example, such interruptions may allow bone marrow to recover. Discontinuation of administration may include not administering hemin for a period of 3 to 14 days, more preferably 5 to 10 days, such as about 7 days.
Additional active agent
Optionally, one or more additional active ingredients may be administered in addition to arsenic trioxide, iron and artemisinin. Thus, one or more additional active agents may be present in the products, pharmaceutical compositions and kits described herein. Examples of such additional active agents include: cytarabine (cytosine arabinoside or Ara-C); anthracyclines, such as doxorubicin, daunorubicin, daunomycin, idarubicin, and mitoxantrone; other chemotherapeutic agents, e.g. hydroxyurea
For example, a pharmaceutical composition as defined herein may additionally comprise one or more additional active agents. Further, (a) use of arsenic trioxide in the treatment of leukemia by co-administration; (b) use of iron in the treatment of leukemia by co-administration; and (c) artemisinin for use in the treatment of leukemia by co-administration each may additionally comprise co-administration with one or more additional active agents. In addition, a method of treating a patient having leukemia may comprise administering to the patient one or more additional active agents in combination. Further, comprising (a) arsenic trioxide; (b) iron; and (c) artemisinin, as a combined preparation for simultaneous, concurrent, separate or sequential use in the treatment of a patient with leukemia may further comprise one or more additional active agents. Still further, the use according to the invention may comprise the manufacture of a medicament for the treatment of leukemia by the co-administration of one or more additional active agents. Still further, the kit may comprise one or more additional active agents.
Treatment of leukemia
Typically the patient to be treated is a mammal. Preferably, the patient is a human.
In general, there is no limitation on the form of leukemia type that is amenable to treatment according to the present invention. For example, the leukemia may be Acute Myeloid Leukemia (AML). The leukemia may be Acute Lymphatic Leukemia (ALL). The leukemia may be Chronic Myelogenous Leukemia (CML). The leukemia may be Chronic Lymphocytic Leukemia (CLL). The leukemia may be hairy cell leukemia.
In a preferred embodiment, the leukemia is selected from AML and ALL. In another preferred embodiment, the leukemia is selected from AML and CML. Particularly preferably, the leukemia is AML.
Treatment of acute myeloid leukemia
The present invention extends to the treatment of all subtypes of AML. For example, the WHO classification of AML includes the following subtypes:
companion t (8; 21) (q 22; q 22); acute myeloid leukemia of (AML1/ETO)
Bone marrow eosinophils with abnormalities and inv (16) (p13q22) or t (16; 16) (p 13; q 22); (CBF beta/MYH 11) acute myelogenous leukemia
Companion t (15; 17) (q 22; q 12); (PML/RAR α) and variant acute promyelocytic leukemia (i.e., APL)
Acute myelogenous leukemia with 11q23(MLL) abnormality
Acute myelogenous leukemia with multisystem dysplasia
Concomitant MDS or MDS/MPD
At least 50% of the cells in 2 or more myeloid systems have no previous MDS or MDS/MPD dysplasia
Treatment of associated acute myelogenous leukemia and myelodysplastic syndrome
Alkylating agent/radiation-related type
Related classes of topoisomerase II inhibitors (some may be lymphatic)
Acute myeloid leukemia not otherwise classified
Differential acute myelogenous leukemia
Immature acute myelogenous leukemia
Acute myelogenous leukemia of maturity type
Acute myelomonocytic leukemia
Acute monocytic/acute monocytic leukemia
Acute erythroleukemia (erythroid/myelogenous and pure erythroleukemia)
Acute megakaryocytic leukemia
Acute basophilic leukemia
Acute myeloproliferative disorder with myelofibrosis
Myeloid sarcoma.
In one embodiment, the AML is in the form of AML other than APL (AML-M3), i.e. the AML is not APL. In another embodiment, the AML is APL.
AML can be refractory AML. For example, the refractory AML can include a failure to achieve complete remission or incomplete complete remission with incomplete blood recovery after prior treatment. The refractory AML can be an ATO refractory APL (also referred to herein as ATO-resistant APL), for example, failing to achieve complete remission or incomplete complete remission with incomplete blood recovery after prior treatment with ATO. For example, such prior treatments with ATO may involve: (i) treatment with ATO as a single active agent; and/or (ii) a double combination of ATO and ART; and/or (iii) any combination of ATOs other than the triple combination of ART, ATO, and iron. ATO resistance can be innate or acquired (i.e., due to early treatment with ATO). If refractory AML is not APL, it will be inherently resistant to ATO.
The term "complete remission" may be a morphologically leukemic state (i.e., bone marrow with less than 5% blast cells according to morphological criteria, and no rod bodies, no evidence of extramedullary leukemia), and an absolute neutrophil count of 1,000/μ L, with platelets >100,000/μ L. The term "complete remission of incomplete blood recovery" may be morphologically leukemic (i.e., bone marrow has less than 5% blast cells according to morphological criteria, and no rod bodies, no evidence of extramedullary leukemia), and a neutrophil count in the blood of <1,000/μ L, or platelets of <100,000/μ L.
The AML can be relapsed AML. After complete remission, relapsed AML can be associated with a recurrence of leukemic blast cells in the blood or more than 5% of blast cells in the bone marrow, not due to any other cause.
The patient to be treated may be one for which established AML therapy is not feasible (e.g., myelosuppressive therapy with e.g., daunorubicin and/or cytarabine). For example, in one embodiment, the patient to be treated is a patient with an age of 65 years or older, preferably 72 years or older, such as 80 years or older, most preferably 85 years or older. Alternatively or additionally, the patient to be treated may suffer from a comorbid disease that interferes with myelosuppressive therapy such as with daunorubicin and/or cytarabine. Such patients may additionally have refractory AML (e.g., chemotherapy-resistant AML or ATO-resistant AML) and/or relapsed AML.
The invention is explained in more detail below by reference to examples, which are not to be construed as limiting.
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