MOLECULAR ENGINEERING OF A NOVEL TERNARY COMPLEX OF ACTINOMYCIN D FOR CANCER STEM CELLS TREATMENT

Abstract

Preparation and characterization of novel DACT forms suitable for pharmaceutical compositions in drug delivery systems for humans.

Claims

1.-31. (canceled)

32. A crystalline form selected from the group consisting of: actinomycin D:diphenic acid:losartan, actinomycin D:diphenic acid:telmisartan, actinomycin D:methylparaben:losartan, actinomycin D:methylparaben:telmisartan, actinomycin D:propylparaben:losartan, actinomycin D:propylparaben:telmisartan, and actinomycin D:tamibarotene 1:10 molar ratio.

33. The crystalline form of claim 32, wherein said crystalline form is actinomycin D:diphenic acid:losartan.

34. The crystalline form of claim 33, wherein said crystalline form is characterized by a powder X-ray diffraction pattern comprising one or more powder X-ray diffraction peaks selected from the group consisting of about: 4.8, 6.5, and 10.2 240.2 2.

35. The crystalline form of claim 32, wherein said crystalline form is actinomycin D:diphenic acid:telmisartan.

36. The crystalline form of claim 35, wherein said crystalline form is characterized by a powder X-ray diffraction pattern comprising one or more powder X-ray diffraction peaks selected from the group consisting of about: 4.5, 6.5, 8.5, and 10.2 20.2 2.

37. The crystalline form of claim 32, wherein said crystalline form is actinomycin D:methylparaben:losartan.

38. The crystalline form of claim 37, wherein said crystalline form is characterized by a powder X-ray diffraction pattern comprising one or more powder X-ray diffraction peaks selected from the group consisting of about: 5.8, 7.8, and 10.2 20.2 2.

39. The crystalline form of claim 32, wherein said crystalline form is actinomycin D:methylparaben:telmisartan.

40. The crystalline form of claim 39, wherein said crystalline form is characterized by a powder X-ray diffraction pattern comprising one or more powder X-ray diffraction peaks selected from the group consisting of about: 5.8, 7.8, 11.8, and 12.2 20.2 2.

41. The crystalline form of claim 32, wherein said crystalline form is actinomycin D:propylparaben:telmisartan.

42. The crystalline form of claim 41, wherein said crystalline form is characterized by a powder X-ray diffraction pattern comprising one or more powder X-ray diffraction peaks selected from the group consisting of about: 7.8, 9.8, 11.8, and 12.5 20.2 2.

43. The crystalline form of claim 32, wherein said crystalline form is actinomycin D:tamibarotene 1:10 molar ratio.

44. The crystalline form of claim 43, wherein said crystalline form is characterized by a powder X-ray diffraction pattern comprising one or more powder X-ray diffraction peaks selected from the group consisting of about: 10.8, 12.2, 16.2, 18.0, and 24.2 20.2 2.

45. A pharmaceutical composition comprising the crystalline form of claim 32 and at least one pharmaceutically acceptable excipient.

46. The pharmaceutical composition of claim 45, wherein the pharmaceutical composition is an oral dosage form, a topical dosage form, a buccal, an intranasal, an inhalable dosage form or an injectable dosage form.

47. A method of treating or preventing a disease for which actinomycin D is indicated, said method comprising the step of administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of claim 45.

48. The method of claim 47, wherein said disease is selected from: Wilms' tumor, rhabdomyosarcoma, lung, breast, colon, rectal head and neck, brain, pancreatic, ovarian cancer, gestational trophoblastic neoplasm, Ewing's sarcoma, metastatic testicular tumors, gestational trophoblastic neoplasm, locally recurrent or locoregional solid tumors (sarcomas, carcinomas, and adenocarcinomas), acute myeloid leukemia (AML), multiple myeloma, Shwachman-Diamond syndrome, prostate cancer, skin cancer, actinic keratosis, Bowen's disease, adjuvant cancer therapy, or neoadjuvant cancer therapy.

49. The method of claim 48, wherein said skin cancer is selected from the group consisting of: basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma.

50. The method of claim 47, wherein said disease is prostate cancer and is selected from the group consisting of: acinar adenocarcinoma, ductal adenocarcinoma, transitional cell (or urothelial) cancer, squamous cell cancer, small cell prostate cancer, carcinoid, sarcoma, and Shwachman-Diamond syndrome.

51. The method of claim 47, wherein said pharmaceutical composition is administered topically or via intratumoral injection.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG. 1. PXRD diffractograms of actinomycin D:diphenic acid:losartan novel form.

[0016] FIG. 2. FTIR spectrum of actinomycin D:diphenic acid:losartan novel form.

[0017] FIG. 3. PXRD diffractograms of actinomycin D:diphenic acid:telmisartan novel form.

[0018] FIG. 4. FTIR spectrum of actinomycin D:diphenic acid:telmisartan novel form.

[0019] FIG. 5. PXRD diffractograms of actinomycin D:methylparaben:losartan novel form.

[0020] FIG. 6. FTIR spectrum of actinomycin D:methylparaben:losartan novel form.

[0021] FIG. 7. PXRD diffractograms of actinomycin D:methylparaben:telmisartan novel form.

[0022] FIG. 8. FTIR spectrum of actinomycin D:methylparaben:telmisartan novel form.

[0023] FIG. 9. PXRD diffractograms of actinomycin D:propylparaben:losartan novel form.

[0024] FIG. 10. FTIR spectrum of actinomycin D:propylparaben:losartan novel form.

[0025] FIG. 11. PXRD diffractograms of actinomycin D:propylparaben:telmisartan novel form.

[0026] FIG. 12. FTIR spectrum of actinomycin D:propylparaben:telmisartan novel form.

[0027] FIG. 13. PXRD diffractograms of actinomycin D:tamibarotene 1:10 molar ratio novel form.

[0028] FIG. 14 FTIR spectrum of actinomycin D:tamibarotene 1:10 molar ratio novel form.

DETAILED DESCRIPTION OF THE INVENTION

[0029] In general, active pharmaceutical ingredients (APIs) in pharmaceutical compositions can be prepared in a variety of different forms. Such compounds can be prepared to have a variety of different chemical forms including chemical derivatives, solvates, hydrates, cocrystals, and/or salts. Such compounds can also be prepared to have different physical forms. For example, they may be amorphous, may have different crystalline polymorphs, or may exist in different solvated or hydrated states. The discovery of new forms of a pharmaceutically useful compound may provide an opportunity to improve the performance characteristics of a pharmaceutical product. Additionally, it expands the array of resources available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristics.

[0030] A specific characteristic that can be targeted includes the crystal form of an API. By altering the crystal form, it therefore becomes possible to vary the physical properties of the target molecule. For example, crystalline polymorphs typically have different aqueous solubility from one another, such that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph. In addition to water solubility, pharmaceutical polymorphs can also differ in properties such as rate of dissolution, shelf-life, bioavailability, morphology, vapor pressure, density, color, and compressibility. Accordingly, it is desirable to enhance the properties of an active pharmaceutical compound by forming molecular complexes such as a cocrystal, a salt, a solvate, or hydrate with respect to aqueous solubility, rate of dissolution, bioavailability, Cmax, Tmax, physicochemical stability, down-stream processibility (e.g., flowability compressibility, degree of brittleness, particle size manipulation), crystallization of amorphous compounds, decrease in polymorphic form diversity, toxicity, taste, production costs, and manufacturing methods.

[0031] During the development of drugs, it is frequently advantageous to have novel crystalline forms of such drug materials that possess improved properties, including increased aqueous solubility and stability. It is also desirable, in general, to increase the dissolution rate of such solid forms and potentially increase their bioavailability if used in an oral delivery setting. This also applies to the development of novel forms of DACT which, when administered orally to a subject could achieve a greater or similar bioavailability and PK profile when compared to an IV or other formulations on a dose-for-dose basis.

[0032] Cocrystals, salts, solvates, and hydrates of actinomycin D of the present invention could give rise to improved properties. For example, a new actinomycin D form for use in oral dosage forms or injectables, including direct injection and infusion, are particularly advantageous. A number of novel actinomycin D forms have been synthesized, characterized, and disclosed herein.

[0033] The present invention further includes compositions of molecular complexes of actinomycin D suitable for incorporation in a pharmaceutical dosage form. Specific molecular complexes pertaining to the disclosure include, but are not limited to, complexes of actinomycin D, diphenic acid and losartan, actinomycin D, diphenic acid and telmisartan, actinomycin D, methylparaben and losartan, actinomycin D, methylparaben and telmisartan, actinomycin D, propylparaben and losartan, actinomycin D, propylparaben, telmisartan, and actinomycin D:tamibarotene 1:10 molar ratio. Obvious variants of the disclosed actinomycin D forms in the disclosure, including those described by the drawings and examples, will be readily apparent to the person of ordinary skill in the art having the present disclosure and such variants are considered to be a part of the current invention.

[0034] In one aspect, the invention provides for a crystalline form of actinomycin D, diphenic acid and losartan. In one embodiment the actinomycin D:diphenic acid:losartan crystalline form is a solvate/hydrate.

[0035] In one embodiment, the actinomycin D:diphenic acid:losartan crystalline form is characterized by a powder X-ray diffraction peaks selected from about 4.8, 6.5, and 10.2 20.2 2. In one embodiment actinomycin D:diphenic acid:losartan crystalline form is characterized by a powder X-ray diffraction peaks comprising a powder X-ray diffraction peak at about 4.8 20.2 2. In another embodiment actinomycin D:diphenic acid:losartan crystalline form is characterized by a powder X-ray diffraction peaks comprising a powder X-ray diffraction peak at about 6.5 20.2 2. In another embodiment actinomycin D:diphenic acid:losartan crystalline form is characterized by a powder X-ray diffraction peaks disappearing a powder X-ray diffraction peak at about 10.2 20.2 2. In another embodiment actinomycin D:diphenic acid:losartan crystalline form is characterized by a powder X-ray diffraction peaks comprising any two powder X-ray diffraction peaks selected from about 4.8, 6.5, and 10.2 20.2 2. In another embodiment actinomycin D:diphenic acid:losartan crystalline form is characterized by a powder X-ray diffraction peaks comprising powder X-ray diffraction peaks selected from about 4.8, 6.5, and 10.2 20.2 2.

[0036] In another aspect, the invention provides for a crystalline form of actinomycin, diphenic acid, and telmisartan. In one embodiment, the actinomycin D:diphenic acid:telmisartan crystalline form is a cocrystal. In another embodiment, the actinomycin D:diphenic acid:telmisartan crystalline form is a solvate/hydrate. In one embodiment, the crystalline form of actinomycin D:diphenic acid:telmisartan is a 1:1:1 complex.

[0037] In another embodiment, the actinomycin D:diphenic acid:telmisartan crystalline form is characterized by a powder X-ray diffraction peaks selected from about 4.5, 6.5, 8.5, and 10.2 20.2 2. In one embodiment, actinomycin D:diphenic acid:telmisartan crystalline form is characterized by a powder X-ray diffraction peaks comprising a powder X-ray diffraction peak at about 4.5 20.2 2. In another embodiment, actinomycin D:diphenic acid:telmisartan crystalline form is characterized by a powder X-ray diffraction peaks comprising a powder X-ray diffraction peak at about 6.5 20.2 2. In another embodiment, actinomycin D:diphenic acid:telmisartan crystalline form is characterized by a powder X-ray diffraction peaks comprising a powder X-ray diffraction peak at about 8.5 20.2 2. In another embodiment, actinomycin D:diphenic acid:telmisartan crystalline form is characterized by a powder X-ray diffraction peaks disappearing a powder X-ray diffraction peak at about 10.220.2 2. In another embodiment, actinomycin D:diphenic acid:telmisartan crystalline form is characterized by a powder X-ray diffraction peaks comprising any three powder X-ray diffraction peaks selected from about 4.5, 6.5, 8.5, and 10.2 20.2 2. In another embodiment, actinomycin D:diphenic acid:telmisartan crystalline form is characterized by a powder X-ray diffraction peaks comprising any two powder X-ray diffraction peaks selected from about 4.5, 6.5, 8.5, and 10.2 20.2 2.

[0038] In another embodiment, the actinomycin D:methylparaben:losartan crystalline form is characterized by a powder X-ray diffraction peaks selected from about 5.8, 7.8, and 10.2 20.2 2. In one embodiment, actinomycin D:methylparaben:losartan crystalline form is characterized by a powder X-ray diffraction peaks comprising a powder X-ray diffraction peak at about 5.8 20.2 2. In another embodiment, actinomycin D:methylparaben:losartan crystalline form is characterized by a powder X-ray diffraction peaks comprising a powder X-ray diffraction peak at about 7.8 20.2 2. In another embodiment, actinomycin D:methylparaben:losartan crystalline form is characterized by a powder X-ray diffraction peaks comprising a powder X-ray diffraction peak at about 10.2 20.2 2.

[0039] In another aspect, the invention provides for a crystalline form of actinomycin, methylparaben, and telmisartan. In one embodiment, the actinomycin D:methylparaben:telmisartan crystalline form is a cocrystal. In one embodiment, the actinomycin D:methylparaben:telmisartan crystalline form is a solvate/hydrate. In one embodiment, the crystalline form of actinomycin D:methylparaben:telmisartan is a 1:1:1 complex.

[0040] In another embodiment, the actinomycin D:methylparaben:telmisartan crystalline form is characterized by a powder X-ray diffraction peaks selected from about 5.8, 7.8, 11.8, and 12.2 20.2 2. In one embodiment, actinomycin D:methylparaben:telmisartan crystalline form is characterized by a powder X-ray diffraction peaks comprising a powder X-ray diffraction peak at about 5.8 20.2 2. In another embodiment, actinomycin D:methylparaben:telmisartan crystalline form is characterized by a powder X-ray diffraction peaks comprising a powder X-ray diffraction peak at about 7.8 20.2 2. In another embodiment, actinomycin D:methylparaben:telmisartan crystalline form is characterized by a powder X-ray diffraction peaks comprising a powder X-ray diffraction peak at about 11.8 20.2 2. In another embodiment, actinomycin D:methylparaben:telmisartan crystalline form is characterized by a powder X-ray diffraction peaks comprising a powder X-ray diffraction peak at about 12.3 20.2 2. In another embodiment, actinomycin D:methylparaben:telmisartan crystalline form is characterized by a powder X-ray diffraction peaks comprising any three powder X-ray diffraction peaks selected from about 5.8, 7.8, 11.8, and 12.2 20.2 2. In another embodiment, actinomycin D:methylparaben:telmisartan crystalline form is characterized by a powder X-ray diffraction peaks comprising any two powder X-ray diffraction peaks selected from about 5.8, 7.8, 11.8, and 12.2 20.2 2. In another embodiment, actinomycin D:methylparaben:telmisartan crystalline form is characterized by a powder X-ray diffraction peaks comprising powder X-ray diffraction peaks selected from about 5.8, 7.8, 11.8, and 12.2 20.2 2.

[0041] In another aspect, the invention provides for a crystalline form of actinomycin D, propylparaben, and losartan. In one embodiment, the actinomycin D:propylparaben:losartan crystalline form is a cocrystal. In one embodiment, the actinomycin D:propylparaben:losartan crystalline form is a cocrystal. In one embodiment, the actinomycin D:propylparaben:losartan crystalline form is a solvate/hydrate. In one embodiment, the crystalline form of actinomycin D:propylparaben:losartan is a 1:1:1 complex.

[0042] In another embodiment, the actinomycin D:propylparaben:losartan crystalline form is characterized by a powder X-ray diffraction peaks selected from about 5.8, 8.0, 9.5, and 15.2 20.2 2. In one embodiment, actinomycin D:propylparaben:losartan crystalline form is characterized by a powder X-ray diffraction peaks comprising a powder X-ray diffraction peak at about 5.8 20.2 2. In another embodiment, actinomycin D:propylparaben:losartan crystalline form is characterized by a powder X-ray diffraction peaks comprising a powder X-ray diffraction peak at about 8.0 20.2 2. In another embodiment, actinomycin D:propylparaben:losartan crystalline form is characterized by a powder X-ray diffraction peaks comprising a powder X-ray diffraction peak at about 9.5 20.2 2. In another embodiment, actinomycin D:propylparaben:losartan crystalline form is characterized by a powder X-ray diffraction peaks comprising a powder X-ray diffraction peak at about 15.2 20.2 2. In another embodiment, actinomycin D:propylparaben:losartan crystalline form is characterized by a powder X-ray diffraction peaks comprising any three powder X-ray diffraction peaks selected from about 5.8, 8.0, 9.0, and 15.2 20.2 2. In another embodiment, actinomycin D:propylparaben:losartan crystalline form is characterized by a powder X-ray diffraction peaks comprising any two powder X-ray diffraction peaks selected from about 5.8, 8.0, 9.0, and 15.2 20.2 2.

[0043] In another aspect, the invention provides for a crystalline form of actinomycin D, propylparaben, and telmisartan. In one embodiment, the actinomycin D:propylparaben:telmisartan crystalline form is a cocrystal. In one embodiment, the actinomycin D:propylparaben:telmisartan crystalline form is a cocrystal. In one embodiment, the actinomycin D:propylparaben:telmisartan crystalline form is a solvate/hydrate. In one embodiment, the crystalline form of actinomycin D:propylparaben:telmisartan is a 1:1:1 complex.

[0044] In another embodiment, the actinomycin D:propylparaben:telmisartan crystalline form is characterized by a powder X-ray diffraction peaks selected from about 7.8, 9.8, 11.8, and 12.5 20.2 2. In one embodiment actinomycin D:propylparaben:telmisartan crystalline form is characterized by a powder X-ray diffraction peaks comprising a powder X-ray diffraction peak at about 7.8 20.2 2. In another embodiment, actinomycin D:propylparaben:telmisartan crystalline form is characterized by a powder X-ray diffraction peaks comprising a powder X-ray diffraction peak at about 9.8 20.2 2. In another embodiment, actinomycin D:propylparaben:telmisartan crystalline form is characterized by a powder X-ray diffraction peaks comprising a powder X-ray diffraction peak at about 11.8 20.2 2. In another embodiment, actinomycin D:propylparaben:telmisartan crystalline form is characterized by a powder X-ray diffraction peaks comprising a powder X-ray diffraction peak at about 12.5 20.2 2. In another embodiment, actinomycin D:propylparaben:telmisartan crystalline form is characterized by a powder X-ray diffraction peaks comprising any three powder X-ray diffraction peaks selected from about 7.8, 9.8, 11.8, and 12.5 20.2 2. In another embodiment, actinomycin D:propylparaben:telmisartan crystalline form is characterized by a powder X-ray diffraction peaks comprising any two powder X-ray diffraction peaks selected from about 7.8, 9.8, 11.8, and 12.5 20.2 2.

[0045] In one embodiment, the crystalline form is actinomycin D:tamibarotene crystalline form. In one embodiment, the crystalline form of actinomycin D:tamibarotene is a 1:10 complex. In another embodiment, the actinomycin D:tamibarotene crystalline form is a co-crystal. In one embodiment, the actinomycin D:tamibarotene crystalline form is characterized by a powder X-ray diffraction peaks selected from about 10.8, 12.2, 16.2, 18.0, and 24.2 20.2 2. In one embodiment, actinomycin D:tamibarotene crystalline form is characterized by a powder X-ray diffraction peaks comprising a powder X-ray diffraction peak at about 10.8 20.2 2. In another embodiment, actinomycin D:tamibarotene crystalline form is characterized by a powder X-ray diffraction peaks comprising a powder X-ray diffraction peak at about 12.2 20.2 2. In another embodiment, actinomycin D:tamibarotene crystalline form is characterized by a powder X-ray diffraction peaks comprising a powder X-ray diffraction peak at about 16.2 20.2 2. In another embodiment, actinomycin D:tamibarotene crystalline form is characterized by a powder X-ray diffraction peaks comprising a powder X-ray diffraction peak at about 18.0 20.2 2. In another embodiment, actinomycin D:tamibarotene crystalline form is characterized by a powder X-ray diffraction peaks comprising a powder X-ray diffraction peak at about 24.2 20.2 2. In another embodiment, actinomycin D:tamibarotene crystalline form is characterized by a powder X-ray diffraction peaks comprising any four powder X-ray diffraction peaks selected from about 10.8, 12.2, 16.2, 18.0, and 24.2 20.2 2. In another embodiment, actinomycin D:tamibarotene crystalline form is characterized by a powder X-ray diffraction peaks comprising any three powder X-ray diffraction peaks selected from about 10.8, 12.2, 16.2, 18.0, and 24.2 20.2 2. In another embodiment, actinomycin D:tamibarotene crystalline form is characterized by a powder X-ray diffraction peaks comprising any two powder X-ray diffraction peaks selected from about 10.8, 12.2, 16.2, 18.0, and 24.2 20.2 2. In another embodiment, actinomycin D:tamibarotene crystalline form is characterized by a powder X-ray diffraction peaks comprising a powder X-ray diffraction peaks selected from about 10.8, 12.2, 16.2, 18.0, and 24.2 20.2 2.

[0046] The present invention includes complexes of actinomycin D, methylparaben, propylparaben, losartan, diphenic acid, telmisartan, and tamibarotene 1:10 molar ratio, which are capable of complexing in the solid-state, for example, through dry or solvent-drop grinding, heating or solvent evaporation of their solution in single or mixed solvent systems, slurry suspension, antisolvent, supercritical fluids, or other techniques known to a person skilled in the art. Solvents and antisolvents used to make the crystalline forms include acetone, ethanol, methanol, ethylacetate (EtOAc), isopropanol (IPA), isopropylacetate (IPAc), diethoxymethane (DEM), Toluene, BuOAc, N-methylpyrrolidone (NMP), and a heptane.

[0047] In one embodiment, the invention includes crystalline forms of actinomycin D, methylparaben, propylparaben, losartan, diphenic acid, telmisartan, and tamibarotene 1:10 molar ratio, which are capable of complexing through solvent evaporation of their solution in single or mixed solvent systems, and slurry suspension.

[0048] In another aspect, the invention provides for a pharmaceutical composition comprising molecular complexes of actinomycin D, methylparaben, propylparaben, losartan, diphenic acid, telmisartan, and tamibarotene 1:10 molar ratio. In one embodiment, the actinomycin D:diphenic acid:losartan molecular complex is a cocrystal. In another embodiment, the actinomycin D:diphenic acid:losartan molecular complex is a solvate/hydrate. In one embodiment, the actinomycin D:diphenic acid:telmisartan molecular complex is a cocrystal. In another embodiment, the actinomycin D:diphenic acid:telmisartan molecular complex is a solvate/hydrate. In one embodiment, the actinomycin D:methylparaben:losartan molecular complex is a cocrystal. In another embodiment, the actinomycin D:methylparaben:losartan molecular complex is a solvate/hydrate. In one embodiment, the actinomycin D:methylparaben:telmisartan molecular complex is a cocrystal. In another embodiment, the actinomycin D:methylparaben:telmisartan molecular complex is a solvate/hydrate. In one embodiment, the actinomycin D:propylparaben:losartan molecular complex is a cocrystal. In another embodiment, the actinomycin D:propylparaben:losartan molecular complex is a solvate/hydrate. In one embodiment, the actinomycin D:propylparaben:telmisartan molecular complex is a cocrystal. In another embodiment, the actinomycin D:propylparaben:telmisartan molecular complex is a solvate/hydrate.

[0049] In one embodiment, the actinomycin D:tamibarotene 1:10 molar ratio, molecular complex is a cocrystal. In one embodiment, the actinomycin D:tamibarotene 1:10 molar ratio, molecular complex is a solvate/hydrate.

[0050] In some embodiments, a pharmaceutical composition of the present invention is delivered to a subject via intratumoral injection. Intratumoral injection is a route of administration by which a pharmaceutical composition, is delivered directly to the tumor via an injection device (e.g., needle and syringe). In some embodiments, a pharmaceutical composition of the present invention is delivered to a subject via a parenteral route, an enteral route, or a topical route.

[0051] Examples of parental routes include, without limitation, intra-abdominal, intra-amniotic, intra-arterial, intra-articular, intrabiliary, intrabronchial, intrabursal, intracardiac, intracartilaginous, intracaudal, intracavernous, intracavitary, intracerebral, intracisternal, intracorneal, intracoronal, intracoronary, intracorporus, intracranial, intradermal, intradiscal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralesional, intraluminal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraocular, intraovarian, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intraocular, intrasinal, intraspinal, intrasynovial, intratendinous, intratesticular, intrathecal, intrathoracic, intratubular, intratympanic, intrauterine, intravascular, intravenous (bolus or drip), intraventricular, intravesical, and subcutaneous.

[0052] Enteral routes of administration include administration to the gastrointestinal tract via the mouth (oral), stomach (gastric), and rectum (rectal). Gastric administration typically involves the use of a tube through the nasal passage (NG tube) or a tube in the esophagus leading directly to the stomach (PEG tube). Rectal administration typically involves rectal suppositories.

[0053] Topical, including transdermal, routes of administration include administration to a body surface, such as skin or mucous membranes. Delivery vehicles of the present disclosure may be administered topically (or transdermally) via a cream, foam, gel, lotion, or ointment, for example.

[0054] The pharmaceutical composition comprises a therapeutically effective amount of at least one of the novel molecular complexes of actinomycin D according to the invention and at least one pharmaceutically acceptable excipient. The term excipient refers to a pharmaceutically acceptable, inactive substance used as a carrier for the pharmaceutically active ingredient(s) and includes antiadherents, binders, coatings, disintegrants, fillers, diluents, flavors, bulkants, colours, glidants, dispersing agents, wetting agents, lubricants, preservatives, sorbents, and sweeteners. The choice of excipient(s) will depend on factors such as the particular mode of administration and the nature of the dosage form. Solutions or suspensions used for intravenous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic.

[0055] A pharmaceutical formulation of the present invention may be in any pharmaceutical dosage form. The pharmaceutical formulation may be, for example, a tablet, capsule, nanoparticulate material, e.g., granulated particulate material or a powder, a lyophilized material for reconstitution, liquid suspension, injectable suspension or solution, suppository, or topical or transdermal preparation or patch. The pharmaceutical formulations generally contain about 1% to about 99% by weight of at least one novel molecular complex of DACT of the invention and 99% to 1% by weight of a suitable pharmaceutical excipient. In one embodiment, the dosage form is an oral dosage form. In another embodiment, the dosage form is a parenteral dosage form. In one embodiment, the pharmaceutical dosage form is a unit dose. The term unit dose refers to the amount of API administered to a patient in a single dose.

[0056] The novel molecular complexes of DACT are therapeutically useful for the treatment and/or prevention of a disease for which it is indicated, e.g., cancer. Accordingly, in another aspect, the invention also relates to methods of treatment using novel molecular complexes of DACT and, or a pharmaceutical formulation containing them. As used herein, the terms treat, treating, or treatment means to alleviate, reduce or abrogate one or more symptoms or characteristics of a disease and may be curative, palliative, prophylactic or slow the progression of the disease. The term therapeutically effective amount is intended to mean that amount of drug that will elicit a desired biological or pharmacological response, i.e., an amount sufficient to treat said disease. The term patient includes mammals, especially humans. In one embodiment, the patient is a human. In another embodiment, the patient is a human male. In another embodiment, the patient is a human female.

[0057] In one embodiment, the invention provides for a method of treating pre-cancer or cancer comprising the step of administering to a cancer patient a therapeutically effective amount of a pharmaceutical composition of the present invention. The present invention further provides for a medicament comprising a pharmaceutical composition of the present invention for use in treating pre-cancer or cancer.

[0058] The dosage may vary depending upon the dosage form employed, sensitivity of the patient, and the route of administration. Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors, which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

[0059] In some embodiments, the cancer is selected from: Wilms' tumor, rhabdomyosarcoma, lung, breast, colon, rectal head and neck, brain, pancreatic, ovarian cancer (e.g., germ cell), gestational trophoblastic neoplasm, Ewing's sarcoma, metastatic testicular tumors (e.g., nonseminoatous), gestational trophoblastic neoplasm, locally recurrent or locoregional solid tumors (sarcomas, carcinomas, and adenocarcinomas), acute myeloid leukemia (AML), multiple myeloma, prostate cancer, skin cancer, actinic keratosis, Bowen's disease, adjuvant cancer therapy, or neoadjuvant cancer therapy. In a preferred embodiment, the cancer is skin cancer, actinic keratosis, or Bowen's disease. In a further embodiment, the skin cancer is selected from the group consisting of: basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma. In another embodiment, the cancer is prostate cancer. In a further embodiment, the prostate cancer is selected from the group consisting of: acinar adenocarcinoma, ductal adenocarcinoma, transitional cell (or urothelial) cancer, squamous cell cancer, small cell prostate cancer, carcinoid, and sarcoma.

EXAMPLES

[0060] The techniques and approaches set forth in the present disclosure can further be used by the person of ordinary skill in the art to prepare variants thereof, said variants are considered to be part of the inventive disclosure.

[0061] Materials used to create the novel forms of the present inventions are commercially available and means to synthesize them as well known. DACT as a starting material used in all experiments in this disclosure was supplied by AdipoGen Life Sciences, CA, USA, with >98% purity by HPLC. All other pure chemicals (Analytical Grade) were supplied by Sigma-Aldrich and used without further purification.

[0062] Analytical techniques used to observe the crystalline forms include powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FTIR). The particular methodology used in such analytical techniques herein should be viewed as illustrative, and not limiting in the context of data collection.

[0063] Powder X-Ray Diffraction (PXRD): All DACT novel molecular complex products were observed by a D-8 Bruker X-ray Powder Diffractometer using Cu K (=1.540562 ), 40 kV, 40 mA. The data were collected over an angular range of 3 to 40 2 in continuous scan mode at room temperature using a step size of 0.05 2 and a scan speed of 6.17/min.

[0064] FTIR analysis was performed on a Perkin Elmer Spectrum 100 FTIR spectrometer equipped with a solid-state ATR accessory.

[0065] The following examples illustrate the invention without intending to limit its scope.

Example 1

Preparation of Actinomycin D:Diphenic Acid:Losartan Molecular Complex

[0066] 30 mg of actinomycin D, 5.8 mg of diphenic acid, and 10.1 mg of losartan (1:1:1 molar ratio) were stirred as an open slurry in 1mL of methanol in a glass vial. After 16-24 hours of stirring mixture was further dried at room temperature until a completely dried mixture is obtained. The resulted material was stored in a screw cap vial and characterized by PXRD. The materials were characterized by PXRD and FTIR corresponding to FIGS. 1 and 2, respectively.

Example 2

Preparation of Actinomycin D:Diphenic Acid:Telmisartan Molecular Complex

[0067] 30 mg of actinomycin D, 5.8 mg of diphenic acid, and 12.3 mg of telmisartan (1:1:1 molar ratio) were stirred as an open slurry in 1 mL of methanol in a glass vial. After 16-24 hours of stirring mixture was further dried at room temperature until a completely dried mixture is obtained. The resulted material was stored in a screw cap vial and characterized by PXRD. All materials were characterized by PXRD and FTIR corresponding to FIGS. 3 and 4, respectively.

Example 3

Preparation of Actinomycin D:Methylparaben:Losartan Molecular Complex

[0068] 30 mg of actinomycin D, 3.6 mg of methylparaben, and 10.1 mg of losartan (1:1:1 molar ratio) were stirred as an open slurry in 1 mL of methanol in a glass vial. After 16-24 hours of stirring mixture was further dried at room temperature until a completely dried mixture is obtained. The resulted material was stored in a screw cap vial and characterized by PXRD. The material was characterized by PXRD and FTIR corresponding to FIGS. 5 and 6, respectively.

Example 4

Preparation of Actinomycin D:Methylparaben:Telmisartan Molecular Complex

[0069] 30 mg of actinomycin D, 3.6 mg of methylparaben, and 12.3 mg of telmisartan (1:1:1 molar ratio) were stirred as an open slurry in 1 mL of methanol in a glass vial. After 16-24 hours of stirring mixture was further dried at room temperature until a completely dried mixture is obtained. The resulted material was stored in a screw cap vial and characterized by PXRD. The material was characterized by PXRD and FTIR corresponding to FIGS. 7 and 8, respectively.

Example 5

Preparation of Actinomycin D:Propylparaben:Losartan Molecular Complex

[0070] 30 mg of actinomycin D, 4.3 mg of propylparaben and 10.1 mg of losartan (1:1:1 molar ratio) were stirred as an open slurry in 1 mL of methanol in a glass vial. After 16-24 hours of stirring mixture was further dried at room temperature until a completely dried mixture is obtained. The resulted material was stored in a screw cap vial and characterized by PXRD. The material was characterized by PXRD and FTIR corresponding to FIGS. 9 and 10, respectively.

Example 6

Preparation of Actinomycin D:Propylparaben:Telmisartan Molecular Complex

[0071] 30 mg of actinomycin D, 4.3 mg of propylparaben, and 12.3 mg of telmisartan (1:1:1 molar ratio) were stirred as an open slurry in 1 mL of methanol in a glass vial. After 16-24 hours of stirring mixture was further dried at room temperature until a completely dried mixture is obtained. The resulted material was stored in a screw cap vial and characterized by PXRD. The material was characterized by PXRD and FTIR corresponding to FIGS. 11 and 12, respectively.

Example 7

Preparation of Actinomycin D:Tamibarotene (1:10) Complex

[0072] 30 mg of actinomycin D and 84 mg of tamibarotene (recrystallized in acetonitrile) (1:10 molar ratio) were stirred as a slurry in an open 20 mL glass vial with 1 mL of acetone. After 12-16 hours the stirring was stopped, and the mixture was dried at room temperature for another 12-16 hours. The solids gathered, were dried and stored in a screw cap vials for subsequent analysis. The material was later characterized by PXRD and FTIR as shown in FIGS. 13 and 14, respectively.