HK1188141A - Picropodophyllin monohydrate or polymorph a in cancer therapy - Google Patents

Description

Picropodophyllin monohydrate or polymorph A in the treatment of cancer

Technical Field

The present invention relates to picropodophyllin monohydrate and picropodophyllin polymorph a for use in therapy.

Background

Solid drugs may exist in different forms, such as crystalline, amorphous or glassy, and may exist in the form of solvates or hydrates. A polymorph is a solid crystalline form derived from a solid state compound having at least two possible crystal arrangements of molecules.

It is a well-known fact that different forms of the same drug may lead to differences in certain pharmaceutically important physicochemical properties, such as stability, solubility, dissolution rate, crystal habit and tabletting behaviour. Some of these changes in physicochemical properties ultimately affect the bioavailability of the drug.

Picropodophyllin is a class of compounds belonging to the class of compounds known as cyclolignans, which have the following chemical structure:

picropodophyllin has not been appreciated for a long time because it is considered to have low or no biological activity. In contrast, its stereoisomer podophyllotoxin, which has a trans configuration on the lactone ring, has been studied for decades due to its cytotoxic properties.

However, studies have shown that picropodophyllin exhibits interesting biological properties and thus potential as a drug.

WO02/102804 discloses that picropodophyllin is a specific and potent inhibitor of the insulin-like growth factor-1 receptor (IGF-1R) and is useful in the treatment of IGF-1R dependent diseases such as various types of cancer, atherosclerosis, psoriasis and restenosis following coronary angioplasty.

WO2007/097707 discloses the use of picropodophyllin in the prevention or treatment of type II diabetes, nephropathy, retinopathy, macular degeneration, retinopathy of prematurity, central retinal vein occlusion, branch retinal vein occlusion, rubeosis iridis glaucoma, thyroid-related eye disease, corneal graft rejection and corneal chemical burns; and for contraceptive use.

WO2009/157858 discloses the use of picropodophyllin for the prevention or treatment of diseases or disorders characterized by a hyper-functioning immune system, such as rheumatoid arthritis, crohn's disease, ulcerative colitis, multiple sclerosis, alzheimer's disease, asthma, eczematous dermatitis and graft rejection after organ transplantation.

Crystal structures of picropodophyllin are disclosed on pages 45-47 of kristallogr.215(2000), and crystal data thereof are reported.

Schrecker et al, in Helvetica Chimica Acta (1954);37; pages 1541-1543, disclose picropodophyllin monohydrate and picropodophyllin polymorphs.

Detailed Description

Brief description of the drawings

FIG. 1 is an X-ray powder diffraction pattern (XRPD) of picropodophyllin monohydrate measured on a zero background quartz single crystal sample carrier.

Figure 2 is an X-ray powder diffraction pattern (XRPD) of picropodophyllin polymorph a measured on a zero background quartz single crystal sample carrier.

One aspect of the present invention is to provide picropodophyllin monohydrate for therapeutic use.

One aspect of the present invention is to provide picropodophyllin polymorph a for therapeutic use.

Picropodophyllin monohydrate described herein has good physicochemical and solid state properties for drug development.

A further aspect of the invention is picropodophyllin monohydrate for therapeutic use, which has physicochemical and solid-state properties that make it suitable for the preparation of pharmaceutical suspensions.

A further aspect of the present invention is picropodophyllin monohydrate, which has good shelf-life stability, for therapeutic use.

One aspect of the present invention is picropodophyllin monohydrate, for therapeutic use, characterized by an X-ray powder diffraction pattern exhibiting a peak at 6.9 ± 0.2 ° 2 Θ.

One aspect of the present invention is picropodophyllin monohydrate for use in therapy characterized by an X-ray powder diffraction pattern exhibiting peaks at 6.9 and 9.2 ± 0.2 ° 2 Θ.

Yet another aspect of the present invention is picropodophyllin monohydrate for use in therapy characterized by an X-ray powder diffraction pattern having peaks at 6.9, 9.2, 13.7 and 15.0 ± 0.2 ° 2 Θ.

One aspect of the present invention is picropodophyllin monohydrate for use in therapy characterized by an X-ray powder diffraction pattern having peaks at 6.9, 9.2, 13.7, 15.0, 20.6 and 21.5 ± 0.2 ° 2 Θ.

Another aspect of the invention is picropodophyllin monohydrate for use in therapy characterized by an X-ray powder diffraction pattern exhibiting a peak at 9.2 ± 0.2 ° 2 Θ.

One aspect of the present invention is picropodophyllin monohydrate for use in therapy characterized by an X-ray powder diffraction pattern exhibiting peaks at 9.2 and 13.7 ± 0.2 ° 2 Θ.

One aspect of the present invention is picropodophyllin monohydrate for use in therapy characterized by an X-ray powder diffraction pattern exhibiting peaks at 9.2, 13.7, 15.0, 20.6 and 21.5 ± 0.2 ° 2 Θ.

A further aspect of the invention is picropodophyllin monohydrate as defined herein, substantially free of polymorphs and/or other crystalline and amorphous forms of picropodophyllin, for use in therapy.

The phrase "substantially free of polymorphs and/or other crystalline and amorphous forms of picropodophyllin" is understood to mean that picropodophyllin monohydrate contains less than 10%, such as less than 5%, or less than 1% of any polymorphs and/or other crystalline and amorphous forms of picropodophyllin.

One aspect of the present invention is picropodophyllin polymorph a for use in therapy.

One aspect of the present invention is picropodophyllin polymorph a for use in therapy characterized by an X-ray powder diffraction pattern exhibiting a peak at 6.9 ± 0.2 ° 2 Θ.

One aspect of the present invention is picropodophyllin polymorph a for use in therapy characterized by an X-ray powder diffraction pattern exhibiting peaks at 6.9 and 7.9 ± 0.2 ° 2 Θ.

Yet another aspect of the present invention is picropodophyllin polymorph a for use in therapy characterized by an X-ray powder diffraction pattern exhibiting peaks at 6.9, 7.9, 9.2 and 9.7 ± 0.2 ° 2 Θ.

Yet another aspect of the present invention is picropodophyllin polymorph a for use in therapy characterized by an X-ray powder diffraction pattern exhibiting peaks at 6.9, 7.9, 9.2, 9.7, 15.0 and 16.7 ± 0.2 ° 2 Θ.

One aspect of the present invention is picropodophyllin polymorph a for use in therapy, which is substantially free of other polymorphs and/or other crystalline and amorphous forms of picropodophyllin.

The phrase "substantially free of other polymorphs and/or other crystalline and amorphous forms of picropodophyllin" is understood to mean that picropodophyllin polymorph a contains less than 10%, such as less than 5%, or less than 1% of any polymorph and/or other crystalline and amorphous forms of picropodophyllin.

A further aspect of the invention is the use of picropodophyllin monohydrate as defined herein for the manufacture of a medicament for the treatment of IGF-1R dependent diseases, such as cancer.

Yet another aspect of the invention is the use of picropodophyllin monohydrate as defined herein for the manufacture of a medicament for the treatment of lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer; breast cancer; head and neck cancer, such as oral cancer, sinus cancer, or pharyngeal cancer (pharyneal cancer); gastrointestinal cancer, such as esophageal cancer, gastric cancer, colon cancer, rectal cancer, gastrointestinal stromal tumor, liver cancer, or pancreatic cancer; genitourinary cancer, such as prostate cancer, bladder cancer or kidney cancer; gynecological cancers, such as ovarian cancer, cervical cancer, endometrial cancer or uterine sarcoma; hematologic cancers, such as myeloid leukemia, lymphocytic leukemia, lymphoma, or multiple myeloma; musculoskeletal system cancers such as ewing's sarcoma, osteosarcoma or soft tissue sarcoma; skin cancer such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, or kaposi's sarcoma; brain and nervous system cancers, such as glioma, glioblastoma, astrocytoma, medulloblastoma, craniopharyngioma, or neuroblastoma; cancer of the endocrine system, such as adrenocortical carcinoma, paraganglioma, pheochromocytoma, or thyroid cancer; or an eye cancer such as retinoblastoma or uveal melanoma.

Examples where picropodophyllin monohydrate as defined herein is effective against non-small cell lung cancer (NSCLC) are adenocarcinoma, squamous cell carcinoma or large cell lung carcinoma.

A further aspect of the invention is the use of picropodophyllin monohydrate as defined herein for the manufacture of a medicament for the treatment of psoriasis; restenosis after coronary angioplasty; type II diabetes; renal disease; eye diseases, such as retinopathy or macular degeneration; rheumatoid arthritis; inflammatory bowel disease, such as crohn's disease or ulcerative colitis; multiple sclerosis; alzheimer's disease; or transplant rejection.

A further aspect of the invention is picropodophyllin monohydrate as defined herein for use in the treatment of IGF-1R dependent diseases, such as cancer.

Yet another aspect of the invention is picropodophyllin monohydrate as defined herein for use in the treatment of lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer; breast cancer; head and neck cancer, such as oral cancer, sinus cancer, or pharyngeal cancer; gastrointestinal cancer, such as esophageal cancer, gastric cancer, colon cancer, rectal cancer, gastrointestinal stromal tumor, liver cancer, or pancreatic cancer; genitourinary cancer, such as prostate cancer, bladder cancer or kidney cancer; gynecological cancers, such as ovarian cancer, cervical cancer, endometrial cancer or uterine sarcoma; hematologic cancers, such as myeloid leukemia, lymphocytic leukemia, lymphoma, or multiple myeloma; musculoskeletal system cancers such as ewing's sarcoma, osteosarcoma or soft tissue sarcoma; skin cancer such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, or kaposi's sarcoma; brain and nervous system cancers, such as glioma, glioblastoma, astrocytoma, medulloblastoma, craniopharyngioma, or neuroblastoma; cancer of the endocrine system, such as adrenocortical carcinoma, paraganglioma, pheochromocytoma, or thyroid cancer; or an eye cancer such as retinoblastoma or uveal melanoma.

A further aspect of the invention is picropodophyllin monohydrate as defined herein for use in the treatment of psoriasis; restenosis after coronary angioplasty; type II diabetes; renal disease; eye diseases, such as retinopathy or macular degeneration; rheumatoid arthritis; inflammatory bowel disease, such as crohn's disease or ulcerative colitis; multiple sclerosis; alzheimer's disease; or transplant rejection.

One aspect of the present invention is a method for the treatment of IGF-1R dependent diseases, such as cancer, comprising administering to a patient in need of such treatment a therapeutically effective amount of picropodophyllin monohydrate as defined herein.

Yet another aspect of the invention is the treatment of lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer; breast cancer; head and neck cancer, such as oral cancer, sinus cancer, or pharyngeal cancer; gastrointestinal cancer, such as esophageal cancer, gastric cancer, colon cancer, rectal cancer, gastrointestinal stromal tumor, liver cancer, or pancreatic cancer; genitourinary cancer, such as prostate cancer, bladder cancer or kidney cancer; gynecological cancers, such as ovarian cancer, cervical cancer, endometrial cancer or uterine sarcoma; hematologic cancers, such as myeloid leukemia, lymphocytic leukemia, lymphoma, or multiple myeloma; musculoskeletal system cancers such as ewing's sarcoma, osteosarcoma or soft tissue sarcoma; skin cancer such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, or kaposi's sarcoma; brain and nervous system cancers, such as glioma, glioblastoma, astrocytoma, medulloblastoma, craniopharyngioma, or neuroblastoma; cancer of the endocrine system, such as adrenocortical carcinoma, paraganglioma, pheochromocytoma, or thyroid cancer; or an eye cancer, such as retinoblastoma or uveal melanoma, comprising administering to a patient in need of such treatment a therapeutically effective amount of picropodophyllin monohydrate as defined herein.

One aspect of the invention is the treatment of psoriasis; restenosis after coronary angioplasty; type II diabetes; renal disease; eye diseases, such as retinopathy or macular degeneration; rheumatoid arthritis; inflammatory bowel disease, such as crohn's disease or ulcerative colitis; multiple sclerosis; alzheimer's disease; or graft rejection, comprising administering to a patient in need of such treatment a therapeutically effective amount of picropodophyllin monohydrate as defined herein.

A further aspect of the present invention is the use of picropodophyllin polymorph a as defined herein for the manufacture of a medicament for the treatment of IGF-1R dependent diseases, such as cancer.

Yet another aspect of the present invention is the use of picropodophyllin polymorph a as defined herein for the manufacture of a medicament for the treatment of lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer; breast cancer; head and neck cancer, such as oral cancer, sinus cancer, or pharyngeal cancer; gastrointestinal cancer, such as esophageal cancer, gastric cancer, colon cancer, rectal cancer, gastrointestinal stromal tumor, liver cancer, or pancreatic cancer; genitourinary cancer, such as prostate cancer, bladder cancer or kidney cancer; gynecological cancers, such as ovarian cancer, cervical cancer, endometrial cancer or uterine sarcoma; hematologic cancers, such as myeloid leukemia, lymphocytic leukemia, lymphoma, or multiple myeloma; musculoskeletal system cancers such as ewing's sarcoma, osteosarcoma or soft tissue sarcoma; skin cancer such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, or kaposi's sarcoma; brain and nervous system cancers, such as glioma, glioblastoma, astrocytoma, medulloblastoma, craniopharyngioma, or neuroblastoma; cancer of the endocrine system, such as adrenocortical carcinoma, paraganglioma, pheochromocytoma, or thyroid cancer; or an eye cancer such as retinoblastoma or uveal melanoma.

Examples where picropodophyllin polymorph a as defined herein is effective in non-small cell lung cancer (NSCLC) are adenocarcinoma, squamous cell carcinoma or large cell lung carcinoma.

A further aspect of the present invention is the use of picropodophyllin polymorph a as defined herein for the manufacture of a medicament for the treatment of psoriasis; restenosis after coronary angioplasty; type II diabetes; renal disease; eye diseases, such as retinopathy or macular degeneration; rheumatoid arthritis; inflammatory bowel disease, such as crohn's disease or ulcerative colitis; multiple sclerosis; alzheimer's disease; or transplant rejection.

A further aspect of the present invention is picropodophyllin polymorph a as defined herein for use in the treatment of IGF-1R dependent diseases, such as cancer.

Yet another aspect of the present invention is picropodophyllin polymorph a as defined herein for use in the treatment of lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer; breast cancer; head and neck cancer, such as oral cancer, sinus cancer (sinural cancer), or pharyngeal cancer; gastrointestinal cancer, such as esophageal cancer, gastric cancer, colon cancer, rectal cancer, gastrointestinal stromal tumor, liver cancer, or pancreatic cancer; genitourinary cancer, such as prostate cancer, bladder cancer or kidney cancer; gynecological cancers, such as ovarian cancer, cervical cancer, endometrial cancer or uterine sarcoma; hematologic cancers, such as myeloid leukemia, lymphocytic leukemia, lymphoma, or multiple myeloma; musculoskeletal system cancers such as ewing's sarcoma, osteosarcoma or soft tissue sarcoma; skin cancer such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, or kaposi's sarcoma; brain and nervous system cancers, such as glioma, glioblastoma, astrocytoma, medulloblastoma, craniopharyngioma, or neuroblastoma; cancer of the endocrine system, such as adrenocortical carcinoma, paraganglioma, pheochromocytoma, or thyroid cancer; or an eye cancer such as retinoblastoma or uveal melanoma.

Yet another aspect of the present invention is picropodophyllin polymorph a as defined herein for use in the treatment of psoriasis; restenosis after coronary angioplasty; type II diabetes; renal disease; eye diseases, such as retinopathy or macular degeneration; rheumatoid arthritis; inflammatory bowel disease, such as crohn's disease or ulcerative colitis; multiple sclerosis; alzheimer's disease; or transplant rejection.

One aspect of the present invention is a method of treating IGF-1R dependent diseases, such as cancer, comprising administering to a patient in need of such treatment a therapeutically effective amount of picropodophyllin polymorph a as defined herein.

Yet another aspect of the invention is the treatment of lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer; breast cancer; head and neck cancer, such as oral cancer, sinus cancer, or pharyngeal cancer; gastrointestinal cancer, such as esophageal cancer, gastric cancer, colon cancer, rectal cancer, gastrointestinal stromal tumor, liver cancer, or pancreatic cancer; genitourinary cancer, such as prostate cancer, bladder cancer or kidney cancer; gynecological cancers, such as ovarian cancer, cervical cancer, endometrial cancer or uterine sarcoma; hematologic cancers, such as myeloid leukemia, lymphocytic leukemia, lymphoma, or multiple myeloma; musculoskeletal system cancers such as ewing's sarcoma, osteosarcoma or soft tissue sarcoma; skin cancer such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, or kaposi's sarcoma; brain and nervous system cancers, such as glioma, glioblastoma, astrocytoma, medulloblastoma, craniopharyngioma, or neuroblastoma; cancer of the endocrine system, such as adrenocortical carcinoma, paraganglioma, pheochromocytoma, or thyroid cancer; or an eye cancer, such as retinoblastoma or uveal melanoma, comprising administering to a patient in need of such treatment a therapeutically effective amount of picropodophyllin polymorph a as defined herein.

One aspect of the invention is the treatment of psoriasis; restenosis after coronary angioplasty; type II diabetes; renal disease; eye diseases, such as retinopathy or macular degeneration; rheumatoid arthritis; inflammatory bowel disease, such as crohn's disease or ulcerative colitis; multiple sclerosis; alzheimer's disease; or graft rejection, comprising administering to a patient in need of such treatment a therapeutically effective amount of picropodophyllin polymorph a as defined herein.

One aspect of the present invention is the use of a pharmaceutical composition comprising picropodophyllin monohydrate or picropodophyllin polymorph a as described herein in admixture with pharmaceutically acceptable adjuvants, diluents and/or carriers.

A further aspect of the present invention is the use of at least one anti-cancer drug in combination with picropodophyllin monohydrate as described herein or in combination with picropodophyllin polymorph a as described herein.

A further aspect of the present invention is the use of at least one anti-cancer drug in combination with picropodophyllin monohydrate as described herein or in combination with picropodophyllin polymorph a as described herein, wherein the at least one anti-cancer drug is administered sequentially, separately or simultaneously with picropodophyllin monohydrate or picropodophyllin polymorph a to a patient in need thereof.

In one aspect of the invention, a kit of parts is provided comprising the following components:

(i) picropodophyllin monohydrate or picropodophyllin polymorph a; and

(ii) anti-cancer drugs;

for sequential, separate or simultaneous administration.

In one aspect of the invention, a kit of parts as described herein is provided for use in therapy.

Yet another aspect of the invention is a kit of parts as described herein for use in the treatment of cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer; breast cancer; head and neck cancer, such as oral cancer, sinus cancer, or pharyngeal cancer; gastrointestinal cancer, such as esophageal cancer, gastric cancer, colon cancer, rectal cancer, gastrointestinal stromal tumor, liver cancer, or pancreatic cancer; genitourinary cancer, such as prostate cancer, bladder cancer or kidney cancer; gynecological cancers, such as ovarian cancer, cervical cancer, endometrial cancer or uterine sarcoma; hematologic cancers, such as myeloid leukemia, lymphocytic leukemia, lymphoma, or multiple myeloma; musculoskeletal system cancers such as ewing's sarcoma, osteosarcoma or soft tissue sarcoma; skin cancer such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, or kaposi's sarcoma; brain and nervous system cancers, such as glioma, glioblastoma, astrocytoma, medulloblastoma, craniopharyngioma, or neuroblastoma; cancer of the endocrine system, such as adrenocortical carcinoma, paraganglioma, pheochromocytoma, or thyroid cancer; or an eye cancer such as retinoblastoma or uveal melanoma.

Picropodophyllin monohydrate as described herein may be administered orally, parenterally, intravenously, intramuscularly, subcutaneously or by injectable routes of administration, buccal, rectal, vaginal, transdermal, nasal or ocular routes, or by inhalation, in the form of a pharmaceutical composition comprising a pharmaceutically acceptable dosage form. The composition may be administered in different dosage forms depending on the condition to be treated and the patient and the route of administration. In one aspect of the invention, picropodophyllin monohydrate as described herein is present in an amount of 1-95% by weight of the total weight of the pharmaceutical composition.

Picropodophyllin polymorph a as described herein can be administered orally, parenterally, intravenously, intramuscularly, subcutaneously or by injectable routes of administration, buccal, rectal, vaginal, transdermal, nasal or ocular routes, or by inhalation, in the form of a pharmaceutical composition comprising a pharmaceutically acceptable dosage form. The composition may be administered in different dosage forms depending on the condition to be treated and the patient and the route of administration. In one aspect of the invention picropodophyllin polymorph a as described herein is present in an amount of 1-95% by weight based on the total weight of the pharmaceutical composition.

One aspect of the present invention is the use of a pharmaceutical composition comprising picropodophyllin monohydrate as described herein, in admixture with pharmaceutically and pharmacologically acceptable adjuvants, diluents and/or carriers. Pharmaceutically and pharmacologically acceptable adjuvants, diluents and/or carriers suitable for a particular pharmaceutical composition will be apparent to those skilled in the art of pharmaceutical compositions. The pharmaceutical composition may be administered to an individual or patient by an administration route appropriate to the type of cancer or medical indication (medical indication) to be treated. For parenteral administration, picropodophyllin monohydrate as described herein may be administered in the form of an injectable dosage form by continuous infusion (which may be intravenous) as a solution or suspension.

For oral administration, picropodophyllin monohydrate as described herein may be administered in the form of a capsule comprising picropodophyllin monohydrate as described herein, either in suspension or in solution.

In one aspect of the invention, the dose of picropodophyllin monohydrate or picropodophyllin polymorph a as described herein may be from 1 to 40 mg per kg body weight per day.

In one aspect of the invention, picropodophyllin monohydrate or picropodophyllin polymorph a as described herein is administered in a dose of 400 mg twice daily.

In yet another aspect of the invention, picropodophyllin monohydrate or picropodophyllin polymorph a as described herein is administered in a dose of 390 mg twice daily.

In one aspect of the invention, picropodophyllin monohydrate as described herein is administered in the form of an oral suspension.

In yet another aspect of the invention, picropodophyllin monohydrate as described herein is administered in the form of an oral suspension comprising 25 mg/ml of picropodophyllin monohydrate as described herein.

A further aspect of the present invention is the use of at least one anti-cancer drug in combination with picropodophyllin monohydrate or picropodophyllin polymorph a as described herein.

Examples of anti-cancer drugs that may be used in combination with picropodophyllin monohydrate or picropodophyllin polymorph a as described herein are cytostatics; it is a targeting anticancer drug of a monoclonal antibody or a selective small molecule inhibitor; a hormone; an anti-hormone; or an immunopotentiator.

Examples of cytostatics useful in combination therapy with picropodophyllin monohydrate or picropodophyllin polymorph a as described herein are alkylating agents, such as melphalan; antimetabolites such as methotrexate or gemcitabine; mitotic inhibitors such as taxanes or vinca alkaloids; cytotoxic antibiotics, such as doxorubicin; topoisomerase II inhibitors, such as etoposide; or other cytostatics such as cisplatin or carboplatin.

Examples of monoclonal antibodies useful in combination therapy with picropodophyllin monohydrate or picropodophyllin polymorph a as described herein are monoclonal antibodies targeting Epidermal Growth Factor Receptor (EGFR), HER2 or vascular endothelial growth factor, such as trastuzumab or bevacizumab.

Examples of selective small molecule inhibitors useful in combination therapy with picropodophyllin monohydrate or picropodophyllin polymorph a as described herein are inhibitors targeting epidermal growth factor receptor, Histone Deacetylase (HDAC), Raf, platelet derived growth factor receptor, vascular endothelial growth factor receptor or c-Kit, such as gefitinib or imatinib.

Examples of hormones useful in combination therapy with picropodophyllin monohydrate or picropodophyllin polymorph a as described herein are estrogens or progestogens.

The anti-hormones useful in combination therapy with picropodophyllin monohydrate or picropodophyllin polymorph a as described herein are anti-estrogens, anti-androgens or enzyme inhibitors.

An example of an immune enhancing agent useful in combination therapy with picropodophyllin monohydrate or picropodophyllin polymorph a as described herein is interferon.

All of the foregoing aspects may be used with any claim, aspect or embodiment of the invention above or below.

In one aspect of the invention, a kit of parts is provided comprising:

(i) picropodophyllin monohydrate as described herein or picropodophyllin polymorph A as described herein, and

(ii) anti-cancer drugs; for sequential, separate or simultaneous administration of picropodophyllin monohydrate or picropodophyllin polymorph a as described herein.

In one aspect of the invention there is provided the use of a kit of parts as defined herein in the manufacture of a medicament for the treatment of an IGF-1R dependent disease, such as cancer.

A further aspect of the invention is the use of a kit of parts as defined herein in the manufacture of a medicament for the treatment of lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer; breast cancer; head and neck cancer, such as oral cancer, sinus cancer, or pharyngeal cancer; gastrointestinal cancer, such as esophageal cancer, gastric cancer, colon cancer, rectal cancer, gastrointestinal stromal tumor, liver cancer, or pancreatic cancer; genitourinary cancer, such as prostate cancer, bladder cancer or kidney cancer; gynecological cancers, such as ovarian cancer, cervical cancer, endometrial cancer or uterine sarcoma; hematologic cancers, such as myeloid leukemia, lymphocytic leukemia, lymphoma, or multiple myeloma; musculoskeletal system cancers such as ewing's sarcoma, osteosarcoma or soft tissue sarcoma; skin cancer such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, or kaposi's sarcoma; brain and nervous system cancers, such as glioma, glioblastoma, astrocytoma, medulloblastoma, craniopharyngioma, or neuroblastoma; cancer of the endocrine system, such as adrenocortical carcinoma, paraganglioma, pheochromocytoma, or thyroid cancer; or an eye cancer such as retinoblastoma or uveal melanoma.

All of the foregoing aspects may be used with any claim, aspect or embodiment of the invention above or below.

Preparation method

Picropodophyllin monohydrate as defined herein, prepared by the process of:

a) adding an aqueous solution of a base to a solution of podophyllotoxin in a protic solvent,

b) heating the reaction mixture from step a) to a temperature of 70 to 75 ℃ for at least 2 hours,

c) cooling the reaction mixture from step b),

d) the product is separated out and the product is separated,

e) the product is washed with a solvent and,

f) drying the product, and

g) the product is adjusted (conditioning) with water.

In another aspect, the base in step a) is NaOAc.

In another aspect, the protic solvent in step a) is ethanol.

In another aspect, step d) may be performed using a filter.

In another aspect, step e) may be performed with ethanol.

In another aspect, step f) may be performed under vacuum.

Picropodophyllin monohydrate was obtained as described in example 1.

Abbreviations

Examples

X-ray powder diffraction (XRPD)

X-ray powder diffraction (XRPD) experiments were performed on an X' Pert Pro diffractometer (PANanalytical b.v., Netherlands) set up in Bragg-Brentano geometry. The diffractometer was equipped with a Ge (111) primary monochromator and a PIXcell detector. Representative samples were placed on a zero background quartz single crystal sample carrier (specimen support, Siltronix, france).

Experiment Using Cu K at ambient temperature and humidity_α1Irradiation (45 kV and 40 mA). The auto-divergent and anti-divergent slits were used to scan in a continuous scan mode over a range of 2-50 deg. 2 theta, observing a length of 10 millimeters, with a step size of 0.0131 deg. 2 theta, typically counting a time of 217.770 seconds.

Those skilled in the art will appreciate that the 2 θ values of the X-ray powder diffraction pattern may vary slightly from machine to machine. Some variation may also be present due to sample preparation and lot-to-lot variation.

Data collection was performed with application software X 'Pert Data Collector (version 2.2D) and instrument control software (version 1.9D), and pattern analysis and peak shape refinement were performed with X' Pert High Score Plus (version 2.2.3). All software was from panalytical b.v., Netherlands.

Example 1

Preparation of picropodophyllin monohydrate

17.3 kg (127 mol) of NaOAc.3H₂O was dissolved in water, filtered and added to a filtered solution of 10.5 kg (25 moles) of picropodophyllin in ethanol (198 l). The reaction mixture was kept at 70-75 ℃ during at least 2 hours and subsequently cooled. The product picropodophyllin was isolated by Nutch filter, washed with ethanol (at least 50%) and dried under vacuum. The product thus obtained was subjected to conditioning with water during at least 96 hours to obtain picropodophyllin monohydrate (8 kg).

XRPD peak position

Picropodophyllin monohydrate

Refined (refined) 2 θ value:

6.9±0.2°2θ

9.2±0.2°2θ

13.7±0.2°2θ

15.0±0.2°2θ

20.6±0.2°2θ

21.5±0.2°2θ

example 2

Solubility study of picropodophyllin monohydrate

The solubility in different media was determined by using LC-UV chromatography. Excess material was weighed into the sample vial and 0.5 ml of medium was added. The material was spun in a special medium at ambient temperature for 24 hours, followed by filtration of the supernatant using a hydrophilic PVDF (Millipore Corp.) 0.22 micron filter. The sample was then mixed 1:1 with mobile phases A and B (see below)Dilute and use Xterra^TMMS C18, 50X 2.1 mm column at 288 nm UV detection for analysis. The mobile phase consisted of acetonitrile, water and trifluoroacetic acid 5:95:0.1 (A) and 99:1:0.1 (B). The gradient distribution is: from 0 to 3 minutes, mobile phase B increased linearly from 20% to 100%, followed by 100% B for the next 2 minutes. The solubility was calculated from a calibration curve using accurately weighed amounts of the substance (dissolved and diluted to different concentrations with a 1:1 mixture of mobile phases a and B).

The picropodophyllin monohydrate was subjected to solubility determination in 1% Sodium Dodecyl Sulfate (SDS).

The picropodophyllin monohydrate after 24 hours of rotation had a solubility in 1% SDS of 0.21 mg/ml, corresponding to 489. mu.M.

Example 3

Preparation of picropodophyllin polymorph A

3.02 grams of picropodophyllin monohydrate were stored under vacuum in a desiccator adjacent to a phosphorus pentoxide tank over the weekend to obtain 2.90 grams (theoretically 2.89 grams) of picropodophyllin polymorph a.

XRPD peak position

Picropodophyllin polymorph A

Refined 2 θ value:

6.9±0.2°2θ

7.9±0.2°2θ

9.2±0.2°2θ

9.7±0.2°2θ

15.0±0.2°2θ

16.7±0.2°2θ

example 4

Biological evaluation

Phase I/II clinical trials were conducted with the IGF-1 receptor inhibitor picropodophyllin monohydrate, a patient with advanced progressive cancer.

390 or 520 mg picropodophyllin monohydrate as monotherapy twice daily for a total duration of at least two weeks were administered to ten patients with progressive non-small cell lung cancer (NSCLC) and no treatment regimen selection. The patient was evaluated at the beginning of the study and every two months thereafter using images.

The mean survival time for ten NSCLC patients was 42 weeks, whereas the expected mean survival time for such patients was less than 20 weeks. At the time of the cutoff, five patients still survived, and two of these patients did not detect disease progression.

After treatment with picropodophyllin as described above, a partial response was detected in one of these NSCLC patients according to RECIST criteria (solid tumor response assessment criteria).

Claims (44)

1. Picropodophyllin monohydrate characterized by an X-ray powder diffraction pattern exhibiting a peak at 6.9 ± 0.2 ° 2 Θ, for therapeutic use.

2. A picropodophyllin monohydrate according to claim 1, characterized by an X-ray powder diffraction pattern having peaks at 6.9 and 9.2 ± 0.2 ° 2 θ.

3. A picropodophyllin monohydrate according to claim 1 or 2, characterized by an X-ray powder diffraction pattern having peaks at 6.9, 9.2, 13.7, 15.0, 20.6 and 21.5 ± 0.2 ° 2 θ.

4. A picropodophyllin monohydrate according to any one of claims 1-3, substantially free of any other polymorphic forms and/or other crystalline and amorphous forms of picropodophyllin.

5. Use of picropodophyllin monohydrate characterized by an X-ray powder diffraction pattern exhibiting a peak at 6.9 ± 0.2 ° 2 Θ in the manufacture of a medicament for the treatment of cancer.

6. Use of picropodophyllin monohydrate characterized by an X-ray powder diffraction pattern exhibiting peaks at 6.9 and 9.2 ± 0.2 ° 2 Θ in the manufacture of a medicament for the treatment of cancer.

7. Use of picropodophyllin monohydrate characterized by an X-ray powder diffraction pattern exhibiting peaks at 6.9, 9.2, 13.7, 15.0, 20.6, and 21.5 ± 0.2 ° 2 Θ in the manufacture of a medicament for the treatment of cancer.

8. The use according to any one of claims 5-7, wherein the cancer is any one of the following cancers: lung cancer; breast cancer; head and neck cancer; gastrointestinal cancer; urogenital cancers; gynecological cancer; cancers of the hematological system; musculoskeletal system cancers; skin cancer; brain and nervous system cancers; cancer of the endocrine system; or eye cancer.

9. The use of claim 8, wherein the cancer is non-small cell lung cancer (NSCLC).

10. The use of claim 9, wherein the non-small cell lung cancer (NSCLC) is adenocarcinoma, squamous cell carcinoma, or large cell lung carcinoma.

11. The use according to claim 8, wherein the cancer is any one selected from the following cancers: small cell lung cancer; oral cancer; sinus cancer; pharyngeal cancer; esophageal cancer; gastric cancer; colon cancer; rectal cancer; gastrointestinal stromal tumors; liver cancer; pancreatic cancer; prostate cancer; bladder cancer; kidney cancer; ovarian cancer; cervical cancer; endometrial cancer; uterine sarcoma; myeloid leukemia; lymphocytic leukemia; lymphoma; multiple myeloma; ewing's sarcoma; osteosarcoma; soft tissue sarcoma; malignant melanoma; basal cell carcinoma; squamous cell carcinoma; kaposi's sarcoma; a glioma; glioblastoma; astrocytoma; medulloblastoma; craniopharyngioma; neuroblastoma; adrenocortical carcinoma; paragangliomas; pheochromocytoma; thyroid cancer; retinoblastoma; or uveal melanoma.

12. Use of picropodophyllin monohydrate characterized by an X-ray powder diffraction pattern exhibiting a peak at 6.9 ± 0.2 ° 2 Θ, for the manufacture of a medicament for the treatment of psoriasis, restenosis following coronary angioplasty, type II diabetes, nephropathy, ocular disease, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, alzheimer's disease, or transplant rejection.

13. Use of picropodophyllin monohydrate characterized by an X-ray powder diffraction pattern exhibiting peaks at 6.9 and 9.2 ± 0.2 ° 2 Θ, for the manufacture of a medicament for the treatment of psoriasis; restenosis after coronary angioplasty; type II diabetes; renal disease; ocular diseases; rheumatoid arthritis; inflammatory bowel disease; multiple sclerosis; alzheimer's disease; or transplant rejection.

14. Use of picropodophyllin monohydrate characterized by an X-ray powder diffraction pattern exhibiting peaks at 6.9, 9.2, 13.7, 15.0, 20.6, and 21.5 ± 0.2 ° 2 Θ, in the manufacture of a medicament for the treatment of psoriasis; restenosis after coronary angioplasty; type II diabetes; renal disease; ocular diseases; rheumatoid arthritis; inflammatory bowel disease; multiple sclerosis; alzheimer's disease; or transplant rejection.

15. A method of treating cancer, wherein a therapeutically effective amount of picropodophyllin monohydrate characterized by an X-ray powder diffraction pattern exhibiting a peak at 6.9 ± 0.2 ° 2 Θ is administered to a patient in need of such treatment.

16. A method of treating cancer, wherein a therapeutically effective amount of picropodophyllin monohydrate characterized by an X-ray powder diffraction pattern exhibiting peaks at 6.9 and 9.2 ± 0.2 ° 2 Θ is administered to a patient in need of such treatment.

17. A method of treating cancer, wherein a therapeutically effective amount of picropodophyllin monohydrate characterized by an X-ray powder diffraction pattern exhibiting peaks at 6.9, 9.2, 13.7, 15.0, 20.6, and 21.5 ± 0.2 ° 2 Θ is administered to a patient in need of such treatment.

18. The method of any one of claims 15-17, wherein the cancer is any one of the following cancers: lung cancer; breast cancer; head and neck cancer; gastrointestinal cancer; urogenital cancers; gynecological cancer; cancers of the hematological system; musculoskeletal system cancers; skin cancer; brain and nervous system cancers; cancer of the endocrine system; or eye cancer.

19. The method of claim 18, wherein the cancer is non-small cell lung cancer (NSCLC).

20. The method of claim 18, wherein the cancer is any one selected from the following: small cell lung cancer; oral cancer; sinus cancer; pharyngeal cancer; esophageal cancer; gastric cancer; colon cancer; rectal cancer; gastrointestinal stromal tumors; liver cancer; pancreatic cancer; prostate cancer; bladder cancer; kidney cancer; ovarian cancer; cervical cancer; endometrial cancer; uterine sarcoma; myeloid leukemia; lymphocytic leukemia; lymphoma; multiple myeloma; ewing's sarcoma; osteosarcoma; soft tissue sarcoma; malignant melanoma; basal cell carcinoma; squamous cell carcinoma; kaposi's sarcoma; a glioma; glioblastoma; astrocytoma; medulloblastoma; craniopharyngioma; neuroblastoma; adrenocortical carcinoma; paragangliomas; pheochromocytoma; thyroid cancer; retinoblastoma; or uveal melanoma.

21. A method of treatment for treating psoriasis; restenosis after coronary angioplasty; type II diabetes; renal disease; ocular diseases; rheumatoid arthritis; inflammatory bowel disease; multiple sclerosis; alzheimer's disease; or transplant rejection, wherein a therapeutically effective amount of picropodophyllin monohydrate characterized by an X-ray powder diffraction pattern exhibiting a peak at 6.9 ± 0.2 ° 2 Θ is administered to a patient in need of such treatment.

22. A method of treatment for treating psoriasis; restenosis after coronary angioplasty; type II diabetes; renal disease; ocular diseases; rheumatoid arthritis; inflammatory bowel disease; multiple sclerosis; alzheimer's disease; or transplant rejection, wherein a therapeutically effective amount of picropodophyllin monohydrate characterized by an X-ray powder diffraction pattern exhibiting peaks at 6.9 and 9.2 ± 0.2 ° 2 Θ is administered to a patient in need of such treatment.

23. A method of treatment for treating psoriasis; restenosis after coronary angioplasty; type II diabetes; renal disease; ocular diseases; rheumatoid arthritis; inflammatory bowel disease; multiple sclerosis; alzheimer's disease; or transplant rejection, wherein a therapeutically effective amount of picropodophyllin monohydrate characterized by an X-ray powder diffraction pattern exhibiting peaks at 6.9, 9.2, 13.7, 15.0, 20.6, and 21.5 ± 0.2 ° 2 Θ is administered to a patient in need of such treatment.

24. Picropodophyllin polymorph a, characterized by an X-ray powder diffraction pattern exhibiting a peak at 6.9 ± 0.2 ° 2 Θ, for therapeutic use.

25. A picropodophyllin polymorph a according to claim 24, characterized by an X-ray powder diffraction pattern exhibiting peaks at 6.9 and 7.9 ± 0.2 ° 2 Θ.

26. Picropodophyllin polymorph a according to claim 24 or 25, characterized by an X-ray powder diffraction pattern with peaks at 6.9, 7.9, 9.2, 9.7, 15.0 and 16.7 ± 0.2 ° 2 Θ.

27. Use of picropodophyllin polymorph a, characterized by an X-ray powder diffraction pattern exhibiting peaks at 6.9 ± 0.2 ° 2 Θ, in the manufacture of a medicament for the treatment of cancer.

28. Use of picropodophyllin polymorph a, characterized by an X-ray powder diffraction pattern exhibiting peaks at 6.9 and 7.9 ± 0.2 ° 2 Θ, in the manufacture of a medicament for the treatment of cancer.

29. Use of picropodophyllin polymorph a characterized by an X-ray powder diffraction pattern exhibiting peaks at 6.9, 7.9, 9.2, 9.7, 15.0 and 16.7 ± 0.2 ° 2 Θ in the manufacture of a medicament for the treatment of cancer.

30. The use of any one of claims 27-29, wherein the cancer is any one of the following cancers: lung cancer; breast cancer; head and neck cancer; gastrointestinal cancer; urogenital cancers; gynecological cancer; cancers of the hematological system; musculoskeletal system cancers; skin cancer; brain and nervous system cancers; cancer of the endocrine system; or eye cancer.

31. The use of claim 30, wherein the cancer is non-small cell lung cancer (NSCLC).

32. The use of claim 31, wherein the non-small cell lung cancer (NSCLC) is adenocarcinoma, squamous cell carcinoma, or large cell lung carcinoma.

33. Use of picropodophyllin polymorph a characterized by an X-ray powder diffraction pattern exhibiting peaks at 6.9 ± 0.2 ° 2 Θ, for the manufacture of a medicament for the treatment of psoriasis; restenosis after coronary angioplasty; type II diabetes; renal disease; ocular diseases; rheumatoid arthritis; inflammatory bowel disease; multiple sclerosis; alzheimer's disease; or transplant rejection.

34. Use of picropodophyllin polymorph a characterized by an X-ray powder diffraction pattern exhibiting peaks at 6.9 and 7.9 ± 0.2 ° 2 Θ, for the manufacture of a medicament for the treatment of psoriasis; restenosis after coronary angioplasty; type II diabetes; renal disease; ocular diseases; rheumatoid arthritis; inflammatory bowel disease; multiple sclerosis; alzheimer's disease; or transplant rejection.

35. Use of picropodophyllin polymorph a characterized by an X-ray powder diffraction pattern exhibiting peaks at 6.9, 7.9, 9.2, 9.7, 15.0 and 16.7 ± 0.2 ° 2 Θ, for the manufacture of a medicament for the treatment of psoriasis; restenosis after coronary angioplasty; type II diabetes; renal disease; ocular diseases; rheumatoid arthritis; inflammatory bowel disease; multiple sclerosis; alzheimer's disease; or transplant rejection.

36. A method of treating cancer, wherein a therapeutically effective amount of picropodophyllin polymorph a characterized by an X-ray powder diffraction pattern exhibiting peaks at 6.9 ± 0.2 ° 2 Θ is administered to a patient in need of such treatment.

37. A method of treating cancer, wherein a therapeutically effective amount of picropodophyllin polymorph a characterized by an X-ray powder diffraction pattern exhibiting peaks at 6.9 and 7.9 ± 0.2 ° 2 Θ is administered to a patient in need of such treatment.

38. A method of treating cancer, wherein a therapeutically effective amount of picropodophyllin polymorph a characterized by an X-ray powder diffraction pattern exhibiting peaks at 6.9, 7.9, 9.2, 9.7, 15.0 and 16.7 ± 0.2 ° 2 Θ is administered to a patient in need of such treatment.

39. The method of any one of claims 36-38, wherein the cancer is any one of the following cancers: lung cancer; breast cancer; head and neck cancer; gastrointestinal cancer; urogenital cancers; gynecological cancer; cancers of the hematological system; musculoskeletal system cancers; skin cancer; brain and nervous system cancers; cancer of the endocrine system; or eye cancer.

40. The method of claim 39, wherein the cancer is non-small cell lung cancer (NSCLC).

41. The use of claim 40, wherein the non-small cell lung cancer (NSCLC) is adenocarcinoma, squamous cell carcinoma, or large cell lung carcinoma.

42. A method of treatment for treating psoriasis; restenosis after coronary angioplasty; type II diabetes; renal disease; ocular diseases; rheumatoid arthritis; inflammatory bowel disease; multiple sclerosis; alzheimer's disease; or transplant rejection, wherein a therapeutically effective amount of picropodophyllin polymorph a characterized by an X-ray powder diffraction pattern exhibiting a peak at 6.9 ± 0.2 ° 2 Θ is administered to a patient in need of such treatment.

43. A method of treatment for treating psoriasis; restenosis after coronary angioplasty; type II diabetes; renal disease; ocular diseases; rheumatoid arthritis; inflammatory bowel disease; multiple sclerosis; alzheimer's disease; or transplant rejection, wherein a therapeutically effective amount of picropodophyllin polymorph a characterized by an X-ray powder diffraction pattern exhibiting peaks at 6.9 and 7.9 ± 0.2o2 Θ is administered to a patient in need of such treatment.

44. A method of treatment for treating psoriasis; restenosis after coronary angioplasty; type II diabetes; renal disease; ocular diseases; rheumatoid arthritis; inflammatory bowel disease; multiple sclerosis; alzheimer's disease; or transplant rejection, wherein a therapeutically effective amount of picropodophyllin polymorph a characterized by an X-ray powder diffraction pattern exhibiting peaks at 6.9, 7.9, 9.2, 9.7, 15.0, and 16.7 ± 0.2 ° 2 Θ is administered to a patient in need of such treatment.