Anticancer agent free of adverse reactions

Abstract

The present invention provides a pharmaceutical composition for treating cancer, the composition comprising as the active ingredient a compound represented by general formula I: C-[-CH2-O-(-CH2CH2-O-)­n-X1-CHR1-O-CO-NR2-CH2-X2]4 (I) (where X1-CHR1-O-CO-NR2 is a linker, X1 is a spacer, R1 is an optionally substituted C1-4 alkyl, R2 is a phenyl or substituted phenyl group, X2 is SN-38, and n is an integer of 200 to 1,000). The composition is characterized by the following: that the composition can be used in a subject having cancer at a dosage regimen that calls for parenteral administration of a single dose of approximately 0.01 to 11 µmol / kg body weight at a frequency of once a week every other week for at least two administrations; and that the composition does not have irinotecan-like adverse reactions but does impart the same or better cancer proliferation-inhibiting activity as irinotecan at a dose that is 1 / 10 (molar ratio) or less that of irinotecan. Also provided is a method for treating cancer.

Description

technical field

[0001] The present invention relates to pharmaceutical compositions and methods for the treatment of cancer, characterized in that the anticancer active substance SN-38 and 4-arm PEG are covalently bound to each other via a linker involving long-term controlled release of SN-38 Administration and dosage of types of anticancer agents. Background technique

[0002] Research is ongoing on PEGylation of low-molecular-weight drugs for increasing their stability in blood and enhancing their potency (Non-Patent Document 1). As such low-molecular-weight drugs, anticancer agents in the form of pegylated drugs such as camptothecin, irinotecan, doxorubicin, SN-38, paclitaxel, docetaxel, cisplatin, and gemcitabine have been developed .

[0003] Among these anticancer agents, SN-38 (formal name: 7-ethyl-10-hydroxycamptothecin) is an active ingredient of irinotecan (also known as "CPT-11"). In this sense, irinotecan is a prodrug of SN-38.

[0004] Irinotecan is an anti...

Examples

Embodiment 1

[0093]

[0094] 1. Production of Azido-Linker-SN-38

[0095]

[0096] SN38 (1.00 g, 2.55 mmol; Haorui) was suspended in 10 mL of anhydrous pyridine, then concentrated to dryness under vacuum at 50°C. Repeat this step with 10 mL of anhydrous THF. in N 2Under atmosphere, the resulting pale yellow solid was dissolved in 50 mL of anhydrous THF and 50 mL of anhydrous DMF, then cooled on ice. A 1.0 M solution of potassium tert-butoxide in THF (2.55 mL, 2.55 mmol) was added, forming an initial dark green color which became a thick orange suspension. After 15 min, 7-azido-1-cyano-2-hexyl N-(chloromethyl)-4-(N,N-diethylformamide)-phenylcarbamate (7.5 mL, 2.8 mmol) in THF. After 15 min at 4°C, the light orange mixture was allowed to warm to room temperature. After 1 hr, HPLC analysis (5 μL sample + 1 mL of CAN / TFA) indicated product / SN38=86 / 14. The pale yellow mixture was diluted with 200 mL of ethyl acetate, washed 2x100 mL of water, 100 mL of saturated aqueous NaCl, and dis...

Embodiment 2

[0108]

[0109] 1. Test conditions

[0110] Toxicity, pharmacokinetic and efficacy studies were performed by intravenously injecting (iv) each test sample into tumor-bearing rats under the conditions shown in Tables 1 and 2.

[0111] [Table 1]

[0112] Rat Groups and Treatments Used for Efficacy Studies

[0113] Group

n*

treat

Dose (mg / kg)**

Pathway / Schedule

1

5

Vehicle Control***

--

iv, qwk x 2 weeks

2

5

DFP-13318

50

iv, qwk x 2 weeks

3

5

DFP-13318

100

iv, qwk x 2 weeks

4

5

DFP-13318

200

iv, qwk x 2 weeks

5

5

irinotecan

70 / 50

iv, qwk x 2 weeks

[0114] Notes: *n: Number of animals, **Dose: Body weight adjusted (10 μL / g), ***Vehicle control: 10 mM acetate buffer, pH 5

[0115] [Table 2]

[0116] Auxiliary group for pharmacokinetic (PK) evaluation

[0117] Group

n*

treat

Dose (mg / kg)**

Pathway / Sched...

Embodiment 3

[0221]

[0222] This example was carried out to demonstrate that after intravenous administration of DFP-13318 for PK / PD (pharmacokinetics / pharmacodynamics) studies, DFP-13318 and its metabolite SN-38 were 29 were accumulated in tumor tissue collected from a tumor-bearing nude rat model.

[0223] In the PK / PD study, as shown in Table 15, 25 nude rats were used.

[0224] [Table 15]

[0225] Rat groups and treatments

[0226] Group

n*

treat

Dose (mg / kg)**

Pathway / Schedule

1

5

Vehicle Control***

--

iv, qwk x 2 weeks

2

5

DFP-13318

50

iv, qwk x 2 weeks

3

5

DFP-13318

100

iv, qwk x 2 weeks

4

5

DFP-13318

200

iv, qwk x 2 weeks

5

5

irinotecan

70 / 50

iv, qwk x 2 weeks

[0227] Notes: *n: number of animals, **dose: body weight adjusted (10 μL / g), ***vehicle control: 10 mM acetate buffer, pH 5.

[0228] Twenty-five tumor fragments (with 20...

technical field

[0001] The present invention relates to pharmaceutical compositions and methods for the treatment of cancer, characterized in that the anticancer active substance SN-38 and 4-arm PEG are covalently bound to each other via a linker involving long-term controlled release of SN-38 Administration and dosage of types of anticancer agents. Background technique

[0002] Research is ongoing on PEGylation of low-molecular-weight drugs for increasing their stability in blood and enhancing their potency (Non-Patent Document 1). As such low-molecular-weight drugs, anticancer agents in the form of pegylated drugs such as camptothecin, irinotecan, doxorubicin, SN-38, paclitaxel, docetaxel, cisplatin, and gemcitabine have been developed .

[0003] Among these anticancer agents, SN-38 (formal name: 7-ethyl-10-hydroxycamptothecin) is an active ingredient of irinotecan (also known as "CPT-11"). In this sense, irinotecan is a prodrug of SN-38.

[0004] Irinotecan is an anti...

Examples

Embodiment 1

[0093]

[0094] 1. Production of Azido-Linker-SN-38

[0095]

[0096] SN38 (1.00 g, 2.55 mmol; Haorui) was suspended in 10 mL of anhydrous pyridine, then concentrated to dryness under vacuum at 50°C. Repeat this step with 10 mL of anhydrous THF. in N 2Under atmosphere, the resulting pale yellow solid was dissolved in 50 mL of anhydrous THF and 50 mL of anhydrous DMF, then cooled on ice. A 1.0 M solution of potassium tert-butoxide in THF (2.55 mL, 2.55 mmol) was added, forming an initial dark green color which became a thick orange suspension. After 15 min, 7-azido-1-cyano-2-hexyl N-(chloromethyl)-4-(N,N-diethylformamide)-phenylcarbamate (7.5 mL, 2.8 mmol) in THF. After 15 min at 4°C, the light orange mixture was allowed to warm to room temperature. After 1 hr, HPLC analysis (5 μL sample + 1 mL of CAN / TFA) indicated product / SN38=86 / 14. The pale yellow mixture was diluted with 200 mL of ethyl acetate, washed 2x100 mL of water, 100 mL of saturated aqueous NaCl, and dis...

Embodiment 2

[0108]

[0109] 1. Test conditions

[0110] Toxicity, pharmacokinetic and efficacy studies were performed by intravenously injecting (iv) each test sample into tumor-bearing rats under the conditions shown in Tables 1 and 2.

[0111] [Table 1]

[0112] Rat Groups and Treatments Used for Efficacy Studies

[0113] Group

n*

treat

Dose (mg / kg)**

Pathway / Schedule

1

5

Vehicle Control***

--

iv, qwk x 2 weeks

2

5

DFP-13318

50

iv, qwk x 2 weeks

3

5

DFP-13318

100

iv, qwk x 2 weeks

4

5

DFP-13318

200

iv, qwk x 2 weeks

5

5

irinotecan

70 / 50

iv, qwk x 2 weeks

[0114] Notes: *n: Number of animals, **Dose: Body weight adjusted (10 μL / g), ***Vehicle control: 10 mM acetate buffer, pH 5

[0115] [Table 2]

[0116] Auxiliary group for pharmacokinetic (PK) evaluation

[0117] Group

n*

treat

Dose (mg / kg)**

Pathway / Sched...

Embodiment 3

[0221]

[0222] This example was carried out to demonstrate that after intravenous administration of DFP-13318 for PK / PD (pharmacokinetics / pharmacodynamics) studies, DFP-13318 and its metabolite SN-38 were 29 were accumulated in tumor tissue collected from a tumor-bearing nude rat model.

[0223] In the PK / PD study, as shown in Table 15, 25 nude rats were used.

[0224] [Table 15]

[0225] Rat groups and treatments

[0226] Group

n*

treat

Dose (mg / kg)**

Pathway / Schedule

1

5

Vehicle Control***

--

iv, qwk x 2 weeks

2

5

DFP-13318

50

iv, qwk x 2 weeks

3

5

DFP-13318

100

iv, qwk x 2 weeks

4

5

DFP-13318

200

iv, qwk x 2 weeks

5

5

irinotecan

70 / 50

iv, qwk x 2 weeks

[0227] Notes: *n: number of animals, **dose: body weight adjusted (10 μL / g), ***vehicle control: 10 mM acetate buffer, pH 5.

[0228] Twenty-five tumor fragments (with 20...

Images