PHARMACEUTICAL COMPOSITION COMPRISING IRINOTECAN FREE BASE FOR ORAL ADMINISTRATION

Abstract

Provided is a pharmaceutical composition including irinotecan free base. The pharmaceutical composition according to the presently claimed subject matter enables the effective oral administration of irinotecan and as such, can increase the convenience of administration of irinotecan and provide a high in vivo absorption rate, compared to conventional injections.

Claims

1. A pharmaceutical composition for oral administration consisting of: 0.1˜10% by weight of irinotecan free base; 5˜80% by weight of polyoxylglyceride; 5˜80% by weight of polyethylene glycol; 5˜80% by weight of acyl glycerol; and 5˜25% by weight of sorbitan fatty acid ester.

2. The pharmaceutical composition according to claim 1, consisting of: 0.1˜10% by weight of irinotecan free base; 30˜70% by weight of polyoxylglyceride; 15˜40% by weight of polyethylene glycol; 5˜20% by weight of acyl glycerol; and 5˜20% by weight of sorbitan fatty acid ester.

3. The pharmaceutical composition according to claim 1, wherein the polyoxylglyceride is one or more selected from the group consisting of caprylocaproyl polyoxylglyceride, lauroyl polyoxylglyceride, linoleoyl polyoxylglyceride, oleoyl polyoxylglyceride, and stearoyl polyoxylglyceride.

4. The pharmaceutical composition according to claim 3, wherein the polyoxylglyceride is caprylocaproyl polyoxylglyceride.

5. The pharmaceutical composition according to claim 1, wherein the polyethylene glycol is selected from the group consisting of polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, and polyethylene glycol 900.

6. The pharmaceutical composition according to claim 1, wherein the acyl glycerol is one or more selected from the group consisting of glyceryl behenate, glyceryl oleate, glyceryl stearate, glyceryl palm itostearate, and a complex thereof.

7. The pharmaceutical composition according to claim 6, wherein the acyl glycerol is an oleoyl glycerol complex having 30 to 65% by weight of monooleoyl glycerol contents; 15 to 50% by weight of dioleoyl glycerol contents; and 2 to 20% by weight of trioleoyl glycerol contents.

8. The pharmaceutical composition according to claim 1, wherein the sorbitan fatty acid ester is one or more selected from the group consisting of sorbitan monostearate, sorbitan diisostearate, sorbitan sesquistearate, sorbitan sesquiisostearate, sorbitan tristearate, sorbitan triisostearate, sorbitan monooleate, sorbitan dioleate, sorbitan sesquioleate, sorbitan trioleate, sorbitan monolaurate, and sorbitan monopalmitate.

9. The pharmaceutical composition according to claim 8, wherein the sorbitan fatty acid ester is sorbitan monooleate.

10. The pharmaceutical composition according to claim 1, consisting of: 0.1˜10% by weight of irinotecan free base; 5˜80% by weight of caprylocaproyl polyoxylglyceride; 5˜80% by weight of polyethylene glycol; 5˜80% by weight of an oleoyl glycerol complex; and 5˜25% by weight of sorbitan monooleate.

11. The pharmaceutical composition according to claim 1, consisting of: 0.1˜10% by weight of irinotecan free base; 30˜70% by weight of caprylocaproyl polyoxylglyceride; 15˜40% by weight of polyethylene glycol; 5˜20% by weight of an oleoyl glycerol complex; and 5˜20% by weight of sorbitan monooleate.

12. The pharmaceutical composition according to claim 1, consisting of: 1.45% by weight of irinotecan free base; 58.08% by weight of caprylocaproyl polyoxylglyceride; 21.69% by weight of polyethylene glycol 300; 9.68% by weight of an oleoyl glycerol complex; and 9.10% by weight of sorbitan monooleate.

13. The pharmaceutical composition according to claim 1, consisting of: 1.43% by weight of irinotecan free base; 34.36% by weight of caprylocaproyl polyoxylglyceride; 38.48% by weight of polyethylene glycol 400; 16.18% by weight of an oleoyl glycerol complex; and 9.55% by weight of sorbitan monooleate.

14. A pharmaceutical composition for oral administration in the form of a capsule, which is obtained by filling the pharmaceutical composition for oral administration according to claim 1 in a capsule.

Description

DESCRIPTION OF DRAWINGS

[0015] FIG. 1 shows the appearance of the pharmaceutical composition for oral administration, containing irinotecan free base, prepared in Example 1.

[0016] FIG. 2 shows the appearance of the formulation prepared in Example 3.

[0017] FIG. 3 shows the appearance of the formulation prepared in Comparative Example 1.

BEST MODE

[0018] As used herein, the term “irinotecan free base” refers to a compound in the non-salt form, i.e., a compound in the free base form.

[0019] The present invention provides a pharmaceutical composition for oral administration consisting of: 0.1˜10% by weight of irinotecan free base; 5˜80% by weight of polyoxylglyceride; 5˜80% by weight of polyethylene glycol; 5˜80% by weight of acyl glycerol; and 5˜25% by weight of sorbitan fatty acid ester.

[0020] Irinotecan free base used as an active ingredient in the pharmaceutical composition of the present invention may be used in a therapeutically effective amount. For example, it may be present in an amount ranging from 1 to 30 mg, typically about 15 mg, per ml of unit formulation of the pharmaceutical composition.

[0021] The pharmaceutical composition of the present invention comprises irinotecan free base as an active ingredient; and polyoxylglyceride, polyethylene glycol, acyl glycerol, and sorbitan fatty acid ester in specific amounts. In an embodiment of the present invention, there is provided a pharmaceutical composition for oral administration consisting of: 0.1˜10% by weight of irinotecan free base; 30˜70% by weight of polyoxylglyceride; 15˜40% by weight of polyethylene glycol; 5˜20% by weight of acyl glycerol; and 5˜20% by weight of sorbitan fatty acid ester.

[0022] In the pharmaceutical composition of the present invention, the polyoxylglyceride, which is used as a solubilizing agent, may be one or more selected from the group consisting of caprylocaproyl polyoxylglyceride, lauroyl polyoxylglyceride, linoleoyl polyoxylglyceride, oleoyl polyoxylglyceride, and stearoyl polyoxylglyceride, preferably caprylocaproyl polyoxylglyceride (e.g., Labrasol™).

[0023] The polyethylene glycol, which is used as a stabilizing agent, may be selected from the group consisting of polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, and polyethylene glycol 900.

[0024] The acyl glycerol, which is used as an emulsifying agent, includes monoacyl glycerol, diacyl glycerol, triacyl glycerol, or a complex thereof, unless otherwise indicated. For example, the acyl glycerol may be one or more selected from the group consisting of glyceryl behenate, glyceryl oleate, glyceryl stearate, glyceryl palmitostearate, and a complex thereof. Preferably, the acyl glycerol may be an oleoyl glycerol complex having 30 to 65% by weight of monooleoyl glycerol contents; 15 to 50% by weight of dioleoyl glycerol contents; and 2 to 20% by weight of trioleoyl glycerol contents. In an embodiment, the oleoyl glycerol complex may be an oleoyl glycerol complex having 32 to 52% by weight of monooleoyl glycerol contents; 30 to 50% by weight of dioleoyl glycerol contents; and 5 to 20% by weight of trioleoyl glycerol contents [e.g., Peceol™ (Gattefosse)]. In another embodiment, the oleoyl glycerol complex may be an oleoyl glycerol complex having 55 to 65% by weight of monooleoyl glycerol contents; 15 to 35% by weight of dioleoyl glycerol contents; and 2 to 10% by weight of trioleoyl glycerol contents [e.g., CAPMUL™ (Abitec)].

[0025] The sorbitan fatty acid ester, which is a nonionic surfactant, may be one or more selected from the group consisting of sorbitan monostearate, sorbitan diisostearate, sorbitan sesquistearate, sorbitan sesquiisostearate, sorbitan tristearate, sorbitan triisostearate, sorbitan monooleate, sorbitan dioleate, sorbitan sesquioleate, sorbitan trioleate, sorbitan monolaurate, and sorbitan monopalmitate, preferably sorbitan monooleate (e.g., Span™ 80).

[0026] In an embodiment of the present invention, there is provided a pharmaceutical composition for oral administration consisting of: 0.1˜10% by weight of irinotecan free base; 5˜80% by weight of caprylocaproyl polyoxylglyceride; 5˜80% by weight of polyethylene glycol; 5˜80% by weight of an oleoyl glycerol complex; and 5˜25% by weight of sorbitan monooleate.

[0027] In another embodiment of the present invention, there is provided a pharmaceutical composition for oral administration consisting of: 0.1˜10% by weight of irinotecan free base; 30˜70% by weight of caprylocaproyl polyoxylglyceride; 15˜40% by weight of polyethylene glycol; 5˜20% by weight of an oleoyl glycerol complex; and 5˜20% by weight of sorbitan monooleate.

[0028] In a particularly preferred embodiment of the present invention, there is provided a pharmaceutical composition for oral administration consisting of: 1.45% by weight of irinotecan free base; 58.08% by weight of caprylocaproyl polyoxylglyceride; 21.69% by weight of polyethylene glycol 300; 9.68% by weight of an oleoyl glycerol complex; and 9.10% by weight of sorbitan monooleate.

[0029] In another particularly preferred embodiment of the present invention, there is provided a pharmaceutical composition for oral administration consisting of: 1.43% by weight of irinotecan free base; 34.36% by weight of caprylocaproyl polyoxylglyceride; 38.48% by weight of polyethylene glycol 400; 16.18% by weight of an oleoyl glycerol complex; and 9.55% by weight of sorbitan monooleate.

[0030] Said pharmaceutical composition of the present invention is obtained in the form of a clear oily solution, i.e., in the form of a lipid solution (e.g., see FIG. 1) and may be directly applied to a patient. Therefore, the pharmaceutical composition of the present invention may be formulated as a pharmaceutical composition for oral administration in the form of a lipid solution.

[0031] In addition, since the pharmaceutical composition of the present invention is obtained in the form of a clear oily solution (i.e., in the form of a lipid solution), it can be formulated into a capsule form without the formation of a precipitate. Accordingly, the present invention includes a pharmaceutical composition for oral administration in the form of a capsule, which is obtained by filling the pharmaceutical composition for oral administration in the form of a lipid solution in a capsule. The capsule may be a capsule conventionally used in the field of pharmaceutics, preferably soft and hard capsules such as gelatin capsules, pullulan capsules, HPMC capsules, and the like.

[0032] The pharmaceutical composition for oral administration according to the present invention may be used to treat cancers, including lung cancer, gastric cancer, pancreatic cancer, non-Hodgkin's lymphoma, cervical cancer, head and neck cancer, brain tumor, ovarian cancer, colon cancer, rectal cancer, and the like.

[0033] The present invention will be described in further detail with reference to the following examples and experimental examples. These examples and experimental examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example 1: Preparation of a Pharmaceutical Composition for Oral Administration Comprising Irinotecan Free Base

[0034] A pharmaceutical composition for oral administration comprising irinotecan free base was prepared according to the components and amounts shown in Table 1. The amounts of Table 1 represent the % by weight of each component. Irinotecan free base was completely dissolved in methylene chloride. Polyoxylglyceride (Labrasol™) polyethylene glycol 300, and the oleoyl glycerol complex (Peceol™) were added thereto. The resulting solution was concentrated under reduced pressure at 40° C. to remove methylene chloride and then sorbitan fatty acid ester (Span™ 80) was added thereto. The resulting solution was stirred at 40° C. to prepare a clear oily solution. The appearance thereof is shown in FIG. 1.

TABLE-US-00001 TABLE 1 Amount L/I Components (% by weight) Active ingredient Irinotecan free base 1.45 Solubilizing agent Polyoxylglyceride (Labrasol ™) 58.08 Stabilizing agent Polyethylene glycol 300 21.69 Excipient Sorbitan fatty acid ester (Span ™ 80) 9.68 Emulsifying agent Oleoyl glycerol complex (Peceol ™) 9.10 Total 100.00

Example 2: Preparation of a Pharmaceutical Composition for Oral Administration Comprising Irinotecan Free Base

[0035] A pharmaceutical composition for oral administration comprising irinotecan free base was prepared according to the components and amounts shown in Table 2. The amounts of Table 2 represent the % by weight of each component. Irinotecan free base was completely dissolved in methylene chloride. Polyoxylglyceride (Labrasol™), polyethylene glycol 400, and the oleoyl glycerol complex (Peceol™) were added thereto. The resulting solution was concentrated under reduced pressure at 40° C. to remove methylene chloride and then sorbitan fatty acid ester (Span™ 80) was added thereto. The resulting solution was stirred at 40° C. to prepare a clear oily solution.

TABLE-US-00002 TABLE 2 Amount L/I Components (% by weight) Active ingredient Irinotecan free base 1.43 Solubilizing agent Polyoxylglyceride (Labrasol ™) 34.36 Stabilizing agent Polyethylene glycol 400 38.48 Excipient Sorbitan fatty acid ester (Span ™ 80) 9.55 Emulsifying agent Oleoyl glycerol complex (Peceol ™) 16.18 Total 100.00

Example 3: Preparation of a Pharmaceutical Composition for Oral Administration Comprising Irinotecan Free Base

[0036] A pharmaceutical composition for oral administration comprising irinotecan free base was prepared according to the components and amounts shown in Table 3. Irinotecan free base was completely dissolved in methylene chloride. Labrasol™, polyethylene glycol 300, and the oleoyl glycerol complex (Peceol™) were added thereto. The resulting solution was concentrated under reduced pressure at 40° C. to remove methylene chloride and then sorbitan fatty acid ester (Span™ 80) was added thereto. The resulting solution was stirred at 40° C. to prepare a clear oily solution. The obtained clear oily solution was filled into a HPMC capsule to prepare a pharmaceutical composition in the form of a capsule. The appearance thereof is shown in FIG. 2.

TABLE-US-00003 TABLE 3 Amount Amount L/I Components per capsule (% by weight) Active Irinotecan free base 7.5 mg 1.45 ingredient Solubilizing Polyoxylglyceride  0.3 mL 58.08 agent (Labrasol ™) Stabilizing Polyethylene glycol 300  0.1 mL 21.69 agent Excipient Sorbitan fatty acid ester 0.05 mL 9.68 (Span ™ 80) Emulsifying Oleoyl glycerol complex 0.05 mL 9.10 agent (Peceol ™) Total 100.00

Experimental Example 1: Measurements of the Amounts of Irinotecan

[0037] The amounts of irinotecan in the formulations prepared in Examples 1 and 2 were measured. A certain amount of irinotecan standard was taken and dissolved in a mixed solution of acetonitrile, methanol, and acetic acid (100:100:1, v/v/v) to prepare a standard solution. The test solutions were prepared by dissolving the certain amount of each pharmaceutical composition in a mixed solution of acetonitrile, methanol, and acetic acid (100:100:1, v/v/v). The prepared standard solution and test solutions were analyzed with a HPLC under the following conditions; and the amounts of irinotecan were calculated by the following equation.

[0038] <HPLC conditions>

[0039] HPLC: Shimadzu LC-20AD

[0040] Detector: Ultraviolet detector

[0041] Wavelength: 255 nm

[0042] Column: 4.6 mm×250 mm, 5 um, C18

[0043] Column temperature: 40° C.

[0044] Injection volume: 15 ul

Amount of rinotecan (%)=AT/AS*CS/CT*P  <Equation for calculating the amounts of irinotecan> [0045] AT: Peak area of irinotecan of the test solution [0046] AS: Peak area of irinotecan of the standard solution [0047] CS: Concentration of irinotecan of the standard solution (mg/ml) [0048] CT: Concentration of irinotecan of the test solution (mg/ml) [0049] P: Purity of the irinotecan standard

[0050] As the results thereof, the amount of irinotecan in the formulation prepared in Example 1 was confirmed to be 100.4%, and the amount of irinotecan in the formulation prepared in Example 2 was confirmed to be 100.2%.

Experimental Example 2: Evaluation of In Vivo Absorption Rate

[0051] The formulations prepared in Examples 1 and 2 were orally administered to ICR mice (6 weeks old, female), using a gastric sonde at a dose of 225 mg/kg. After the administration, blood samples were collected at 0 minute, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours from the mouse by retro-orbital sinus/plexus sampling and then centrifuged at 6000×g, at 4° C. for 20 min. Each supernatant was taken to obtain plasma samples. A mixture of acetonitrile and 1 mM phosphoric acid (9:1, v/v) (300 μL) was added to the obtained plasma samples (100 μL). Each resulting sample was stirred on the vortex mixer and then centrifuged at 14,000×g at 4° C. for 20 minutes. Each supernatant (200 μL) was taken and then 600 μL of 0.1 M potassium phosphate (pH 4.2) was added thereto. The concentrations of irinotecan and SN-38 in the blood samples were analyzed, using an HPLC-FLD detector.

[0052] The in vivo absorption patterns of the formulations prepared in Examples 1 and 2 in ICR mice were evaluated, using a HPLC under the following conditions.

[0053] <HPLC conditions>

[0054] HPLC: Agilent 1260

[0055] Detector: Fluorescence detector

[0056] Wavelength: 228(excitation)-543(emission) nm for 20 min(SN-38)

[0057] Column: 4.6 mm×250 mm, 5 um, C18

[0058] Column temperature: 30° C.

[0059] Injection volume: 30 ul

[0060] The pharmacokinetic parameters for irinotecan and its active metabolite (SN-38) were shown in Table 4 below.

TABLE-US-00004 TABLE 4 Material for C.sub.max T.sub.max AUC_.sub.0-8 h AUC_.sub.0-inf analysis (ng/ml) (h) (ng .Math. h/ml) (ng .Math. h/ml) Example 1 Irinotecan 2175.18 1 8237.02 10930.32 SN-38 319.05 0.5 1367.98 3224.13 Example 2 Irinotecan 2371.07 1 9053.62 12121.42 SN-38 361.95 0.5 1563.20 3718.80

[0061] As shown in Table 4, it can be seen that the pharmaceutical compositions obtained according to the present invention are rapidly absorbed with a Tmax of 1 hour and exhibits high bioavailability.

Comparative Examples

[0062] Formulations comprising irinotecan free base were prepared according to the components and amounts shown in Table 5. The amounts of Table 5 represent the % by weight of each component. Irinotecan free base was completely dissolved in methylene chloride. Any one of polyoxylglyceride (Labrasol™), polyethylene glycol 300, polyethylene glycol 400, oleoyl glycerol complex (Peceol™), and sorbitan fatty acid ester (Span™ 80) was added thereto. The resulting solutions were concentrated under reduced pressure at 40° C. for removing methylene chloride, so as to prepare the formulations of Comparative Examples 1 to 5. All of the formulations of Comparative Examples 1 to 5 were in the form of an opaque solution having precipitations. FIG. 3 shows the appearance of the formulation of Comparative Example 1.

TABLE-US-00005 TABLE 5 Comparative Example (% by weight) L/I Components 1 2 3 4 5 Active Irinotecan free base 1.48 1.48 1.48 1.48 1.48 ingredient Solubilizing Polyoxylglyceride 98.52 — — — — agent (Labrasol ™) Stabilizing Polyethylene glycol 300 — 98.52 — — — agent Polyethylene glycol 400 — — 98.52 — — Additive Excipient Sorbitan fatty acid ester — — — 98.52 — (Span ™ 80) Emulsifying Oleoyl glycerol complex agent (Peceol ™) — — — — 98.52 Total 100.00 100.00 100.00 100.00 100.00