ES2354434T3 - PREPARATION OF A WATER SOLUTION CONTAINING A CAMPTOTECHINE. - Google Patents

Abstract

A preparation in aqueous solution containing 7 ethyl-10-piperidinopiperidinocarbonyloxychoxyteothecin, said preparation comprising the following components (A) and (B): (A) 7-ethyl-10-piperidinopiperidinocarbonyloxy camptothecin and (B) Acetic acid and sodium acetate, and the solution between 2 and 5 having a pH.

Description

Technical Field [0001] The present invention relates to a preparation in stable aqueous solution having excellent solubility for camptothecins.

Background in the art [0002] Camptothecin (CPT) is an alkaloid found in the fruits and roots of the tree of happiness (camptotheca acuminata) in China. 7-Ethyl-10-piperidinopiperidinocarbonylaxicamptothecin (CPT-11) (patent document 1), which is a semi-synthetic derivative of camptothecin, is an important compound since it has the high antitumor activity of camptothecin simultaneously at a reduced toxicity. Said 7-ethyl-10-piperidinopiperidinocarbonylaxyaxoteothecin is metabolized in the living organism to produce 7-ethyl-10-hydroxycamptothecin (SN-38) which is a semi-synthetic derivative that exhibits such activity (patent document 2). The administration of camptothecins such as 7-ethyl-10-piperidinopiperidinocarbonyloxymptothecin is mainly carried out by intravenous injection. Accordingly, camptothecins such as 7-ethyl-10-piperidinopiperidinocarbonyloxymptothecin are currently commercially available and are used as preparations that have been isotonized with sorbitol or the like. Several attempts have been made to produce camptothecin preparations, including among the examples of such attempts a controlled release preparation in which a camptothecin derivative is incorporated into a collagen and 2-hydroxyethyl methacrylate copolymer (patent document 3) and a controlled release preparation in which camptothecin or a derivative thereof is included in a vehicle comprising an acetic polyacid copolymer and a glycolic acid copolymer (patent document 4). However, camptothecins have a low water solubility and heating is necessary to obtain a preparation in aqueous solution, and there is a demand for the development of an aqueous solution preparation containing camptothecins that can be produced in a simple way without the need heating

[Patent document 1] Japanese patent publication No. 1991-4077 [Patent document 2] Japanese patent publication No. 1987-47193 [Patent document 3] Open Japanese patent application No. 1995-277981 [Patent document 4] Application Japanese Patent No. 1998-17472

U.S. Patent 6,476,043 B1 describes a medicinal product with a reduced gastrointestinal toxicity, comprising a solution of a camptothecin derivative and a solution consisting essentially of sodium chloride.

JP 2004 277374 A describes a preparation in aqueous solution containing camptothecins and excipients.

Description of the invention Problems that are solved with the invention [0004] One of the objects of the present invention is to provide a preparation in aqueous solution containing camptothecins that does not require heating for its production, the camptothecins having been solubilized in a stable manner.

Means for solving the problems [0005] In view of the situation described, the authors of the present invention have carried out an exhaustive study and have observed that when acetic acid and sodium acetate are incorporated in the preparation in aqueous solution containing camptothecins , and the preparation in aqueous solution is adjusted to a particular pH range, the solubility of the camptothecins in the aqueous solution increases and a stable aqueous solution preparation containing camptothecins having a solubility greater than that of the camptothecins of conventional products. The present invention has been completed on the basis of said finding. [0006] Accordingly, the present invention provides a preparation in aqueous solution containing a camptothecin, said preparation comprising the following components (A) and (B).

(TO)

 The camptothecin defined in claim 1, and

(B)

 Acetic acid and sodium acetate, and

the preparation having a pH between 2 and 5.

Merits of the invention [0007] In the case of the aqueous solution preparation of the present invention, camptothecin can be dissolved in a high concentration without requiring heating in the production process.

Best embodiments of the invention [0008] Component (A) is the effective component of the aqueous solution preparation of the present invention. Said camptothecin is 7-ethyl-10-piperidinopiperidinocarbonyloxymptothecin (hereinafter sometimes referred to as CPT-11). [0009] The sodium acetate in component (B) used in the aqueous solution preparation of the present invention can be generated by adding acetic acid and an alkaline agent to the aqueous solution preparation. Examples of alkaline agents used in such a case include sodium hydroxide, sodium carbonate and sodium hydrogen carbonate, the use of sodium hydroxide being preferable. Alternatively, sodium acetate can be generated in the preparation in aqueous solution by saline exchange with another compound. [0010] The aqueous solution preparation of the present invention preferably contains component (B), in particular acetic acid and sodium acetate in a content of between 0.1 and 10% by weight as regards acetic acid.

The content of acetic acid and sodium acetate in terms of acetic acid per 100 mg of camptothecin in the aqueous solution preparation of the present invention is preferably in the range of 10 to 2000 mg, more preferably 10 to 1000 mg, especially preferably from 20 to 500 mg in order to improve the solubility of camptothecin in the aqueous solution preparation. [0011] In addition, the incorporation into the aqueous solution preparation of the present invention of component (C), namely (i) cyclodextrin, (ii) ascorbic acid and sodium ascorbate, (iii) propylene glycol or (iv) at least a compound selected from the group consisting of sodium hydrogen sulfite, sodium sulphite, potassium pyrosulfite, sodium erythorbate, sodium thioglycolate, sodium pyrosulfite and thioglycerin, is preferable since such incorporation improves the solubility of camptothecin in the preparation.

[0012] Cyclodextrin (i) of component (C) is an irreducible maltooligosaccharide comprising 6 to 12 glucose molecules that have been cycled through a -1,4-glucosidic junction; Examples include -cyclodextrin, -cyclodextrin, -cyclodextrin and derivatives thereof. Examples of cyclodextrin derivatives include maltosyl cyclodextrin, glycosyl cyclodextrin, dimethyl cyclodextrin and hydroxypropyl cyclodextrin. Preferable examples of cyclodextrins include -cyclodextrin, -cyclodextrin and hydroxypropyl -cyclodextrin. [0013] The aqueous solution preparation of the present invention preferably contains cyclodextrin in a content between 1 and 20% by weight, in particular 1.5 to 14% by weight, with a view to improving the solubility of camptothecin . With a view to improving the solubility of camptothecin in the aqueous solution preparation, the cyclodextrin content per 100 mg of camptothecin in the aqueous solution preparation of the present invention is preferably in the range of 30 to 1000 mg, in in particular, from 90 to 700 mg.

When cyclodextrin is used, the content of component (B), in particular acetic acid and sodium acetate, is preferably used in a content as regards acetic acid comprised between 0.1 and 5.0% by weight, more preferably from 0.3 to 3.0% by weight, with 0.5 to 2.0% by weight being preferable in order to improve the solubility of camptothecin. [0014] The incorporation into the aqueous solution preparation of the present invention of component (C) (ii) ascorbic acid and sodium ascorbate is preferable, since the resulting aqueous solution preparation will exhibit a better solubility of camptothecin.

[0015] Sodium ascorbate can be generated by adding an alkaline agent to ascorbic acid in the aqueous solution preparation. Examples of alkaline agents employed in such a case include sodium hydroxide, sodium carbonate and sodium hydrogen carbonate, the use of sodium hydroxide being preferable. Alternatively, sodium ascorbate can be generated in the preparation in aqueous solution by saline exchange with another compound. The aqueous solution preparation of the present invention preferably contains ascorbic acid and sodium ascorbate in a content as regards ascorbic acid comprised between 5 and 20% by weight, in particular between 6 and 15% by weight.

When ascorbic acid and sodium ascorbate are used, component (B), in particular acetic acid and sodium ascorbate, is preferably used in a content as regards acetic acid comprised between 0.5 and 8% by weight, in particular , between 0.7 and 6% by weight in view of the solubility of camptothecin. [0017] The acetic acid, ascorbic acid and its sodium salts are preferably incorporated in a total content as regards the corresponding acids comprised between 0.1 and 20% by weight, more preferably between 0.3 and 15% by weight, being especially preferably between 0.4 and 14% by weight in view of the solubility of camptothecin.

Acetic acid, ascorbic acid and its sodium salts are preferably incorporated in a total content as regards the corresponding acids of 500 to 2000 mg, in particular 800 to 1500 mg per 100 mg of camptothecin in the preparation in aqueous solution of the present invention with a view to improving the solubility of camptothecin in the aqueous solution preparation.

[0018] When propylene glycol (iii) is used for component (C), it is preferably incorporated into the aqueous solution preparation of the present invention in a content between 40 and 70% by weight, in particular between 50 and 60% in weigh.

Preferably, propylene glycol is incorporated in a content between 1 and 4 g, in particular between 2 and 3 g per 100 mg of the camptothecin of the aqueous solution preparation of the present invention with a view to improving the solubility of the Camptothecin in the preparation in aqueous solution.

When propylene glycol is used, the content of component (B), in particular acetic acid and sodium acetate as regards acetic acid is preferably in the range of 0.5 to 8% by weight, more preferably between 0, 7 and 6% by weight with a view to improving the solubility of camptothecin. [0019] The incorporation into the aqueous solution preparation of the present invention of component (C) (iv), at least one compound selected from the group consisting of sodium hydrogen sulfite, sodium sulfite, potassium pyrosulfite, sodium erythorbate, sodium thioglycolate, sodium pyrosulfite and -thioglycerin is preferable since the resulting aqueous solution preparation will have a better solubility of camptothecin. [0020] The compound selected from the components (C)

(iv) it is preferably incorporated into the aqueous solution preparation of the present invention in a content between 1 and 300 mg, in particular, in a content between 10 and 200 mg per 100 mg of camptothecins with a view to improving the solubility of camptothecin.

[0021] The aqueous solution preparation of the present invention is preferably at a pH between 2 and 5, more preferably between 2.5 and 4.8 at room temperature (25 ° C) with a view to improving the solubility of camptothecin. Preferably, the pH is adjusted using an acid such as acetic acid, hydrochloric acid and sulfuric acid, or a sodium-containing alkali such as sodium hydroxide, sodium carbonate and sodium hydrogencarbonate. [0022] The aqueous solution preparation of the present invention is useful as an antitumor preparation, since camptothecin is an effective component that has excellent therapeutic effects for malignant tumors. Examples of applicable malignant tumors include lung cancer, uterine cancer, ovarian cancer, gastric cancer, colorectal cancer, breast cancer, lymphoma and pancreatic cancer. [0023] Preferably, the dosage form of the aqueous solution preparation of the present invention is a preparation for injection, in particular, a preparation for intravenous administration. In obtaining said preparation for injection, the preparation may contain, in addition to camptothecin, additives such as distilled water for injection, sugars represented by glucose, mannose and lactose, inorganic salts represented by sodium chloride, an organic amine such as HEPES and PIPES, and the components that are normally used in an injection such as stabilizers, excipients and a buffer. Camptothecin is preferably incorporated in the preparation for injection in an amount between 1 and 50 mg / mL, in particular in an amount between 10 and 30 mg / mL.

Example [0024] The present invention will be described in greater detail with the examples; however, the present invention should not be considered limited by it.

Example 1 [0025] Acetic acid was added to the aqueous solution presented in Table 1 to adjust the pH and 250 mL to 500 mg of CPT-11 was added to 10 mL of this solution. The mixture was subjected to ultrasound for 10 minutes for dispersion and dissolution of CPT-11 in the aqueous solution and stirred at room temperature during the period indicated in Table 1. Next, the solution was partitioned into aliquots and it was centrifuged at 3000 r / min for 30 minutes, and the supernatant was filtered through a 0.45 µm filter. 1 mL of the filtrate was accurately measured and up to 50 mL was completed with 90% aqueous methanol solution. The amount of CPT-11 in the solution was measured by HPLC under the conditions described below. [0026] HPLC conditions: Column: Symmetry Shield RP18 (3.5 µm, 4.6 x 50 mm) Column temperature: 50ºC Flow rate: 2.0 mL / min Mobile phase: solution A (50 mmol / L format buffer ( pH 5.5) / acetonitrile / methanol = 850/100/50) and solution B (50 mmol / L format buffer (pH 5.5) / acetonitrile / methanol = 750/250/50). Linear gradient of solution B from 0 to 100% in 15 minutes, followed by 5 minutes of equilibrium with 100% solution A. Injected quantity: 10 µL Detection wavelength: 254 nm [0027] Table 1 shows the measurement results for the amount of CPT-11 in each aqueous solution after stirring for 1 or 2 days at room temperature. The results are shown in the amount of CPT-11 in 1 mL of aqueous solution (CPT-11 in mg / mL).

[0028]

Table 1

Amount (mg) of components added per 5 mL of aqueous solution

pH of aqueous solution * 1 Stirring period

Sodium acetate

Cyclodextrin type 1 day 2 days

Examples of the present invention

one

100 - 4.0 28.07 27.87

2

100 ß 92.5 4.0 29.46 29.13

3

100  336 4.0 31.66 31.52

4

100  672 4.0 30.89 32.09

5

100 Hydroxypropyl ß 308 4.0 31.12 31.18

Comparative examples

one

250 lactic acid 4.0 - 19.03

2

Malic Acid 250 4.0 - 18.89

3

Citric Acid 250 4.0 - 20.06

1 The pH was adjusted by adding acetic acid

[0029] All preparations in aqueous solution which

they contained camptothecin according to the present invention 10 exhibited excellent solubility for CPT-11. For other

part, these preparations in aqueous solution did not present

no color change or precipitation of crystals when

they were left at room temperature (25 ° C) for 3 days without

To be in the shade Also, no precipitation of CPT-11 crystals was perceived after stirring the

Preparations

eleven

Example 2 [0030] To 250 mL of the aqueous solution presented in Table 2, 250 to 500 mg of CPT-11 was added. He underwent

Ultrasound the mixture for 10 minutes for the dispersion and dissolution of CPT-11 in the aqueous solution, and it was stirred at room temperature during the period indicated in Table 2. Next, a distribution was made by aliquots and centrifuged at 3000 r / min for 30 minutes and

10 the supernatant was filtered through a 0.45 µm filter. 1 mL of the filtrate was accurately measured and up to 50 mL was completed with 90% aqueous methanol solution. The amount of CPT-11 in the solution was measured by HPLC under the same conditions as in example 1.

[0031] Table 2 shows the measurement results for the amount of CPT-11 in each of the aqueous solutions after stirring for 1 to 2 days at room temperature. The results are shown in the amount of CPT-11 in 1 mL of aqueous solution (CPT-11 in mg / mL).

20 [0032]

Table 2

No.

Amount (mg) of the components added per 5 mL of the aqueous solution pH of the aqueous solution Stirring period

Acetic acid

Sodium acetate Ascorbic acid NaOH 1 day 2 days

Examples of the present invention

6

200 twenty 700 2.8 44.54 44.61

7

200 twenty 500 2.9 38.70 38.45

8

200 fifty 700 3.2 43.64 44.07

9

200 100 700 3.6 45.87 47.24

10

200 twenty 700 fifteen 3.1 43.45 43.56

eleven

200 twenty 700 twenty 3.2 41.97 41.79

12

200 twenty 700 fifty 3.7 42.41 42.50

13

200 twenty 700 100 4.2 38.16 39.11

Comparative example

4

250 4.0 * 2 - 20.91

* 2 The pH was adjusted by adding sodium hydroxide.

[0033] The aqueous solution preparations containing the camptothecin according to the present invention, No. 6 to 13, exhibited excellent solubility for CPT-11. On the other hand, these preparations in aqueous solution did not show any color change or precipitation of crystals when they were left at room temperature (25 ° C) for 3 days without being in the shade. Likewise, no precipitation of CPT-11 crystals was perceived after the agitation of the

10 preparations On the other hand, the preparation containing only ascorbic acid showed insufficient solubility.

Example 3

[0034] Acetic acid was added to the aqueous solution shown in Table 3 to adjust the pH to 4.0 and 250 mL to 500 mg of CPT-11 was added to 10 mL of this solution. The mixture was ultrasound for 10 minutes for dispersion and dissolution of CPT-11 in the aqueous solution and

The mixture was stirred at room temperature for the period indicated in Table 3. The solution was then distributed in aliquots and centrifuged at 30 r / min for 30 minutes and the supernatant filtered through a 0 filter, 45 µm 1 mL of filtrate was accurately measured and

25 completed up to 50 mL with 90% aqueous methanol solution. The amount of CPT-11 in the solution was measured under the same conditions as in example 1.

13

[0035] Table 3 shows the results of the measurements for the amount of CPT-11 in each aqueous solution after stirring for 1 or 2 days at room temperature. The results are shown as the amount of CPT11 in 1 mL of aqueous solution (CPT-11 in mg / mL).

[0036]

Table 1

No.

Amount (mg) of components added per 5 mL of aqueous solution pH of aqueous solution * 3 the Stirring period

 Sodium acetate

Component added 1 day 2 days

Examples of the present invention

14

30 Sodium Hydrogen Sulphite 200 4.0 25.38 25.30

fifteen

30 100 sodium sulphite 4.0 27.93 27.82

16

30 Sodium Thioglycolate 50 4.0 22.15 22.38

17

30 200 potassium pyrosulfite 4.0 25.70 25.79

18

30 Sodium Pyrosulfite 50 4.0 21.80 21.97

19

30 -thioglycerin 50 4.0 19.63 20.32

twenty

30 Sodium Erythorbate 50 4.0 21.99 21.69

* 3 The pH was adjusted by adding acetic acid

[0037] Preparations in aqueous solution containing camptothecin according to the present invention, No. 14 to 20, exhibited excellent solubility of CPT-11. On the other hand, these preparations in aqueous solution did not show any color change or precipitation of crystals when

15 were left at room temperature (25 ° C) for 3 days without being in the shade. Likewise, no

14

precipitation of crystals of CPT-11 after stirring the preparations.

Example 4 [0038] They were added to 10 mL of aqueous solution at pH 4.0 containing 100 mg of sodium acetate, 20 mg of acetic acid, 60 mg of sodium sulphite and 3000 mg of propylene glycol of 250 to 500 mg of CPT -11 and the mixture was ultrasound for 10 minutes for dispersion and dissolution of CPT-11 in the aqueous solution. Next, the amount of CPT11 was measured per 1 mL of aqueous solution (CPT-11 mg / mL) by repeating the procedure of example 1, and the amount was 32.26 mg / mL on day 1 and 31.20 mg / mL on day 2. In the comparative solution that did not contain sodium acetate, acetic acid or sodium sulphite, the amount of CPT-11 dissolved was 18.46 mg / mL on day 1 and 18.12 mg / mL on day 2.

Example 5 [0039] The following preparations for injection, 1 to 7, were obtained following the same procedure as described above. To 100 mL of the solution having several additives, 100 mg of irinotecan hydrochloride (CPT-11) was added and the mixture was stirred thoroughly to dissolve the irinotecan hydrochloride. To this solution was added the solution that had several additives preliminary dissolved in it to a total volume of 5 mL.

Preparation 1 [0040]

Irinotecano hydrochloride

100 mg

Sodium acetate Acetic acid

50 mg 120 mg

fifteen

Water for injection 5 mL in total pH 4.0

Preparation 2

[0041]

Irinotecan hydrochloride 100 mg Sodium acetate 100 mg Acetic acid 380 mg ß-cyclodextrin 92.5 mg Water for injection 5 mL in total pH 4.0

Preparation 3

[0042]

Irinotecan hydrochloride 100 mg Acetic acid 380 mg Sodium hydroxide 46 mg -cyclodextrin 672 mg Water for injection 5 mL in total pH 4.0

Preparation 4

[0043]

Irinotecan hydrochloride 100 mg Ascorbic acid 700 mg Acetic acid 200 mg Water for injection 5 mL in total pH 3.6

Preparation 5

[0044]

Irinotecan hydrochloride 100 mg

16

Sodium acetate 20 mg Sodium ascorbate 700 mg Acetic acid 200 mg Water for injection 5 mL in total pH 4.5

Preparation 6

[0045]

Irinotecan hydrochloride 100 mg Sodium ascorbate 20 mg Sodium hydroxide 100 mg Acetic acid 20 mg Water for injection 5 mL in total pH 4.5

Preparation 7

[0046]

Irinotecan hydrochloride 100 mg Sodium acetate 30 mg Acetic acid 100 mg Sodium sulphite 100 mg Water for injection 5 mL in total pH 4.0

[0047] The aqueous solution preparations containing camptothecin (injections) of preparations 1 to 7 were yellow transparent aqueous solutions and no precipitation of irinotecan hydrochloride was perceived in any of the solutions.

Claims (4)

1. A preparation in aqueous solution containing 7-ethyl-10-piperidinopiperidinocarbonyloxyacoteothecin, said preparation comprising the following components

(TO)

 and (B):

(TO)

7-ethyl-10-piperidinopiperidinocarbonyloxy camptothecin and

(B)

 Acetic acid and sodium acetate, and the solution between 2 and 5 having a pH.

2. The aqueous solution preparation containing 7-ethyl-10-piperidinopiperidinocarbonyloxy camptothecin according to claim 1, said preparation further comprising component (C)

(C)

(i)

cyclodextrin

(ii)

 ascorbic acid and sodium ascorbate

(iii) propylene glycol, or

(iv)

 at least one compound selected from the group consisting of sodium hydrogen sulfite, sodium sulphite, potassium pyrosulfite, sodium erythorbate, sodium thioglycolate, sodium pyrosulfite and -thioglycerin.

3.

 The aqueous solution preparation containing 7-ethyl-10-piperidinopiperidinocarbonyloxy camptothecin according to claim 1 or 2, said aqueous solution preparation being an antitumor preparation.

Four.

 The aqueous solution preparation containing 7-ethyl-10-piperidinopiperidinocarbonyloxy camptothecin according to any one of claims 1, 2 or 3, the

preparation

in solution watery a  preparation for

injection.

18