WO2008056657A1

WO2008056657A1 - Lyophilized preparation comprising phenanthridine derivative

Info

Publication number: WO2008056657A1
Application number: PCT/JP2007/071542
Authority: WO
Inventors: Shinya Fujita; Hiroyuki Yoshida
Original assignee: Nippon Kayaku Kabushiki Kaisha
Priority date: 2006-11-07
Filing date: 2007-11-06
Publication date: 2008-05-15
Also published as: JP2010006704A

Abstract

Disclosed is a lyophilized preparation comprising a phenanthridine derivative represented by the general formula (A) or (B) and at least one saccharide selected from the group consisting of xylitol, glucose, lactose, maltose, trehalose and sorbitol. The lyophilized preparation has excellent storage stability and shows good redissolvability after being stored. Therefore, the lyophilized preparation can be prepared into a clinically useful pharmaceutical preparation for injection for use as an anti-tumor agent by dissolving the lyophilized preparation in water for injection or the like before use. (A) (B) wherein R1 represents a lower alkyl group having 1 to 5 carbon atoms; R represents an aliphatic hydrocarbon chain having 2 to 6 carbon atoms; X- represents an acid residue or a hydro acid residue.

Description

Specification

Lyophilized formulations of funinanthridine derivatives

Technical field

[0001] The present invention relates to a lyophilized preparation containing a phenanthridine derivative useful as an antitumor agent, and more particularly, comprising a phenanthridine derivative and a specific saccharide. It relates to lyophilized preparations that are dissolved in irrigation water and become pharmaceutical preparations for injection.

Background art

[0002] General formula (A) or general formula (B)

[Chemical 1]

[Wherein R represents a lower alkyl group having 1 to 5 carbon atoms, and R represents an aliphatic hydrocarbon chain having 2 to 6 carbon atoms. ]

Patent Document 1 describes that a phenanthridine derivative represented by a phenanthridine derivative represented by the formula (1) exhibits excellent antitumor effects against various tumor cell lines. But For lyophilized preparations using saccharides, there is no specific description.

[0003] Patent Document 1: Pamphlet of International Publication No. 1998/23614

Disclosure of the invention

Problems to be solved by the invention

[0004] The phenanthridine derivative represented by the general formula (A) or the general formula (B) is unstable in an aqueous solution and is difficult to use as it is as a pharmaceutical preparation for injection. In addition, the phenanthridine derivative represented by the general formula (A) or the general formula (B) can be simply dissolved in water and freeze-dried to obtain a freeze-dried preparation. It was difficult to use it as an injectable pharmaceutical preparation because of its low solubility and poor resolubility. Therefore, there has been a demand for a freeze-dried preparation that can be used as an injectable pharmaceutical preparation of the phenanthridine derivative represented by the general formula (A) or the general formula (B).

Means for solving the problem

[0005] As a result of intensive studies to solve the above problems, the present inventors have found that a freeze-dried preparation obtained by adding a specific saccharide becomes a stable and re-dissolvable pharmaceutical preparation for injection. The present invention has been completed.

That is, the present invention relates to the following (1) to (9).

(1) General formula (A)

[Chemical 3]

[Wherein, R represents a lower alkyl group having 1 to 5 carbon atoms, R represents an aliphatic hydrocarbon chain having 2 to 6 carbon atoms, and X— represents an acid residue or a hydrogen acid residue. ]

Phenanthridine derivatives represented by xylitol, glucose, lactose, maltose A freeze-dried preparation containing one or more sugars selected from the group consisting of sugar, trehalose and sorbitol.

(2) —General formula (B)

[Chemical 4]

[Wherein, R represents a lower alkyl group having 1 to 5 carbon atoms, and R represents an aliphatic hydrocarbon chain having 2 to 6 carbon atoms. ]

And a lyophilized preparation containing at least one saccharide selected from the group consisting of xylitol, glucose, lactose, maltose, trehalose and sorbitol.

(3) —The lyophilized preparation according to the above (1), wherein the R force of the general formula (A) is an S methyl group, R is a trimethylene group, and X— is a chloride ion.

(4) The lyophilized preparation according to the above (2), wherein the R force of the general formula (B) is an S methyl group and R is a trimethylene group.

(5) The lyophilized preparation according to any one of (1) to ( ⁴ ) above, wherein the saccharide is sorbitol, glucose or trehalose.

(6) The lyophilized preparation according to any one of (1) to (5) above, wherein the saccharide is glucose.

(7) The freeze-dried preparation according to any one of the above (1) to (6), which contains 0.25 to 9 parts by weight of a saccharide with respect to 1 part by weight of a phenanthridine derivative.

(8) The lyophilized preparation according to any one of (1) to (7) above, wherein the preparation contains 10 to 70% by weight of a phenanthridine derivative and 25 to 85% by weight of a saccharide.

(9) The freeze-dried preparation according to any one of (1) to (8) above, which is dissolved in an injectable solution and used as an injectable pharmaceutical preparation. The invention's effect

[0009] A freeze-dried preparation containing a phenanthridine derivative represented by the general formula (A) or the general formula (B) of the present invention and a specific saccharide has excellent storage stability and re-solubility. At the time of use, it can be dissolved in water for injection to make a pharmaceutical preparation for injection that is clinically useful as an antitumor agent.

BEST MODE FOR CARRYING OUT THE INVENTION

[0010] The contents of the present invention are described in detail below.

The lyophilized preparation of the present invention is one or more selected from the group consisting of a phenyridine derivative represented by the general formula (A) or the general formula (B), and xylitol, glucose, lactose, maltose, trehalose and sorbitol. Containing saccharides.

[0011] As the lower alkyl group having 15 carbon atoms in the general formula (A) or the general formula (B), for example, a methyl group, an ethyl group, an npropyl group, an isopropyl group, an nbutyl group, an isobutyl group, s butyl group, t butyl group, n pentyl group and the like. A methyl group is particularly preferable.

[0012] Examples of the aliphatic hydrocarbon chain having 2 to 6 carbon atoms in the general formula (A) or the general formula (B) include CH CH -CH CH CH CH CH CH (CH) CH — CH C (

2 2 2 2 2 2 3 2 2

CH) CH CH CH CH CH CH CH CH CH CH CH CH CH

3 2 2 2 2 2 2 2 2 2 2 2 2 2

Examples thereof include polymethylene chains having 2 to 6 carbon atoms, such as CH 2 CH 2 CH 2 CH—. In particular, C

2 2 2 2

C 3-4 polymethylene chains such as H CH CH CH CH CH CH— are preferred.

2 2 2 2 2 2 2

That's right. Of these, a trimethylene chain is particularly preferred.

[0013] The acid residue of X- in the general formula (A) is an acid residue that forms a normal salt, for example, a halide ion such as chloride ion, bromide ion, iodide ion, fluoride ion as X- And sulfate ion, nitrate ion, p-toluenesulfonate ion and the like. Further, the hydrogen acid residue is an acid residue that forms a hydrogen salt and has 1 or 2 hydrogen atoms, and examples thereof include hydrogen sulfate ion and dihydrogen phosphate ion. Of these, chloride ions are particularly preferred.

[0014] In the phenanthridine derivative represented by the general formula (A) used in the freeze-dried preparation of the present invention, a compound having R force S methyl group, R is trimethylene group, and X- is chloride ion is preferable. In addition, in the phenanthridine derivative represented by the general formula (B), a compound in which 1 ^ is a methyl group and R is a trimethylene group is preferable.

The phenidine lysine derivative represented by the general formula (A) or the general formula (B) used in the freeze-dried preparation of the present invention can be produced by the method described in Patent Document 1, but is not limited to the production method. Also, those obtained by other manufacturing methods of! / Can be used in the present invention.

[0015] The phenanthridine derivative represented by the general formula (A) easily releases 1 equivalent of an acid derived from an X-acid residue or a hydrogen acid residue from the molecule by base treatment. The structure of the phenanthridine derivative represented by (B) can be taken, and conversely, the phenanthridine derivative represented by the general formula (B) can be converted with an acid containing an X-acid residue or a hydrogen acid residue. By treatment, a phenanthridine derivative represented by the general formula (A) can be easily obtained. Depending on the conditions, the phenanthridine derivative represented by the general formula (A) and the phenanthridine derivative represented by the general formula (B) may exist in a mixed state.

[0016] The saccharide contained in the lyophilized preparation of the present invention improves the stability and resolubility of the lyophilized preparation containing the phenanthridine derivative represented by the general formula (A) or (B). As long as it is not particularly limited, one or more saccharides selected from xylitol, glucose, lactose, maltose, trehalose, sorbitol, etc. can be mentioned. In the case of a lyophilized preparation of a phenanthridine derivative in which a force S methyl group, R is a trimethylene group, X— is a chloride ion, or an R force S methyl group of the general formula (B), and a phenanthridine derivative in which R is a trimethylene group Glucose that has been used as a pharmaceutical additive is particularly preferred. In the present invention, saccharides include hydrates thereof.

The amount used is usually about 0.25 to 9 parts by weight per 1 part by weight of the phenanthridine derivative contained in the lyophilized preparation, and is preferably in the range of about 0.5 to 4 parts by weight. A range of about 0.7 to 2 parts by weight is particularly preferred.

[0017] Contains a phenanthridine derivative represented by the general formula (A) or the general formula (B) and one or more saccharides selected from the group consisting of xylitol, glucose, lactose, maltose, trehalose, sorbitol, and the like. The content of each lyophilized product In particular, a phenidine lysine derivative of 10 to 70% by weight, a saccharide lysine derivative of 20 to 60% by weight and a saccharide of 35 to 70% by weight are particularly preferable.

[0018] The freeze-dried preparation of the present invention is prepared by, for example, dissolving a phenidine lysine derivative represented by the general formula (A) or the general formula (B) and a saccharide in water for injection and the like, and after aseptic filtration, into a vial or the like. After filling, freezing and vacuum lyophilization in which water is sublimated under reduced pressure, the vial is purged with nitrogen, sealed with a rubber stopper, and wrapped with an aluminum cap.

When preparing a freeze-dried preparation of the present invention by dissolving a phenanthridine derivative and a saccharide in water for injection or the like, the phenanthridine represented by the general formula (A) or the general formula (B) in 1 mL of a solution such as water for injection The content of the derivative is not particularly limited, but is preferably about 0.1 mg to 50 mg, and particularly preferably about 1 mg to 30 mg.

If necessary, the lyophilized preparation of the present invention may contain various auxiliary agents used in ordinary pharmaceuticals, that is, auxiliary agents such as preservatives, soothing agents, emulsifiers, and carriers.

[0019] The freeze-dried preparation thus obtained can be stored for a long period of time even at room temperature, and is used by re-dissolving water for injection or 5% glucose solution as a solution at the time of use. If necessary, the solution may be pharmaceutically acceptable solvent (propylene glycol, polyethylene glycol, etc.), solubilizer (ethanol, polyoxyethylene hydrogenated castor oil 60, etc.), buffer (sodium taenoate, Sodium lactate etc.), pH adjusters (hydrochloric acid, sodium hydroxide etc.) etc. may be added.

[0020] Hereinafter, the present invention will be described in more detail by way of examples. The present invention is not limited to these examples. In the examples, “part” means “part by weight” and “%” means “% by weight”.

[0021] Example 1

2, 3 methylenedioxy 7 hydroxy-8 methoxy 5, 6 propanobenzo [c] phenanthridinium chloride (R force S methyl group of formula (A), R is trimethylene group, X— is chloride in water for injection 200 mg and 200 mg of xylitol were added and dissolved by heating. Water for injection is added to make a total volume of 10 mL. After aseptic filtration, this solution is filled in 2 mL glass vials, lyophilized according to a conventional method, and the resulting sample vial is purged with nitrogen and sealed with a rubber stopper. Tighten it with an aluminum cap. A lyophilized preparation of tylenedioxy 7-hydroxy-8-methoxy 5,6-propanobenzo [c] phenanthrene lysium chloride was obtained.

[0022] Example 2

Add 2,3 methylenedioxy-7 hydroxy-8 methoxy-5,6 propanobenzo [c] phenanthridinium chloride 200 mg and 200 mg glucose to water for injection and dissolve by heating. Water for injection is added to make up a total volume of 10 mL. This solution is aseptically filtered and then filled into 2 mL glass vials, lyophilized according to a conventional method, and the resulting sample vial is purged with nitrogen and sealed with a rubber stopper. A lyophilized preparation of 2,3 methylenedioxy-7-hydroxy-8-methoxy 5,6-propanobenzo [c] phenanthridinium chloride was obtained by tightening with a cap.

[0023] Example 3

To water for injection, 2,3 methylenedioxy-7 hydroxy-8 methoxy-5,6 propanobenzo [c] phenanthridinium chloride 200 mg and 200 mg lactose were added and dissolved by heating. Water for injection is added to make a total volume of 10 mL. This solution is aseptically filtered and filled into glass vials by 2 mL, lyophilized according to a conventional method, and the resulting sample vial is purged with nitrogen and sealed with a rubber stopper. Tightened with an aluminum cap, a freeze-dried preparation of 2,3 methylenedioxy-7-hydroxy-8-methoxy5,6-propanobenzo [c] phenanthridinium chloride was obtained.

[0024] Example 4

To water for injection, 2,3 methylenedioxy 7 hydroxy-8 methoxy 5,6 propanobenzo [c] phenanthridinium chloride 200 mg and 200 mg maltose were added and dissolved by heating. Water for injection is added to make up a total volume of 10 mL. This solution is aseptically filtered and then filled into 2 mL glass vials, lyophilized according to a conventional method, and the resulting sample vial is purged with nitrogen and sealed with a rubber stopper. A lyophilized preparation of 2,3 methylenedioxy-7-hydroxy-8-methoxy 5,6-propanobenzo [c] phenanthridinium chloride was obtained by tightening with a cap.

[0025] Example 5

2, 3 methylenedioxy 7 hydroxy-8 methoxy 5, 6 propa Nobenzo [c] phenanthridinium chloride 200 mg and 200 mg trehalose were added and dissolved by heating. Water for injection is added to make a total volume of 10 mL. After aseptic filtration, this solution is filled into glass vials in 2 mL portions, freeze-dried according to a conventional method, and the resulting sample vial is purged with nitrogen and sealed with a rubber stopper. Tightened with an aluminum cap, a lyophilized preparation of 2,3 methylenedioxy 7-hydroxy-8-methoxy 5,6-propanobenzo [c] phenanthridinium chloride was obtained.

[0026] Example 6

To water for injection, 2,3 methylenedioxy-7 hydroxy-8 methoxy-5,6 propanobenzo [c] phenanthridinium chloride 200 mg and 200 mg sorbitol were added and dissolved by heating. Water for injection is added to make a total volume of 10 mL. After aseptic filtration, this solution is filled into glass vials in 2 mL portions, freeze-dried according to a conventional method, and the resulting sample vial is purged with nitrogen and sealed with a rubber stopper. Tightened with an aluminum cap, a lyophilized preparation of 2,3 methylenedioxy 7-hydroxy-8-methoxy 5,6-propanobenzo [c] phenanthridinium chloride was obtained.

[0027] Comparative Example 1

400 mg of 2,3 methylenedioxy 7 hydroxy-8 methoxy-5,6 propanobenzo [c] phenanthridinium chloride was added to water for injection and dissolved by heating. Water for injection is added to make up a total volume of 20 mL. This solution is aseptically filtered and filled into glass vials in 2 mL portions, freeze-dried according to a conventional method, and the resulting sample vial is purged with nitrogen and sealed with a rubber stopper. Clamped with a cap, a lyophilized preparation of 2,3 methylenedioxy-7 hydroxy-8 methoxy-5,6-propanobenzo [c] phenanthridinium chloride was obtained.

[0028] Comparative Example 2

To water for injection, 2,3 methylenedioxy-7 hydroxy-8 methoxy-5,6 propanobenzo [c] phenanthridinium chloride 200 mg and 200 mg mannitol were added and dissolved by heating. Water for injection is added to make a total volume of 10 mL. After aseptic filtration, this solution is filled into glass vials in 2 mL portions, freeze-dried according to a conventional method, and the resulting sample vial is purged with nitrogen and sealed with a rubber stopper. 2, 3 Methylenedioxy 7-hydroxy-8-methoxy 5, 6-propanobenzo [c] phenanthridinium chloride A freeze-dried preparation was obtained.

[0029] Comparative Example 3

To water for injection, 2,3 methylenedioxy-7 hydroxy-8 methoxy-5,6 propanobenzo [c] phenanthridinium chloride 200 mg and 200 mg inositol were added and dissolved by heating. Water for injection is added to make a total volume of 10 mL. After aseptic filtration, this solution is filled into glass vials in 2 mL portions, freeze-dried according to a conventional method, and the resulting sample vial is purged with nitrogen and sealed with a rubber stopper. Tightened with an aluminum cap, a lyophilized preparation of 2,3 methylenedioxy 7-hydroxy-8-methoxy 5,6-propanobenzo [c] phenanthridinium chloride was obtained.

[0030] Test Example 1

The freeze-dried preparations obtained in Examples 1 to 5 and Comparative Examples 1 to 3 were stored at 40 ° C. for 6 months, the solubility before and after storage and the amount of impurities by HPLC measurement (peak area) Ratio). The solubility is the time (seconds) required for dissolution when 2 mL of water for injection is added and shaken. Those that did not dissolve after 90 seconds of shaking were considered insoluble. The results are shown in Table 1 below.

[0031] [Table 1] Solubility (second) Impurity (%)

¾5 force

Before storage After storage Before storage After storage Example 1 Xylitol 37 20 2. 01 1. 90 Example 2 Glucose 41 20 1. 98 1. 96 Example 3 Lactose 43 20 1. 96 2.00 Example 4 Mal 1 40 20 1. 95 2. 01 Example 5 卜 Rehalose 37 20 2. 06 2. 05 Comparative Example 1 None 48 Insoluble 2. 17 3. 23 Comparative Example 2 Mannitol 44 Insoluble 1. 94 2. 19 Comparative Example 3 Inositol 55 Insoluble 2. 11 2. 60

[0032] As is apparent from the above results, the freeze-dried preparation of the present invention had better solubility after storage than the comparative preparation, and could suppress an increase in impurities.

[0033] Test Example 2

The freeze-dried preparations obtained in Examples 2, 5, and 6 and Comparative Examples 1 to 3 were stored at 60 ° C for 4 weeks. Solubility before and after storage and the amount of impurities by HPLC measurement. (Peak area ratio) Was measured. The evaluation method is the same as in Test Example 1. The results are shown in Table 2 below.

[0034] [Table 2]

As is apparent from the above results, the freeze-dried preparation of the present invention has good solubility after storage and can suppress an increase in impurities as compared with the comparative preparation.

[0036] Example 7

To water for injection, 2,3 methylenedioxy-7 hydroxy-8 methoxy-5,6 propanobenzo [c] phenanthridinium chloride 400 mg and 400 mg glucose were added and dissolved by heating. Water for injection is added to make a total volume of 20 mL. After aseptic filtration, this solution is filled into 2.5 mL glass vials, lyophilized according to a conventional method, and the resulting sample vial is purged with nitrogen and sealed with a rubber stopper. Then, it was tightened with an aluminum cap to obtain a lyophilized preparation of 2,3 methylenedioxy-7-hydroxy-1-8-methoxy-1,5-6-propanobenzo [c] phenanthridinium chloride.

[0037] Example 8

800 mg of glucose was added instead of 400 mg of glucose in Example 7, and a freeze-dried preparation of 2,3-methylenedioxy 7-hydroxy-8-methoxy-5,6-propanobenzo [c] phensuridinium chloride was obtained in the same manner. .

[0038] Example 9

In the same manner as in Example 7, 2000 mg of glucose was added instead of 400 mg of glucose, and lyophilized preparation of 2,3 methylenedioxy-7 hydroxy-8 methoxy 5,6 propanobenzo [c] phenanthridinium chloride Got.

[0039] Test Example 3

The freeze-dried preparations obtained in Examples 7 to 9 were stored at 60 ° C for 2 months, before and after storage The solubility during re-dissolution and the amount of impurities (peak area ratio) by HPLC measurement were measured, and the color difference before and after storage was compared. The color difference was measured using the Lab color system specified by JIS Z 8730 using a color difference meter CR-321 (manufactured by Minolta Co., Ltd.), and the color change ΔE before and after storage was calculated. A smaller ΔΕ indicates a smaller color change. The results are shown in Table 3 below.

[Table 3]

[0041] From the above results, in Examples 7 and 8 in which glucose was added 1 to 2 times by weight of phenanthridine chloride, the solubility after storage was good and no increase in impurities was observed. . In Example 9, in which 5 times by weight of sugar was added, discoloration after storage was observed, which had sufficient solubility.

Industrial applicability

[0042] The lyophilized preparation of the present invention has excellent storage stability and good re-solubility after storage, and is clinically useful as an antitumor agent by dissolving in water for injection at the time of use. It is necessary to use IJ as a pharmaceutical product.

Claims

The scope of the claims

General formula (A)

[In the formula, represents a lower alkyl group having 1 to 5 carbon atoms, and R represents an aliphatic hydrocarbon chain having 2 to 6 carbon atoms. ]

[3] The R force of the general formula (A), an S methyl group, R is a trimethylene group, and X— is a chloride ion. The lyophilized formulation described.

[4] The freeze-dried preparation according to claim 2, wherein in the general formula (B) is a methyl group, and R is a trimethylene group.

[5] The freeze-dried preparation according to any one of claims 1 to 4, wherein the saccharide is sorbitol, glucose or trehalose.

[6] The freeze-dried preparation according to any one of [1] to [5] above, wherein the saccharide is glucose.

[7] The lyophilized preparation according to any one of claims 1 to 6, which contains 0.25 to 9 parts by weight of a saccharide with respect to 1 part by weight of a phenanthridine derivative.

[8] The lyophilized preparation according to any one of [7] to [7] above, wherein the preparation contains 10 to 70% by weight of a phenanthridine derivative and 25 to 85% by weight of a saccharide.

[9] The freeze-dried preparation according to any one of claims 1 to 8, which is dissolved in an injectable solution and used as an injectable pharmaceutical preparation.