JP2003277281A - Medicine for preventing and curing phlebitis - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a means for preventing and/or curing phlebitis caused by intravenus administration of an antineoplastic agent (e.g. vinorelbine tartarate). <P>SOLUTION: This medicine for preventing and/or curing phlebitis caused by intravenus administration of an antineoplastic agent (e.g. vinorelbine tartarate) contains, as the effective component, an emulsion containing a vegetable oil (e.g. soybean oil) and, if necessary, yolk lecithin and/or glycerin. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a medicament for preventing and / or treating phlebitis caused by intravenous administration of an antitumor agent.

[0002]

2. Description of the Related Art Vinorelbine tartrate (commercially available as "Navelbine" from Kyowa Hakko Kogyo Co., Ltd.), a vinca alkaloid antitumor agent, is an antitumor agent used for the treatment of non-small cell lung cancer and is administered intravenously. Used by. Although this antitumor agent has an excellent antitumor action, it is known that intravenous administration causes acute local phlebitis, and in some cases, this antitumor agent can be administered only once due to severe phlebitis. In some cases, it may be necessary to discontinue during administration. As a method for avoiding this phlebitis, it is recommended to thoroughly wash away the drug solution in the blood vessel after administration with physiological saline, but this method has a problem that the occurrence of phlebitis cannot always be avoided.

Heretofore, a method of administering an antithrombin agent and an endothelial cell protective agent as a method for avoiding local phlebitis due to intravenous administration of vinorelbine (Maisano, R. et.
al., Anticanser Res., 17 (4A), 2775-2777, 1997), a method of administering human albumin (Weiss, J. et al., Onkol
ogie, 22, 416-418, 1999), a method of administering a histamine (H ₂ ) blocker, cimetidine (Vasssilomanolakis,
M. et al., Support Care Cancer, 9, 108-11, 2001) have been reported.

On the other hand, it has been suggested that phlebitis can be prevented by administration of a fat emulsion in peripheral parenteral nutrition after surgery (Matsusue, Journal of Japan Society for Parenteral and Enteral Nutrition, 9, 182-184,
1994). Although this paper reports the results of studies on the relationship between fat emulsion and phlebitis preventive effect in terms of pH, etc., it does not suggest the action of fat emulsion on acute local phlebitis induced by antitumor agents. It does not teach.

[0005]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention The present invention provides means for preventing and / or treating local phlebitis caused by intravenous administration of an antitumor agent such as vinorelbine. That is the issue. As a result of intensive research to solve the above problems, the present inventor
It was found that the occurrence of phlebitis can be prevented and / or treated by intravenously administering an emulsion containing a vegetable oil before, during, and / or after administration of an antitumor agent. The present invention has been completed based on the above findings.

That is, the present invention provides a medicament for preventing and / or treating phlebitis caused by intravenous administration of an antitumor agent, which comprises an emulsion containing a vegetable oil as an active ingredient. Is.

According to a preferred embodiment of the present invention, the above-mentioned medicine in which the vegetable oil is soybean; further the above-mentioned medicine containing egg yolk lecithin and / or glycerin as a surfactant; 40 parts by weight of the above drug; pH of the above drug in the range of 6.5 to 8.5; one or more timings selected from the group consisting of before, during, and after administration of the antitumor agent. The above-mentioned medicament for administration to the above; and the above-mentioned medicament, wherein the antitumor agent is vinorelbine.

From another aspect, the present invention provides a pharmaceutical composition for the treatment of malignant tumor, which comprises an antitumor agent and an emulsion containing a vegetable oil. In this pharmaceutical composition, the occurrence of phlebitis is reduced or avoided as compared with the case where the antitumor agent is intravenously administered alone. According to a preferred embodiment of the present invention, the above-mentioned pharmaceutical composition wherein the vegetable oil is soybean; and the above-mentioned pharmaceutical composition further containing egg yolk lecithin and / or glycerin as a surfactant;
The above pharmaceutical composition wherein the amount of vegetable oil in 100 parts by weight of the emulsion is 1 to 40 parts by weight; the above pharmaceutical composition having a pH in the range of 6.5 to 8.5; and the antitumor agent is vinorelbine. A pharmaceutical composition as described above is provided.

[0009] From still another aspect, there is provided a method for preventing and / or treating phlebitis caused by intravenous administration of an antitumor agent, the method comprising the steps of administering the antitumor agent before, during and after administration. The present invention provides a method comprising the step of intravenously administering an emulsion containing a vegetable oil at one or more times selected from the group consisting of:

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The medicament of the present invention is a medicament for preventing and / or treating phlebitis caused by intravenous administration of an antitumor agent, wherein an emulsion containing a vegetable oil as a main component is an active ingredient. It is characterized by including as.

The phlebitis to which the drug of the present invention is applied is
Phlebitis caused by intravenous administration of an antitumor agent,
More specifically, it is phlebitis caused by injection or administration of an antitumor agent by infusion. The type of the antitumor agent is not particularly limited, and any antitumor agent may be used as long as it induces inflammation in the vein selected as the administration route or the vein around the vein during intravenous administration.

[0012] As a preferred target of application of the medicine of the present invention,
Examples include phlebitis caused by vinca alkaloid antitumor agents. Examples of vinca alkaloid antitumor agents include vinblastine, vincristine,
Examples thereof include vindesine, vinorelbine, and physiologically acceptable salts thereof. Vinorelbine is known to cause acute and severe phlebitis when administered intravenously, and the phlebitis caused by this antitumor agent is a particularly suitable subject for application of the medicament of the present invention. Vinorelbine is "Navelbine" (Vinorelbin d tartrate: Vinorelbind
Itartate) is used clinically. In addition, examples of other antitumor agents to which the drug of the present invention is applied include doxorubicin and mitomycin.

The emulsion containing the vegetable oil, which is the active ingredient of the medicine of the present invention, is an emulsion prepared mainly from the vegetable oil. The type of vegetable oil is not particularly limited, and for example, vegetable oil selected from soybean oil, rapeseed oil, corn oil, olive oil and the like can be used. You may use combining 2 or more types of vegetable oils. Of these, soybean oil is preferred from the viewpoint of emulsion stability and nontoxicity to living bodies.

The method for preparing the emulsion containing vegetable oil is not particularly limited, and it can be prepared by a method well known to those skilled in the art, usually using one or more surfactants. The type of the surfactant is not particularly limited, but it is preferable to use one or more polymer surfactants in order to avoid the pH dependency of the emulsion.
For example, a protein having a high affinity with water, such as egg yolk lecithin, can be used as a surfactant. When egg yolk lecithin is used as a surfactant, a low molecular weight surfactant such as glycerin can be used in combination for adjusting the osmotic pressure. The combination of egg yolk lecithin and glycerin is particularly preferably used in the medicament of the present invention.

The emulsion containing the vegetable oil can be easily produced by, for example, stirring the vegetable oil, the surfactant, and water at high speed using a stirrer such as a homogenizer. The concentration of vegetable oil in the emulsion is not particularly limited, but is usually 1 to 4 with respect to 100 parts by weight of the emulsion.
It is preferably 0 part by weight, particularly 5 to 30 parts by weight (the numerical range indicated by "to" in the present specification is a range including the lower limit and the upper limit). In a preferred example, 50 g soybean oil in 250 ml emulsion,
The medicament of the present invention can be prepared so as to contain 3 g of egg yolk lecithin and 5.5 g of glycerin. The pH of the emulsion is not particularly limited, but is usually 6.5 to 8.5.
It is preferably in the range of.

As the drug of the present invention, a fat emulsion (sometimes called a lipid injection) which is clinically used for parenteral nutrition before and after surgery may be used as it is. As a fat emulsion, a preparation such as "Intrafat", "Intralipid", "Soramid", or "Intralipos" (all of which is the name of a commercial preparation) is used clinically as a preparation containing soybean oil as a main component. Therefore, these fat emulsions may be used as they are as the medicament of the present invention. A fat emulsion marketed as a 10% or 20% fat emulsion under the name of "intralipos" can be particularly preferably used as the pharmaceutical agent of the present invention.

The pharmaceutical composition of the present invention is administered intravenously before administration of an antitumor agent, at the time of administration, or after administration, or at two or more times selected from these, at the time of administration of the antitumor agent. can do. Although the method for administration is not particularly limited, for example, an antitumor agent is prepared as a drip infusion, and the drug of the present invention is placed in a drip tube used for intravenous administration of the drip. Can be appropriately selected, such as a method of introducing as a mixture, a method of directly adding the drug of the present invention to a solution of an antitumor agent, and administering the mixture as a mixture intravenously. When a commercially available 10% or 20% fat emulsion is used as the drug of the present invention, it may be diluted with physiological saline about 10 to 50 times and used.

The medicine of the present invention may contain one or more kinds of formulation additives usually used for preparation of a medicine for intravenous administration. For example, it may contain a pH adjusting agent, a preservative, a soothing agent, a solubilizing agent, and the like. It may also contain vitamins derived from vegetable oils. A pharmaceutical composition containing an emulsion containing a vegetable oil, which is an active ingredient of the medicament of the present invention, and one or more antitumor agents may be prepared in advance, and the pharmaceutical composition may be administered to a patient.
The method of mixing the antitumor agent and the emulsion containing vegetable oil is not particularly limited, and an appropriate method such as a method using a normal stirrer or a method using ultrasonic waves can be adopted. The compounding ratio of the antitumor agent and the emulsion containing the vegetable oil is not particularly limited, but the weight ratio of the antitumor agent and the vegetable oil can be selected from the range of about 1/5 to 5 times.

The dose of the drug of the present invention can be appropriately selected according to conditions such as the type of antitumor agent, the degree of phlebitis, the weight of the patient, the age, etc. It can be selected according to the usual dose of the preparation.
For example, when a commercially available 10% or 20% fat emulsion is used as the drug of the present invention, about 100 to 1,000 ml can be administered as a drip infusion, before, during, or after administration of the antitumor agent. The above-mentioned dose can be administered once or divided into a plurality of doses at any time, or at two or more times selected from these.

For example, 10% or 20% of the medicine of the present invention
If using a fat emulsion, add 50 ml of the fat emulsion formulation to
Administration is started as an intravenous infusion appropriately diluted so as to be intravenously administered in about 5 minutes, and when the administration of about 1/3 is completed, the antitumor agent is fully administered over 15 minutes from the side tube of the infusion tube, A method of continuing the administration of the fat emulsion for about 10 minutes after the administration of the antitumor agent can be exemplified. However, the administration method of the present invention is not limited to the above specific administration method.

[0021]

The present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited to the following examples. "Navelbine" as an antitumor agent in Examples
(Vinorelbine tartrate) was used. Example 1 (1) Animal used: Japanese white rabbit (2 kg) (2) Soybean oil emulsion distilled water 84 parts by weight purified soybean oil 10 parts by weight purified egg yolk oil 1 part by weight Glycerin 5 parts by weight or more are mixed with a homogenizer at 2000 rpm for 10 minutes. It was manufactured by The coarse particles were removed by a filter.

(3) Administration liquid Administered drug concentration Navelbine 5 mg / mL Navelbine stock solution + soybean oil emulsion 5mg / mL (Soybean oil concentration in emulsion: 20% by weight)

(4) Administration method Experiment 1 (mixed administration): The navelbine stock solution and soybean emulsion were mixed in equal amounts, ultrasonically mixed and administered intravenously. Experiment 2 (simultaneous administration): Navelbine stock solution and an equal amount of soybean emulsion were mixed dropwise with Ringer's solution in a container and administered intravenously. Experiment 3 (pre-administration of soybean oil emulsion): Navelvin stock solution (10 μg / mL) was administered after administration of the soybean oil emulsion. Experiment 4 (conventional method): Navelbine stock solution (10 μg / mL)
Was administered, and then saline was administered. Experiment 5 (blank): Only physiological saline was administered. Frequency of administration: Once per day, administration was limited to one day.

(5) Evaluation method The red region was measured the day after the administration, and both ears were obtained as samples.
The red area (mm ² ) of the administration site was measured. The pathological specimen was observed under a microscope. (6) Evaluation results Table 1 shows the results of measuring the red area. Reduction of inflammation was also confirmed in the pathological specimen. From the above results, it is clear that the administration of the drug of the present invention can reduce the occurrence of phlebitis upon administration of navelbine.

[0025]

[Table 1]

[0026]

INDUSTRIAL APPLICABILITY The medicament of the present invention is useful for preventing and / or treating phlebitis caused by intravenous administration of an antitumor agent.

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Claims (6)

[Claims] 1. A medicine for preventing and / or treating phlebitis caused by intravenous administration of an antitumor agent, which comprises:
A medicine comprising an emulsion containing a vegetable oil as an active ingredient. 2. The medicine according to claim 1, wherein the vegetable oil is soybean. 3. The medicine according to claim 1, which contains egg yolk lecithin and / or glycerin. 4. The medicine according to any one of claims 1 to 3, wherein the antitumor agent is vinorelbine tartrate or a salt thereof. 5. The medicine according to any one of claims 1 to 4, which is for administration at one or more times selected from the group consisting of before administration, during administration, and after administration of the antitumor agent. 6. A pharmaceutical composition for the treatment of malignant tumor, comprising an antitumor agent and an emulsion containing vegetable oil.