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Irinotecan preparation

A technology for irinotecan preparations, which is applied in the field of irinotecan preparations and pharmaceutical compositions containing the preparations, can solve the problems of maintaining SN-38 concentration and difficulty in stabilization, so as to improve the stability of preparations and improve blood retention sexual effect

Inactive Publication Date: 2007-05-09
TERUMO KK +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, since SN-38 is difficult to stabilize in the liposome membrane and disappears rapidly in the blood, it is difficult to maintain the concentration of SN-38 in the plasma for a long time

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0163] In order to confirm the realization of the high-load liposome preparation method of irinotecan hydrochloride, an attempt was made to introduce high-concentration drugs by remote filling method (preparation example 1) or passive filling method (comparative formulation example 1). Except for the different methods of introduction, all irinotecan hydrochloride loaded liposome preparations (hereinafter referred to as CPT-11 preparations) use PEG-PE (post-introduction) lipids as carriers.

[0164] (Preparation example 1)

[0165] (1) Preparation of mixed lipids: Dissolve 0.422g of hydrogenated soybean phosphatidylcholine (HSPC) and 0.176g of cholesterol (Chol) in 25ml of tert-butanol (Kanto Chemical Company) heated at 60°C, and then cool in an ice bath , Freeze-dried to prepare a mixed lipid of HSPC:Chol=54:46 (molar ratio).

[0166] (2) Preparation of liposomes: Add 10ml of 250mM ammonium sulfate solution to 0.598g of the above-prepared mixed lipids to make them fully swelled, ...

Embodiment 2

[0180] The filling amount required to obtain the highly loaded CPT-11 formulation of the present invention in the remote filling method is measured.

[0181] (Preparation example 2)

[0182] In the (4) drug embedding of Preparation Example 1, the PEG-PE prepared in the same manner as (1) to (3) was introduced into the liposome dispersion and added to the 10mg / ml CPT-11 / RO aqueous solution. The CPT-11 preparation was obtained in the same manner as in Preparation Example 1, except that the amount was changed to an amount of 0.1, 0.2, 0.4, and 0.8 at the ratio of CPT-11 / HSPC (w / w). The composition and particle size of the obtained CPT-11 formulation are shown in Table 1.

[0183] As shown in Table 1, in the remote filling method, by increasing the drug filling amount (drug / HSPC ratio), it is possible to achieve a highly loaded CPT-11 preparation with a sufficient clinical effect.

[0184] [Table 1]

[0185] Preparation example

Embodiment 3

[0193] A liposome having a different membrane composition from that of Preparation Example 1 was used as a carrier to prepare a CPT-11 preparation. That is, the membrane component is PEG-PE composed of mixed lipids as shown below and then introduced into liposomes (preparation example 3) or PEG-PE is first introduced into liposomes (refer to preparation example 1), by the same as in preparation example 1. The remote filling method is used to embed irinotecan hydrochloride.

[0194] (Preparation example 3)

[0195] (1) Preparation of mixed lipids: Dissolve 1.5317g hydrogenated soybean phosphatidylcholine (HSPC), 0.6419g cholesterol (Chol) and 0.005g rhodamine dihexadecanoyl in 50mL of tert-butanol heated to 60°C After phosphatidylethanolamine (R-DHPE), it was cooled in an ice bath and freeze-dried to prepare a mixed lipid of HSPC:Chol:R-DHPE=54:46:0.1 (molar ratio).

[0196] (2) Preparation of liposomes: Except for using 0.37 g of the mixed lipids prepared above, as in Preparation ...

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Abstract

An irinotecan preparation having irinotecan and / or a salt thereof highly carried by a closed vesicle carrier, which exhibits a strikingly prolonged retention in blood as compared with that of conventional irinotecan liposome preparations and is capable of being present in blood for a prolonged period of time. There is provided an irinotecan preparation comprising closed vesicles formed of a lipid membrane wherein irinotecan and / or a salt thereof is sealed in a concentration of at least 0.07 mol / mol (medicine mol / total membrane lipid mol). The irinotecan preparation preferably has an ion gradient between an inner water phase and an outer water phase within the closed vesicles. The closed vesicles are preferably liposomes, and the liposomes preferably have only the external surface thereof modified with a surface modifier containing a hydrophilic polymer.

Description

Technical field [0001] The present invention relates to an irinotecan preparation which is highly loaded with irinotecan and / or its salt in a closed vesicle carrier and a pharmaceutical composition containing the preparation. Background technique [0002] Topoisomerase inhibitors are a class of drugs used in cancer treatment, such as camptothecin. Camptothecin is a pentacyclic alkaloid extracted and isolated from a Chinese native plant: Camptotheca acuminata by Wall and others in the United States in 1966. It has high anti-tumor activity and a broad anti-tumor spectrum. Patent Document 1). Existing cancer chemotherapy agents show anti-tumor activity by inhibiting type II topoisomerase, and camptothecin inhibits type I topoisomerase to inhibit topoisomerism that plays a role in DNA replication, repair, gene recombination and transcription The role of enzymes. [0003] However, camptothecin has some problems in its use as a medicine. Among them, several water-soluble camptothecin a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4745A61K9/127A61K47/04A61K47/18A61K47/24A61K47/30A61P35/00
CPCA61K31/4745A61K9/1271A61P35/00A61K47/18A61K47/30
Inventor 吉野敬亮野泽滋典矶崎正史泽田诚吾加藤几雄松崎健
Owner TERUMO KK
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