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In-situ gel film agent with biological adhesion and preparation method thereof

A technology of bioadhesion and in-situ gelation, which is applied to medical preparations with non-active ingredients, medical preparations containing active ingredients, organic active ingredients, etc., and can solve problems such as short half-life, poor absorption, and small drug loading. question

Inactive Publication Date: 2014-10-15
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0035] The technical problem to be solved by the present invention is to solve the problem of low drug loading, short residence time in the rectum, uneven drug distribution, large local irritation, slow drug onset, poor absorption, and poor patient compliance in the existing rectal drug preparations. , and the problem of low solubility and short half-life of the drug fluorouracil for the treatment of rectal cancer, a bioadhesive fluorouracil in-situ film agent and a preparation method thereof are provided. clathrate

Method used

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  • In-situ gel film agent with biological adhesion and preparation method thereof
  • In-situ gel film agent with biological adhesion and preparation method thereof
  • In-situ gel film agent with biological adhesion and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0230] Example 1: Drug solubilization test Fluorouracil is an insoluble drug with low water solubility. To make it rapidly exert its pharmacological effect, the prerequisite is to dissolve it in the liquid medium of the gel. Aiming at the property of poor water solubility of fluorouracil, the invention adopts hydroxypropyl-β-cyclodextrin inclusion method to improve its water solubility.

[0231] Prepare different concentrations of hydroxypropyl-β-cyclodextrin aqueous solutions, add excess 5-fluorouracil to the solution, shake with a constant temperature oscillator for 72 hours, centrifuge the suspension, and take the supernatant to determine the concentration of 5-fluorouracil at different concentrations. Solubility in solutions of hydroxypropyl-β-cyclodextrin. see results figure 1 . It can be seen from the figure that hydroxypropyl-β-cyclodextrin has a strong solubilization ability for 5-fluorouracil

Embodiment 2

[0232] Example 2: To investigate the effect of different formulations of P407 and P188 in the gel matrix material on the phase transition temperature.

[0233] Ploxamer407 (pluronic127 referred to as P407) and Poloxamer188 (pluronic68 referred to as P188) are mixed in a certain proportion as a gel skeleton material that affects the phase transition temperature.

[0234] (1) Prepare a deionized aqueous solution with a series of changes in the concentration of P407 and P188, stir at low temperature for more than 24 hours to prepare a gel matrix, and measure its phase transition temperature. Draw a three-dimensional gelation temperature map, see the results figure 2 .

[0235] (2) Phase change temperature test The present invention requires that as long as the sample is liquid at normal temperature, the temperature at body temperature can become semi-solid, that is, as long as the sample is 30-37 ℃ phase change temperature all meet the requirements.

[0236] Gel temperature me...

Embodiment 3

[0243] Example 3: Investigate the influence of bioadhesives and clathrates on the gelling temperature of film formulations.

[0244] Preparation of test samples: In this example, the ratios of fixed P407 / P188 were (17.5 / 2.0, 19.0 / 5.0), and the inclusion complexes of fluorouracil-hydroxypropyl-β-cyclodextrin were (6.5%, 9.1% , 13.0%), the adhesives are (0.2%, 0.3%, 0.4%) respectively, that is, 100mL liquid in-situ adhesive film contains P407 17.5g, 19.0g, P188 2.0g, 5.0g, fluorouracil-hydroxypropyl- β-cyclodextrin inclusion complexes were 3.5g, 9.1g, 13.0g (of which fluorouracil were 0.5g, 0.7g, 1.0g), respectively, and adhesives were 0.2g, 0.3g, 0.4g.

[0245] The gel temperature measurement method is as described above.

[0246] Selection requirements: The gel temperature is more suitable in the range of 35-37°C.

[0247] Table 2 Effect of bioadhesives and clathrates on the gelation temperature of film formulations (n=5, °C) (P407 / P188 is 17.5 / 2.0)

[0248]

[0249] ...

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Abstract

The invention provides a water-soluble cyclodextrin derivative clathrate of fluorouracil, and an in-situ gel film agent containing the clathrate and having biological adhesion and a preparation method thereof. According to the invention, cyclodextrin derivative-hydroxypropyl-beta-cyclodextrin is used to include fluorouracil hardly soluble in water so as to allow the solubility of fluorouracil in water to be improved and fluorouracil to have a slow release effect, so the in-situ gel film agent is prepared; the in-situ gel film agent is a novel cavity drug delivery preparation and comprises the hydroxypropyl-beta-cyclodextrin clathrate of fluorouracil, a temperature-sensitive gel skeletal material and a biologically adhesive material. The preparation is a freely flowable solution before usage, rapidly forms a gel film on the surface of a cavity, has a great drug release area, good biological compatibility and good gel strength and biological adhesion, is capable of firmly adhering on the mucous membrane of the cavity, prolongs action time, realizes uniform drug distribution, is beneficial for absorption of the drug and diffusion of the drug to peripheral tissue and improves bioavailability and treatment effects of the drug.

Description

technical field [0001] The invention relates to a hydroxypropyl-β-cyclodextrin inclusion compound of fluorouracil, a bioadhesive in-situ film agent containing the same and a preparation method thereof, belonging to the field of pharmaceutical preparations. Background technique [0002] Colorectal cancer (including colon cancer and rectal cancer) is a malignant tumor with an increasing incidence in my country. It has ranked the third among malignant tumors and has a tendency to catch up with gastric cancer. Because it penetrates into the pelvic cavity, it is difficult to operate and recurs after surgery. High transfer rate. At present, the treatment of rectal cancer is based on radical resection, supplemented by comprehensive treatment of radiotherapy and chemotherapy. Fluorouracil (also known as 5-fluorouracil, 5-Fu) is an antimetabolite antineoplastic drug that can inhibit thymidine deoxynucleotide synthetase and hinder DNA synthesis. It is a basic drug for the treatment of...

Claims

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Application Information

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IPC IPC(8): A61K9/00A61K47/40A61K47/34A61K47/38A61K31/513A61P35/00
Inventor 郑稳生王璐璐相莉方夏琴张宇佳陈少华张秀立刘盟盟
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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